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THE MALARIAL FEVERS, 
 HAEM0GL0BINUK1C FEVER 
 
 AND 
 
 THE BLOOD PROTOZOA OF MAN 
 
 BY 
 
 CHARLES F. CRAIG, M. D. 
 
 Captain, Medical Corps, U. S. Army 
 
 ATTENDING SURGEON, NEW YORK CITY. LATE PATHOLOGIST AND BACTERIOLOGIST TO THE STERNBERG 
 U. S. ARMY GENERAL HOSPITAL, CHICKAMAUGA PARK, GA. ; THE JOSIAH SIMPSON GENERAL 
 HOSPTTAL, FORTRESS MONROE, VA. ; THE CAMP COLUMBIA HOSPITAL, HAVANA, CUBA; THE 
 U. S. ARMY GENERAL HOSPITAL, PRESIDIO OF SAN FRANCISCO, CAL. ; THE DIVISION 
 HOSPITAL, MANILA, P. I. LATE MEMBER OF THE U. S. ARMY BOARD FOR 
 THE STUDY OF TROPICAL DISEASES IN THE PHILIPPINE ISLANDS. 
 MEMBER OF THE SOCIETY OF TROPICAL MEDICINE AND 
 HYGIENE, LONDON; THE AMERICAN SOCIETY OF 
 TROPICAL MEDICINE, AND THE NATIONAL AS- 
 SOCIATION FOR THE STUDY AND PRE- 
 VENTION OF TUBERCULOSIS 
 
 ILLUSTRATED BY FOUR COLORED PLATES 
 
 TWENTY-FIVE CLINICAL CHARTS 
 
 AND TWENTY-EIGHT PHOTOMICROGRAPHS AND DRAWINGS 
 
 NEW YORK 
 
 WILLIAM WOOD AND COMPANY 
 
 MDCCCCIX 
 
C?4 
 
 Copyright, 1909 
 By WILLIAM WOOD AND COMPANY 
 
 Printed by 
 
 The Maple Press 
 
 York. Pa. 
 
TO THE OFFICERS 
 OF 
 
 THE MEDICAL CORPS 
 
 OF THE 
 
 UNITED STATES ARMY, 
 
 THIS BOOK IS AFFECTIONATELY 
 DEDICATED BY THE AUTHOR 
 
PREFACE. 
 
 While several excellent works dealing with the laboratory side of the subject 
 have appeared within recent years, no complete treatise upon the malarial 
 fevers has been printed in English since the author's work entitled "The 
 Aestivo-autumnal (Remittent) Malarial Fevers," published in 1901. Thayer's 
 excellent monograph upon this subject in Allbutt and Rolleston's "System of 
 Medicine" and the author's in Osier's "Modern Medicine" consider the subject 
 but briefly from necessity, and the many important discoveries made in the 
 etiology of these fevers, and the advances made in the prophylaxis of malarial 
 disease during the past ten years are such as to justify us in the publication of 
 the present work. The author has endeavored to record in this work all im- 
 portant advances and facts of interest to the student and clinician, and to this 
 end has consulted a mass of literature, the most important papers being noted in 
 the literary reference found at the end of each chapter. For many of these 
 references I am indebted to the extensive bibliographies in Thayer and 
 Hewetson's "Malarial Fevers," of Baltimore, and Zieman's monograph upon 
 malaria in Mense's "Handbuch der Tropenkrankheiten." In every case the 
 author has tried to give proper credit for the observations quoted, and if he has 
 failed it has not been intentionally. 
 
 The work is very largely the result of personal experience gained in the 
 United States military hospitals in this country, Cuba, and the Philippines, and, 
 as such, embodies the results of over ten years of investigation, and the study of 
 thousands of cases of malarial fever. The importance of a thorough under- 
 standing of malarial disease cannot be overrated, and with the acquisition of 
 the Philippine Islands and of Porto Rico it is more imperative than ever that 
 the American physician be able to distinguish these fevers, and properly treat 
 them. The author has never changed his opinion that infinite suffering could 
 have been avoided and scores of lives saved in our camps during the Spanish 
 War had our physicians been thoroughly familiar with the malarial fevers, 
 especially the aestivo-autumnal infections. Further experience has only con- 
 firmed his opinion that every physician practising in malarial localities should 
 .be able to recognize the malarial plasmodia in the blood and that blood exami- 
 nations should be relied upon in the diagnosis of malarial disease. 
 
 In addition to the consideration of the malarial fevers, the author has 
 thought it best to add chapters treating of haemoglobinuric fever and the blood 
 protozoa of man. While he is of the opinion that haemoglobinuric fever is a 
 disease suis generis, the fact that it occurs in malarial regions and often compli- 
 
VI PREFACE. 
 
 cates malarial disease renders a consideration of the condition necessary in any 
 complete work upon the malarial fevers. The chapters dealing with the blood 
 protozoa have been included in order to make the work complete as regards the 
 examination of the blood, of so much importance in the diagnosis of malaria. 
 As the protozoa described occur in regions in which the malarial fevers abound 
 and as these organisms might be found in the blood while examining this fluid 
 for the plasmodia, the author deemed that a brief description of the blood 
 protozoa of man would prove of service in a work devoted primarily to the 
 malarial fevers. 
 
 The author would indeed be ungrateful were he to omit expressing his 
 gratitude to the many officers of the Medical Corps of the United States Army, 
 who have aided him, directly or indirectly, in the preparation of this work. 
 Brigadier- General George H. Torney, Surgeon-General, U. S. Army, has, by 
 his support and encouragement, placed the author under many obligations, 
 which he can never hope to repay, but which are here thankfully ac- 
 knowledged; to Major-General Robert M. O'Reilly, and Brigadier-Generals 
 Sternberg and Girard, the author is indebted for opportunities afforded for 
 the study of the malarial fevers; to Colonels G. B. Girard and Byrne, and 
 Lieutenant-Colonels Richard, Crosby, Carter, and Harris, the author's thanks 
 are due for encouragement and assistance. The author also desires to express 
 his gratitude to Colonel Wm. B. Leishman, of the Royal Army Medical Corps, 
 to whom he is indebted for literature and specimens, and to Professor Novy, 
 of Ann Arbor, for many favors. 
 
 The photomicrographs were taken at the Bureau of Science, in Manila, 
 and to this institution, and its director, Dr. Paul Freer, and the director of the 
 biological department, Dr. Richard P. Strong, the author desires to express his 
 gratitude and appreciation. It is the earnest hope of the author that this 
 volume may be of value in the elucidation of the fevers of tropical and sub- 
 tropical countries. 
 
 CHARLES F. CRAIG. 
 New York, April io, 1909. 
 
CONTENTS. 
 
 PART I. 
 
 The Etiology of the Malarial Fevers. 
 
 Chapter I. — Synonyms; Definition; Historical; Geographical Distribution 
 
 of the Malarial Fevers 3 
 
 Chapter II. — Etiology; Classification of the Parasites of the Malarial 
 Fevers; Morphology and Biology of the Malarial Plasmodia in the 
 Blood of Man 14 
 
 Chapter III. — Development of the Malarial Plasmodia within the 
 Mosquito: Mosquitoes; Structure; Ova; Larva?; Pupa;; Habits; 
 Distribution; Classification; Mosquitoes proven to Transmit Malaria; 
 The Relation of Number of Infected Mosquitoes to Malarial Infection 
 in Various Localities 56 
 
 Chapter IV. — Methods of Transmission of the Malarial Plasmodia: by 
 the Atmosphere; by Water; by Inoculation of Malarial Blood; by 
 Inoculation by the Mosquito; Cultivation of Malarial Plasmodia; 
 Immunity : 79 
 
 Chapter V. — Predisposing Causes, General and Local; Period of Incuba- 
 tion of the Malarial Fevers; Congenital Malaria 104 
 
 PART II. 
 
 The General and Special Pathology of the Malarial Fevers. 
 
 Chapter I. — The General Pathology of the Malarial Fevers; Morphologi- 
 cal Changes in the Erythrocytes and Leucocytes; Anaemia; Differen- 
 tial Blood Count; Phagocytosis; Melanaemia; the Urine; the Etiology 
 
 of the Fever 127 
 
 Chapter II. — The Special Pathology of Acute Malarial Infections. . . . 148 
 Chapter III. — The Pathology of Latent Malarial Infections and of 
 
 Malarial Cachexia 161 
 
 PART III. 
 
 The Symptomatology and Clinical Varieties of the Malarlal Fevers. 
 
 Chapter I. — Clinical Classification; Tertian Malarial Fever; Quartan 
 Malarial Fever; Aestivo-autumnal Malaria; Analysis of Symptoms; 
 
 Examination of the Blood 169 
 
 vii 
 
Vlll CONTENTS. 
 
 Chapter II. — Clinical Illustrations of the Tertian and Quotidian Aestivo- 
 
 autumnal Malarial Fevers 194 
 
 Chapter III. — The Pernicious Forms of the Malarial Fevers 215 
 
 Chapter IV. — Latent Malaria; Masked Malaria; Recurrent Malaria; 
 Etiology of Latency and Recurrence; Intracorpuscular Conjugation of 
 the Malarial Plasmodia 228 
 
 Chapter V. — Subcontinued and Remittent Malarial Fevers; Mixed 
 Malarial Infection; Chronic Malarial Infection and Malarial Cachexia ; 
 Spontaneous Recovery 252 
 
 PART IV. 
 
 The Sequel.e, Complications, and Prognosis of the Malarial Fevers. 
 
 Chapter I. — The Sequeke of the Malarial Fevers 267 
 
 Chapter II. — The Complications of the Malarial Fevers 276 
 
 Chapter III. — Coincident Typhoid and Malarial Infection 284 
 
 Chapter IV. — The Prognosis of the Malarial Fevers 298 
 
 PART V. 
 The Diagnosis, Prophylaxis, and Treatment of the Malarial Fevers. 
 
 Chapter I. — The Laboratory Diagnosis of the Malarial Fevers; Staining 
 Methods; Examination of the Blood; Examination of Malarial 
 Mosquitoes 307 
 
 Chapter II. — The Clinical Diagnosis of the Malarial Fevers; the Differ- 
 ential Diagnosis of the Malarial Fevers 330 
 
 Chapter III. — The Prophylaxis of the Malarial Fevers 342 
 
 Chapter IV. — The Treatment of the Malarial Fevers 360 
 
 PART VI. 
 Fiaemoglobinuric Fever. 391 
 
 PART VII. 
 
 The Blood Protozoa of Man. 
 
 Chapter I. — The Leishman-Donovan Bodies; Leishmania-donovani . . 411 
 
 Chapter II. — Trypanosoma Gambiense (Trypanosoma Ugandense) . . 428 
 Chapter III. — The Spirochaetes; Spirochaeta Recurrentis; Spirochaeta 
 
 Duttoni; Spirochaeta Novyi; Spirochaeta Carteri (Spiroschaudinnia) . 445 
 
 Chapter IV. — Histoplasma Capsulatum 460 
 
 Index to Authors 463 
 
 General Index 469 
 
LIST OF PLATES AND ILLUSTRATIONS 
 
 PLATE. FACING PAGE 
 
 I. Species of Malarial Plasmodia, as observed in the Blood 26 
 
 II. Stained specimens of Tertian and Quartan Malarial Plasmodia 32 
 
 III. Stained specimens of Tertian and Quotidian Aestivo-autumnal Plas- 
 modia, and of the Gametes of the various Species of Malarial 
 Plasmodia 42 
 
 IV. Leishmania donovani. Trypanosoma gambiense. Spirochceta duttoni 
 Histoplasma capsulatum 411 
 
 FIGURE. PAGE 
 
 1. Plasmodium vivax. Photomicrograph 20 
 
 2. Plasmodium vivax. Photomicrograph 20 
 
 3. Plasmodium vivax. Photomicrograph 25 
 
 4. Plasmodium vivax. Photomicrograph 25 
 
 5. Plasmodium vivax. Photomicrograph 25 
 
 6. Plasmodium malarias. Photomicrograph 29 
 
 7. Plasmodium malarias. Photomicrograph 29 
 
 8. Plasmodium malarias. Photomicrograph 29 
 
 9. Plasmodium falciparum tertianum. Photomicrograph 38 
 
 10. Tertian aestivo-autumnal "ring f orm " and microgametocyte. Photo- 
 micrograph 50 
 
 11. Aestivo-autumnal tertian macrogamete. Photomicrograph 53 
 
 12. Tertian aestivo-autumnal microgametocyte. Photomicrograph .... 53 
 
 13. Development of Plasmodium, vivax within the Mosquito 61 
 
 14. Comparison of Head of Anopheles and Culex 64 
 
 15. Venation of Wing in Anophelinae. (Modified from Theobald) 65 
 
 16. Internal Anatomy of the Anophelinae. (After Nuttall and Shipley) . . 66 
 
 17. Ova of Mosquitoes 67 
 
 18. Larva of Anopheles and Culex'. (After Howard and Theobald) .... 68 
 
 19. Pupa of Anophelinae. (After Nuttall and Shipley) 71 
 
 20. Comparison of Resting Position of Anopheles and Culex 74 
 
 21. Characters of Scales upon Mosquitoes 75 
 
 22. Characteristics of Scales, upon Various Species of Mosquitoes. (Arranged 
 from Theobald) 76 
 
 23. Appearances in the Red Blood Cells which have been mistaken for 
 Plasmodia 311 
 
 24. Diagram of Typical Anophelina. (Modified from Theobald) 323 
 
 25. Method of Mounting and Preserving Mosquitoes 326 
 
 26. Leishmania donovani. (After Leishman) 417 
 
 27. Leishmania donovani. Photomicrograph 422 
 
 28. Trypanosoma gambiense 435 
 
 IX 
 
LIST OF CLINICAL CHARTS 
 
 CHART. PAGE 
 
 A. Tertian Malarial Fever 174 
 
 B. Quartan Malarial Fever 177 
 
 C. Aestivo-autumnal Malarial Fever, Pneumonic form 225 
 
 1. Tertian Aestivo-autumnal Malarial Fever 179 
 
 2. Tertian Aestivo-autumnal Malarial Fever 181 
 
 3. Tertian Aestivo-autumnal Malarial Fever 183 
 
 4. Tertian Aestivo-autumnal Malarial Fever 185 
 
 5. Quotidian Aestivo-autumnal Malarial Fever 187 
 
 6. Quotidian Aestivo-autumnal Malarial Fever 196 
 
 7. Quotidian Aestivo-autumnal Malarial Fever 198 
 
 8. Quotidian Aestivo-autumnal Malarial Fever 200 
 
 9. Quotidian Aestivo-autumnal Malarial Fever 202 
 
 10. Quotidian Aestivo-autumnal Malarial Fever 204 
 
 11. Tertian Aestivo-autumnal Malarial Fever 206 
 
 12. Tertian Aestivo-autumnal Malarial Fever 208 
 
 13. Tertian Aestivo-autumnal Malarial Fever 210 
 
 14. Tertian Aestivo-autumnal Malarial Fever 211 
 
 15. Tertian Aestivo-autumnal Malarial Fever 213 
 
 16. Sub-continued Aestivo-autumnal Malarial Fever 255 
 
 17. Combined Tertian and Tertian Aestivo-autumnal Malaria 257 
 
 17^. Combined Quartan Malarial Fever and Typhoid Fever 291 
 
 18. Combined Typhoid and Aestivo-autumnal Malarial Fevers 295 
 
 19. Typhoid Fever. Decline 334 
 
 20. Acute Tuberculosis of Lungs 336 
 
 21. Infective Endocarditis. (After Dock) 338 
 
 'LIBRAF... . TOP 
 
 G« 
 
 .ffiNi A, 
 
 COLLEGE 
 
 XI 
 
PART I 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
CHAPTER I. 
 
 Synonyms; Definition; Historical; Geographical Distribution of the 
 Malarial Fevers. 
 
 Synonyms. — English: Intermittent and Remittent fevers, Tertian, Quartan 
 and Aestivo-autumnal fevers, Estivo-autumnal fever, Paludal fever, Climatic 
 fever, Ague, Marsh fever, Jungle fever, Coast fever, Mountain fever, Hill fever, 
 Swamp fever, Cold fever, Paludism, Gnat fever, Haemamoebiasis, Cameroon 
 fever. German: Wechselfieber. Dutch: Koorts. French: Paludisme, Fievre 
 paludiene, Maladies palustres, Febbre intermittente, Fievre pernicieuse. 
 
 Definition. — By the term "the malarial fevers" we mean a group of 
 specific fevers due to infection of the red blood-corpuscles of man by closely 
 related animal parasites belonging to the Protozoa, class Spprozoa, genus 
 Plasmodium. 
 
 Zoologically considered, the malarial parasites belong to the Protozoa, class 
 Sporozoa, order Haemosporidia, genus Plasmodium. From a biological stand- 
 point the name Plasmodium, given by Marchiafava and Celli as a generic term 
 for the organisms causing the malarial fevers, is most unfortunate, as they are 
 not inhabitants of the blood plasma exclusively, but pass the greater portion of 
 their life cycle in man within the erythrocytes. For this reason the generic 
 name, Haemamoeba, suggested by Grassi, is preferable, but the term '"Plasmo- 
 dium" will have to be retained because of the law of priority. 
 
 The same objection may be raised to the name "malarial" first used by the 
 Italians, and meaning "bad air." This term was applied to these fevers because 
 of the supposed relations of miasmatic conditions to their causation, but in the 
 light of our present knowledge of the etiology of this class of fevers, the name 
 is erroneous and, according to some writers, should be abandoned. However, 
 the name has become so firmly established in medical nomenclature that, in 
 the opinion of most authorities, it will have to be retained. 
 
 The malarial fevers occur epidemically or endemically and are accompanied 
 by a symptom-complex, which is more or less characteristic of each variety. 
 Periodicity is one of the most marked clinical phenomena, and is due to the 
 growth and sporulation of the plasmodia. All varieties of malaria are distin- 
 guished by yielding to quinin, which is also the most efficient of prophylactics. 
 Biologically, the malarial fevers may be divided into tertian, quartan, and 
 aestivo-autumnal; clinically, into intermittent, remittent and continuous, but 
 the latter classification is not scientific as it does not indicate disease entities, 
 but only the type of fever which may be present. The malarial fevers are all 
 transmitted by mosquitoes belonging to the Anophelince, and as far as we at 
 present know this is the only method of transmission. 
 
 Historical. — The history of the malarial fevers may be divided into four 
 periods, as follows: 
 
 3 
 
4 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 First Period. From the earliest historical time to the discovery of cin- 
 chona bark. 
 
 Second Period. From the discovery of cinchona bark to the discovery 
 of the plasmodia. 
 
 Third. Period. From the discovery of the plasmodia to the discovery of 
 the method of transmission by the mosquito. 
 
 Fourth Period. From the discovery of the method of transmission to 
 the present time. 
 
 First Period. — It is more than probable that the ancient Egyptians 
 possessed some knowledge of what are now termed the "malarial fevers," 
 for, according to W. Groff, the annual recurrence of malaria is indicated in 
 inscriptions upon the temple ruins at Denderah. In the fifth century B. C, 
 Hippocrates gave a clear description of these fevers, distinguishing them from 
 other continued fevers and dividing them into tertian, quartan, quotidian, and 
 semitertian. He recognized that the malarial fevers are most frequent in the 
 summer and autumn and in the vicinity of bodies of water. Celsus, in the 
 first century A. D., distinguished the pernicious forms of malaria, as well as 
 the forms described by Hippocrates. His description of the malignant 
 tertian fever proves beyond doubt that this form of malaria was well known 
 at the time he wrote. He says: 
 
 "But of tertians there are two sorts. One commencing and terminating 
 like the quartan, with this difference only that it affords one day's interval, 
 and returns on the third; the other, far more dangerous, returning, it is true, on 
 the third day, but generally occuping by the accession six-and-thirty out of 
 the forty-eight hours, sometimes even more or less; nor does it entirely subside 
 in the remission, but only becomes mitigated." 
 
 Varro, Columella, Avicenna, and Palladius all described the forms of 
 malarial fever observed by them, and regarded the emanations arising from 
 swamps and the swarms of minute animals present in swamp water as probable 
 causes of certain forms of malaria. .During the years of Roman sovereignty 
 enormous aqueducts were constructed and drainage works undertaken for 
 the sole purpose of rendering Italy free from the terrible scourge of malaria, 
 and that many of these operations were successful is proven by the ruins of 
 once populous cities in localities which to-day are uninhabitable on account of 
 the prevalence of these fevers. 
 
 During the darkness and superstition of the Middle Ages no additions were 
 made to our knowledge of malaria and it was not until the middle of the 17 th 
 century, when cinchona bark was introduced into Europe, that an impetus 
 was given to the study of these fevers. 
 
 Second Period. — Cinchona bark was introduced into Europe in 1640 
 by the Viceroy del Cinchon, who had observed its action in Ecuador in natives, 
 and Europeans suffering from malaria. The introduction of this drug greatly 
 stimulated the study of the malarial fevers, as by its use it was possible to distin- 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 5 
 
 guish these fevers from other diseases, and to Morton, Sydenham, Lancisi, 
 and Torti, we owe much of our knowledge regarding the clinical symptoms 
 of these fevers. Morton, of London, in 1697, described minutely the pernicious 
 fevers of malarial origin, recognized the specific action of cinchona bark, and 
 believed that the emanations from swamps and marshes had much to do with 
 their causation. Lancisi, in 1 717, published an elaborate study upon the etiology 
 of the malarial fevers, in which he considered that they were due to inorganic 
 and organic substances found in the air of marshy districts, and even suspected 
 that insects, such as mosquitoes, might transmit these fevers. In 1723, 
 Sydenham described the intermittent forms of malaria and recognized the 
 specific action of cinchona. Torti, in 1753, published a classical treatise upon 
 these fevers in which, for the first time, the term "malaria," destined to distin- 
 guish these infections, was used. Meckel, in 1847, described the pigmented 
 leucocytes so often observed in malarial blood, while Frerichs and Virchow 
 confirmed his results. It is very probable, from their descriptions, that the 
 latter investigators actually saw the malarial plasmodia, but did not recognize 
 their true nature. 
 
 With the perfection of the compound microscope there was rendered 
 visible to the eye of man a hitherto invisible world of living creatures and a 
 new era began in the study of the etiology of disease. While the theory that 
 the malarial fevers might be due to parasitic infection was very ancient, Varo, 
 (B. C. 1 29-1 18) having conjectured that the cause might be minute animal 
 life in some form, the only observer who had definitely declared his belief that 
 invisible organisms were the cause of malaria was Lancisi, and it was not until 
 1849, when J. K. Mitchell suggested that certain spores occuring in marshy 
 districts might be the etiological factor, that attention was forcibly directed 
 to the relation micro-organisms might bear to these fevers. 
 
 Following Mitchell's suggestion, Salisbury, in 1866, described certain 
 small vegetable cells of the family Palmella, which he found in the soil of malarial 
 localities upon the banks of the Ohio and Mississippi Rivers, and which he be- 
 lieved to be the cause of malaria. He claimed that these spores rose into 
 the air at night and fell to the ground at sunrise, thus explaining the danger 
 of night air, and the inocuousness of the air during the day in malarial regions. 
 He also claimed to have demonstrated the same spores in the urine and 
 perspiration of persons suffering from malaria, and for a considerable period 
 his observations were accepted, and the spores of Palmella were regarded as 
 the cause of these fevers. 
 
 In 1879, after the results of Salisbury had been shown to be erroneous, 
 Klebs and Tommasi-Crudeli announced their discovery of the Bacillus malarice, 
 a bacillus found in the water and soil of malarious regions, capable of cultiva- 
 tion upon ordinary culture media, and producing, when injected in man, in 
 pure culture, undoubted symptoms of malarial infection. The observations 
 of these investigators, while never confirmed by careful workers, were accepted 
 as true by a large proportion of the scientific world, and such authorities as 
 
6 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 Marchifava and Cuboni claimed to have found this bacillus in the blood of 
 their malarial patients. The final discovery, in 1880, of the true cause of malaria, 
 although not generally admitted until 1884, proved that the bacillus of Klebs 
 and Tommasi-Crudeli stood in no causative relation to the malarial fevers, 
 and affords us an illustration of the fallibility of human judgment in scientific 
 research. 
 
 Third Period. — In 1880, Laveran, a French army surgeon, working in 
 Constantine, Algeria, described certain parasites occurring in the blood of 
 malarial patients which he considered to be the cause of the disease. His 
 first communication was made to the Academy of Medicine in Paris, and was 
 followed in 1881 by a more detailed description of the organism. He described 
 three forms of the parasite. The first consisted of oval or crescentic bodies 
 with hyaline protoplasm containing pigment, arranged either in clumps or in a 
 wreath-like form. This was undoubtedly the crescentic form of the aestivo- 
 autumnal plasmodium. The second form described consisted of small hyaline 
 bodies containing pigment, and from these bodies there arose occasionally long, 
 thin, hyaline filaments which possessed the property of motion. This form 
 was undoubtedly the flagellate form of the plasmodium. The third form 
 described by him consisted of spherical, slightly granular bodies, with motion- 
 less pigment, which were evidently degenerative forms of the two foregoing 
 classes. 
 
 Richard, a French army surgeon serving atPhilippeville, Algeria, confirmed 
 Laveran's discovery, and recognized the young, hyaline, intracorpuscular 
 Plasmodia, but for over four years Laveran's plasmodium was regarded with 
 but little scientific interest, the bacillus of Klebs and Tommassi-Crudeli being 
 believed to be the true cause of the malarial fevers. However, in 1885, Marchi- 
 afava and Celli described carefully the hyaline intracorpuscular parasites and 
 proposed the name u Plasmodium malaria;" for the organisms. In the same 
 year, Golgi proved that quartan malaria depended upon a specific form of the 
 plasmodium, and shortly afterward he demonstrated and described the parasite 
 causing tertian fever. He also called attention to the probably distinct type of the 
 crescentic and ovoid forms of the plasmodium, and to him we owe the discovery 
 that the malarial paroxysm always coincides with the segmentation or sporula- 
 tion of a group of parasites. Occurring every forty-eight hours, the segmenta- 
 tion causes a tertian fever, while if it occurs every seventy-two hours a 
 quartan fever results. Marchiafava and Celli had been strong supporters of 
 the bacterial causation of the malarial fevers, and when, in 1885, these authors 
 admitted that they were mistaken, and, although they had previously regarded 
 Laveran's parasites as degenerative changes in the red blood-corpuscles, 
 became enthusiastic advocates of their parasitic nature, their descriptions of 
 the plasmodia attracted wide attention, and were soon confirmed by numerous 
 observers, as Councilman and Abbot, Sternberg, Osier, Dock, Grassi and 
 Feletti, Antolisei, Bastianelli and Bignami, Mannaberg, and many others. 
 During this period the morphological structure of the plasmodia was carefully 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 7 
 
 studied, and from this study of the morphology of the plasmodia there arose 
 two distinct schools, one believing in the unity of all forms of the plasmodia, 
 the other believing that the plasmodia of malaria are divided into distinct 
 species. The first school, represented by Laveran, believes that the malarial 
 Plasmodium is a single organism occurring in many forms; while the second 
 school believes that there are several species of plasmodia, each producing its 
 characteristic type of fever, and each easily distinguished by differences in 
 morphology and in its life cycle. 
 
 The minute study of the plasmodia resulted in the description of the life 
 cycle of all the species, and the demonstration of the occurrence in the blood of 
 certain forms, spherical, ovoid, and crescentic in shape, that did not sporulate, 
 but under favorable conditions became flagellated, the nature of which was 
 vainly guessed at until it was shown that these forms were intended to continue 
 the life of the plasmodia outside of the human body. Although by Laveran's 
 great discovery the diagnosis of malaria was placed upon a scientific basis, 
 but little was known regarding the means of transmission of the plasmodia; 
 while Gerhardt, Mariotti, Marchiafava, Celli, Bignami, Bastianelli, Baccelli, 
 Sacharov, Elting, and others had proved that the malaria fevers may be trans- 
 mitted by direct inoculation from man to man, and that the type of paraseti 
 injected is found again in the blood of the inoculated individual, yet until the 
 researches of Ross we possessed no definite knowledge of how infection occurred 
 in nature or of the life cycle of the plasmodia outside of the human body. 
 
 Fourth Period.— To the brilliant work of Ross, Bignami, Bastianelli, 
 and Grassi the world is indebted from the elucidation of the method of trans- 
 mission of the malarial fevers. That malaria may be transmitted by insects 
 is by no means a modern conception, for Varro and Columella both suggested 
 that these fevers might be transmitted in this way, while Lancisi mentioned 
 the mosquito as an agent in the spread of the disease. In more modern times 
 Nott (1848) considered this method of transmission as already proven, and 
 King (1882) advocated the same method of transmission and adduced some 
 evidence in its support. In the Goulstonian lectures of 1894, Manson elabo- 
 rated the theory of mosquito transmission, awakening renewed interest in 
 this phase of the study of malaria. In 1895, Ross of the Indian Army Medical 
 Service studied the changes occurring in the aestivo-autumnal plasmodia 
 within certain species of mosquitoes, and in 1897 observed the encysted forms 
 of these plasmodia within the stomach wall of mosquitoes of the genus 
 Anopheles. Ross continued his observations upon birds infected with 
 Halteridium, the parasite of avian malaria, demonstrating that in Culex 
 fatigans which have bitten infected birds, the parasites become encysted in 
 the stomach wall, and undergo a series of developmental changes resulting in 
 the formation of multitudes of sporozoites which accumulate in the cells of 
 the salivary glands and reinfect susceptible birds when the insect bites. Mac- 
 Callum, in 1898, studying the same parasite, observed that two forms of the 
 fully developed halteridium occurred in the infected birds, one of which is 
 
8 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 flagellated and the other nun-flagellated. He observed that the llagella> 
 breaking away from the flagellated form, penetrated the non-flagellated organ- 
 isms, and after penetration a motile body resulted which moved about among 
 the blood-corpuscles. Later he observed the same phenomena in studying 
 the aestivo-autumnal parasites, and considered that this process was one of 
 fertilization. MacCallum's researches have been confirmed by Bastianelli, 
 Bignami, and Grassi, who, working with the parasites of human malaria and 
 with mosquitoes of the genus Anopheles, have demonstrated that fertilization 
 occurs in the stomach of the mosquito and is followed by encystment in the 
 stomach wall. Their observations proved that the plasmodia undergo the 
 same developmental cycle in anopheles mosquitoes that the halteridium undergoes 
 in Cnlex fatigans. 
 
 In 1898, Bignami was successful in producing an attack of aestivo-autumnal 
 malaria in man by allowing mosquitoes which had bitten an infected individual 
 to bite a patient who had never had malaria. In the same year, Bastianelli, 
 Bignami, and Grassi were successful in producing a double tertian infection in 
 man by the bites of infected Anopheles. In February, 1899, they were for the 
 first time successful in infecting Anopheles maciilipennis with quartan parasites, 
 and traced the developmental stages of this organism in the mosquito. They 
 were also successful in producing aestivo-autumnal malaria by the bites of 
 infected mosquitoes. These results have been confirmed by numerous ob- 
 servers and prove beyond question that the malarial fevers are transmitted 
 by mosquitoes and that there are at least three species of malarial plasmodia. 
 
 Geographical Distribution. — The malarial fevers are world-wide in 
 their distribution, but certain localities are entirely free from malarial infection. 
 In the Eastern hemisphere such infections are rare above 62 N. Latitude, 
 while in the Western hemisphere they are but rarely found above 45 N. Lati- 
 tude. They are most common and most severe in low-lying coast regions, 
 mountainous countries being comparatively exempt. The deltas of large 
 rivers, especially the rivers of tropical countries, are hot-beds of malarial 
 disease, and this is also true of all bodies of water situated in such localities. 
 As we approach the equator we meet less often with the benign forms of malarial 
 infection, the prevailing types being the severe and often fatal aestivo-autumnal 
 infections. 
 
 While the aestivo-autumnal fevers are thus more strictly bounded as 
 regards distribution than are either the tertian or the quartan forms of malaria, 
 they are yet so widely spread as to make their recognition of the first importance 
 to American practitioners, for they not only occur in the semi-tropical regions 
 of the United States, but are very prevalent in our colonial possessions, such as 
 the Philippine Islands and Porto Rico and along the line of the Panama Canal. 
 In these regions the aestivo-autumnal fevers are endemic, and have proven to be 
 the greatest obstacle to colonization by the white race. Malaria is a greater foe 
 to civilization in the tropics than is any other one factor, and Koch justly says: 
 "Malaria is met with everywhere; the officer in his bureau, the traveler in the 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 9 
 
 interior, the soldier upon the march, all must recognize that soon or late they are 
 to become the victims of malaria." 
 
 The distribution of the malarial fevers depends upon the presence of 
 mosquitoes belonging to the Anophelina:; the presence of infected individuals; 
 proper climatic conditions as to temperature and moisture; and susceptibility 
 of the individual bitten by infected mosquitoes to malaria. Unless all of these 
 factors be present the malarial fevers will not be found except as imported 
 cases, and the country so fortunate as to be thus unsuitable to the propagation of 
 malaria will remain free from the disease. The presence of species of the 
 Anophelinse does not presuppose the existence of malaria, as some of the 
 Anophelina? are incapable of transmitting malaria, while even in localities 
 where the right species are present no malaria will be found unless an infected 
 individual has entered the district and infects the mosquitoes. 
 
 Given all of the factors mentioned, the malarial fevers may be endemic in 
 certain regions, or may become epidemic in regions ordinarily free from such 
 infections. Extensive pandemics of malaria are described by many writers, 
 one of which, in 1558, covered all of Europe, while many epidemics have 
 occurred, the last between 1866 and 1872, spreading over much of Europe and 
 a large portion of India and North America. Local epidemics of malaria are 
 often observed in places which may have been free from infection for many 
 years. An instance of this kind occurred under my observation in a city in 
 Connecticut. Some years before the Spanish-American War this city occasion- 
 ally reported the presence of tertian malarial fever, but the cases were few in 
 number and no other form of malaria was ever observed. After the return of a 
 company of militia at the close of the war mentioned, several cases of remittent 
 fever were observed which upon investigation were found to be infections with 
 the aestivo-autumnal malarial plasmodia. The introduction of this organism 
 was traced to the returning soldiers, some of whom had suffered from this form 
 of malaria while in Cuba upon special service. In this instance the conditions 
 necessary for the spread of the disease were all present in the city with the 
 exception of the infected individuals; the right species of Anopheles, warmth and 
 moisture, and a susceptible people, awaited only the returning soldier infected 
 with the aestivo-autumnal plasmodium, and thus a form of malaria never before 
 observed in the State of Connecticut became prevalent in this city. Such 
 instances could be multiplied and well illustrate the facility with which malaria 
 may be introdcued into localities previously free from these fevers. 
 
 The most important places in which malaria is endemic are the following: 
 
 North America. — In North America malaria occurs rarely above the 
 forty-fifth parallel. Along the entire Atlantic coast line these fevers are ob- 
 served, the New England States showing the fewest and the mildest cases, the 
 disease increasing in severity as the Southern States are reached, where the 
 aestivo-autumnal fevers not infrequently result fatally. The most severe forms 
 prevail along the low regions of the southern coast line, and especially in the 
 swamps of the Gulf States. Texas, Georgia, and Florida are badly infected 
 
IO THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 in some portions with aestivo-autumnal malaria; this form is also common 
 along the southern portion of the Mississippi and its tributaries and there are 
 regions in the delta of the Mississippi that are uninhabitable because of the 
 prevalence of the most deadly forms of aestivo-autumnal infection. Along the 
 Missouri and Arkansas Rivers the malarial fevers are very prevalent, and the 
 disease is common in the States of Mississippi, Missouri, Arkansas, Kansas, 
 Oklahoma, and certain parts of New Mexico. The States of North and South 
 Carolina, Virginia, Maryland, and West Virginia are all infected, but to a less 
 extent. Ohio, Indiana, Illinois, Michigan, Minnesota and Wisconsin are 
 infected with the benign tertian type of malaria, but only in limited localities, 
 and to a much smaller extent than are the Southern States. Of the Western 
 States, Wyoming, Utah, Arizona, and California are more or less malarial, and 
 in the valleys of the Sacramento and San Joaquin in California, pernicious 
 forms of aestivo-autumnal malaria are not uncommon, while the benign tertian 
 infections are very prevalent. The regions about the Great Lakes are almost 
 free from malaria except in certain localities about Lake Michigan and Lake 
 Ontario, while Canada appears to be free from these fevers except in the most 
 Southern portions bordering upon the Great Lakes, and the infections are all 
 of mild character. 
 
 Almost all of the islands of the West Indies are badly infected with the 
 malarial fevers, especially Cuba, where aestivo-autumnal malaria is most 
 prevalent and fatal in character. Barbados and St. Vincent are said to be free 
 from malaria, and in Porto Rico the benign intermittents are the most common 
 forms observed. 
 
 Mexico and Central America are hot-beds of the most deadly forms of 
 aetsivo-autumnal infection, and the low-lying coast lines of these countries are 
 among the most dangerous of the lurking places of this form of disease. The 
 dreaded Chagres fever of Panama is a form of aestivo-autumnal infection, and, 
 together with yellow fever, compelled the French to abandon the digging of the 
 Panama Canal. 
 
 In South America malarial infections are common in the northern part of 
 Brazil, in Uruguay, Paraguay, Bolivia, Venezuela, Guiana, and Colombia. The 
 Argentine Republic, Peru, and Ecuador suffer less from malaria, but all are 
 infected. 
 
 Europe. — Great Britain may be said to be entirely free from malarial 
 infection, imported cases being the only ones observed in that country. In 
 Germany, malarial infections occur along the coast of the Baltic, and they are 
 not uncommon in the swamps of Hanover and Westphalia, and along the 
 Rhine and its tributaries. In Holland and Belgium malaria is endemic in the 
 river bottoms and in marshy regions. In France these infections occur along 
 the Loire and Rhone, the West Coast, the river Brenne, and the Sologne. In 
 these regions only the benign forms are observed, and this is also true of the 
 malaria of Germany. 
 
 In Spain the valleys of the Tago and the Quadalquivir are infected, and 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. II 
 
 pernicious forms occur in all the countries bordering upon the Mediterranean; 
 in Greece, Crete, Italy, Sicily, and Turkey, aestivo-autumnal infections are 
 common, as are also the tertian and quartan fevers; in Italy, especially, occur 
 the most malignant forms in the regions around the Roman Campagna and 
 the Pontine marshes, as well as in the valley of the Po and along the entire 
 West Coast. Sardinia and Corsica are also infected with the pernicious forms 
 of aestivo-autumnal malaria. In Austria-Hungary malarial infections are 
 present in Galicia, in the valley of the Danube, and along the Adriatic. In 
 Turkey severe infections occur along the Danube; in Russia malarial infections 
 are prevalent in the valleys of the Volga, Dniester, and Dnieper, and they are 
 also common along the coast lines of the Black and Caspian Seas and the Sea 
 of Azov. 
 
 Asia. — Asia Minor, Persia, Arabia, India, and Ceylon, as well as portions 
 of China and nearly all of the islands of the Malay Archipelago are infected 
 with the malarial fevers. The valleys of all of the great rivers, such as the 
 Indus and the Ganges, are heavily infected, and pernicious forms are common; 
 even upon the lofty tablelands of the Himalayas malarial infections are often 
 met with, and the region of jungle country known as the Terai, at the foot of 
 the Himalayas, is considered one of the most dangerous of malarial districts. 
 Java and Sumatra are badly infected with malaria, as are certain parts of 
 Borneo. The Philippine Islands, until quite recently considered as being 
 comparatively free from malaria, have been proved to be badly infected, the 
 islands of Luzon, Samar, Mindoro, and Mindanao showing infection with all 
 the species of malarial plasmodia. In the island of Luzon, the foot hills of the 
 Zambales Mountains and the part of the great Pampangan Plain in the region 
 of the foot hills, are infected with the most pernicious forms of aestivo-autumnal 
 malaria, while there are certain regions in the islands of Samar and Mindoro 
 that are shunned by the natives on account of the deadly malarial infections 
 which are present. 
 
 Africa. — In Africa are some of the most dangerous lurking places of 
 malarial infections, the worst areas being those along the West Coast, and the 
 valleys of the Senegal, Congo, and Niger rivers, as well as the regions around 
 the great lakes and the jungles and lake shores of Abyssinia. In Egypt the 
 only infected districts are situated in the delta of the Nile; Tunis, Tripoli, 
 Algiers, the oases of the Sahara, and the East Coast are infected with all forms 
 of the malarial plasmodia, but aestivo-autumnal infections are most common. 
 The islands of St. Helena, the Seychelles, and Rodriguez are free from malaria, 
 and the same is true of Cape Colony, the Orange Free State, and of German 
 Southwest Africa. Madagascar, Mauritius, and Reunion are infected with 
 malaria, pernicious forms occurring in all of these islands. The continent of 
 Australia is free from malaria, as are most of the islands of Polynesia. 
 
 The resume given indicates the most important regions in which the 
 malarial fevers are endemic, but there are numerous districts in which a few 
 sporadic cases occur at rare intervals, but which at any time may become 
 
12 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 endemic foci, provided certain species of the Anophelinre are present, together 
 with individuals harboring the malarial plasmodia. In our own country the 
 return of hundreds of our soldiers from the Philippine Islands infected with the 
 various forms of malaria so prevalent there, especially the aestivo-autumnal, 
 will inevitably result in the infection of localities hitherto free from malarial 
 disease, and unless these infections be promptly recognized, such localities 
 will become endemic foci of the malarial fevers. 
 
 A knowledge of the geographical distribution of these fevers is of much 
 practical value, as localities known to be infected can thus be avoided, and 
 those who travel through them, or reside within them, can take the proper 
 precautions to prevent infection. A knowledge of the distribution of these 
 fevers is also of great assistance in the diagnosis of unusual or obscure forms of 
 fever and in the prophylaxis of malaria. The blood of every patient coming 
 from a malarial region should be examined, and if the plasmodia are found, 
 quinin should be administered and the proper measures taken to protect the 
 community from the infection. 
 
 Monographs upon the Malarial Fevers. 
 
 1889. Kelsch and Kiener. Traite des maladies des pays chauds. Paris. 
 
 1890. Schellong. Die Malariakrankheiten, etc. Berlin. 
 
 1895. Thayer and He wetson. The Malarial Fevers of Baltimore. Baltimore. 
 
 1895. Baccelli. Studien uber Malaria. Berlin. 
 
 1896. Rho. La Malaria. Torino. 
 
 1897. Thayer. Lectures upon the Malarial Fevers. New York. 
 
 1898. Laveran. Traite du paludisme. Paris. 
 
 1898. Zieman, H. Ueber Malaria und andere Blutparasiten. Jena. 
 
 1899. Mannaberg. Die Malaria Krankheiten. Nothnagel's Encyclopaedia. 
 Berlin. 
 
 iqoo. Celli. Malaria. London. 
 
 1900. Marchiafava and Bignami. Malaria. Twentieth Century Practice. 
 New York. 
 
 1 90 1. Grassi. Die Malaria: Studien eines Zoologen. Jena. 
 1901. Neveu-Lemaire. Les hematozoaires du paludisme. Paris. 
 
 1901. Ruge, R. Einfiihrung in das Studium der Malariakrankheiten. Jena. 
 1 90 1. Craig, C. F. The Aestivo-autumnal (Remittent) Malarial Fevers. New 
 
 York. 
 1904. Stephens and Christophers. Practical Study of Malaria and other 
 
 Blood Parasites. London. 
 
 1906. Zieman, H. Malaria. Handbuch der Tropenkrankheiten. Mense. 
 Leipzig. 
 
 1907. Thayer. Malaria. System of Medicine, Albutt and Rolleston. London. 
 1907. Craig, C. F. The Malarial Fevers. Modern Medicine. Osier. Phila- 
 delphia. 
 
 Historical Literature. 
 
 Hippocrates. The Genuine Works of Hippocrates. Adams Trans. New York. 
 Celsus. De Medicina, libri viii. 
 Varro. "Rerum Rusticarum," Lib. i 
 Columella. " De re Rustica," Lib. i, Cap. 5. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 1 3 
 
 Palladius. "Dere Rustica," Lib, i, Cap. 7. 
 
 1697. Morton. " Opera Omnia. " Lugduni. 
 
 1717. Lancisi. De noxiis paludum effluviis. Rome. 
 
 1723. Sydenham. "Opera Medica. " Genevae. 
 
 1743. Torti. Therapeuticae specialis ad febres quasdam perniciosas. Editio 
 
 quarta. Venetiis. 
 1847. Meckel. Ueber schwarzes Pigment in der Milz und im Blut einer 
 
 Geisteskranken. Zeitschr. f. Psychiatric, S. 198. 
 1894. Virchow. Zur pathologischen Physiologie des Blutes. Virch Archiv, 
 
 ii, 587- 
 1849. Mitchell. On the Cryptogamous Origin of Malarious and Epidemic 
 
 Fevers. Philadelphia. 
 1866. Salisbury. Amer. Jour. Med. Sciences, January. 
 1870. Colin. Traite des fievres intermittentes. Paris. 
 
 1879. Klebs and Tomassi-Crudeli. Studien uber Ursache des Wechsel- 
 fiebers und uber die Natur der Malaria. Arch. f. exp. Path. u. Pharmak., 
 xi, 311. 
 
 1880. Tomassi-Crudeli. Studi ulteriori sul Bacillus malarue. Bull, dell 
 R' accad, med. di Roma, vi, 9-12. 
 
 1880. Tomassi-Crudeli. Malarial Fever. The Practitioner, Nov., xxv, 320. 
 
 Laveran. Note sur un nouveau parasite, etc. Bull, de l'acad. de med. 
 
 de Paris, se. du 23 Nov. 
 
 Laveran. C. R. Acad. Sc. Paris. T. xciii, p. 627. 
 
 Fayrer. On the Climate and Fevers of India. London. 
 
 Richard. Sur le parasite de la malaria. Compt. rend, des l'acad. des 
 
 sciences, Paris, se. 20 Febr. 
 
 Richard. Le parasite de rimpaludisme. Rev. Scientifique, Paris, p. 
 
 113- 
 
 Marchiafava and Celli. Die Veranderungen der rothen Blutscheiben 
 
 bei Malariakranken. Fortschritte der Med., Leipzig, i, 573. 
 
 Marchiafava and Celli. Weitere Untersuchungen uber die Malaria 
 
 infection. Fortschritte der Med, iii, No 24, 787. 
 
 Golgi. Sulla infezione malarica. Gaz. degli Osp., No. 53, 419. 
 
 Councilman and Abbott. A Contribution to the Pathology of Malarial 
 
 Fever. Am. Jour. Med. Sci., Apr., vol. 89, 416. 
 
 Osler. An Address on the Hematozoa of Malaria. Brit. Med. Jour., 
 
 i> 556. 
 
 Sternberg. The Malarial Germ of Laveran. Med. Record, May 1 and 
 
 8, 489. 
 
 1886. Councilman. On Certain Flements Found in the Blood in Cases of 
 Malarial Fever. Trans. Assoc. Amer. Phys., i, 90. 
 
 1887. Councilman. Further Observations on the Blood in Cases of Malarial 
 Fever. Med. News, i, 59-63. 
 
 Sacharoff. Untersuchungen uber den Parasiten des Malariafiebers. 
 Protocols of the Caucassian Med. Soc, at Tiflis, No. 6, 147. 
 
 17. Ross, R. On Some Peculiar Pigmented Cells Found in Two Mosquitoes 
 fed on Malarial Blood. Brit. Med. Jour., vol. ii, p. 1786. 
 Ross, R. The Role of the Mosquito in the Evolution of the Malarial 
 Parasite. The Lancet, vol. ii, p. 488. 
 Grassi, B., Bastianelli, G., et Bignami, A. Contributions as follows 
 
 1898. Rend, della R. Accad dei Lincei, vol. vii, Series 5a. 
 
 1899. Ibid., vol. viii, Series, 5a, p. 434. 
 
 1899. Atti Soc. per gli studi della malaria, vol. i, p. 14. 
 
CHAPTER II. 
 
 Etiology ; Classification ot the Parasites of the Malarial Fevers ; Morphology 
 and Biology of the Malarial Plasmodia in the Blood of Man. 
 
 Classification of the Malarial Parasites. — From the time of the discovery 
 by Laveran of the malarial plasmodia to the present, much attention has been 
 devoted by zoologists to the proper classification of these organisms, and many 
 different opinions have been advanced concerning their exact zoological posi- 
 tion. Laveran proposed the name "Oscillaria malaria" for the parasite, 
 but later accepted Osier's name of " Haematozoon. " In 1887, Metchnikoff 
 placed the organisms among the Sporozoa, and proposed the name " Haema- 
 tophyllum malaria" for the malarial parasite of man. To Danilewsky we 
 owe the new division of the Sporozoa into a group known as the Haemosporidia 
 in which he placed the malarial plasmodia. The genus " Plasmodium" 
 was created by Marchiafava and Celli, and all the plasmodia of man placed 
 in this genus by these authors. At the present time, then, it is conceded by all 
 zoologists that the parasites causing the malarial fevers belong to the Protozoa; 
 order Sporozoa; sub-order Haemosporidia, and genus Plasmodium. 
 
 The existence of distinct species of plasmodia associated with equally 
 distinct types of malarial fever has been abundantly demonstrated by many 
 careful observers, and the work of Marchiafava and Bignami, Celli, Grassi, 
 Golgi, and others has resulted in the separation of at least three species of 
 Plasmodium, differing in their morphology and life history as well as in the 
 effects they produce in man when blood containing them is inoculated or 
 when infected mosquitoes are allowed to bite susceptible individuals. 
 
 Laveran and his followers believe that the parasite producing malarial 
 fever is a polymorphous organism, assuming very great differences in morph- 
 ology under differing conditions of environment, and that, in Laveran's words, 
 "there does not exist a constant relation between the forms under which the 
 haematozoa appear in the blood and the clinical manifestations of paludism; 
 one can only say that certain forms of the parasite are more often seen in certain 
 cases, the crescents, for instance, in relapses and in malarial cachexia." Some 
 of Laveran's followers even claim to have observed interchangeability of the 
 various species which have been described, but their observations still await 
 confirmation, and the great weight of evidence to-day, both morphological and 
 experimental, is in favor of the existence of several species of malarial plasmodia. 
 The existence of at least three species of plasmodium, the tertian, quartan, and 
 aestivo-autumnal, has been accepted by every investigator in America, England, 
 
 14 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 1 5 
 
 Germany, Italy, and in tropical regions, as India and Africa, but considerable 
 uncertainty exists as to the species concerned in the production of the various 
 forms of aestivo-autumnal infection. The Italian authorities, together with 
 nearly every investigator who has studied malaria in the tropics, have made 
 a subdivision of the aestivo-autumnal parasite into at least two varieties, the 
 quotidian and the tertian, and a great amount of labor has been expended in 
 differentiating these varieties and in endeavoring to demonstrate their specific 
 characteristics. From personal experience I have no hesitation in stating that 
 the tertian and quotidian aestivo-autumnal plasmodia can be as easily differen- 
 tiated as the benign tertian and quartan plasmodia, when suitable material 
 is available for study, and while I cannot accept the existence of a pigmented 
 and unpigmented quotidian aestivo-autumnal parasite, I believe that the 
 aestivo-autumnal infections are produced by two distinct organisms, the 
 quotidian and the tertian aestivo-autumnal plasmodium. 
 
 Several of the classifications proposed for the parasites of malaria are of 
 interest and will be briefly noticed. 
 
 Labbe's Classification. — Labbe placed all of the blood parasites belong- 
 ing to the Protozoa in the Sporozoa, dividing them into two classes: Haemo- 
 sporidia and Gymnasporidia, in the latter division placing the malarial parasites 
 of man as well as the HaUeridium and Proteosoma of birds. 
 
 Kruse's Classification. — Kruse divides the Sporozoa into four orders, 
 placing the malarial parasites in the Gregarinida, sub-order Haemogregarinidcz; 
 genus Plasmodium, the generic term first given by Marchiafava and Celli. 
 
 Grassi and Feletti's Classification. — These authors placed all of the 
 malarial parasites in two genera: Haemamoeba and Laverania. In the genus 
 Haemamoeba, they mention four species of malarial parasites as occurring 
 in man: H. malaria (quartan), H. vivax. (tertian), H. praecox. (pernicious), 
 and H. immaculata (pernicious). In the genus Laverania, they place the 
 crescentic parasites, giving them the specific name "Laverania malarice." 
 Neither the generic or specific name in this instance can stand, as both were 
 founded upon the belief that the crescents were a distinct species of parasite. 
 
 Mannaberg's Classification. — Mannaberg divides the malarial para- 
 sites as follows: 
 
 i. Malarial parasites that sporulate, but do not form syzygies (crescents). 
 
 a. Quartan plasmodium. 
 
 b. Tertian plasmodium. 
 
 2. Malarial parasites that sporulate and form syzygies (crescents). 
 
 a. Pigmented quotidian plasmodium. 
 
 b. Non-pigmented quotidian plasmodium. 
 
 c. Malignant tertian plasmodium. 
 
 Thayer and Hewetson's Classification. — In their classical work upon 
 the malarial fevers Thayer and Hewetson divide the parasites of malaria into 
 three species, the tertian, quartan and aestivo-autumnal parasites. 
 
 Sacharoff's Classification. — Sacharoff divides the plasmodia into two 
 
1 6 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 genera, Hacmamoebcc and Laverania; in the first genus he includes three species, 
 as follows: 
 
 Hacmamocba praccox (aestivo-autumnal). Grassi. 
 Haemamocba febris lertianae (tertian). Golgi. 
 Haemamoeba febris quartanae (quartan). Golgi. 
 In the second genus, Laverania, he includes one species, characterized by a 
 crescentic shape. In this Sacharoff followed Grassi and Feletti, believing that 
 the crescents were a distinct species of parasite. 
 
 Zieman's Classification. — Zieman divides the malarial plasmodia into 
 four species, the tertian, quartan, pernicious (aestivo-autumnal), and pernicious 
 — varietas Africana. 
 
 Luhe's Classification.— The classification of Liihe, accepted by many 
 authorities, divides the malarial parasites into two genera, Laverania and 
 Plasmodium. In the genus Laverania he places the aestivo-autumnal parasite, 
 while in the genus Plasmodium he places the tertian and quartan parasites, as 
 well as those occurring in warm-blood animals other than man, and in birds. 
 According to Luhe, the three parasites of man should be thus classified: 
 Genus, Laverania. 
 
 Species, Laverania malar iae. Gr. et Fe. 1890. 
 Genus, Plasmodium. Marchiafava and Celli. 
 
 Species, Plasmodium malaria:. Marchia et Celli. Quartan parasite. 
 Plasmodium vivax. Gr. et Fe. Tertian parasite. 
 As has been stated, the generic name "Laverania" can not be retained and 
 the generic name "Plasmodium" should be substituted for it. 
 
 Scbaudinn's Classification. — The classification of the parasites of 
 malaria most generally accepted by zoologists and students of malaria has been 
 that of Schaudinn, who divided the organisms into three species as follows: 
 
 1. Plasmodium vivax. Gr. et Feletti. Tertian parasite. 
 
 2. Plasmodium malariae. Marchiaf et Celli. Quartan parasite. 
 
 3. Plasmodium immacidatum. Gr. etFe. Aestivo-autumnal parasite. 
 The specific name "immaculatum" can no longer be retained, however, for 
 
 the aestivo-autumnal plasmodium, for Blanchard has shown that Grassi pre- 
 viously used this name for a parasite occurring in birds, thus preventing its use 
 for the human parasite. This fact renders the specific name proposed by 
 Welch "falciparum" the proper name for the aestivo-autumnal plasmodium, 
 and Blanchard's classification, which follows, the most recent and generally 
 accepted of the many which have been mentioned. 
 
 Blanchard's Classification. — This classification divides the parasites 
 of malaria into three species, as follows: 
 
 1. Plasmodium malariae. Marchiaf. et Celli. Quartan parasite 
 
 2. Plasmodium vivax. Gr. et Fe. Tertian parasite. 
 
 3. Plasmodium falciparum. Blanchard. Aestivo-autumnal parasite. 
 While almost all authorities now admit the existence of three species of 
 
 malarial plasmodia, the tertian, quartan, and aestivo-autumnal, the question of 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 1 7 
 
 the existence of more than one species of the latter organism is still an undecided 
 one. By many authorities the aestivo-autumnal plasmodia are divided into 
 two varieties, a tertian and quotidian, while by some the quotidian is subdivided 
 into a pigmented and unpigmented quotidian parasite. Other authorities 
 maintain that there is but one aestivo-autumnal plasmodium, the variations 
 observed in the temperature curve being due to variations in the time of the 
 developmental cycle, which may be 24 or 48 hours in length. Personally, as J 
 have stated, there is no doubt in my mind that the two varieties of this parasite 
 first described by Marchiafava and Bignami, tertian and quotidian, are distinct 
 species and are distinguishable upon both morphological and clinical grounds. 
 I have arrived at this conclusion after the careful study of the plasmodia found 
 in many hundred cases of aestivo-autumnal fever and after years o f study of 
 malarial infections in both tropical and temperate regions. These plasmodia 
 can be differentiated morphologically, and the infections produced by them are, 
 when uncomplicated, clinically distinct. Anyone who can differentiate the 
 tertian and quartan plasmodia morphologically should have no trouble in dis- 
 tinguishing between the tertian and quotidian aestivo-autumnal plasmodia if 
 blood from the spleen, obtained by puncture, be examined. To one who has 
 had the opportunity of studying a large number of aestivo-autumnal infections 
 the two parasites can be readily distinguished by the forms occurring in the 
 peripheral blood. 
 
 The argument that the tertian and quotidian temperatures observed in 
 aestivo-autumnal malaria are due to the sporulation of a parasite which at one 
 time completes its developmental cycle in the human body in 24 hours and at 
 another time in 48 hours would appear to be illogical, and can as well be used in 
 the case of the tertian and quartan plasmodia by those who still maintain that 
 there is but one species of malarial plasmodium. 
 
 I have not been able to demonstrate the existence of a pigmented and an 
 unpigmented quotidian plasmodium as specifically distinct forms, for while it 
 is not uncommon to observe only unpigmented quotidian plasmodia in the 
 peripheral blood upon a cursory examination in aestivo-autumnal infections, 
 the spleen invariably shows pigmented organisms, and, as a rule, an extended 
 search will reveal pigmented organisms in the peripheral blood. 
 
 In view of the division of the aestivo-autumnal plasmodia into two species, 
 I would suggest the following classification of the malarial plasmodia: 
 
 Division, Protozoa. 
 
 Class, Sporozoa. 
 
 Sub-class, Telosporidia. 
 
 Order, Haemosporidia. 
 
 Genus, Plasmodium. 
 
 Species I. — Plasmodium malariae. Marchiaf. et Celli. (Quartan 
 malarial parasite.) 
 II. — Plasmodium vivax. Grassi et Feletti. (Tertian malarial 
 parasite.) 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 III. — Plasmodium falciparum. Blanchard. (Tertian aestivo- 
 
 autumnal parasite.) 
 IV '. — Plasmodium falciparum quotidianum. Craig. (Quotidian 
 
 aestivo-autumnal parasite.) 
 
 Morphology and Biology of the Malarial Plasmodia in the 
 
 Blood of Man. 
 
 General Considerations. — The malarial plasmodia are found in man 
 within or upon the red blood-corpuscles and are essentially parasites living 
 at the expense of these cells. In this situation they destroy the red corpuscles, 
 producing the well-known anaemia peculiar to the malarial fevers, together 
 with the pigmentation, or melanaemia, which is due to the destruction of the 
 haemoglobin of the infected cells. Owing to the researches and discoveries 
 of Ross, Grassi, Marchiafava, Celli, and others, it is now necessary in describing 
 the malarial plasmodia to consider the forms present in two life cycles, that 
 within man and that within mosquitoes belonging to the Anophelinas. The 
 life cycle completed within man, the intermediate host, is known as the endog- 
 enous or asexual cycle, and the growth and sporulation of the parasites is 
 called shizogony; the cycle completed within the mosquito, or definitive host, 
 is known as the exogenous, or sexual cycle, and the process of development of 
 the parasites as sporogony. In this chapter will be considered the morphology 
 and biology of the forms of the malarial plasmodia concerned in schizogony, 
 together with those forms concerned in sporogony which may be demonstrated 
 in the blood of man. Following the classification of Schaudinn the forms 
 observed in schizogony are known as the schizont and the merozoite, the first 
 term being applied to the parasites from their earliest development in the red 
 blood-corpuscles to the time of sporulation, while the latter term is applied to 
 the liberated spore; these forms occur only in the blood of man and are unable 
 to develop outside of the human body. The forms of the plasmodia observed in 
 human blood, and which are intended to undergo development in the b«dy of 
 the mosquito, are known as gametes, ard are sexually differentiated, the female 
 gamete being known as the macrogamete and the male as the micro gametocyte. 
 These, in turn, are unable to undergo development in the human body, it 
 being necessary that they reach the stomach of the mosquito before further 
 development can occur. Under certain conditions simulating those that are 
 present in the stomach of the insect, the micro gametocytes, while still present in 
 human blood which has been removed for examination, undergo further develop- 
 ment and liberate active filaments, the micro gametes, which penetrate the 
 macrogametes and fertilize them; this process occurs normally within the 
 mosquito, but inasmuch as it can be observed in specimens of blood, I shall 
 describe the forms concerned in this chapter, together with the forms concerned 
 in schizogony. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 19 
 
 All varieties of the malarial plasmodia appear at first within the red blood- 
 corpuscles as hyaline disks or ring-like bodies devoid of motion. The forms 
 which undergo schizogony gradually acquire amoeboid motility and develop 
 a certain amount of pigment, at the same time enlarging and encroaching more 
 and more upon the cell containing them. The pigment is derived from the 
 haemoglobin of the red cell which is destroyed by the growth of the plasmodium 
 within it. After a certain period of growth the plasmodia divide into numerous 
 minute spores which are liberated by the rupture of the red corpuscles containing 
 them, and which invade other corpuscles and repeat the process of development 
 briefly described. Among the spores, however, which are liberated at the time 
 of sporulation, there are some that do not undergo schizogony, but after penetrat- 
 ing the red blood-corpuscles develop into forms intended to undergo their 
 life cycle within the mosquito. These forms do not sporulate, but grow at the 
 expense of the red cell and are finally found free in the blood plasma from which 
 they escape when the blood is removed by the mosquito. These bodies may be 
 differentiated into two varieties, as has been mentioned, and are incapable of 
 further development in man, although Schaudinn believed that the female 
 form, or macrogamete, if not removed from the blood by the mosquito, after 
 a certain period of time underwent parthenogenesis, giving rise to numerous 
 young spores which entered the red corpuscles and developed as in schizogony. 
 Schaudinn thus explained the occurrence of relapses in malaria, but his observa- 
 tions still await confirmation. 
 
 In describing the malarial plasmodia as observed in the blood of man, I 
 shall describe each species separately, first giving the morphology of the forms 
 concerned in schizogony, the schizont and the merozoite, and then the forms 
 concerned in sporogony, which are demonstrable in human blood, namely, 
 the macro gametes, the micro gametocyte and the microgamete. 
 
 The Morphology and Biology of Plasmodium Vivax (the tertian malarial 
 parasite). Schizogony (human or asexual cycle). 
 
 Plasmodium vivax or the tertian malarial parasite completes its develop- 
 ment in the blood in 48 hours and produces the well-known type of malarial 
 fever associated with a chill and fever occurring upon every second day. This 
 type of malaria is the most common type in temperate regions and in many 
 subtropical and tropical localities, and has been more thoroughly studied than 
 has any other form of the disease. The organism causing this variety of 
 malaria is the most easily recognized of the malarial plasmodia and is the one 
 which should be selected for study by those who desire to acquire proficiency 
 in the recognition of the various stages in the development of the human 
 plasmodia and the forms to be observed in the peripheral blood. 
 
 Historical Summary. — The tertian plasmodium was first described as a 
 distinct species by Golgi in 1886. He called attention to differences in the 
 morphology of this plasmodium as compared to the quartan plasmodium, and 
 noted that sporulation occurred every 48 hours instead of every 72, as in the 
 latter parasite. He also called attention to the rapid amoebid motion of this 
 
20 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 Plasmodium; the light red color of the pigment and the smallness of the grains; 
 the great enlargement of the infected red cells and their rapid loss of haemoglobin; 
 and the difference in size of the two organisms, the tertian when fully grown 
 being much larger than the quartan. He described the greater number of 
 segments or spores in the tertian plasmodium, their smaller size, and irregular 
 arrangement. Golgi stated that a quotidian fever might be due to a double 
 infection with the tertian plasmodium, each group sporulating upon successive 
 days. 
 
 The observations of Golgi were soon confirmed by those of Antolisei and 
 Bastianelli and Bignami, and have since been confirmed by every student of 
 this type of malaria. 
 
 Unstained Preparations. — The tertian malarial plasmodium, or Plasmo- 
 dium vivax, appears first within the red blcod-corpuscle in schizogony as a small, 
 non-motile, hyaline disk or "ring," the trophozoite, measuring about 2 microns 
 in diameter; its outline is very indistinct and in many instances the organism 
 at this stage of its development is overlooked by reason of the absence of 
 amoeboid motion and because of its delicate, veil-like appearance. As the 
 
 Fig. i. — Plasmodium vivax. (Tertian 
 plasmodium.) Double infection of 
 red corpuscle with "ring forms." 
 Photomicrograph, X 1200. 
 
 Fig. 2. — Plasmodium vivax. (Tertian plas- 
 modium.) Young amoeboid forms. Photo- 
 micrograph, X 1200. 
 
 parasite grows older, becoming the schizont, it develops very marked amoeboid 
 activity, constantly changing its shape, but is still indistinct in outline, requiring 
 very careful examination to distinguish it in the infected red corpuscle. 
 
 In the course of from six to eight hours minute granules of a reddish- 
 brown pigment develop within the hyaline cytoplasm and the outline of the 
 organism becomes more clearly distinguishable. The pigment is of a peculiar 
 reddish-brown color, and in the form of very fine granules arranged irregularly 
 throughout the protoplasm, and is in very active, dancing motion, produced 
 by currents within the protoplasm. As development proceeds amoeboid 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 2 1 
 
 motion becomes less pronounced, and when the organism is fully grown no 
 amoeboid motion can be detected. The pigment, at first small in amount, 
 increases gradually as the organism enlarges, is actively motile until just before 
 sporulation, and is always in the form of fine granules pretty evenly distributed 
 throughout the cytoplasm until just prior to segmentation when it collects in 
 larger masses or in a single irregular mass (see Fig. 3). 
 
 In the beginning of its development the plasmodium occupies but a small 
 portion of the red corpuscle, but as it continues to grow it encroaches more and 
 more upon the infected corpuscle, until when full-grown it entirely fills the cell 
 which is much swollen and decolorized. The growth of the plasmodium is 
 gradual, covering 48 hours, at the end of which time it divides into a number of 
 small segments or spores. 
 
 At the end of 24 hours the plasmodium fills more than half of the red 
 corpuscle, contains much actively motile pigment, and varies greatly in shape, 
 due to the marked amoeboid motion of the organism. Very often at this stage 
 of development multiple infections of the red cell may be suspected by reason of 
 the appearance of two or more spherical pigmented bodies in the same red 
 corpuscle, but careful examination will reveal the fact that the pigmented 
 spherical bodies are but portions of the amoeboid pseudopodia of a single 
 orga lism, the remainder of the organism being situated deeper within the 
 infected cell, and thus rendered invisible for the time being. The infected red 
 cell at this stage is considerably larger than normal and lighter green in color 
 (see Fig. 3). 
 
 At the end of 36 hours the plasmodium has attained its greatest size and 
 almost fills the infected corpuscle. The amoeboid motion is sluggish, but the 
 pigment, which has still further increased in amount, is very actively motile, 
 and is distributed in the form of fine granules throughout the protoplasm; the 
 outline of the plasmodium is well defined, contrasting well with the light green 
 border of the red corpuscle which surrounds it. The infected red cell is almost 
 twice as large as are the uninfected cells and much lighter in color (see Fig. 4) . 
 
 At the end of 48 hours segmentation or sporulation occurs; the pigment 
 becomes collected at the center or to one side of the plasmodium in the form of a 
 compact clump, and fine radial striations are observed extending from the center 
 toward the periphery of the plasmodium, dividing it into several avoid segments 
 or spores. As a rule, these spores are arranged in two rows, one row surrounding 
 the center of the plasmodium and another surrounding the first row; but very 
 often the spores are arranged irregularly; they are always devoid of pigment, 
 and vary in number from 12 to 24, the average being about sixteen. They are 
 called merozoites. In the fresh specimen the merozoite when free in the blood 
 plasma, measures from 1.5 to 2 microns in diameter, is oval in shape, almost 
 colorless, and presents a spherical, refractive center, and a less refractive mass 
 of protoplasm surrounding it. The merozoites are capable of penetrating the 
 red blood-corpuscles and thus the human life cycle or schizogony of the plasmo- 
 dium is continued (see Fig. 5). 
 
22 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 Staining Reactions of Plasmodium Vivax. — In preparations of blood 
 containing Pla sm odium vivax stained by the Romanowsky method or any of its 
 modifications the exact structure of the parasite can be easily demonstrated. 
 The staining methods which are of value in the study of the malarial plasmodia 
 will be fully described in a later chapter of this work; by their use the plasmodia 
 are shown to consist of a mass of protoplasm, and a vesicular nucleus, rich in 
 chromatin. This is true of all species of the plasmodia, but the structure can be 
 more easily studied in Plasmodium vivax because it exceeds the other species in 
 size and because all stages of its development can be observed in the peripheral 
 blood. 
 
 Historical Summary. — The first observations upon the structure of the 
 malarial plasmodia in stained specimens of blood were made by Celli and Guar- 
 nieri, who used methylene blue as the staining reagent. They described a 
 deeply stained ectoplasm and a dimly stained endoplasm, the latter forming 
 the center of the parasite. In the "ring-forms" they described a deeply stained 
 spot situated between the ectoplasm and the endoplasm, which later observers 
 have demonstrated to be the chromatin of the nucleus. 
 
 Grassi and Feletti, as the result of their study of stained malarial parasites, 
 considered that the dimly stained endoplasm described by Celli and Guarnieri 
 was in reality a large vesicular nucleus, containing nuclear juice, a nuclear net- 
 work, and chromatin, and having a delicate, generally invisible, nuclear mem- 
 brane ; they also described contractile vacuoles in the protoplasm of the plasmodia 
 and note that it is only the protoplasm that contains the pigment granules. 
 
 Romanowsky, using his now well-known staining method, demonstrated 
 that the plasmodia consist of an outer, deeply stained portion, the protoplasm, 
 and an inner unstained portion, the nucleus. The latter is spherical or oval in 
 shape and presents at some portion of its periphery a deeply stained mass, the 
 chromatin of the nucleus, the remainder of the nucleus being unstained and 
 consisting of nuclear juice. This description applies only to the young plasmodia, 
 as in the older organisms he found that the vesicular nucleus disappeared and 
 that the chromatin became distributed in the protoplasm of the plasmodia. 
 
 The observations of Romanowsky regarding the structure of the malarial 
 plasmodia have been again and again confirmed, and but little has been added 
 to our knowledge in this direction by subsequent observers, with the exception 
 of the differentiation of those forms concerned in sporogony. It may be stated 
 that the staining reactions are similar for all species of human plasmodia, and 
 that they prove that these organisms consist of a mass of protoplasm, containing 
 at some period of development more or less pigment and a vesicular nucleus 
 rich in chromatin. 
 
 With Wright's modification of the Romanowsky stain, which I habitually 
 use, and which I have found most satisfactory in staining these organisms, the 
 chromatin is the only portion of the nucleus which takes the stain, the young 
 schizont consisting of a deeply stained mass of chromatin, surrounded by an un- 
 stained space, which in turn is surrounded by the deeply stained protoplasm. 
 As development advances the chromatin of the nucleus divides, becomes dis- 
 tributed in the protoplasm where it stains in a characteristic manner, increases 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 2 7, 
 
 in amount, and finally becomes collected into small masses forming the chro- 
 matic portion of the nucleus of the merozoites. 
 
 In schizogony, if Wright's method of staining be employed, Plasmodium 
 vivax presents the following staining reactions during its various stages of 
 development: 
 
 The youngest sclnzont, which develops from the trophozoite shortly after the 
 latter infects the red blood-corpuscle, presents the so-called "ring-form," con- 
 sisting of a spherical mass of chromatin stained a brilliant red or violet, sur- 
 rounded by an unstained spherical or oval area; this area often presents a milky 
 white color and is in contact at one portion of its periphery with a spherical, 
 unstained area, considerably larger than the milky area, which appears to be 
 stained in the same manner as the red blood cell. The milky zone, as it is 
 called, represents the unstained portion of the vesicular nucleus, while the larger 
 area, stained apparently in the same way as the red cell, represents a vacuole 
 which has developed by the side of the nucleus. Immediately surrounding the 
 vacuole and the vesicular nucleus is a ring-like mass of protoplasm stained a 
 deep blue; this ring of protoplasm is very thin at one portion of its periphery 
 where it almost comes in contact with the chromatin which is situated eccen- 
 trically in the nucleus. The appearance of the plasmodium at this stage is that 
 of a blue ring of protoplasm surrounding an area of the color of the red cell, at 
 one portion of which is a spherical milky area containing a bright red mass of 
 chromatin (see Fig. i). 
 
 In those schizonts in which limited amoeboid motion was present at the 
 time of fixation of the specimens, many forms of the "ring" may be observed, 
 due to minute pseudopodia arising from the protoplasm of the plasmodium. 
 In very many instances it will be observed that the protoplasm is thicker at 
 i certain portions or very delicate filaments of blue-stained cytoplasm may' be 
 seen connecting various portions of the periphery of the "ring"; in such in- 
 stances the chromatin mass may be situated at any portion of the protoplasmic 
 filaments, very often at their extremity, or at the point of attachment to the 
 body of the plasmodium. The vacuole in such plasmodia cannot be distin- 
 guished (see Fig. 2). 
 
 As the schizont becomes larger and pigment begins to appear we observe 
 that the latter is situated in the cytoplasm of the parasite, which, by reason of 
 their active amoeboid motion, present in stained specimens many bizarre 
 forms. The unstained vesicular nucleus is still present and contains the chroma- 
 tin, which has divided into delicate filaments and dots, staining pink, but less 
 intensely than when it was collected in a compact mass. The nuclear vacuole 
 may be present after pigment formation, but at a later period of development 
 both it and the vesicular portion of the nucleus disappear, and the chromatin 
 becomes distributed in the cytoplasm in the form of minute filaments and 
 granules, which may stain intensely, but generally very dimly. At a certain 
 period of development the chromatin divides into very fine filaments and only 
 prolonged staining will demonstrate its presence. In those plasmodia in which 
 
24 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 the vacuole is present, it appears as a round or oval, unstained area, surrounded 
 by the blue-stained cytoplasm. 
 
 As the time for sporulation approaches this plasmodium presents very 
 marked changes in its structure. The cytoplasm increases in amount, stains a 
 deep blue, and is heavily pigmented. The chromatin also increases in amount, 
 is collected in irregular clumps, and stains an intense red or violet; the filament- 
 ous structure of the chromatin has disappeared and it now consists of large 
 grains and compactly formed masses arranged irregularly throughout the 
 protoplasm. The vesicular portion of the nucleus has disappeared. 
 
 In the presegmenting plasmodia, the protoplasm, containing the pigment 
 granules, stains a well-defined blue, the pigment being arranged in irregular 
 masses staining a peculiar greenish-brown. The chromatin, staining an in- 
 tense red, is collected into roughly spherical masses, arranged more or less 
 regularly in the cytoplasm, which as yet shows little evidence of division. 
 
 In the segmenting or sporulating plasmodia the chromatin is collected in 
 compact, deep red spherical masses, each surrounded by an unstained area, in 
 turn surrounded by a small mass of cytoplasm; the pigment is collected into a 
 single clump or in irregular masses situated in a small portion of residual proto- 
 plasm. When the infected red cell disintegrates, the segments or merozoites 
 are liberated, the pigment and residual protoplasm are engulfed by leucocytes, 
 and the merozoites again infect red blood-corpuscles. 
 
 Each merozoite, when stained by Wright's method, is seen to consist of a 
 mass of protoplasm stained a deep blue, enclosing an unstained oval area which 
 contains a spherical dot of chromatin stained a deep red or violet. The chroma- 
 tin is placed eccentrically and the protoplasm is much thicker at that portion of 
 the parasite furthest removed from the nucleus. The merozoites measure from 
 1.5 'to 2 microns in diameter. 
 
 The description of Plasmodium vivax which has been given refers only to 
 the forms concerned in the human cycle of development or schizogony, the 
 development of the plasmodium having been traced from its entrance into the 
 red blood-corpuscle to sporulation. Schizogony is initiated in nature by the 
 entry into the red blood-corpuscles of sporozoites introduced into the blood of 
 man by the bite of an infected mosquito. After entry into the red cells the 
 sporozoites become trophozoites and are of two varieties, those which develop into 
 schizonts and continue the infection in man, and those which develop into 
 gametes, intended to continue the infection in the mosquito. The trophozoites 
 which are destined to become schizonts are characterized by the "ring-form," 
 and such forms always greatly out-number the trophozoites which develop into 
 gametes. 
 
 Changes in the Infected Blood-corpuscles. — The changes which occur 
 in the red blood-corpuscles infected with Plasmodium vivax are of great impor- 
 tance from a diagnostic standpoint, as these changes alone will suffice to 
 differentiate this plasmodium from either the quartan or aestivo-autumnal 
 plasmodia. 
 
THE ETIOLOGY OF THE MALARIAL FKVKKS. 
 
 25 
 
 The red corpuscle infected with Plasmodium vivax is always larger than 
 normal, even when the parasite is in the earliest stages of development. Not 
 only is the red cell enlarged, but it is paler in color than normal, and in examining 
 the blood for the tertian plasmodium it is often most easily discovered by 
 selecting the red cells which appear larger and paler than normal and carefully 
 
 Fig. 3. — Plasmodium vivax. (Tertian 
 Plasmodium.) Half-grown parasite. 
 Photomicrograph, X 1200. 
 
 Fig. 4. — Plasmodium vivax. (Tertian 
 Plasmodium.) Presegmenting para- 
 site. Photomicrograph, X 1200. 
 
 examining them. While the enlargement is not marked before the plasmodia 
 become pigmented, the red cell enlarges rapidly after pigmentation occurs, and 
 when the plasmodium is fully developed is generally twice as large as an unin- 
 fected corpuscle, and almost devoid of color. In the stained specimens the 
 enlargement is very noticeable and the corpuscle is often much distorted in 
 
 Fig. 5. — Plasmodium vivax. (Tertian plasmodium.) Sporulatim 
 parasite. Photomicrograph, X 1200. 
 
 shape. A very important degenerative change occurring in red cells infected 
 with the tertian plasmodium leads to the occurrence of small refractive granules 
 situated within the protoplasm and which stain a reddish color when the 
 Romanowsky stain or any of its modifications are used. With Wright's stain 
 this red stippling of the infected red corpuscle is well marked, and such cells are 
 
26 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 known as "stippled cells," and the granules as Schuffner's granules or dots. In 
 those cells containing the youngest "ring-forms" Schuffner's dots may not be 
 present, but after pigment appears almost every infected corpuscle will show 
 this form of degeneration in stained specimens. 
 
 The occurrence of these granules is of great importance in making a 
 differential diagnosis between the tertian plasmodium in its early stages of 
 development and similar stages of development of the quartan plasmodium. 
 While I have very rarely seen Schuffner's dots in cells infected with undoubted 
 quartan plasmodia, contrary to the statements of certain authorities who 
 believe that this form of degeneration occurs only in tertian infection, the occur- 
 rence is of such great rarity as to be of no practical importance, and malarial 
 infections in which Schuffner's dots are found in the infected red cells may 
 practically always be diagnosed as tertian infections, provided, of course, that a 
 double infection with some other species of plasmodium be not present. 
 
 The occurrence of these granules in cells containing the "ring-forms" is 
 conclusive proof that these rings are of the benign tertian variety, for Schuffner's 
 granules never occur in cells infected with "ring-forms" of the quartan or 
 aestivo-autumnal plasmodia. 
 
 The characteristic changes occurring in the red blood-corpuscle infected 
 with Plasmodium vivax are the following: enlargement at every stage of develop- 
 ment of the plasmodium; decolorization progressive with the growth of the 
 plasmodium; changes in shape, and the occurrence of Schuffner's granules or dots 
 in the protoplasm of the cell. As it is probable that this form of degeneration of 
 the protoplasm of the infected red cell is due to certain poisonous products 
 elaborated by the plasmodium during its development, and as these granules 
 occur almost exclusively in infections with Plasmodium vivax, it is evident that 
 this organism elaborates certain poisonous materials differing from those elabo- 
 rated by the other species of plasmodia. 
 
 The Morphology and Biology of Plasmodium Malariae. (the 
 quartan malarial parasite). Schizogony (human or asexual cycle). 
 
 Plasmodium malariae, or the quartan malarial parasite, completes its develop- 
 ment in the blood of man in 72 hours, producing that type of malarial fever 
 characterized by a chill and a rise in temperature at the end of every third 
 day. This is the most uncommon form of malarial infection, and in some 
 localities is so rare as to be observed but a few times in many thousand cases of 
 malarial disease. All stages of development common to schizogony occur in the 
 peripheral blood, and the organism is easily differentiated from the other species 
 of malarial plasmodia. 
 
 Historical Summary. — The description of this species of human plasmodium 
 marked the first attempt to divide the plasmodia into distinct species, and to 
 Golgi, who, in 1886, described very fully this organism, we owe the recognition 
 of it as a definite species. He studied 22 cases of quartan fever and followed 
 the complete cycle of the development of this plasmodium in the blood of the 
 cases studied. He called attention to the rela+ion of sporulation to the clinical 
 
EXPLANATION OF PLATE I. 
 
 Tertian Plasmodium. (Plasmodium vivax.) Unstained specimens, 
 i. Normal red blood-corpuscle. 
 
 2. Hyaline "ring form." 
 
 3, 4, 5. Young pigmented forms. 
 
 6. Pigmented form, nearly half-grown. 
 
 7. Three-quarters grown pigmented form. 
 
 8. Full grown pigmented plasmodium. 
 
 9. 10. Sporulating plasmodium. 
 
 11. Macrogamete. 
 
 12. Microgametocyte. (Flagellated body.) 
 
 (Note the gradual enlargement of the infected red blood-corpuscle, and the 
 diminution in the haemoglobin.) 
 
 Quartan Plasmodium. (Plasmodium malaria.) Unstained specimens. 
 
 1. Normal red blood-corpuscle. 
 
 2. Hyaline plasmodium. 
 
 3. Young pigmented plasmodium. 
 
 4 to 11. Various stages in the growth of the pigmented plasmodia. 
 
 11. Full-grown pigmented plasmodium. 
 
 12, 13. Sporulating plasmodia. 
 14. Macrogamete. 
 
 1 5. Vacuolated macrogamete. 
 16. Microgametocyte. (Flagellated body.) 
 Quotidian Aestivo-autumnal Plasmodium. (Plasmodium, falciparum, quotidi- 
 anum.) Unstained specimens. 
 1. Normal red blood-corpuscle. 
 
 2 to 8. Various hyaline "ring forms" of the plasmodium. 
 8, 9, 10. Pigmented forms of the plasmodium. 
 
 11. Intracorpuscular crescent, (gamete.) 
 ' 12 and 13. Sporulating plasmodia. 
 
 14. Macrogamete. '(F ema l e crescent.) 
 
 15. Microgametocyte. (Male crescent.) 
 
 16. Flagellated form of microgametocyte. 
 
 Tertian Aestivo-autumnal Plasmodium. (Plasmodium falciparum.) 
 
 1. Normal red blood-corpuscle. 
 
 2. Hyaline "ring form." 
 
 3,4, 5. Pigmented "ring forms" of the plasmodium. 
 6, 8, 9, 10, 11. Pigmented forms of the plasmodium. 
 
 12. Sporulating form of the plasmodium. 
 
 13. Macrogamete. 
 
 14. Microgametocyte. 
 
 15. Ovoid macrogamete. 
 
 16. Flagellated form of microgametocyte. 
 
1 
 
 Plate I 
 
 % 
 
 4 
 
 m »»&r* 
 
 W 4Hr 
 
 Igf 
 
 mm* 
 
 2 
 10 
 
 Tertian Plasmodium. 
 
 '* 
 
 
 11 12 
 
 13 
 
 Quartan Plasmodium. 
 
 S 
 
 7 
 
 --■■>. ■...--.:. 
 
 1 
 9 
 
 10 
 
 11 
 
 15 16 
 
 Quotidian Aestivo-autumnal Plasmodium. 
 
 10 11 12 13 14 15 
 
 Tertian Aestivo-autumnal Plasmodium. c. f. craig. del. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 27 
 
 symptoms, the chill and fever occurring at the end of every 72 hours, at which 
 time segmentation of the plasmodia always occurred. He described very 
 carefully the morphology of the organism during its various stages of develop- 
 ment, noted that the more severe the clinical symptoms the greater the number 
 of plasmodia in the blood, and that infection with three groups of this Plasmo- 
 dium resulted in a quotidian fever 
 
 Golgi's observations regarding Plasmodium malariae were confirmed by 
 Osier in same year and by Antolisei in 1890, and this species has been accepted 
 by almost every observer who has had the opportunity of studying quartan 
 malarial infections. 
 
 Unstained Preparations. — Like the tertian plasmodium, the organism 
 causing quartan malaria, or Plasmodium malaria, appears at first within the 
 red blood-corpuscle as a small amoeboid body called the trophozoite. It is 
 sluggishly amoeboid as compared to the benign tertian plasmodium, and is 
 hyaline in appearance. Those trophozoites which are to undergo schizogony 
 soon develop into schizonts, while those intended to undergo development 
 in the mosquito develop into gametes. The quartan schizont is a small, 
 sluggishly amoeboid, hyaline body, measuring about 1.8 to 2.5 microns in 
 diameter, at its earliest stage of development. Although at this period of 
 development these organisms are believed to be indistinguishable from similar 
 forms of the benign tertian plasmodium, there is, in reality, but little difficulty 
 in distinguishing them, the quartan schizont being much more sharply cut 
 and refractive and the infected red cell not enlarged and slightly more greenish 
 in color. 
 
 "Within a few hours the quartan plasmodium begins to develop pigment 
 in the form of a few rather coarse granules of a dark brown color, situated at 
 the periphery of the organism and possessing but very little motility, thus 
 differing from the pigment in Plasmodium vivax, which is in the form of very 
 minute reddish-brown granules, very actively motile. At this early pigmented 
 stage the plasmodium is very sluggish in its amoeboid movements, and is 
 generally of a spherical or triangular shape, filling about one-quarter of the red 
 corpuscle, which is not in the least enlarged. 
 
 The plasmodium slowly increases in size, and in doing so loses its amoeboid 
 motility; the pigment increases in quantity and becomes collected at he ex- 
 treme periphery of the organism in the form of large, very dark brown grains 
 which are absolutely immotile. The protoplasm of the plasmodium is very 
 distinct and appears to be of greater consistence than the protoplasm of Plas- 
 modium vr, ax. The infected red corpuscle is normal in size and slightly darker 
 in color. 
 
 In 24 hours the distinguishing features of the quartan plasmodium are 
 fully developed. The organism is sharply outlined, is very refractive, and its 
 protoplasm often presents a peculiar, very finely granular appearance; the 
 pigment is dark brown in color, in the form of coarse granules, and is generally 
 collected around the edge of the plasmodium, sometimes forming an almost 
 
28 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 complete wreath around it; the pigment is motionless. The shape of the 
 Plasmodium at this stage of development is usually triangular, ovoid, or round, 
 and it occupies about one-half of the infected red cell. Amoeboid motion is 
 generally absent. The invaded corpuscle is smaller, if anything, than the 
 healthy ones and is of a darker green color (see Fig. 6). 
 
 At the end of 36 hours all of the phenomena noted are more pronounced, 
 the organism filling about two-thirds of the corpuscle, which appears to be 
 retracting about it; the pigment is increased in amount, is motionless, and 
 collected in rough masses at the border of the plasmodium. Amoeboid motion 
 is entirely absent. The growth of Plasmodium malar iae from this time on is 
 very slow, and it is not until about eight hours before sporulation that preseg- 
 menting forms are to be seen in the peripheral blood. Such plasmodia are 
 spherical in shape, bordered by a thin greenish layer representing the remains 
 of the infected red corpuscle. Numerous clumps of dark brown, sometimes 
 almost black, pigment are present in the protoplasm, not now confined to the 
 periphery of the plasmodium, but scattered through the protoplasm in an 
 irregular manner. The pigment is not motile nor is amoeboid motion present 
 in the plasmodium. The infected red cell is slightly smaller than the normal 
 corpuscles and distinctly darker in color (see Fig. 7). 
 
 In many instances segmentation or sporulation occurs before the red 
 corpuscle is completely filled by the plasmodium, the pigment collecting 
 toward the center of the plasmodium and six or more segments or spores 
 appearing within the corpuscle. More commonly, however, at the end of 72 
 hours, the plasmodium entirely fills the invaded cell and sporulation occurs 
 in the following manner: the pigment becomes collected at the exact center 
 of the plasmodium in a solid, almost black, spherical mass, or in a star-like 
 arrangement distributed from the center, and about the same time all trace 
 of the infected red corpuscle disappears, the plasmodium being apparently 
 extracellular; in a short time radial striations are observed shooting out from 
 the pigmented center, and these, joining at their extremities, form from six 
 to fourteen oval segments or spores, the merozoites. As a rule, the number 
 of spores does not exceed ten. The spores are generally arranged in a per- 
 fectly symmetrical manner around the central pigment in a single row, giving 
 the so-called daisy or "Marguerite" appearance to the plasmodium at this 
 stage. The number and the beautifully regular arrangement of the merozoites 
 would alone serve to distinguish this stage of the quartan from the corres- 
 ponding stage of the tertian plasmodium, but the quartan merozoites are also 
 more oval in shape, more refractile and somewhat larger, measuring about 2.5 
 microns in diameter (see Fig. 8). 
 
 When segmentation is complete each merozoite becomes free in the blood 
 plasma and, in the human cycle, again invades the red corpuscles, some 
 becoming schizonts, while others become gametes. 
 
 At the time of sporulation the pigment and the residual protoplasm 
 containing it is liberated and most of it is engulfed by phagocytic leucocytes, 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 2Q 
 
 some of the pigment, however, remaining free in the Mood for a considerable 
 time. There is a slight difference in size between individual sporulating bodies, 
 even in the same individual, and rarely sporulation may be observed in plasmodia 
 that do not occupy more than two-thirds of the red corpuscle, but as a general 
 
 Fig. 6. — Plasmodium malarias. (Quartan plasmodium.) Presegmenting 
 parasite. Photomicrograph, X 1200. 
 
 rule there is not as much variation in the size of the sporulating forms of 
 Plasmodium malariae as there is in the same forms of Plasmodium vivax. 
 The star-like arrangement of the pigment between the segments, which Thayer 
 considers so characteristic, is generally observed, but I have observed exactly 
 
 Fig. 7. — Plasmodium malarias. (Quartan 
 Plasmodium.) Sporulating parasite. 
 Photomicrograph, X 1200. 
 
 Fig. 8. — Plasmodium malariae. (Quartan 
 Plasmodium.) Sporulating parasite 
 Photomicrograph, X 1800. 
 
 the same arrangement of pigment in tertian segmenting forms; it is probably 
 of accidental occurrence, doubtless more common in the quartan plasmodium, 
 but not at all peculiar to the species. 
 
 Staining Reactions of Plasmodium Malariae. — The structure of 
 Plasmodium malariae, the quartan malarial parasite, as shown by Wright's 
 
30 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 method of staining, is similar to that of Plasmodium vivax, the benign tertian 
 parasite, in that it consists of a small amount of protoplasm surrounding a 
 vesicular nucleus rich in chromatin, but certain differences exist in the staining 
 qualities of the protoplasm and nucleus of the plasmodium, and of the infected 
 red corpuscle which are of service in differentiating this species from the plasmo- 
 dium of tertian malaria or the plasmodia of the aestivo-autumnal infections. 
 
 The youngest schizont when stained is larger than the schizont of the tertian 
 Plasmodium, but exhibits the same ring-like appearance, consisting of a blue 
 ring of protoplasm surrounding a milky spherical zone containing the red 
 chromatin and a vacuole, developed at one side of the nucleus. The proto- 
 plasm of the plasmodium of quartan fever stains a deeper blue than does that of 
 the tertian organism, and the chromatin, which stains a very dark red, is situated 
 nearer the center of the milky or vesicular portion of the nucleus. The vacuole, 
 which causes the "ring" at this stage of development is only observed in those 
 plasmodia that are destined to become schizonts. 
 
 The staining reactions during later stages of development are like those of 
 Plasmodium vivax, already described, the vacuole disappearing and with it the 
 "ring-form," the organism spreading out into the red cell, finally filling it. 
 The protoplasm throughout development stains more intensely blue than that of 
 the tertian plasmodium, and the chromatin a more intense red. The latter, 
 when distributed throughout the protoplasm, is in the form of larger, thicker 
 filaments, in more definite clumps than is the chromatin of Plasmodium vivax, 
 and in the presegmenting and segmenting forms the chromatin is in more com- 
 pact clumps or masses and stains a darker red in color. Around each mass of 
 chromatin in these fully developed forms there is an unstained milky area, 
 representing the vesicular portion of the nucleus of the developing merozoites. 
 Because of the deeper staining and circular form of the quartan plasmodia, 
 their outline is much more distinct in stained preparations than in the case of 
 the tertian plasmodium, and in the nearly full-grown forms the red cell is very 
 plainly visible as a narrow rim of pink-stained protoplasm surrounding the 
 perfectly circular plasmodium. 
 
 If stained preparations be made during the second day of development the 
 very characteristic "band forms" of the Plasmodium malariae can be observed, 
 consisting of a band of deep blue protoplasm stretching across the infected red 
 corpuscles, enclosing a mass of chromatin stained an intense red color. I have 
 never observed such "band forms" in any other variety of malarial infection, 
 and a diagnosis of quartan malarial fever is justified when such forms are 
 present. 
 
 The merozoites or spores consist of a deep blue mass of protoplasm and of 
 a compact mass of dark red chromatin situated eccentrically in relation to the 
 protoplasm. The chromatin in most instances is surrounded by a very small 
 unstained area, the vesicular portion of the nucleus. 
 
 The pigment in the quartan plasmodium is but little affected by the stain, 
 appearing a dark brown in color, although in those instances in which it is 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 3 1 
 
 collected in loosely arranged masses the stain gives it a very well-defined green- 
 ish-brown tinge. 
 
 Changes in the Infected Blood-corpuscle. — The changes observed in 
 the infected red blood- corpuscle in quartan malarial fever are less marked than 
 those occurring in tertian infections, but are fully as characteristic. A study of 
 such infections as regards the blood will convince the most skeptical that 
 Plasmodium malariae produces an entirely different effect upon the cells in- 
 vaded by it than does Plasmodium vivax. It will be remembered that the red 
 corpuscles invaded by the latter organism increased greatly in size, due to their 
 distention by the growing parasite, and became much paler in color. In in- 
 fections with Plasmodium malariae the red cell instead of enlarging remains 
 normal in size, or more often becomes smaller than the uninfected cells, and 
 instead of becoming paler in color is darker green than the healthy red cells. 
 It would appear that in quartan malaria the plasmodium causes a shrinkage of 
 the red corpuscle about it during its development instead of expanding the red 
 cell as does the tertian plasmodium. 
 
 I have already spoken of the occurrence of Schuffner's granules or dots 
 which are observed within the cytoplasm of the invaded red corpuscles in tertian 
 infections; such a form of degeneration is probably never present in quartan 
 infections, although in a very few such infections I have observed a stippling 
 indistinguishable from that produced by Schuffner's dots in invaded red blood- 
 corpuscles. However, such an appearance occurs so rarely that it is of no 
 practical importance and does not alter the fact that the presence of Schuffner's , 
 dots in a red corpuscle infected with a malarial plasmodium indicates that the 
 organism present is Plasmodium vivax. 
 
 The lack of enlargement of the infected red blood-corpuscle, its darker 
 green color, and the absence of Schuffner's dots serve to differentiate Plasmo- 
 dium malariae and Plasmodium vivax, the red cells infected with the quartan 
 plasmodium exhibiting all of the characteristics mentioned, but are of no value 
 in differentiating Plasmodium malariae from the plasmodia of the aestivo- 
 autumnal infections which produce very similar changes within the red cor- 
 puscles. In the latter infections, however, other changes occur within the red 
 cells which serve to make the distinction possible. 
 
 As in the tertian infections, certain of the merozoites produced by the 
 sporulation of the quartan plasmodium, and certain of the sporozoites intro- 
 duced by the bite of the infected mosquito do not develop into schizonts and 
 undergo schizogony, but develop into gametes, which undergo sporogony within 
 the mosquito. These forms will be described after we have considered the 
 schizogony of the aestivo-autumnal plasmodia. 
 
 The Plasmodia of Aestivo-autumnal Malarial Fevers. — As I have 
 already stated I believe that the plasmodia causing the aestivo-autumnal 
 malarial fevers are divided into two distinct species, which differ from one 
 another in morphology, in their period of development, and in the pathogenic 
 conditions they bring about in the infected individual. Many observers hold 
 
32 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 that there is but one aestivo-autumnal plasmodium, which varies in its morphol- 
 ogy and the period of time required for its development, but from over ten 
 years' study of malarial infections of this type I am forced to conclude that these 
 authorities are mistaken and that two forms of aestivo-autumnal fever occur, 
 each form due to a specific plasmodium. That quotidian and tertian forms of 
 aestivo-autumnal malaria exist has been abundantly proven by Marchiafava 
 and Bignami, Bastianelli, Caccini, Mannaberg, James, Manson, Jackson, and 
 myself, as well as others, and the plasmodia concerned in their etiology have 
 been carefully studied and described. 
 
 Historical Summary. — Golgi, in 1885, was the first to call attention to the 
 probably distinct type of the crescentic and ovoid parasite, and suggested the 
 possibility of its being a distinct species of the malarial plasmod . ; but to Council- 
 man we owe the first statement of the diagnostic value of these forms. In 1887 
 he says : ' ' The character of these bodies (the malarial parasite) varies in different, 
 forms of the disease. Although they seem in some cases to run into one another, 
 still, in general, we can say that where the plasmodia inside the red corpuscles 
 are seen (large pigmented forms) the patient has intermittent fever, and where 
 the crescentic and elongated forms are found he has either some form of remittent 
 fever or malarial cachexia. We are not only able to diagnose the disease as such, 
 but in most cases the particular form." 
 
 Golgi, in 1889, was the first to observe that the small, hyaline, intracellular 
 rings and the crescent and the ovoid pigmented bodies were associated with 
 malarial fevers of remittent character with long intervals between the parox- 
 ysms. He believed that the ring forms were the first stages of the crescent and 
 ovoid forms. 
 
 The type of fever in which these plasmodia are found, and which is now 
 known as aestivo-autumnal fever, differs very materially from the ordinary 
 intermittent (tertian and quartan) fevers met with in northern latitudes. Under 
 the term "aestivo-autumnal fever" is included the majority of the cases of so- 
 called pernicious malarial fevers, and in this class of cases, which are especially 
 prevalent in the malarial districts around Rome where they studied, Marchia- 
 fava and Celli, in 1889, discovered and described very minutely the appearance 
 and life history of the parasites concerned in their etiology. About the same 
 time Canalis published the results of his investigations upon the parasites 
 associated with irregular and remittent malarial fevers, and although his 
 interpretation of some of the phenomena observed differed widely from those 
 of Marchiafava and Celli, the morphological descriptions of the parasites were 
 very similar, and confirmed Golgi's theory of the existence of a separate species 
 of the malarial parasite causing remittent malarial fever. A brief summary 
 of the investigation of the above-mentioned authors is here given: 
 
 Marchiafava and Celli's observations may be summed up as follows: For 
 some time before the onset of a paroxysm of fever, three forms of the aestivo- 
 autumnal parasite may be seen in the blood, i.e., minute round or ring forms, 
 having a small, dark center, composed of pigment or haemoglobin; intracellular, 
 minute amoeboid, hyalin parasites, containing one to three small pigment gran- 
 
EXPLANATION OF PLATE II. 
 
 Tertian Plasmodium. {Plasmodium vivax.) Stained by Oliver's Modification 
 of Wright's Stain. 
 
 i to 6. " Ring forms " of the plasmodium. 
 
 6. Amoeboid, unpigmented form of the plasmodium. 
 
 7. Two "ring forms" in corpuscle showing Schuffner's dots. 
 
 8. Amoeboid "ring form" in corpuscle showing Schuffner's dots. 
 
 9 to 17. Various stages in the development of the pigmented plasmodium. 
 
 17. Microgametocyte. 
 
 1 8. Nearly full-grown plasmodium, showing minute division of the chromatin . 
 
 19. 20, 21. Presegmenting plasmodia. 
 22, 23, 24. Sporulating plasmodia. 
 
 25. Microgamete. (Flagellum.) 
 
 26. Sporozoites. 
 
 Note. — With this stain the chromatin of the nucleus stains crimson, the pro- 
 toplasm blue, while the vesicular portion of the nucleus remains unstained. 
 
 Quartan Plasmodium. (Plasmodium malarice.) Same stain as the tertian plas- 
 modium. 
 
 1 to 8. "Ring forms" of the quartan plasmodium. 
 
 8 to 13. Pigmented forms of the plasmodium. At 11 a so-called "band- 
 form" is shown. 
 13, 14, 15. Presegmenting plasmodia. 
 16, 17, 18, 19. Sporulating quartan plasmodia. 
 
 20. Microgamete. 
 
 21. Sporozoites. 
 
 Note the presence of Schuffner's dots in the infected red corpuscle in tertian 
 malaria; the larger size of the tertian plasmodium; the difference in the character 
 of the pigment, and the greater number of spores or segments. 
 
Plate II 
 
 6 
 
 * H 
 
 
 
 10 
 
 12 
 
 ff * i Ik'VJ* 
 
 ^U-c' 
 
 13 
 
 -•S ♦'*.■•' 
 
 15 
 
 16 
 
 17 
 
 
 IX 
 
 ^0 
 
 
 20 
 
 
 21 
 
 
 
 Tertian Plasmodium. 
 
 • V: 
 
 v .1 
 
 v.-* 
 
 
 ^ 
 
 
 ?•*• 
 
 15 
 
 l(i 
 
 10 
 
 17 
 
 11 
 
 ■ ; . 
 
 IS 
 
 @00 
 
 Go 
 
 19 
 
 14 
 
 Quartan Plasmodium. 
 
 C. F. CRAIG. DEL. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 33 
 
 ules, and somewhat larger round bodies having a block of pigment at some 
 portion within them. The red corpuscles containing the parasites were smaller 
 than the normal corpuscles, darker green in color, and crenated, while the 
 haemoglobin was often seen to be retracted from the periphery of the corpuscle 
 for a whole or part of its circumference. Segmenting bodies were very rarely 
 seen in the circulating blood, but were found in large numbers in the internal 
 organs, especially the spleen and the capillaries of the brain. They observed 
 that sporulation always occurred before the onset of a paroxysm, and that the 
 parasites pursued a developmental cycle of 24 hours or less. At the time of the 
 paroxysm, and for some time afterward, the small amoeboid hyalin parasites, 
 which comprise the new generation, may be seen in the blood. They describe 
 the crescentic organisms and also intervening forms between the intracellular 
 bodies and the crescents. They note the minuteness of the aestivo-autumnal 
 parasite as compared with the tertian and quartan forms. They found the 
 crescents in greater number in the spleen, but observed many cases without the 
 formation of crescents. No segmentation of the crescents was ever noted, and 
 neither is the development of the pigment always to be observed. In those 
 fevers in Rome showing daily paroxysms only the small, hyalin, amoeboid, 
 intracellular parasite is observed in the peripheral blood, and only in those 
 cases showing a longer interval between the paroxysms is the parasite with the 
 few pigment granules to be observed. 
 
 Canalis' contribution is a very extensive one. He divided the cycle of 
 development of these parasites into two phases: a rapid cycle and a slower cycle 
 in which the crescentic forms appear. The rapid cycle he considers to be of 
 about two days' duration, though it may be only 24 hours in length. During 
 the first hours the parasites are intracellular, amoeboid, hyalin, occupying one- 
 sixth of the red corpuscle, the outer portion of the parasite being clear, while 
 the center appears shaded or greenish, presenting the appearance of a nucleus. 
 The outer portion may be very refractive. The blood-corpuscles which are 
 invaded are very often smaller than normal and are greenish in color. As the 
 parasite grows it becomes more amoeboid, and a few fine particles of reddish- 
 brown pigment may be seen within the outer ring-like portion. The parasite 
 gradually grows larger, the ring-like appearance disappears, the amoeboid move- 
 ment ceases, the pigment granules melt into one small solid block at the center 
 or one side of the parasite, and a faint radial striation appears, and from six to 
 ten ovoid or round segments are eventually produced. They are much smaller 
 than the segments of tertian or quartan plasmodia. The containing corpuscle 
 may be entirely disintegrated or may appear as a dim, shadowy sphere sur- 
 rounding the segments. Segmenting bodies are very rarely seen in the per- 
 ipheral blood, but free pigment and pigmented leucocytes are common. 
 
 The second, or slow cycle, in which cresceirts develop, according to Canalis, 
 may occur in connection with the rapid cycle or where the course of the disease 
 has been interfered with by some drug, especially quinin. Canalis always 
 found that crescents were not developed until some time after the onset of the 
 fever, generally not until fifteen days had elapsed. The small, intracellular, 
 amoeboid forms were observed to become oval in shape, while the pigment 
 collected toward the center; a crescentic form was gradually acquired; the red 
 corpuscle disappeared, and the now fully developed crescent was set free in the 
 blood. He observed the double outline of the crescent, and considered that it 
 was due to an enveloping membrane. The crescents were afterward observed 
 to acquire an oval form and finally become perfectly round. In the crescentic 
 and ovoid forms the pigment was always motionless, but in the round form it 
 often became very mobile and was arranged in a perfect circle. He describes a 
 
 3 
 
34 TH E ETIOLOGY OF THE MALARIAL FEVERS. 
 
 process of sporulation as occurring in the crescents and also observed the develop- 
 ment of flagellate bodies from the round bodies, of which he says: "They 
 represent, assuredly, one of the last stages in the development of the parasite, 
 for I have never seen them appear in the blood before the formation of the round 
 bodies." Canal is considered that the length of this cycle varied, the period 
 from the amoeboid stage to the crescentic lasting from three to four days, the 
 round bodies taking a day longer. 
 
 In this truly admirable paper it is unfortunate that the author committed 
 himself to the sporulation theory of the crescents, for in the light of our present 
 knowledge such a theory is untenable, unless Schaudinn's observations concern- 
 ing the parthenogenesis of the macrogamcte be confirmed. 
 
 That a distinct species of plasmodium is always associated with the 
 aestivo-autumnal fevers has been confirmed by nearly every student of the 
 subject, and Bignami, Sanfelice, Plehn, Mannaberg, Dock, Thayer, Hewetson, 
 and others have confirmed much that appeared in the articles of Marchiafava 
 and Celli and Canalis. However, it was not until the observations of Marchia- 
 fava and Bignami were published that attention was directed to the fact that 
 two species of plasmodia are associated with these fevers instead of a single 
 species. Their observations are briefly as follows: 
 
 These investigators very thoroughly studied the parasites occurring in the 
 aestivo-autumnal fevers, and, as the result of their studies, have separated these 
 parasites into two species, one causing a paroxysm every 24 hours, the other 
 every 48 hours, approximately, which they have termed the quotidian and 
 malignant tertian aestivo-autumnal parasites. The fever due to the quotidian 
 parasite may be regular and resemble the ordinary double tertian curve, but 
 more often the temperature curve shows evidence of anticipation or retardation, 
 being irregular, and the symptoms vary much in their severity. A continuous 
 of slightly remittent fever is not unusual. The quotidian parasite, as described 
 by them, is a very small amoeboid, hyalin, ring-like, intracorpuscular body in 
 the peripheral blood, which prior to segmentation develops a small number of 
 minute pigment granules. Segmentation generally occurs within the red cell, 
 and almost always in the internal organs, especially in the spleen. The rings 
 are very pale and often very careful search is required before they are dis- 
 covered ; they are actively amoeboid, and never exceed one-third of the corpuscle 
 in size. The infected corpuscle has a greenish, brassy color, is often shrunken, and 
 the haemoglobin retracted. After some days crescentic and ovoid bodies appear. 
 
 Marchiafava and Bignami's malignant tertian parasite produces a febrile 
 paroxysm lasting practically 48 hours, and often the temperature curve shows 
 such variations, caused by the anticipation and conjunction of paroxysms, 
 as to present a continued fever. According to them, the febrile curve presents, 
 in the majority of cases, the following characteristic points: a rapid and sudden 
 rise, a stationary stage, with slight remissions, a slight pseudocrisis, a pre- 
 critical rise, marked often by the highest temperature, and at last a sharp 
 crisis during which the temperature often falls far below normal. 
 
 The malignant tertian parasite, as described by these authors, resembles 
 the quotidian very closely, but is larger and presents a greater amount of pigment 
 within the protoplasm. It is often one-half the size of the red corpuscle. 
 Like the quotidian, segmentation occurs mostly within the vessels of the internal 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 35 
 
 organs. The infected corpuscles are almost invariably shrunken, dark green 
 in color, and often crenated and degenerated. Crescents and ovoid forms appear 
 after a few days. The differences between the quotidian and malignant tertian 
 aestivo-autumnal plasmodia as given by Marchiafava and Bignami are as follows : 
 
 i. The length of the cycle of development: 24 hours in the quotidian and 48 
 hours in the malignant tertian parasite. 
 
 2. The larger size of the malignant tertian parasite in all stages of develop- 
 ment and the greater amount of pigment in the pigmented forms of the tertian 
 organism. 
 
 3. The greater amoeboid activity of the malignant tertian parasite, which is 
 retained for a longer period of time in the large pigmented forms. 
 
 4. The length of the amoeboid unpigmented stage which in the malignant 
 tertian parasite may last for 24 hours. 
 
 Mannaberg distinguishes three varieties of the aestivo-autumnal plasmodia; 
 an unpigmented quotidian, a pigmented quotidian, and the malignant tertian para- 
 site. This classification is also accepted by Manson, and Grassi and Feletti 
 also describe the pigmented and unpigmented quotidian parasites. 
 
 In 1893 Golgi published an important paper giving the results of his re- 
 searches regarding the plasmodium of aestivo-autumnal infections, in which he 
 vigorously combated the existence of more than one variety of the aestivo- 
 autumnal organism, and stated that the forms found in the peripheral blood 
 were chiefly accidental, the infection being present almost entirely within the 
 internal organs. 
 
 At the present time almost all authorities who have studied thoroughly the 
 aestivo-autumnal malarial fevers and who have had sufficient clinical material 
 agree with Marchiafava and Bignami in describing more than one species 
 of aestivo-autumnal plasmodium; all accept a quotidian and tertian variety, and 
 some believe that an unpigmented quotidian plasmodium occurs in certain 
 localities. From personal observation I have not been able to confirm the 
 existence of an unpigmented quotidian organism, but neither can I deny it, as 
 such infections may not occur in the regions in which I have studied malarial 
 fever. I am of the opinion, however, that only one quotidian plasmodium 
 occurs in these infections, and that the species of plasmodia concerned in the 
 etiology of aestivo-autumnal malaria are two in number, namely, Plasmodium 
 falciparum and Plasmodium falciparum quotidianum. 
 
 The Morphology and Biology of Plasmodium Falciparum Quotidi- 
 anum (the quotidian aestivo-autumnal parasite). — Schizogony (human or 
 asexual cycle). 
 
 Unstained Preparations. — Plasmodium falciparum quotidianum completes 
 its cycle of development in man in twenty-four hours, and appears at first 
 within the red blood-corpuscle as a very small (0.8 to 1 micron in diameter) 
 amoeboid, hyalin body, "ring "-shaped or circular in contour, the trophozoite. 
 In those individuals which undergo schizogony, the trophozoite quickly becomes 
 a schizont, enlarging slightly and occupying about one-sixth of the red corpuscle. 
 At the earliest stage of the quotidian schizont the outline of the organism is 
 very indistinct, and were it not for its active amoeboid motion, it would be very 
 easily overlooked. As the organism enlarges the outline becomes much more 
 
6 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 distinct. When fully grown it is very clear cut and the entire plasmodium is 
 very refractive. The spherical forms are perfectly hyalin in appearance, but 
 the "ring forms" consist of a narrow hyalin ring of protoplasm enclosing a 
 small oval or circular area showing the yellowish-green color of the blood-cor- 
 puscle. Most authorities attribute this appearance to the fact that the center of 
 the parasite is much thinner than the periphery, thus allowing the normal color 
 of the corpuscle to show through; the true explanation of the "ring form" 
 is that the center of the "ring" is composed of a nutritive vacuole. When in 
 motion the "ring forms" often appear triangular in shape, the movement 
 consisting of a rapid, wavy motion of the border of the plasmodia and the 
 shooting out of minute protoplasmic elongations which are retracted almost 
 as quickly as they are thrown out. The amoeboid motion is very rapid and 
 the organism has to be carefully watched in order to be distinguished. Some- 
 times the "ring form" is lost, the organism becoming a pale hyaline disk. 
 The movement is very erratic, and there are long periods of repose during 
 which the ring form is retained. The invaded corpuscle, even at this early 
 stage in the development of the plasmodium, is generally smaller than those 
 which are normal, presents a shrunken, wrinkled appearance, and is dark 
 green in color. Crenation is often observed and double or triple infections of 
 the red cell. The so-called "signet-ring" appearance, so common at this 
 stage of development in the aestivo-autumnal tertian plasmodium, does not 
 occur in this species. In the peripheral blood the hyalin, round, or ring- 
 shaped plasmodia, just described, are the ones commonly observed, although a 
 small number of pigmented forms are not uncommon in most cases of infection 
 with this plasmodium. 
 
 Just prior to pigmentation the plasmodium becomes a little larger, loses 
 its ring form, becomes more refractive and sharply denned, much more so than is 
 the malignant tertian plasmodium at the same stage of development. In this 
 species of plasmodium I have never observed a pigmented ring form, so common 
 in the malignant tertian species, the pigmented bodies always being oval or 
 round in shape with a homogeneous protoplasm. The pigment appears as a 
 single, or at most two granules, either in the center or at one side of the plas- 
 modium, and is always perfectly motionless. Sometimes the pigment appears 
 as a rather coarse irregular block situated at the center of the parasite, and such 
 forms I consider to be presegmenting organisms. The pigment is almost 
 black in color and is never distributed throughout the protoplasm, as in Plas- 
 modium vivax, or arranged about the periphery of the organism, as in Plas- 
 modium malaria. In very rare instances the pigment may consist of three or 
 four very fine granules, but they are always in intimate association with one 
 another. At this stage of its development the plasmodium is never larger than 
 one-fourth of the invaded corpuscle, which is always shrunken, dark green in 
 color, and much smaller than the normal red cells. As a rule, the invaded 
 corpuscles exhibit marked crenation and areas of retraction of the hemoglobin. 
 From the very peculiar color of the invaded cells, they have been called "brassy 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 37 
 
 corpuscles," and it is in this form of malarial infection that the brassy color 
 of the infected red cell is most marked. 
 
 Segmentation occurs but very rarely in the peripheral blood, but may be 
 easily observed in blood obtained by splenic puncture or, at postmortem, in 
 blood from the spleen, liver, brain, and especially the bone-marrow. Segmen- 
 tation occurs at the end of twenty-four hours, the plasmodium at this time 
 not occupying more than one-fourth of the red cell, thus differing from the 
 benign tertian and quartan plasmodia which fill the corpuscle. In the 
 segmenting forms the pigment is collected in a solid granule or small block 
 at the center of the parasite, while the protoplasm of the organism appears 
 slightly granular. As segmentation commences, fine radial striations can be 
 detected, starting from the center, and soon the plasmodium breaks up into from 
 six to eight very minute round or oval segments, the merozoites. The beauti- 
 fully regular segmenting forms so often observed in quartan infections are but 
 rarely observed. Segmentation always occurs within the red blood-corpuscle, 
 and because of the small size of the segments and their limited number, the 
 red corpuscle is only partially filled by the young plasmodia. Shortly after 
 segmentation is complete the red cell disintegrates, thus liberating the merozoites 
 which invade normal red corpuscles and so continue the infection. As in 
 tertian and quartan infections, the merozoites are of two kinds, those intended 
 to undergo schizogony and those which undergo sporogony. The forms develop- 
 ing from the latter will be described in considering the mosquito cycle of these 
 parasites. 
 
 Staining Reactions of Plasmodium Falciparum Quotidianum. — 
 As the staining reactions of this species of plasmodium are identical in large 
 measure with those of Plasmodium falciparum, I will describe them in dealing 
 with the latter organism. 
 
 Morphology and Biology of Plasmodium Falciparum. — (The tertian 
 aestivo-autumnal parasite. Malignant tertian or subtertian parasite of some 
 authors.) Schizogony (human or asexual cycle). 
 
 This is the most common species of aestivo-autumnal plasmodium and is 
 the one which has been most frequently observed and studied. The majority 
 of infections with aestivo-autumnal malaria are due to this parasite, and even in 
 those limited regions where the quotidian plasmodium has been observed the lat- 
 ter is very rare in comparison with the tertian species. In many instances of quoti- 
 dian aestivo-autumnal infection a combined infection exists with the malignant 
 tertian plasmodium and this has caused much confusion in the description 
 which have been given of the aestivo-autumnal plasmodia by various observers. 
 In those cases, however, in which the two organisms occur alone, they may 
 be readily differentiated by their morphological characteristics and their cycle 
 of development. 
 
 Unstained Preparations. — Like the quotidian species, the tertian aestivo- 
 autumnal plasmodium, or Plasmodium falciparum, appears first within the 
 infected red corpuscle as a round or oval hyalin ring or disk, but even in the 
 
3© THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 earliest stage of development of the scJiizont important differences are to be 
 noted between this and the quotidian species. The young tertian plasmodia 
 are considerable larger than those of the quotidian species, occupying from 
 one-quarter to one-third of the infected red cell, which, while smaller than 
 the normal cells surrounding it, and greenish in color, is not shrunken and 
 wrinkled at this early stage of development as in quotidian infections. The 
 ''ring forms" are irregular in outline, one portion of the "ring" being broader 
 than the remainder, giving rise to the so-called "signet-ring" appearance, 
 never observed in quotidian infections. The organism is more highly refractive 
 and sharply outlined, and the amoeboid motion is more sluggish and more 
 easily observed. The ring form is often lost, a clear, hyalin disk resulting. 
 
 Fig. 9. — Plasmodium falciparum tertianum. (Aestivo-autumnal tertian.) Two "ring 
 forms" and two young gametes. Photomicrograph, X 1200. 
 
 Very rarely is more than one parasite seen in a single corpuscle, except when 
 intracorpuscular conjugation, a process common to all malarial plasmodia, 
 is present. The changes in the outline of the plasmodium are very marked, 
 and it is much more easily recognized than is the quotidian plasmodium 
 (see Fig. 9). 
 
 In the course of from 20 to 24 hours the hyalin forms become pigmented, 
 the pigment occurring in the form of very fine, reddish-brown granules some- 
 what resembling those found in the benign tertian plasmodium. The pigment 
 is in larger amount than in the quotidian plasmodium, is sluggishly motile, and 
 makes its appearance while the plasmodia are ring-shaped, being situated 
 within the enlarged area, thus giving the organisms a still greater resemblance 
 to a signet ring. The organism gradually loses the ring-form and becomes 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 39 
 
 larger, sometimes filling one-half of the corpuscle; at the same time it becomes 
 more clearly defined, its protoplasm more refractive and faintly granular in 
 appearance. The amoeboid motion still continues, though very sluggishly, and 
 the pigment tends to collect in a solid block, which has a marked vibratory 
 movement. The pigmented form is more common in the peripheral blood 
 than is the pigmented form of the quotidian plasmodium, but is rare as com- 
 pared with the tertian or quartan pigmented forms. 
 
 In this plasmodium segmentation occurs at the end of 48 hours in the vast 
 majority of infections, although rarely segmentation may occur two or three 
 hours earlier. At this time the plasmodium has grown to be one-half to two- 
 thirds as large as the red corpuscle, the pigment has become motionless and 
 collected in a solid block near or at the center, and distinct radial striations are 
 visible starting from the center of the organism, dividing it into from 10 to 15 
 segments or merozoites. In some instances as many as 24 merozoites have been 
 counted. The merozoites are larger than those of the quotidian species, are 
 oval in shape, and appear very refractive. Segmentation occurs within the red 
 blood-corpuscle, but its situation is not so easy to distinguish in this species as in 
 the quotidian. The sporulating forms occur very rarely in the peripheral 
 blood, and I have observed but one case in which such forms occurred in blood 
 removed from the peripheral circulation in the thousands of cases of tertian 
 aestivo-autumnal infection which I have studied. 
 
 The young merozoites are liberated in the blood plasma by the disintegra- 
 tion of the red blood-corpuscle and infect normal red cells, thus continuing the 
 human cycle of the plasmodium. Besides the merozoites which continue the 
 human cycle of development there are others which enter ihe red corpuscles 
 and develop into gametes, thus rendering possible the infection of the mosquito. 
 
 Staining Reactions of Plasmodium Falciparum and Falciparum 
 Plasmodium Quotidianum. — The staining reactions of these two species 
 of malarial plasmodia are similar in most respects to the staining reac- 
 tions of the benign tertian and quartan plasmodia, when Wright's method of 
 staining is employed. These plasmodia are seen to consist, in the unpig- 
 mented and early pigmented stages, of a ring of blue-stained protoplasm sur- 
 rounding a large nutritive vacuole, at one side of which is situated a small, 
 vesicular, milky appearing nucleus containing one or two small masses of 
 chromatin stained a deep red or violet. In the aestivo-autumnal "rings" the 
 chromatin is often seen to project outward from the periphery of the blue- 
 stained ring of protoplasm, an appearance never observed in Plasmodium 
 vivax and Plasmodium malariae. The blue-stained protoplasm in the quotidian 
 ring forms is very small in amount, forming a very delicate thin ring, while in 
 the malignant tertian plasmodium the blue-stained protoplasm is thicker and at 
 one portion of the circumference of the ring spreads out into a very definite 
 enlargement in which the pigment, if it be present, is generally situated. 
 
 Changes in the Infected Red Blood-corpuscles. — I have already 
 described the changes observed in the infected red blocd-corpuscles in tertian 
 
40 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 and quartan malarial fevers. It will be remembered that in infections with 
 Plasmodium vivax, the invaded red corpuscle enlarges, becomes pale, and a 
 peculiar form of degeneration occurs which results in the appearance in stained 
 specimens of the so-called Schuffner's dots; while in infections with Plasmodium 
 malariac the invaded red cells generally became slightly smaller, deeper green in 
 color, and stained specimens show the absence of Schuffner's dots. The red 
 blood-corpuscles when invaded by either species of the aestivo-autumnal 
 Plasmodia become much smaller than the normal red corpuscles, and much 
 darker green in color. In infections with the quotidian species the red cells are 
 greatly shrunken, appear wrinkled, are brassy in color, and are almost always 
 much crenated; in infections with the malignant tertian plasmodium these 
 changes are not so marked, the red cell being smaller than normal, but seldom 
 presenting a wrinkled appearance, and is less often crenated. Brassy appear- 
 ing corpuscles are very common, however, in malignant tertian infections, 
 although the reduction in the size of the red corpuscle is less marked than in 
 infections with the quotidian plasmodium. In neither type of infection do the 
 invaded red cells show the presence of Schuffner's dots, although many of them 
 present deeply stained, bluish granules, which have been called Marshall's 
 dots or granules by some authorities, and which are undoubtedly due to some 
 form of degeneration of the cytoplasm of the cells, caused by the aestivo-autum- 
 nal plasmodia. 
 
 So far as the changes in the infected red blood-corpuscles are concerned, 
 the aestivo-autumnal plasmodia resemble the quartan plasmodium rather than 
 the benign tertian, but in the aestivo-autumnal infections the invaded red 
 corpuscles are much smaller than are the corpuscles infected with Plasmodium 
 malariae and much deeper green in color, while the wrinkling and crenation of 
 the corpuscles, so common in aestivo-autumnal infections, especially the 
 quotidian, are very seldom if ever observed in the cells invaded by the quartan 
 plasmodium. 
 
 The Sporogenic Forms of the Malarial Plasmodia Occurring in 
 Human Blood. — I have so far described the forms of the various species of 
 malarial plasmodia occurring in the blood of man which are concerned in 
 schizogony only, but there occur other forms which do not sporulate in human 
 blood and which are intended to continue the existence of the malarial plasmo- 
 dia in mosquitoes. It is a question whether these latter forms, which may be 
 called sporogenic forms as they are concerned in sporogony, are introduced into 
 the blood of man by the bite of the infected mosquito or whether they are 
 elaborated during the development of the plasmodia in human blood. By 
 some it is considered that the sporozoites introduced by the infected mosquitoes 
 are of two varieties, those which develop into schizonts and those which develop 
 into gametes, while other authorities believe that all of the sporozoites injected by 
 the mosquito develop into schizonts, and that after a certain period of time certain 
 of the merozoites produced by the sporulation of the schizonts become differen- 
 tiated into forms which develop into gametes. According to Schaudinn, the 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 41 
 
 stimulus to the production of the gametes or sporonts is due to the reaction of the 
 host, man, upon the plasmodium, and that such forms occur only after the 
 infection has lasted for some time appears to be conclusive proof of this theory. 
 Personally, I believe with Schaudinn that the gametes are produced only after 
 the plasmodia have undergone sporulation for some time, and that, therefore, 
 they are of human origin, being differentiated during the process of schizogony, 
 and not introduced as such by the infected mosquito. In other words, all of the 
 sporozoites introduced by the insect develop into schizonts, the gametes or 
 sporonts developing from the schizonts after a certain time, some of the merozoites 
 being thus differentiated. The development of the merozoites into gametes is 
 much slower than into schizonts, taking, according to Schaudinn, twice as long. 
 In his work upon Plasmodium vivax he found that the development of the 
 gamete from the merozoite took 96 hours, while, as is well known, the develop- 
 ment of the merozoite into the sporulating schizont occupies only 48 hours. 
 Ruge does not agree with Schaudinn in this, but believes that the gametes 
 develop coincidently with the sporulating schizonts, and that the majority of the 
 gametes perish during apyrexia. I cannot agree with the theory of Ruge for it 
 is well known that the gametes (crescents) of aestivo-autumnal fever may exist 
 for months in the blood, during which time apyrexia has been practically 
 constant. 
 
 The gametes are invariably of two kinds, male and female. They can be 
 differentiated from one another and occur in varying proportions, the male 
 organisms being the most numerous. Stephens and Christophers found 
 in aestivo-autumnal infections, 53 micro gametocytes (males) to 2>3 macro- 
 gametes (females), but Ruge found, in benign tertian infections, that the 
 proportion varied very greatly in different cases, some infections showing 
 equal numbers of male and female gametocytes, while in others he found only 
 
 1 micro gametocyte to 50 macro gametes. It is very probable that the proportion 
 varies somewhat in every case, due to the conditions favoring development 
 brought about by the reaction of the system to infection. 
 
 The differentiation of the intracellular gametes from the schizonts is not 
 difficult in most instances, if the following morphologic data be remembered: 
 
 1. Absence of "ring form" in all cases, the chromatin in the youngest 
 stage or trophozoite, being situated in the center of the organism, surrounded 
 by the protoplasm. Thus there is an absence of the nutritive vacuole which 
 produces the ring like appearance in this stage of the schizont. 
 
 2. The cytoplasm in the male gamete is more dense, and stains a deeper 
 blue, than in the schizont, while in the female gametes it is less dense and stains 
 very faintly. 
 
 3. The pigment is larger in amount in the gametes and more rod-like in 
 form or in larger granules. 
 
 4. In benign tertian and in quartan infections the mature intracellular 
 gametes are larger than the mature schizonts, there being a difference of from 
 
 2 to 6 microns in the diameter of the organisms. 
 
42 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 5. In aestivo-autumnal infections the gametes are crescentic in form and 
 are thus easily distinguished from the full-grown schizont. 
 
 Ruge states that any small unpigmented plasmodium showing the chroma- 
 tin situated within the blue-stained protoplasm, with no unstained area between 
 it and the protoplasm, should be considered as a gamete. Maurer describes 
 the young gamete as circular in form, and composed of a broad, blue-stained 
 band, enclosing a small amount of achromatic substance in which lies a large 
 granule of bright red chromatin. In very deeply stained specimens a thick 
 deep red border surrounds the organism, which is especially prominent in the 
 crescentic gametes. As growth proceeds the disk form is lost, the achromatic 
 substance disappears, the chromatin becomes broken up into small threads, 
 and very coarsely granular pigment is developed. In the crescentic gametes 
 a deep red border is observed surrounding them, which Maurer calls the 
 capsule of the crescent. Maurer's description applies to specimens stained 
 by Romanowsky's method, and I have confirmed all that he says many times 
 in specimens stained by the method of Wright. 
 
 Schaudinn claims that in benign tertian infections, the male gametes or 
 micro gametocytes gradually disappear after the attack of fever has ceased, until 
 in from three to six weeks only the female gametes or macro gametes can be 
 found in the blood. I have not found that this is the case in aestivo-autumnal 
 malaria, for in such infections I have observed both male and female gametes 
 in the blood for weeks after the active symptoms had ceased, and in practically 
 the same numbers during the entire period of observation. 
 
 In considering the forms of the malarial plasmodia, which may be observed 
 in the blood of man, and which are intended to undergo development within 
 mosquitoes belonging to the Anophelinae, we have to consider, for each species 
 of plasmodium, the gametes in general, and the macrogamete, the microgame- 
 tocyte, and the micro gamete in particular. The development of these forms 
 will be considered in the next chapter of this work. 
 
 The Sporogenic Forms of Plasmodium Vivax Occurring in the 
 Blood of Man. — In the study of the blood of benign tertian cases it will be 
 observed that a certain number of the fully developed pigmented plasmodia 
 do not sporulate, but become free in the blood as spherical bodies which are of 
 two kinds, those which produce flagella or microgametes, and which are called 
 micro gametocytes, and those which do not form flagella, which are called 
 macrogametes. The first are the male organisms, the second the female. In 
 the stomach of the mosquito the microgametes, liberated from the micro- 
 gametocyte, penetrate and fertilize the macrogametes, thus producing a sporont. 
 In very rare instances this process of fertilization may be observed in blood 
 which has been removed from the body for some time, and it is very common 
 to observe the process of flagellation, as it is called, and the liberation of the 
 flagellum or micro gamete. In fresh specimens of tertian blood, the gametes 
 cannot be distinguished until they are fully developed, but in stained specimens 
 they can be distinguished without much difficulty in all stages of development. 
 
EXPLANATION OF PLATE III. 
 
 Quotidian Aestivo-autumnal Plasmodium. {Plasmodium falciparum quotidi- 
 anum.) Stained with Oliver's Modification of Wright's Stain, 
 i to ii. "Ring forms" of the quotidian Plasmodium. 
 ii, 12. Pigmented forms of the quotidian Plasmodium. 
 
 13. Presegmenting Plasmodium. 
 
 14. Sporulating plasmodium. 
 1 5. Microgametocyte. 
 
 16. Macrogametes. 
 Chromatin, red; protoplasm, blue; vesicular portion of nucleus, unstained. 
 
 Tertian Aestivo-autumnal Plasmodium. (Plasmodium falciparum.) Same stain. 
 1, 2. "Ring forms" of the tertian aestivo-autumnal plasmodium. 
 
 3. Pigmented "ring form." 
 
 4, 5, 6, 7. Pigmented forms of the plasmodium. 
 
 8. Young gamete. 
 
 9. Nearly full-grown form, showing peculiar chromatin border. 
 
 10. Full-grown form. 
 
 11, 12. Sporulating pla modia. 
 
 13. Microgametocyte. 
 
 14. Macrogamete. 
 
 Group A. Gametes of Plasmodium Vivax. (Tertian plasmodium.) 
 
 1. Young microgametocyte. 
 
 2, 3. Fully grown microgametocytes. 
 
 4. Young macrogamete 
 
 5, 6. Fully grown macrogametes. 
 
 7. Extracellular macrogamete. 
 
 8. Flagellated microgametocyte. 
 
 Group B. Gametes of Plasmodium malaria. (Quartan plasmodium.) 
 
 1. Young microgametocyte. 
 
 2, 3. Fully grown microgametocytes. 
 
 4, Young macrogamete. 
 
 5, 6. Fully grown macrogametes. 
 
 7. Extracellular macrogamete. 
 
 8. Flagellated microgametocyte. 
 
 Group C. Gametes of Plasmodium falciparum. (Tertian aestivo-autumnal 
 Plasmodium.) 
 
 1. Young gamete. 
 
 2. Microgametocyte. 
 
 3. Macrogamete. 
 
 4. 5. Microgametocytes. (Crescents.) 
 
 6, 7. Macrogametes. (Crescents.) 
 
 8. Ookinetes. 
 
 9. Sporozoites. 
 
Plate III 
 
 i 
 
 4 I Q 
 
 ft 
 
 10 11 12 13 14 15 
 
 Quotidian Aestivo-autumnal Plasmodium. 
 
 /■'"' 
 (1^ 
 
 /* 
 O 
 
 G 
 
 2 
 
 
 # 
 
 jtf& 
 
 
 ■i*i- 
 
 
 
 A 4* 
 
 
 
 12 
 
 14 
 
 Tertian Aestivo-autumnal Plasmodium. 
 
 
 
 
 1 '^ 2 ^I 3 
 
 Group A. 
 
 3 
 
 
 
 V&P 6 
 
 Group B. 
 
 
 Group C. 
 
 C. F. CRAIG. DEL. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 43 
 
 Fresh Preparations. — The Gametes. — In fresh specimens of blood the 
 gametes of Plasmodium vivax cannot with certainty be distinguished as such 
 until they are fully developed and liberated in the blood plasma by the disin- 
 tegration of the red cell in which they have developed. At this time they can 
 be easily differentiated into two forms, the macrogamete and the micro- 
 gametocyte. 
 
 The Macrogamete. — The tertian macrogamete is a large, pigmented 
 organism, measuring from 9 to 11 microns in diameter; the protoplasm appears 
 slightly granular, and the pigment is in the form of large granules or clumps, 
 arranged about the periphery of the organism, or commonly in a wreath-like 
 form some distance from the periphery. The pigment is not motile, and 
 exflagellation never occurs in the forms presenting this arrangement of the 
 pigment granules. In rare instances a flagellum may be seen attached to the 
 circumference of the macrogamete, and such an appearance always indicates an 
 attempt at fertilization, and may be observed in the blood much more fre- 
 quently than is generally supposed. Sometimes more than one flagellum or 
 micro gamete may be seen attached to the macrogamete, and their movements 
 are peculiar and characteristic. Instead of the rapid serpentine lashings seen 
 in the microgametes, when attached to the micro gametocyte, the movements 
 are of an entirely different character. The microgametes appear to straighten 
 and then relax, revolving apparently very rapidly upon their axes; sometimes 
 they may be seen to pull themselves loose from the macrogamete and again 
 become attached to it. In the meanwhile the pigment within the macrogamete 
 has maintained its circular arrangement, and is at most very slowly motile. 
 The movements observed are produced by the efforts of the microgamete to 
 penetrate the macrogamete, a process which normally occurs within the stomach 
 of the mosquito. 
 
 The Microgametocyte. — The micro gametocyte of Plasmodium vivax 
 measures from 8 to 10 microns in diameter, is spherical in outline when fully 
 developed, and free in the blood plasma, and contains a large amount of pigment 
 in the form of large and small granules, distributed throughout the protoplasm. 
 When first liberated from the red blood-corpuscle in which it has developed, 
 the pigment is sluggishly motile, but in those micro gametocytes in which micro- 
 gametes are developing, the pigment soon becomes very actively motile, much 
 more so than in any other form of malarial plasmodium, while the protoplasm 
 of the organism also appears to be in motion, marked undulations of the 
 periphery being often apparent. In those instances in which the pigment is 
 immotile it is collected in small, irregular clumps throughout the protoplasm 
 instead of about the periphery or in a wreath-like arrangement, as in the 
 macrogamete. If a micro gametocyte in which the pigment is in active motion 
 be watched, in a variable length of time, — from five minutes to half an hour or 
 more- -the pigment will be seed to collect toward the center of the protoplasm, 
 the motility becoming somewhat lessened, and suddenly, as though an explosion 
 had occurred within the organism, there appear at certain portions of the 
 
44 TH E ETIOLOGY OF THE MALARIAL FEVERS. 
 
 periphery long, thin, colorless, thread-like, actively moving filaments, which 
 vary in number from two to six, and which undulate rapidly, lashing about 
 among the red corpusles to which they often impart a perculiar spinning motion. 
 These filaments are the micro gametes. 
 
 There may now occur one of several things: either the microgametes may 
 break loose from the parent plasmodium, which is the normal procedure, or, 
 unable to do so, may become motionless and degenerate, or the micro gametocyte 
 may undergo degeneration before the microgametes have succeeded in freeing 
 themselves. In the first instance, after the microgamete has lashed about among 
 the red blood-corpuscles for a variable length of time, seemingly trying to free 
 itself from the micro gametocyte, it at last succeeds, and moves off in a serpentine 
 manner among the red cells. In some instances the efforts of the microgamete 
 to free itself are very vigorous, resulting in its pulling the micro gametocyte about 
 for appreciable distances in the microscopic field. After it becomes free the 
 serpentine motion may be retained for a long time, even an hour or more. If it 
 chances that only a single microgamete arises from the micro gametocyte, the 
 latter quickly degenerates after the liberation of the microgamete. 
 
 In those instances in which the microgametes are unable to free them- 
 selves from the plasmodium, after a time they become motionless, and the 
 entire organism shrinks, becomes vacuolated, and finally disintegrates. In 
 rare instances the micro gametocyte undergoes degeneration before the micro- 
 gametes are extruded or before they are able to free themselves from the parent 
 body; in such instances the micro gametocyte undergoes fragmentation, each 
 fragment containing pigment. Careful observation will show that these frag- 
 ments remain attached to one another for a long time by very delicate threads 
 of protoplasm; if microgametes have developed before fragmentation, they 
 become motionless and disintegrate, but the fragments containing the pigment 
 may persist for a long time, and have been mistaken for new parasites of the 
 blood. In one instance the pigment in one of these fragments was observed to 
 be in active motion after a period of eight hours at room temperature. 
 
 The microgametocyte, after the microgametes have been liberated, quickly 
 degenerates, either becoming vacuolated, or breaking up into small spherical 
 bodies containing pigment. Not infrequently the entire organism remains as 
 an irregular mass of cytoplasm containing the pigment in the form of irregular 
 clumps collected toward the center, and absolutely motionless. 
 
 The Microgametes. — In fresh specimens of blood the tertian microgamete 
 appears as a very slender, thread-like body, perfectly colorless, and having a 
 serpentine, undulating motion, enabling it to progress among the blood-corpuscles 
 which are displaced or moved about by its motions. A careful study of micro- 
 gametes shows that considerable variations occur in individual specimens as 
 regards appearance. I have already spoken of the variation in number and of 
 the manner in which they free themselves from the microgametocyte. While 
 still attached to the latter they often present a clubbed extremity, which changes 
 its form, sometimes appearing blunt, sometimes pointed; after liberation of the 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 45 
 
 organism the extremities both appear pointed, and are difficult to distinguish. 
 The micro gametes measure from two to four times the diameter of the micro- 
 gametocyte, but it is not uncommon to observe micro gametes that are from five 
 to eight times as long as the diameter of the parent organism. Besides the 
 clubbed extremity that is often present, the microgametes sometimes show small 
 nodular swellings along their course in which are a few pigment granules 
 derived from the body of the micro gametocyte. After liberation the micro- 
 gametes appear to extrude this pigment and at the time they fertilize the macro- 
 gametes they are entirely hyaline in appearance. In rare instances short, very 
 thick forms are observed, which have a very sluggish serpentine motion. 
 
 Stained Preparations. — In stained preparations of blood infected with 
 Plasmodium vivax all stages in the development of the gametes can be easily 
 recognized. During their intracorpuscular development they can be distin- 
 guished from the schizonts during the trophozoite phase somewhat more easily 
 than during later stages of development, but after they have become extracor- 
 puscular they can be distinguished without difficulty in nearly every instance of 
 infection. The merozoites which are destined to develop into gametes cannot be 
 differentiated even in stained preparations, from those destined to become 
 schizonts. 
 
 The Gametes. — The gametes of Plasmodium vivax, in their earliest stage 
 of development, when stained by Wright's method, consist of a perfectly circular 
 mass of blue-stained protoplasm, in the center of which is a spherical dot of chro- 
 matin stained a deep red or violet. The achromatic zone, or nutrient vacuole, 
 which gives the "ring" appearance to the young schizont, is not present in the 
 trophozoites which become gametes, and the organism at this stage of develop- 
 ment is larger than is the schizont. In those gametes which have become pig- 
 mented, the pigment is greater in amount than in the schizonts, and is distributed 
 throughout the protoplasm. In such gametes the protoplasm stains blue and 
 the chromatin, which is arranged in fibrils throughout the protoplasm, stains a 
 pinkish red, and is not collected in masses at any stage in the development of the 
 gamete while it is intracorpuscular. The gametes are always circular in shape 
 at every stage of intracorpuscular development. 
 
 The following observations are of diagnostic importance in differentiating 
 the benign tertian gametes from the schizonts. 
 
 1. The gamete is larger throughout its development than is the schizont. 
 
 2. It is much less amoeboid, and, therefore, is circular in contour in every 
 stage of development in the red corpuscle. 
 
 3. No nutritive vacuole is present in the young gametes, and thus they are 
 not "ring-like" in form. In stained preparations there is no achromatic zone 
 surrounding the chromatin dot as in the schizont. 
 
 4. The gametes show very little amoeboid motion at any stage of their 
 development. 
 
 5. The pigment in the gametes is much greater in amount and earlier 
 developed than in the schizonts. It is present in almost the earliest forms, and 
 
46 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 in the fully developed gamete is still motile, while it is motionless in the fully 
 grown schizont. 
 
 6. The chromatin divides earlier in the gamete than in the schizont, is 
 loosely arranged, and never separates into distinct masses. 
 
 7. The period of development within the red corpuscle is almost twice as 
 long for the gamete as for the schizont; hence the greater amount of pigment in 
 the former and its larger size. 
 
 After development, the gametes, if they are not ingested by mosquitoes, 
 degenerate, and disappear after some weeks, although Schaudinn claims that 
 the female gamete or macrogamete, under such circumstances, may undergo par- 
 thenogenesis and thus produce new generations of schizonts, leading to a relapse 
 of the infection. 
 
 In stained specimens the gametes may be differentiated into male and 
 female forms, the micro gametocytes and the macro gametes. 
 
 The Macrogametes. (Female gametes.) In stained specimens the proto- 
 plasm of the macrogametes stains an intense blue, much darker than does the 
 protoplasm of the schizonts. The nuclear chromatin is small in amount at all 
 stages, consisting in the earliest stage of development of a minute dot and later 
 of a few small dots or rods situated near the periphery of the organism, stained a 
 bright red in color. The pigment is very dark, almost black in color, and is in 
 the form of large rods, as much as 1 to 3 microns in length, in the fully developed 
 macrogametes. It is very sluggish in motion and is apt to be collected in ir- 
 regular masses toward the periphery or the center of the organism. It is very 
 often observed arranged in a wreath-like manner close to the border of the 
 organism. The macrogametes are always circular in contour. 
 
 The macrogametes may be distinguished from the micro gametocytes by: 
 
 1. In the fresh specimen, a granular protoplasm containing much nutrient 
 material, visible as large refractive granules. When stained, by the dark blue 
 color of the protoplasm. 
 
 2. The macrogamete has a smaller amount of nuclear chromatin, sometimes 
 only a few dots, situated about the periphery of the organism. 
 
 3. A longer period of development and greater persistence in the blood of 
 man after the active symptoms of malaria have ceased. 
 
 4. Larger size, measuring from 13 to 16 microns. 
 
 5. Darker colored pigment, consisting of large rods measuring from 1 to 3 
 microns in length. The benign tertian macrogamete is the only form of the 
 malarial plasmodia presenting such large rods of pigment. 
 
 6. Less active movement of the pigment and its arrangement in a wreath- 
 like formation. 
 
 The Microgametocytes. — The micro gametocytes of Plasmodium vivax, in 
 their various stages of development, differ somewhat in the appearances they 
 present in stained specimens. During their earliest intracorpuscular stage they 
 are distinguished from other forms by the pale blue staining of their protoplasm, 
 which, in the larger forms, sometimes appears hyaline even in stained prepara- 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 47 
 
 tions. The chromatin is large in amount and stains an intense red. In the 
 fully developed form, just before the development of the micro gametes or flagella, 
 the chromatin is seen to be divided into from four to eight masses, which are 
 collected at the periphery of the organism. In those organisms which are 
 stained while undergoing exflagellation, the chromatin may be traced into the 
 flagella, and when the process is complete the body of the micro gametocyte is 
 generally entirely free of chromatin. In such forms the protoplasm stains a 
 pale blue, while the pigment, in the form of minute dots or very slender, short 
 rods, stains a greenish- blue in color. The pigment is larger in amount than in 
 the macrogamete. 
 
 In the micro gametocytes the chromatin is much larger in amount than in the 
 macrogametes, sometimes comprising from one-third to one-half of the parasite; 
 it is often collected into large irregular masses or in well-defined fibrils, some of 
 which are of considerable thickness. According to Zieman, the proportion of 
 chromatin to plasma in the micro gametocytes is from i to i to i to 4, while in the 
 macro gometes it is from 1 to 8 to 1 to 12. 
 
 In stained specimens the shape of the micro gametocytes is oval or circular 
 prior to the development of the microgametes , and they are smaller than the 
 macrogametes, and are seldom larger than the fully developed schizont. 
 
 The following points serve to differentiate the micro gametocyte of Plasmo- 
 dium vivax from the macrogametes: 
 
 1. The pale blue staining of the protoplasm. 
 
 2. The larger amount of chromatin and its arrangement in masses. 
 
 3. In the fresh specimen the lesser amount of amoeboid motion. 
 
 4. In fresh specimens the greater amount of pigment which is much more 
 motile and greenish in color. The movement of the pigment which has aptly 
 been characterized as a "swarming motion" serves to distinguish the micro- 
 gametocyte from either the fully developed schizont, in which the pigment is 
 motionless, and from the macrogamete, in which the pigment is either motionless 
 or very slightly motile and generally arranged in a wreath-like manner. 
 
 5. The presence of flagella or microgametes. 
 
 6. The smaller size of this form of the plasmodium. 
 
 The Microgametes. — The micro gamete of Plasmodium vivax in stained 
 preparations of blood is seen to consist of a mass of pale blue stained protoplasm 
 containing a considerable amount of brilliant red chromatin, in the form of 
 threads, granules, or irregular masses. The shape of the organism is thread- 
 like with pointed ends, and it may well be likened to a spirochaete devoid of an 
 undulating membrane. Most of the microgametes consist very largely of 
 chromatin, only a small amount of protoplasm being visible, but occasionally 
 the chromatin is small in amount or even absent. Where no chromatin is 
 present it is certain that the microgametes are sterile. The above description 
 applies to the free microgametes, the appearance of those still attached to the 
 parent body having already been noticed. 
 
 The Sporogenic Forms of Plasmodium Malariae Occurring in Human 
 
48 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 Blood. — The gametes of Plasmodium malariae, the quartan malarial Plasmo- 
 dium, are very similar to those of Plasmodium vivax. in both fresh and stained 
 specimens of blood, and I shall describe them but briefly, as much that has been 
 said regarding the gametes of Plasmodium vivax is equally true of the gametes of 
 Plasmodium malari.c. 
 
 The Gametes. — The gametes resemble very closely those of Plasmodium 
 vivax in all stages of intracorpuscular development, and can only be dis- 
 tinguished by their smaller size and the absence of swelling of the infected 
 red blood-corpuscle. After becoming fully developed and extracorpuscular, 
 male and female forms may be distinguished, the micro gametocytes and the 
 macro gametes. 
 
 The Macrogametes.— The macrogametes of Plasmodium malariae are 
 very hard to distinguish from the schizonts, as the quartan plasmodium is 
 always round in form and lacks amoeboid motion after the development of 
 pigment. In the earliest stage the absence of the nutritive vacuole, or achromatic 
 zone, in stained specimens, is distinctive of a gamete, but the quartan sclvizont 
 also loses the achromatic zone at an early stage of development, and the dis- 
 tinction becomes impossible. In the fully developed macro gamete the granular, 
 solid appearing protoplasm and the greater amount of very [coarse pigment 
 renders the distinction less difficult. In stained specimens the free macro- 
 gametes are distinguished by their large size (n to 12 microns in diameter) and 
 smaller amount of undivided chromatin. 
 
 The Microgametocytes. — The description already given of the micro- 
 gametocyte of Plasmodium vivax is true, in most respects, of the microgameto- 
 cytes of the quartan plasmodium. There is the same pale staining protoplasm, 
 the large amount of chromatin, the swarming pigment, and the development 
 of microgametes or flagella, which are formed in the same manner, and present 
 the same appearances in both fresh and stained specimens of blood. They 
 differ from the tertian microgametocytes in their smaller size and less motile 
 pigment, which is in larger granules. 
 
 The Microgametes. — The description given of the microgametes of 
 Plasmodium vivax is equally true for the microgametes of the quartan plasmo- 
 dium and, so far as I am aware, we have no data sufficient to distinguish this 
 form of the two plasmodia. 
 
 The Sporogenic Forms of Plasmodium Falciparum and Plasmodium 
 Falciparum Quotidianum Occurring in Human Blood. 
 
 The sporogenic forms, or gametes, of the aestivo-autumnal plasmodia are 
 distinguished from similar forms of other human malarial plasmodia by their 
 crescentic shape, a peculiarity which makes their differentiation easy and 
 possible to even the tyro in the examination of malarial blood. As the differ- 
 ences between the gametes of the malignant tertian and the quotidian aestivo- 
 autumnal plasmodia are merely differences in size and in shape, I shall not 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 49 
 
 describe these forms separately, but shall consider the general morphology of 
 the aestivo-autumnal gametes in both fresh and stained specimens of blood, 
 noting the differential points between the two species as suggested by the general 
 description. 
 
 The crescents occur only in the blood of aestivo-autumnal infections, and 
 only after the infection has persisted for some time. Canalis claims that he has 
 never but once seen crescentic bodies in the peripheral blood before the fifteenth 
 day of the disease, but, in most instances, they may be found in cases after 
 the disease has been active for something over a week, twelve days being the 
 average time for their development. They persist in the blood for weeks after 
 the active symptoms of infection have ceased and gradually disappear unless 
 new infection occurs. They are not affected by quinin, nor do we know of any 
 drug that is capable of destroying this form of the plasmodia. This is also 
 probably true of the gametes of the benign tertian and quartan plasmodia. 
 
 Although the crescentic shaped gametes develop in a considerable proportion 
 of aestivo-autumnal infections, it is by no means true that every such infection 
 shows these forms, and from personal observation, both in the tropics and in 
 this country, I believe that not over 50 per cent, of such infections present 
 crescents in the peripheral blood. If blood from the spleen be examined or 
 smears of the bone-marrow, crescents will be observed in a greater proportion 
 of cases, but in many aestivo-autumnal infections the formations of gametes 
 appears to be entirely absent. Manson believes that crescents are more 
 frequently observed in cases of malaria which have been contracted in the 
 tropics, but have returned to temperate regions, and that in the tropics it is 
 much more rare to observe this form of plasmodia. I do not agree with this, 
 for I have found that the percentage of cases showing crescents in the tropics 
 is practically the same as in temperate regions. It often requires a long and 
 patient search to demonstrate the presence of crescents in the blood of individuals 
 who have suffered from aestivo-autumnal infections, and, while I believe that a 
 prolonged search would show crescents in 50 per cent, of such cases, still in the 
 study of several hundred cases I have only been able to demonstrate this 
 form in a little over 33 per cent. Rogers found that crescents were present 
 in only 10 per cent, of the cases he observed in Europe. 
 
 The crescentic gametes of the aestivo-autumnal plasmodia, like the 
 gametes of the benign tertian and quartan plasmodia, develop within the red 
 corpuscle, and, when fully grown, can be differentiated into male and female 
 forms, the micro gametocytes and the macro gametes. Their after-development 
 is similar, the micro gametocyte developing microgametes which become free 
 and fertilize the macrogametes. The process of microgamete formation, or 
 flagellation, as it is called, may be observed in blood which has been removed 
 from the body for some time and in which a sufficient amount of moisture 
 is present, and does not differ from the same process as observed in the gametes 
 of tertian and quartan plasmodia, which has already been described. The 
 crescentic micro gametocyte becomes oval and later round in form, after which 
 4 
 
$0 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 the microga nicies or tlagella are developed as in the other malarial plasmodia 
 (see Fig. 10). 
 
 Fresh Preparations. — The crescentic gametes of the aestivo-autumnal 
 Plasmodia are developed within the red corpuscles and during their intra- 
 corpuscular stage are distinguished from the schizonts by their limited amoeboid 
 motion, the early development of a greater amount of pigment within them, 
 the crescentic or ovoid form acquired during the latter stages of intracorpuscular 
 development, and their longer period of development. Their protoplasm is 
 more opaque and granular in appearance and the pigment is darker in color. 
 Just before the gametes are liberated from the red corpuscles they have become 
 definitely crescentic in shape and may be differentiated into male and female 
 forms. The red cell has shrunk about the parasite, forming a membrane- like 
 covering, one portion of which, that connecting the poles of the crescent, 
 
 Fig. io. — Tertian aestivo-autumnal "ring form" and microgametocyte. 
 (Ovoid form.) Photomicrograph X 1200. 
 
 forms a hemispherical projection, the so-called "bib" of the crescent. In 
 the youngest crescentic forms the pigment is distributed throughout the proto- 
 plasm, but in the older forms it becomes collected at the center or toward one 
 of the extremities. The border of the crescent is sharply defined, being 
 represented by a single or double refractive outline, often of a bright green 
 color, due to the color of the red corpuscle which forms an enveloping mem- 
 brane. The pigment in the crescentic gametes is generally immotile, but in a 
 few instances I have observed sluggish motility. 
 
 The Macrogamete. — The macro gamete, or female crescent, in both 
 species of aestivo-autumnal plasmodia, is distinguished from the microgame- 
 tocyte, or male crescent, by its slender form, the arrangement of pigment, and the 
 fact that it does not develop microgametes or flagella. This form measures 
 from 11 to 15 micra in length by 2 to 3 micra in breadth. The pigment 
 is dark brown in color, immotile, and either concentrated in the center of the 
 crescent in a dense mass or arranged in a wreath-like manner near the center 
 of the parasite. The protoplasm is opaque and granular in appearance. After 
 becoming extracellular, which normally occurs within the stomach of the 
 mosquito, but which may often be observed in human blood, the macrogamete 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 5 1 
 
 becomes first ovoid and then circular in shape, having a clear-cut hyaline border, 
 a granular protoplasm, and the pigment arranged in a wreath-like manner 
 about the center of the organism. Not infrequently the pigment is divided 
 into small, almost black dots, arranged in a perfect circle midway between the 
 center and the periphery of the parasite. 
 
 The macro gametes of the quotidian aestivo-autumnal plasmodium are 
 distinguished from those of the tertian by their smaller size, the pointed 
 extremities of the crescent, the smaller amount of pigment, and its division 
 into fine granules instead of into rods, the less granular protoplasm, and the 
 absence, at any time, of a double outline. The quotidian macro gamete never 
 measures more than 8 or 9 microns in length, while the malignant tertian 
 generally exceeds 12 microns. 
 
 The Microgametocyte. — The micro gametocytes of both species of 
 aestivo-autumnal plasmodia are shorter and plumper in appearance than are 
 the macrogametes, being kidney-shaped rather than crescentic. They measure 
 7 to 10 microns in length by 3 to 5 microns in breadth, and may have a double 
 or single border of a greenish color. The protoplasm is less opaque and 
 granular than in the macrogametes and the pigment is in finer particles and 
 distributed throughout the protoplasm or collected at the poles of the crescent. 
 As in the other malarial plasmodia, the micro gametocytes, when liberated from 
 the corpuscle in which they have developed, produce microgametes or flagella. 
 This process is often observed in properly collected specimens of human blood 
 and is essentially the same as the like process already described in the benign 
 tertian and quartan plasmodia. The crescentic or kidney-shaped microgame- 
 tocyte becomes ovoid and then round, the pigment becomes very actively motile, 
 the entire protoplasm of the organism appears violently agitated, and soon one 
 or more slender filaments are projected from the periphery of the organism 
 and lash about among the surrounding blood-corpuscles. These filaments 
 are the microgametes. The micro gametocytes of the quotidian aestivo-autumnal 
 plasmodium are distinguished from those of the malignant tertian plasmodium 
 by their small size, seldom measuring over 7 microns in length, and by their 
 very plump appearance which often renders them ovoid rather than crescentic 
 in shape. The pigment is also smaller in amount and less motile. 
 
 The Microgametes. — In fresh specimens of blood the microgametes of the 
 aestivo-autumnal plasmodia appear as very delicate, hyalin filaments, having 
 an active serpentine motion, enabling them to move about among the blood- 
 corpuscles. The microgametes cannot be distinguished from those occurring in 
 quartan and tertian infections, nor can the microgametes of the two species of 
 aestivo-autumnal plasmodia be distinguished from one another. 
 
 Stained Preparations. — The staining reactions of the aestivo-autumnal 
 gametes are essentially similar to those of the tertian and quartan gametes, 
 when Wright's stain is used, the protoplasm staining blue, the chromatin red, 
 the achromatic zone surrounding the chromatin in the schizont being absent 
 in these forms. 
 
52 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 The Gametes. — In their earliest stages of development, the aestivo- 
 autumnal gametes are distinguished from the schizonts by their spherical shape, 
 by the deep blue staining of their cytoplasm, by the situation of the chromatin 
 within the center of the parasite instead of at one side, and by the presence 
 of a deep red line surrounding the exterior of the gamete, in some instances. 
 In stained specimens the signet-ring appearance so frequently observed in 
 aestivo-autumnal schizonts is not observed in the gametes. 
 
 The Macrogamete. — In stained specimens the protoplasm of the macro- 
 gamete is colored a deep blue, most intense at the poles of the crescent; the 
 chromatin stains a brilliant red and is situated at or near the center of the 
 crescent. The pigment stains a greenish-brown and often surrounds the 
 chromatin as a distinct wreath, or is collected in small circular masses near 
 the chromatin. The remains of the red blood-corpuscle surrounding the 
 crescent are stained a salmon or bright pink and not infrequently a deep red 
 band may be observed surrounding macro gametes which are apparently free 
 in the blood plasma. The pink stained remains of the red blood-corpuscle 
 often appear as. an irregular, jagged rim around the crescent, and the "bib" 
 as a faintly staining mass occupying the concavity of the macrogamete, having 
 a brightly stained, pink border. 
 
 In stained specimens of blood the aestivo-autumnal macrogametes present 
 the following features which enable us to distinguish them from the micro- 
 gametocytes: 
 
 i. The long slender shape of the crescent. 
 
 2. The situation of the chromatin in a dense mass at or near the center of 
 the crescent. 
 
 3. The deep blue staining of the protoplasm. 
 
 4. The concentration of the pigment in little masses or in a wreath-like 
 manner about the chromatin. 
 
 The Microgametocyte. — The protoplasm of the microgametocyte stains 
 a delicate blue, and in many instances it is almost impossible to stain it at all. 
 The chromatin stains a delicate red and is in the form of a loose network 
 spread over the greater portion of the crescent. The pigment is granular in 
 appearance and is distributed throughout the crescent. The amount of stained 
 protoplasm is very small as compared with the protoplasm of the macrogamete, 
 and the chromatin is often almost invisible on account of the delicate fibrils 
 of which the chromatin network is composed. The staining of the red blood- 
 corpuscle surrounding the microgametocyte is similar to that already described 
 for the corpuscle containing the macrogamete. In stained specimens containing 
 the oval and round forms of the microgametocyte, the chromatin is found to 
 be collected in irregular masses, staining a deeper red, and situated toward the 
 periphery of the plasmodium. The following features enable us to distinguish 
 the aestivo-autumnal microgametocyte from the macrogamete in stained specimens 
 of blood: 
 
 1. The plump kidney shape of the crescent. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 53 
 
 2. The pale blue staining of the protoplasm. 
 
 3. The pale red staining of the chromatin, which is arranged in a loose 
 network, occupying a large portion of the crescent. 
 
 4. The distribution of the pigment throughout the protoplasm of the 
 crescent. 
 
 There are no essential differences in the staining reactions of the macro- 
 gamete and micro gametocytes of the quotidian and malignant tertian aestivo- 
 autumnal plasmodia. 
 
 Fig. 11. — Aestivo-autumnal tertian 
 macro gamete. Note slender form. 
 Photomicrograph, X 1200. 
 
 Fig. 12. — Tertian aestivo-autumnal micro- 
 gametocyte. Note plump form. Photo- 
 micrograph, X 1200. 
 
 The Microgametes. — As in the quartan and benign tertian plasmodia, 
 the microgametes of the aestivo-autumnal plasmodia are seen to consist, in 
 stained specimens, of a filamentous mass of chromatin, enclosed by a small 
 amount of protoplasm. No essential differences are noted in the microgametes 
 of any of the malarial plasmodia, so far as staining reactions are concerned. 
 
 Literature upon the Classification and Morphology of the Malarial Plasmodia. 
 
 1885. Marchiafava and Celli. Weitere Untersuchungen uber die Malaria- 
 infection. Fortschritte der Med., No. 24, p. 787. 
 
 1886. Osler. An Address on the Haematozoa of Malaria. Phil. Med. Times. 
 1886. Councilman. On Certain Elements Found in the Blood in Cases of 
 
 Malarial Fever. Trans. Assoc, of Amer. Phys., vol. i, p. 90. 
 
 1888. Celli and Guarnieri. Sulla struttura intima della plasmodium 
 malarise. Rif. med., 7 Sett, 12 Ott. 
 
 1889. Golgi. Sullo sviluppo de' parassiti malarici nella febbre terzana. Arch, 
 per le sc. med., vol. xiii, p. 173. 
 
 1889. Canalis. Studi sull' infezione malarica, Giornale medico del esercito e 
 della marina, Dec, p. 1329. 
 
 1890. Grassi and Feletti. Ueber die Parasiten der Malaria. Centralbl. f. 
 Bakt., vii, p. 396, 430. 
 
 1890. Antolisei. L'ematozoo della quartana. Riforma Medica, Nos. 12 
 and 13, p. 68. 
 
54 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 1S90. Idem. Sull' ematozoo della terzana. Rif. Med., Nos. 26 and 27, pp. 1 52, 
 
 158. 
 1890. Antolisei and Angelini. Nota sul ciclo biologico dell' ematozoa 
 
 falciforme. Rif. Med., Nos. 54, 55, 56; pp. 320, 326, 332, 
 i8qo. Axtot.isei. Considerazioni intorno alia classificazione del parasitti 
 
 dell malaria. Rif. Med., Nos. 99, 100, 101, 102, 103; pp. 590, 596, 602, 
 
 60S; 614. 
 1890. Bastianelli and Bignami. Sull' infezione malarica primavirile. Rif. 
 
 Mod., Nos. 144-146, pp. 860, 866, 872. 
 1890. Kruse. Ueber Blutparasiten. Virch. Archiv. Bd. 120, p. 541; Bd. 121, 
 
 P- 3 59- 
 1S90. Bastianelli and Bignami. Observazioni sulle febbri malariche aest i ve- 
 autunnali. Rif. Med., Nos. 223, 2241pp. J 334> J 34°- 
 
 1890. Romaxowskv. Sur la structure des parasites du paludisme. Vratsch, 
 No. 52, Russian. 
 
 1891. Celli and Sanfelice. Ueber die Parasiten des roten Blutkorperchens 
 in Menschen und in Tieren. Fortschr. der Med., No. 13, July 1. 
 
 1891. Dock. Die Blutparasiten der tropischen Malariafieber. Fortschr. 
 
 der Med., ix, p. 187. 
 1 89 1. Mannaberg. Beitrage zur Morphologie und Biologie des Plasmodium 
 
 Malarias Terzianae. Centralbl. fur klin. Med., No. 27. 
 
 1891. Marchiafava and Bignami. La quotidiana e terzana estivo-autunnali. 
 Rif. Med., No. 217, p. 703. 
 
 1892. Dock. The Parasite of Quartan Malarial Fever. International Med. 
 Magazine, 1, p. 28. 
 
 1892. Marchiafava and Bignami. Aestivo-autumnal Malaria. The New 
 
 Sydenham Society, vol. cl, London, 1894. 
 1802. Kruse. Der gegenwartige Stand unserer Kenntniss der parasitaren 
 
 Protozoen. Hygien. Rundschau, ii, Nos. 9, 11, pp. 357, 453. 
 C892. Ruge. Ueber die Plasmodien bei Malaria Erkrankungen. Deutsch. 
 
 militarartzliche Zeitschr., xxi, p. 49. 
 
 1892. Marchiafava and Bignami. Ueber die Varietaten der Malariaparasiten. 
 Deutsch med. Wochenschr., Nos. 51, 525 pp. 1157, 1188. 
 
 1893. Mannaberg. Die Malaria Parasiten. Wien. 
 
 1893. Laveran. Au sujet de l'hematozoaire du paludisme. Compt. rend. soc. 
 
 de biol. Par. March 24, No. 11, p. 312. 
 1893. Sacharoff. Zur Biologie der Malariaparasiten. Ref. in Centralbl. f. 
 
 Bakt., xv, No. 24, p. 962. 
 1893. Labbe. A propos des formes a. flagella des hematozoaires malariques. 
 
 Compt. rend. soc. de biol., Dec. 9, p. 980. 
 1893. Bignami and Bastianelli. Stidi sulla infezione malarica. Bull. R. 
 
 Accad. Med. Roma., Anno xx. 
 1S94. Labbe. Recherches zoologiques et biologiques sur les parasites endo- 
 
 globularides du sang des vertebres. Arch, de zoologie experim. et gen., 
 
 ser. iii, t. ii, pp. 55-258. 
 1896. Sacharoff. Ueber den Entstehungsmodus der verschiedenen varietaten 
 
 der Malariaparasiten. Centralbl. f. Bakt., xix, No. 8, p. 268. 
 
 1896. Zieman. Ueber Blutparasiten bei heimischen und tropischer Malaria. 
 Central, f. Bakt., xx, No. 18 and 19. 
 
 1897. Sternberg., G. M. The Malarial Parasite and other Pathogenic Pro- 
 tozoa. Am. Medico-Surgical Bull., xi, No. 7, p. 328. 
 
 1897. Zieman. Zur Morphologie der Malariaparasiten. Centralbl. f. Bakt., 
 xxi, No. 17, 18, 20, 21. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 55 
 
 1897. McCallum. On the Flagellated Form of the Malarial Parasite. Lancet, 
 No. 13, p. 1240. 
 
 1898. Zieman. Neue Untersuchungen liber die Malaria, etc. Deutsche med. 
 Wochenschr., No. 8, p. 123. 
 
 1898. Gautier. Malariastudien. Zeitschr. f. Hyg. u. Infekt., Bd. xxviii, p. 439. 
 
 1898. Ewing, James. Comparative Morphology of Malarial Plasmodia. Med. 
 News, lxxiii, No. 25, p. 728. 
 
 1899. Bignami and Bastianelli. Sulla struttura dei parassiti malarici. 
 Ann. dig. sperimentali, Anno xx. 
 
 1899. Laveran. Les Hematozoaires endoglobulaires. (Haemocytozoa). Cin- 
 
 quantenaire de I. soc. d Biol. Paris, Oct. 27, p. 124. 
 1899. Schuffner. Beitrag. zur Kenntnis der Malaria. Deutsch. Arch. f. klin. 
 
 Med., lxiv, p. 428. 
 
 1899. Craig, C. F. Observations upon Flagellated Malarial Plasmodia. New 
 York Med. Jour., Dec. 23, 1899. 
 
 1900. Luhe. Ergebnisse der neueren Sporozoenforschung. Jena. 
 
 1900. Craig, C. F. The Parasites of Aestivo-autumnal (Remittent) Malarial 
 Fever. Phil. Med. Jour., April 7. 
 
 1900. Idem. Observations upon the Quartan Malarial Parasite and upon the 
 Staining Reactions of the Tertian, Quartan and Aestivo-autumnal 
 Parasites. Med. News, November 3, 1900. 
 
 1901. Argutinsky. Malariastudien. Arch. f. mikroskop. Anat.,Bd. lix, p. 3 1 5. 
 1901. Grassi. Die Malaria. Studien eines Zoologen. Jena. 
 
 1901. Maurer. Die Malariaparasiten. Munch, med. Wochenschr., xlix, No. 9, 
 
 P- 337- 
 
 1901. Ewing, James. Parasitology. Jour. Exper. Med., No. 5, p. 429. 
 
 iyoi. Lazear. Structure of the Malarial Parasites. Johns Hopkins Hosp. 
 Rep., vol. x, p. 1. 
 
 1 90 1. Schuffner. Zur Tiipfelung der roten Blutscheiben bei Febris inter- 
 mittens tertiana. Deutsch. Archiv. f. klin. Med., lxxi, No. 4 and 5. 
 
 1901. Craig, C. F. The Aestivo-autumnal (Remittent) Malarial Fevers. New 
 York. 
 
 1902. Arguntinsky. Malariastudien. Zur Morphologie des Tertiansparasiten. 
 Arch. f. mikroskop. Anat., Bd. lxi, p. 331. 
 
 1902. Schaudinn. Studien uber krankheitserregende Protozoen. II. Plas- 
 modium vivax; etc. Arb. a.d. Kaiserl. Gesundheitsamte, Bd. xix, No. 2, 
 p. 169. 
 
 1902. Maurer. Die Malaria perniciosa. Centralbl. f. Bakt., Bd. xxxii, No. 
 10, p. 695. 
 
 1902. Ruge. Fragen und Probleme der moderner Malaria-forschung. Centralbl. 
 f. Bakt., Bd. xxxii, No. n, p. 776. 
 
 1903. Argutinsky. Zur Kenntnis des Tropicaparasiten. Centralbl. f. Bakt., 
 Bd. xxxiv, p. 144. 
 
 1904. Rowley. Some Unusual Forms of Malarial Parasites. Johns Hopkins 
 Hosp. Bull., vol. xv, No. 154, p. 1. 
 
 1906. Zieman. Malaria. In Handbuch der Tropenkrankheiten. Mense. 
 Leipzig. 
 
 1907. Manson. Tropical Diseases. New York. 
 
 1907. Thayer. Malaria. System of Medicine. Allbut and Rolleston. Lon- 
 don, vol. ii, Part ii, p. 241. 
 
 1907. Craig, C. F. The Malarial Fevers. Modern Medicine. Osier. Phila- 
 delphia and New York, vol. i, p. 392. 
 
 1909. The Classification of the Malarial Plasmodia. Boston Med. and Surg. 
 Journ., May 27, vol. clx, No. 21, p. 677. 
 
GOLLEG: tORS 
 
 COLL S\IY 
 
 CHAPTER III. 
 
 Development of the Malarial Plasmodia Within the Mosquito: Mosquitoes; 
 Structure; Ova; Larvae; Pupae; Habits; Distribution; Classification. Mosquitoes 
 Proven to Transmit Malaria; The Relation of Number of Infected Mosquitoes 
 to Malarial Infection in Various Localities. 
 
 Development of the Malarial Plasmodia within the Mosquito. — In the 
 previous chapter I have described the forms of the malarial plasmodia destined 
 to undergo development within the mosquito and which may be observed in the 
 blood of man. Thus I have described the macro gametes, the micro gametocytes 
 and the micro gametes, and also the fertilization of the macrogamete by the 
 micro gamete, a process which may be observed in human blood after it has been 
 removed from the body, but which normally occurs in the middle intestine of 
 the mosquito. In this chapter I shall describe the changes occurring after the 
 fertilization of the macrogamete and trace the cycle of development of the 
 plasmodia within the mosquito. 
 
 Historical Summary. — The conception that mosquitoes transmit malaria 
 is by no means a recent one, such a theory having been held by the early Roman 
 observers, Varro, Columella, and Vitruvius. Many of the people of both civilized 
 and uncivilized nations have believed that these fevers are due to the mosquito, 
 and Koch is authority for the statement that in German East Africa the native 
 name for malaria, Mbu, is also the native name for the mosquito, and that the peo- 
 ple firmly believe that the fever is due to the bite of these insects. In 1848, 
 Nott, of New Orleans, in a paper upon yellow fever, speaks of the transmission of 
 malaria by the mosquito as a fact, and in 1883, King, of Washington, advocated 
 this theory very vigorously, and compiled a great mass of evidence in its favor. 
 After the appearance of King's paper, numerous writers published arguments 
 in favor of such a method of transmission, chief among whom may be mentioned 
 Laveran, in 1884 ; Flugge, in 1891 ; Pfeiffer, in 1892, and Manson, in 1 894 . 
 
 In 1896, in his Goulstonian lectures, Manson anew directed attention to 
 this subject, and while some of his deductions have been proven to be erroneous, 
 it is unquestionably true that to this author we owe the stimulation of interest 
 which resulted in the discovery of the true relation of the mosquito to the 
 malarial fevers. Manson stated in these lectures his belief that the crescentic 
 and flagellated parasites are the extracorporeal sporulating homologues of the 
 intracorporeal sporulating plasmodia, and that, as the mosquito had been proven 
 to remove from man Filaria noctuma, acting afterward as a host of this parasite, 
 so the same insect might remove these extracorporeal bodies of the malarial 
 parasites and constitute the host for these particular bodies. Manson did not, 
 at that time, believe that the mosquito inoculated malaria into man, but that 
 the insect removed from man certain stages of the plasmodium which afterward 
 underwent development within the mosquito, and which were then liberated 
 in the water and dust and thus infected man. 
 
 56 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 57 
 
 To Ross, a Surgeon-Major of the Indian Army Medical Service, we owe the 
 discovery of the true relation of the mosquito to the malarial fevers. Stimulated 
 by Manson's theories regarding this subject, this investigator, in 1895, studied 
 the development of the parasites of aestivo-autumnal fever in the mosquito, and 
 proved that the crescents underwent definite changes within the stomach of 
 the insect, flagella developing in the same manner as has been described when 
 this process occurs in the blood of man. Later this investigator, in 1897, 
 described the large cyst-like bodies situated in the outer layer of the stomach 
 wall, and considered that these were developmental forms of the plasmodia 
 within the tissues of the mosquito, and that he had at last been successful in 
 finding the mosquito in which the malarial plasmodia underwent their extra- 
 corporeal cycle of development. 
 
 In 1896 Bignami stated it as his belief that the mosquito inoculated 
 malaria in man during the act of biting, the organisms being introduced with 
 the saliva of the insect, and that this method of transmission of the disease is of 
 greater importance than transmission by air or water. 
 
 In 1898 Ross studied very carefully the malaria of birds, due to proteosoma 
 and halteridium. In mosquitoes which had been allowed to bite birds infected 
 with proteosoma, he found in the stomach wall large pigmented bodies similar 
 to those observed previously in mosquitoes which had bitten malarial subjects; 
 he found that these bodies increased in size until they protruded from the 
 stomach wall of the insect, and that there developed within them a large number 
 of delicate thread-like bodies, which, after rupture of the cyst in which they 
 had developed, were liberated into the body-cavity of the insect. He was able 
 to trace these bodies to the cells and ducts of a gland located in the thorax, and 
 which possesses an efferent duct leading into the proboscis. This gland Ross 
 considered as a venemo-salivary gland, and he then advanced the theory that 
 the thread-like bodies were injected into the bird when the insect bit, and that 
 they began anew the life cycle of the proteosoma in the bird. He proved this 
 theory experimentally by allowing infected mosquitoes to feed on healthy birds, 
 and found that "1. Out of 28 originally healthy sparrows subjected to the 
 bites of gray mosquitoes previously fed on diseased sparrows, 22, or 79 per cent., 
 became infected, all with a very large number of parasites, in from five to eight 
 days. 2. Out of two crows and four weaver-birds, one of the crows and all of 
 the weaver-birds showed a copious proteosoma infection within nine or ten days 
 of being bitten by gray mosquitoes fed previously on sparrows with proteosoma." 
 Ross was thus able to prove beyond question that the malaria of birds is trans- 
 mitted by the mosquito, and he stated it as his belief that what had been found 
 true of bird malaria would also be found true of human malaria. 
 
 In 1897 MacCallum, in studying the development of halteridium, a blood 
 parasite of birds, observed that the fully developed extracellular halteridium 
 consisted of two forms, one of which was flagellated, the other non-flagellated. 
 He observed that the flagella, breaking away from the flagellated form, pene- 
 trated the ncn-flagellated organisms, and that after penetration a motile body re- 
 sulted which moved about among the blood-corpuscles, and which was capable of 
 penetrating and destroying them. His observation was confirmed later by Ross, 
 Koch, and Marchoux. The discovery of MacCallum explained the occurrence 
 of pigment within the cystic bodies in the stomach of the mosquito and also 
 demonstrated that the development of these organisms is sexual in nature, and 
 that the flagella alone are incapable of development. 
 
 The demonstration, experimentally, that mosquitoes transmit malaria to 
 man we owe to Italian investigators who, following the work of Ross and Mac- 
 Callum, endeavored to produce malaria in man by allowing infected mosquitoes 
 
58 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 to bite healthy individuals. In 1S98, in Rome, Bignami endeavored bo produce 
 malaria in man in this way, but was not successful, probably because he did not 
 use the right species of mosquito in his experiments. Later in the same year this 
 observer was successful in producing an attack of aestivo-autumnal malaria in 
 man by allowing mosquitoes which had bitten an infected individual to bite a 
 patient who had never had malaria. In the same year, Bastianclli, Bignami, 
 and Grassi were successful in producing a double tertian infection in man by 
 the bites of infected Anopheles. In February, 1899, they were successful in 
 infecting Anopheles maeitli pcmiis with quartan plasmodia, and were able to 
 trace the developmental stages of this species of Plasmodium in the mosquito. 
 They were also able to report a second successful experiment with the benign 
 tertian Plasmodium and another with the aestivo-autumnal Plasmodium. In 
 April, 1S99, Bastianelli and Bignami reported three successful inoculation 
 experiments, the first, a double tertian infection; the second, a tertian infection, 
 and the third, an infection with one of the aestivo-autumnal plasmodia. The 
 experiments of the Italian observers have been again and again confirmed by 
 numerous investigators whose results will be considered fully in the chapter of 
 this work dealing with the methods of transmission of the malarial fevers. 
 
 General Description of the Mosquito Cycle (Sporogony). — I have 
 already described the process of flagellation, as it is called, and the fertilization 
 of the macro gamete, or female plasmodium, by the microgamete, or male Plasmo- 
 dium. This process occurs in nature in the middle intestine of the mosquito, 
 after the insect has bitten an infected individual. The result of this fertilization 
 is known as the zygote or sporont. After a certain period of time the zygote 
 becomes elongated and finally motile and is then known as the ookinete. The 
 ookinete penetrates the wall of the middle intestine and eventually becomes 
 situated on the outer side of the epithelium and the basement membrane of the 
 intestine between the adipose tissue and the muscular wall. Here the organism 
 becomes spherical in shape and forms a cyst known as the oocyst. At this 
 stage the protoplasm is granular and reticular in appearance, the pigment is 
 reduced in amount, and the entire organism is enclosed within a well-defined 
 capsule. The oocyst is formed at about the third or fourth day after infection 
 of the mosquito. About the fifth or sixth day the oocyst enlarges and within it 
 are formed spherical refractive bodies known as sporoblasts. At this stage the 
 organism is increased so much in size that it projects from the intestinal wall. 
 Besides the sporoblasts, the cyst contains some pigment and minute granules 
 which resemble fat. At the end of a week the sporoblasts have produced a large 
 number of delicate filaments having pointed extremities and containing a small 
 amount of nuclear chromatin. These filaments are the sporozoites, measure 
 about 14 microns in length, and are arranged in a ray-like manner about a 
 central mass which may contain pigment. At this stage the capsule of the 
 oocyst is very distinct. The sporozoites are finally liberated by the rupture of the 
 oocyst and gradually make their way to the cells and tubules of the salivary 
 glands of the insect. When this has occurred the mosquito, in the act of biting, 
 will inoculate the sporozoites, which, penetrating the red blood-cells, develop 
 into merozoitcs, and the human cycle of the plasmodium begins. The entire 
 
THE ETIOLOGY OF THE MALARIAL LEVERS. 59 
 
 cycle of development in the mosquito is completed in from 10 to 14 days, so that 
 the insect may bite two or three times before it is infectious. 
 
 The following biological terms are applied to the forms of the malarial 
 plasmodia concerned in sporogony, or development within the mosquito. 
 
 1. Macrogamete, in tertian and quartan infections the female spherical 
 bodies, and in aestivo-autumnal infections the female crescent. 
 
 2. Micro gametocyte, in tertian and quartan infections the male spherical 
 bodies, and in aestivo-autumnal infections the male crescent. 
 
 3. Microgamete, the liberated flagellum of the micro gametocyte. 
 
 4. Zygote or sporont, the result of the fertilization of the macrogamete by 
 the microgamete. 
 
 5. Ookinete, the motile stage of the zygote or sporont. 
 
 6. Oocyst, the cystic stage of the ookinete. 
 
 7. SporoUasls, developed within the oocyst. 
 
 8. Sporozoites, bodies developed within the sporoblasts and liberated by the 
 rupture of the oocyst, which are introduced into man by the mosquito, and 
 which are capable of beginning the human life cycle, or schizogony, of the 
 plasmodia by infecting the red blood-corpuscles. 
 
 The cycle of development within the mosquito has been studied in all 
 species of malarial plasmodia, and infection of man by the mosquito has been 
 demonstrated with all species of the plasmodia. 
 
 Detailed Description of Sporogony of the Plasmodia of Malaria. — A 
 great amount of study has been devoted to the changes occurring in the plasmo- 
 dia of malaria during sporogony, and it may be stated that every stage of this life 
 cycle has been thoroughly investigated and described by numerous writers 
 upon the malarial fevers. The following description is derived partly from 
 personal observations and partly from the observations of others, notably those 
 of Schaudinn, Grassi, Bastianelli, and Bignami. 
 
 Previous to the formation of the microgametes, the micro gametocytes undergo 
 certain changes which are of interest. The nucleus gives off a large amount of 
 chromatin, which becomes arranged about the periphery of the organism, and 
 which enters into the formation of the thread-like microgametes. It would 
 appear that this chromatin is taken up by the microgametes just before the latter 
 emerge from the body of the micro gametocyte, for in stained specimens it is 
 but seldom that any chromatin is observed in the residual body immediately 
 after the appearance of the microgametes. 
 
 The only change observed in the mac ogamete prior to fertilization con- 
 cerns the nucleus, a portion of the substance of which is claimed by Schaudinn 
 to be eliminated. 
 
 When fertilization occurs, the microgamete penetrating the macrogamete, 
 the chromatin of the former constitutes a pronucleus which fuses with the 
 female pronucleus of the macrogamete, and a fertilization spindle is thus formed, 
 which is often very well defined in properly prepared specimens. The organism 
 resulting from the union of the micro- and macrogamete, or the zygote, does not 
 
6o THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 encyst, but develops into an elongated vermicule or ookinete. This body is 
 somewhat oval in shape, the anterior extremity bei.ig very narrow and pointed 
 while the posterior extremity is broad and rounded in appearance. The 
 nucleus is situated a little posterior to the middle of the body and is composed 
 very largely of chromatin, which takes a deep red stain with Wright's method of 
 staining. The pigment is collected in a loosely arranged mass near the posterior 
 extremity and later in the development of the ookinete may be extruded or may 
 be retained until the formation of the sporozoites, when it is liberated together 
 with a portion of residual protoplasm. The movements of the ookinete are 
 very active, consisting of contractions of the body and of a rapid progressive 
 motion, gliding in character, no satisfactory explanation of which has as yet 
 been given. Schewiakoff believes that the gliding progressive motion is due to 
 the secretion and extrusion of a gelatinous thread which pushes the organism 
 forward as it is formed, while Crawley thinks that the motion is due to wave- 
 like contractions of the protoplasm. However the motion is produced, it 
 enables the ookinete to force its way through the epithelial lining of the mos- 
 quito's stomach and reach that portion of the stomach wall immediately 
 beneath the epithelial lining where it rests and the oocyst is formed. When it 
 reaches this locality the ookinete becomes spherical in shape and secretes a 
 delicate covering membrane, continuing to grow until it projects from the 
 stomach wall toward the body cavity of the insect. 
 
 The nucleus divides and each daughter nucleus is surrounded by a portion 
 of protoplasm, forming the sporoblasts; the sporozoites are developed within 
 the sporoblasts by the repeated division of the nucleus of each sporoblast, the 
 small nuclei thus produced accumulating upon the surface of the sporoblast and 
 forming delicate protoplasmic prolongations, each consisting of a little proto- 
 plasm and a clump of chromatin, eventually forming the sporozoites. When 
 development is complete, the cyst is filled with a multitude of sporozoites together 
 with some residual protoplasm, and in many instances considerable pigment. 
 When the cyst ruptures, the sporozoites are liberated in the body cavity of the 
 insect and are carried by the blood to the salivary glands, from which they pass 
 down the proboscis to the blood of man when the mosquito bites. The 
 sporozoites are actively motile, spindle-shaped, and measure about 14 microns 
 in length. 
 
 The time consumed in sporogony has been variously estimated at from 
 10 to 14 days, the average being 10 to 12 days. It varies, in all probability, 
 with each species of plasmodium, but never exceeds 14 days. 
 
 The fertilization of the macrogamete by the micro gamete, first observed in 
 human malaria by MacCallum, has been observed by Koch, in Africa, and by 
 Ashburn and myself, in the Philippine Islands, in blood from malarial cases 
 removed for some time from the body. 
 
 To those who are interested in tracing the development of the malarial 
 plasmodia within the mosquito, the following description, arranged in periods 
 of time may prove useful. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 6l 
 
 First and Second Days After Ingestion of Malarial Blood. — The 
 fusiform and spindle-shaped ookinetes penetrate the epithelial lining of the 
 insect's stomach and reach the muscular layer, where they encyst and form the 
 oocyst. In stained specimens the ookinete presents at or near the center a deep 
 red chromatin mass, representing the nucleus, the chromatin being in the form 
 of short, very delicate threads or granules. The pigment is collected in a dense 
 clump at the posterior end or is distributed throughout the protoplasm; the 
 
 Fig: 13. — Development of Plasmodium vivax within the Mosquito. 
 1, Ookinete; 2, Oocyst; 3, 4, 5, Oocysts showing the development of sporoblasts; 6 and 7, 
 Oocyst showing development of the sporozoites, which are fully formed in 7; 8, Sporozoites 
 within a cell of the salivary gland; 9, Sporozoites; 10, Entrance of sporozoite into a red blood- 
 corpuscle; 11, Middle intestine (stomach) of mosquito, showing several oocysts in the wall of 
 the organ. 
 
 protoplasm contains numerous vacuoles and stains a light blue color. The 
 oocyst at the end of two days is about the size of a red blood-corpuscle, con- 
 tains considerable pigment distributed throughout the protoplasm, and the 
 chromatin is found in small granules or in minute irregular masses, collected 
 toward the center of the organism. 
 
 Third and Fourth Days. — During the third and fourth days the oocyst 
 increases to twice its original size, and develops a well-marked cyst wall. The 
 pigment is not increased in amount, and is collected in small masses; the proto- 
 plasm is vacuolated and the chromatin is distributed throughout it in fine 
 granules or delicate threads. 
 
62 THE ETIOLOGY OF THE MALARIAL LEVERS. 
 
 Fifth and Sixth Days. — At the end of the sixth day the cyst has in- 
 creased very greatly in size, measuring from 35 to 75 microns in diameter, and 
 projects from the wall of the stomach outward toward the body cavity of the 
 insect. The protoplasm appears granular, and large, very refractive spherical 
 bodies may be distinguished within it, the sporoblasts. The pigment has not 
 increased in amount and, owing to the great increase in size of the organism, 
 appears to have greatly diminished; in some instances the cyst, at this stage, is 
 devoid of pigment. The chromatin is collected in the sporoblasts and stains 
 red, while the protoplasm stains a very pale blue. 
 
 Seventh to Eighth Days. — Under favorable circumstances, and in some 
 species of Anophelina, the cysts have attained their full growth in eight days. 
 At this time a well-marked double outlined membrane surrounds them, which 
 is perfectly smooth in contour; the sporoblasts form common centers from which 
 radiate multitudes of delicate, elongated, spindle-shaped, or thread-like bodies, 
 the sporozoites. The sporozoites appear to originate from the outer layers of the 
 sporoblasts, each sporozoite being attached by its inner extremity to a small 
 portion of the residual protoplasm of the sporoblast. When isolated and 
 stained each sporozoite measures from 12 to 14 microns in length, and contains 
 one or more masses of chromatin imbedded in the light blue protoplasm. When 
 fully developed the sporozoites become detached from the sporoblasts and the 
 cyst is then observed to be filled with multitudes of these delicate filamentous 
 organisms. 
 
 The above description applies to the tertian aestivo-autumnal plasmodium, 
 but practically the same appearances are observed in the mosquito cycle of the 
 benign tertian and quartan plasmodia. It should be remembered that in any 
 one insect all of the plasmodia are not in the same stage of development at the 
 same time, some being more advanced than others, but the periods as given are 
 true for the vast majority of aestivo-autumnal plasmodia, in most species of 
 Anophelina. Unless the temperature be suitable, the development may be 
 delayed to 12 or even 14 days, and in Myzomyia funesta, a very common malaria 
 carrier, the cycle of development at 8o° F. always takes 12 days. 
 
 After the sporozoites are liberated into the body cavity of the insect by the 
 rupture of the cyst wall they may be observed in fluid from any portion of the 
 body of the insect, and if the cells of the salivary glands be examined numerous 
 sporozoites will be seen within them, as well as within the salivary ducts. 
 
 Mosquitoes. 
 
 A good working knowledge of the structure, habits, distribution, and 
 classification of mosquitoes is essential to the student of malaria and to the 
 practitioner of medicine, especially in tropical countries, where these insects are 
 responsible for the spread of some of the most prevalent and dreaded infections 
 of man. We have already reviewed the relation of mosquitoes belonging to 
 the Anophelinae to malaria; in addition we now know that Filaria bancrojti is 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 63 
 
 transmitted by Culex fatigans, as proven by Manson and others; Filaria phili- 
 pinensis by Culex fatigans, proven by Ashburn and myself; that dengue is 
 transmitted by Culex fatigans, as shown by Graham and Ashburn and the 
 writer; and that yellow fever is alone transmitted by Stegomyia calopus, as con- 
 clusively proven by the U. S. Army Board composed of Reed, Carroll, Lazear, 
 and Agramonte. It is not improbable that further research will show that 
 these insects are responsible for the transmission of still other diseases, but 
 enough is known of their activity in this respect to make a knowledge of them of 
 great importance to the medical practitioner. In the preparation of this sum- 
 mary of our knowledge regarding mosquitoes I am greatly indebted to the works 
 of Theobald and Giles and much of the material included is copied almost 
 verbatim from their contributions. 
 
 Of the Culicidae, the sub-family Anophelinae is the only one of interest 
 to the student of malaria, as only mosquitoes belonging to this sub-family have 
 been proven to transmit malarial fevers. 
 
 General Description of Anophelinae. — The following description 
 applies to mosquitoes in general, as regards anatomical structure, and includes 
 only those points of value in diagnosis or that are essential to a clear under- 
 standing of the relation of these insects to the transmission of malaria. 
 
 External Anatomy of the Mosquito. — The mosquito is divided into 
 three well-marked areas for purposes of description: the head, the thorax, 
 and the abdomen. 
 
 The Head. — The head varies somewhat in form in different species, and 
 presents- upon each side a prominent compound eye, larger in the males than in 
 the females. The space separating the eyes above is known as the occiput, and 
 that separating the eyes in front the vertex; the back of the head is the nape 
 or neck. The occiput and vertex are of importance in classification on account 
 of the scales and bristles with which they may be covered. A process projects 
 forward from the head which is called the clypeus, and which varies in structure 
 in different species. The mouth, or proboscis, is prolonged forward into a 
 hollow tube, fitted both for piercing and sucking, and is composed of the labrum, 
 epipharynx, or upper lip ; two sharp lancets or mandibles; the hypopharynx; and 
 the labium or lower lip, which terminates in two jointed organs known as the 
 lab ell a. 
 
 The hypopharynx and the labrum form the sucking tube through which 
 the blood is drawn when the insect feeds; the hypopharynx is pierced by the 
 salivary duct through which the saliva flows into the sucking tube and thence 
 into the wound. The palpi arise close to the proboscis, one on either side, and 
 vary in size, shape, and the number of segments composing them. In the 
 Anophelinae they are as long as the proboscis in the female, thus serving to 
 distinguish them from the mosquitoes of the sub-family Culex, in which the 
 palpi in the female are very short. The antennae also arise from the head, 
 beside the palpi, and are long jointed structures surrounded by hairs in the 
 female, but in the male terminate in minute plumes. 
 
64 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 The Thorax. — The thorax is situated between the head and the abdomen, 
 and is composed of the mesotkorax, the scutellum, the prothoracic lobes, and the 
 posterior portion or metatkorax. The greater portion of the thorax is comprised 
 in the mesothorax, having posteriorly a small area called the scutellum, which 
 n the Anopliclinac has a rounded border, while in the other families it is tri- 
 lobed. The prothoracic lobes are placed laterally, while the metathorax is 
 situated most posteriorly, is rounded in contour, and placed beneath the 
 scutellum. The thorax is of importance in classification because of the 
 character of the scales which cover it. 
 
 The Wings. — The wings arise from the upper portion of the thorax, 
 are two in number, and their venation is of great importance in classification. 
 Fig. 15 gives the venation of the wing common to all mosquitoes, and the fork 
 cells, A and B, are of the greatest importance in distinguishing sub-families 
 and genera. 
 
 Fig. 14. — Comparison of head of female Anopheles and Culex. 
 1, Head of Anopheles, showing the palpi closed along the proboscis; 2, Head of Anopheles, 
 showing the equal length of the palpi and the proboscis; 3, Head of Culex, showing the short 
 palpi. 
 
 The Legs. — The legs arise from the pro-, meso-, and metathorax, and 
 are six in number. They are of but little value in classification and will not, 
 therefore, be further described. 
 
 The Abdomen. — The abdomen is composed of eight well-defined segments. 
 In the male the last segment terminates in the genital organs, and in the female 
 in two lobes. Scales clothe this portion of the insect in most species, and their 
 shape and arrangement are of great value in differentiation and identification 
 of various species. 
 
 Internal Anatomy. — To the student of malaria the chief points of interest 
 in the internal anatomy of the mosquito are situated in the alimentary canal, 
 which may be said to commence at the distal end of the proboscis, terminating 
 at the anus. The salivary glands, really appendages of the alimentary canal, 
 have also to be considered in this relation. 
 
 The Alimentary Canal. — Commencing with the sucking tube of the 
 
THE ETIOLOGY OF THE MALARIAL LEVERS. 
 
 65 
 
 proboscis, which has opening into it the salivary duct, and proceeding backward, 
 the following structures are successively reached: 
 
 1. The true mouth, situated just behind the clypeus. 
 
 2. The buccal cavity. 
 
 3. The pharynx, or pumping organ, by winch the insect is enabled to 
 suck blood or other fluids. 
 
 4. The oesophagus, extending from the pharynx to the oesophageal 
 valve; three blind tubules or. sacs diverge from the oesophagus and serve as 
 receptacles for food. 
 
 5. The oesophageal valve, which acts as a valve between the oesophagus 
 and the mid-gut or middle intestine. 
 
 6. The mid-gut, a straight tube which terminates in a dilatation. 
 
 7. The "stomach." The portion of gut between the "stomach," which is 
 situated at the level of the 6th abdominal segment and the anus, is known 
 as the hind gut. 
 
 Fig. 15. — -Venation of Wing in Anophelinae. 
 1 to 6, First to six longitudinal veins; A, first sub-marginal cell (first fork-cell); B, second 
 posterior cell (second fork-cell.); C, sub-costal cell; D, marginal cell; E, second sub-marginal 
 cell; F, first posterior cell; G, third posterior cell; H, anal cell; I, auxiliary cell: The fork-cell; 
 A and B, are of especial importance in classification. (Modified from Theobald.) 
 
 The Malpighian tubes, arising from the hind-gut, as well as the ovaries 
 in the female, and their appendages, and the genital organs of the male will not 
 be described, as they are of little interest in classification or in the differen- 
 tiation of species. 
 
 The Salivary Glands. — The salivary glands are of great interest because 
 through them are transmitted the sporozoites causing malarial infection in man. 
 As has been stated, the groove in the sucking tube is connected with the salivary 
 glands by the salivary duct, at the base of the hypopharynx is placed a pumping 
 organ controlled by voluntary muscles, and it is by means of this organ that 
 the saliva is forced into the proboscis and thence into the wound. The common 
 salivary duct passes backward underneath the buccal valve and divides into 
 two tubes which pass backward through the neck into the thorax where they 
 connect the two salivary glands. Each of the salivary glands consists of three 
 5 
 
66 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 blind caeca, lined with large, granular cells, and possessing a central, well- 
 defined canal, opening into the thoracic branches of the common duct, previ- 
 ously mentioned. It is in these cells that the malarial sporozoites are found at 
 the termination of the mosquito cycle of development of the plasmodia. 
 
 Life History of the Anophelinae. — The Anophelinae, in common with 
 all mosquitoes, pass through a larval and pupal stage before development into 
 the perfect insect and these stages in their life history are always passed in water 
 so far as we at present know. I have several times observed Anopheles larvae 
 in semi-fluid mud, and it is probable that development can occur in such an 
 environment, provided enough moisture is retained by the soil. 
 
 The Ova. — The eggs of the Anophclinae are deposited upon the surface 
 of water, and are arranged separately, and not in boat-shaped masses as in 
 Cidex. The Anopheles ova are easily recognized by their lateral floats, some 
 of which are very beautiful. The ova are oval in shape, and hatch in from 
 one day, as in Myzomyia ludlowii, to several days, as in other species. 
 
 Fig. 16. — Internal Anatomy of the Anophelinae. 
 A, Pharynx; B, oesophagus; C, dorsal reservoirs; D, oesophageal valve; and caeca; E, 
 beginning of mid-gut; F, mid-gut; G, Malpighian tube; H, stomach; I, mid-gut ends; J, 
 ileum; K, colon; L, rectum; M, anus; N, ventral reservoir; O, salivary glands; P, salivary 
 duct. (After Nuttall and Shipley.) 
 
 The Larvae. — The larvae of all mosquitoes are either siphonate or asi- 
 phonate. The asiphonate larvas always belongs to the Anophelinae, and live 
 only in water, either fresh or salt. It may be said with certainty that any of the 
 larvae of the Anophelinae will develop in any collection of water, although 
 certai-i species breed by preference in certain localities. Theobald states that 
 "practically all kinds of collections of water are acceptable to the larvae; some 
 prefer rain-water barrels, cisterns, and the water in tins, calabashes, and 
 jam-pots; others ponds, slow-running streams, and along the banks of large 
 rivers; others live in the water collected in bromelias, and in the water that 
 collects in hollow bamboos, gaining their e ltrance through exit holes left by 
 boring insects. The domestic forms which are best known usually choose 
 barrels and cisterns. The importance of the sylvan species is, however, just 
 as great, as it is by means of these that fever is contracted in the jungle as well 
 as in the habitations of man." 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 6 7 
 
 At Camp Stotsenburg, the most malarial post in the Philippine Islands, 
 Anophles larvae were repeatedly found in hollow bamboo posts, as well as in 
 small stagnant collections of water around the native huts, thus proving con- 
 clusively that the old idea that Anopheles breed only in clear, running water is 
 incorrect. It is noteworthy, however, that Anopheles larvae were only found in 
 bamboo posts which allowed the ingress of sunlight by reason of being open at 
 the top, while in posts in which the opening was so placed as to exclude sunlight 
 only Culex larvae were found. 
 
 The larvae, like the adult insect, is divided into three main portions, the 
 head, the thorax, and the abdomen. While in Culex the head is larger than the 
 thorax and projects laterally, in the Anophelinae the head is smaller and the 
 thorax projects laterally beyond the boundary of the head. The thorax pre- 
 sents upon each side bunches of bristles and is unsegmented. The abdomen 
 is composed of nine segments. While in Culex Stegomyia, etc., the eighth 
 
 Fig. 17. — Ova of Mosquitoes. 
 1 and 2, Ova of M. culicifacies (Anopheles); 3 and 4, Ova of N. maculipalpis (Anopheles), 
 (Note the lateral floats on the Anopheles ova); 5, Ova of Culex; 6, Ova of Stegomyia. 
 
 abdominal segment presents upon its dorsal surface a well-marked respiratory 
 siphon, in the Anophelinae this is represented by two slightly raised openings, 
 which are used for respiration, but which do not in the least resemble the 
 siphon of Culex or of other species. The arrangement of the respiratory apara- 
 tus of the Anophelinae forces the members of this sub-family to lie horizontal 
 to the surface of the water during respiration, instead of at an angle, as in 
 Culex, and this serves as an easy method of differentiating them. An exception 
 to this rule has been noted in a few Culicinae. The color of the larvae is 
 usually gray, brown, or greenish. Anopheles larvae are not very resistant and 
 are usually short lived although a few species have been known to hibernate 
 through a long winter. The length of the larval stage varies in the different 
 species. In Myzomyia ludlowii the larval stage occupies from 9 to 10 days. 
 
68 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 The Pupae. — The pupal stage lasts from a few hours to several days, 
 depending upon the temperature. During this time the pupae are very active, 
 constantly coming to the surface of the water to breathe, but as they are not 
 easily differentiated from the pupae of Culex, a detailed description is not con- 
 sidered necessary. Fig. 19 gives a good general idea of the structure of the 
 pupa. 
 
 The Imagine. — When the time has arrived for the emergence of the 
 imagine or adult insect, the pupa rises to the surface of the water, the skin over 
 
 Fig. 18. — -Larva of Anopheles and Culex. 
 1, Larva of Anophelinse. Note horizontal position in reation to surface of the water, 
 and the absence of syphon (A) . Larva of Culex. Note angular position in relation to surface 
 of the water, and presence of the syphon, at A. (Fig. 1, after Howard; 2, after Theobald.) 
 
 the thorax breaks open, and the perfect insect gradually emerges from the pupal 
 case, which serves as a resting place for it until its wings are dried and it is able 
 to take flight. 
 
 Habits of the Anophelinae. Feeding. — As a rule, all Anophelinae are 
 night feeders, but it is not at all unusual to observe Anopheles, of various species, 
 feeding in the late afternoon, and I have often seen Myzomyia funesta biting in 
 the early morning and even at noon in the tropics. During the daytime most 
 Anopheles hide in the woods or beneath the leaves of bushes and small trees or 
 in dark corners of houses or native huts in the tropics. I have observed hun- 
 dreds of Myzomyia ludlowii and Myzorhynchus barbirostris around the base- 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 69 
 
 board of toilet sinks and upon clothing in dark closets during the daytime in 
 the Philippines. It is undoubtedly true that the vast majority of mosquitoes 
 never attack man, feeding upon fruit and vegetable juices, especially upon the 
 juices of fruits, as the banana, and. upon flowers, only attacking man as the op- 
 portunity offers and when convenient. The males are not blood suckers, but 
 subsist entirely upon the juices of fruits and flowers. As the females alone 
 feed upon blood it was for a long time supposed that this was essential to the 
 laying of eggs, but later observations have shown that this is not so, and Theo- 
 bald says: "it may therefore safely be said that mosquitoes breed mainly with- 
 out the stimulus of human blood." Many species have been observed sucking 
 the blood of invertebrates, such as insects. 
 
 Flying DisTANCE.-^Mosquitoes do not cover very great distances in 
 flying. Formerly it was supposed that the limit of flying distance for mos- 
 quitoes was a half-mile, but it is now known that this distance is exceeded very 
 commonly, and Theobald gives the average flying distance as one mile. I am 
 sure, from personal observation in the Philippine Islands, that Anopheles 
 mosquitoes often fly from two to two and a half miles in search of food, for 
 at Camp Stotsenburg no breeding places of Anopheles existed in the post 
 proper, so far as we could determine, and the nearest breeding places discovered 
 were at least two miles away; yet, at times, Anopheles were very numerous in 
 the post and malaria was very prevalent. 
 
 Resting Position. — The position assumed by the insect while resting has 
 always been used as a differential point in the classification of mosquitoes. 
 Regarding this it may be said that all of the Anophelinae (with the exception, 
 according to Giles, of Myzomyia culicifacies) when at rest form a complete 
 angle to the resting surface, the proboscis, head, thorax, and abdomen, being in 
 a straight line, while in Culex the proboscis, head and thorax, form an angle 
 with the abdomen, thus giving the insect a hunchback appearance (see Fig. 20). 
 
 Hibernation. — In the tropics mosquitoes breed throughout the entire 
 year, but are much less numerous in the dry than in the rainy season. In 
 temperate and cold regions they may pass through the cold season as fully 
 developed adults, as larvae, or even in the ova. According to Theobald, the 
 fertilized females of A . maculipennis hibernate in the adult stage in cellars, out- 
 houses, stables, etc., while A. bifurcatus and A. nigripes exist throughout the 
 winter in the larval stage even under thick ice. If a warm spell occurs during 
 a winter some of the hibernating mosquitoes emerge from their hiding places 
 and bite, thus causing outbreaks of malaria during the winter season. It is 
 also true that the ova of some species of Anopheles will withstand a considerable 
 amount of drying, and I have not infrequently observed the development of 
 larvae in dry mud which has been placed in water and protected from outside 
 contamination. In the tropics I believe that many species of Anopheles would 
 disappear if it were not for the resisting powers of the ova to drying and sun- 
 light, and that it is this property which enables these insects to exist through the 
 dry season in areas in which water is almost absent. Just as in the temperate 
 
70 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 and cold regions these insects are able to resist freezing, so in the tropics nature 
 has provided them with ample resisting powers against drying and the effects of 
 the tropical sun. 
 
 Classification. — The classification adopted in this work is that of 
 Theobald, a classification which has been accepted by nearly every scientific 
 worker upon mosquitoes, such as Blanchard, Daniels, Ludlow, Graham, Lutz, 
 and Goeldi. This classification is based largely upon the character of the 
 scales which clothe the head, thorax, wings, and abdomen of the insects. 
 Fig. 21 illustrates the shape and variation in these scales as given by Theobald 
 and also gives the nomenclature applied to them. 
 
 The general characteristics of the sub-family Anophelinae, as given by 
 Theobald, are as follows: Head, numerous upright forked scales. Thorax 
 scaly or hairy, metanotum always nude, scutellum always simple, with scales 
 or hairs. Abdomen hairy or scaly. Palpi in the female as long as the probos- 
 cis. Wings, long fork cells, the first submarginal longer than the second 
 posterior cell. Up to the present time Theobald has described 18 genera of 
 Anophelinae, but, while it is probable that each genus contains species which 
 are able to transmit malaria, only a few of the genera are at present of interest to 
 us in this relation. Of the 18 genera, eight are represented by but a single 
 species, and none of these have been proven to transmit malaria. These 
 genera are Feltinella; Bironella; Aldrichia; Chagasia; Chrystya; Kerteszia; 
 Myzorhynchella and LopJwscelomyia. 
 
 For the differentiation of the other genera Theobald gives the following 
 table: 
 
 A. Fork cells long. 
 
 a. Thorax and abdomen with hair-like curved scales. 
 
 a. Head with upright forked scales only. 
 
 i. Wing scales large and lanceolate, wing unspotted, or if spotted 
 the spots due to collections of similarly colored scales. Genus, 
 Anopheles. Meig. 
 
 2. Wing scales small, narrowly lanceolate, the wings with spotting 
 of varied color. Genus, Myzomyia. Bl. 
 
 3. Wings with patches of large inflated scales. Genus, Cyclo- 
 
 leppteron. Theo. 
 /?. Median area of head with some flat scales. Genus, Stethomyia. 
 Theo. 
 
 b. Thorax with narrow curved scales; abdomen hairy; wing scales 
 
 small and lanceolate. Genus, Pyretophorus. Bl. 
 
 c. Thorax with hair-like curved scales and some narrow ones in front ; 
 
 abdomen with apical lateral scale tufts and scaly venter; no ven- 
 tral tuft; wing scales lanceolate. Genus, Arribalzagia. Theo. 
 
 d. Thorax with hair-like curved scales; no lateral abdominal tufts; a 
 
 distinct apical ventral tuft and dense scales palpi in the female; 
 wings with dense, large, lanceolate scales. Genus, Myzorhynchus. 
 Bl. 
 
 e. Thorax and abdomen with scales; thoracic scales narrow-curved 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 7 1 
 
 or spindle-shaped; abdominal scales as lateral tufts and dorsal 
 patches of flat scales. Genus, Nyssorhynchtts. Bl. 
 
 f. Abdomen nearly completely scaled with long irregular scales and 
 
 with lateral scale tufts. Genus, Celha. Theo. 
 
 g. No lateral tufts and smaller wing scales. Genus, Neocellia: Theo. 
 
 The following brief descriptions of the principal genera of interest to 
 students of malaria are largely those given by Theobald, to whom I am indebted 
 for much that appears in this chapter upon mosquitoes. 
 
 Genus, Anopheles. Meigen, 1818. Occurs mostly in temperate regions, 
 although certain species occur in tropical countries, especially in the hill regions. 
 This genus is found in Europe, the United States, North Africa, hill districts 
 of India, in Australia, West Indies, West Africa, all of North America. Fifteen 
 species are included in this genus, the type species being A. maculipennis, a 
 common species in Europe and North America. Some of the species have been 
 
 Fig. 19. — Pupa of Anophelinae. (After Nuttall and Shipley.) 
 
 proven to transmit malaria, as A. maculipennis and A. algeriensis. The 
 larvae of A. maculipennis occur in water barrels and pools, others in small natural 
 collections. Adult A. maculipennis hibernate. Theobald believes that all 
 species may act as the hosts of the malarial plasmodia. 
 
 Genus, Myzomyia. Blanchard, 1902. This genus occurs in Europe, 
 Africa, Asia, the Philippine Islands, but does not occur in North or South America, 
 the West Indies, or Australia. The type species is M. funesta Giles, one of the 
 most common of malarial carriers in tropical regions in Asia and. Africa. Five 
 of this genus have been proven to transmit malaria, namely, M. listonii Liston: 
 M. funesta Giles; M. turkhudii Liston; M: culicifacies Giles, and M. nili Theobald. 
 M. culicifacies is of especial interest, as its resting position is like that of non- 
 malarial mosquitoes. M. rossii Giles has been proven incapable of transmitting 
 malaria. These mosquitoes vary greatly in their breeding habits, some breeding 
 around human habitations, while others are sylvan species. Recently M. lud- 
 lowii Theobald, a common species in the Philippine Islands, has been proven a 
 host for the aestivo-autumnal plasmodia. About twenty-one species occur in 
 this genus. 
 
 Genus, Stethomyia. Theobald, 1902. Contains but two species, 5. nimba 
 Theobald and 5. fragilis Theobald. The former is probably the transmitter of 
 jungle malaria in South America. The latter occurs in the Federated Malay 
 States. 
 
72 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 Genus, Pyretcphorus. Blanchard, 1902. Occurs only in Asia, Africa, and 
 Australia. They are all large mosquitoes and have beautifully spotted wings. 
 The larvae live in puddles, streams, pools, rice fields, and in flowing water. 
 Three species have been proven to transmit malaria: P. costalis Loew; P. 
 chaudoyei Theobald, and P. ardensis Theobald. Over twenty-six species have 
 been described. 
 
 Genus, Arribalzagia. Theobald, 1902. Only one species belongs to this 
 genus, A. maculipes Theobald. This species occurs in the Brazils and is prob- 
 ably a transmitter of malaria. 
 
 Genus, Myzorhynchus. Blanchard, 1902. This genus is distinguished 
 by the densely scaled palpi, hairy thorax, and densely scaled proboscis. They 
 are all large dark insects, breeding in swamps, and beneath tropical vegetation. 
 They occur in South Europe, Asia, Africa, and Australia. Four species have been 
 found in the Philippine Islands. 
 
 Genus, Nyssorchynchus. Blanchard, 1902. About twenty species occur 
 in this genus. Mosquitoes of this genus are generally house breeders or develop 
 in pools or puddles in close proximity to human habitations. They occur in India 
 Africa, Australia, and in the Philippine Islands. N. stephensii has been proven 
 to act as a host for the malarial plasmodia. 
 
 Genus, Cellia. Theobald, 1903. Seven species occur in this genus, the 
 most marked characteristics being the scaled abdomen with dense lateral tufts, 
 and the heavily scaled wings. The larvae live in any open water and some 
 species are commonly found in human habitations. The following species have 
 been found to harbor the malarial plasmodia. C. argyrotarsis, C. albimanus, and 
 C. pharoensis. 
 
 For a detailed description of the species mentioned in the foregoing 
 summary the reader is referred to Theobald's monographs upon the Culicidae. 
 
 Geographical Distribution of Mosquitoes. — Mosquitoes occur where- 
 ever malaria does, but it does not follow that malaria is always present even 
 though mosquitoes are abundant. In order that the malarial fevers may 
 spread in any locality, the right species of mosquitoes must be present, together 
 with individuals infected with some species of the plasmodia. To the student 
 of malaria, the geographical distribution of mosquitoes resolves itself into the 
 determination of the distribution of the Anophelinae only, and, as has been said, 
 the distribution of malaria and that of mosquitoes belonging to this sub-family 
 exactly coincide, and the amount of malaria in any country, or in any given 
 locality is an index of the number of Anopheles present. This fact is of impor- 
 tance from a prophylactic standpoint, as the determination of the species of 
 mosquito present in any locality enables us to avoid those inhabited by 
 Anopheles or to take the proper precautions against infection. In the selection 
 of camp sites of a more or less permanent character or of the sites for permanent 
 military posts, a preliminary "mosquito survey" will often prove of inestimable 
 value, both as regards the future health of the camp or post and the cost of 
 maintaining it. The same is true of the selection of building sites of any 
 character where mosquitoes and malaria are apt to be present. I have already 
 spoken of the geographical distribution of the malarial fevers, and it is not, there- 
 fore, necessary to give in detail the countries in which the malarial mosquitoes 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 73 
 
 occur, as to do so would be but a repetition of what has already been said regard- 
 ing the distribution of malaria. It may be of value, however, to mention those 
 species of the Anophelinae which have been proven by experiment to transmit 
 the malarial fevers, and to mention the countries in which such species occur, 
 with special reference to the West Indies, the United States, and the Philippine 
 Islands. 
 
 The following members of the sub-family Anophelinae have been found 
 experimentally to transmit the malarial fevers or to act as hosts of the malarial 
 plasmodia: 
 
 Genus, Anopheles. A. maculipennis, Meig; A. bifurcatus, Linn; A. algeri- 
 ensis, Theo. ; A. jasoensis, Tsuzuki; A. formosaensis, Donne; A. cohaesus, 
 Donne; A. quadrimaculatus , Say; A. albipes, Giles; A. vagus; A.vincenti; A. 
 martini; A. pursati. 12 species. 
 
 Genus, Myzomyia. M. listoni, Liston; M. fnnesta, Giles; M. turkhudii, 
 Liston; M. culicifacies, Giles; M. nili, Theo. ; M. his paniola, Theo.; M.lud- 
 lowii, Theo. ; M. lutzii, Theo. 8 species. 
 
 Genus, Stethomyia. S. nimba, Theo. i specie. 
 
 Genus, Pyretophorus. P. costalis, Loew; P. chaudoyei, Theo.; P. ardensis, 
 Theo.; P. superpictus, Grassi; P. jeyporensis, Theo. 5 species. 
 
 Genus, Arribalzagia. A. maculipes, Theo. i specie. 
 
 Genus, Myzorhynchus. M. sinensis, Wied; M. barbirostris, Van der Wulp; 
 M. pseudopicius, Grassi; M. pahidis; Theo.; M. mauritianus, Grandpre and 
 Charmoy; M. coustanii, Lav. 6 species. 
 
 Genus, Nyssorhynchus. N. fuliginosus, Giles; N. stephensii, Liston; N. 
 maculipalpis; Giles, N. theobaldii, Giles. 4 species. 
 
 Genus, Cellia. C. argyrotarsis, Robineau-Desvoidy; C. pharoensis, Theo.; 
 C. albimanus, Wied. 3 species. 
 
 From the above summary it will be seen that no less than forty species 
 of the Anophelinae have been proven experimentally to be hosts of the malarial 
 plasmodia. The geographical distribution of these species is as follows: 
 
 West Indies. — Cellia argyrotarsis. Cellia albimanus. 
 
 Canada. — Anopheles maculipennis. 
 
 United States. — Anopheles maculipennis. Anopheles quadrimaculaius . 
 Cellia argyrotarsis. 
 
 Central and South America. — Anopheles albipes. Arribalzagia maculipes. 
 Pyretophorus lutzii. Cellia argyrotarsis. Myzomyia lutzii. C. albimanus. 
 
 Europe. — Anopheles maculipennis. Anopheles bifurcatus. Myzorhynchits 
 pseudopicius. Pyretophorus superpictus. Myzomyia hispaniola. 
 
 Asia. — India. — Myzomyia culicifacies. Myzomyia hstonii. Myzomyia turk- 
 hudii. Pyretophorus jeyporensis. Myzorhynchus barbirostris. Myzorhynchus 
 sinensis. Nyssorhynchus theobaldi. Nyssorhynchus stephensii. Nyssorhynchus 
 fuliginosus. Nyssorhynchus maculipalpis. 
 
 Japan. — Anopheles jesoensis. Anopheles formosaensis. Anopheles cohaesus. 
 
 Africa. — Myzomyia funesta. Myzomyia nili. Pyretophorus costalis. Pyre- 
 tophorus ardensis. Pyretophortis chaudoyei. Myzorhynchus barbirostris. Myzor- 
 hynchus mauritianus. Myzorhynchus paludis. Cellia pharoensis. 
 
74 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 Madagascar. — Myzorhynchus coustanii. 
 
 Mauritius. — Myzorhynchus mauritianus. 
 
 The Philippine Islands. — -The following malarial mosquitoes have been 
 found in the Philippine Islands by Ludlow, Whitmore, Banks, and the writer: 
 Myzomyia funesta. Myzomyia ludlowii. Myzorhynchus barbirostris. Myzor- 
 hynchus sinensis. Nyssorhynchus fuliginosus. 
 
 Further observation will undoubtedly demonstrate that other species occur 
 in these islands. 
 
 Number of Infected Mosquitoes in Malarial Regions. — The number 
 of mosquitoes showing infection in malarial regions will depend upon the 
 number of infected individuals present, the season of the year, certain atmos- 
 pheric conditions, and the amount of care exercised by the inhabitants in protect- 
 ing themselves from these insects. Thus the figures given by various observers 
 differ very greatly in this respect, as would be expected. 
 
 Fig. 20. — Comparison of Resting Position of Anopheles and Culex. 
 1, Resting position of Culex, on vertical surface; 2, resting position of Anopheles on vertical 
 surface. (The resting position upon a horizontal surface may be observed by turning the 
 page so that the vertical line becomes horizontal.) 
 
 Celli, in Italy, found that of the Anopheles examined by him, 2.5 per cent, 
 were infected with the malarial plasmodia; A. Plehn, in Kamerun, examined 
 860 Anopheles and found 2.2 per cent, infected; La Monaco examined 1,420 
 Anopheles and found 1 in 164 infected during August, and 3 in 103 infected 
 in September; Sargent, in Algiers, found 1.6 per cent, of the Anopheles which 
 he examined infected, and Zieman, in Africa, found that of the mosquitoes col- 
 lected in the huts of the natives no less than 16.6 per cent, showed infection 
 with malarial plasmodia. 
 
 At Camp Stotsenburg, in the Philippine Islands, during the height of the 
 malarial season, as high as 35 per cent, of the Anopheles examined have shown 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 75 
 
 infection, but at other times the percentage has been very small, sometimes 
 less than i per cent. 
 
 Daniels found that 47.5 per cent, of the mosquitoes which he allowed to 
 bite malarial patients became infected. 
 
 It is now a well-established fact that certain of the Anophelinae are incapable 
 of acting as hosts to the malarial plasmodia, and the following observations of 
 Stephens and Christophers and of Hirshberg are of interest in this connection. 
 
 Stephens and Christophers, at Mian Mir, India, dissected 259 Myzomyia 
 culicifacies, and found 12 or 4.6 per cent, infected with malarial sporozoites; 
 of 496 Myzomyia rossii dissected by them not one was found infected. At 
 
 Fig. 21. — Character of Scales upon Mosquitoes. 
 1, 2, 3, and 4, Upright forked scales; 5, spatulate scale; 6, spindle scale; 7 and 8, broad and 
 narrow curved scales; 9, linear scale; 10, lanceolate scale; 11 and 12, hair scales: 13, broad 
 asymetrical scale. 14; ordinary butterfly scale. 
 
 Enur, in India, the same observers dissected 69 Myzomyia culicifacies and found 
 6 or 8.6 per cent, infected with sporozoites; of 364 Myzomyia rossii dissected at 
 the same time not one was found infected. 
 
 Hirshberg, in his experiments, found that out of 58 Anopheles puncti- 
 pennis, none developed malarial sporozoites, while of 48 Anopheles maculi- 
 pennis, eight were positive for sporozoites. 
 
 Not only are some of the Anophelinae unable to act as hosts for the plasmodia, 
 but some species can only act as host for a certain species of plasmodia; this 
 fact has been proven again and again and serves to explain why certain types 
 of malaria are limited to certain localities. In Japan it has been found that 
 Anopheles formosaensis and Anopheles cohaesus can only transmit the aestivo- 
 autumnal infections, while Anopheles jesoensis is able to act as a host for both 
 
76 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 the benign tertian and the aestivo-autumnal infections. On the other hand, 
 Anopheles maculipennis, the most common mosquito occurring in temperate 
 regions, is able to transmit tertian, quartan, and aestivo-autumnal malaria. 
 
 While at the present time the malarial mosquitoes are more or less localized 
 in their distribution and certain types of malaria are thus confined to limited 
 regions, the increase of transportation facilities and of commerce will inevitably 
 lead to a more general distribution of these insects, and thus regions free from 
 
 :—0 
 
 Fig. 22. — Showing characteristics of Scales on various portions of body of different species 
 of the Anophelinae, which have been proven to transmit malaria. 
 
 i, Anopheles; 2, Myzomyia; 3, Pyretophorus; 4, Cellia; 5, Myzorhynchus; 6, Nyssorhynchus. 
 (Arranged from Theobald.) 
 
 malarial infection will become infected, and the more severe types of malaria, 
 the aestivo-autumnal, will invade territory hitherto infected with the benign 
 tertian type. 
 
 Number of Species. — Nearly 1000 species of mosquitoes have been 
 described, of which the Anophelinae number some 150 species. Most of these 
 insects are wood dwellers and do not come in contact with man, but it is probably 
 true that most, if not at all, of the Anophelinae which are capable of transmitting 
 the malarial fevers are semi-domesticated species, and prefer to live within 
 reach of human habitations. 
 
THE ETIOLOGY OF THE MALARIAL LEVERS. 77 
 
 Literature upon the Development of the Malarial Plasmodia within the Mosquito 
 
 and upon Mosquitoes. 
 
 Development of the Malarial Plasmodia within the Mosquito. 
 896. Manson. The Life History of the Malaria Germ Outside the Human 
 Body. The Brit. Med. Jour., Mar. 14, 21, 28, p. 641, 512, 774. 
 
 896. Ross, Ronald. Observations on Malarial Parasites. Brit. Med. Jour., 
 Feb. 1. 
 
 897. Idem. On Some Peculiar Pigmented Cells Found in Two Mosquitoes 
 Fed on Malarial Blood. Brit. Med. Jour., vol. ii, p. 1786. 
 
 897. MacCallum. On the Flagellated Form of the Malarial Parasite. The 
 Lancet, No. 13, p. 1240. 
 
 898. Ross, Ronald. Pigmented Cells in Mosquitoes. Brit. Med. Jour., 
 vol. i. 
 
 898. Idem. Report on the Cultivation of Proteosoma Labbe in Gray Mosqui- 
 toes. Calcutta, May 21, 1898. 
 
 898. Idem. The Role of the Mosquito in the Evolution of the Malarial Parasite. 
 The Lancet, vol. ii, p. 488. 
 
 898. MacCallum. On the Haematozoan Infections of Birds. Jour. Exper. 
 Med., Jan. 
 
 899. Ross, Ronald. Life History of the Parasites of Malaria. Nature, vol. 
 lx, No. 1553, p. 322. 
 
 899. Idem. Infection of Birds with Proteosome by the Bites of Mosquitoes. 
 
 The Indian Med. Gaz., vol. xxxiv, Jan. 1. 
 899. Thayer, W. S. Recent. Investigations upon Malaria. Med. News, vol. 
 
 lxxiv, No. 20, p. 617. 
 899. Bastianelli and Bignami. Sullo sviluppo dei parasiti della terzana 
 
 nell' Anopheles claviger. Bull. d. R. Accad. med. di Roma, Anno xxv, 
 
 Fasc. 3, Apr. 19. 
 899. Grassi, Bignami and Bastianelli. Ulterioti richerche sul ciclo dei 
 
 parassiti malarici umani nel corpo del zanzarone. R. Accad. dei Lincei, 
 
 vol. viii, 8 Gennaio. 
 899. Koch, R. Ueber die Entwicklung der Malaria parasiten. Zeitschr. f. 
 
 Hyg., Bd. xxxii. 
 899. Grassi, Bignami and Bastianelli. Resoconto degli studi fatti sulla mala- 
 ria durante il mese di gennaio. R. Accad. dei Lincei, vol. viii, Feb. 5. 
 899. Nuttall. Die Mosquito-Malaria-Theorie. Centralbl. f. Bakt., etc. 
 
 Feb. 14, 21, 28, and Mar. 18. 
 899. Daniels. On the Transmission of Proteosoma to Birds by the Mosquito. 
 
 Proceedings Royal Soc, vol. lxiv, p. 443. 
 
 899. Grassi. Ancora sulla malaria. R. Accad. dei Lincei, vol. viii, Fasc. 
 6, Sept. 17. 
 
 900. Ross, Ronald. Malaria and Mosquitoes. Nature, vol. lxi, No. 1587, 
 p. 522. 
 
 900. Zeiman. Zweiter Bericht uber die Malaria iind Moskitos. Deutsch. 
 med. Woch., Nos. 47 and 48. 
 
 900. Manson. Experimental Proof of the Malaria-Mosquito Theor3 T . The 
 Lancet, p. 923. 
 
 901. Ross, Ronald. Summary of Researches on the Propagation of Malaria, 
 etc. Brit. Med. Jour., vol. i, p. 193. 
 
 901. Woldert. Cultivation of the Aestivo-autumnal Parasite in the Mos- 
 quito. Jour. Am. Med. Assoc, No. 9. 
 901. Chatterjee. Parasites in Anopheles. Indian. Med. Gaz., p. 371. 
 
78 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 1902. Schuffner. Die Beziehungen der Malariaparasiten zu Mensch und 
 
 Mucke, etc. Zeitschr. f. Hyg., etc., vol. lxi, p. 89. 
 1902. Schaudinn. Stu. ii. Krankheit. Protozoen. Arb. a. d. Kaiserl. Ges., 
 
 Bd. xix, 2. 
 
 1902. Favre. Die Beziehung von Malaria zu Anopheles. Wratsch, No. 37. 
 1904. Schaudinn. Generations- und Wirtswechsel bei Trypanosomen und 
 
 Spi'rochaeten Arb. a. d. Kaiserl. Gesundheitsamt. Bd. xx, Heft 3. 
 1904. Jancso. ' Zur Frage der Infektion der Anopheles claviger., etc' Cen- 
 
 tralb. f. Bakt., Bd. xxxvi, p. 624. 
 1904. Galli- Valeric Sur la presence doocystes chez Anopheles. Lutzi, 
 
 Theobald. Centralbl. f. Bakt., Bd. xxxv, No. 1. 
 1904. Plehn, A. Ergebnisse der neuesten Forschungen auf dem gebiet der 
 
 Malaria epidemiologic. Archiv. f. Hyg., Bd. xlix, p. 1. 
 
 1906. Zieman. Malaria. Mense's " Handbuch der Tropenkrankheiten," Bd. 
 iii, Halb Bd. i. 
 
 Literature upon Mosquitoes. 
 
 1 90 1 to 1906. Theobald, F. V. A Monograph of the Culicidae of the World. 
 vol. i and ii, 1901 ; vol. iii, 1903 ; vol. iv, 1906. British Museum, London. 
 
 1903. Sergent. Moustiques et maladies infectieuses. Encycl. Scientif. des 
 Aide-Memoires. Paris. 
 
 1904. Giles. Hand-book of the Gnats or Mosquitoes, 2d Ed., New York, Wm. 
 Wood & Co. 
 
 1904. Idem. A Revision of the Anophelinae. (Published in above work.) 
 
 1904. Felt. Mosquitoes or Culicidae of New York, Bull. 323, New York State 
 Mus. 
 
 1904. Smith, J.. B. Mosquitoes. Report New Jersey State Agri. Station. 
 
 1905. Blanchard. Les Moustiques. Paris. 
 
 1907. Howard. Mosquitoes. Osier's "Modern Medicine," vol. i, p. 370. Phil. 
 1907. Theobald. Mosquitoes or Culicidae. Allbutt and Rolleston's " System 
 
 of Medicine," vol. ii, part ii, p. 122, London. 
 
CHAPTER IV. 
 
 Methods of Transmission of the Malarial Plasmodia : By the Atmosphere ; By 
 Water; By Inoculation of Malarial Blood; By Inoculation by the Mosquito; Culti- 
 vation of Malarial Plasmodia ; Immunity. 
 
 Up to within very recent times it was held by many students of malaria 
 that the disease might be transmitted to man in one of three ways, either by the 
 air, by water, or by the bite of an infected mosquito. The theories of the 
 transmission of malaria by the air or by water are very ancient, and, until the 
 role played by the mosquito in the transmission of these fevers was discovered, 
 both had ardent advocates, although there was but little experimental evidence 
 upon which to base either theory, and that little of no scientific value. The 
 only method of the transmission of malaria that has been proven scientifically is 
 that by the bite of an infected mosquito, and at the present time this is the only 
 known method of transmission. While it would, perhaps, in the light of our 
 present knowledge, be rash to assert that the malarial fevers can be transmitted 
 only by the mosquito, the fact remains that no other method of natural trans- 
 mission has been discovered, and, therefore, that as far as we can see, the 
 malarial fevers are only transmitted to man by the bite of mosquitoes belonging 
 to the Anophelinae. Before considering the experimental evidence upon which 
 the mosquito theory of the transmission of malaria is based, a short review will 
 be given of the air and water theories of transmission. 
 
 Transmission by the Atmosphere. — This is the most ancient of all of the 
 theories of malarial transmission, and it was the belief in this method that led to 
 the term "malarial" as applied to these fevers. The advocates of this theory 
 believed that the malarial germs reached man through the respiratory tract, 
 being inhaled, as in dust, or from the infected air of malarial regions. This 
 theory was accepted by multitudes of observers, yet never had a single experi- 
 mental fact that proved it or that was of sufficient importance to serve as a 
 logical argument in favor of such a method of transmission. On the contrary, 
 there are many facts, well known to the strongest adherents of this theory, that 
 conclusively prove such a method of transmission to be impossible. Among 
 these may be mentioned the strictly local character of malarial infection; the 
 protection afforded by heights; the greater prevalence of the disease in moist 
 regions and during the rainy season, when dust is not present; the fact that 
 these fevers are not carried by the wind; and the protection afforded the crews 
 of ships when the ships are anchored at some distance from the shore. To this 
 theory we owe the common opinion that the air of malarious localities is poison- 
 ous; that the vapors and fogs arising from marshes and lowlands are laden 
 
 79 
 
So THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 with malaria; and numerous other fanciful opinions, which, even though we 
 now know them to be false, are yet held by many, and in some localities con- 
 stitute a stumbling-block whenever measures looking to the prophylaxis of 
 malaria are a subject for discussion. 
 
 The strictly local character of malarial infections has long been used as 
 an argument against the transmission of the disease by the air. Almost every 
 authority has agreed that malaria spreads but a little way in a horizontal or 
 vertical direction. Celli quotes a typical example of this given by Marchiafava 
 and Spadoni. In Celli's words: 
 
 "Near Sinigaglia there is a canal between the river Misa and the sea; the 
 water stagnating there was, up till a little time back, the fomites of malarial infec- 
 tion. The inhabitants of the nearest houses and more especially of the houses 
 with the doors and the windows looking on this canal, suffered from malaria, 
 while those of the houses a little more distant remained immune." 
 
 There are very numerous instances of this kind in the literature upon ma- 
 laria; Bignami instances that while the hospital of San Michele di Ripa Grande 
 is free from malaria, there are most dangerous malarial foci in the immediate 
 neighborhood and that the inhabitants of Sezze who live near a marsh suffer 
 greatly from malaria, while those living near the hills in the vicinity do not 
 suffer from the disease. Marchiafava and Bignami instance certain cities, as 
 Genzano and Albano, situated between the Pontine Marshes and Rome, as 
 disproving the theory of transmission by air, because, while receiving the 
 emanations from the most deadly malarial localities in these marshes, they are 
 entirely free from malarial fevers. 
 
 It has long been known that ships anchoring a goodly distance off the most 
 malarial coasts escape infection, which would not occur if the germ of the 
 disease were carried by air currents. During the campaign in Madagascar, 
 according to Vincent and Burot, the troops operating upon shore were almost 
 decimated by malaria, while the crews of the war ships, hardly 300 feet from 
 shore, did not suffer at all from these fevers. 
 
 During an investigation of latent malaria in natives living about Camp 
 Stotsenburg, in the Philippine Islands, I found that the little barrios or villages 
 differed greatly in the amount of malarial infection present in them. The per- 
 centage of infected children varied from as high as 60 per cent, to as low as 5 
 per cent., yet all of the barrios were situated within a radius of two miles. 
 Such a variation could not occur were the malarial fevers transmitted by the 
 atmosphere. Not only did the barrios vary in the number of infections, but 
 certain portions of individual barrios were most malarious, while other portions 
 were free from infection. 
 
 It has long been known that malaria does not develop in high regions 
 in some instances, even though such regions be surrounded by the most highly 
 infected territory; in other words, the infection of malaria does not travel far 
 in a vertical direction. For centuries the inhabitants of the Pontine marshes 
 have protected themselves from malaria by sleeping in elevated shelters, and 
 the inhabitants of all malarial regions recognize that the upper stories of houses 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 8l 
 
 are less apt to be infected with these fevers than are the lower. Toniassi- 
 Crudeli found that at Girgento, the custodians of the temples suffer greatly 
 from malaria, while people sleeping in houses a short distance away, but upon 
 higher ground, do not suffer at all; Celli instances the case of the workers in the 
 marshes at the foot of the Lepini Mountains, who at night go up into the foot- 
 hills to sleep and who thus escape malarial infection. The town of Norma 
 is built upon the summit of an almost perpendicular mass of rock, 343 meters 
 high, and the inhabitants are free from malaria. According to Celli, the 
 town of Ninfa, situated at the foot of the rock upon which Norma is built, 
 and which was once a flourishing Papal seat, now consists of ruins, the only 
 inhabited house being a mill, where malaria is so severe that the workers have 
 to be changed every week during the malarial season. While, as a rule, malaria 
 is not met with upon highlands, there are many exceptions, and in the Philip- 
 pines one of the worst malarial foci in all the islands is situated in the foot-hills 
 of the Zambales Mountains. Height is only protective when conditions are 
 present preventing the development of Anophelinae, and the mere fact that a 
 country is elevated should not be considered as proving that it is free from 
 malaria. 
 
 It would appear that the most convincing argument against the transmission 
 of malaria by the air is the fact that the disease is not conveyed by winds, for 
 it is impossible to believe that if the malarial germ were present in the air it 
 would not be carried by the wind. The malarial fevers are strictly local 
 infections, being confined within certain well-defined limits, even in infected 
 localities. 
 
 Transmission by Water. — The believers in the theory that water is 
 capable of transmitting malaria have instanced numerous occurrences which 
 appear to support their contention. The oft-quoted Argo incident, used so 
 often as an almost impregnable argument in favor of such a mode of trans- 
 mission, is of little scientific value in the light of our present knowledge. Boudin 
 reported this epidemic, which occurred upon the French transport "Argo," 
 in 1834. In July of that year, three French transports sailed from Bona, 
 Algiers, bound for Marseilles, and loaded with French soldiers. While upon 
 two of the transports the troops continued in good health, upon one, the ' ' Argo, 
 there occurred a severe epidemic of what was regarded as malarial fever, 
 thirteen of the crew dying, while 98 were admitted to the hospital when the 
 ship reached Marseilles. The cause of the epimedic was supposed to be a 
 number of barrels of water from a swamp, shipped at Bona, where malaria was 
 prevalent. A review of the facts in this celebrated case show that it is almost 
 impossible that any of the patients suffered from malaria, for the incubation 
 period was shorter than has ever been observed; every man of the 120 consti- 
 tuting the crew was affected; in every case the symptoms were described as per- 
 nicious in character, and in no case was there a recurrence of the disease. It is 
 very evident that these men suffered from some form of acute poisoning, perhaps 
 due to the swamp water, but more probably due to some article of food. The 
 6 
 
82 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 simultaneous occurrence of the disease in every one of a crew of 120 men is 
 positive proof that it could not have been due to the malarial plasmodia. 
 
 Other similar epidemics have been reported as occurring upon ships, but 
 none of them are of any scientific value as proof of the transmission of malaria 
 by means of water. 
 
 As an instance of the erroneous conclusions that may be drawn from appear- 
 ances, the following description of an epidemic of malaria, noted by Davidson, 
 is of interest: The troops stationed at Tilbury Fort suffered greatly from 
 malaria, while those residing about the railway station, and the coast guards, 
 were in excellent health. The water-supply of the fort came from a neighboring 
 swamp, while that of the station and of the coast guards was from a spring. 
 While the water tanks at the fort were being repaired, the soldiers also used 
 the spring water, and the malaria disappeared. Hence the inference was 
 clear that the swamp water produced the malaria, and at that time such an 
 inference was justifiable, but how easily, at the present time, the disappearance 
 of malarial fever at this station can be explained. The tanks which were 
 uncovered served as breeding places for mosquitoes; while the tanks were 
 being repaired the mosquitoes could not breed and malaria disappeared. 
 
 Numerous investigators have endeavored to produce malaria in man by 
 the use of water from malarial districts, but all such experiments have ended 
 in failure. Celli was the pioneer in this line of research and his experiments 
 are given in the following table: 
 
 Method 
 
 No. experi- 
 mented on 
 
 Duration of ex- 
 periment 
 
 Water from 
 
 Result. 
 
 By ingestion. 
 
 6 
 
 8-15 days. 
 
 Pontine marshes. 
 
 Negative. 
 
 
 12 
 
 12-21 days. 
 
 Sicily. 
 
 Negative 
 
 
 3° 
 
 5-30 days. 
 
 Tuscan Ma- 
 remma. 
 
 Negative. 
 
 
 25 
 
 6-24 days. 
 
 Vallomonica. 
 
 Negative. 
 
 By inhala- 
 
 16 
 
 2-1 5 days. 
 
 Pontine marshes. 
 
 Negative. 
 
 tion. 
 
 
 Twice a day. 
 20-30 min- 
 utes. 
 
 
 
 By entero- 
 
 5 
 
 2-14 days. 
 
 Pontine marshes. 
 
 Negative. 
 
 clysm. 
 
 
 
 
 
THE ETIOLOGY OF THE MALARIAL LEVERS. 83 
 
 Some of the above experiments were undertaken by Zeri at Celli's sug- 
 gestion, and all of them were negative so far as the production of malaria was 
 concerned. Since the discovery of the transmission of malaria by the mosquito, 
 it has been suggested that perhaps the plasmodia, after passing through their 
 life cycle in the mosquito, may exist in water in the form of resistant spores, 
 or that the eggs of the mosquito, when ingested in water, may be capable of 
 conveying the infection. Nunmerous observers have shown, however, that 
 the malarial plasmodia are not present in the eggs of infected mosquitoes, and 
 no form of the plasmodia has ever been found in the water of malarious regions. 
 Laveran, and later Manson, suggested that water might become infected 
 by the dead bodies of infected mosquitoes, and Ross undertook to prove this 
 hypothesis. He gave a native water containing the dead bodies of mosquitoes 
 infected with malarial plasmodia, the ingestion of which was followed in 
 eleven days by an attack of fever, with plasmodia in the blood. The ex- 
 periment was of no positive value as it was carried out in a malarial region, 
 and, although repeated in many individuals, was never again successful. 
 
 Transmission by Inoculation of Malarial Blood. — While the direct 
 inoculation of the blood of a patient suffering from malaria into a healthy 
 individual probably occurs very rarely in nature, it is well known that the 
 malarial fevers may be easily transmitted in this way. These fevers have been 
 successfully reproduced in this way by Gerhardt, Mariotti, Marchiafava, 
 Celli, Bignami, Bastianelli, Baccelli, Sacharoff, Elting, and many others. It 
 has invariably been found that the species of plasmodium in the blood injected 
 is found again in the blood of the individual so infected, and is followed by the 
 clinical symptoms of that type of fever usually produced by the species of 
 plasmodium experimented with. For instance, the subcutaneous inoculation 
 of blood from a person suffering from a benign tertian infection into a healthy 
 individual is followed by the occurrence of tertian fever in that individual, 
 and the appearance in his blood of Plasmodium vivax. This fact proves 
 conclusively that there are different species of malarial plasmodia, each capable, 
 and capable only, of producing the characteristic clinical symptoms with which 
 it is always associated. 
 
 Gerhardt, in 1884, was the first to successfully inoculate malarial fever in 
 man, and his work was soon confirmed by that of others. Antolisei and 
 Angelini produced typical tertian fever in two cases by the inoculation of the 
 blood of a patient suffering from this form of fever, while Gualdi and Antolisei 
 produced quartan fever in the same way; in 1889 the same observers inoculated 
 a man with blood containing hyaline and crescentic forms of the aestivo- 
 autumnal plasmodia, and on the ninth day afterward typical "ring" forms of 
 the organism were found in the blood, and an irregular fever developed. 
 Crescentic forms appeared upon the tenth day after the onset of the fever. 
 
 Calandrucio inoculated himself from a case of quartan malaria, produced 
 by inoculation, and in 18 days developed a typical quartan fever, the plasmodia 
 being found in his blood. Bein produced tertian fever, with characteristi ; 
 
84 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 paroxysms, in four cases, by the inoculation of blood containing the tertian 
 Plasmodium withdrawn by leeches, and in one case produced a tertian attack 
 by the inoculation of blood from an experimental case of tertian malaria. 
 
 An experiment of Di Mattei is of interest, both because two types of fever 
 were produced at different times in the same case, and because he claimed to 
 have produced an aestivo-autumnal fever by the inoculation of blood containing 
 only the crescentic form of the plasmodium. The patient experimented upon 
 had suffered from quartan malaria for some time previously, but had recovered. 
 He was inoculated with blood from a case of irregular fever, which showed 
 only crescents at the time of inoculation. About eight days after inoculation 
 the patient's blood showed non-pigmented, hyalin parasites. No fever occurred 
 until sixteen days after inoculation, and it was nine days after the onset of 
 the fever before crescents were found in the blood, or 25 days after inoculation. 
 Di Mattei followed this experiment by injecting into the same patient blood 
 from a case of quartan malaria, and in fifteen days quartan fever appeared, 
 and quartan plasmodia were present in large numbers in the blood. While Di 
 Mattei considered that the blood inoculated contained only crescents, it is 
 evident, from what we know of the development of the malarial plasmodia, 
 that he must have inoculated asexual forms of the organism. 
 
 Sacharoff produced aestivo-autumnal malaria in himself by the inocula- 
 tion of infected blood which had been removed from the body for four days. 
 He allowed leeches to suck the blood of a case of pernicious malaria whose 
 blood contained immense numbers of hyalin, non-pigmented "ring" forms of 
 the aestivo-autumnal plasmodia. The leeches were kept upon ice for four days, 
 at the end of which time he injected 1 c.c. of blood from one of them into his 
 arm. At the end of 12 days he had a malarial paroxysm, accompanied by a 
 chill, which was repeated upon the following day, and an examination of his 
 blood demonstrated the presence of numerous typical "ring" forms of the 
 aestivo-autumnal plasmodia. 
 
 From the foregoing it is evident that the malarial fevers may be inoculated 
 from man to man by the injection of infected blood and that the species of 
 plasmodium inoculated is always found in the blood of the infected individual. 
 
 Transmission by the Mosquito. — The one method of the transmission 
 of malaria which has been confirmed by abundant experimental evidence, and 
 which to-day is accepted by all authorities, is that by the bite of infected 
 mosquitoes. I believe that this is the only way in which these fevers are 
 naturally transmitted, and certainly it is the only way which has been actually 
 proven and which is, therefore, worthy of our belief. In a most convincing 
 manner Marchiafava and Bignami refute the arguments of the air and water 
 theorists, and sum up in favor of the transmission of the disease by the mosquito 
 as follows: 
 
 "Thus, admitting that malaria in man is the result of inoculation by mos- 
 quitoes, it is not difficult to explain why it is practically not carried by the wind; 
 it is also easy to understand why the danger of acquiring malaria is greatest in 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 85 
 
 the evening and the night. We see at once why the infection does not rise far 
 above the ground; we comprehend readily the danger of sleeping in malarious 
 districts; and finally this theory explains perfectly the well-known prophylactic 
 efficiency of mosquito-nets in regions where malaria prevails. Also this agrees 
 with what we know of the habits of mosquitoes in malarious countries, which 
 sting especially at evening and during the night, do not fly far from marshes, or 
 places where the proper conditions of their existence prevail, are in hiding 
 during the day out of the way of the winds, are most numerous in places where 
 malaria prevails, disappear from places where works of sanitation have removed 
 the conditions necessary to their existence, do not fly to any great height above 
 the ground," and many other arguments. 
 
 Nuttall, in an elaborate review of the evidence in favor of the transmission 
 of malaria by the mosquito, mentions the following facts, which I have tabulated 
 below: 
 
 1. The Malarial Season. 
 
 A. Corresponds to a period of warmth and moisture, conditions most 
 favorable for the development of mosquitoes. 
 
 B. Develops after the first rains, which form pools in which mosquitoes 
 may develop. 
 
 C. Malaria often ceases after excessive rains, when such pools are flooded 
 and washed out, thus destroying the mosquito larvae. 
 
 D. Malaria is most prevalent in wet years, when mosquitoes are most 
 numerous. 
 
 2. The Malarial Country. 
 
 A. Malaria is most common in low, moist countries, swamps, jungles, low 
 sea-boards, river deltas and valleys, and in such places mosquitoes most abound. 
 
 B. Malaria becomes more common as the equator is approached, which is 
 also true of the abundance of mosquitoes. 
 
 3. Conditions Affording Protection from Malaria and Mosquitoes. 
 
 A. Protection of the body, such as is afforded by closing the windows and 
 doors at night and using mosquito-nets, gauze, veils, curtains, etc., has long 
 been recognized by the inhabitants of malarial countries as protective against 
 the malarial fevers. 
 
 B. Thickly built houses exclude malaria. Malarial fever seldom penetrates 
 far into cities, as mosquitoes are stopped by walls, hedges, etc., and are at- 
 tracted by the lights in the suburbs. 
 
 C. Intervening woods and expanses of water protect from malaria, the 
 woods by obstructing the passage of the mosquitoes, acting as a sort of screen; 
 the bodies of water because the mosquitoes perish in them or do not attempt to 
 cross them, as these insects are incapable of prolonged flight. 
 
 D. Cultivation of the soil: Malaria is often prevented by cultivation of the 
 soil, due to the fact that this destroys the stagnant pools and swamps, or "mos- 
 quito nurseries." 
 
 E. Flooding the land will prevent malaria by destroying the breeding 
 places of the mosquitoes. 
 
86 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 F. Avoidance of sleeping out-of-doors at night or exposure after sunset: 
 The mosquitoes bite mostly at night, and when asleep the individual is bitten 
 frequently, thus increasing the chances of infection. 
 
 G. Use of fires: Fires indoors or out protect against malaria because the 
 mosquitoes are attracted by them, and fly into them and perish before reaching 
 the person. 
 
 H. Immunity of persons working in sulphur mines in malarious regions 
 due to the fact that mosquitoes are driven away by the smell of sulphur. 
 
 4. Influence of Occupation. — The more exposed a person is to the night 
 air in malarial regions, by reason of his occupation, the more liable is he to con- 
 tract malaria, as he is thus exposed to the bites of mosquitoes. 
 
 5. Effect of Turning Up the Soil. — Malaria often follows the turning up 
 of the soil, as in extensive excavation works, and this is due to the fact that 
 the inequalities of the excavated land gives rise to small pools, which form 
 suitable breeding places for mosquitoes. 
 
 6. Elevation and Malaria. — Malaria is most dangerous near the ground, 
 and people living in the upper stories of houses suffer much less severely from 
 these fevers than those living upon the ground floor. Mosquitoes fly low, and 
 the nearer the ground one is the more apt is he to be bitten. 
 
 7 The Coincidence of Malaria and Mosquitoes. — Wherever there is 
 malaria there we may be sure of finding mosquitoes belonging to the 
 Anophelinae. 
 
 It is evident from the above that the epidemiological data concerning the 
 malarial fevers present strong presumptive evidence in favor of the trans- 
 mission of the disease by the mosquito, but we do not have to deqend upon 
 this evidence alone, for we are now possessed of a mass of experimental evidence 
 which proves beyond all doubt that the malarial fevers are inoculated into man 
 by the mosquito. To the brilliant work of Manson, Ross, Bignami, Bastianelli, 
 Marchiafava, and Grassi the world is indebted for the elucidation of one of the 
 most important of etiological questions. 
 
 I have already considered the development of the malarial plasmodia 
 within the mosquito and have given a brief historical summary of the growth 
 of our knowledge concerning this question; here it is my purpose to give 
 in detail the most interesting of the experimental evidence proving that the 
 mosquito transmits the malarial fevers. 
 
 Bignami was the first to succeed in producing malaria by the bites of 
 infected mosquitoes. His patient, one Sola, who had been an inmate of the 
 Santo Spirito Hospital for six years, suffering from a nervous disorder, but 
 who had never had malaria, offered himself voluntarily as a subject for the 
 experiment. The mosquitoes used were from Maccarese, an intensely malarious 
 locality, and the following is Bignami's record of the experiment: 
 
 "Sola slept in the room in which the infected mosquitoes had been liberated 
 from September 26 to the end of October. During the latter part of October 
 the patient complained of malaise and headache. On the afternoon of October 
 
THE ETIOLOGY OF THE MALARIAL LEVERS. 87 
 
 3 1, he had a slight elevation of temperature to 37. 2° C. (99 F.). On November 1, 
 at about 3 p. m., he was taken with a severe chill which lasted until 5 o'clock, 
 the temperature rising rapidly to above 39 C. (102.2 F.). Between 9 and 10 
 o'clock a feeling of cold was again experienced. The fever continued all night, 
 falling in the early morning (November 2) to 38. 2° C. (100. 8° F.), and rising 
 again that evening to 39. 3 C. (102. 7 F.). The patient was restless and com- 
 plained of severe headache, but there were no grave symptoms. In the night, 
 about 11 o'clock, he had another chill of short duration. During this night the 
 temperature remained above 39 C. (102.2 F.), and on the morning of November 
 3 rose above 40. 4 C. (104. 7°F.), the patient being very restless and complaining 
 of much suffering. The fever broke in the afternoon with a gentle perspiration. 
 
 "At quarter after five in the afternoon a hypodermic injection of one gram 
 of quinine was given and repeated at night. The fever fell, and at 8 a. m., on 
 November 4, the temperature was 36.7 C. (98 F.). The administration of 
 quinine was continued during the following days, the patient continuing to have 
 slight elevations of temperature which did not reach 38 C. (100. 4 F.) except 
 once, on November 6. From November 7 onward the patient was entirely 
 without fever, and rapidly regained his appetite and strength. 
 
 "An examination of the blood made with the greatest care on November 2 
 gave negative results, no malarial parasites being found. On the morning of 
 November 3 a few young annular parasites, motile and discoid, without pigment, 
 and presenting the characteristic appearance of the parasites of aestivo-autumnal 
 fever were found. These forms increased in number during the day, and were 
 quite numerous during the afternoon hours. In some there was a beginning 
 pigmentation at the border consisting of very fine granules of pigment. 
 
 " We see, therefore, that there was produced experimentally in Sola a grave 
 malarial fever with a temperature curve such as is frequently seen in a primary 
 aestivo-autumnal infection. The fever began briskly, continued with slight 
 remissions from November 1 to 3, and began to fall on the evening of the latter 
 day when the specific remedy was administered. The parasites found in the 
 blood belonged to the aestivo-autumnal species. 
 
 "This is perhaps the first time that, in the primary aestival infection 
 acquired in the natural way, examinations of the blood have been made from the 
 beginning of the fever. We find that after forty hours the parasites begin to 
 be found, at first in small numbers, but rapidly becoming more and more numer- 
 ous. 
 
 "According to the opinion of all who followed this experiment, it was con- 
 ducted in such a way as to silence all objections. Sola is a robust individual, 
 notwithstanding his nervous malady, who has never in his life had malarial fever, 
 and who has not been outside of the Santo Spirito Hospital for six years. The 
 room where the experiment was conducted was an annex of the San Carlo ward, 
 in which, within the memory of the hospital physicians, there has never been an 
 autochthonous case of malarial fever, nor has there ever been any malaria in the 
 neighboring houses. 
 
 " Now in a room in the San Carlo ward of the Santo Spirito Hospital (Rome) 
 Sola acquired a malarial infection produced by aestivo-autumnal parasites, with 
 a well-marked fever and symptoms so grave as to call for the prompt adminis- 
 tration of quinine. The fever, indeed, was exactly such a one as is ordinarily 
 caught by laborers in the Roman Campagne in the summer and autumn months, 
 a fever beginning with the typical curve of the aestivo-tertian or sometimes 
 with a continued curve. This identical fever, such as prevails at Maccarese, 
 was taken by Sola in a place where there was of Maccarese neither the water 
 nor the soil nor the air, but the mosquitoes alone. We are then forced to the 
 
88 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 conclusion that the fever was acquired by inoculation by the mosquitoes. While 
 in this case there could be no doubt that the mosquitoes were responsible for 
 the fever, it was not definitely determined just what species of mosquitoes 
 was concerned, as there were three different species liberated in the room. 
 After this experiment. Grassi, Bastianelii, and Bignami worked with A. maculi- 
 pennis, and never failed to produce the disease when they were used. The 
 following, a successful experiment performed by Bastianelii and Bignami, and 
 quoted in their own words, is of interest in many ways: 
 
 "A patient suffering from a relapsing aestivo-autumnal infection, in whose 
 blood were many crescents and round and flagellated bodies, slept, from 
 December 10 to 18, in a room in which had been set free about 50 individuals 
 of .4. maculapennis, brought from Maccarese. The temperature of the room 
 was maintained at from 18° to 22 C. (64. 4 to 71. 6° F.). Most of the mos- 
 quitoes stung the patient, and became infected with crescent bodies, and sub- 
 sequent examinations showed in the middle intestine the characteristic forms in 
 process of development. But it was also observed that the mosquitoes remain- 
 ing in the room at the given temperature during the last days of December did 
 not have in the intestines mature sporozoa with sporozoites, but only the growing 
 forms. Evidently at a temperature of from 18 to 22 C. the life cycle of the 
 parasite is completed very slowly. But these same mosquitoes, confined for a 
 few days in an incubator at a temperature of 30 C. (86° F.), were found to 
 contain forms of a later development. There were noted, enclosed in the intes- 
 tines, typical capsules filled with sporozoites, and also broken and empty capsules, 
 and in the salivary glands were numerous sporozoites. 
 
 "When this fact was noted, three mosquitoes of this group were kept in an 
 incubator at 30 C. for two days, and on January 2 they were made to sting a 
 new subject, A. R. , who lent himself knowingly and willingly to the experi- 
 ment. It is needless to say that this man had never had malaria. On January 
 5 two of the same mosquitoes were made to sting the same person again, who 
 then had been stung in all five times by three specimens of A. maculapennis . 
 
 "After this part of the experiment, the three mosquitoes were dissected, 
 and examined under the microscope, with the following results: A. maculi- 
 pennis. No 1. In the intestines were found many capsules with sporozoites, and 
 some capsules which had been ruptured and completely emptied of their contents. 
 In the salivary glands were found two infected tubules; in one the cells were 
 swollen, of ovoid form, and filled with granules of uniform size. When pressure 
 was made on the preparation there issued a very large number of sporozoites of 
 typical form, uniform in appearance, and all of equal length; in the other tubule 
 were also seen cells, containing filiform sporozoites of characteristic appearance. 
 
 "A. maculipennis. No. 2. In the intestine were very numerous capsules, 
 some still whole and filled with sporozoites, others ruptured and shrunken, and 
 containing a granular residuum of a pale yellow color. In some of these ruptured 
 capsules were seen brown bodies of various size and shape, some elongated, others 
 short and deformed. In the salivary glands all the tubules were infected except 
 one or two. In them were seen cells containing typical sporozoites, cells filled 
 with granules similar to those described in A. maculipennis, No. 1, and cells 
 filled with round hyaline bodies of variable size. In addition there were also 
 found typical filiform sporozoites along the excretory ducts of the gland. 
 
 "A. maculipennis. No. 3. The intestine was filled with mature sporozoa. 
 Many capsules were broken and shrunken, and contained a pale yellow detritus; 
 others contained a large central body of granular aspect, surrounded by a hyaline 
 halo and without any recognizable structure. These were possibly mature 
 sporozoa in process of degeneration. The salivary glands were not found infected. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 89 
 
 "From the results of these examinations we may conclude that of the three 
 specimens of A. macnlipennis employed, only two had inoculated the patient 
 with malaria. 
 
 "On the evening of January 10, the patient had a sense of heat and a head- 
 ache, but the temperature was normal. On January n, 12, and 13, there was 
 no fever and the patient felt well. On January 14, that is, after from 9 to 12 
 days' incubation, there was no fever until 8 o'clock in the morning, but then the 
 temperature began to rise rapidly and reached 39. 5 C. (103. i° F.) at noon. From 
 this time the fever remained continuous up to January 18. The temperature 
 fell to normal in the morning of the eighteenth. (Two grams of quinine were given 
 hypodermically on the sixteenth, and repeated on the seventeenth, and re- 
 covery was complete and rapid. 
 
 "On examination of the blood on the morning of January 16, there were 
 found scanty aestivo-autumnal parasites with very fine pigment granules at the 
 periphery. There were found also plasmodia without pigment and with 
 granules in normal red blood-corpuscles and in brassy bodies. The parasites 
 disappeared after the exhibition of quinine on January 17. Thus the infection 
 was rapidly cut short and no crescent bodies were seen. 
 
 "We have in this case a typical example of aestivo-autumnal infection, be- 
 ginning with a continued fever, as is usual with this group of malarial infec- 
 tions. The course of the disease was in every respect identical with that in the 
 first case of malarial fever experimentally produced by the stings of mosquitoes 
 (the Sola case, described by Bignami)." 
 
 From the above it will be seen that in this case the disease was caused by 
 the bites of only two insects, and this is not surprising when one considers the 
 immense number of sporozoites in the infected salivary glands of a single 
 mosquito. There i no reason to doubt but that one mosquito may infect a 
 large number of individuals. 
 
 One of the most striking confirmations of the truth of the mosquito theory 
 of the transmission of the malarial fevers is found in the experiments of Sambon 
 and Low. These investigators spent an entire summer at Ostia, a most 
 malarious region in the Roman Campagna, residing in a mosquito-proof hut. 
 During the day, the time was spent mostly out of doors, but early in the evening 
 the observers retired to their hut and there spent the night. Neither investigator 
 developed malaria, although many individuals, residing in the same locality, 
 without protection from mosquitoes, suffered severely from the disease. Ostia 
 is so malarious that it was formerly said that to spend one night at that place 
 would result in a malarial paroxysm, and this was proven recently when of 
 sixteen police officers who spent one night at Ostia, all developed malaria 
 within two weeks; yet Sambon and Low lived through an entire summer at 
 this place and did not suffer from malaria, because they spent the nights in a 
 mosquito-proof hut. As showing the manner of life of the laborers in the 
 Roman Campagna and how severely they suffer from malaria, the following 
 quotation from an editorial in the British Medical Journal of December 8, 
 1900, describing the experiments at Ostia is of interest: 
 
 "Ostia, like all other malarious districts in the Roman Campagna, has no 
 indigenous population. The little wretched town of mean buildings gathered 
 
90 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 round the old mediaeval castle is inhabited by a fluctuating population, which 
 comes there from all parts of Italy, but chiefly from the south. In winter a large 
 number of laborers come to plough the fields and sow the corn, but they leave 
 before the end of June. In summer other workman come for short periods to 
 harvest the corn and maize. The life of these laborers is wretched in the extreme ; 
 they may well be called 'white slaves. ' They suffer fearfully from malaria. 
 They were sometimes met returning bare-footed to their distant homes, under 
 the scorching sun, delirious from fever. They often fall by the roadside, and 
 many have died in the ditch in sight of the great gray cupola. 
 
 "They work from dawn to sunset closely watched by overseers on horse- 
 back, who drive them like beasts. If they dare complain an infantry regiment 
 is called out to keep them in order. Their food is dry bread. Those who can 
 afford it add a morsel of cheese or an onion to the fare. They sleep in little huts 
 made of boughs and straw. Many have no covering between themselves and 
 the starry heavens. The people who gather reeds at the mouth of the river live 
 in huts built on piles, which look exactly like the tree houses or pile dwellings 
 of the New Guinea Papuans." 
 
 Can any one reading this description of industrial conditions in "sunny 
 Italy" wonder at the terrible mortality from malaria that has ever been charac- 
 teristic of that country. 
 
 In 1900, Manson, believing that the experiments of the Italian investigators, 
 while conclusive to the scientific world, were vitiated in the public mind by 
 the fact that they were performed in a malarial country, conceived the idea of 
 having infected mosquitoes sent from Italy to him in London and using these 
 mosquitoes to produce malaria in a healthy individual, in that city, where 
 malaria is unknown, unless it is imported in the person of an infected patient. 
 Accordingly, Sambon sent Manson some mosquitoes fed upon a case of benign 
 tertian malaria in Rome, and these mosquitoes were used in an experiment 
 upon Manson's son, the late Dr. P. Thurburn Manson. The experiment is 
 given in the latter's own words: 
 
 "I am twenty-three years of age, was born in China, but have lived in this 
 country (England) since I was three; have never been abroad since, nor in any 
 district in this country reputed to be malarial. I am healthy. 
 
 "The first consignment of mosquitoes arrived at the London School of Trop- 
 ical Medicine on July 5. Only some half-dozen had survived the journey. 
 They were in a languid condition and would not feed satisfactorily. One may 
 have bitten me. By July 7, they were all dead. The second consignment ar- 
 rived on August 29. They had been infected in Rome on August 17, 20, and 23, 
 by being fed upon a patient with a double benign tertian infection. The patient 
 was reported to have had numerous parasites, including many gametes in his 
 blood. On arrival twelve insects were lively and healthy looking. I fed five 
 of them on August 29, three on August 31, one on September 2, and one on 
 September 4. They bit my fingers and hands readily. The bites were followed 
 by a considerable amount of irritation, which persisted for two days. 
 
 "The third consignment arrived on September 10. They had been fed in 
 Rome on September 6 and 7 on a patient suffering from a simple tertian infection 
 but with very few parasites in his blood. There were some 50 to 60 mosquitoes 
 in good condition. Twenty-five bit me on September 10 and 10 on September 12. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 91 
 
 "Up till September 13, I had been perfectly well. On the morning of the 
 thirteenth I rose feeling languid and out of sorts with a temperature of 99 F. 
 By midday I was feeling chilly and inclined to yawn. At 4.30 p. m. I went to 
 bed with severe headache, sensation of chilliness, lassitude, pains in the back and 
 bones and a temperature of 101.4 F. Repeated examinations failed to discover 
 any malarial parasites in my blood. 
 
 "September 14. — I slept fairly well, but woke at 3 a. m. with slight sweating 
 and a temperature of 10 1°. During the day my temperature ranged between 
 101 and 102 . The symptoms of September 13 were exaggerated and anorexia 
 was complete. Several examinations of the blood were made again with negative 
 results. 
 
 "September 1 5.- — Woke at 7 a. m. feeling distinctly better, with a temperature 
 of 100. 4 . No malarial parasites were discovered on repeated examinations of 
 my blood by my father. About 2 p. m. I commenced to feel slightly chilly; this 
 soon wore off, and I became hot and restless. By 4.30 p. m. temperature was 
 103. 6°. It remained about 103 till 9 p. m. when profuse sweating set in. I am 
 told there was some delirium. 
 
 "September 16. — I woke at 8 a. m. feeling quite well; temperature 98. 4 . I 
 made several blood examinations and found one doubtful half-grown tertian 
 parasite. In the afternoon and evening there was a recurrence of fever (tem- 
 perature 102.8, relieved by sweating. 
 
 "September 17. — Again felt quite well on waking after a good night's sleep; 
 temperature 99 . At 10 a. m. several half-grown parasites, a gamate, and two 
 pigmented leucocytes were discovered in the first blood film examined. During 
 the day many tertian parasites were found. Their presence was confirmed by 
 my father and others. About 2 p. m. the sensation of chilliness returned. Tem- 
 perature 101.8 . By 5 p. m. temperature had reached 103 . There was then 
 copious sweating. The edge of the spleen could be felt on deep inspiration, and 
 there was a slight feeling of discomfort in the region of that organ. Dr. Fred- 
 erick Taylor and Mr. Watson Cheyne confirmed the presence of splenic enlarge- 
 ment. By 9 p. m. the temperature had fallen to 99. 2 , and I was feeling better. 
 Quinine (10 grains) was given. 
 
 "September 18. — Woke after a good night, feeling perfectly well (tempera- 
 ture 97 ). Ten grains of quinine were taken and subsequently five grains every 
 eight hours. I continued perfectly well all day. A few three-quarters grown 
 tertian parasites and some gametes were found during the forenoon and afternoon. 
 At 10 p. m. the parasites had disappeared, the last being found at 5 p. m. 
 
 "September 19. — No parasites discovered. Temperature normal. Feeling 
 quite well. There is no splenic enlargement, and no tenderness. Appetite 
 returns. 
 
 "September 25. — In good health. No recurrence of malarial symptoms. 
 A second experiment with mosquitoes sent from Rome and infected with the 
 benign tertian plasmodium was performed upon another individual in London, and 
 was successful. In both Dr. Manson's case and in the latter, relapses occurred 
 and tertian plasmodia were always easily demonstrated in the blood." 
 
 In 1899, Grassi, Bignami, and Bastianelli found that over 75 per cent, of 
 Anopheles caught in rooms occupied by malarial .patients showed developmental 
 forms of the plasmodia within them, and they were successful in infecting A. 
 maculipennis with the quartan plasmodium. 
 
 The experiments given comprise but a small portion of these which demon- 
 strate beyond all doubt that the malarial fevers are transmitted from man to 
 
92 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 man by the mosquito, and while it is not yet proven that this is the only mode of 
 transmission, it is but reasonable to suppose that this is the case. Schaudinn 
 claimed to have traced developmental forms of the plasmodium in the eggs 
 of mosquitoes and thus considered that the disease might be transmitted by 
 the adult insect to its progeny through the eggs and larvae, as in the case of 
 Texas fever and relapsing fever. His researches have not been confirmed and 
 the experiments of Marchiafava and Bignami would appear to indicate that 
 such hereditary transmission of the plasmodia does not occur. Neither the 
 eggs or the larvae of infected Anopheles showed the presence of any form of the 
 plasmodia, nor were Anopheles, born in the laboratory, the progeny of infected 
 insects, able to produce malaria in man, although six individuals were thus ex- 
 perimented with. At the present time the only known method of the transmis- 
 sion of the malarial fevers is through the bite of infected mosquitoes, and the 
 plasmodia are not present in the ova of these insects. 
 
 Cultivation of Malarial Plasmodia. — No one as yet has been able to 
 cultivate the malarial plasmodia in artificial media outside of the human 
 body. Coronado, a Spaniard, is the only investigator who has claimed to have 
 been successful in the cultivation of the plasmodia, but his experiments have 
 been repeated by other observers, none of whom have been able to confirm his 
 results. He claimed to have cultivated the plasmodia in unsterilized water. 
 In tubes of such water containing mud from the bottom of the supposedly 
 infected pool, a small amount of malarial blood was placed, and in 24 hours 
 Coronado claimed that cultures developed, and the entire life cycle of the 
 plasmodia could be followed. His description of this life cycle is at vatiance 
 with that occurring either in man or in the mosquito, and it is evident that his 
 results are erroneous, and that he observed some other organism in the grossly 
 contaminated water. 
 
 The plasmodia, however, have been kept alive outside of the human body 
 for several days. Sacharoff was the first to be successful in such experiments, 
 finding that in malarial blood obtained by leeches, from the human subject, the 
 plasmodia remained alive for over a week, provided the leeches were kept upon 
 ice. No reproductive changes occurred during this time. He also found that 
 the aestivo-autumnal plasmodia remained actively amoeboid for seven days, 
 and capable of causing malaria for four days; under such conditions, the 
 benign tertian plasmodium remained amoeboid for only forty-eight hours. 
 Rosenbach found that the benign tertian plasmodium remained alive in the 
 blood of leeches or forty-eight hours, and he considered that during this time 
 growth occurred, and possibly multiplication. 
 
 Blumer, experimenting with blood containing aestivo-autumnal plasmodia, 
 found that the small hyaline parasites continued present for over a week in the 
 leech if it were kept upon ice, but he was not able to demonstrate amoeboid 
 motion, nor could any evidence of growth or reproduction be discovered. 
 
 Hamburger and Mitchell have performed similar experiments, which are 
 described by Thayer, as follows: 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 93 
 
 "Mr. Hamburger took the blood from a case of aestivo-autumnal fever with 
 quotidian paroxysms at a time when only small amoeboid and ring-shaped, non- 
 pigmented hyalin bodies were present. During the next several days he was 
 able to distinguish a slight increase in size, with the accumulation, in nearly 
 every organism, of a few small, motile pigment granules. On the eight day 
 the organisms were distinctly visible, each with a small group of slightly motile 
 granules in the middle or at some point on the periphery of the parasite. Specimens 
 stained on the eighth day showed characteristic ring-shaped bodies. The ex- 
 periment of Hamburger, which I was able to follow, furnishes the first demon- 
 stration of the actual growth of the parasite and the accumulation of pigment 
 outside of the human body. (This was written before the discovery of the 
 development of the plasmodia within the mosquito.) 
 
 "Mr. Mitchell placed a leech upon an individual suffering with a combined 
 aestivo-autumnal and double tertian infection. The blood showed two groups 
 of active tertian organisms and a few crescentic and ovoid forms. In the 
 body of the leech the tertian organisms were to be made out for ten days. The 
 pigment was active for four days, but no amoeboid movement was to be made out 
 in the parasites. The crescentic and ovoid bodies remained unchanged; no 
 flagellate forms were observed." 
 
 In the light of our present knowledge concerning the transmission of these 
 fevers by the mosquito, it is interesting to note that in the leech the ere cents and 
 ovoids underwent no further development, and that flagellated parasites were 
 entirely absent. 
 
 In view of Roger's successful efforts in the cultivation of Le'shmania- 
 donovani in citrated blood, I have endeavored to cultivate the plasmodia of 
 malaria in a similar manner, the method pursued being as follows: 
 
 The patient's arm is corded above the elbow and sterilized. A large 
 superficial vein is selected and five cubic centimeters of blood is removed from 
 it with a sterilized glass syringe, and added to tubes containing from i to 2 c.c. 
 of citrate solution, the tubes being then kept at room temperature, at blood 
 temperature, and at a temperature of 22 C. I experimented in th's way with 
 blood containing the gametes (crescents) of the aestivo-autumnal plasmodia, and 
 with blood containing tertian gametes, but was unable to observe any indica- 
 tions of development in the organisms beyond flagellation, which occurred soon 
 after the blood was added to the citrate solut on. The intracellular plasmod a 
 underwent no developmental changes, but soon degenerated, although some 
 could be distinguished in the red corpuscles as long as three days after remov- 
 ing the blood from the patient. There appeared to be no difference, as regards 
 appearance, in the organisms kept at room temperature, in the incubator, or 
 at 22 C. 
 
 Immunity. — There has for years been considerable question as to whether 
 immunity to the malarial fevers exists in individuals or races. There can be 
 no doubt that both natural and acquired immunity to the malarial fevers is 
 possible, and that the presence of immunity against these fevers is not so very 
 uncommon in individuals residing in malarial localities. Koch firmly believes 
 that immunity to malaria exists because of the common occurrence of sponta- 
 
94 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 neous recovery and the freedom from the disease observed in certain groups 
 of people, as the coast negroes of East Africa, and the Chinese coolies of 
 Sumatra. In these people the immunity is undoubtedly acquired during a 
 long residence in malarial localities. 
 
 In considering this portion of our subject it will be convenient to do so 
 under the following divisions: Natural immunity, absolute and relative, and 
 acquired immunity, absolute and relative. 
 
 Natural I m munity. — By natural immunity We understand an immunity 
 occurring naturally, the individual never having suffered from the disease. 
 Natural mmunity is generally hereditary, and, in most instances, is absolute, 
 but occasionally is relative, the individual, under certain conditions, succumbing 
 to infection. An absolute natural immunity against malaria is sometimes 
 observed in individuals and families, but it is never a racial characteristic. 
 Maurel concluded from his exhaustive studies upon racial immunity that no 
 human race is immune from malaria, although many races have an acquired 
 immunity. A natural relative immunity is often observed in the descendants 
 of the inhabitants of very malarial communities, an immunity which is protective 
 until unusual exposure or hardship so undermines the natural resistant powers 
 that an infection results. An absolute natural immunity is observed in rare 
 instances, and almost every writer upon malaria has given examples of such 
 immunity. Celli instances the case of four individuals, living at Sezze, in the 
 Pontine marshes, a most malarious region, who have resided there for years, 
 have never taken any precautions against malaria, yet who have never suffered 
 from the disease. "They work very laboriously, have insufficient and bad food, 
 frequently sleep on the marshes, in the open air and in such a manner as to be 
 continually bitten by mosquitoes; still they have never had malaria, are very 
 healthy, have a rosy color, and their liver and spleen are normal in size." 
 
 Marchiafava and Bignami note an interesting case of natural absolute 
 immunity in a family residing in one of the worst malarial portions of the 
 Roman Campagna. The grandfather, the father, and the two sons, although 
 exposed continually to infected mosquitoes, have never had malaria, although 
 almost every one living in the same place for any length of time develops the 
 disease. 
 
 I have observed a few instances of natural immunity among American 
 soldiers, both in Cuba and in the Philippine Islands. These men, although 
 living in most malarial regions and taking no precautions against infection, 
 never suffered from the disease, while their companions, even those who were 
 cautious regarding exposure to mosquito bites, one by one developed paroxysms 
 of fever with the plasmodia in the blood. 
 
 We thus see that an absolute natural immunity is present in some individuals, 
 and while it is comparatively rare yet I believe that more extended observation 
 will demonstrate that it is much more common than is generally supposed. 
 My experience with the malarial fevers as they occur among our troops would 
 appear to show that a not inconsiderable proportion of the men possess a natural 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 95 
 
 immunity to these fevers, probably relative in character, in most instances, but 
 absolute in a goodly number. Natural immunity is never a racial characteristic, 
 for no race of men is immune, as a race, to the malarial fevers. 
 
 Acquired Immunity. — By the term "acquired immunity" we understand 
 an immunity acquired through an attack or attacks of a disease. It is some- 
 what doubtful if an acquired immunity against the malarial fevers is ever absolute 
 in character, although many sufferers from these fevers never have more than 
 one attack. In the vast majority of instances an immunity acquired against 
 malaria is relative in character, being overcome by many factors, such as 
 exposure, starvation, mental or physical strain, an unusually large amount of 
 the infective principle, or excessive changes in temperature. The immunity 
 acquired by repeated attacks of malaria is always relative in character. 
 
 Long residence in a malarious country will, undoubtedly, if the individual 
 survives repeated attacks of the disease, confer upon him a relative immunity 
 to malaria. In other words, the malarial poison produces certain changes in 
 the human organism which render it at least partially immune to further attacks. 
 This immunity, however, is often gained at the expense of the vitality of the 
 individual, and the penalty inflicted is a chronic malaria cachexia, which mark- 
 edly lowers the health of these immunes. The history of acquired immunity is 
 simply that of repeated attacks of malarial fever, each one a little less severe 
 than the preceding, until at last a spontaneous cure is effected which is 
 permanent. It should not be forgotten that in many individuals supposed to be 
 immune to malaria, the immunity consists in the absence of symptoms only 
 for the examination of the blood of such individuals will often reveal malarial 
 plasmodia undergoing schizogony. In these individuals, the condition present 
 might perhaps better be called an increased tolerance to the plasmodia rather 
 than an immunity in the restricted sense in which the word is often employed. 
 This subject will be considered more fully in the chapter dealing with latent 
 and recurrent malarial infections, as in such instances the malarial infection 
 is really latent in character. 
 
 It is a well recognized fact that the inhabitants of malarial countries are 
 often more resistant to the infection than are new-comers, and in most instances 
 this immunity, which is relative, has been acquired through repeated attacks 
 of the disease. The black races in some portions of Africa, although not 
 naturally immune to malaria, enjoy a relative immunity, and even when they 
 contract malaria suffer much less severely from it than does the European. 
 Plehn has demonstrated that the Kamerun negroes rarely have malarial fever, 
 and generally recover spontaneously; whereas Europeans suffer very severely 
 in the same locality. The same is said of the Malays and the Chinese by 
 Martin, while Tommasi-Crudelli has noticed differences in the resisting power 
 of the inhabitants of certain localities in Italy. 
 
 The natives of the Philippines, living in the most malarial localities, enjoy 
 an increased resistance to these fevers, a resistance which may be broadly 
 called an acquired immunity, for while the plasmodia are often found in the 
 
9 6 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 blood, symptoms are absent or are so slight as to escape attention. This 
 resistance to the infection is very marked when compared to the lack of 
 resistance shown by the American troops stationed in the same locality. At 
 Camp Stotsenburg, out of a brigade of American troops, over 600 entered the 
 hospital in one month, suffering from initial attacks of malaria; in the native 
 population, which far outnumbered the troops, only a very few cases of malaria 
 were observed, although the natives were living under much poorer sanitary 
 conditions and were much more exposed to the bites of mosquitoes. It is 
 probable, however, that a very large proportion of the natives would have been 
 found infected had their blood been examined; hey had simply acquired, from 
 repeated attacks, an immunity to the malarial poison and therefore presented 
 no symptoms of the disease. 
 
 The apparent immunity of native races to malaria was unexplained until 
 Koch made his observations in Africa regarding the occurrence of malaria in 
 native children. He proved conclusively that in malarial regions a very large 
 proportion of infants and children show the malarial plasmodia in their blood, 
 even though no symptoms of the disease be present, while, in the majority 
 of instances, the blood of adults does not show any trace of malarial infection. 
 From his findings he concluded that the adult natives, in the tropics, are immune 
 to malaria because of having suffered from repeated attacks in infancy and 
 childhood. 
 
 In West Africa Koch found that 100 per cent, of children under two years 
 of age showed malarial plasmodia in their blood and that the percentage of 
 infections decreased with advancing age; thus, children from two to five years of 
 age showed 48 per cent, infected, and from 5 to 10 years 23.5 per cent, infected, 
 while those over ten years of age were free from infection. In Kaiser Wilhelm's 
 Land (New Guinea) his findings were as follows. 
 
 Place 
 
 Age 
 
 No. examined Percentage infected. 
 
 Bogadjine 
 
 Under 2 years 
 
 10 
 
 8 cases or 80% 
 
 
 2 to 5 vears 
 
 12 
 
 5 cases or 41.6% 
 
 
 5 to 55 years 
 
 86 
 
 cases or 0% 
 
 
 Under 2 years 
 
 6 
 
 6 cases or 100% 
 
 
 2 to 5 years 
 
 13 
 
 6 cases or 46.1 % 
 
 
 5 to 10 years 
 
 17 
 
 4 cases or 23.5% 
 
 
 10 to 40 years 
 
 39 
 
 cases or 0% 
 
 In Java, according to Koch, of 297 children examined under one year of 
 age only 66, or 22.1 per cent., were found infected, while of 429 children over one 
 year of age 47, or 10.9 per cent., were infected. It will thus be seen that the 
 percentage of infections in children varies in different localities, but he claims 
 that the adult ratio is practically zero in tropical countries where malaria is 
 very prevalent. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 97 
 
 Koch's results have been confirmed by Stephens and Christophers and by 
 James. Stephens and Christophers, at Accra, West Africa, found from 23 to 
 90 per cent, of babies infected; up to eight years of age 20 to 57 per cent., up to 
 12 years of age 28 to 30 per cent.; and after the twelfth year infection was found 
 to be rare. At Lagos, of children under two years of age 50 to 100 per cent, 
 were infected; from two to five years, 40 to 75 per cent., and from five to ten 
 years 25 per cent. 
 
 James, in India, found that the percentage of malarial infection among 
 native children varied greatly in different localities, being zero in some places 
 and as high as 86 per cent, in others. Thus, at Mian Mir, children up to three 
 years of age showed 80 per cent., infected; up to five years, 66 per cent ; up to ten 
 years, 50 per cent., while after ten years none were infected. At Ennur, children 
 up to three years of age showed 65 per cent, infected; up to five years, 51 per 
 cent.; up to ten years, 46 per cent.; and up to fifteen year', 16 per cent. He 
 found no infection in natives over fifteen years of age. He also states that in the 
 most malarious localities the immunity of the adult is very apparent, but in 
 those localities in which the malarial ratio is low, an immunity of the adult does 
 not appear to be established. 
 
 The truth of Koch's assertions regarding the immunity of adult natives in 
 malarial regions has been seriously injured by the observations of numerous 
 investigators, and it may safely be said that adult natives, in most malarial 
 regions, show plasmodia in their blood in a considerable percentage of those 
 examined. 
 
 Hope, in Pabna, found that while 922 adult natives showed plasmodia in 
 their blood, only 862 children examined at the same time presented them; in 
 other words, that the adult malarial ratio was larger than the malarial ratio in 
 children. 
 
 Annett, Dutton, and Elliot, working in Nigeria, obtained the results given 
 below: 
 
 Age of child 
 
 Per cent, infected 
 
 to 1 year, 
 
 27-3% 
 
 1 to 2 years, 
 
 63.0% 
 
 2 to 3 years, 
 
 63.0% 
 
 3 to 4 years, 
 
 51-0% 
 
 4 to 5 years, 
 
 48.8% 
 
 5 to 6 years, 
 
 34-8% 
 
 6 to 7 years, 
 
 6.6% 
 
 7 to 8 years, 
 
 27-5% 
 
 8 to 9 years, 
 
 25.0% 
 
 9 to 10 years, 
 
 14-0% 
 
 10 years and above, 
 
 10.0% 
 
9 8 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 It will be observed that these investigators found 10 per cent, of adults 
 infected. 
 
 The following rules governing immunity in malarial regions may be said to 
 be fairly well proven by the observations of many investigators: 
 
 i. In severely infected regions, provided conditions are favorable for the 
 propagation of malaria, a relative immunity is generally observed in the adult 
 population, and is more promptly acquired, as more reinfections occur in 
 childhood. 
 
 2. In slightly infected regions a relative immunity is not rapidly acquired, 
 as fewer children are infected and reinfections are less common. 
 
 3. In countries in which seasons, such as winter, occur which are unfavor- 
 able to malaria, an acquired immunity to the disease is rarely observed, as 
 reinfections are thus rendered less numerous. 
 
 In this connection the observations of Panse in East Africa (Tonga) are of 
 great interest as they serve to show that in some regions the above rules do not 
 hold good. He examined 2,227 natives in a highly malarious locality with the 
 following results: 
 
 Age 
 
 No. examined 
 
 No. infected 
 
 Per cent, infected 
 
 Under 1 \2 year 
 
 Between 1 /2 and 1 vr 
 
 1 year of age 
 
 2 years of age 
 
 16 
 
 9 
 
 25 
 
 20 
 
 28 
 
 48 
 
 84 
 
 3i4 
 
 1683 
 
 6 
 
 6 
 
 22 
 
 17 
 
 25 
 
 34 
 
 52 
 
 125 
 
 258 
 
 37-5% 
 66.6% 
 88.0% 
 8^-o% 
 
 3 years of age 
 
 89.2% 
 70.8% 
 61.9% 
 39-4% 
 15-3% 
 
 Between 4 and 5 yrs 
 
 Between 6 and 7 yrs 
 
 Half-grown children 
 
 Adults 
 
 Summary: Of children under 1 year of age, 48 per cent, were infected. 
 Of children between 1 and 3 years, 87.6 per cent, were infected. 
 Of children between 4 and 7 years of age, 65.1 per cent, were in- 
 fected. 
 
 The results given by Panse agree with my own in the examination of native 
 Filipinos, and they seem to me to be more nearly correct than those of Koch, for 
 while they undoubtedly show a gradual diminution of the number of cases of 
 infection with advancing age, they also show that only a certain proportion of 
 the adult population acquire an immunity, which I believe will be found to be 
 true of the population of most malarial communities. It certainly is not often 
 found to be the case that all the adults in such a community are immune to 
 malaria, and, indeed, it is impossible to believe in any such wide-spread im- 
 munity following attacks of malaria; yet Koch and others have claimed ab- 
 solutely negative results in the examination of the blood of adults in malarial 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 99 
 
 regions. I think it is evident that such results must be very exceptional, and 
 require the most careful confirmation before they can be accepted as true of 
 malarial regions in general. 
 
 In one of the most malarial localities in the Philippine Islands (Camp 
 Stotsenburg) I examined the blood of 45 adults and 180 children, all Filipinos, 
 and all of whom at the time of examination were free from symptoms of malaria. 
 I was able to obtain the exact age in but 147 of the 180 children, and only this 
 number is included in the table of results which follows: 
 
 No. examined 
 
 1 to 5 yrs 
 
 5 to 10 yrs 
 
 10 to 15 yrs, 
 
 Adults 
 
 40 
 54 
 53 
 45 
 
 No. infected 
 
 3° 
 20 
 
 13 
 28 
 
 Per cent, infected 
 
 72.5% 
 3 7 • o % 
 24-5% 
 62.2% 
 
 In my examinations it will be noticed that of the 45 adults examined, no less 
 than 62 per cent, showed infection with the malarial plasmodia, despite the fact 
 that my examinations of the blood of children demonstrate that the percentage 
 of infections diminished with advancing age; this apparent contradiction I can- 
 not explain, but it is probable that a study of the blood of a larger number of 
 adults would materially reduce this great percentage of infections. From the 
 results obtained, however, it is very evident that the adult Filipino in this 
 locality has developed but little immunity to the malarial fevers, and I think it 
 is probable that these people possess little or no immunity to malaria, although 
 in malarial localities such adults have from childhood suffered from repeated 
 attacks of the disease. I have notes upon several native adults of this region, 
 who, within two years, have been admitted to the hospital from 8 to 16 times 
 with malarial infection. This lack of immunity to malaria in the native adults 
 of the Philippines appears to me to be a very significant and important fact 
 from the standpoint of social economy, for it is invariably true that a people 
 suffering from long-continued malarial infection are poor producers, especially 
 along agricultural lines, where strength and endurance are demanded. It is a 
 fact that will have to be taken into account in our endeavors to make this people 
 prosperous, for I am convinced that malarial infection is very prevalent among 
 them, often in an insidious form, and that it offers a serious barrier to effort 
 upon their part. The gratuitous distribution of quinine to the people of certain 
 districts of the Philippines would do much toward increasing their capacity for 
 labor. 
 
 From what has been said it is evident that an acquired relative immunity 
 against the malarial fevers is not uncommon under certain conditions and in 
 some localities, and that it is always due to repeated attacks of malarial infection. 
 
IOO 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 The efforts that have been made to produce an artificial immunity to malaria 
 will be mentioned in speaking of the serum treatment of the disease. 
 
 My results concerning the proportion of infected adults in malarial regions 
 in the tropics have recently been confirmed by A. Plehn, whose investigations 
 were conducted in Kamerum, West Africa. He found as follows: 
 
 Age 
 
 No. examined 
 
 No. infected 
 
 Per cent, infected 
 
 Between 2 and 5 
 
 Between 5 and 10 
 
 Adults 
 
 iS 
 26 
 
 40 
 43 
 
 *7 
 
 24 
 34 
 26 
 
 94% 
 92% 
 85% 
 60% 
 
 
 He concludes as the result of his researches that the adult West Coast 
 African negro is not immune to malaria, but has established a tolerance to the 
 plasmodia, as shown by the fact that the attacks are so mild as to present no 
 characteristic symptoms. In this way these natives are relatively immune to 
 malaria because they have established an immunity to the malarial toxin or 
 toxins. 
 
 The Theories of Immunity as Applied to Malaria. — As is well known, 
 there are two theories of immunity that are supported by medical scientists, that 
 of Ehrlich and that of Metchnikoff, and each theory has many able supporters. 
 Both schools believe in the various antibodies, Metchnikoff and his followers 
 believing that all are produced by the leucocytes, while the school of Ehrlich 
 does not designate any specific body cell as producing them; Ehrlich believes 
 that there are many different complements, while Metchnikoff believes that there 
 are but two, microcytase and macrocytase, both produced entirely by the phago- 
 cytes, and liberated by phagolysis or destruction of the phagocytes. Complement 
 has been extracted from the leucocytes by the followers of both theories, so that 
 some complement, at least, is produced by the leucocytes. The most enthusiastic 
 of Ehrlich's followers, however, believe that complement only occurs in normal 
 blood serum. Metchnikoff also believes that antitoxins when introduced into 
 the body act by stimulation of the phagocytes, leading to increased absorption 
 of the toxin and consequently to its destruction. He is positive in the belief 
 that immunity in every disease depends upon the phagocyte. 
 
 The immunity in malaria must depend upon certain reactions between the 
 cells of the tissues and the plasmodia or their toxins; the exact modus operandi is 
 not known, but may be explained theoretically by ether Metchnikoff's or 
 Ehrlich's conception of the cause of immunity. The fact that no malarial toxin 
 has as yet been discovered does not militate against Ehrlich's theory as applied 
 to this disease, but it is probable that immunity in malaria depends not only 
 upon antibodies evolved in the blood serum, but also upon substances liberated 
 during phagolysis, and, to a marked degree, upon the process of phagocytosis. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. IOI 
 
 Whether the antibodies evolved are antiplasmodial, that is, capable of destroy- 
 ing the plasmodia, or antitoxic in nature, or both, is entirely problematical. 
 
 Causes of Natural Immunity to Malaria. — Natural immunity to the 
 malarial fevers is comparatively rare and is individual in character. It 
 probably depends upon factors which are operative in other infections, but I 
 am inclined to believe that phagocytosis is of greater importance in malaria than 
 it is in most other acute infections. The chief factors concerned in natural 
 immunity against the malarial fevers are probably the following: 
 
 i. Antiplasmodial and antitoxic substances in the blood serum. 
 
 2. Antiplasmodial and antitoxic substances in the leucocytes, which are 
 liberated by phagolysis. 
 
 3. Phagocytosis. 
 
 4. Absorption of toxic material by the leucocytes. 
 
 5. Absence of specific cell receptors. 
 
 6. Distribution of the cell receptors in non-vital organs. 
 
 Any one or all of these factors may be concerned in natural immunity in 
 malaria, and it is not necessary to discuss here the manner in which they act; 
 it should be remembered that the whole subject of the production of immunity 
 in malaria is theoretical, and we can only reason from analogy with other 
 infectious diseases. 
 
 Causes of Acquired Immunity in Malaria. — As has been shown, re- 
 peated attacks of the malarial fevers result in an acquired relative immunity to 
 the disease, and this immunity may be more or less racial in character. This 
 condition may be brought about by complex factors, the chief of which are 
 probably: 
 
 1. Production of antiplasmodial and antitoxic substances in the blood 
 serum. 
 
 2. Phagolysis of leucocytes, and consequent liberation of antiplasmodial 
 and antitoxic substances. 
 
 3. Overproduction and excretion of such substances by the polymorpho- 
 nuclear leucocytes. 
 
 4. Resorption of toxin by the leucocytes. 
 
 5. Phagocytosis. 
 
 The immunity observed in individuals after repeated attacks of malaria is 
 probably an acquired active antitoxic immunity, as shown by the fact that the 
 plasmodia may be present and undergo normal schizogony, but no symptoms of 
 malaria are produced. As I have shown, this form of immunity consists in a 
 relative tolerance to the presence of the plasmodia and their toxins, thus strongly 
 indicating that such malarial toxins exist and that it is possible for antitoxic 
 substances to be produced in the blood of patients suffering from this 
 disease. 
 
 The antiplasmodial substances may consist, I believe, in both plasmodi- 
 cidal and plasmodilytic agents, for it is not uncommon, during malarial attacks, 
 to observe numerous extracellular plasmodia in the blood serum undergoing 
 
102 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 marked degenerative changes, such as vacuolation and fragmentation. To 
 these phenomena the term "plasmcdiolysis" might well be applied. 
 
 While antiplasmodial substances may be of great importance in the 
 production of immunity against malaria, it cannot be denied that phagocytosis 
 is very common in this disease, and undoubtedly plays a very important part 
 in the defense of the organism against the infection. 
 
 The question is often asked: Does one form of malaria protect against 
 another? We have but very little data upon this point, although we do know 
 that various forms of the infection may occur together or may follow one 
 another. The question is only of importance when an immunity has become 
 established to one form of the disease, and regarding this we have Koch's 
 observations in the Bismarck Archipelago. Only one form of malaria, the 
 quartan, occurs in this Archipelago, and many of the natives have acquired an 
 immunity to this form. In numerous instances, however, Koch observed the 
 development of tertian and aestivo-autumnal malaria in these quartan immunes 
 when they visited places in which these forms of malaria were present. 
 
 This observation would appear to prove conclusively that immunity to 
 quartan malaria does not protect against either the benign tertian or the aestivo- 
 autumnal fevers. This fact agrees with out conceptions of the specificity 
 of the various malarial plasmodia, and would appear to be a conclusive argument 
 against the unity of the species which have been described. 
 
 Literature upon Methods of Transmission of Malaria, Cultivation of the 
 Plasmodia, and upon Immunity. 
 
 Methods of Transmission. 
 
 1877. Boudin. Traite de geographie et de statisque medicale, i, p. 142, Par. 
 
 1881. Tomassi-Crudeli. Malaria and the Ancient Drainage of the Roman 
 Hill. The Practitioner, xvii, p. 295. 
 
 1884. Mariotti and Ciarrochi. Sulla transmissibilita dell, infezione da ma- 
 laria. Lo Sperimentale, Dec, s. iv, liv, p. 263. 
 
 1884. Gerhardt. Ueber Intermittens Impfungen. Zeitschr. f. k. Med., p. 375. 
 
 1887. Tomassi-Crudeli. Die Ursache der Malaria. Deutsch. med. Woch., 
 Nov., No. 46, p. 992. 
 
 1889. Antolisei and Angelini. Due altri casi di febbre malarica sperimen- 
 tale. Rif. Med., Sept. 28 and 29, Nos. 226-227, pp. 13 52-13 58. 
 
 1889. Gualdi and Antolisei. Una quartana sperimentale. Rif. Med., 
 Nov. 13, No. 264, p. 1580. 
 
 1889. Gualdi and Antolisei. Inoculazione della forme semilunari. di 
 Laveran. Rif. Med., Nov. 25, No. 274, p. 1639. 
 
 1891. Di Mattel Contributo alio studio dell' infezione malarica sperimentale 
 nell' nomo e negli animali. Rif. Med., No. 121, p. 544. 
 
 1 89 1. Bein. Aetiologische und experimentelle Beitrage zur Malaria. Charite 
 Annalen, 1891, p. 181. 
 
 1894. Sacharoff. Ueber die Einfluss der Kalte auf der Lebensfahigkeit der 
 Malariaplasmodien. Cent. f. Bakt., Feb. 5, xv, Nos. 5-6, p. 158. 
 
 1895. Baccelli. Studien iiber Malaria. Berlin. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. IO3 
 
 1895. Di Mattel Beitrage zum Studium der experimentellen malarischen 
 
 Infection an Menschen und an Thieren. Archiv. f. Hyg., pp- 191-500. 
 1900. Manson. Patrick. Experimental Proof of the Mosquito-Malaria 
 
 Theory. The Brit. Med. Jour. Sept. 29, p. 949. 
 
 (For literature concerning the transmission of malaria by the mosquito 
 
 see bibliography given at the end of Chapter III.) 
 
 Literature upon Cultivation of the Malarial Plasmodia. 
 
 1890. Rosenbach. Das Verhalten der in den Malariaparasiten enthaltenen 
 Kornchen. Deutsch. med. Woch., No. 16, p. 325. 
 
 1890. Sacharoff. Ueber Conservirung von Malariaplasmodien in lebenden 
 Zustande in Blutegeln. Wratsch., p. 644. 
 
 1891. Rosenbach. Die Cinsirverung lebeden Malariaparasiten. Berliner 
 klin. Woch., Aug. 24, p. 839. 
 
 1892. Coronado. Reproducion experimental del hemotozoaire de Laveran. 
 Chron. Medico-Quirurgica de la Habana, Nov., xviii, No. 22; Ibid., 1893, 
 xix, p. 375. 
 
 1897. Thayer. Lectures on the Malarial Fevers, New York, p. 26. 
 
 Literature upon Malarial Immunity. 
 
 1900. Koch. Zweiter Bericht iiber die Thatigkeit der Malariaexpedition. 
 
 Deutsch. med. Woch., No. 5, p. 88. 
 1900. Stephens and Christophers. Rep. Malarial. Com. Royal Soc, Lond., 
 
 1889— 1900. Series 3, p. 6. 
 
 1900. Celli. Ueber Immunitat gegen Malariainfection. Cent. f. Bakt., 24, 
 No. 3, p. 107. 
 
 1 90 1. Idem. Nochmals iiber Immunitat gegen Malariainfection. Cent. f. 
 Bakt., 25, p. 300. 
 
 1 90 1. Annett, Dutton and Elliot. Report of Malaria Expedition to Nigeris. 
 Thompson Yates Laboratory Reports, 3, p. 19. 
 
 1902. Panse. Die Malaria unter den Eingeborenen in Tanga. Archiv. f. 
 Schiffs- und Tropenhyg., No. 12. 
 
 1903. Plehn, A. Die acuten Infectionskrankheiten bei den Negern der 
 aquatorialen Kiisten Westafrikas. Virchow's Archives, vol. clxxiv, 
 Supplement. Ford. 
 
 1905. Strachan. Alleged Negro Immunity to Malaria. Brit. Med. Jour., 
 March 18. 
 
 1906. Plehn, A. Ueber Malaria-Immunitat. Archiv. f. Schiffs- u. Tropenhyg., 
 vol. x, No. 2. 
 
 1906. Craig, Chas. F. Observations upon Malaria. Philippine Jour, of 
 Science, vol, i, No. 5, June, p. 523. 
 
 1907. Craig, Chas. F. A Study of Latent and Recurrent Malarial Infection, 
 Etc. Jour, of Infectious Diseases, vol. iv, No. 1, Jan., pp. 108-140. 
 
CHAPTER V. 
 
 Predisposing Causes, General and Local; Period of Incubation of the 
 Malarial Fevers; Congenital Malaria. 
 
 Predisposing Causes. — While the malarial plasmodia are the direct 
 cause of the malarial fevers and while the transmission of these fevers depends 
 entirely, so far as we at present know, upon infected mosquitoes belonging to 
 the Anophellnae, there are certain factors which enter indirectly into the 
 etiology of malarial disease, either by favoring the development of the plasmodia 
 within man or the mosquito or by favoring the development of mosquitoes 
 capable of transmitting the disease. Such factors are known as predisposing 
 causes and may be divided into general and local. 
 
 General Predisposing Causes. — General conditions predisposing to the 
 malarial fevers are climate, locality, altitude, time of day, moisture, character 
 of the soil, winds, rain, season, and atmospheric conditions. 
 
 Climate. — A careful examination of the geographical distribution of the 
 malarial fevers convinces us that climate is of immense importance in the 
 etiology of these fevers. These infections are most common and pernicious 
 in tropical regions, so that heat may be considered as an essential predisposing 
 cause of the malarial fevers. The mild tertian and quartan infections, while 
 common in all malarial localities, are peculiarly the fevers of the temperate 
 malarial zones, while the more severe and often pernicious aestivo-autumnal 
 infections are most common in tropical countries. Thus climate influences 
 not only the amount of malaria in a locality, but also the type of infection. In 
 temperate climates malaria occurs only during the warmer seasons, while in 
 the tropics it occurs throughout the year, although cases are more numerous 
 during certain periods. All climatic conditions favoring the development of 
 mosquitoes of the genus Anopheles act as predisposing causes of the malarial 
 fevers, provided infected individuals are present, otherwise climate has no effect 
 whatever upon the prevalence of these fevers, except a local effect in provoking 
 an attack in already infected individuals. 
 
 Locality. — This portion of our subject has already been considered under 
 the geographical distribution of the malarial fevers and in the chapter dealing 
 with immunity. It has been shown that the prevalence of malaria is greatly 
 influenced by locality, and that certain types of infection are present most 
 frequently in certain limited regions. Not only are tertian and quartan 
 infections most common in temperate regions, but even in such localities the 
 two types vary in prevalence, while the prevailing type in most tropical regions 
 
 104 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 105 
 
 are the aestivo-autumnal infections. Climatic influences are not the only 
 ones which operate in thus limiting the varieties of malarial infection in certain 
 localities, for it is probable that the variety of Anopheles present is of much 
 greater importance in regions in which all the types of malarial infection are 
 present. Thus it will be found, that in regions in which the benign tertian 
 infections are most prevalent, especially if such regions be situated in the 
 tropics, the prevailing type of Anopheles present is one that transmits Plasmo- 
 dium vivax. As showing the influence of locality upon the type of malarial 
 infection, the following instance may be of interest: 
 
 At Camp Stotsenburg, Pampanga Province, Luzon, P. I., during five 
 months, I observed 386 cases of malaria in which the plasmodia were demon- 
 strated in the blood. Of these cases 98 were infected with the benign tertian 
 Plasmodium (Plasmodium vivax) ; eight with the quartan plasmodium (Plas- 
 modium malariae), and 272 were infected with the aestivo-autumnal plasmodia, 
 of which 258 were infected with the tertian aestivo-autumnal plasmodium 
 (Plasmodium falciparum) and 14 with the quotidian aestivo-autumnal 
 plasmodium (Plasmodium falciparum quotidianum) . There were eight combined 
 infections with the benign tertian and tertian aestivo-autumnal plasmodia. 
 
 At Camp Gregg, 40 miles distant from Stotsenburg, where the climatic 
 conditions were exactly similar, Captain Chamberlain, of the Army Medical 
 Corps, during twelve months observed 162 cases of malaria in which the type 
 of plasmodium was recognized. Of the 162 cases, 83 were infected with the 
 benign tertian plasmodium, 4 with the quartan plasmodium, and 75 with the 
 aestivo-autumnal plasmodia. At Camp Gregg the quotidian aestivo-autumnal 
 infections were more prevalent than at Camp Stotsenburg, no less than 16 of 
 the 75 aestivo-autumnal infections being of this type. 
 
 From the above it will be seen that while at Camp Stotsenburg the aestivo- 
 autumnal infections greatly outnumbered other types, at Camp Gregg the 
 benign tertian infections were greatest in number, although climatic conditions 
 were practically the same. Similar variations in the type of malarial infection 
 have been noted by numerous observers and can best be explained by the 
 occurrence in such localities of certain species of Anopheles which transmit 
 only a certain species of the malarial plasmodium. Thus at Camp Stotsenburg 
 the mosquitoes most prevalent were those that transmit the aestivo-autumnal 
 plasmodia, while at Camp Gregg the tertian transmitting mosquitoes were 
 most numerous. 
 
 Altitude. — The malarial fevers occur especially in lowlands along the 
 coast and rivers of warm countries. This is an etiological fact which has been 
 observed since the very earliest study of malarial infections. Mountainous 
 regions are generally free from malaria, although there are many exceptions 
 to this rule. In the Philippine Islands certain valleys are almost free from 
 malaria, while the hills in the vicinity are notoriously infected. In Italy, 
 while there are numerous examples of the protection afforded against malaria 
 by residence upon hills surrounding malarious districts, Grassi has found 
 
106 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 malaria present at a height of 8,400 feet, while in the Rocky Mountains malaria 
 has been observed on the eastern slope at a height of over 6,000 feet. It should 
 be remembered, however, that many cases diagnosed as malaria in the Rocky 
 Mountains, or as mountain fever, are really cases of typhoid fever. 
 
 In South America, in the Andes, malarial fevers have been observed at an 
 elevation of 10,000 feet. Elevation is a protection against malaria only when 
 mosquitoes and the conditions favoring their existence are absent, and where 
 these infections do occur at high elevations it will invariably be found that 
 the climatic and telluric conditions are favorable to the development of these 
 insects. Relapses of malarial infections acquired elsewhere are common 
 in high cool regions and this should not be forgotten, as pointed out by Thayer, 
 when malaria is reported in a district supposed to be free from the disease. 
 Thayer has reported a case, in which a relapse of a benign tertian infection 
 occurred while the individual was traveling in a healthy portion of the Alps, 
 18 months after the last attack of the fever. 
 
 It has been observed that persons living in malarious localities and sleeping 
 in the lower stories of houses are more apt to become infected than those 
 sleeping in the upper stories. For a long time this was held to be due to the 
 low-lying, noxious "malarial" vapors which penetrated the lower floors 
 but did not rise to the upper stories of dwellings. The true explanation is 
 that mosquitoes do not fly, as a rule, to any great height, and thus those persons 
 sleeping in the lower stories of dwellings are more frequently bitten. 
 
 Time of Day. — It has always been observed that there is much more 
 danger of contracting malaria at night than during the day, a fact formerly 
 attributed to the malarial gases and vapors which arise over damp ground 
 during the hours of night. In the light of our present knowledge of the method 
 of transmission of these fevers the fact is easily explained, for the mosquitoes 
 that transmit the disease are nearly all night feeders, and do not bite, as a rule, 
 until after dark or during twilight. 
 
 Moisture. — Moisture is absolutely essential for the propagation of 
 malaria, as water is necessary for the development of the ova of mosquitoes. 
 Marshes and low-lying damp regions are usually conducive to malaria, and 
 where malaria is most prevalent there moisture is found in abundance. Even 
 in the most malarial of tropical regions a short wet season is followed by a 
 great decline in malarial infection and a total disappearance of the disease 
 when there is a prolonged draught. The influence of moisture is explained by 
 the fact that mosquitoes are most numerous and breed most abundantly in 
 moist regions. 
 
 Character of the Soil. — The geological formation of the soil is of very 
 great importance in the prevalence of malaria. An impervious subsoil is a 
 predisposing cause of malaria in that it favors the production of stagnant pools 
 and collections of water in which mosquitoes may breed. Tropical jungles, low 
 marshy lands, or lands covered with stagnant pools of water are most apt to 
 be malarious not because of the character of the soil, but because, as Mar- 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 107 
 
 chiafava well says, "beneath a more or less thick stratum of humus there is an 
 impervious layer" which gives rise to pools of water and general moisture of the 
 soil. From the days of the earliest Romans, who constructed extensive drainage 
 canals, up to the present time, it has been recognized that thorough drainage of 
 a malarial region resulted in the disappearance of the disease, but it was not 
 until the discovery of the relation of the mosquito to malarial transmission was 
 announced that we had any adequate explanation of this fact. 
 
 While the porosity of the soil is obviously of great importance, the con- 
 formation of the soil is of still greater, as this determines the regulation of the 
 moisture. Even though pools be formed, if the conformation is such that they 
 can be quickly drained, malaria may not be prevalent, as the ova of the mos- 
 quitoes do not have time to develop; on the other hand, if the conformation be 
 such that water collects in pools and hollows which cannot be drained, then 
 malaria may become prevalent. 
 
 While moisture and the collection of water in pools sufficiently large to 
 enable the larvae of mosquitoes to breed is essential to the prevalence of- malaria, 
 these fevers may occur in regions in which, at first glance, the character of the 
 soil would indicate that such an occurrence would be impossible. Lutz has 
 proven that certain species of Anophelinae may develop in collections of water 
 formed between the leaves of trees or plants in tropical and subtropical regions, 
 and that extensive malarial infection may exist where the common breeding- 
 places of these mosquitoes are absent. In many localities noted for the preva- 
 lence of malaria the soil may be dry and no breeding places of mosquitoes be 
 apparent, but close inspection will reveal the fact that Anopheles are present, 
 breeding probably at some distance from the infected locality, in small jungle 
 pools or in artificial collections of water about the quarters of the natives living 
 in the vicinity. This is the case at Camp Stotsenburg, in the Philippine Islands, 
 where malaria was so prevalent that it had to be abandoned as a brigade post. 
 The soil is volcanic in nature, and even after the heaviest rains, becomes per- 
 fectly dry in a few hours. There is no stagnant water within one mile of the 
 post, and no breeding-places of Anopheles. Still these insects are numerous at 
 times and as they must fly at least a mile before reaching the post, it will be seen 
 that in this instance the prevalent idea that they fly but a short distance is 
 disproved. It was invariably found that when the grass about Camp Stotsen- 
 burg was allowed to grow to any length the number of mosquitoes increased, 
 with a coincident rise in a number of cases of malarial infection; on the other 
 hand, when it was cut, both mosquitoes and malaria diminished very 
 appreciably. 
 
 In this instance, while the soil of the infected region could not be considered 
 as a predisposing factor in the prevalence of malaria, the soil of the region sur- 
 rounding the Camp and the carelessness of the natives regarding the artificial 
 collections of water about their houses resulted in severe infection of an area in 
 which mosquitoes could not breed but which they could reach by flying. 
 
 The building of canals, railways, harbors, and extensive military works; 
 
108 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 plowing and ditching; the clearing of land and the construction of highways, 
 have often been followed by outbreaks of malaria among the workmen and the 
 inhabitants of the surrounding country. This was formerly attributed to the 
 turning up of the soil and the consequent liberation of "malarial" gases, but we 
 know now that such operations favor malaria only inasmuch as suitable breed- 
 ing-places for mosquitoes are formed, water collecting in the holes and hollows 
 inevitably produced during extensive work involving the digging up of the soil. 
 In regions where neither the suitable mosquito or infected individuals are 
 present, such operations are never followed by the appearance of the 
 disease. 
 
 The character of the soil is of little importance so long as breeding-places 
 for mosquitoes are not present, the question of soil in relation to malaria 
 depending entirely upon the relation which it bears to the propagation of the 
 malarial mosquitoes. 
 
 Winds. — Some authorities have considered that the malarial fevers may 
 be transmitted by the winds, Scheube stating that "when they blow over 
 marshes or other sources of malaria they may carry the disease to fever-free 
 spots. I believe that such an occurrence is so rare as to be of no practical im- 
 portance, as it is obvious that winds can only transmit malaria by blowing 
 infected mosquitoes to uninfected localities, and it is a well-known fact that these 
 insects hide in the grass and beneath foliage when winds are blowing. A few 
 instances are recorded where winds appear to have transmitted malaria by 
 transmitting infected mosquitoes. Thus Brunnhoff mentions an epidemic of 
 malaria upon a German ship lying two miles away from a malarial coast, 
 although none of the crew had visited the shore. Such an epidemic can only be 
 explained by supposing that infected mosquitoes reached the vessels, pre- 
 sumably by action of the wind, as two miles is a much longer distance than these 
 insects usually fly. 
 
 If is probable, however, that winds exercise a considerable protective in- 
 fluence against malaria, as mosquitoes do not fly about when the wind is blow- 
 ing. It is a common observation in the tropics that on windy days mosquitoes 
 are seldom troublesome, whereas in the same locality, upon still days, these in- 
 sects may be so numerous as to render life a burden. 
 
 Rain. — Rain favors the production of malaria because it favors the breed- 
 ing of mosquitoes. Added to this, rainy weather, by diminishing the resisting 
 powers of the individual, favors the development of the disease in that individual 
 after he has become infected by the mosquito. In the tropics the malarial 
 fevers are especially prevalent during and immediately after the rainy season, 
 and in the temperate zones a dry spring is followed by a decrease in the number 
 of cases of malaria in an infected locality. In many regions, however, where 
 abundant rains occur, malaria is rare, even though the Anophelinae are present. 
 This is explained by the fact that in such regions the rains are so heavy and con- 
 tinued that the breeding places of mosquitoes are washed out and the ova and 
 larvae do not have a chance to develop, or that no infected individuals are 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 I09 
 
 resident in the locality. In the former instance an unusually heavy rainfall may 
 act as a protection against malaria. 
 
 Season. — Malaria may justly be considered as a seasonal disease. This is 
 so because the insects transmitting these fevers require a certain amount of 
 heat and moisture in order to develop, and these conditions are fulfilled only 
 during certain seasons of the year. Added to this we know that the malarial 
 plasmodia will undergo development only in the stomachs of mosquitoes living 
 under proper conditions as regards temperature, it having been proved by 
 Jancso that the oocysts develop best at a temperature of between 20 and 30 C, 
 while if the temperature be lower than 16 C. the organisms perish. 
 
 In temperate regions initial attacks of the malarial fevers occur only during 
 the warm months, while in the tropics these fevers occur throughout the year, 
 although even in such regions a marked seasonal variation is observed. Not 
 only does the season of the year profoundly influence the number of cases of 
 malaria observed in a given locality, but it also influences the type of infection 
 present at various times. In temperate regions the benign tertian fever occurs 
 in the spring and early summer months almost alone, the quartan and aestivo- 
 autumnal fevers beginning to appear in July and August, and being most 
 numerous during September and October, at which time the benign tertian 
 fever cases have diminished in number. In the tropics this difference in type 
 as related to season is not so marked, although the aestivo-autumnal types are 
 more common in the late summer and autumn months than at other seasons. 
 In both temperate and tropical regions cases of malaria are observed throughout 
 the year, but the cases occurring in the early spring are almost without excep- 
 tion instances of relapse, and most of those occurring in the tropics during the 
 latter portion of the dry season are of the same character. 
 
 The seasonal variation in malaria observed in different countries is re- 
 markable and at first sight difficult of explanation until we remember the 
 method of transmission of these fevers, which in each locality depends entirely 
 upon local conditions as regards climate and other factors influencing the 
 propagation of malarial mosquitoes. 
 
 As illustrating the influence of season upon the prevalence of these fevers in 
 different localities the following tables are given: In Baltimore this subject has 
 been thoroughly studied by Thayer and the following table given by him 
 illustrates the effect of season upon the total number of cases of malaria occurring 
 in that city, and also the variation in the type of malarial infection. 
 
 Type 
 
 Jan. 
 
 Feb. 
 
 Mar. 
 
 Apr. 
 
 May 
 
 June 
 
 July 
 
 Aug. 
 
 Sept. 
 
 Oct. 
 
 Nov. 
 
 Dec. 
 
 
 12 
 3 
 5 
 
 
 12 
 
 1 
 1 
 1 
 
 28 
 
 2 
 
 1 
 
 Si 
 
 1 
 S 
 
 
 76 
 
 2 
 
 
 68 
 
 3 
 
 1 
 
 131 
 
 3 
 
 37 
 
 3 
 
 161 
 
 
 99 
 
 3 
 
 153 
 
 2 
 191 
 
 4 
 
 168 
 
 1 
 
 203 
 
 11 
 
 54 
 4 
 
 63 
 6 
 
 17 
 2 
 
 22 
 2 
 
 Quartan 
 
 Total 
 
 20 
 
 IS 
 
 31 
 
 57 
 
 78 
 
 72 
 
 174 
 
 263 
 
 3SO 
 
 383 
 
 127 
 
 43 
 
no 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 From the table it will be seen that the malarial season is at its height in 
 Baltimore during the months of August, September, and October, the great 
 increase in the number of cases at this time being due to the aestivo-autumnal 
 fevers. It will also be noted that the benign tertian type occurred during the 
 spring and early summer months. 
 
 The following table given by Celli includes 93,000 cases of malaria ob- 
 served in hospitals in Rome and well illustrates the seasonal variation of these 
 fevers in Italy. As in Baltimore, the greatest number of cases was observed 
 during the months of August, September, and October, but a marked decrease 
 occurred during the months of June, which is not true of the fevers of Baltimore. 
 Celli concludes, and I think rightly, that most of the fevers occurring up to 
 June are relapses, with the exception of the benign tertian cases, and concludes 
 "the true malarial season is in the second half of the year; its duration varies 
 in different years; relapses occur during the whole of the first six months of the 
 following year, gradually declining from January to June." 
 
 Months 
 
 Years 
 
 1864 1865 1873 1874 1877 1878 1892 1893 1894 1895 1896 1897 1 
 
 Total 
 
 January . . 
 February . 
 March. . . . 
 
 April 
 
 May 
 
 June 
 
 July 
 
 August . . . 
 September 
 October . . 
 November 
 December 
 
 Total 
 
 284 
 
 195 
 
 228 
 
 198 
 
 189 
 
 170 
 
 168 
 
 151 
 
 112 
 
 114 
 
 83 
 
 88 
 
 439 
 
 340 
 
 1492 
 
 57° 
 
 1056 
 
 476 
 
 775 
 
 437 
 
 431 
 
 475 
 
 271 
 
 205 
 
 853 
 
 681 
 
 711 1 
 
 653 
 
 669 
 
 409 
 
 1135 
 
 2824 
 
 2185 
 
 1761 
 1280 
 
 777 
 
 595 
 
 528! 
 
 747 
 
 675 
 
 584 
 
 331 
 
 865 
 
 2647 
 
 2019 
 
 173 2 
 
 1186 
 
 661 
 
 543 
 
 502 
 
 576 
 
 5°4 
 
 375 
 
 1858 398 
 
 2373 1604 
 
 1995 1896 
 
 1460 1495 
 
 795 1245 
 
 695' ii93 
 
 638 
 519 
 544 
 564 
 480 
 339 
 
 240 
 
 189 
 
 249 
 
 236 
 
 314 
 
 129 
 
 177 
 
 125 
 
 163 
 
 175 
 
 243 
 
 94 
 
 231 
 
 119 
 
 125 
 
 Ib5 
 
 2 44 
 
 98 
 
 223 
 
 148 
 
 157 
 
 180 
 
 235 
 
 115 
 
 244 
 
 JI9 
 
 159 
 
 IOS 
 
 229 
 
 120 
 
 205 
 
 119 
 
 138 
 
 150 
 
 155 
 
 88 
 
 608 
 
 553 
 
 813 
 
 582 
 
 5°2 
 
 320 
 
 694 
 
 741 
 
 761 
 
 1298 
 
 1181 
 
 939 
 
 410 
 
 586 
 
 984 
 
 1357 
 
 684 
 
 505 
 
 500 
 
 911 
 
 855 
 
 1191 
 
 532 
 
 403 
 
 404 
 
 831 
 
 678 
 
 898 
 
 361 
 
 215 
 
 311 
 
 427 
 
 427 
 
 767 
 
 252 
 
 137 
 
 4423 
 
 5043 
 
 6046 
 
 6947 
 
 4690 
 
 2634 
 
 90 
 
 58 
 
 61 
 
 76 
 76 
 
 73 
 43i 
 905 
 799 
 703 
 732 
 386 
 
 4673 
 
 3732 
 
 3906 
 
 3921 
 
 3575 
 
 2553 
 
 8844 
 
 17678 
 
 15203 
 
 J 27S5 
 
 9531 
 
 6621 
 
 In tropical regions the seasonal variation of malaria is as marked, as re- 
 gards the number of cases, as in temperate regions, but not as regards the type 
 of malaria, the aestivo-autumnal fevers being predominant in most localities 
 throughout the year. The seasonal variation in the tropics depends upon the 
 character of the wet and dry seasons and varies considerably in different locali- 
 ties, and in different years. The following table illustrates the seasonal varia- 
 tion in malaria at Camp Stotsenburg, Island of Luzon, Philippine Islands, 
 while the two tables following show the variation at Camp Gregg, forty miles 
 from Stotsenburg. 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 Ill 
 
 Table showing seasonal variation in cases of malaria at Camp Stotsenburg, 
 Luzon, P. I. 
 
 Year 
 
 Month 
 
 Number of Cases 
 
 i9°4 
 
 August 
 
 September . . . 
 
 24 
 
 57 
 24 
 
 58 
 
 75 
 
 76 
 27 
 20 
 10 
 14 
 17 
 1 1 
 29 
 3 1 
 43 
 54 
 
 
 October 
 
 
 November 
 
 December 
 
 
 January 
 
 February 
 
 March 
 
 April 
 
 May 
 
 June 
 
 
 
 July 
 
 August 
 
 September . . . 
 
 
 October 
 
 
 November 
 
 December 
 
 
 
 
 Total 
 
 
 386 
 
 Tables showing the seasonal variation in malaria at Camp Gregg, Luzon, 
 P. I. Compiled by Major Chamberlain, U. S. Army. 
 
 TABLE A 
 
 
 TABLE 
 
 B. 
 
 Year 
 
 Month 
 
 No. of Cases Year 
 
 Month 
 
 No. of Cases 
 
 i9°4 
 
 January 
 
 2 1903 .... 
 
 January 
 
 27 
 
 
 February 
 
 4 
 
 February 
 
 21 
 
 
 March . . 
 
 6 
 
 March . . 
 
 8 
 
 
 April . . . 
 
 6 
 
 April . . . 
 
 12 
 
 
 May . . . 
 
 1 
 
 May . . . 
 
 9 
 
 
 June . . . 
 
 2 
 
 June . . . 
 
 11 
 
 
 July ... 
 
 6 
 
 July ... 
 
 .| 16 
 
 
 August 
 
 20 
 
 August 
 
 13 
 
 
 Septembe 
 
 r. 23 
 
 Septembe 
 
 r. 14 
 
 
 October 
 
 33 
 
 October 
 
 8 
 
 
 Novembei 
 
 r. 41 
 
 Novembei 
 
 3 
 
 
 December 
 
 18 
 
 December 
 
 6 
 
112 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 In considering the table of malarial infections at Camp Stotsenburg, it 
 will be observed that while the malarial fevers are present throughout the year, 
 they begin to increase in September, that the greatest number of cases occur 
 during the months of November, December, and January, and that a marked 
 decrease commences in Februrary and March. The increase commences 
 toward the latter portion of the rainy season in this part of the Philippines, and 
 the greater number of cases occur just following this season, and at this time 
 mosquitoes are most numerous. At Camp Gregg the malarial season differs 
 from that at Camp Stotsenburg, as shown by Tables A and B, and this difference 
 must be due to local conditions, as the seasons are the same in both places. 
 It will thus be seen that we should be conservative in drawing conclusions 
 regarding the seasonal occurrence of malaria in different regions based upon 
 the occurrence of malaria in any particular region, as these fevers are local 
 diseases and what is true regarding their occurrence in one locality may be 
 very erroneous in another. 
 
 However, I believe, from observations made both in this country and in 
 the tropics, that the aestivo-autumnal infections are most numerous in the 
 late summer and autumn months, and that even in the tropics these fevers 
 observe a seasonal variation almost as marked as in temperate regions. While 
 in the tropics of the aestivo-autumnal types occur throughout the year, it 
 has been my exeprience that, at least in Cuba and the Philippine Islands, these 
 fevers begin to increase in number during August, and reach their maximum 
 during December and January, most of the cases observed during the early 
 spring and summer being relapses rather than initial infections. 
 
 Atmospheric Conditions. — Certain atmospheric conditions act as pre- 
 disposing causes of malaria in so far as they encourage the propagation of 
 mosquitoes or deplete the health of infected individuals. In considering the 
 relation of climate, season, winds, and rains to malaria, some of the more 
 important of these conditions have been mentioned, but certain of them deserve 
 a more extended notice. 
 
 As mentioned, temperature exercises a marked influence upon the preva- 
 lence of malaria, these fevers being most abundant during the warm months 
 of the year. While this is so, the correlation between malaria and temperature 
 is a complex problem and there are exceptions to the general rule that are 
 difficult of explanation. Celli calls attention to the fact that in the province 
 of Rome during 1879 malaria was more prevalent than for eight years, but the 
 mean temperature was the lowest of these years; the rainfall in the months of 
 March, April, and May was the highest of these years, and it is probable that 
 mosquitoes were more numerous. Many apparent contradictions to the 
 influence of temperature are explained by the habits of the various species of 
 malaria transmitting mosquitoes and by certain local conditions affecting their 
 development. 
 
 Atmospheric depressions, by producing moisture of the ground, 
 are of importance in the etiology of the malarial fevers, for, as has been 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 113 
 
 mentioned, these fevers are most common where the soil is moist, thus affording 
 opportunities for the breeding of the malarial mosquitoes. It should be remem- 
 bered, however, that no condition of the atmosphere per se is capable of produc- 
 ing malarial infection, but that the atmosphere is of importance only as a 
 predisposing factor in the presence of infection or as it favors the propagation 
 of the insects transmitting the disease. 
 
 Local Predisposing Causes of the Malarial Fevers. — Among local 
 conditions which may act as predisposing causes of the malarial fevers may 
 be mentioned the following: 
 
 1. Race. — The occurrence of these fevers in regard to different races has 
 been discussed in the chapter dealing with immunity, and there it has been 
 shown that the relative immunity enjoyed by certain dark-skinned races in 
 malarial localities is the result of repeated infections during childhood and 
 early adult life. That people inhabiting malarial regions are less susceptible 
 to infection than new-comers is a fact that cannot be disputed, but the 
 examination of the blood of such persons will often result in the demonstration 
 of the plasmodia, although no symptoms of infection are present. In this case 
 there is no immunity to the plasmodia, but rather to the effects of the parasites. 
 Thayer and Hewetson have shown in the United States that the negro is 
 relatively less liable to malaria than the whites, the relative susceptibility 
 of the negro being nearly two-thirds less. According to Hirsch, the Caucasian 
 race is more susceptible to malaria than any other, and it is undoubtedly true 
 that the white man recently arrived in malarial regions of the tropics develops 
 the disease promptly while the dark-skinned races escape for long periods of 
 time. It is probable that the thicker skin of the negro and of the Malay, 
 as well as the use of grease or oil, together with the natural odor of the skin, 
 may be of importance in protecting these races from the bites of mosquitoes. 
 
 Those individuals residing in a malarial locality present the more chronic 
 forms of infection, while new arrivals present the acute and severe types. 
 Scheube claims that in Europeans the quotidian or remittent types of malaria 
 are most common, while the natives, or less predisposed races, show the 
 benign tertian and quartan forms of fever. This has not been my experience 
 in Cuba or in the Philippines, for I have observed aestivo-autumnal infections 
 as frequently in the natives as in Americans, and the tertian and quartan 
 fevers more frequently in newly arrived American soldiers. 
 
 2. Sex. — When equally exposed both sexes present the same ratio of 
 infection, but, as a matter of fact, malaria is more common in men than in 
 women, as the latter are not as often exposed to the bite of the mosquito. In 
 those countries in which the women work in the fields and are exposed during 
 the late afternoon and the night to the bites of these insects, malaria is as common 
 in the women as in the men, while in the case of babies and young children there 
 is no appreciable difference as regards sex. Parturition has been regarded by 
 some as a predisposing cause of malaria, but the evidence is not satisfactory, 
 although I have observed cases in which the strain of this period has made 
 
114 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 manifest an already existing infection. In malarial regions the appearance of 
 fever after childbirth should always lead to the examination of the blood, 
 and not infrequently it will be found that the symptoms are due to malaria. 
 Pregnancy exercises no protective influence against malaria and a severe 
 attack of any of the malarial fevers in the later months of pregnancy may be 
 followed by miscarriage. 
 
 While under similar conditions sex has no influence as regards malarial 
 infection, it is of some importance in the prognosis of these fevers. It has 
 been my experience, as well as that of Davidson, that in native races more 
 fatal cases of malaria are observed among women than among men, and among 
 female children than among male children. In the Philippine Islands I 
 observed that almost all of the children dying from malarial infections were 
 females and that male children presented less marked symptoms than female. 
 
 3. Age. — Children are more susceptible to infection than adults, and 
 the younger the child the more susceptible it is. This has been well proven 
 by the observations of Koch, Stephens and Christophers, Annett, Dutton, and 
 Elliott, and others, in their studies of malarial infection among the natives 
 of various regions. My own observations in the Philippines also show that 
 young children are more susceptible than older ones, but that in this instance 
 the adults suffer from malaria as much, or even more, than do the children. 
 Old age is protective in malarial localities because of the development of a 
 relative immunity due to repeated attacks in childhood and early adult life. 
 
 4. Occupation. — The occupation of man becomes a predisposing factor in 
 the production of these fevers in proportion to the chances that occupation gives 
 him of infection by the mosquito. Laborers working at ditching, railway 
 building, and other occupations which necessitate exposure to the night air and, 
 therefore, to mosquitoes, are especially liable to contract these fevers. An 
 instance of this was the terrific mortality from aestivo-autumnal malaria during 
 the French work upon the Panama Canal. 
 
 5. Social and Hygienic Conditions. — The poor are the greatest sufferers 
 from malaria because they are not as well nourished and are not, as a rule, 
 protected from the bites of mosquitoes. This is well illustrated in tropical 
 countries where the native suffers greatly from malaria in the same locality in 
 which the well-to-do white escapes by reason of better hygienic conditions and 
 measures taken to prevent mosquito bites. Celli has studied this phase of the 
 subject very thoroughly in Italy and has shown that the social condition of the 
 Italian peasant is indirectly responsible for the ravages of malaria in that 
 country. Because of improper food, miserable housing, insufficient and bad 
 clothing, and excessive work, the unfortunate peasant of Italy falls an easy 
 victim to malaria, and what is true in that country is equally true of every 
 region where these fevers are prevalent and poverty exists. 
 
 Bad sanitary conditions predispose to malaria by depleting the health and 
 encouraging the propagation of the mosquito which acts as the agent of trans- 
 mission. A careful police of private grounds in malarial regions should be 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 115 
 
 insisted upon, and particular attention should be paid to the character of habita- 
 tions and the food supply of the people. Malaria is purely an economic 
 question, and can be controlled by any community willing to spend the time 
 and mnoey necessary for the accomplishment of this end. 
 
 6. Other Conditions Influencing Infection. — There are numerous 
 other factors that contribute to the production of malarial fevers, among which 
 may be mentioned previous ill health and all those conditions which lower the 
 individual's resisting powers, such as exposure to heat, cold, and excessive 
 moisture; dissipation, overeating, overwork, either mental or physical; loss of 
 sleep, severe operations, and in short, anything which interferes with the normal 
 physiological processes. There can be no doubt that an infection with a small 
 number of malarial plasmodia is overcome in a great many instances by the 
 healthy individual, but should the normal resisting powers be lowered such an 
 infection would result in the symptoms of the disease. 
 
 The Occurrence of Malaria in Uninhabited Regions. — Certain instances 
 are of record in which .malaria has been reported as prevalent in regions unin- 
 habited by man. Such regions have been reported in Africa and India, and a 
 number of theories have been evolved in order to account for the malaria of 
 these regions. The discovery by Dionisi of a plasmodium in the blood of bats 
 very closely resembling human plasmodia, and by Koch of a plasmodium in 
 monkeys almost identical morphologically with the benign tertian plasmodium 
 of man, has led some observers to consider that the human plasmodia are 
 capable of existence in certain other animals, and that man is infected by 
 mosquitoes who have acquired their infection from these animals. Manson 
 suggests the possibility that the malarial plasmodia may pass from mosquito 
 to mosquito through the infection of the mosquito egg by the sporozoites, and 
 that the cycle thus established may continue indefinitely, thus accounting for the 
 development of malaria in regions uninhabited by man. 
 
 While it is perhaps too early to be dogmatic upon this subject, I believe the 
 concensus of opinion is that malaria can only be transmitted to man by the 
 bite of an infected mosquito that has derived its infection from man, and that 
 the occurrence of malaria in regions in which infected man is absent is not 
 proven, and so far as our present knowledge goes would appear to be impossible. 
 
 The Incubation Period of the Malarial Fevers. — We possess but little 
 definite knowledge of the incubation period of the malarial fevers when natur- 
 ally acquired, but it is safe to say that it must vary very greatly in individual 
 cases. We know from experience that the plasmodia may be demonstrated in 
 the peripheral blood for days, and even weeks, before the development of 
 symptoms of the disease, and that such instances of latency are not uncommon. 
 We do possess, however, a considerable mass of data regarding the incubation 
 period of these fevers after the direct inoculation of infected blood, and after 
 experimental infection by the bites of mosquitoes. 
 
 The Incubation Period after the Direct Inoculation of Infected 
 Blood. — In a previous chapter I have shown that the malarial fevers are in- 
 
n6 
 
 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 oculable from man to man by the injection of blood from an infected individual 
 into a healthy one. The period of incubation of the various types of malaria 
 following this procedure is given in the table that follows, together with the 
 name of the observer and the species of plasmodium inoculated. 
 
 
 
 
 Period of 
 
 
 Observe: 
 
 
 Species Inoculated 
 
 Incubation 
 
 Type of Fever 
 
 Antolisei and 
 
 Ange- 
 
 
 
 
 lini. 
 
 
 Tertian. 
 
 ii days. 
 
 Tertian. 
 
 Antolisei and 
 
 Ange- 
 
 
 
 
 lini. 
 
 
 Tertian. 
 
 1 1 days 
 
 Tertian. 
 
 Bein. 
 
 
 Tertian. 
 
 12 days 
 
 Tertian. 
 
 Bein. 
 
 
 Tertian. 
 
 12 days 
 
 Tertian. 
 
 Baccelli 
 
 
 Tertian. 
 
 6 days. 
 
 Tertian. 
 
 Mannaberg. 
 
 
 Tertian. 
 
 21 days. 
 
 Tertian. 
 
 Gualdi and 
 
 Anto- 
 
 
 
 
 lisei. 
 
 
 Quartan. 
 
 io days. 
 
 Quartan. 
 
 Gualdi and 
 
 Anto- 
 
 
 
 
 lisei. 
 
 
 Quartan. 
 
 12 days. 
 
 Quartan. 
 
 Gualdi and 
 
 Anto- 
 
 
 
 
 lisei. 
 
 
 Quartan. 
 
 1 5 days. 
 
 Quartan. 
 
 Di Mattei. 
 
 
 Quartan. 
 
 1 8 days. 
 
 Quartan. 
 
 Di Mattei. 
 
 
 Quartan. 
 
 1 1 days 
 
 Quartan. 
 
 Calandrucio 
 
 
 Quartan. 
 
 1 8 days. 
 
 Quartan. 
 
 Baccelli. 
 
 
 Quartan. 
 
 12 days. 
 
 Quartan. 
 
 Gerhardt. 
 
 
 Aes. autumn, quotid. 
 
 7 days. 
 
 Aes. autumn, quotid. 
 
 Gerhardt. 
 
 
 Aes. autumn, quotid. 
 
 12 days. 
 
 Aes. autumn, quotid. 
 
 Bignami. 
 
 
 Aes. autumn, tertian. 
 
 6 days. 
 
 Aes. autumn, tertian. 
 
 Bignami. 
 
 
 Aes. autumn, tertian. 
 
 io days. 
 
 Aes. autumn, tertian. 
 
 Bastianelli an 
 
 d Big- 
 
 
 
 
 nami. 
 
 
 Aes. autumn, tertian. 
 
 3 days. 
 
 Irregular type. 
 
 Bastianelli an 
 
 d Big- 
 
 
 
 
 nami. 
 
 
 Aes. autumn, tertian. 
 
 4 days. 
 
 Irregular type. 
 
 Bastianelli an 
 
 d Big- 
 
 
 
 
 nami. 
 
 
 • Aes. autumn, tertian. 
 
 5 days. 
 
 Irregular type. 
 
 Bastianelli and Big- 
 
 
 
 
 nami. 
 
 
 Aes. autumn, tertian. 
 
 4 days. 
 
 Irregular type. 
 
 Panichi. 
 
 
 Aes. autumn, tertian. 
 
 5 days. 
 
 Irregular type. 
 
 From a consideration of the above table it will be observed that the in- 
 cubation period after direct inoculation of malarial blood varies within narrow 
 limits for each type of malaria, the longest incubation period observed being 
 21 days in a case of tertian fever, while Elting records the shortest period in 
 aestivo-autumnal fever, the symptoms developing 33 hours after inoculation. 
 While the period of incubation observed after such experiments is of scientific 
 interest it should be remembered that the data is obtained by the inoculation of 
 the disease in an unnatural manner, for we have no evidence of the direct 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 117 
 
 transmission of malaria in nature. It is obvious that in such a method of 
 transmission only the forms concerned in the human cycle of the plasmodium 
 undergo development and therefore that we can draw no conclusions regarding 
 the period of incubation of malaria following the bite of infected mosquitoes 
 from such experiments. Fortunately, we possess data concerning the period of 
 incubation after the bite of infected mosquitoes, and while the natural period of 
 incubation is undoubtedly very variable, it is probable that in most instances it 
 approximates that observed in experimental cases of malaria produced by 
 infected insects. 
 
 The Incubation Period after Experimental Inoculation by the 
 Mosquito. — In the inoculation of blood containing only the forms of the 
 malarial plasmodia belonging to the human cycle, it is reasonable to suppose 
 that the period of incubation will be shorter than that observed when the 
 mosquito transmits the sporozoites to man. That this is so has been proven 
 experimentally by Marchiafava and Bignami, Grassi, Bastianelli, Bignami, 
 Manson, Jancso, and other observers. 
 
 Marchiafava and Bignami mention one instance in which the period of 
 incubation after the bites of mosquitoes infected with the aestivo-autumnal 
 plasmodia was from nine to twelve days, and one in which the period of 
 incubation after the bites of mosquitoes infected with the tertian plasmodium 
 was between sixteen and nineteen days. Grassi, Bignami, and Bastianelli 
 report a case in which the incubation of aestivo-autumnal fever after the bite 
 of infected mosquitoes was from twelve to thirteen days, and Bastianelli and 
 Bignami, a case in which the incubation period of aestivo-autumnal fever was 
 from nine to twelve days, and also another case in which tertian fever developed 
 in 18 days after the bites of mosquitoes infected with this species of plasmodium. 
 In quartan infections, the period of incubation is longer, averaging from two 
 to nearly three weeks. 
 
 From these observations it will be seen that the period of incubation of 
 the malarial fevers after the bites of infected mosquitoes varies considerably 
 according to the type of infection, but is always longer than when the blood 
 of an infected individual is injected directly into a healthy person. The 
 following summary well illustrates this point: 
 
 Incubation after Direct Inoculation. — In six cases of tertian fever, 
 the average period of incubation was 12 days. 
 
 In seven cases of quartan fever the average period of, incubation was 
 13.5 days. 
 
 In nine cases of aestivo-autumnal infection the average period of incuba- 
 tion was six days. 
 
 Incubation after Inoculation by the Mosquito. — The incubation in 
 tertian fever averages 14 days; in quartan fever, nearly three weeks; in aestivo- 
 autumnal infections, 10 to 12 days. 
 
 Incubation Period after Natural Infection. — It is obvious that the 
 period of incubation after natural infection is generally a very difficult problem, 
 
Il8 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 and can only be determined in a very small proportion of cases; the literature 
 contains very scanty information upon this phase of our subject, the most 
 satisfactory data we possess being furnished by Marchiafava and Bignami, 
 Celli, and Jackson. 
 
 Marchiafava and Bignami were so fortunate as to observe three cases in 
 which they could be sure of the period of incubation. These cases are here 
 given in the words of the authors: 
 
 "CasE I. — A robust young man, twenty- five years of age, living in the 
 central part of Rome, had never had malarial fever. On November 4, 18Q4, 
 he was obliged to go to Sermonetta, a notoriously malarious town near the 
 Pontine marshes. He arrived in the city at 10 o'clock, slept that night, tor- 
 mented by swarms of mosquitoes, in a house on the outskirts of Sermonetta, 
 and in the morning returned to Rome, where he resumed his usual occupation. 
 For six days he was in good health, then he had two days of malaise, and on 
 November 13th, that is to say, nine days after his stay in Sermonetta, he was 
 taken down with an aestivo-autumnal tertian fever, the parasites of this form 
 being found in the blood. 
 
 "Case II. — An engineer, living in Rome, who had never suffered from 
 malaria, was constrained by the duties of his calling to pass a day, in October, 
 1895, in a place in the Pontine marshes, and he slept that night in a cabin in poor 
 repair in which were many mosquitoes. At the end of ten days an aestivo- 
 autumnal infection, with irregular fever developed, of which he had several 
 relapses, extending up to the following spring. 
 
 "Case III. — A lady, who for many years, had enjoyed good health, passed a 
 week at Fiumicino in the month of October, 1894. Three days after her return 
 to Rome an aestivo-autumnal malarial fever declared iself, and not being'promptly 
 treated, developed into a choleraic pernicious attack; following this the patient 
 remained profoundly anaemic, with a sanguinolent diarrhoea, and died at the end 
 of a few weeks." 
 
 In the last case the period of incubation was probably from nine to ten 
 days. 
 
 Jackson gives a most interesting instance in which a limited epidemic of 
 malaria occurred in a troop of United States Cavalry, under circumstances in 
 which the period of incubation could be accurately determined. Out of 
 45 men belonging to a troop of the 6th U. S. Cavalry, exposed at the same 
 time and under similar conditions to infection, 18 developed tertian aestivo- 
 autumnal fever, the incubation period in all varying between ten and eleven 
 days. 
 
 In two cases Zieman noted an incubation of 10 and 11 days in aestivo- 
 autumnal fever, and Navarre describes an incubation of 12 days in certain 
 sailors who went ashore in a malarious locality for three hours and sailed 
 immediately afterward. 
 
 It will be observed that in all of these instances the period of incubation 
 of naturally acquired aestivo-autumnal infections agrees exactly with the 
 period of incubation as observed in cases experimentally produced by the 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. IIQ 
 
 bites of infected mosquitoes. But though the period of incubation for these 
 infections, as well as for tertian and quartan infections, in the vast majority 
 of cases, is as has already been noted, instances do occur in which the incubation 
 is greatly prolonged. Sternberg quotes the instance of certain sailors who 
 were infected while their ship lay for two days in a malarious port, and who 
 developed the disease, one after 48, the other after 184 days after leaving the 
 port. The following instances, observed by myself, well illustrate the variation 
 in the length of the period of incubation in the malarial fevers: 
 
 In August, 1899, a surgeon of the United States Army was stationed in a 
 malarious locality a few miles from Havana, Cuba, remaining at this station 
 until September, when he returned to New York, and was then ordered to 
 San Francisco. While at the station in Cuba he enjoyed good health until 
 a day or two before leaving, when he felt somewhat indisposed but no definite 
 symptoms developed. After reaching San Francisco he remained well until 
 March, 1900, but during that month suffered at times from malaise and 
 diarrhea. On April 1st. he had a slight chill and his temperature rose to 
 106. 2 F. His blood showed numerous hyalin and pigmented forms of the 
 tertian aestivo-autumnal plasmodium, and though this attack was quickly 
 overcome by quinine, he has had several relapses. 
 
 In this instance it is undoubtedly true that his infection occurred in Cuba, 
 as aestivo-autumnal malaria does not occur in either New York or San Francisco 
 and he was in no other places than these after leaving Havana. In this case, 
 then, the incubation period was at least seven months. It is probable that 
 had he remained in Cuba, the incubation period would have been greatly 
 shortened, but the change to more favorable climatic conditions and the 
 consequent benefit to his general health delayed the onset of the symptoms. 
 
 In another instance two officers of the Army, stationed at a malarious 
 post in the Philippines, never suffered from malaria while there, but one, one 
 month after returning to the United States, developed an attack of tertian 
 malaria, while the other, four months after his return, developed an attack of 
 tertian aestivo-autumnal malaria. Neither of these officers had been in 
 malarious regions after leaving the Philippines. These officers were both 
 five weeks in making the journey from the Philippine Islands to their station 
 in the United States, so that in the case of the one infected with tertian fever, 
 the incubation period must have been at least nine weeks, while in the aestivo- 
 autumnal infection, the incubation period must have been at least twenty-one 
 weeks. 
 
 I might give many more instances proving that the incubation period in 
 the malarial fevers varies very greatly at times, but these will suffice. The 
 cause of this variation may be sought in the number of sporozoites inoculated by 
 the mosquito, the resistance of the individual inoculated, the character of the 
 sporozoites as regards infectivity, and natural conditions favoring the develop- 
 ment of the plasmodia within the infected individual. Certain it is that in a 
 large proportion of the cases presenting long periods of incubation, the theory 
 
120 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 first advocated by Thayer is true, namely, that while no symptoms are pro- 
 duced the parasites multiply and perform their life-cycle in small numbers. I 
 am the more convinced of this as it is borne out in the examinations of the blood 
 of soldiers returning from the tropics. While serving at the United States 
 Army General Hospital at the Presidio, I examined the blood of every case 
 admitted for the malarial plasmodia, without regard to the presence of symp- 
 toms. This routine practice led to the surprising discovery that nearly 40 per 
 cent, of the men showing malarial parasites in their blood presented no symp- 
 toms of the disease, and further observations embracing 1,297 cases of malaria 
 in Americans have shown that 307, or nearly 24 per cent., presented parasites in 
 the blood but no symptoms of infection. In many of these cases I have observed 
 the plasmodia for days and even weeks in small numbers in the peripheral 
 blood, and in tertian and quartan infections followed the normal life-cycle in 
 man, and during this time no symptoms of malaria have developed. It is 
 evident that the long period of incubation in such cases depends upon the small 
 number of the plasmodia, and this in turn, upon the resistance of the individual. 
 It is not too much to say that if this routine practice of examining the blood of 
 every individual in malarious districts or of those coming from such districts 
 could be followed, our ideas regarding the period of incubation in malaria and 
 the relation of these fevers to other diseases would be greatly modified. 
 
 The question arises, How long may a susceptible individual live in a 
 malarious country before acquiring the disease ? It is, of course, impossible to 
 answer this question for all cases; but in the great majority of instances a suscep- 
 tible individual living in a region infected with the tertian or aestivo-autumnal 
 types of the disease will acquire the fever in from three to six weeks, while it is 
 probable that quartan infection is not acquired under two to four months. 
 Marchoux states that recruits arriving in Senegal develop the disease in from 14 
 to 16 days after arrival (aestivo-autumnal fever) and of the hundreds of cases of 
 malaria occurring in our soldiers in Cuba and in malarious regions in the 
 Philippines, almost 95 per cent, of those whom I questioned gave a history of 
 having resided in these countries for from two to six weeks before the onset of the 
 disease. One month was the most common period given by the men as inter- 
 vening between landing in Cuba and the first chill, and the same is true of cases 
 observed in the more malarial portions of the Philippine Islands. 
 
 Congenital Malaria. — For many years it was believed that malaria could 
 be transmitted through the placenta and that in some instances babies were 
 already infected with the disease at birth. Before the discovery of the malarial 
 plasmodia this theory was generally accepted and served to explain the large 
 infant mortality from these fevers in badly infected regions. The fact that 
 severe malarial attacks were capable of producing abortion or, more frequently 
 miscarriage, appeared to give added weight to the placental transmission of 
 these fevers, and the cases reported by the older writers upon apparently suffi- 
 cient clinical grounds, led many observers to regard this method of transmission 
 as proven and of great practical importance in malarial countries. The dis- 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 121 
 
 covery of the malarial plasmodia, and the method of transmission of the fevers 
 produced by these parasites, rendered most of the evidence in favor of placental 
 transmission of little scientific value, as none of the cases reported had been 
 examined as to the presence of the plasmodia in the blood or tissues, and the 
 large infant mortality was fully accounted for by the facility with which in- 
 fected mosquitoes bite the youngest infants. 
 
 A few of the older reported cases deserve some credit, however, such, for 
 instance, as that of Duchek, in which the babe showed marked splenic enlarge- 
 ment, and at autopsy, three hours after birth, much pigmentation in this 
 organ and free pigment in the blood of the portal vein. This case cannot be 
 considered as conclusive since similar appearances of the spleen and °f the 
 blood might be produced by other infections. In a few instances malarial 
 plasmodia have been found in the blood of newly-born babes, but in all such 
 instances the interval elapsing between the birth of the children and the exami- 
 nation of the blood has been sufficient to allow of postnatal infection. Such 
 cases have been reported by Bein, Bouzian, Peters, and a few other observers. 
 
 Opposed to the inconclusive evidence offered in favor of congenital malarial 
 infection we have the observations of many noted students of this disease which 
 prove, I believe, that the malarial fevers cannot be transmitted to the foetus 
 through the placenta. The placental blood of malarious mothers, the blood of 
 infants born to such mothers, and the blood of infants whose mothers have 
 aborted by reason of malarial infection, has been examined by many competent 
 investigators, and not one has reported the presence of malarial plasmodia in 
 such blood except in instances in which infection of the child might have oc- 
 curred after birth. Bignami examined the blood of a foetus of three months 
 and of another of six months from women who had aborted because of perni- 
 cious attacks of malaria, with a negative result in both instances; in a third case, 
 that of a pregnant woman, who died of pernicious malarial fever, the autopsy 
 showed the lesions usually found in such cases, and the blood contained 
 multitudes of plasmodia, but the blood of the foetus was free from plasmodia, 
 and the organs showed no lesions of malarial character. Similar cases have 
 been reported by Bastianelli, Caccini, and Schaudinn. Bignami has demon- 
 strated that the malarial plasmodia cannot develop within the nucleated red 
 blood-cells of the foetus, and believes that this is also true as regards the 
 young red corpuscles. 
 
 In an elaborate study of this subject, Sereni concludes that placental trans- 
 mission of the malarial plasmodia is impossible. He has never observed the 
 plasmodia in newly-born children of malarial mothers, although he states that 
 the placenta contained numerous parasites. Zieman, in Kamerum, has never 
 observed plasmodia in the blood of newly-born negroes, although in four cases 
 the mothers were suffering from malaria at the time of giving birth. He believes 
 that the placenta offers an impassable barrier to the plasmodia. A most 
 interesting case reported by Thayer supplies conclusive evidence that the 
 transmission of malaria through the placental circulation does not occur. 
 
122 THE ETIOLOGY OF THE MALARIAL FEVERS. 
 
 A woman, suffering from a severe quartan infection, gave birth to a seven 
 months' foetus during an attack of the fever. The blood of the child did not 
 show any plasmodia nor did a malarial infection develop later, but an examina- 
 tion of the placenta developed the interesting and significant fact, which bears 
 out Zieman's conclusion, that while upon the maternal side numerous plasmodia 
 could be demonstrated, there was a complete absence of them upon the foetal 
 side of the organ. ' From the evidence at hand I believe that we are justified in 
 stating that placental infection with the malarial plasmodia does not occur, 
 and, therefore, that congenital malaria does not exist. 
 
 Literature upon Predisposing Causes, Period of Incubation, and Congenital 
 
 Malaria. 
 
 Predisposing Causes of Malaria. 
 
 For the literature and data concerning the predisposing causes of the ma- 
 larial fevers consult the monographs of Marchiafava and Bignami, Thayer, 
 Mannaberg, Zeiman, Laveran Celli, and Craig, which have already been men- 
 tioned. 
 
 The Incubation Period of the Malarial Fevers. 
 
 Consult the monographs above mentioned, the list of references given at 
 the end of Chapter IV, as regards the period of incubation after direct inocula- 
 tion of malarial blood, and the references given under the "Transmission of ma- 
 laria by the Mosquito," for the work of Grassi, Bastianelli, and Bignami. 
 1899. Elting. Ueber Malaria nach experimentellen Impfungen. Zeitschr. f. 
 
 klin. Med., Bd. 36, Nos. 5-6. 
 1899. Di Mattel Beitrag zum Studium der experimentellen malarischen 
 
 Infektion am Menchen und Tieren. Archiv. f. Hyg., xxii, No. 3, p. 191. 
 1 901. Buchanan. Experimental Inoculation of Malarial Fever in Nagpur. 
 
 Indian Med. Gazette, p. 127. 
 
 1903. Laveran. Anopheles et Paludisme. Comptes Rendus. April 6. 
 
 1904. Billet. De l'incubation dans le paludisme. Bull med. de l'Algerie, p. 
 285-292. 
 
 1904. Mariotti-Bianchi. II periodo l'incubazione dell' infezione malarica. 
 Atti della Societa per gli Studi della Malaria, vol. v, p. 81. 
 
 1905. Jackson. Concerning the Invasion Period of the Malignant (estivo- 
 autumnal) Tertian Malarial Parasite. Am- Med., vol. viii, 67. 
 
 Congenital Malaria. 
 
 1858. Duchek. Ueber Intermittens. Vierteljahrsschr. f. d. prakt. Helik. 
 
 vol. xi, No. 60, p. 73. 
 1889. Felkin. Foetal Malaria, as Illustrated by Two Cases. Edinb. Med., 
 
 Journ., June, p. 1101. 
 1894. Bastianelli. Sulla transmissione dei parasiti della malaria della 
 
 madre al feto. Bull, della Soc. Lancisiana degli osped. di Roma, xii, 
 
 p. 48. 
 1897. Bignami. Sulla questione della malaria congenita. Supple, al Poli- 
 
 clinico, iv, p. 763. 
 1897. Winslow. A Case of Congenital Malaria. Bost. Med. and Surg. Jour., 
 
 Ma Y 2 7> P- 5'4- 
 
THE ETIOLOGY OF THE MALARIAL FEVERS. 1 23 
 
 1902. Peters, L. Malarial Fever in Infancy, Probably Maternal in Origin. 
 Johns Hopkins Hosp. Bull., vol. viii, p. 139. 
 
 1903. Sereni. Sulla transmissibilita dei parassiti della malaria della madre 
 al feto. Bull. d. R. Accad. di Med. di Roma, Fasc. 1-2-3. 
 
 1906. Zieman. Article upon the "Malarial Fevers" in Menses " Handbuch der 
 Tropenkrankheiten. ' ' 
 
 1907. Thayer. " Malaria" in Allbut and Rolleston's "System of Medicine," 
 p. 247. 
 
PART II. 
 
 THE GENERAL AND SPECIAL PATHOLOGY OF THE 
 MALARIAL FEVERS. 
 
ALUMNI ASSOCIATION, 
 
 COLLEGE OF PHYSICIANS AnDSU 
 COLUMBIA UNIVEkSU Y 
 NEW YORK 
 
 CHAPTER I. 
 
 The General Pathology of the Malarial Fevers; Morphological Changes in 
 the Erythrocytes and Leucocytes; Anaemia; Differential Blood Count; Phago- 
 cytosis; Melanaemia; The Urine; The Etiology of the Fever. 
 
 Primarily, malarial infections exert the most marked effect upon the blood, 
 as the plasmodia live at the expense of the red blood-corpuscles, and probably 
 elaborate toxins which materially affect all of the elements of this fluid. 
 The pathological changes which occur in the blood as the result of malarial 
 infections are due to primary and secondary causes. The primary cause is the 
 infection of the erythrocytes with the plasmodia and the changes brought about 
 by such infection; the secondary is the anaemic condition which is the inevitable 
 result of all malarial infection. 
 
 Morphological Changes in the Erythrocytes and Leucocytes. — 
 Certain morphological changes occur in the cells of the blood as the result 
 of the invasion of the red corpuscles by the plasmodia, and these changes 
 vary with the species of plasmodia concerned. The chief changes occurring 
 in the erythrocytes are: 
 
 Changes in Size. — As I have already noted the red blood-corpuscles 
 when invaded by Plasmodium vivax, the tertian parasite, become swollen, and 
 as the parasite increases in size the red corpuscles also enlarge until, when 
 the parasite is fully developed, the red cell is twice or three times as large as the 
 uninvaded cells surrounding it. t This is a characteristic change in tertian 
 infections. In cells invaded by Plasmodium malariae, on the other hand, there 
 is no increase in size, but the invaded red cell is of the same size as the normal 
 cells, or, in a few instances, somewhat smaller. In infections with the aestivo- 
 autumnal plasmodia, the invaded red cell is always smaller than the normal 
 cells, a change which is as characteristic of these infections as the enlarged 
 erythrocyte is of tertian malarial infection. 
 
 Changes in Form. — The red corpuscle invaded by the tertian plasmodium 
 is generally somewhat distorted in shape when the parasite is fully grown, 
 but is never crenated. In quartan infections the shape of the red cell is pre- 
 served, as it generally is in aestivo-autumnal infections, but in the latter crena- 
 tion of the cell is very common, especially in the quotidian aestivo-autumnal 
 infections. 
 
 Changes in Color. — In tertian infection the color of the infected red cells 
 is much paler than normal, and when the parasite is fully developed the red 
 cell may be almost colorless; even in newly invaded cells the color is much less 
 marked than in the normal red corpuscles, and this serves as a diagnostic 
 
 127 
 
128 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 feature in differentiating this plasmodium from quartan and aestivo-autumnal 
 organisms. In the latter infections the color of the red cell invaded by the 
 parasite is not diminished, but, especially in the aestivo-autumnal infection, 
 increases. In infections with the quartan parasite the color of the infected red 
 cell is normal or else it is slightly more greenish than normal; in the aestivo- 
 autumnal infections the infected red cell is generally darker green in color than 
 normally, and may appear "brassy," the cell being smaller and appearing 
 shrivelled. This change is most marked after a paroxysm, when the parasites 
 have become pigmented, and the dark olive-green color of the invaded cells is 
 generally present after the administration of quinine, which appears capable of 
 producing this change in the infected corpuscles in both aestivo-autumnal and 
 quartan infections. Marchiafava and Bignami believe that the "brassy" 
 appearance indicates necrosis of the red cell and that after this occurs the plas- 
 modium within the cell perishes. I believe that while the increase in color may 
 indicate necrosis of the red cell, this necrosis is the essential result of its invasion 
 by the plasmodium, and that the latter does not die, but undergoes sporulation 
 in such cells. This is easily demonstrated in smears of blood from the spleen 
 in aestivo-autumnal infections, in which many brassy red corpuscles may be 
 seen to contain sporulating plasmodia. The "brassy" cells are most numerous 
 in quotidian aestivo-autumnal infections. 
 
 Retraction of Haemoglobin ( Partial Decolorization of the 
 Erythrocyte.) — Many infected red corpuscles, especially in aestivo-autumnal 
 infections, show a retraction or concentration of the haemoglobin at some por- 
 of tion the periphery of the cell or within it, small areas being colorless. In many 
 instances this haemoglobin membrane, as it may be called, is retracted about 
 the contained parasite, and it is to this change in the red cell that the "bib" 
 and double outline of the crescent or gamete is due. In malarial infections the 
 uninvaded red cells often present colorless areas, or vacuoles, which are many 
 times mistaken for hyaline parasites by the novice in blood examinations, and 
 the almost colorless center of anaemic red cells, so often observed in malaria, is 
 not infrequently mistaken for a plasmodium. 
 
 Changes in the Staining Reactions of the Erythrocytes. — In ter- 
 tian infections, and rarely in quartan and aestivo-autumnal infections, speci- 
 mmens of blood stained by one of the modifications of Romanowsky's method, 
 show reddish-stained granules in the protoplasm of the invaded red cells, known 
 as Schuffner's dots. I have already spoken of the diagnostic significance of these 
 dots as regards tertian infections and stated that this change in the staining 
 reaction of the red cell is characteristic, generally, of such infections. As is well 
 known, many of the erythrocytes in severe cases of malarial infection present 
 the phenomena described as polychromasia and basophilic degeneration. This 
 is evidenced by areas in the red cell or the whole cell staining a brownish color or 
 the cell is filled with granules which are basophilic in character. This condition, 
 however, is not characteristic of malaria, for it occurs in all severe anaemias and 
 in many other diseases, as has been shown by many observers, notably Maxi- 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 1 29 
 
 mow, Askanazy, Litter, Bloch, Fish, Cabot, Ewing, Schwalbe and Solley, 
 Grawisz, and Stengel, White and Pepper. 
 
 The exact nature of polychromasia and basophilia is as yet a matter of 
 controversy, some authorities regarding the process as degenerative in nature, 
 while others maintain that it is not of necessity a regressive process. It is 
 not advisable here to consider the arguments as to the significance of 
 these basic staining granules, but it would appear that so far as the study of 
 the process in malaria is concerned, the evidence all points to its degenerative 
 nature. 
 
 The only observations regarding the significance of basophilia of special 
 interest to the student of malaria are those of A. Plehn. He suggests that the 
 granules which are basophilic in character and which are observed in the red 
 cell in malaria, are in reality latent forms of the plasmodia. He believes that 
 multiplication of these latent forms occurs in the blood, followed by destruction 
 of the red cells, which process continues until conditions are favorable for the 
 development of the large amoeboid plasmodia. He also states that after the 
 disappearance of the amoeboid forms these latent bodies remain, continuing as 
 the latent form of the plasmodium. 
 
 The observations of Plehn have not been confirmed by any observer, while, 
 on the other hand, all those who have studied the subject unite in considering 
 the basophilia of malaria as identical with that occurring in other diseases. 
 Solly, from his studies of tertian malarial blood, found granulations of the red 
 cell in only two out of thirty cases, and concludes that there is no evidence that 
 the granulations are latent malarial plasmodia. I have observed basophilia 
 in a very great number of specimens of malarial blood, and agree with Solley 
 that there is no evidence whatever that the granulations are a form of the 
 malarial plasmodium. To believe that the erythrocyte contains at the same 
 time a growing amoeboid plasmodium and multitudes of latent forms (the 
 dots) is impossible, and when it is remembered that the same process is ob- 
 served in the erythrocytes in other diseases, I believe that Plehn's hypothesis is 
 untenable, and unsupported by any evidence of value. No morphological 
 changes of importance occur in the leucocytes in malaria with the excep- 
 tion of those observed in phagocytosis, which will be discussed later in this 
 chapter. 
 
 Malarial Anaemia. — Every malarial infection, whether acute or chronic, 
 is accompanied by anaemia, the inevitable result of the destruction of the red 
 cells by the invading plasmodia, and, to a lesser extent, by the action of the 
 toxins liberated in the blood by the escape of the parasites from the red cells. 
 In no disease is the destruction of the red corpuscles more rapid than in malaria 
 and in no other class of infections is anaemia of greater diagnostic importance, 
 especially if it has appeared suddenly and is accompanied by chills and fever. 
 The anaemia of malaria affects both the red and white corpuscles and the 
 haemoglobin, and has been thoroughly studied by nearly every writer upon these 
 fevers, but to Kelsch we owe the first exhaustive study of this subject, and his 
 9 
 
I30 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 work, completed in 1876, stands to-day almost alone in its thoroughness and 
 scientific accuracy. 
 
 The Red Corpuscles. — No matter how slight an attack of malaria we 
 may be observing, we shall invariably find a reduction in the number of red 
 blood-corpuscles, and the more severe the attack may be the greater will be the 
 reduction in. these cells. In severe aestivo-autumnal infections, and even in 
 tertian and quartan infections of extraordinary severity, the red corpuscles may 
 fall from normal to 3,000,000 per cu. mm. within 48 hours, and in pernicious 
 attacks the reduction may be even greater. Turk describes a loss of 1,000,000 
 red cells in one day; Mannaberg, 1,000,000 in two days, and Kelsch, 2,000,000 
 in two days, in acute aestivo-autumnal infections. I have observed a loss of 
 nearly 2,000,000 red cells in thirty-six hours in a case of tertian aestivo-autumnal 
 malaria. Marchiafava and Bignami state that in a case of quotidian malaria 
 the red cells were reduced 1,000,000 within 24 hours, and Dionisi found that in 
 an acute attack of tertian aestivo-autumnal fever which had lasted three days 
 the red blood count showed only 2,625,000 red cells per cu. mm. In pernicious 
 attacks of aestivo-autumnal malaria Kelsch states that in one day the red cells 
 may be reduced to 1,000,000 per cu. mm. in initial attacks, while if the patient 
 has already suffered from malaria and is thus anaemic, a pernicious attack 
 generally reduces the red cells to from 1,000,000 to 2,000,000 per cu. mm. In a 
 case of pernicious quotidian aestivo-autumnal malaria, which proved fatal, I 
 found that the red blood-corpuscles only numbered 860,000 per cu. mm. a few 
 hours before death, the attack having lasted about five days. In this case there 
 was no rise in the temperature until just before death, so that the anaemia pro- 
 duced was not dependent upon high temperature. 
 
 A reduction in the number of red blood-corpuscles follows every paroxysm 
 for a certain period of time, but it will always be observed that while during 
 the first few days of an initial infection the reduction is marked, the continuance 
 of the disease, after a certain amount of anaemia has been produced, is not 
 characterized by a further reduction, but the number tends to remain at a 
 certain level, no matter how long the infection may last. In each recurrence 
 it will be found that the reduction in the number of red corpuscles is less and 
 less marked, and in chronic infections, while there is more or less anaemia, 
 there is but a slight reduction of red cells after a paroxysm. 
 
 The return to the normal number of red corpuscles after mild or even 
 severe attacks of tertian and quartan fever which have been promptly stopped 
 by treatment is usually fairly rapid, but cases untreated, or in which many 
 relapses have occurred, are followed by a chronic and persistent anaemia, 
 which is one of the most marked characteristics of people inhabiting malarial 
 regions. In aestivo-autumnal infections the return to the normal number of 
 red cells is much slower than in tertian and quartan infections, and after a 
 moderately severe attack it will be found that the normal number of red cells 
 is not reached, as a rule, before the end of two months, although in rare instances 
 recovery is rapid. In one case under my observation the red cells fell to 690,000 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 131 
 
 per cu. mm. in three days, and increased to 2,100,000 per cu. mm. in three weeks, 
 after treatment, and it was several months before the normal number of red 
 corpuscles was regained. 
 
 Dionisi has contributed some very valuable data concerning the anaemia 
 of the aestivo-autumnal infections and his conclusions are here given: 
 
 " 1. In aestivo-autumnal fever, the reduction in the number of the red blood- 
 corpuscles bears a direct relation to the number of the organisms. Where the 
 parasites are numerous there is a constant reduction of from 200,000 to 1,000,000 
 with each febrile paroxysm; where the parasites are scanty the reduction is less. 
 
 "2. When crescentic bodies are present in addition to the other forms, they 
 seem to exert no influence on the blood changes. 
 
 "3. When, after a paroxysm, the number of corpuscles has suffered a sud- 
 den and very marked diminution, the suceeding paroxysms may be followed by 
 but a slight reduction only, or even by an increase. 
 
 "4. In relapses, the reduction per paroxysm is less than in a primary infec- 
 tion. 
 
 "5. In infections determined by the amoeboid forms (acute aestivo-autum- 
 nal infections) there is, during apyrexia, no complete return of the red corpuscles 
 to their normal number. Some attempts at restitution may be seen during the 
 first several days of apyrexia, while after this, during perhaps eight to fifteen days, 
 there may be a steady reduction of from 100,000 to 500,000 red blood-corpuscles 
 without the appearance of any parasites in the blood. 
 
 "6. Only after marked and continuous reductions following each paroxysm 
 does there occur in the afebrile period a relative restitution of the red blood-cor- 
 puscles; this may be slow or rapid. 
 
 "7. If the increase in the corpuscles has begun, the presence of crescents 
 has no deleterious effect. 
 
 "8. In tertian and quartan fevers the same changes are observed, excepting 
 that in the afebrile period there is a rapid and almost complete restitution of 
 the red blood-corpuscles." 
 
 My observations upon the reduction in the red blood-corpuscles in aestivo- 
 autumnal fevers confirm those of Dionisi in all essential particulars, but I 
 believe that the reduction observed after the disappearance of the symptoms, 
 and which lasts for a few days, is due to plasmodia whch have escaped destruc- 
 tion by quinine, which, while not numerous enough to produce symptoms, 
 destroy a certain number of red corpuscles. This may also serve to explain 
 the slow restitution of the red blood-corpuscles in this class of infections, for, 
 as I shall demonstrate, many individuals harbor the aestivo-autumnal plas- 
 modia for weeks without presenting any definite symptoms of malarial infection. 
 
 The Leucocytes. — In acute malarial infection the leucocytes are reduced 
 in number, both absolutely and relatively to the red blood-corpuscles. Thus 
 the malarial fevers, like typhoid, dengue, kala-azar, and trypanosomiasis, are 
 characterized, as a rule, by a marked leucopenia, only the pernicious forms 
 showing a leucocytosis. During the first hours of an acute attack of any of 
 the forms of malaria there may be a more or less marked leucocytosis, some- 
 times only visible during the first fifteen or twenty minutes, at others still 
 
132 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 demonstrable until the decline of the fever. Generally the leucocytosis is 
 only observable for a short time at the onset of the paroxysm, soon giving 
 place to the characteristic leucopenia. Kelsch found that the leucocytes 
 gradually decreased in number as the paroxysm continued and that after the 
 attack the leucocytes number from a half to a third of the normal number. 
 After recovery the leucocytes increase very gradually until the normal number is 
 reached, but this increase is very slow as compared to the rapidity of the decrease 
 during the active stages of the infection. 
 
 In tertian, quartan, and in ordinary aestivo-autumnal infections the 
 leucocytes during the attack number from 3,000 to 5,000 per cu. mm. as a rule, 
 although many cases are observed in which these cells number from 2,000 to 
 2,500 per cu. mm. 
 
 In the pernicious forms of malaria, generally due to the aestivo-autumnal 
 Plasmodia, a marked leucocytosis is often observed. Kelsch first noted this 
 fact, and gives instances in which he found 20,000, 25,000, and as high as 
 35,000 leucocytes per cu. mm. I have never observed a case of pernicious 
 malaria in which there was not a marked leucocytosis, and in one instance, due 
 to the quotidian plasmodium, the leucocytes numbered over 40,000 per cu. mm. 
 When recovery occurs, the leucocytosis quickly disappears, but in fatal cases 
 it perists to the end, so that the occurrence of a marked leucocytosis, which 
 tends to increase, is a bad prognostic sign in pernicious malaria. 
 
 The Differential Leucocyte Count. — Recently much attention has been 
 paid to the changes occurring in the relative proportion of the various leucocytes 
 in acute malarial infections. Rogers called attention to the relative increase 
 in the mononuclear leucocytes, and his observations have been confirmed by 
 numerous investigators. Stephens and Christophers state that there is always 
 an increase in the large mononuclears, and they consider this increase of great 
 diagnostic importance. Billet found a marked increase in the mononuclears 
 and considers that an increase in the polynuclears indicates a complication. 
 Poch, in his studies of the blood in tertian and quartan infections, found a 
 marked initial increase in the polynuclears, succeeded by an increase in the 
 mononuclears. Zieman describes a polynuclear increase at the beginning 
 of the febrile attack, which, at the height of the fever, disappears rapidly, 
 and is succeeded by a relative increase in the large mononuclears. These 
 changes occur in initial attacks and in recurrences, but not in cachexia. From 
 my own observations, I believe that in all forms of malarial infection, during 
 acute attacks, whether initial attacks or recurrences, there occurs a relative 
 increase in the mononuclear leucocytes, chiefly the large mononuclears, and 
 that this increase occurs in the vast majority of the cases, but not in all. An 
 increase in the polynuclear leucocytes is often observed during the onset of 
 the febrile paroxysm, especially when the leucocytosis is marked, but a poly- 
 nuclear increase occurring during the subsidence of the fever or in the apyrexial 
 period indicates a complication. The following differential blood counts 
 illustrate those commonly obtained in malarial infections: 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 J 33 
 
 Polynuclears, 
 Small mononuclears, 
 Large mononuclears 
 and transitionals, 
 Eosinophiles, 
 
 Polynuclears, 
 Small mononuclears, 
 Large mononuclears 
 and transitionals, 
 Eosinophiles, 
 
 Polynuclears, 
 Small mononuclears, 
 Large mononuclears 
 and transitionals, 
 Eosinophiles, 
 
 52 
 
 .0%' 
 
 16 
 
 •3% 
 
 3 2 
 
 4% 
 
 
 •3%) 
 
 Count in tertian malaria. 
 
 55-°% 
 20.6% 
 
 22.2% 
 3-°% J 
 
 45-°% 
 18.4% 
 
 5.o% 
 35-6% 
 
 1.0% 
 
 Count in quartan malaria. 
 
 Count in aestivo-autumnal infections. 
 
 The above counts are intended merely to illustrate those obtained in 
 malarial disease and it should not be expected that all counts will show as large 
 an increase in the mononuclear leucocytes, although in the majority of instances 
 the large mononuclears will constitute from 15 to 20 per cent, of the leucocytes 
 observed. The greatest increase is observed during apyrexia, the least during 
 the height of the fever. The differential leucocyte count is of some value in 
 differentiating the aestivo-autumnal remittent fevers from typhoid, as in the 
 latter there is no increase in the large mononuclear cells, although there is a 
 leucopenia and an increase in the small mononuclears. Rodgers has con- 
 tributed several valuable studies upon the diagnosis of malaria and typhoid by 
 means of the differential blood count, and where the plasmodia cannot be 
 found or the Widal test applied this method may be of great assistance in dif- 
 ferential diagnosis. It is of but little value, however, in differentiating between 
 malaria and such diseases as kala-azar, dengue, or trypanosomiasis, as in the 
 latter a large mononuclear increase is often observed. While in something 
 over 50 per cent, of cases of malarial infection a relative increase in the large 
 mononuclear leucocytes is observed it has not been my experience that very 
 much weight can be given in diagnosis to a mononuclear increase in malarial 
 infection. 
 
 The Haemoglobin. — Besides the reduction in the number of the red and 
 white blood-corpuscles, there is generally a marked reduction in the haemo- 
 globin in all malarial infections, but especially in the aestivo-autumnal infections. 
 This reduction is usually proportionate to the loss in red corpuscles, but in 
 some cases the haemoglobin is less than normal in proportion to the loss in 
 the red corpuscles, and in pernicious cases, the loss of haemoglobin may be 
 rapid and great, from 10 to 40 per cent, being lost in two or three days. How- 
 ever, little weight can be given to the reduction in haemoglobin as regards 
 the prognosis of individual cases, for in some of the most pernicious forms 
 of malaria that I have observed, there has been but a slight reduction in the 
 
134 TH E PATHOLOGY OF THE MALARIAL FEVERS. 
 
 haemoglobin, while in many mild tertian infections there is often a very marked 
 reduction. 
 
 Rossoni has thoroughly investigated the effect of malarial infections upon 
 the haemoglobin index of the blood and his conclusions, which have been 
 confirmed by numerous investigators, are as follows: 
 
 "i. No acute -infection results in as active a deglobulization as does ma- 
 larial fever. 
 
 "2. In all cases of malarial fever there is an immediate diminution in the 
 number of corpuscles and in the amount of haemoglobin. This loss generally 
 bears a direct relation to the duration of the infection. In pernicious cases, 
 however, a diminution of as much as two-thirds of the total amount may take 
 place in from one to three days. 
 
 "3. The gravity of pernicious cases does not always bear a direct relation 
 to the extent of the loss in haemoglobin. 
 
 "4. The destruction of haemoglobin and corpuscles bears, generally, a direct 
 relation to the number of parasites in the blood. Occasionally, however, cases 
 with high fever and marked losses in haemoglobin and corpuscles may show but 
 few parasites in the circulating blood. A long continued diminution of haemo. 
 globin is often associated with the presence of crescents. 
 
 "5. The loss in haemoglobin and corpuscles is rarely evident during the 
 paroxysm, but begins with apyrexia and may continue for several days afterward. 
 
 "6. Recovery from malarial anaemia is slower than from the other acute 
 anaemiae. 
 
 "7 Usually the haemoglobin and corpuscles are equally diminished, but 
 sometimes the haemoglobin is a valuable point in differential diagnosis between 
 malarial fever and enteric fever or pneumonia. 
 
 "8. The restitution of the haemoglobin in malarial anaemia is often incom- 
 plete, and individuals living in malarial districts have often a slightly smaller 
 percentage of haemoglobin than those living elsewhere." 
 
 Phagocytosis. — In examining the blood of patients suffering from 
 malarial infections, it will almost invariably be noticed that many of the leuco- 
 cytes contain brown or blackish pigment, portions of plasmodia, or even whole 
 plasmodia. These leucocytes are the so-called phagocytes which can always 
 be demonstrated in malarial blood at some time during the infection. These 
 pigment containing cells were observed and described as occurring in the blood 
 before the plasmodia of malaria were discovered, and Laveran, Marchiafava, 
 Celli, Golgi, Metchnikoff, Bignami, Osier, Barker, Dock, and Thayer have 
 all added to our knowledge of these cells. In the tertian and quartan infections 
 phagocytes were observed to be most numerous during or just after the par- 
 oxysms, while in the aestivo-autumnal infections these cells appeared at less 
 regular intervals. Marchiafava and Celli first proved that the phagocytes 
 are capable of engufilng and destroying living plasmodia, Laveran having held 
 that the pigment observed in these cells was engulfed only after the fragmenta- 
 tion and death of the plasmodia. That Marchiafava and Celli were right in 
 their observations may be proven by any one interested, for one of the most 
 interesting and instructive phenomena visible under the microscope, is the 
 engulfing of extracellular malarial plasmodia by the phagocytic leucocytes. 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 135 
 
 Golgi, as the result of his researches upon phagocytosis in tertian and 
 quartan malaria, and Marchiafava, Bignami, and Bastianelli, as the result of 
 theirs in aestivo-autumnal fevers, have demonstrated that phagocytosis occurs 
 most commonly during the early hours of a malarial attack, and that during 
 apyrexia this process almost disappears. Golgi considered that to phagocytosis 
 we owe spontaneous recovery in malaria, and his opinion agrees with that of 
 Metchnikoff, who believes that these cells, either by engulfing and digesting 
 the plasmodia or by excreting products inimical to their growth, bring about 
 recovery in most cases of malarial infection. 
 
 The Phagocytic Cells. — The cells which act as phagocytes in malaria are: 
 the large mononuclear and transitional leucocytes, as well as certain of the 
 polynuclear cells; the endothelium of the liver and Kupffer's cells; the cells of 
 the splenic pulp, and the uninuclear leucocytes in the bone marrow. The 
 small mononuclears and the eosinophiles have been said, by some observers, 
 to be phagocytic, but these cells are not generally so. In one or two instances, 
 I have observed entire plasmodia within coarsely granular eosinophiles, so 
 it is impossible to deny that, under certain conditions, these cells may become 
 phagocytic, but they are not so normally. 
 
 The large mononuclears and the transitionals in the peripheral blood, and 
 to a lesser degree the polynuclears, are the chief phagocytic agents in all 
 malarial infections, and while the total number of leucocytes in these infections 
 is decreased, it will be noted that the phagocytic cells are relatively increased, 
 thus adding support to Metchnikoff 's theory that to these cells we owe sponta- 
 neous recovery in malaria. 
 
 The endothelial cells of the liver are found in the peripheral circulation 
 acting as phagocytes in only the most pernicious cases of malaria, but in the 
 liver these cells, as well as the cells of Kupfer, are actively phagocytic, show- 
 ing within them pigment, plasmodia, and even red blood-cells containing the 
 plasmodia. In fatal cases, these cells are often observed lying free in the 
 capillaries, crowded with pigment and parasites, and even those cells still 
 attached to the vessel walls contain much pigment and fragments of 
 plasmodia. 
 
 The cells of the splenic pulp are very actively phagocytic and here we find 
 immense cells, from 10 to 20 times the size of the small mononuclear, containing 
 great blocks of pigment, plasmodia in various stages of development, and 
 even entire infected red blood-corpuscles. These large cells are known as 
 macrophages, and are characteristic of malarial infection. The splenic vessels, 
 in fatal cases of malaria, are crowded with these macrophagi, with free malarial 
 pigment, and degenerated cellular material, and, as Marchiafava and Bignami 
 suggest, it is probable that many of the melaniferous cells observed in the 
 vessels of the liver are really derived from the splenic pulp. 
 
 Degenerative Changes in the Phagocytic Cells. — In pernicious cases 
 of malaria there occur in the peripheral blood numerous phagocytic cells 
 which are evidently undergoing degeneration, and sections of the liver, the 
 
I36 THE PATHOLOGY OF THE MALARIAL LEVERS. 
 
 spleen, and smears of the bone marrow, in such cases, show numerous degenera- 
 ing phagocytes. The forms of degeneration occurring in these cells comprise 
 vacuolization, fatty degneration, and fragmentation of the nucleus. Such 
 forms of degeneration occur rarely in leucocytes which present no evidence of 
 phagocytosis. The degenerative changes are most common and marked in 
 the large mononuclear leucocytes and in the macrophages. Bignami has claimed 
 that the malarial spores are capable of developing after the necrosis of the 
 phagocyte which has engulfed them, but his theory has never been proven and 
 it is extremely doubtful whether any form of the malarial plasmodia is capable 
 of development after it has once been engulfed and acted upon by the phagocytic 
 cell. 
 
 Time of Occurrence of Phagocytosis. — In tertian and quartan malarial 
 fevers phagocytosis is most marked during or directly after the chill, and this is 
 true also in uncomplicated cases of tertian and quotidian aestivo-autumnal 
 malaria during an acute attack. If, however, the disease has persisted for 
 some time or there is a double infection, the cyclical appearance of phagocyto- 
 sis cannot be demonstrated without repeated observations and most careful 
 study, and often not even then. In pernicious cases phagocytes are, as a rule, 
 very numerous, especially the large mononuclear variety, and the macrophages. 
 Quinine tends to increase phagocytosis, especially in pernicious cases. In 
 many instances of severe aestivo-autumnal infection an examination of the 
 blood at any time will show a marked phagocytosis, due in all probability to 
 the rapid and irregular multiplication of the plasmodia. 
 
 Substances Engulfed by the Phagocytes. — In malarial infections the 
 following are found within phagocytic cells: first and most common, free pig- 
 ment; second, extracellular plasmcdia, many of which are flagellated; third, 
 shrunken and degenerated red corpuscles, both with and without parasites 
 (these occur only within macrophages) ; fourth, segmenting plasmodia (common 
 in blood from the spleen); fifth, crescentic and ovoid forms (very rarely). The 
 amount of pigment and cellular detritus absorbed by the phagocytes is enor- 
 mous, and there can be no doubt that these cells are of inestimable value to the 
 organism in taking from the capillaries and small vessels this material which 
 might so easily occlude them. In this way alone phagocytosis in malaria is of 
 the very greatest importance, for without it we would observe pernicious 
 symptoms in the majority of our cases. 
 
 The Significance of Phagocytosis. — The fact that the phagocytes not 
 only engulf and clear the vessels of pigment and cellular deteritus, but that 
 they can, and do, engulf and destroy large numbers of living plasmodia proves 
 that this process must be one of vital significance. It is undoubtedly true that 
 the sporulation of the plasmodia acts as the stimulating factor to phagocytosis, 
 for, as I have shown, this process is most marked during a malarial paroxysm, 
 and this fact would appear to indicate that phagocytosis is an important, if not 
 the most important, means of defense possessed by the organism against 
 malarial infection. Two theories have been advanced regarding the signifi- 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 137 
 
 cance of this process, one, advocated by Metchnikoff and his followers, that 
 phagocytosis in malaria is an active protective process and is the cause of 
 spontaneous recovery; the other, advocated by Bastianelli, that it has but little 
 to do with spontaneous recovery, and that the facts are not sufficient to prove 
 that the phagocyte is, as Metchnikoff believes, an active enemy of the malarial 
 plasmodia. 
 
 We believe that there can be no doubt in the mind of a careful observer 
 that the phagocytic cells perform a very active part in the destruction of living 
 malarial plasmodia, and that, therefore, the phagocyte is an active enemy of 
 these organisms. We believe that it is also clear that this process exercises 
 an important mission in enabling the organism to recover from the infection, 
 but we doubt that phagocytosis is the direct and only cause of spontaneous 
 recovery. The immense value of the process in ridding the vessels of the viscera 
 the bone marrow, and the peripheral capillaries of free pigment, cellular 
 detritus, and degenerated plasmodia must be admitted, for after pernicious 
 attacks of malaria, only a few days supervene before the body is practically 
 cleansed of the results of the infection, such as pigment, degenerated red cells 
 and leucocytes, and fragmented and moribund plasmodia. 
 
 In many malarial infections, especially the aestivo-autumnal fevers, 
 phagocytosis has considerable prognostic value. From my own observations 
 I would say that the following rule will hold true in almost every case of aestivo- 
 autumnal malaria: The greater the phagocytosis the more severe is the in- 
 fection and the more grave the prognosis. Especially is this true if in the per- 
 ipheral blood occur numerous large mononuclear phagocytes or macrophages. 
 I am convinced that a marked phagocytosis in aestivo-autumnal malaria, far 
 from being a feavorable sign, is almost typical of a pernicious infection, and if no 
 cyclical course can be traced after repeated examinations, is absolutely typical, 
 and should be the signal for the institution of the most energetic therapeutic 
 measures. 
 
 It would appear, from the evidence at hand, that phagocytosis is one of the 
 weapons possessed by the organism which enable it to overcome malarial in- 
 fection, both by the property possessed by the phagocyte of engulfing and 
 destroying the living plasmodia, and by removing from the organism the pig- 
 ment and cellular detritus which would otherwise accumulate and injure the 
 tissues. This process cannot be considered as the cause of spontaneous re- 
 covery, acting alone, but it is one of the most important factors concerned in 
 such recovery, and may be the principal factor in many instances. It is cer- 
 tainly true that Metchnikoff is correct in considering the phagocyte as an active 
 agent in ridding the body of malarial plasmodia, and it may well be that in the 
 phagocyte we have the true explanation of malarial immunity. 
 
 Melanaemia. — The occurrence within the blood of malarial pigment, 
 either free or enclosed within the leucocytes, is known as melanaemia, and, next 
 to the occurrence of the plasmodia within the red corpuscles, is the most char- 
 acteristic change occurring in the blood n malarial infections, and is the one 
 
130 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 which has been longest known to the students of these fevers. This pigment 
 may be brown, brownish-yellow, or black in color, and may occur in the form of 
 blocks, granules, rods, grains, irregular clumps, fine needles, or cylindrical, 
 polyhedral, circular or irregular masses. This condition is only present in 
 malarial infections, and is often of great service in diagnosis where the parasites 
 are few in number or in chronic malarial poisoning. 
 
 Historical. — The history of the discovery and explanation of pigment in 
 the blood in malaria is of interest, but we can only touch upon it in this con- 
 tribution. Meckel, in 1847, was the first to describe pigment as occurring in 
 the blood in malaria, and his observations were soon confirmed by those of 
 Virchow and Frerichs, and these authorities considered that the pigment was 
 derived from the spleen or liver, although Frerichs believed that it origi- 
 nated in the spleen alone, being due to the destruction of the blood in that 
 organ. Meigs and Colin wrote excellent descriptions of this condition, but 
 to Arnstein we owe the discovery that the pigment originates in the circulating 
 blood during the malarial paroxysm, being deposited afterward in the liver, 
 spleen, bone marrow, and other viscera. He, together with Kelsch, came to the 
 conclusion that the destruction of the red blood-cells in malaria gave rise to the 
 pigment, which remained in solution in the blood until the latter became 
 saturated, when it was precipitated in granules which were then engulfed by the 
 leucocytes. This theory was accepted until the investigations of Laveran, 
 Marchiafava, and Celli, who demonstrated that the pigment is not formed 
 after the disintegration of the red corpuscles, but is formed during the growth 
 of the malarial plasmodia within them, being, in fact, the changed hemoglobin 
 of the corpuscles absorbed by the plasmodia during their growth. The true 
 malarial pigment, or melanin, is elaborated during the development of the 
 plasmodia within the infected cell and is liberated when sporulation of the 
 parasites occurs. 
 
 Varieties of Pigment. — Two varieties of pigment are present in the 
 blood in malarial infections: one, melanin, the true malarial pigment, is black in 
 color, and is found in both the blood and tissues; the other, haemosiderin, is 
 yellow in color, and is found only in the tissues. The first gives no reaction for 
 iron; the second does. 
 
 As regards the origin of the two varieties, I am fully in accord with Big- 
 nami, who says: "The melanaemia, index of an acute infection, is derived 
 only from the direct transformation of haemoglobin into melanin through the 
 action of the parasites within the red corpuscles, as Marchiafava and Celli have 
 demonstrated; that the melanosis of the viscera, spleen, liver, bone-marrow, etc., 
 index of a previous infection, has a double origin. In chief part it is derived 
 from the melanaemia, that is, from the deposition in the viscera of the black 
 pigment formed during the acute infection in the circulating blood; in part it has 
 a local origin, that is, it is derived from the slow transformation of the blocks of 
 ochre-colored pigment which are deposited or formed in the spleen and in the 
 other viscera from the enormous quantity of altered red blood-corpuscles, 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. I39 
 
 which, in grave infections, die before the direct action of the parasites has 
 transformed their haemoglobin into black pigment." 
 
 Chemical Characteristics of Melanin and Haemosiderin. — Melanin 
 (the black pigment) is not acted upon by strong acids, but is decolorized by the 
 potassium and ammonium salts; it is very soluble in sulphide of ammonium, but 
 insoluble in strong acids. No trace of iron has ever been demonstrated in 
 melanin, but this fact does not prove that it is not present. In all probability, 
 melanin is closely allied to haematin, as is held by Carbone, who believes that it 
 is identical with the latter. 
 
 Haemosiderin (the yellow pigment) is insoluble in strong acids, caustic 
 potash, alcohol and water; turns black when treated with sulphide of am- 
 monium, and gives a blue color when treated with ferrocyanide of potassium 
 and hydrochloric acid. Thus it will be seen that this pigment, unlike melanin, 
 gives an iron reaction. 
 
 Distribution of Melanin and Haemosiderin. — Melanin occurs in the 
 blood and tissues in the form of minute granules of a dark brown or nearly 
 black color, which tend to accumulate in small irregular clumps when situated 
 in the viscera. In tertian infections the melanin is generally of a golden-brown 
 color, while in quartan and aestivo-autumnal infections it is darker, generally 
 almost black. This pigment, formed, as has been said, within the red cells or, 
 more properly, within the body of the plasmodium, is liberated with the seg- 
 ments during sporulation, and is taken up by the leucocytes or is deposited in 
 certain tissues, especially in the brain, spleen, liver, and bone-marrow. This 
 pigment is engulfed by the large mononuclear leucocytes, the polynuclear 
 leucocytes, and rarely by the eosinophiles, but not by the endothelial cells of 
 the liver and spleen, or by Kupfer's cells in the liver. In the tissues this pig- 
 ment may often be seen in large quantities, much of it having reached this 
 locality by diapedesis of leucocytes containing the pigment or by the rupture of 
 capillary vessels which have become occluded by phagocytic leucocytes and 
 masses of melanin. This pigment occurs free in the blood plasma, but, while 
 used as a diagnostic evidence of malarial infection, such free pigment cannot be 
 relied upon in diagnosis, as extraneous particles of dirt, so common in blood 
 specimens, cannot be differentiated morphologically from melanin. Pigmented 
 leucocytes, provided the pigment contained within them is dark brown or black 
 in color, are of value in diagnosis. In pernicious malaria melanin occurs in 
 considerable amount in the kidneys and the lungs, as well as the muscular wall 
 of the heart, and in cases characterized by intestinal irritation this pigment is 
 common in the villi of the intestine. 
 
 The yellow pigment, or haemosiderin, occurs within the tissues, never in 
 the peripheral blood. In the liver and spleen, and in smaller quantity in the 
 bone-marrow, kidneys, and other viscera, this pigment occurs in the form of 
 fine grains, larger masses of an amber color, and large blocks or masses of a 
 golden-yellow color. It is especially abundant in fatal cases of pernicious 
 aestivo-autumnal fevers, occurring in such cases chiefly in the liver and spleen. 
 
1 4° THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 This pigment is also derived from the haemoglobin of the red corpuscles, but 
 from corpuscles which have not been invaded by the plasmodia. Unlike 
 melanin, this pigment is observed within the endothelial cells of the viscera and 
 in Kupfer's cells, as well as in the cells of the spleen and within the epithelium 
 of the kidney tubules. Melanin occurs chiefly in the phagocytic cells in the 
 capillaries of the viscera, while haemosiderin occurs most frequently within the 
 tissue cells of the viscera. 
 
 There is some evidence which goes to prove that melanin may be derived 
 from haemosiderin, under certain conditions, and Bignami believes that this 
 change occurs after the acute infection in haemosiderin formed during the 
 paroxysms of the fever. 
 
 Summary of Blood Changes. — Summing up our knowledge as regards 
 the changes in the blood in the malarial fevers, it may be briefly stated as fol- 
 lows: A marked reduction in the number of red corpuscles, both by parasitic 
 invasion and as the result of poisons elaborated by the plasmodia during their 
 development, as well as changes brought about in the blood-forming glands by 
 the malarial infection; a corresponding reduction in the number of white cells, 
 with, in most cases, a relative increase in the large mononuclear leucocytes; a 
 marked reduction in the haemoglobin, and the presence in the blood of black 
 and brownish-yellow pigment, in greater or lesser amount. 
 
 The Urine in Malarial Infections. — In most malarial infections the urine 
 shows some departure from the normal, and in aestivo-autumnal infections, and 
 the more severe tertian and quartan infections, very grave pathological condi- 
 tions may be present. A number of observers have studied the urine in malaria 
 and have described the conditions present, notably Rem-Picci, Thayer, Celli, 
 and Botazzi and Pensuti. 
 
 Quantity. — In tertian and quartan infections the amount of urine passed 
 in 24 hours is generally increased, while in aestivo-autumnal infections the 
 quantity is normal or decreased. In certain cases of aestivo-autumnal infection 
 the quantity is greatly increased. During the malarial paroxysm a large 
 amount of urine is often passed, due to the increased vascular tension present 
 during the cold stage; the smallest amount of urine passed is generally during 
 the interval between the paroxysms. 
 
 Polyuria is not infrequently observed during convalescence from all malarial 
 infections, but especially in the convalescence of tertian and quartan cases. 
 Rem-Picci observed it in 60 of 150 cases, and I would even put the percentage 
 higher, as I have found it present in at least 80 per cent, of all cases in which 
 special attention was paid to the urine. Polyuria, however, is not confined to 
 the stage of convalescence, for it is observed during the attacks or immediately 
 following each paroxysm of the fever. It may last a few days or several weeks. 
 I observed an interesting case in which the patient recognized the impending 
 occurrence of a malarial paroxysm by the greatly increased amount of urine he 
 passed just before the onset of the chill. The daily amount of urine passed 
 when polyuria is present averages from two to three liters, but may be much 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 141 
 
 greater. One patient under my observation, after a tertian aestivo-autumnal 
 attack, passed from 20,000 to 25,000 c.c. of urine per day, for several weeks. 
 This is a very unusual occurrence, however, especially in aestivo-autumnal 
 infections, in which polyuria is not as common as in tertian and quartan 
 infections. 
 
 Specific Gravity. — During the attack the specific gravity is increased, 
 although the amount of urine passed may be excessive. After the attack, 
 the specific gravity is generally normal, unless polyuria be present, when it 
 varies with the amount excreted, but is generally low. In cases presenting 
 polyuria during convalescence, the specific gravity of the urine is low, varying 
 between 1.005 and 1.010. In many cases of mild infection there is no variation 
 from normal in the specific gravity. 
 
 Color. — As in all febrile diseases the color of the urine is increased during 
 the attack, being usually reddish and smoky in appearance. It generally 
 deposits a considerable sediment of urates or phosphates upon standing. The 
 color of the urine in the polyuria of convalescents is usually a pale lemon- 
 yellow. 
 
 Reaction. — The urine, both during the attack and in convalescence is 
 acid in reaction, the acidity being greatly increased during the paroxysms when 
 the urine is diminished in amount. The acidity is normal when the urine is 
 excreted in normal quantity. 
 
 Total Solids. — The total solids are increased, especially during a 
 malarial attack. 
 
 Urea. — The amount of nitrogen excreted in the 24 hours is increased above 
 normal, this increase being greatest during the fever. Sometimes the increase 
 is most marked before the fever, while after the paroxysm, in the afebrile 
 period, the amount of urea eliminated is lowest, but is not below normal. In 
 rare instances the greatest amount of urea is excreted during the afebrile period. 
 The increase in nitrogen and urea eliminated during malarial attacks is 
 undoubtedly due to increase of tissue waste brought about by the action of the 
 infection upon the organism. 
 
 The urine in cases of malarial polyuria following the paroxysms generally 
 shows a decreased amount of urea. 
 
 Uric Acid. — According to Rem-Picci, no special law controls the excretion 
 of uric acid during attacks of malaria, but an increase during the fever is 
 rarely observed in aestivo-autumnal infections, in my experience. 
 
 Phosphates. — This subject has been studied by Rem-Picci, Bernasconi, 
 Rosenstein, Gee, and Freund, and all agree in stating that at the beginning of 
 the paroxysms there is a marked decrease in the phosphates in the urine, followed, 
 during apyrexia, by a marked increase in the excretion of phosphoric acid, thus 
 proving that during the fever there is a retention of phosphates in the body. 
 The amount of phosphates excreted during the 24 hours by malarial patients 
 is greater than normal. The phosphates are generally increased in the urine 
 of patients suffering from the polyuria of convalescence. 
 
142 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 Chlorides. — The chlorides are markedly increased during the fever, 
 but decrease in the afebrile period, the decrease beginning during the decline 
 in the temperature. In convalescence we rarely observe an increase in the 
 chlorides. 
 
 Sodium and Potassium. — The amount of sodium and potassium elimi- 
 nated, as well as the period of elimination, varies considerably in different 
 patients. Rem-Picci found that about one half of his cases showed diminished 
 sodium and potassium during pyrexia, while the other half showed a diminution 
 during apyrexia. More sodium was eliminated during pyrexia in one half, 
 while in the other half more sodium was eliminated during apyrexia. The 
 increased excretion of sodium may be peculiar to malaria, but the lack of 
 careful observations upon the urine of other fevers due to protozoa leaves 
 this matter still in doubt. 
 
 Iron. — Colasanti and Iacoangelini have demonstrated that more iron is 
 present in the urine of malarial patients than that of other fevers, and that 
 the quantity of iron is greater after than during the paroxysm. The increase 
 in iron is greatest in the most severe infections. 
 
 Albumin. — Albuminuria occurs with varying frequency in malarial 
 patients depending upon the type of infection and upon the locality. In the 
 tropics albuminuria is much more common in malaria than in the temperate 
 zones, and even in the tropics it is more common in certain severely infected 
 regions. Albumin appears in the urine of a certain proportion of cases of the 
 more severe tertian and quartan infections, and in the majority of cases of 
 aestivo-autumnal fevers. In the latter infections hyaline, epithelial, and 
 granular casts are not infrequently observed, and it can be stated as a rule that 
 all fatal cases of malaria show albuminous urine before death. This subject 
 will be further discussed in the chapter dealing with the complications of 
 malaria. 
 
 Peptone is found very rarely in the urine after the decline of the tempera- 
 ture as reported by Botazzi and Pensuti. 
 
 Nucleo-albumin has been found in the urine of malarial patients by 
 Mannaberg, urobilin by Kieweit de Jonge. 
 
 Indican. — In severe aestivo-autumnal infections, especially those accom- 
 panied by severe irritation of the gastrointestinal canal, the urine shows a 
 a marked increase in the amount of indican excreted. 
 
 The Diazo-reaction. — The diazo-reaction occurs not so very infrequently 
 in cases of malaria, especially in long-continued aestivo-autumnal infections. 
 Thayer and Hewetson, Mannaberg, Zieman, and the writer have all observed 
 this reaction in the urine of malarial patients, and it is generally acknowledged 
 that this test is untrustworthy in the diagnosis between malaria and typhoid. 
 Horcicka found this test positive in 7 per cent, of the tertian cases, in 12 per 
 cent, of quartan cases, and in 33 per cent, of the aestivo-autumnal infections 
 observed by him. 
 
 Toxicity of the Urine. — Several observers have endeavored to ascertain 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. I43 
 
 whether the toxicity of the urine is increased in malarial infections, much good 
 work in this line having been accomplished by Brousse, Roque and Lemoine, 
 and Botazzi and Pensuti. 
 
 Brousse's conclusions from his work are as follows: 
 
 "1. The urotoxic coefficient calculated by Bouchard's formula, the mean 
 coefficient being 0.464, rises during the paroxysm, and the physiological effects 
 observed are those which usually follow the injection of urine-dyspnoea, myosis, 
 fall of temperature, exophthalmos, and, furthermore, convulsions. 
 
 "2. This toxicity is diminished during the period of convalescence in inter- 
 mittent fever very much below that of the urine during the paroxysm, and, 
 moreover, below that of normal urine." 
 
 On the other hand, Botazzi and Pensuti, following the method of Brousse 
 in injecting malarial urine into animals, do not agree with the latter observer, 
 but conclude that the experiments do not prove the existence of a specific 
 toxin in malarial urine. Their conclusions, which are deserving of the greatest 
 consideration, are as follows: 
 
 " 1. That in the malarial fevers the febrile urine is less toxic than that 
 passed during the apyretic stage. 
 
 "2. That the urine emitted during the period of apyrexia is more toxic than 
 normal urine. 
 
 "3. That the toxicity of the urine of malarial patients augments constantly 
 with the succession of febrile attacks, though in some cases this augmentation 
 appears in the form of unexpected and irregular exacerbations. 
 
 "4. That, as there is nothing specific in the course of the intoxications 
 produced in rabbits with malarial urine, there is no need to suppose the presence 
 of specific toxins or substances of the nature of leucomaines, for the salts of 
 potassium, phosphoric acid, the urinary pigments, the peptones — all of which 
 substances are eliminated in increased quantities — are a sufficient explanation. 
 
 " 5. That the injection of febrile urine is followed by a slower intoxication, 
 characterized by sopor, by increased diuresis, by diarrhoea, and mydriasis, while 
 the apyretic urine produces a more acute effect, sometimes fulminating, char- 
 acterized by clonic and tonic spasms, myosis, "exorbitisme," spastic expiration. 
 
 " 6. That to explain this different picture one may suppose that with febrile 
 urine the polyuria and diarrhoea are due chiefly to the increased richness in urea, 
 while the peptones may contribute to the production of sopor. In the afebrile 
 urines the salts of potassium, the phosphoric acid, the urinary pigments, and 
 especially the urobilin, manifesting themselves as substances essentially con- 
 vulsive, determine an hypertoxicity. 
 
 "7. Finally, besides the haemocytolysis, the destruction of the cellular 
 elements of the tissues, and the formation and elimination of toxic substances, 
 there must exist intermediate factors which account for the absence of increased 
 toxicity after the first febrile paroxysms, and the irregular elevation and dimi- 
 nution in the urotoxic coefficient in some other cases." 
 
 The work of Botazzi and Pensuti would appear to show that while the 
 urine in malarial cases has an increased toxicity at certain times, this toxicity 
 is not due to a specific toxin, but to the products of tissue waste and haemoly- 
 sis. Up to the present time no one has succeeded in demonstrating a specific 
 malarial toxin in the urine of patients suffering from the disease. 
 
144 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 Etiology of the Fever. — In the regularly intermittent malarial fevers, 
 it is well known that the onset of the fever is coincident with the sporulation of 
 the plasmodia. The same is true in the more irregular aestivo-autumnal 
 infections, although the time of sporulation of the plasmodia is not so easily 
 recognized, as segmenting forms do not usually occur in the peripheral blood. 
 In these cases, however, blood from the spleen, obtained by puncture, 
 will also show a preponderance of segmenting forms at the onset of the 
 fever. 
 
 To what is the fever due ? Many and various have been the theories held 
 by scientists regarding this question. Laveran believed that the febrile attack 
 was due to nerve irritation; Richard, that it is the index of the reaction of the 
 human organism to the malarial plasmodia; Golgi, that the febrile paroxysm 
 is due to the invasion of the red blood-corpuscles by the young plasmodia, 
 while Antolisei concluded that the invasion of the red cells by the plasmodia 
 had little to do with the rise of temperature, which he believed to be due to 
 the setting free in the blood-plasma of the newly-born plasmodia at the time 
 of segmentation. 
 
 To Baccelli, however, we owe the most reasonable theory of the rise of 
 temperature in malaria, and the one which is to-day accepted by most authorities. 
 He suggested that during sporulation, and the consequent liberation of the 
 young plasmodia in the blood plasma, certain toxic products, evolved during 
 the growth of the plasmodia, were also liberated, and that these produced the 
 rise in temperature and the characteristic symptoms of a malarial paroxysm. 
 The toxic products he considered to be chemical poisons of unknown nature, 
 the amount liberated depending upon the number of plasmodia reaching the 
 stage of sporulation. This theory has been accepted by Marchiafava, Bignami, 
 Golgi, Thayer, Zieman, and many other students of malaria. I believe that 
 this theory explains most rationally the rise in temperature in the malarial fevers, 
 by a probable direct action of the toxin upon the heat centers and upon the 
 vasomotor system, and reasoning from analogy, it is impossible to believe 
 otherwise than that the fever of malaria is due to the liberation of toxic products 
 in the blood during the sporulation of the plasmodia. 
 
 While we must admit that as yet we have no positive proof of the existence 
 of a specific malarial toxin or toxins, yet certain facts have been ascertained 
 which go far toward establishing this theory upon experimental evidence. That 
 toxic products are eliminated in the urine in malaria I have already shown, 
 although no specific toxin has been found in this fluid. The same is true of 
 the perspiration at the time of the paroxysm, as shown hy Queirolo, who 
 found that such perspiration was very toxic to guinea-pigs, while the perspira- 
 tion of normal individuals was not. The occurrence in the spleen, liver, 
 brain, and other viscera of areas of focal necrosis, identical with those described 
 by numerous observers, such as Welch, Reed, and Flexner, as occurring in 
 other acute infections, like typhoid and diphtheria, and as due to toxic 
 substances circulating in the blood, is almost positive proof that malaria is 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. I.45 
 
 a toxaemia, for Flexner has proven that such focal areas of necrosis are charac- 
 teristic of a general toxaemia. 
 
 The recent experiments of Rosenau, Francis, Parker, and Beyer with 
 filtered blood from malarial cases, would appear to indicate that the blood 
 serum contains a toxin capable of causing the symptoms of malaria when 
 injected into a healthy individual. They have demonstrated this toxin in the 
 blood during the chill in tertian infection, but were unable to demonstrate it 
 in the blood in a case of aestivo-autumnal infection during the decline of the 
 paroxysm. They say: "While this poison reproduced the symptoms of the 
 disease, still the data are too limited to consider it the malarial toxin." The 
 researches of Celli, Mannaberg, Gualdi, and others regarding a malarial toxin 
 in the blood resulted negatively, but there is some reason to believe that those 
 of Rosenau and his confreres, conducted under modern precautions, have been 
 successful in demonstrating the malarial toxin. However that may be, the 
 occurrence of areas of focal necrosis, the growth of connective tissue, which 
 follows malarial infection, the clinical symptoms of these fevers, the degenerative 
 changes occurring in the blood and in the tissue cells, all point to a specific 
 toxin as the etiological factor. 
 
 In the light of our present knowledge, we are forced to conclude that 
 the rise of temperature in all malarial fevers is due to a toxic substance or substances 
 produced by the Plasmodia during their development, and liberated at the time of 
 sporulation of these organisms. While it is probable that toxic materials are 
 formed during the degeneration and breaking up of the red corpuscles in 
 malaria, I believe that such materials have but little to do with the production 
 of the fever and the characteristic symptoms of the disease. 
 
 The periodicity of the rise in temperature is easily explained by the intervals 
 of time elapsing between the sporulation of the plasmodia, and in the case 
 of continued fevers, by the fact that multiple groups of plasmodia are present 
 which sporulate at short intervals, thus causing an almost constant discharge 
 of toxic material into the circulation. In this way all variations in the tempera- 
 ture curve observed in malaria may be explained, the sporulation of the 
 plasmodia initiating the temperature and the clinical symptoms. 
 
 If sporulation be delayed we have an anomalous temperature curve, while 
 if a double or triple infection with various species of plasmodia occur we 
 have an irregular or almost continuous temperature curve. Infection with 
 two groups of tertian plasmodia produces a quotidian curve, as does infection 
 with three groups of quartan organisms, provided both varieties sporulate at 
 intervals of twenty-four hours. A quotidian curve is also produced by the 
 quotidian aestivo-autumnal plasmodium while a double infection with this 
 organism may produce an almost continuous temperature. In those instances 
 in which two groups of quartan parasites sporulate at intervals of 24 hours, 
 a temperature curve is produced characterized by a rise of temperature upon 
 two days, with one day of normal temperature intervening. The temperature 
 and the severity of the clinical symptoms vary according to the species of 
 
146 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 Plasmodia infecting the individual and the number of plasmodia present. 
 Thus the plasmodia causing the aestivo-autumnal fevers evidently produce 
 a toxin which is more powerful than that of the plasmodia of tertian and 
 quartan infections, for in the former class of infections we meet with the vast 
 majority of pernicious symptoms, and this though the plasmodia may not be as 
 numerous as in the milder infections. In general, however, the symptoms 
 increase in severity with the number of plasmodia present, even in the aestivo- 
 autumnal infections. 
 
 In rare instances fatal pernicious infections are observed in which there is 
 little, if any rise of temperature. I have observed a fatal case of aestivo- 
 autumnal infection in which throughout the disease the temperature was 
 normal or subnormal, yet in which the blood from the spleen showed immense 
 numbers of sporulating aestivo-autumnal plasmodia. How can such an 
 absence of temperature be explained ? At the present time we cannot explain 
 these cases, except to say that in malaria, as in other diseases, many exceptions 
 are noted to the general rule, and unexplainable idiosyncrasies occur. 
 
 After a malarial infection has persisted for a considerable length of time, it 
 is commonly observed that even though the plasmodia may be demonstrated 
 in the blood and undergo sporulation as usual, the fever becomes modified or 
 disappears. While we are unable to state definitely the reason for the disap- 
 pearance of the fever in these infections, it is probable that the continued action 
 of the toxin or toxins upon the organism has resulted in its acquiring a relative 
 immunity to the fever-producing toxin, or has stimulated the production of 
 antitoxic substances. 
 
 The subject of spontaneous recovery is a most interesting one and one that 
 will well repay careful investigation, for in its explanation lies the secret of im- 
 munity to these fevers. If we understood the etiology of spontaneous recovery 
 we would undoubtedly be able to devise some method of producing immunity, 
 and eventually of ridding the world of one of its greatest scourges in the form of 
 disease. 
 
 Literature upon the General Pathology of the Malarial Fevers. 
 
 1847. Meckel. Ueber schwarzes Pigment in der Milz und dem Blut einer 
 
 Geisteskranken. Zeitschr. f. Psychiatrie, p. 193. 
 1849. Virchow. Zur pathologischen Physiologie des Blutes. Virchow's 
 
 Archiv, ii, p. 587. 
 
 1874. Arnstein. On Malarial Pigment and its Origin. Virchow's Archiv, 
 Bd. lxi, p. 494. 
 
 1875. Kelsch. Contributions a l'anatomie pathologique des maladies palus- 
 tres endemiques. Arch, de Physiologie, p. 690. 
 
 1876. Idem. Nouvelle contribution a l'anatomie pathologique des maladies 
 palustres endemiques. Arch, de Physiologie. ii serie, iii, p. 490. 
 
 1889. Rossoni. Lavori dei congressi della societa italiana di medicina interna, 
 
 ii congresso, Roma, Oct., p. 121. 
 1 89 1. Dionisi. Lavori del III congresso della societa italiano di medicina 
 
 interna, Milan, Oct., p. 169. Also Lo Sperimentale, iii and iv, p. 284. 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 147 
 
 1894. Colosanti and I acoangelini. Atti di XI cong. de medicina interna. 
 
 Roma, iii, p. 42. 
 1892. Baccelli. Ueber das Wesen der Malariainfection. Deutsch. med. 
 
 Woch., Aug. 11, No. 32, p. 721. 
 1894. Dock. Pernicious Malarial Fever. Am. Jour. Med. Sciences, vol. cvii, 
 
 No. 4, p. 379. 
 1894. Golgi. Ueber die romischen Sommer-Herbst-Malariafieber. Deutsch. 
 
 Med. Woch., Mar. 29, No. 13. 
 
 1894. Botazzi and Pensuti. Sulla tossicita dell' orina dei malarici. Lo 
 Sperimentale. Firenze, xlviii, p. 232, 254. 
 
 1895. Billings. The Leucocytes in Malarial Fever. J. Hopkins Hosp. Bull., 
 No. 43, p. 105. 
 
 1895. Rem-Picci. La secrezione urinaria nella infezione malarica. Bull. dell. 
 Regia Accad., medica di Roma. 
 
 1896. Rem-Picci. Nuovo contributo alio stidio della eliminazione dei fosfati. 
 Ibid. 
 
 1897. Plehn, A. Ueber Blutbefund und Therapie tropischer Malaria- Erkrank- 
 ungen. Sonderabdruck a.d. Wiener klin. Rundschau, No. 28. 
 
 1898. Bignami. Die Tropenfieber und die Sommer und Herbstfieber, etc. 
 Centralbl. f Bakt., Bd. xxiv, Nos. 18-19, p. 650. 
 
 1898. Zieman. Ueber malaria und andere Blutparasiten. Jena. 
 
 1899. Plehn, A. Die Tropenanaemie, etc. Deutsch. med. Woch., Nos. 28-30, 
 p. 465-482-500. 
 
 1899. Glogner. Ueber die im Malayischen Archipel verkommenden Malaria- 
 erreger, etc., Virchow's Archiv, Bd, clviii, p. 444. 
 
 1901. Plehn, A. Weiteres iiber Malaria, Immunitat und Latency. Jena. 
 
 1902. Billet. De la fievre quarte. Bull. Med. de l'Algerie. 
 
 1902. Brown, P. K. Acute Lymphemia with Aestivo-autumnal Malaria. 
 Boston Med and Surgical Jour., iii, p. 20. 
 
 1903. Rogers. Malarial Remittent Fever. Jour. Tropical. Med., Sept. 1, p. 
 272. 
 
 1904. Kieweit de Jonge. Het urobilinegehalte der urin biz malaria. Mede- 
 derlingen wit het Generskundig Laboratorium. 
 
 1904. Zeri, A. La infezione malarica perniciosa. II Policlinico, vol. ii, No. 4. 
 
 1905. Horcicka. Ueber die Diazoreaktion bei Malaria und Typhus abdom- 
 inalis. Arch. f. Schiffs- u. Tropen-Hyg., p. 533. 
 
 1907. Stephens and Christophers. Practical Study of Malaria and Blood 
 Parasites. London, 1908. 
 Consult also the monographs upon malaria which have been mentioned 
 in preceding chapters. 
 
CHAPTER II. 
 The Special Pathology of Acute Malarial Infections. 
 
 The pathological lesions occurring in the viscera in acute malarial infections 
 are similar in character for all species of plasmodia, although more severe 
 lesions are usually found in aestivo-autumnal infections. The visceral path- 
 ology of malaria has been thoroughly studied by numerous observers, among 
 whom may be mentioned Bignami, Laveran, Guarnieri, Councilman, Abbott, 
 .Dock, Bastianelli, Thayer, Barker, Monti, and Ewing. In recent years our 
 knowledge of the changes occurring as the result of malaria in the viscera has 
 been greatly added to by such studies, and we have come to understand better 
 the extensive pathological lesions which often follow these infections. I cannot 
 better introduce this portion of our subject than by quoting Marchiafava and 
 Bignami's admirable remarks concerning the pathology of malaria. They say: 
 
 "The malarial infection develops in the blood; here only, and chiefly within 
 the red corpuscles, can the parasite live. From this it follows that the parasite 
 invades the red corpuscles and nourishes itself at their expense, transforming 
 the coloring matter of the corpuscles into black pigment (which, after the 
 multiplication or the destruction v of the parasite, is incorporated into the white 
 cells) or otherwise injuring the red corpuscles. In consequence of this infection 
 of the blood, we find, in addition to the destruction of the cells, a production of 
 the detritus of the red corpuscles and of the parasites, the presence of pigmented 
 white cells, and the penetration of erythrocytes containing parasites, and of 
 leucocytes containing pigment, into the capillaries of all the organs. It can be 
 understood from this primary localization of the infection how the principal 
 changes must be found in the hematopoietic organs in addition to the blood, 
 and how alterations are to be encountered in all the organs and tissues." 
 
 This brief summary furnishes the key to the special pathology of malaria, 
 and it should be remembered that any of the species of malarial plasmodia may 
 cause pernicious symptoms leading to the death of the patient, and that the 
 pathological lesions are practically similar for all species of plasmodia. 
 
 Appearance of the Cadaver. — -The skin of a patient dying of malaria has 
 a peculiar dusky-brown, yellowish, or grayish hue, more pronounced the longer 
 the infection has lasted, and most pronounced in patients suffering from 
 malarial cachexia. The wasting of the tissues depends upon the duration of 
 the disease. Rigor mortis appears early, and is only moderate in extent, but 
 postmortem discoloration is often intense and appears soon after death. Not 
 infrequently jaundice is present and the body resembles that of a yellow-fever 
 cadaver externally. 
 
 148 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 149 
 
 The Brain. — As most patients dying of pernicious malarial infection suffer 
 from cerebral symptoms, the brain presents marked pathological lesions. In 
 no organ are the pathological changes more exquisitely illustrated than in the 
 brain, especially in those patients who have died of cerebral forms of the in- 
 fection. In rare cases the brain will appear almost normal. 
 
 Macroscopic. — Externally the blood-vessels are generally congested, and 
 the entire organ appears hyperaemic. Small capillary hemorrhages are often 
 observed and oedema is generally present. In those cases in which no cerebral 
 symptoms have been present during life there is but little evidence of hyper- 
 aemia. Externally the brain does not appear pigmented save in very rare 
 instances. 
 
 Upon section the cut surface is generally hyperaemic, and small hemor- 
 rhages, capillary in character, may be present in the gray matter, and even in 
 the white matter. The lateral ventricles are dilated and filled with fluid, which 
 may be blood-stained, and the choroid plexus is markedly congested. In the 
 majority of instances the cortex is of a brownish or chocolate color, due to 
 melanosis, and often the gray matter is more or less pigmented. In some cases 
 of aestivo-autumnal infection, however, the brain may not appear pigmented. 
 Small hemorrhages are often found in the white substance and also in the 
 cerebellum. In not a few cases of pernicious malaria the brain appears anaemic 
 and no pigmentation can be detected. The congestion and hemorrhages are 
 due to blocking and rupture of the capillaries by the plasmodia, free pigment, 
 cellular detritus, and pigmented leucocytes. 
 
 Microscopic. — As a rule, the capillaries of the brain are filled with blood 
 corpuscles, many of which contain plasmodia. The plasmodia may be found 
 to be in various stages of development, or, which is very common, all of them 
 at about the same stage of development. If the plasmodia contain much pig- 
 ment, as in tertian and quartan infections, and in some aestivo-autumnal 
 infections, the brain appears greatly pigmented, while the reverse is also true. 
 The plasmodia may be so numerous that almost every red corpuscle is invaded, 
 or they may be very few in number. In some, instances they are so numerous 
 as to occlude the lumen of the capillaries, thus forming thrombi. The small 
 arteries and veins are less rich in infected corpuscles. In rare cases the entire 
 cycle of development of the plasmodium may be found illustrated in one capil- 
 lary. Besides infected blood corpuscles, the following structures may be 
 observed in the capillaries: 
 
 a. Free plasmodia. 
 
 b. Macrophages. 
 
 c. Free pigment. 
 
 d. Pigmented leucocytes. 
 
 e. Endothelial cells. 
 
 (a) Free Plasmodia. — In some cases large numbers of extracellular or 
 free plasmodia, always pigmented, are observed in the capillaries. These 
 plasmodia are always round, oval, crescentic, or segmenting bodies, with pig- 
 
150 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 ment in the form of a solid, minute block, situated at or near the center. These 
 plasmodia are most numerous in tertian aestivo-autumnal infections. 
 
 (b) Macrophages. — Immense white blood-corpuscles containing free 
 pigment and plasmodia are generally seen, often so large as to distend and 
 entirely block the capillary in which they are situated. Most of these cells are 
 of endothelial origin. Smaller phagocytic leucocytes are often present and may 
 be so numerous as to occlude the capillaries. 
 
 (c) Free Pigment. — Many of the capillaries contain much free pigment, 
 which sometimes occurs in such large quantities as to block the capillaries and 
 form thrombi. This condition is generally present in cases which have pre- 
 sented marked comatose symptoms. 
 
 (d) Pigmented Leucocytes. — Most of the leucocytes present in the brain 
 capillaries are pigmented, and often contain red corpuscles containing plasmo- 
 dia. The leucocytes are usually present in small numbers. 
 
 (e) Endothelial Cells. — The endothelial cells lining the capillaries are 
 generally swollen and are undergoing fatty degeneration; they are often pig- 
 mented, and, by reason of their distention, may occlude the capillaries. They 
 often occur free in the capillary and may contain plasmodia. 
 
 Changes in the Nerve-cells. — To Marchiafava and Monti we are in- 
 debted for valuable contributions upon the lesions occurring in the nerve-cells 
 (ganglion cells) as the result of pernicious malaria. These lesions occur in 
 both the protoplasm and nucleus of the nerve-cell. In the protoplasm the 
 chromatic bodies of Nissle disappear, and the protoplasm appears very granular, 
 or, in the severest cases, the protoplasm appears to be disintegrated and rarefied. 
 The nucleus in such cells may appear normal or, especially in the pyramidal 
 cells, the nuclear membrane and nucleolus disappear as well as the chromatin, 
 or one or the other of these elements may persist. Notable changes are ob- 
 served in the branches of the cortical cells, consisting of attenuation and nodal 
 formations along them, or they may present a beaded appearance. Sometimes 
 very large, bleb-like swellings occur along their dendrites, connected by very 
 slender filaments of protoplasm. In rare instances nodes are observed along 
 the axis cylinders. All of the lesions above described are most marked in fatal 
 cases of comatose aestivo-autumnal malaria. 
 
 Spinal Cord. — Usually the spinal cord presents no lesions of importance in 
 malaria but in rare instances lesions similar to those described for the brain are 
 observed. 
 
 The Retina. — Guarnieri has studied the lesions occurring in the retina in 
 pernicious malaria and finds that they consist in congestion and hemorrhages, 
 the congested vessels containing parasite-infected red corpuscles, macrophages, 
 pigmented leucocytes, and free pigment. Many of the capillaries are occluded, 
 thus leading to impairment of function. 
 
 The Lungs. — The gross pathology of the lungs in cases dying of pernicious 
 malaria is not characteristic, there being usually, according to the stage of 
 the disease and the severity of the infection, hypostatic congestion, oedema, 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 151 
 
 capillary hemorrhages, or areas of broncho-pneumonia present. Pigmenta- 
 tion is generally present but cannot be distinguished from the pigmentation of 
 anthracosis. 
 
 Microscopic. — Sections from the lungs show the following changes: 
 The alveolar capillaries are generally congested and often contain large numbers 
 of pigmented or parasite-laden leucocytes which are often much degenerated. 
 These cells are most numerous in the smaller arteries and capillaries. The 
 polynuclear leucocytes are seldom observed. The endothelium of the capil- 
 laries is often swollen and contains small particles of pigment, but this condition 
 is very much less marked than in the brain, liver, and spleen. 
 
 When broncho-pneumonia has occurred, the exudation into the alveoli is 
 mostly composed of polynuclear leucocytes, and the alveolar cells, while only in 
 rare instances are pigmented leucocytes or phagocytes observed, though the 
 alveolar capillaries are often crowded with them. Neither is free pigment 
 common in this exudation, but in one case I have observed parasite-infected red 
 cells in the alveolar exudation in a case in which the symptoms were those of a 
 severe lobar pneumonia. Marchiafava and Bignami claim that this lack of 
 diapedesis of the pigmented leucocytes and macrophages is due to the fact that 
 these cells are degenerated and have lost the power of amoeboid motion by 
 which they are normally enabled to pass through the capillary walls. In cer- 
 tain cases areas of hemorrhage, microscopic in character, are observed in 
 section of the lung. 
 
 When pneumonia complicates the pernicious malarial fevers it is, without 
 doubt, due to the diplococcus of pneumonia, or streptococci, and the symptoms 
 and lesions are influenced by the coexisting malarial infection. 
 
 The Heart. — There is but little that is characteristic in the appearance of 
 the heart in cases of pernicious malaria. In very severe cases the organ is 
 somewhat pigmented and the heart muscle is flabby and anaemic. The 
 chambers of the heart, especially the right ventricle, may contain clots, in which 
 may be demonstrated infected red corpuscles, and pigmented leucocytes and 
 endothelial cells. 
 
 Microscopical. — The endomysium may contain many mast cells, and 
 rarely fatty degeneration of the muscle fibers occurs. The capillaries of the 
 muscular wall of the heart may contain numerous plasmodia, both free and 
 within red corpuscles, as well as pigmented leucocytes. Ewing describes a case 
 in which cardiac failure was the most prominent symptom and in which the 
 heart muscle contained a greater proportion of plasmodia and pigmented 
 leucocytes than either the spleen or liver. A somewhat similar case has been 
 reported by Benvenuti, but it is problematical whether malarial infection can so 
 weaken the heart muscle through the engorgement of the capillaries and their 
 occlusion as to cause the death of the patient. 
 
 The Stomach and Intestines. — Macroscopically, the only change usually 
 observed in the stomach and intestines is more or less pigmentation, the mucous 
 membrane being of a dull slate color or a dark brown or chocolate color. In 
 
1^2 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 cases dying of the choleraic form of pernicious malaria, the lesions are more 
 marked, consisting of hyperaemia, necrosis, and even ulceration of the mucous 
 membrane. In such cases the mucous membrane is swollen, inflamed, and 
 areas of capillary hemorrhage and superficial necrosis are observed. The 
 intestine may contain blood-stained mucus. Peyer's patches, as well as the 
 solitary glands, are often greatly swollen in severe choleraic malaria. 
 
 Microscopic. —Sections of the stomach and of the intestines show that the 
 capillaries are distended with blood, and in the intestines, especially, the 
 capillaries of the villi are crowded with parasite-infected corpuscles, free 
 Plasmodia and pigment, phagocytes, and endothelial cells. These may occlude 
 the capillaries, forming thrombi, with resulting necrosis and ulceration of the 
 mucous membrane in places. The epithelium lining the mucous membrane is 
 often necrotic, and there may be present a very general superficial necrosis of 
 this membrane, involving only the epithelial layer. Beneath the areas of 
 necrosis there is a dense infiltration with leucocytes, and bacteria cf various 
 species are found in the necrotic tissue and invading the submucosa beneath 
 the necrotic areas. 
 
 The Adrenal Glands. —Barker has carefully described the lesions of acute 
 malaria occurring in the adrenal glands. The arteries and veins contain many 
 Plasmodia, bacteria, pigmented leucocytes, plasmodia within red corpuscles, 
 and a few macrophages. The vessels are distended, and there occur areas of 
 capillary and venous dilatation. Polynuclear and mononuclear leucocytes are 
 present containing plasmodia, the polynuclear cells being present throughout the 
 gland, the mononuclear being found between the vessel walls and the adrenal 
 cells of the zona fasciculata. The endothelial cells of the organ act as phago- 
 cytes, as in the liver and spleen, and a few of the adrenal cells may contain 
 pigment and infected corpuscles. Evidences of degeneration are observed in 
 the adrenal cells, many of which are swollen, fatty, and vacuolized, and show 
 fragmented nuclei. The changes in these glands are very suggestive of a 
 toxaemia. 
 
 The Liver. — The lesions of acute malarial infection are generally well 
 marked in this organ and many of them are absolutely characteristic. 
 
 Macroscopic. — The organ is generally enlarged, sometimes markedly so, 
 but usually the enlargement is slight and sometimes not appreciable. The 
 consistence of the organ is reduced. Pigmentation is always present, the 
 color varying from a brownish shade to black upon section. The capsule 
 is smooth and the lobules generally indistinct. The gall bladder is generally 
 distended with almost black bile, and the walls of this organ may be greatly 
 pigmented. Upon section, the cut surface varies in color from a very dark 
 brownish-red or a slate color to black, and is bathed in blood, as the organ is 
 usually greatly congested. It is not uncommon to find the cut surface mottled 
 with light yellow spots due to fatty degeneration. 
 
 Microscopic. — The lesions characteristic of malarial infection are found 
 in the capillaries, in the liver cells, and in the connective tissue of the organ. 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 1 53 
 
 The capillaries contain many large macrophagi, containing much pigment, 
 Plasmodia and sometimes, red corpuscles. In many of the capillaries the lumen 
 of the vessel is occluded by these macrophagi, or by free pigment and cellular 
 detritus. The number of parasite-infected red corpuscles is very limited in this 
 organ, as a rule, although I have seen sections in which they were very numerous. 
 The endothelial cells are very active as phagocytes and large irregular masses 
 of protoplasm, filled with pigment and degenerated plasmodia, and formed by 
 the fusion of two or more endothelial cells, are not infrequently observed 
 blocking the capillaries of the liver. 
 
 The cells of Kupfer form a considerable proportion of the phagocytic cells, 
 being swollen and containing pigment and fragmented plasmodia. 
 
 The liver cells exhibit various forms of degeneration, being swollen, 
 atrophied, necrotic or vesiculated. In many cases the liver cells contain fine 
 granules of yellow pigment (haemosiderin) and in some instances the proto- 
 plasm is entirely replaced by this pigment. This pigmentation of the liver 
 cells is not characteristic of malaria, and is generally most pronounced toward 
 the center of the liver lobules. A peculiar hyaline degeneration of the nuclei 
 of the liver cells is rarely observed in pernicious cases of malaria, which is 
 characteristic of this class of infections. 
 
 The central veins of the lobules are dilated with corpuscles and in many 
 places small haemorrhagic areas have been formed by the rupture of capillaries 
 and smaller blood-vessels, and the surrounding liver tissue becomes infiltrated 
 with infected red corpuscles, leucocytes, phagocytes and free pigment. The 
 congestion of the capillaries causes pressure atrophy of the columns of liver 
 cells in places, and entire liver lobules may thus be practically composed of 
 dilated capillaries, the liver cells having completely atrophied. 
 
 Focal Necrosis. — Areas of focal necrosis, such as have been described by 
 Reed in typhoid, and by Welch and Flexner in diphtheria, are often observed 
 in the liver in severe pernicious malarial infections. These areas certainly 
 indicate that a specific toxin circulates in the blood in malaria, and both Barker 
 and Flexner believe that they are due to a general toxaemia. The areas of focal 
 necrosis vary in size, the liver cells are undergoing hyaline degeneration, while 
 polynuclear and mononuclear cells are present in abundance, and capillary 
 thrombi are seen, oftentimes multiple in character. Following the necrosis 
 there is a proliferation of connective tissue in the vicinity, starting from the 
 portal spaces, with the formation of new bile ducts and changes in the liver 
 cells similar to those in the early stages of cirrhosis. 
 
 The changes occurring in the connective tissue of the liver consist in an 
 infiltration of the portal spaces by round cells and the proliferation of connective 
 tissue following focal necrosis. The question of a malarial cirrhosis is one of 
 personal susceptibility, in large measure, as is shown by the rarity of this condi- 
 tion in malarial regions and among those who have suffered from repeated 
 attacks of the disease, but I believe that such a form of cirrhosis does rarely 
 
154 TH E PATHOLOGY OF THE MALARIAL FEVERS. 
 
 The periphery of the liver lobules and the portal spaces are generally 
 much pigmented, but occasionally the pigment is scattered in irregular masses 
 throughout the lobules being contained in macrophages within the capillaries, 
 or in haemorrhagic areas within some portion of the lobule. In some cases the 
 spaces between the capillary wall and the liver cells are greatly enlarged and are 
 filled with phagocytic Kupfer's cells, containing free pigment, infected red 
 corpuscles, free plasmodia, and even small leucocytes. 
 
 The Spleen. — The spleen presents the most characteristic lesions of 
 malarial infection of all the viscera, and a smear from the cut surface of this 
 organ will clinch the diagnosis of malaria in every doubtful case. 
 
 Macroscopic. — The spleen is always enlarged, sometimes enormously so. 
 The enlargement generally depends upon the length of time the infection has 
 lasted, the largest spleens being observed in cases which have suffered from 
 repeated and severe acute attacks of the disease. As a rule, the organ is pig- 
 mented externally, varying in color from a light chocolate to black. The capsule 
 is tense and smooth, and the consistence greatly diminished. The cut surface 
 is of a chocolate, slate, or jet-black color, and in many cases the splenic pulp 
 is so soft as to be diffluent. The Malpighian corpuscles may be invisible or 
 visible as minute white dots scattered through the parenchyma. In cases 
 dying from an initial pernicious attack, the spleen may not be pigmented. The 
 enlargement of the spleen is often slight in aestivo-autumnal infections. 
 
 Microscopic. — The venous sinuses of the spleen are congested and 
 dilated, thus hindering the circulation, and resulting in the production of 
 irregular haemorrhagic areas in the parenchyma. The sinuses contain multi- 
 tudes of plasmodia, either free or in red corpuscles, as well as enclosed in im- 
 mense macrophages and smaller mononuclear or polynuclear cells. The 
 number of infected red cells within the sinuses is often enormous, almost every 
 corpuscle containing one or more plasmodia, and this is especially true in 
 aestivo-autumnal infections. I have, however, observed cases in which but 
 few red corpuscles were demonstrable in the spleen. 
 
 The cells of the splenic pulp are pushed apart by the multitudes of red 
 corpuscles which contain plasmodia in various stages of development, the pig- 
 mented forms and the sporulating bodies being most frequently observed. 
 Free plasmodia are less common but by no means rare. In aestivo-autumnal 
 fever, in cases which have lasted for several days, crescents are found, but I 
 have never observed them in large numbers and they are often absent even 
 when they may be demonstrated in the peripheral blood. 
 
 Besides the parasite-infected red corpuscles, the sinuses contain an im- 
 mense number of phagocytic cells, consisting of small cells, resembling lympho- 
 cytes, which are few in number, and immense macrophages, which are much 
 more numerous in the spleen than in the liver. The latter cells often pre- 
 sent evidence of degeneration, as shown by fatty changes and necrosis of the 
 protoplasm. 
 
 The smaller vessels of the spleen are congested and filled with infected red 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 155 
 
 cells, phagocytic leucocytes and endothelial cells, and free pigment and plasmo- 
 dia. Free pigment is present throughout the pulp sinuses, lying in large blocks 
 or clumps or in the form of minute rods and granules. Here, as in the liver, 
 two forms of pigment occur: the dark brown or nearly black malarial pigment 
 or melanin, and the golden-yellow pigment derived from the degenerated and 
 broken-down red corpuscles, haemosiderin. 
 
 Areas of focal necrosis, exactly similar to those described as occurring in the 
 liver are sometimes observed in the parenchyma of the spleen, and pressure 
 necrosis of minute areas, due to the distended or ruptured capillaries, is a com- 
 mon lesion. 
 
 The connective tissue of the spleen is not increased in very acute infections, 
 but in those cases which die of an acute attack following repeated attacks of 
 malaria, the connective tissue of the trabeculae may be increased in amount. 
 Pigmentation of the fibrous trabeculae is almost always observed, but the Mal- 
 pighian corpuscles are not pigmented, although a considerable amount of pig- 
 ment generally surrounds these bodies. Thrombosis is a common lesion in the 
 spleen. In rare instances there is but little evidence in the spleen of malarial 
 infection, even though death has occurred from that disease. Bloombergh and 
 Coffin report a case in which no plasmodia could be demonstrated in sections of 
 the spleen, although the plasmodia were demonstrated in the peripheral blood, 
 and I have observed at least two fatal cases of malaria in which the plasmodia 
 were so few in smears from the spleen that a long search was required before 
 they could be demonstrated. 
 
 The Kidneys. — As a rule, the macroscopical appearance of the kidney is 
 not at all characteristic of malaria. The organs are generally slightly enlarged, 
 the capsule smooth, the consistence decreased, while there may be marked con- 
 gestion, and in rare instances, considerable pigmentation. The cut surface is 
 generally congested, and the cortex may appear slightly thickened. The 
 capsule strips readily. The appearances presented in an acute parenchy- 
 matous nephritis are by no means rare, accompanied by small haemorrhages in 
 the cortex of the organ. 
 
 Microscopical. — Aside from the purely malarial lesions present, the 
 microscopic pathology of the kidneys in pernicious malaria is that of an acute 
 or subacute parenchymatous nephritis, but the lesions peculiar to malaria are 
 much less marked than in the other viscera, especially the brain, liver, and spleen. 
 
 The Malpighian tufts are often found congested and the seat of small 
 capillary haemorrhages. There is but little pigmentation, but sometimes the 
 glomeruli appear greatly pigmented, the pigment being situated within phagocytic 
 cells in the capillaries, and in the endothelial and epithelial cells. Plasmodia, 
 either free or within red corpuscles, may be seen occasionally within the glomeru- 
 lar capillaries, but they are generally few in number. The epithelium of 
 Bowman's capsule shows some proliferation, and the capsular space may be 
 filled by it or by fibrinous material, in which may be imbedded pigmented 
 leucocytes and plasmodia. 
 
156 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 The epithelium lining the convoluted tubules presents cloudy swelling, 
 fatty degeneration, or necrosis. The straight tubules often contain hyaline, 
 epithelial, or granular casts. The intertubular capillaries are somewhat con- 
 gested and in them free pigment in small amount is observed, as well as endo- 
 globular plasmodia, pigmented leucocytes, and macrophages. In some 
 instances capillary haemorrhages have occurred into the parenchyma and 
 areas of pressure necrosis may be present. 
 
 In very rare instances the organ may appear greatly pigmented macroscop- 
 ically, the cortex appearing dark gray in color, while the pyramidal vessels may 
 be distinctly outlined by the large pigment deposits within them. 
 
 The lesions in the kidneys which result from malarial infection are un- 
 doubtedly due to a toxic poisoning, as the plasmodia are present in too small 
 numbers to produce the grave lesions which are not seldom found in these organs. 
 
 The Bone-marrow. — Macroscopically, the bone-marrow varies in color 
 according to the length of time the infection has lasted. In the long bones, in 
 recent cases, the normal yellow color of the marrow is found; while if the in- 
 fection has lasted for some time the color varies from red to black. Generally 
 in acute cases there is a chocolate color observed. There may be an extensive 
 hyperplasia of the marrow in severe and rapidly fatal cases. 
 
 Microscopic. — In sections of bone-marrow the lesions observed are very 
 similar to those observed in the spleen. The capillary vessels contain numer- 
 ous endoglobular plasmodia in advanced stages of development, sporulating 
 bodies, and, if the infection has persisted long enough, crescents. They also 
 contain numerous macrophages inclosing granules and clumps of pigment, as 
 well as red blood-corpuscles and plasmodia. External to the capillaries, in the 
 marrow pulp, plasmodia are found in various stages of development, and 
 numerous crescentic plasmodia or gametes may be present in aestivo-autumnal 
 infections. Here are also found many large macrophages, some of which are 
 undergoing degenerative changes. Nucleated red corpuscles are common as 
 well as pigmented medullary cells. The leucocytes may be greatly increased in 
 number. 
 
 The pathological changes in the other viscera are of little importance and 
 do not merit description. 
 
 The following autopsy record of a case dying of a quotidian aestivo-autum- 
 nal infection is inserted to illustrate the lesions most commonly found in the 
 malarial fevers. 
 
 R. G. C. — Age fifty-two years. White. Clinical diagnosis, pernicious 
 quotidian aestivo-autumnal fever. 
 
 Body that of a man apparently fifty years of age, somewhat emaciated. 
 Skin yellowish in color. Rigor mortis slight. Postmortem discoloration 
 marked over dependent portion of the body. Finger-nails not congested. 
 Pupils regularly dilated. Marked anaemia of the mucous membranes and of 
 the skin. 
 
 Brain. — The dura mater appears normal. The amount of cerebrospinal 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 1 57 
 
 fluid is increased. The surface of the cerebrum is pale, and upon section the 
 medulla appears hyperaemic, and the cortex is a dark slate color. The lateral 
 ventricles are filled with fluid. The choroid plexus is not congested. The 
 cerebellum, upon section appears normal. 
 
 Thoracic and Abdominal Cavities. — The pleural cavities are free 
 from fluid. The liver reaches about one centimeter below the border of the 
 last rib. The omentum contains a large amount of fat, and reaches the level 
 of the umbilicus. The appendix is about three centimeters in length, and 
 lies in the right iliac fossa; it is normal in appearance. The bladder is filled 
 with urine. Abdominal aorta shows no sclerosis. 
 
 Liver. — The liver measures 28 x 21 centimeters. The organ is purplish- 
 black in color externally and the capsule is smooth. The gall-bladder contains 
 a large number of gall-stones and much inspissated bile. Upon section the 
 cut surface of the liver is slate colored, and the lobules are ill defined. The 
 organ is greatly congested. Weight, 1,640 grams. 
 
 Spleen. — The spleen measures 19 x 12 centimeters. The organ is almost 
 black in color externally and the capsule is distended and smooth. Upon 
 section the cut surface is black in color, with light gray areas scattered through 
 it, marking the location of the Malpighian corpuscles. The consistence of 
 the organ is very much decreased, it being almost diffluent. Weight, 440 
 grams. 
 
 Pancreas. — The pancreas measures 22 x 4.5 centimeters. Upon section 
 the cut surface appears congested. Weight, 115 grams. 
 
 Kidneys. — Both kidneys appear somewhat congested. The capsule is 
 smooth and slightly adherent. Upon section the cut surface is congested, but 
 the cortex and pyramids are distinct, the cortex being slightly thickened. 
 Weight of each kidney, 125 grams. 
 
 Lungs. — The lungs are crepitant throughout and appear normal. 
 
 Pericardial Cavity. — The pericardial cavity contains about 3 ex. of 
 clear straw-colored fluid. Both layers of the pericardium appear normal. 
 
 Heart. — The amount of extracardial fat is increased. The blood-vessels 
 are congested. Upon section of the heart the ventricles are found to contain 
 small clots. The muscular walls are about normal in thickness, and the 
 valves of the heart are normal in appearance. 
 
 Microscopical Examination. — The Liver. — The fibrous tissue in the 
 portal spaces is slightly increased in amount, and large numbers of small round 
 cells are present in this tissue. All the blood-vessels in the sections are increased 
 in thickness. The liver cells are swollen, smoky, and granular in appearance, 
 and in many of them the nucleus has disappeared. In others the nucleus is 
 present, exhibiting necrotic changes, as evidenced by loss of staining power, 
 and the absence or diminished staining of the chromatin granules. The 
 protoplasm of the liver cells contains much fine yellow pigment, but this pigment 
 is not found within the nucleus of the cells. 
 
 The intralobular capillaries contain a great deal of black pigment, numer- 
 
158 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 ous macrophages, and smaller mononuclear leucocytes. The free pigment 
 in the capillaries is in the form of irregular blocks, and the yellow pigment, 
 so common in the protoplasm of the liver cells, does not appear within the 
 capillaries. The macrophages which crowd the capillaries contain within 
 their protoplasm an immense amount of black pigment, evidently derived 
 from broken-doAvn plasmodia; they also contain infected red blood-corpuscles 
 and free plasmodia of the quotidian aestivo-autumnal variety. The number of 
 plasmodia present is comparatively small, but the amount of pigment is immense, 
 and it occurs in clumps so large that many of the capillaries are occluded by 
 it. This condition is especially noticeable in the capillaries near the portal 
 spaces. On account of the small caliber of the capillaries the macrophages 
 are often compressed, appearing as long, slender, pigment-bearing cells. The 
 plasmodia present are small, round, or oval bodies, containing a few small 
 granules or grains of pigment, generally collected at the center of the organism. 
 Most of these are presegmenting plasmodia. No crescents {gametes) are 
 present in the liver. The stellate cells of Kupfer contain black pigment and 
 sometimes small plasmodia. 
 
 In numerous situations throughout the capillaries of the liver there occur 
 large, bleb-like plasmodia, containing pigment, which are probably degenerating 
 parasites. There is not a single capillary in the sections that does not contain 
 pigment-bearing cells or a few plasmodia. 
 
 The Spleen. — The Malpighian bodies are somewhat fibrous, and at their 
 border there is a large amount of yellowish-brown pigment. The splenic pulp 
 contains a small number of red corpuscles showing small, round, or oval plas- 
 modia within them, all of which are pigmented. The sinuses contain numerous 
 infected red cells, immense numbers cf macrophages, and large masses of 
 free pigment The macrophages contain the following: (1) large irregular 
 collections of brownish-black pigment; (2) red corpuscles containing pigmented 
 aestivo-autumnal plasmodia; (3) free plasmodia, most of them pigmented 
 and showing signs of segmentation; (4) fine granules of a yellowish pigment 
 which is distinct from the large amount of dark brown or black pigment present. 
 Some of the macrophages show all of these bodies within their protoplasm, 
 while others, and they are in the majority, show only one or two free plasmodia 
 and irregular collections of pigment. As a rule, the macrophages are about 
 six to eight times as large as a normal red corpuscle, but many are present which 
 are much larger and entirely block the capillaries. 
 
 Besides the macrophages there are many mononuclear leucocytes and 
 endothelial cells, which are free from plasmodia or pigment. The polynuclear 
 leucocytes are comparatively few in number. Everywhere throughout the 
 sections there are very large masses of free pigment situated in the splenic 
 sinuses, and in many places rupture of the sinues has occurred and areas of 
 pressure necrosis have formed. 
 
 Throughout the sections of the spleen may be seen crescentic forms of the 
 quotidian aestivo-autumnal plasmodium, but only in small numbers. In the 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 1 59 
 
 spleen there are also bleb-like degenerating plasmodia, like those in the liver. 
 The sporulating forms of the plasmodium are remarkably few in number, 
 but many of the macrophages contain sporulating bodies. 
 
 The Kidneys. — Sections of the kidneys show the lesions of acute paren- 
 chymatous nephritis and some lesions characteristic of pernicious malarial 
 infection. The Malpighian tufts are greatly congested, the capillaries being 
 distended with blood, some of them having ruptured, thus causing hemorrhages 
 with Bowman's capsule. Many of these capillaries contain free plasmodia, 
 round or oval in shape and generally pigmented. The capillaries also contain 
 a small number of infected red corpuscles, free pigment, degenerated plasmodia, 
 and phagocytic cells. The number of plasmodia, both free and within red 
 cells, is very much smaller than in sections of the liver or spleen. 
 
 The epithelium of the tubules is much swollen and is rapidly proliferating 
 while the protoplasm of the cells is smoky and finely granular in appearance, 
 and contains in many instances pigment grains of a yellowish color. One 
 of the most interesting features of the kidney sections is the occurrence within 
 the tubules of collections of black pigment and here and there a few plasmodia. 
 A few infected red cells are also present within the tubules. The intertubular 
 capillaries contain numerous free pigmented plasmodia, infected red cells and 
 macrophages. The walls of the capillaries are not thickened. The amount 
 of pigment present in the kidney is very slight as compared with that present 
 in the liver and spleen, and the same is true of the number of plasmodia. 
 
 The Brain. — The changes observed in the sections of the brain may be 
 divided into those occurring within the capillaries and those within the brain 
 substance proper. The small capillaries of the brain, especially those of the 
 cortex, are crowded with pigmented, free plasmodia, leucocytes containing pig- 
 ment, and in some places by small collections of yellow pigment. The infected 
 capillaries are most numerous in the cortical portion of the brain, but they are 
 by no means rare in the medullary portion. The pigment within the capillaries 
 is generally collected in irregular masses, is brownish-black in color, and, in 
 some places, entirely occluded the lumen of the capillary. The plasmodia 
 present in the capillaries are mostly free, small in size, oval or round in shape, 
 and contain pigment, which is generally collected at or near the center in the 
 form of a few small grains or a single black block. It is remarkable how uni- 
 form these plasmodia are in appearance and how rarely an infected red cell is 
 observed. In some places the capillaries are occluded by immense macrophages 
 containing much pigment and numerous plasmodia. 
 
 The changes occurring within the substance of the brain consist in a necro- 
 sis of the protoplasm of some of the cortical cells, as is evidenced by the ir- 
 regular staining reactions of the protoplasm and nucleus. Sections of the 
 heart, lungs, stomach, and intestines were not examined as they presented no 
 evidences of malarial infection. 
 
 The above autopsy record illustrates the common findings after death 
 from pernicious malaria, but much greater changes are often observed, changes 
 
l6o THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 so characteristic that a glance suffices to diagnose the cause of death, while in 
 rare instances the lesions of malaria may be so slight as to be of little service in 
 diagnosis. 
 
 Literature upon the Special Pathology of the Malarial Fevers. 
 
 i S7 5—7 6. Kelsch. Contribution a l'anatomie pathologique des maladies palus- 
 tres endemiques. Arch, de phys. et path., No. 5, p. 6qo. 
 
 1885. Councilman and Abbott. A Contribution to the Pathology of Malarial 
 Fever. Am. Jour. Med. Sciences, vol. lxxxix, p. 416. 
 
 1893. Dock. Pernicious Malarial Fever. Am. Jour. Med. Sciences, April, p. 
 
 379- 
 
 1895. Barker. A Study of Some Fatal Cases of Malarial Fever. Johns 
 
 Hopkins Hosp. Reports, vol. v, p. 221. 
 
 1895. Monti. Atti. d. R. Accad. med. d. Roma, series II, vol. iii, p. 249. 
 
 1896. Bignami. Richerche sulla Anat. Pathol, della Perniciosa. Atti. d. R. 
 Accad. d. med. d. Roma, vol. v, series ii. 
 
 1897. Guarnieri. Richerche sulla alterazioni della retina nella infezione acuta 
 da malaria. Arch, per lesc. med., xxi, No. i. 
 
 1897. Thayer. Lectures upon the Malarial Fever. New York, p. 211. 
 
 1 90 1. Ewing. Contribution to the Pathological Anatomy of Malarial Fever. 
 
 Jour, of Exper. Med., No. 5, p. 119. 
 1 90 1. Craig, C. F. The Aestivo-autumnal Fevers, New York, p. 91. 
 
CHAPTER III. 
 
 [ The Pathology of Latent Malarial Infections and of Malarial Cachexia. 
 
 Pathology of Latent Malarial Infections. — By a latent malarial in- 
 fection we mean a malarial infection which is not manifested by any symptoms, 
 and in which an examination of the blood may or may not show the presence 
 of the plasmodia. The pathology of such infections has received but little 
 attention, and if we confine the term "latent infection" only to those cases in 
 which no symptoms are present and no plasmodia are found upon repeated 
 examinations of the blood, it will at once be seen why the pathology of this 
 condition has not been investigated. Such cases of malarial infection will only 
 be discovered at autopsy, the patient having died from some other disease, and 
 outside of the tropics and the more malarial regions of the temperate zones, 
 such cases will necessarily be very rare. In this chapter I shall only touch upon 
 the pathology of those cases in which no plasmodia were demonstrated in the 
 blood and no clinical symptoms of malaria were detected before death. 
 
 During my service at the U. S. Army General Hospital at he Presidio of 
 San Francisco I observed seven cases in which the autopsy showed latent 
 malarial infection in which before death no symptoms of malaria had developed 
 and no plasmodia had been detected in the peripheral blood. Three of these 
 cases were benign tertian infections and four aestivo-autumnal infections of the 
 tertian type. 
 
 Pathology of Latent Tertian Malaria. — The pathologic lesions present 
 were confined entirely to the liver and spleen, and this was also true of the 
 aestivo-autumnal infections. In numerous cases coming to autopsy from 
 other diseases, accompanied by a latent malarial infection in which the plasmo- 
 dia were found in the blood before death, but in which there were no definite 
 symptoms of malaria, it was observed that the chief pathologic lesions of 
 malaria were also found in the liver and spleen, but that other organs presented 
 slight lesions. Thus it will be seen that from the mildest latent infections to 
 the severe acute infections there is a gradual progress in the pathological lesions, 
 first manifested in the liver and spleen and spreading, according to the extent 
 and severity of the infection, to all the organs. 
 
 The Spleen. — In these latent infections the most marked lesions were 
 always present in the spleen. The organ in the tertian infections was con- 
 siderably enlarged and dark bluish in color externally, the capsule smooth and 
 tense, the notches distinct, and the organ somewhat decreased in consistence. 
 Upon section the color was a dark browish-red, but did not present that browish 
 or black color found n well-marked acute infections; this, of course, is easily 
 
 TT 161 
 
1 62 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 understood from the fact that the plasmodia present were comparatively few in 
 number and that therefore little pigment was formed. 
 
 Microscopically ', the sections of the spleen showed intense congestion of the 
 splenic sinuses, together with pigmentation, especially marked along the edges 
 of the Malpighian bodies and along the fibrous trabecular The connective 
 tissue of the organ was not increased. The cells of the splenic pulp were greatly 
 increased in number and many of the cells showed marked division of the 
 nucleus. Many also were pigmented and distorted in shape. 
 
 The splenic sinuses and capillaries showed the presence of numerous 
 infected red cells and pigmented leucocytes. While these infected cells were 
 not nearly as numerous as in acute infections or as in more advanced latent 
 infections, still they were sufficiently numerous as to be very noticeable. The 
 plasmodia were in about the same stage of development in each case, but it 
 so happened that the patients had died at such a period that the entire cycle of 
 the tertian plasmodium within the human body could be worked out from 
 examination of the sections of the spleen from these cases. As far as could be 
 ascertained the plasmodia presented no essential difference in their appearance 
 from those found within the red cells in the peripheral circulation during an 
 acute infection. The sporulating bodies were numerous in one case, the seg- 
 ments appearing, however, slightly more refractive and more clearly outlined 
 than when found in the peripheral blood. Their staining reactions were 
 exactly the same. 
 
 The chief point of importance in the pathology of these cases is that the 
 entire human cycle of the plasmodium can be completed within the spleen, 
 thus proving conclusively that the seat of the initial malarial infection is in 
 this organ, for no plasmcdia could be demonstrated in the blood of these cases. 
 While this has been the opinion of nearly all authorities for several years, few 
 observations are on record in which, as in these cases, no malarial symptoms 
 or plasmodia could be determined during life, but the entire human cycle of 
 the organism was found in sections of the spleen, and no where else in the body. 
 
 Besides the infected red cells, numerous leucocytes were observed containing 
 pigment in the form of large and small granules, and a few containing malarial 
 plasmodia. Macrophages were also present containing much pigment in 
 large blocks, and often one or more half or nearly full-grown plasmodia. A 
 small amount of free pigment was observed lying within the splenic sinuses. 
 
 The Liver. — Macroscopically, the liver did not differ in appearance from 
 that of a normal organ, so far as the pathology of malaria is concerned. Upon 
 section marked venous congestion was present in all of the cases. The sections 
 of the liver showed microscopically a few pigmented leucocytes within the 
 capillaries, some of the leucocytes containing degenerated plasmodia. There 
 was but little pigment present in the organ, most of it being within leucocytes. 
 No macrophages were observed, most of the pigmented leucocytes being of 
 the polynuclear type. A very careful search was made in the sections of 
 the liver for infected red corpuscles, but in no one of the cases was an infected 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 1 63 
 
 red corpuscle observed. It will thus be seen that the lesions in these latent 
 cases were almost entirely confined to the spleen, the liver being but very slightly 
 involved. 
 
 Pathology of Latent Aestivo-autumnal Malaria. — The pathology 
 of latent aestivo-autumnal malarial infections differs but little from that of 
 tertian infections and chiefly in the type of the plasmodia present. 
 
 The Spleen.— Macroscopically, the spleen appeared much as the spleen 
 in the tertian infections, save that in all cases it was not as much enlarged nor 
 as much pigmented. Upon section the consistence was found decreased, the 
 Malpighian bodies nearly invisible, the color a dark mahogany-red — in one case 
 brown — the substance of the spleen being almost diffluent in two of the cases. 
 Upon microscopical examination the same changes were found as in the tertian 
 latent cases, the splenic sinuses being congested, the cells of the splenic pulp 
 increased in number and showing marked division of the nucleus, considerable 
 pigmentation present, and the presence of infected red corpuscles and melan- 
 iferous leucocytes. The infected red cells were not as numerous as in the tertian 
 latent infections. The plasmodia observed within the red corpuscles were 
 almost uniformly in one stage of growth, but in the sections of the spleen from 
 the four cases all stages in the human life cycle of the aestivo-autumnal Plasmo- 
 dium (tertian) could be observed. The younger forms were similar in appear- 
 ance to the young forms observed in the peripheral blood, being small, hyaline 
 rings, presenting in smears from the spleen, marked amoeboid motion. The 
 older plasmodia were disk-shaped or ring-like, and contained more or less 
 pigment in the form of very fine reddish-brown granules, the pigment being 
 very slightly motile. In one case numerous sporulating bodies were observed, 
 the sporulation always occurring within the red cell. The segments varied 
 in number, the largest number counted being 24, the smallest 12. A peculiarity 
 about the segments was that each appeared to present the "ring-form" which 
 is usually found in the red cell at the earliest stage of infection. This appear- 
 ance was so distinct that the infected corpuscle appeared to be filled with minute 
 " rings." The pigment in the sporulating bodies was collected either at the 
 center or to one side, and none of the segments contained any pigment. 
 
 No crescents were observed in the sections of the spleen from any of the 
 cases. Numerous pigmented leucocytes were observed and macrophages 
 containing much pigment and one or two plasmodia. Considerable free pig- 
 ment was present in the same localities as noted in the tertian cases. 
 
 The Liver. — The pathologic changes in the liver were similar to those 
 observed in the tertian latent cases. No infected red cells were found, although 
 a considerable number of melaniferous leucocytes were observed, together 
 with some free pigment. 
 
 The chief point of value in the pathology of latent malaria is the demonstra- 
 tion that the malarial plasmodia are capable of undergoing their entire human 
 life cycle within the spleen, thus proving the time-honored theory that the 
 spleen is the seat of all malarial infections. Most of these cases were present 
 
164 THE PATHOLOGY OF THE MALARIAL FEVERS. 
 
 in the hospital for several weeks; repeated blood examinations were made; 
 they were carefully studied clinically, and in none of them was malarial infection 
 suspected. It is obvious that puncture of the spleen would probably have 
 resulted in the discovery of the malarial infection in these cases, but this 
 procedure is dangerous, even in experienced hands, and is certainly not advisable 
 as a routine measure. 
 
 The Pathology of Malarial Cachexia. — Since the separation of kala-azar 
 and malaria upon etiological and pathological grounds, the pathology of 
 malarial cachexia is much better understood than when these two infections 
 were confused. Almost every writer upon malaria describe marked pathological 
 lesions in chronic malarial poisoning, but it is more than probable that many 
 of them are due to complicating diseases rather than to the malarial infection. 
 
 The Blood. — In the majority of patients suffering from repeated attacks 
 of malaria, in whom a cachectic condition has developed, there is present a 
 greater or less degree of anemia, the red cells seldom numbering over 3,000,000 
 per cu. mm. and often not over 1,500,000 per cubic millimeter. The haemo- 
 globin is proportionately reduced, and there is often an increase in the large 
 mononuclear leucocytes. In severe cases nucleated red cells may be present, 
 and poikilocytosis is often marked. 
 
 From their researches Dionisi and Bignami have separated four types of 
 postmalarial anaemia, as follows: 
 
 "1. Anaemiae in which the examination of the blood shows alterations 
 similar to those observed in secondary anaemia, from which they differ only in 
 that the leucocytes are diminished in number. The greater part of these cases 
 go on to recovery; a few, without any further change in the haematological situ- 
 ation, pursue a fatal course. 
 
 "2. Anaemiae in which the examination of the blood shows alterations simi- 
 lar to those seen in pernicious anaemia — presence of gigantoblasts. These cases 
 end fatally. 
 
 "3. Anaemiae which are progressive, as the result of compensation by the 
 marrow for losses brought about by the infection. At autopsy the marrow of 
 the long bones is found to be wholly yellow, while the marrow of the flat bones 
 is also poor in nucleated red cells. 
 
 "4. Chronic anaemiae of the cachectic, which differ from the above-men- 
 tioned types by clinical and anatomical characters, in that the special symptoms 
 of malarial cachexia prevail, while one observed postmortem, a sort of sclerosis 
 of the bone-marrow." 
 
 I agree fully with Dionisi and Bignami regarding the forms of anaemia 
 following acute malaria, and have observed very severe anaemiae of the secondary 
 type frequently A pernicious anaemia following malaria has, in my ex- 
 perience, been very rare, only one case being observed in over 5,000 patients. 
 
 Aside from the blood, the chief pathological lesions in malarial cachexia 
 occur in the spleen, the liver, and the bone-marrow. 
 
 The Spleen. — In most instances the spleen is greatly enlarged, sometimes 
 weighing several pounds; is generally greatly pigmented; the capsule more or 
 
THE PATHOLOGY OF THE MALARIAL FEVERS. 165 
 
 less roughened by adhesions; the color of the cut surface being slate, brown, or 
 black; the Malpighian corpuscles standing out as almost white areas. The con- 
 nective tissue of the organ is often increased macroscopically. Microscopically, 
 the lesions consist in marked enlargement and fibrosis of Malpighian cor- 
 puscles, increased connective tissue along the trabeculae, which encroaches upon 
 the parenchyma in places, enormous distention of the splenic sinuses, and the 
 replacement of the splenic pulp by connective tissue containing large and small 
 round cells. Pigmentation is very marked, the pigment being collected about 
 the Malpighian corpuscles and along the fibrous trabeculae and in the walls of 
 the blood-vessels. Hyperplasia of the cells of the splenic pulp occurs in places, 
 especially about the enlarged follicles. 
 
 The Liver. — The liver may be enlarged or it may be atrophied, according 
 to the length of time the cachexia has lasted. The perilobular connective 
 tissue may be increased and there may be a hyperplasia of the liver parenchyma. 
 Severe chronic venous congestion may be present and angiomata may be 
 formed in the liver substance. The pigmentation is excessive at times, while 
 in those patients who have suffered from cachexia for years the malarial pig- 
 mentation may have entirely disappeared. In greatly pigmented livers the 
 outline of the lobules may be distinctly traced by the deposit of pigment, much 
 of the pigment being extravascular. 
 
 The question as to the occurrence of cirrhosis of the liver as the result of 
 prolonged malaria infection is still sub fudice. While in many instances the 
 liver in cachetics is atrophic, inquiry will generally develop the fact that the 
 atrophy is as apt to be due to one of several causes as to the malarial infection. 
 I am inclined to believe that in susceptible individuals severe and continued 
 malarial infection may produce cirrhosis of the liver, but such cases are very 
 rare, and I have never observed one in which the cirrhosis of the liver could not 
 have been attributed to other causes. 
 
 The Bone-marrow. — The changes in the bone-marrow are due princi- 
 pally to the anaemia produced by repeated attacks of malaria. The marrow of 
 the long bones is generally red in color and there is a marked increase in the 
 consistence. The fatty tissue has been replaced by vascular medullary tissue, 
 composed of large cells showing mitotic nuclei, lymphoid cells, giant cells, and 
 normoblasts. Pigmentation may be almost absent even when the other viscera 
 are markedly pigmented. In long-continued cases the nucleated cells are 
 rare, and in some cases the microscopical lesions are those of pernicious 
 anaemia. 
 
 Forms of Degeneration. — In the liver, spleen, and kidney, cloudy swelling 
 and fatty degeneration of the cells of the parenchyma is noted and amyloid 
 degeneration is not uncommon. While this change is not characteristic 
 of malaria, it occurs so frequently in malarial cachexia as to be of importance. 
 In the kidneys it is most usually observed, affecting the smaller blood-vessels 
 and the walls of the tubules. It also occurs in the intestine in the vessels of the 
 villi and in the spleen, affecting chiefly the capillaries of the follicles. The 
 
l66 THE PATHOLOGY OF THE MALARIAL FEYERS. 
 
 liver is not as often the seat of amyloid degeneration as in other diseases, the 
 condition being most noticeable at the periphery of the lobules. 
 
 The changes in the other viscera are not of special interest. The heart 
 muscle is often flabby and below normal in thickness, while the anaemia present 
 renders it pale in color. Fatty degeneration of the heart muscle is not com- 
 monly observed, and pigmentation is generally absent. The intestinal canal 
 shows no changes of importance except amyloid degeneration in a small propor- 
 tion of the cases. The lungs show no lesions characteristic of malarial cachexia. 
 
 The enlargement of the spleen, so long relied upon as indicative of chronic 
 malarial infection, can no longer be held as of much assistance in diagnosis in 
 regions where kala-azar is prevalent, as in such regions the spleen index is 
 most unreliable as showing the proportion of malarial infections. It is probable 
 that careful study of the fevers occurring in the tropics will demonstrate that 
 enlargement of the spleen is common to many of them. 
 
 Literature upon the Pathology of Latent Malarial Infection and Malarial Cachexia. 
 
 Pathology of Latent Malaria Infection. 
 
 1903. Craig, C. F. The Pathology of Latent Malarial Infection as Observed 
 at Autopsy. American Medicine, vol. vi, No. 4, p. 145. 
 
 Pathology of Malarial Cachexia. 
 
 The monographs upon malaria which have been referred to in previous 
 chapters, especially those of Thayer, Marchiafava and Bignami, Ziemann, and 
 Mannaberg. 
 1892-3. Bignami. Studi sull' anatomia patologica della infezione malarica 
 
 chronica. Bull. dell. R. accad. med. d. Roma, xix, f. ii, p. 186. 
 1894. Bignami and Dionisi. Die Postmalarischen und die experimentellen 
 
 chronischen toxischen Anaemien. Cent. f. allg. path, anat., v, No. 10, p. 
 
 43 2 - 
 
PART III. 
 
 THE SYMPTOMATOLOGY AND CLINICAL VARIETIES OF THE 
 
 MALARIAL FEVERS. 
 
CHAPTER I. 
 
 Clinical Classification; Tertian Malarial Fever; Quartan Malarial Fever; 
 Aestivo-autumnal Malaria; Analysis of Symptoms; Examination of the Blood. 
 
 Clinical Classification. — It is often extremely difficult to classify the 
 malarial fevers from a clinical standpoint. A division of these infections 
 into intermittent, remittent, and continuous fevers, so often followed, is useful, 
 but is at best a rough classification which does not indicate disease entities, 
 and is confusing in many ways. It may be stated that any malarial fever may 
 be intermittent, remittent, or continuous. For instance, while a single tertian 
 infection is undoubtedly intermittent in type, we can conceive of a tertian 
 infection in which several groups of plasmodia sporulating at various periods 
 may give rise to a remittent or even continuous temperature curve, and in 
 practice benign tertian infections remittent in type are not so very uncommon. 
 The same holds true of quartan infections and especially of the aestivo-autumnal 
 fevers. It is also a fact that infection with a single generation of any one of 
 the malarial plasmodia will result in an intermittent fever" In other words, 
 all malarial infections are intermittent in character and only become remittent 
 or continuous when more than one generation of the plasmodium matures 
 at different intervals of time, or when the typical character of the temperature 
 curve is disturbed by inadequate treatment or by the natural resisting powers 
 of the individual. While the term "remittent malaria" is generally applied to 
 infections produced by the aestivo-autumnal plasmodia, the name is a misnomer, 
 as the aestivo-autumnal infections are as truly intermittent as are the tertian 
 and quartan. For this reason, I believe that classification should rest upon 
 etiology in these infections and that clinical classification resting upon any other 
 basis is unscientific and inevitably leads to confusion and a loose method of 
 diagnosis. It is of the greatest importance in the treatment of malaria that 
 we know to which species of plasmodium the fever is due, and this we can only 
 know, in most instances, by an examination of the blood. A classification 
 based upon the character of the temperature curve is very misleading and tends 
 to lead to carelessness in making the blood examination or to neglect of that 
 most important procedure. Stastistics of the type of malaria present in any 
 locality based entirely upon the character of the temperature curve are worse 
 than useless and should receive but little consideration in the study of malarial 
 endemicity. 
 
 The following classification is adopted in this work, as it would appear 
 to be the best from both a clinical and etiological point of view: 
 
 i. Tertian malaria, due to Plasmodium vivax. 
 
 169 
 
170 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 2. Quartan malaria, due to Plasmodium malariae. 
 
 3. Tertian aestivo-autumnal malaria, due to Plasmodium falciparum. 
 
 4. Quotidian aestivo-autumnal malaria, due to Plasmodium falciparum 
 quotidanum. 
 
 As I have already stated, I hold with Marchiafava and Bignami and others 
 that there are two distinct types of aestivo-autumnal infection, both from 
 a clinical and etiological standpoint, and I have already considered the morpho- 
 logical differences between the two types or species of plasmodia, but we do 
 not have to rely solely upon such differences in distinguishing these fevers, 
 for both varieties are distinct clinically in uncomplicated cases. I am aware 
 that many observers have failed to recognize two forms of aestivo-autumnal 
 malaria, but I am sure that any unprejudiced observer will admit the existence 
 of these two forms of infection, if he studies uncomplicated cases of aestivo- 
 autumnal fever in which quinine has not been given and in regions where these 
 infections are endemic. 
 
 As to the relative frequency of these two forms of malaria it is undoubtedly 
 true that the tertian aestivo-autumnal infection is altogether the most frequent. 
 From the data I possess, comprising several thousand cases of aestivo-autumnal 
 fever, the tertian plasmodium was found in about 75 per cent, of the cases. 
 . The impression which prevails among many physicians, that a remittent 
 temperature curve is characteristic of all aestivo-autumnal infections, is a false 
 one, for irregularity or remittence is by no means confined to the aestivo- 
 autumnal infections, which, if uncomplicated, are as truly intermittent as are 
 either the benign tertian or quartan fevers. While it is true that irregularities 
 of temperature are more apt to occur in aestivo-autumnal cases, because they 
 are more resistant to treatment and are more commonly produced by multiple 
 groups of plasmodia, it is not true that a remittent temperature curve is 
 characteristic of them and that a diagnosis can be based upon such remittency. 
 Any malarial fever may become irregular or remittent, from a multitude of 
 causes, one of the chief of which is the unscientific use of quinine. 
 
 Clinically, all aestivo-autumnal fevers should be classed as severe forms 
 of malarial fever, in contradistinction to the tertian and quartan types which 
 are classed as mild or benign types of malarial infection. This classification 
 of the aestivo-autumnal fevers as severe forms is of great importance. While, 
 of course, comparatively few aestivo-autumnal infections result fatally, and 
 while most are readily amenable to proper treatment and many are cured 
 spontaneously, the fact remains that almost all of the pernicious malarial 
 fevers are caused by the aestivo-autumnal plasmodia, and every case showing 
 the presence in the blocd of these plasmodia should be considered as serious 
 in nature and treated accordingly. 
 
 The old idea that pernicious malaria is due to a particular species of 
 Plasmodium has long ago been abandoned, and we now have upon record 
 fatal cases of malaria due to all four species of plasmodia, although most 
 fatal infections have been due to the tertian aestivo-autumnal parasite. In 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 171 
 
 my own experience this species has occurred most frequently in fatal infections, 
 but the quotidian plasmodium occurs more frequently than either the benign 
 tertian or the quartan plasmodia. The aestivo-autumnal plasmodia occurring 
 in the blood in fatal infections differ in no way from those occurring in aestivo- 
 autumnal infections in general, and it is probably the susceptibility of the 
 patient and the number of the plasmodia present which determines the pernicious 
 character of the attack rather than the species of aestivo-autumnal plasmodium 
 present. 
 
 Some authorities have striven to establish a class of malarial infections 
 characterized by long intervals between the paroxysms, the so-called "long- 
 interval fevers," in which six, eight, or even ten days elapse between the attacks 
 of fever. Such a classification is not consistent with what we know of the 
 plasmodia causing the different types of malaria, and is undeserving of con- 
 sideration. Such cases are simply relapses of a malarial infection, and are as 
 apt to be due to the tertian or quartan plasmodium as to either of the aestivo- 
 autumnal plasmodia. In rare instances a case is observed which apparently 
 shows some such regularity, but the resemblance is only apparent, for an exami- 
 nation of the blood will demonstrate that the cycle of development of the 
 plasmodium causing it is completed as usual, although clinical symptoms may 
 be absent or atypical at certain times; in other words, the infection is latent. 
 
 Symptoms of Tertian Malarial Fever. — The paroxysms of fever in 
 benign tertian malaria occur every forty-eight hours and are initiated by the 
 sporulation of the tertian plasmodium or Plasmodium vivax. The time of 
 the onset of the paroxysm can be accurately judged by the stage of growth of the 
 organism as observed in the peripheral blood. The onset of the paroxysm 
 always occurs during the segmentation of the plasmodium, and quotidian 
 paroxysms are caused by double infections with the tertian plasmodium. 
 
 This, the most common and mildest form of malarial fever, occurs in both 
 temperate and tropical countries, being the most common type in the tem- 
 perate zones, and in certain localities in the tropics. Of 2,803 cases of malaria 
 observed by myself in soldiers returning from the Philippines and from Cuba, 
 839 suffered from tertian malaria, of which 220 were double tertian infections. 
 In Baltimore, of 542 cases of malaria observed by Thayer and Hewetson, 338 
 were tertian infections, while of 71 cases studied by Mannaberg in Vienna all 
 but 10 were infected with this organism. In uncomplicated cases this type of 
 malaria presents a typical temperature curve, showing in single infections a rise 
 of temperature every second day; in double infections, a rise of temperature 
 every day; while in infections with numerous groups of tertian plasmodia there 
 may be a remittent or sub-continued temperature curve. In cases presenting 
 quotidian paroxysms it is often possible to destroy one group of parasites by 
 small doses of quinine, and when this is done the regular tertian paroxysm will 
 reappear. 
 
 The paroxysm, when typical, is divided into three stages, chill, fever, and 
 sweating. The prodromal symptoms are generally malaise, loss of appetite,. and 
 
172 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 more or less dull headache and slight aching in the extremities. After these 
 symptoms have persisted for a few days (and during this period the plasmodia 
 may often be observed in the peripheral blood in small numbers) the patient is 
 seized with a severe chill, but although he feels extremely cold the temperature 
 continues to rise, and at the acme of the chill has reached 103 , 104 , or even 
 106 F. The chill is immediately followed by a pronounced sense of heat, and 
 in a short period of. time the patient will complain as bitterly of this as he pre- 
 viously had of the cold. During the stage of fever, delirium may be present and 
 there is generally severe headache. During the onset of the chill, nausea and 
 vomiting are common, but they do not persist, as a rule, during the stage of 
 fever. After the fever has lasted for a few hours, it rapidly declines to normal, 
 accompanied by very severe sweating, the entire skin being bedewed with 
 moisture, often so pronounced that the bed-clothing is saturated. The follow- 
 ing detailed description is true of most tertian malarial paroxysms: 
 
 The Cold Stage or Chill. — As I have mentioned, there are generally 
 some prodromal symptoms of the approaching malarial chill as evidenced by 
 yawning, a general sense of discomfort, headache, and often nausea and vomit- 
 ing. The feeling of cold usually commences at the feet and gradually pro- 
 gresses upward, although very often the first chilly sensations are felt along the 
 spine. In tertian infections the chill is severe, the patient shaking very vigor- 
 ously, but it is not so severe as in most quartan infections. In certain mild 
 cases the chill may be absent, the patient complaining only of chilly sensations. 
 The facial expression of the patient during the chill is one of cyanosis, the lips 
 being blue and the skin bluish-red in color. The extremities are cyanotic and 
 the skin presents the well-known condition characterized as "goose-flesh." 
 The pulse is rapid, generally rather diminished in volume and often irregular. 
 Headache is very often intense. During the chill the temperature rises very 
 rapidly, reaching 104 F. or more in severe cases, but careful examination will 
 demonstrate that the temperature had begun to rise before the onset of the chill. 
 The urine is increased in quantity and decreased in specific gravity. The 
 duration of this stage varies from an hour to two hours in the most serious 
 cases. 
 
 The Hot Stage. — At the beginning of the hot stage the patient complains 
 of flushes of heat, rapidly succeeded by cold sensations. Soon the sensations 
 of cold are entirely lost and the patient complains bitterly of the intense heat 
 due to the high temperature. The facial appearance is that of intense con- 
 gestion, the conjunctivae being injected, and the entire surface of the body 
 reddened, the congestion being especially marked in the hands. The pulse 
 is full, bounding, and often dicrotic. The respirations are rapid and hurried, 
 and there may be a slight cough due to congestion of the lungs. The headache 
 increases and may be very intense and of a throbbing character. 
 
 In the mild tertian attacks there are no nervous symptoms present beyond 
 a severe headache, but in the severe cases there may be marked delirium or a 
 drowsy condition merging into semi-coma, or even coma. This condition 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 1 73 
 
 is almost always present in those rare cases of tertian fever which become 
 pernicious. 
 
 The chief cymptoms complained of by the patient during the hot stage are 
 the intense heat of the fever and the headache. The temperature may reach its 
 highest point during this stage, but very often it is highest at the end of the cold 
 stage. It is not uncommon during the hot stage to observe skin eruptions. 
 Herpes is very frequently seen, especially about the lips, and urticaria and a 
 general erythema not infrequently occur. These eruptions sometimes lead to a 
 suspicion of some eruptive disease being the cause of the chill. Herpes of the 
 penis may occur during the hot stage of the paroxysm or may develop later. The 
 duration of this stage varies from four to six hours, but may be shorter or longer. 
 
 The Sweating Stage. — As the fever begins to decline, it will be noticed 
 that the perspiration appears first upon the forehead and face, and the patient 
 at once begins to feel better, the decrease in the unpleasant symptoms being 
 proportionate to the severity of the sweating. Commencing, as has been said, 
 on the face, the perspiration rapidly involves the entire body and is often so 
 severe that water may be seen trickling from the skin of the arms, thighs, and 
 legs. The sweating stage lasts, as a rule, from two to three hours, at the end 
 of which time the temperature has declined to normal, all of the unpleasant 
 symptoms have disappeared, and the patient falls into a sleep which may 
 last for several hours. As a rule, the temperature goes somewhat below normal 
 and the decline, if rapid, as it often is, is accompanied by considerable weakness 
 of the circulation, the pulse being slow and of low tension. In very rare cases 
 this stage may be accompanied by collapse and death. During the sweating 
 stage the urine may be increased in amount. 
 
 The average duration of the entire tertian paroxysm is from eleven to 
 fourteen hours, but it should be remembered that there are paroxysms so 
 slight as to be hardly recognized, especially in children, while, on the other 
 hand, the length of the paroxysm may be prolonged to twenty-four hours. 
 In young children the onset of the malarial paroxysm is often accompanied 
 by convulsions. (Chart A.) 
 
 Physical examination of the patient will often show an enlarged and 
 tender spleen, but this sign cannot be relied upon except in those cases which 
 have had severe and repeated infections. An enlarged and tender spleen 
 occurs too frequently in other acute infections to be of more than confirmative 
 evidence in the diagnosis of malaria. Albuminuria is present in a considerable 
 proportion of the cases of tertian infection. Of over 1,000 cases of tertian 
 infection personally observed by the writer nearly 46 per cent, showed albumin 
 in the urine, and it is probable that a careful examination of the urine in all 
 such cases would result in showing a larger percentage than this. Hyaline and 
 granular casts are found in the urine in the most severe cases, but not as fre- 
 quently as in the aestivo-autumnal infections. Polyuria is very frequently 
 observed immediately following the paroxysm, and it may persist for days and 
 even weeks. 
 
m 
 
 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 U 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 1 75 
 
 Symptoms of Quartan Malarial Fever. — The symptoms of quartan 
 malarial infection are very similar to those of tertian infections, although they 
 are generally more severe in character. 
 
 Frequency of Quartan Infections. — This is the most rare form of 
 malarial infection, being absent in many malarial localities, and occurring 
 very rarely in others, while in some regions it is the prevailing type of infection. 
 It is probably most common in temperate regions, but is not infrequently 
 observed in the tropics together with aestivo-autumnal infections. The 
 following table illustrates the relative frequency of this type as observed in 
 different localities: 
 
 No. of cases 
 
 Quartan 
 
 Observer. observed. 
 
 infections. 
 
 Maillot, in Algeria, 2 33& 
 
 26 
 
 Finot, in Blida, 421 1 
 
 2 1 
 
 Laveran, in Algiers, 311 
 
 7 
 
 Thayer and Hewetson, in 
 
 
 Baltimore, U. S. A., 1680 
 
 i5 
 
 Griesinger, in Tubingen, 414 
 
 3 
 
 Mannaberg, in Vienna, 144 
 
 8 
 
 In my own experience, comprising over 5,000 cases of malaria in which the 
 Plasmodia were demonstrated in the blood, only 26 cases of quartan infection 
 were observed. Practically all of the cases were in soldiers returning from the 
 Philippines and from Cuba, where they had contracted their infection. The 
 percentage of quartan infection in the Philippine Islands is higher, however, 
 than in many other tropical countries, as is shown by the fact that Koch only 
 observed one case of this infection in tropical Africa and Zieman reports its 
 absence from Kamerun, while I observed 18 cases in the Philippines in the 
 course of about twelve months. In certain regions in Italy this type of infection 
 is the prevailing one, tertian and aestivo-autumnal infections being almost 
 unknown. 
 
 In most localities in the temperate zones quartan infections occur most 
 frequently in the late summer and during the autumn months, but in the 
 tropics they occur at more irregular intervals which vary with the time of the 
 rainy season, these infections appearing several weeks after the cessation of the 
 rains or, in other words, toward the latter part of the malarial season 
 
 The Symptoms. — The paroxysms of quartan malaria are characterized 
 by their regularity in uncomplicated infections, the febrile attacks occurring 
 at the end of every 72 hours, but, here again, we may have double infections, 
 in which the attacks occur upon two days in succession, with an afebrile day 
 interposed, or triple infections, in which the attacks occur daily. Double and 
 triple infections are comparatively rare. Mannaberg saw two cases of double 
 quartan, and Thayer and Hewetson three cases of triple quartan. I have 
 never seen a triple quartan infection and only one double infection. Irregular 
 and sub-continued quartan infections are rarely observed, though such cases 
 have been described by Antolisei and Feletti. 
 
176 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 As in tertian infections the febrile paroxysm in quartan malaria corresponds 
 with the sporulation of the quartan parasite, of Plasmodium malariae, and the 
 time of the occurrence of the paroxysm may be accurately foretold by the 
 stage of the development of the plasmodia in the peripheral blood. 
 
 The symptoms observed during a quartan paroxysm are so similar to those 
 already described in tertian infections that a detailed account of them is not 
 necessary. There are the same stages of chill, fever, and sweating as are seen 
 in the tertian infections, but, as a rule, the symptoms are more severe and 
 pernicious attacks are more common. The nervous symptoms especially 
 are apt to be more pronounced, and slight delirium is very common. 
 (Chart B.) 
 
 The quartan paroxysm is not as prolonged as is the tertian, lasting from 
 eight to ten hours, but the attacks may be shorter than this or may extend 
 over twenty-four hours. I have never observed a quartan infection in which 
 the paroxysm lasted over 12 hours. 
 
 During the fall in temperature collapse symptoms may develop, and the 
 temperature generally falls considerably below normal, and may remain 
 so during the apyrexial period and for some weeks after recovery. In both 
 tertian and quartan malaria the paroxysms are most apt to occur during the 
 day, usually during the afternoon or late morning, but in both forms of infection 
 the paroxysms may occur during the night. In cases of double or triple infection 
 the febrile periods are apt to be irregular in the time of occurrence, the chill 
 appearing one day in the afternoon and, perhaps, the next day in the 
 morning. 
 
 Aestivo-autumnal Malaria. — The aestivo-autumnal malarial infections 
 are caused by two distinct plasmodia, one completing its cycle of development in 
 the human body in 24 hours and the other in 48 hours. The symptoms of the 
 two infections differ greatly, especially the temperature, and in uncomplicated 
 cases the tertian aestivo-autumnal infections may be diagnosed by the tempera- 
 ture curve alone. Either of the aestivo-autumnal plasmodia is capable of 
 causing pernicious symptoms, but personal observations appear to show that the 
 tertian species is the one most commonly concerned, about 75 per cent, of the 
 pernicious cases I have observed being due to this plasmodium. 
 
 The aestivo-autumnal infections have long been distinguished by the term 
 "remittent fevers," it being supposed that in these infections the temperature 
 curve, instead of presenting the marked intermittency observed in tertian and 
 quartan fevers, was remittent or irregular in character. This is not always so, 
 however, for these fevers, when uncomplicated or uninfluenced by quinine, are 
 as truly intermittent as are the tertian and quartan infections. It is undeniable 
 that remittency and irregularities in the temperature curve are more common in 
 the aestivo-autumnal fevers, but too much stress should not be laid upon this 
 point in diagnosis. 
 
 Frequency of Occurrence. — The aestivo-autumnal infections are es- 
 sentially tropical malarial infections, and it is to these forms of malaria that the 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
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170 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 term "tropical malaria" is applied by some writers. As aestivo-autumnal 
 malaria occurs also in temperature climates, and does not differ in its symptoms 
 from the same infection occurring in the tropics, the term "tropical malaria" 
 should be abandoned if by it we mean a form of malaria peculiar to the tropics. 
 It is true that in the tropics these infections are more apt to become pernicious, 
 but this fact is not due to any difference in the plasmodia, but to the debilitated 
 condition of the patient brought about by the tropical climate and by other 
 factors, such as repeated infection, infection with a great number of plasmodia, 
 and, in the case of soldiers, by exposure and overexertion beneath a tropical 
 sun, followed by the chilling of the cool tropical evenings. 
 
 The relative frequency of the occurrence of aestivo-autumnal infections 
 varies very greatly in different localities. In the temperate zones these in- 
 fections are rare, but in the tropics they comprise the great bulk of malarial 
 disease, but even in the tropics they are much more frequent in some localities 
 than in others. At Camp Stotsenburg in the island of Luzon, there occurred 
 from three to four cases of aestivo-autumnal infection to one of tertian, but 
 at Camp Gregg, only forty miles from Stotsenburg, the prevailing type of in- 
 fection was the benign tertian. 
 
 The occurrence of many cases of tertian infection in certain localities in the 
 Philippine Islands led to the report that aestivo-autumnal malaria was in- 
 frequent there, but a more careful study of the subject has demonstrated that 
 the Philippines are not an exception to the great rule that in the tropics the 
 aestivo-autumnal infections are the prevailing type. In 2,000 cases of malaria 
 in soldiers returning from the Philippines and in natives of those islands, in 
 which the plasmodia were demonstrated in the blood, no less than 1,662 were 
 infected with the aestivo-autumnal plasmodia. These personal observations 
 are confirmed by those of Jackson, Chamberlain, and others, so that we may 
 state positively that the prevailing types of malarial fever in the Philippine 
 Islands are the aestivo-autumnal. 
 
 The tertian aestivo-autumnal infections occur very much more frequently 
 than do the quotidian infections, the latter type being comparatively rare. 
 Thus of 1,662 aestivo-autumnal infections, personally observed, 1,473 were due 
 to the tertian aestivo-autumnal plasmodium and only 189 to the quotidian 
 aestivo-autumnal plasmodium. 
 
 The aestivo-autumnal infections occur most frequently in temperate 
 regions during the months of July, August, September, and October, but in the 
 tropics they persist throughout the year, although they are most numerous 
 during the latter portion of the rainy season and at the beginning of the dry 
 season. 
 
 In describing the symptoms of the aestivo-autumnal infections I shall 
 mention here only those observed in ordinary attacks, leaving the description 
 of the symptoms of pernicious attacks for a succeeding chapter. The symptoms 
 of this group of malarial fevers are very apt to be atypical and the descriptions 
 which follow apply only to the fevers as usually observed. 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 I 79 
 
l8o . THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 Symptoms of Tertian Aestivo-autumnal Malaria (Non -pernicious 
 Type). — Patients suffering from this type of malaria will generally present the 
 following symptoms: 
 
 Prodromal. — The prodromal symptoms are loss of appetite, slight head- 
 ache, evanescent pains in the back and legs, nervousness, increased urination, 
 and a general feeling of malaise. In some instances the onset is sudden, the 
 patient having felt well until the appearance of marked symptoms. As in 
 tertian and quartan infections, three stages may be distinguished. The 
 paroxysms occur every forty-eight hours and correspond in time with the 
 sporulation of Plasmodium falciparum. 
 
 The Cold Stage or "Chill." — This is generally initiated by yawning 
 and the patient complains of headache, slight nausea, perhaps accompanied by 
 vomiting, and often intense nervousness. In a majority of the cases there are 
 no distinct chills, but the patient complains of chilly "creeping" sensations 
 along the spinal column and slight flushings of cold especially noticeable along 
 the posterior aspect of the buttocks and thighs. At the same time the head- 
 ache increases, there is present a feeling of extreme weakness, and generally 
 profound mental depression, sometimes so great as to be the most prominent 
 symptom. The skin presents the appearance of "goose-flesh," and it and the 
 mucous membranes are cyanosed ; the extremities are cool and feel heavy to 
 the patient. There is severe pain and aching in the legs and back, greatest, 
 as a rule, in the lumbar region. The pulse is generally weak and increased 
 in frequency and may be very irregular. The respirations are rapid and 
 rather shallow. The tongue is broad and flabby and heavily coated. During 
 this stage the temperature gradually rises and may reach 103 F. or more. 
 This portion of the attack does not last over half an hour in the majority of 
 the cases, and the patient seldom shakes with the chill as in tertian and quar- 
 tan infections. 
 
 The Hot Stage. — Gradually the patient experiences a sensation of heat, 
 coming first as localized flushings, but soon becoming general. The facial ap- 
 pearance is that common to fever, the eyes being suffused and brilliant, the face 
 red, and the skin dry and hot. Headache is intense and there is present 
 either great mental depression or nervous excitement. The pain in the back 
 and limbs is often agonizing in character, and in some instances there is severe 
 pain over the abdomen, either over the spleen or in the right iliac region. The 
 temperature is elevated and in uncomplicated cases very characteristic. Nausea 
 and vomiting are frequently present, the vomiting sometimes being very severe. 
 Diarrhoea is a common complication. The urine is increased in quantity and 
 is generally albuminous. The pulse is rapid and dicrotic in character, the 
 respirations rapid, and there may be severe dyspnoea. 
 
 The Sweating Stage or Stage of Remission. — The hot stage continues 
 for several hours (sixteen to eighteen or twenty) and is followed by the falling 
 of the temperature accompanied by more or less sweating. During the latter 
 stage the symptoms gradually decline in severity and finally disappear, the 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 181 
 
102 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 temperature going a degree or a degree and a half below normal. A slight 
 sweating is generally observed, but it is not nearly so marked as in tertian 
 and quartan infections. 
 
 The period of normal temperature or intermission may last only two or 
 three hours, when another paroxysm ensues. As a rule, attacks of this fever 
 occur toward evening, extend throughout the next day, and subside during 
 the first hours of the third day, the entire paroxysm thus lasting thirty-six hours 
 or more and occurring every 48 hours. While the symptoms described are 
 often more severe in this type of malaria than they are in tertian and quartan 
 infections, there is nothing diagnostic about them except the curve exhibited 
 by the temperature. In uncomplicated cases the behavior of the temperature 
 is absolutely characteristic, and the temperature curve is one that is not met 
 with in any other disease. This peculiarity of tertian aestivo-autumnal 
 infections was first pointed out by Marchiafava and Bignami, and the writer 
 has been able to confirm their observations in every uncomplicated case of 
 such infection. At the onset of the fever the temperature rises suddenly to 
 103 or 104 F. Following the sudden rise there occur slight oscillations 
 which cover several hours, during which time the temperature falls from one- 
 half to one degree. This period of slight oscillation is followed by a distinct 
 fall or pseudocrisis, the temperature dropping from one and a half to two 
 or even three degrees. This fall in the temperature is often considered by 
 the physician as the true crisis of the paroxysm; on the contrary, however, 
 the fever again rises to a point higher than that before attained and then falls 
 rapidly. This peculiar temperature curve can be divided into five stages: 
 (1) the initial rise; (2) the period of slight remissions; (3) the pseudocrisis; 
 (4) the precritical rise; (5) the true crisis. Another point of value in diagnosis 
 between this type of fever and the benign tertian and quartan types is the 
 length of the febrile period. This varies, but generally the temperature remains 
 elevated over 24 hours, and often from 38 to 40; in other words, the paroxysm 
 really covers two days, while the period of intermission is very short. (Chart 1 .) 
 
 Symptoms of Quotidian Aestivo-autumnal Malaria. — The quotidian 
 aestivo-autumnal fever is characterized by a febrile paroxysm occurring every 
 twenty-four hours, corresponding to the sporulation of Plasmodium falciparum 
 quotidianum. Otherwise it varies but slightly in its symptomatology from 
 the tertian type. As in the latter form, the three stages described may generally 
 be observed, but in the quotidian type the chilly sensations are more severe 
 and there is often a distinct chill. Sweating is also more pronounced, but is 
 not so marked as in the simple tertian and quartan fevers. The temperature 
 curve is entirely different. It consists in the abrupt rise of the temperature to 
 103 F. or more, succeeded by as abrupt a fall. The attack lasts, as a rule, only 
 about eight or ten hours. The temperature curve seldom remains regular 
 for long at a time, for the attacks tend to run into one another, thus giving rise 
 to more or less continuous fever. This is especially true of the pernicious 
 attacks. (Chart 5.) 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 I8 3 
 
1S4 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 To one who has studied aestivo-autumnal malarial infections in regions 
 where they are endemic and who has been so fortuate as to observe such 
 infections uninfluenced by treatment or other complicating factors, the great 
 difference in the temperature curves of the tertian and quotidian type is alone 
 sufficient to distinguish them, and when we add to this difference the variation 
 in the morphology and developmental history of the two plasmodia concerned, 
 we must admit that aestivo-autumnal malaria is caused by two species of plas- 
 modia, as first described by Marchiafava and Bignami. 
 
 Analysis of the Symptoms of Malarial Infections. — It will be of 
 interest and value to consider more in detail the symptoms observed in the 
 various types of malarial infection. 
 
 The Temperature Curves — I have already spoken of the temperature 
 curves exhibited by malarial infections, and, while in uncomplicated cases a 
 diagnosis of the type of infection might be arrived at from a study of the 
 temperature alone, there are so many variations from the typical temperature 
 in all forms of malarial infection that it is seldom safe to depend upon this 
 symptom in making a diagnosis. The curves presented in single benign tertian 
 and in quartan malaria are characteristic, the febrile paroxysm in the one occur- 
 ring at the end of every 48 hours, in the other at the end of every 72 hours, 
 but in double or triple infections or in mixed infections, the temperature curve 
 may be so altered as to be of no service in diagnosis. In the tertian aestivo- 
 autumnal cases the temperature curve is very characteristic in uncomplicated 
 cases, but many cases occur in which the curve is so altered as to be unrecogniza- 
 ble. In a large proportion of tertian aestivo-autumnal cases, the characteristic 
 temperature curve already described will be observed, but there are many 
 deviations from the classical type. These deviations, in all forms of malaria, 
 are due to several factors, among the most important of which are the following: 
 improper medication with quinine; double infections or infections with more 
 than one species of the malarial plasmodium; anticipation of the attacks, 
 especially common in the pernicious fevers; retardation of the attacks; slight 
 elevations of temperature between the attacks, and complication with some 
 other disease. 
 
 The most beautifully typical malarial temperature curve may be rendered 
 atypical and very confusing by the administration of small doses of quinine 
 at irregular intervals, and this is one of the most common causes of irregularity 
 in the curve. 
 
 The most important alterations in the tertian aestivo-autumnal tempera- 
 ture curve produced by the factors enumerated are: 
 
 1. A curve almost identical with that of the benign tertian, produced by 
 the short duration of the paroxysm. (Chart No. 2.) 
 
 2. A curve characterized by a long period of slight remissions, due to 
 prolongation of the paroxysms. (Chart No. 3.) 
 
 3. A curve showing no well-marked initial elevation of the temperature, 
 thus causing a more or less continuous fever line. 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 J8; 
 
 H 
 
l86 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 4. A continuous curve showing only slight remissions, due to overlapping 
 of the paroxysms. (Chart No. 4.) 
 
 5. A curve showing a very marked pseudocrisis, thus causing the fever 
 line to resemble that of a double tertian or quotidian aestivo-autumnal 
 infection. 
 
 6. A curve in which the five stages described are reversed. 
 
 Besides these' modifications there occur many which are so complex that 
 it becomes impossible to recognize the disease with which we are dealing with- 
 out a microscopical examination of the blood. 
 
 In the aestivo-autumnal fevers a temperature chart which shows only the 
 morning and evening temperature is worse than useless as a guide in study or 
 diagnosis, and the use of a chart showing the temperature every three or four 
 hours is imperative. To secure the most typical temperature curve the chart 
 should be a three-hourly one, and only by the use of such a chart can the peculiar 
 curve of tertian aestivo-autumnal malaria be demonstrated. 
 
 In the quotidian form of aestivo-autumnal malaria the temperature curve 
 is not very characteristic. The temperature rises quickly and falls as quickly, 
 the entire attack lasting, as a rule, about eight hours, but sometimes longer, 
 while in the typical form the temperature, during the crisis, falls considerably 
 below normal. This is a very marked peculiarity of the quotidian form, and in 
 no other disease does the temperature fall so far below normal without a fatal 
 result to the patient. I have seen many cases in which the temperature fell to 
 95 F. during the crisis, and several in which it fell even lower, without any 
 symptoms of collapse developing. As the curve in this form of aestivo- 
 autumnal infection resembles so closely that of a double tertian infection, we 
 are forced to depend upon the microscope in order to exclude the latter, and 
 there is no greater proof of the value of a microscopical examination of the blood 
 than is found in the ease with which the various forms of malarial fever may 
 be diagnosed and differentiated by it, and such an examination is often instru- 
 mental in saving life. 
 
 The Chills.— In benign tertian and in quartan infection the chills are 
 pronounced in the vast majority of instances, although very rarely such in- 
 fections are observed in which the patients complain only of chilly sensations. 
 In the aestivo-autumnal infections, however, the chill is slight or almost absent, 
 especially in the tertian form. In the majority of cases the patients simply com- 
 plain of chilly sensations along the spinal column and seldom shake with the 
 chill. In the quotidian infections the chill is more pronounced than in the ter- 
 tian form, and in both occur cases in which the chill may be very severe and 
 exhausting. There are also many cases in which the chill is so slight as not to 
 attract the attention of the patient. As a rule, the chilly sensations or the chill 
 do not last over three-quarters of an hour, and in the aestivo-autumnal in- 
 fections often not over fifteen to twenty minutes. In general, it may be said 
 that shaking chills occur commonly in simple tertian and quartan malaria, very 
 rarely in aestivo-autumnal infections. 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
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188 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 The Sweating. — In simple tertian and quartan infections the sweating 
 which occurs during the decline of the febrile paroxysm is generally profuse and 
 sometimes very exhausting. In these cases the entire skin is covered with per- 
 spiration, often so great in quantity that the water may be seen trickling down 
 the trunk and limbs, saturating the bed-clothing. In the tertian aestivo-autumnal 
 infection the sweating is not excessive, and is often so slight as not to at- 
 tract attention. In the quotidian form the sweating is generally more severe, 
 but not, as a rule, so marked as in the simple tertian or quartan infections. In 
 both forms of aestivo-autumnal fever, however, the sweating stage may be 
 prolonged and exhausting. 
 
 Facial Appearance. — In primary acute attacks of all forms of malaria the 
 face is flushed or congested, the eyes suffused and brilliant, while an anxious ex- 
 pression is often present and the patient looks very sick. Exceptions to this 
 rule are observed in which the face is pale and the patient appears indifferent or 
 even cheerful. In cases which have suffered from relapses the face is usually 
 brownish-yellow in color, slightly flushed and haggard looking. 
 
 The Skin. — In primary acute attacks of malaria there is no alteration in 
 the color of the skin, but in the majority of patients who have suffered from 
 relapses, especially of the aestivo-autumnal fevers, the skin assumes a grayish 
 or yellowish hue and appears very anaemic. In some aestivo-autumnal in- 
 fections, notably the so called "bilious remittent fever," the skin may be mark- 
 edly jaundiced, so much so as to suggest yellow fever. 
 
 During acute attacks of all of the malarial fevers various skin eruptions may 
 make their appearance, especially urticarial eruptions, which I have observed 
 often in aestivo-autumnal fever. Herpes of the lips is a very common symptom 
 in some localities and in some infections, but is not as common in all localities as 
 has been supposed. Thus F. Plehn, in Africa, observed herpes only once in 714 
 cases of malaria, and my own experience in the Philippines is corrobative of that 
 of this observer. Of over 500 cases of malaria observed in Luzon, P. I., I saw 
 only about 10 cases in which herpes occurred, while at San Francisco and in 
 Cuba this condition was much more common, although all of the cases observed 
 at San Francisco were in the person of soldiers returning from the Philippines 
 and who had contracted their malaria in those islands. It would thus appear 
 that locality has much to do with the frequency of the occurrence of this symp- 
 tom. Herpes of the nostrils is not uncommon, and in several cases of aestivo- 
 autumnal malarial I have observed herpes of the penis occurring with or 
 immediately after a paroxysm of fever. 
 
 Peeling of the skin is sometimes observed in aestivo-autumnal infections, 
 occurring during an acute attack. I remember such a case in which the peeling 
 was very extensive, portions of the epidermis several centimeters in diameter 
 being thrown off. 
 
 The Mouth and Tongue. — The mouth, during the paroxysms, is dry, 
 the tongue thickly coated with a dirty white or brownish fur, and either broad 
 and flat or pointed and narrow. In severe cases of aestivo-autumnal fever the 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 189 
 
 tongue is dry and coated with a thick brown fur, while in pernicious cases 
 sordes may form upon the lips and teeth as in typhoid fever. 
 
 Symptoms Connected with the Circulatory System. — The organs of 
 circulation are generally but slightly affected during a malarial paroxysm. 
 The heart sounds are usually clear, but often a slight systolic murmur may be 
 heard over the mitral region. In many instances, however, the heart sounds 
 are muffled or the second sound is increased in volume. During the chill, 
 especially if it be severe, (and, therefore, more commonly in the simple tertian and 
 quartan infections than in the aestivo-autumnal), the pulse is weak and rapid; 
 during the stage of fever it is full, easily compressible, and often remarkably 
 dicrotic. It is increased in frequency, averaging from 120 to 140 beats per 
 minute. During the decline of the fever the pulse is full in volume and dicrotic, 
 while it is decreased in frequency. Sometimes there is present a marked 
 bradycardia. In not a few cases of aestivo-autumnal infection the pulse will be 
 found intermittent and sometimes alarmingly irregular, and I have observed 
 instances in which the first symptom of the malarial paroxysm consisted in 
 temporary failure of the heart's action. In many cases the patient complains of 
 a dull or acute precardial pain. The area of heart dullness is not altered in 
 uncomplicated cases. 
 
 Symptoms Connected with the Respiratory System.- — -The respirations 
 are always increased in frequency during an acute attack of any of the malarial 
 fevers, and in severe cases often appear to be slightly labored. This condition 
 is due to the greater or lesser amount of congestion present in the lungs and the 
 high temperature. Dyspnoea is present in some of the more severe infections, 
 and acute bronchitis, of mild character, is a very common symptom during acute 
 attacks of aestivo-autumnal fever. In rare instances symptoms indistinguishable 
 from those of pneumonia may appear, accompanied by a limited amount of 
 blood-stained sputum. 
 
 Physical examination of the lungs may show slight areas of lessened 
 resonance and a few rales, chiefly sibilant in character. Moist rales are some- 
 times heard. The physical signs of an acute bronchitis are often demonstrable. 
 
 Symptoms Connected with the Digestive System. — In all cases of 
 malaria there is loss of the appetite, often observable for days before the onset 
 of the febrile paroxysm. A feeling of oppression in the stomach or actual pain 
 in that region are common symptoms during the paroxysm and sometimes 
 for days afterward. Nausea is a very common symptom in all forms of 
 malarial infection, whether acute or chronic, occurring in fully 90 per cent, of 
 all cases, and this symptom is often very distressing and exhausting. Vomiting 
 occurs in a large proportion of all cases and in some instances is so severe and 
 persistent as to endanger the patient's life. Diarrhoea is another common 
 symptom, occurring during the paroxysm or immediately afterward, and rarely 
 may be of serious import. Constipation is more commonly observed, however, 
 and may be present for days before the onset of the fever. 
 
 Pain over the stomach and abdomen is not infrequently met with and has 
 
I90 THE SYMPTOMATOLOGY OF THE MALARLA.L FEVERS. 
 
 been the cause of many mistaken diagnoses. I have repeatedly seen cases 
 of malaria with severe pain in the region of the appendix diagnosed as appendi- 
 citis, and in more than one instance the microscope saved the patient an 
 operation. In some cases there is general pain over the abdomen simulating 
 very closely that of a general peritonitis. I have observed instances in which 
 the abdominal pain was agonizing in character, and controlled only by large 
 doses of morphine. 
 
 Symptoms Connected with the Glandular System. — Enlargement 
 of the spleen during an acute initial attack of malaria is by no means constant. 
 While there can be no doubt but that the organ is enlarged slightly in all acute 
 infections, the enlargement in many cases is not demonstrable, and a very large 
 proportion of the cases do not present a palpable spleen. In cases, however, 
 which have suffered from malarial infection for a considerable period of time, 
 and in which there have been many relapses, the splenic enlargement is gener- 
 ally noticeable, the organ being plainly palpable, and often extending nearly to 
 the umbilicus or perhaps beyond it. Laveran claims that every case of malaria 
 shows an enlargement of the spleen, while Kelsch and Kiener, A. Plehn, and 
 others state that this organ is often not enlarged. It is probable that much of 
 the confusion regarding this matter is due to lack of accuracy in making the 
 physical examination and in clearly defining the method of examination. Thus 
 in many cases careful percussion will show enlargement of the organ, although 
 it may not be palpable. From my own experience I have learned that palpable 
 enlargement is much less common than has hitherto been supposed, but that 
 in almost every case the organ will be found enlarged upon percussion. Manna- 
 berg claims that in 88 per cent, of cases suffering from malaria, the spleen is 
 palpable, while in the remaining 12 per cent, it is enlarged to percussion. 
 
 The spleen is palpable in aestivo-autumnal malaria more frequently 
 than in simple tertian or quartan infections, because the aestivo-autumnal 
 infections are more resistant to treatment and more prone to relapse. In 
 recent infections the organ is soft and rounded and very tender upon pressure, 
 while in old infections it is hard and presents a well-defined, rather sharp 
 margin. 
 
 In acute infections the liver is often slightly enlarged and tender, especially 
 in cases which have suffered from numerous relapses. 
 
 Symptoms Connected with the Urinary System. — In many cases of 
 malaria polyuria is a prominent symptom, occurring before, during, or after a 
 paroxysm. Pain in the lumbar region, over the kidneys, is a very common 
 symptom, and direct pressure upon these organs is sometimes exquisitely 
 painful. In a large proportion of the cases, however, the lumbar pain is not 
 referable to the kidneys. 
 
 Symptoms Connected with the Nervous System. — While symptoms 
 referable to the nervous system occur in all forms of malaria, it is in the aestivo- 
 autumnal fevers that they are most frequent and most important. The 
 malarial toxin appears to have a marked affinity for the tissues of the nervous 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. I9I 
 
 system and its action upon the vasomotor centers is well illustrated in the 
 phenomena of the malarial paroxysm, i.e., chill, fever and sweating. Delirium 
 occurs in a fairly large percentage of cases of aestivo-autumnal malaria, and 
 in severe tertian and quartan cases, and is usually of a mild, quiet type; active 
 maniacal delirium is sometimes observed. Headache occurs in practically 
 every case and is very often severe and most distressing. It is usually referred 
 to the forehead and occiput, and persists throughout the paroxysm, and often in 
 the afebrile interval. Soreness of the scalp is often complained of after the 
 paroxysm. Stupor is a common accompaniment of the more severe forms of 
 all the malarial fevers, and coma is common in pernicious cases. Vertigo 
 and tinnitus aurium are common and annoying symptoms. Patients suffering 
 from the aestivo-autumnal infections are often extremely nervous, both during 
 and between the paroxysms, and not infrequently this condition deepens into 
 a mild form of melancholia; such cases should be carefully watched, as suicidal 
 tendencies are apt to develop. 
 
 Pain in the back and limbs is always present during acute attacks of malaria, 
 and may be very severe, and is always one of the most disagreeable things the 
 patient is called upon to bear. 
 
 The more severe nervous symptoms occasionally observed in severe 
 malarial attacks, such as aphasia, paraplegia, hemiphegia, epileptiform 
 convulsions, and mania will be considered in the chapter dealing with the 
 complications of malaria. 
 
 Examination of the Blood. — I have already noted and described the 
 blood changes occurring during malarial infection, and will consider here the 
 blood findings as regards the plasmodia during the clinical periods of the 
 fevers. 
 
 Simple Tertian Malaria. — During the febrile paroxysm an examination 
 of the blood will show the presence of: 1. Sporulating plasmodia. 2. Fully 
 developed pigmented intracellular plasmodia. 3. Young hyaline ring-forms. 
 Examined at various hours during the afebrile period, the plasmodia may 
 be followed in development from the unpigmented and slightly pigmented 
 organism, filling only a portion of the infected cell, to the fully grown plasmodium, 
 containing much pigment and filling and distending the infected red corpuscle. 
 An hour or two before the onset of the paroxysm, the blood contains only 
 fully developed forms and sporulating bodies. 
 
 In double infections all stages of the plasmodium can be found at the same 
 time. 
 
 Quartan Malaria. — An examination of the blood in quartan malaria 
 gives the same results as in simple tertian as regards the stage of development of 
 the plasmodium. 
 
 Tertian Aestivo-autumnal Malaria. — During the febrile period, an 
 examination of the peripheral blood shows the small, more or less amoeboid, 
 hyaline, intracorpuscular plasmodia, from one-tenth to one-sixth the size of the 
 red corpuscle. 
 
I92 THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. 
 
 During the afebrile stage the young pigmented forms are found in the 
 peripheral blood. 
 
 Before the onset of a paroxysm the pigmented forms are more numerous 
 and have attained their largest size, about one-fourth that of the infected red 
 cell. 
 
 At the commencement of a paroxysm the plasmodia are generally remark- 
 ably few in number in the peripheral blood, but the young unpigmented forms 
 appear about at the acme of the fever. 
 
 In this form of malarial infection it is but very rarely that sporulating forms 
 are found in the peripheral blood, but blood secured by puncture of the spleen 
 at the time of the paroxysm will show multitudes of these bodies. 
 
 Quotidlvn Aestivo-autumnal Malaria. — The examination of the blood 
 in cases of quotidian aestivo-autumnal malaria gives results substantially the 
 same as those obtained in the tertian type as given above, so far as the time of 
 appearance of the plasmodia in the peripheral blood is concerned, so that it is 
 unnecessary to describe them separately. 
 
 In mixed infections and in irregular aestivo-autumnal infections the 
 examination of the blood will show the presence of the plasmodia concerned, 
 but it is difficult in such cases to trace the cycle of development of the parasites 
 of any one group. 
 
 Malaria in Children. — Because malarial infections in children present 
 important differences in their symptomatology from the same infections occur- 
 ring in adwlts, it is necessary that we should speak of such infections somewhat 
 in extenso. 
 
 Frequency. — It has already been mentioned that in malarial localities the 
 children suffer much more severely than do the adults, and that malaria tends to 
 disappear with increasing years. It is not necessary here to recapitulate the 
 evidence collected upon this point which has been given in a preceding chapter 
 but the important point should be remembered that in children malaria is very 
 often latent and that in malarial localities the children furnish almost all of the 
 pernicious cases. The infantile mortality from malaria in the tropics is enor- 
 mous and very largely preventable. 
 
 The symptoms of malarial infection in young children are so slight in many 
 instances that for days and even weeks such an infection may be present without 
 attracting attention. In the Philippines I have often seen children playing about 
 the streets with a temperature of ioo° to 101 F. and their blood swarming 
 with plasmodia. In young children the onset of a malarial paroxysm is often 
 marked by convulsions and the nervous symptoms are pronounced throughout 
 the attack. In other cases the onset is preceded by yawning and drowsiness, 
 or by severe headache. The chill is frequently absent or very slight, but the 
 hot stage is marked, the temperature prolonged, and the sweating very slight 
 or entirely absent. In many cases the only symptom of importance is the fever 
 which may be almost continuous or very irregular, lasting from a few hours to 
 several days. Spontaneous recovery is common and relapses are frequent. 
 
THE SYMPTOMATOLOGY OF THE MALARIAL FEVERS. i 93 
 
 Enlargement of the spleen is not apparent in more than half of the 1 a e , 
 Pain in the stomach is a common symptom in children and vomiting and diar- 
 rhoea occur very frequently. In certain cases a fatal diarrhoea may occur, and 
 convulsions and coma are common in pernicious cases. In children over three 
 years of age the symptoms are more like those occurring in the adult, and the 
 diagnosis is more easily made in older children. 
 
 It is obvious that, in malarial localities especially, the diagnosis of these 
 infections in children is of the very greatest importance from both a prophylactic 
 and therapeutic standpoint. The atypical character of the symptoms renders a 
 clinical diagnosis difficult, and in many instances impossible, and we have to 
 depend upon the microscope in arriving at a diagnosis. In every malarial 
 locality the blood of all the children should be examined and this procedure 
 should be as much a part of the sanitary police of a locality as the proper dis- 
 posal of sewage or the care of the water supply, for it will thus be possible to 
 distinguish those infected with malaria and to institute proper measures for 
 prevention and cure of the disease. It is not too much to expect that the en- 
 forcement of such a measure in badly infected localities will in time render 
 them practically free from malaria. 
 
 13 
 
CHAPTER II. 
 
 Clinical Illustrations of the Tertian and Quotidian Aestivo-autumnal 
 Malarial Fevers. 
 
 Because of their interest and importance I have selected for description 
 in this chapter a number of typical cases of tertian and quotidian aestivo-autum- 
 nal fever observed in soldiers returning from Cuba in 1898 and 1899. I have 
 selected these cases from hundreds of others because they were studied for 
 several days before quinine was administered, and thus all of the typical 
 phenomena of the paroxysm were observed. From the charts shown it will be 
 observed that these cases conformed to one of two types of fever, tertian or 
 quotidian, and the examination of the blood demonstrated that they were due to 
 two distinct plasmodia, which could be differentiated morphologically. I 
 believe that the following cases prove conclusively that two varieties of aestivo- 
 autumnal fever occur, each characterized by its own peculiar clinical course 
 and by the presence in the blood of a specific plasmodium. 
 
 In considering these cases I have aimed to give only the salient features, 
 both clinical and microscopical in each instance, and it should be remembered 
 that there are many exceptions to the typical types as illustrated in this chapter. 
 Cases occur in which the temperature curve is more or less continuous, and in 
 which there are found multiple groups of parasites or combined infections with 
 more than one species of malarial plasmodium. In such cases the symptoms are 
 often atypical, and the temperature curves are most irregular and confusing. 
 It matters not how typical the temperature curve may be, however, in a case of 
 aestivo-autumnal fever, it can be easily made atypical by the administration of 
 insufficient doses of quinine given at irregular intervals. Such treatment, far 
 too common, will cause the most typical temperature curve, whether tertian or 
 quotidian, to become irregular and often altogether unrecognizable as one of 
 malaria, and is the most prolific source of the existing confusion regarding the 
 classification of the aestivo-autumnal fevers. In combined infections with 
 both the tertian and quotidian plasmodium, a more or less continued or slightly 
 remittent temperature curve is seen, while in cases in which quinine in un- 
 suitable doses has been given, an irregular, intermittent temperature curve is 
 most common. Where, however, no combination of the two species of plasmo- 
 dium exists and quinine has not been administered, it will almost invariably be 
 found that either a tertian or quotidian temperature curve will be observed in 
 aestivo-autumnal infections in which only one group of plasmodia is under- 
 going development. 
 
 194 
 
THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 1 95 
 
 Cases of Quotidian Aestivo-autumnal Malaria. 
 
 There is nothing peculiar about the temperature curve in this form of 
 malarial fever, it very closely resembling an ordinary double tertian curve. It 
 is a notable fact, however, that many cases of pernicious malarial fever present 
 this type of temperature curve, and the blood has shown the characteristic 
 quotidian aestivo-autumnal plasmodium. None of the cases described in this 
 chapter were pernicious in character, as I have purposely selected those of a 
 milder type, because they are so much more common. 
 
 Case I. Chart 6. — Hamilton. The patient, a soldier, arrived at Santiago, 
 Cuba, in August, 1898. He was there about one month when he developed 
 measles, which was followed by dysentery. About the middle of October he 
 began to have chills and fever. His chills occurred, as a rule, every day, but 
 were sometimes irregular. Besides the chills he suffered from nausea, vomiting, 
 severe headache, and diarrhoea. Has had several attacks followed by recovery 
 under treatment. He was feeling well on his arrival at the hospital, June 23, 
 1899. Upon the 26th he began to run a temperature characterized by quotidian 
 paroxysms, but had no distinct chill until the 30th. Up to the latter date he 
 suffered from nausea, some headache, and general pains. On the 30th he had a 
 distinct chill, suffered from nausea, vomiting, sweating, severe frontal headache, 
 and general pain, especially severe between the shoulders. His bowels were 
 constipated. 
 
 Physical Examination. — Patient is anaemic and emaciated. Skin 
 slightly yellow; face flushed; tongue heavily coated with a thick, yellowish fur, 
 and flabby; lungs and heart normal; pulse full and bounding; spleen enlarged 
 and tender, reaching about 4 cm. below ribs; liver normal. Some tenderness 
 over abdomen on deep pressure, probably due to pressure on spleen. 
 
 Examination or the Blood. — The blood was examined daily at intervals 
 until the parasites disappeared. It was found that they were most numerous 
 in the peripheral blood during or just after a paroxysm, but at no time were 
 they numerous enough to show more than one infected corpuscle, on the average, 
 to the field. The parasites were typical of the quotidian aestivo-autumnal 
 variety, and two forms were observed in the peripheral blood: the "ring" forms 
 and the pigmented bodies. The ring forms were very small, indistinct in out- 
 line, perfectly circular when at rest, and very actively amoeboid. They never 
 showed the "signet ring" appearance so common in the tertian variety, and 
 were never more than one-sixth the size of the infected red corpuscle. Some 
 infected corpuscles contained two, and a few even three plasmodia. The 
 pigmented forms were about one-fourth the size of the infected cell, which was 
 always shrunken, brassy green in color, and generally crenated. The outline 
 of the pigmented forms was sharply defined, and they were perfectly circular in 
 shape, amoeboid motion being absent. The pigment occurred in the form of 
 one or, at most, two rather large, almost black dots, either centrally or per- 
 ipherally situated. The pigment was almost motionless. No segmenting forms 
 
196 
 
 THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 
 
 
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THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 1 97 
 
 or crescents (gametes) were observed in this case. The plasmodia disappeared 
 from the peripheral blood two days after the commencement of the administra- 
 tion of quinine. 
 
 Treatment. — Quinine, in doses of grm. 0.325, every four hours. 
 
 Upon reference to the temperature chart it will be seen that there is nothing 
 very distinctive about the temperature curve, beyond its quotidian character, 
 and -the fact that during the first three paroxysms the patient had no chills, 
 suffering only from chilly sensations, while during the fourth paroxysm even 
 the chilly sensations were absent. The first distinct chill occurred during the 
 fifth paroxysm. The temperature curve might well be taken for that of a 
 double tertian infection, the microscope alone being serviceable in differen- 
 tiating the type of infection present. The temperature reached normal after 
 two days' treatment. The subnormal temperature of 95. 4 F. upon the 29th 
 is worthy of notice, as it has been my experience that in no disease does the 
 temperature so often reach low sub-normal points as in this form of aestivo- 
 autumnal fever. 
 
 Case II. Chart 7. — S. F. S. The patient, a soldier, suffered for several 
 weeks in Santiago, Cuba, from attacks of fever, accompanied by chilly sensa- 
 tions, headache, backache, slight nausea, and sweating. He grew gradually 
 weaker and was transferred to the United States, arriving at the hospital on 
 January 23, 1899. His temperature remained normal until the twenty-sixth, 
 when he had a chill, which was repeated every day for four days. During 
 this time he suffered from severe headache, with much mental depression, 
 backache, darting pains down the legs, and nausea. 
 
 Physical Examination. — Much emaciated; skin of a peculiar grayish- 
 yellow hue; tongue thickly coated and flabby; expression listless and depressed; 
 heart and lungs normal; pulse rapid, full and strong; spleen enlarged and 
 tender, reaching about 6 cm. below the border of the ribs; liver slightly en- 
 larged; bowels constipated. 
 
 Examination or the Blood. — The blood was examined daily at regular 
 intervals and showed very numerous quotidian aestivo-autumnal plasmodia. 
 Ring-forms and pigmented forms were common, and upon one occasion two 
 segmenting forms were observed in the peripheral blood. The organisms 
 appeared to be most numerous during the latter portion of the paroxysm. 
 The ring-forms were very minute, indistinct in outline, and actively amoeboid. 
 The pigmented forms were circular or oval in shape, and contained one or two 
 nearly black pigment dots. The segmenting forms were intracorpuscular and 
 in one instance the segments numbered six, in the other eight. Numerous 
 corpuscles showed double or triple infection. 
 
 Treatment. — Quinine grm. 0.65 every four hours. 
 
 The temperature chart in this case shows an unusually high range of fever 
 for a quotidian aestivo-autumnal infection, but is not otherwise remarkable. 
 It resembles, even more closely than that of Case I, an ordinary double tertian 
 chart, and it would obviously be impossible to make a diagnosis of the type of 
 
198 
 
 THE AESTIVO-AUTUMXAL MALARIAL FEVERS. 
 
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THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 1 99 
 
 infection in this case without the aid of the microscope, and this case well il- 
 lustrates the importance of a microscopical examination of the blood in the 
 diagnosis of malaria. The prompt subsidence of so pronounced an infer lion 
 under large, repeated doses of quinine is worthy of attention. 
 
 Case III. Chart 8. — C. T. The history in his case is briefly as follows: 
 The patient had never been in the tropics and his malaria was contracted at 
 Fortress Monroe, Va. His illness began with a slight chill, nausea, vomiting, 
 and severe headache and backache. He has slight epistaxis and complained of 
 some abdominal tenderness. His temperature reached 103 .8° after the chill. 
 
 Physical examination showed an enlarged spleen, general abdominal 
 tenderness, hot, dry skin, flushed face, injected conjunctivae, and a pointed, 
 tremulous tongue thickly coated with a white fur; the pulse was full, and rather 
 slow. The case was regarded at first as one of typhoid fever, but no Widal 
 reaction could be obtained, and an examination of the blood showed large 
 numbers of quotidian aestivo-autumnal plasmodia. 
 
 Examination of the Blood.— The blood showed numerous intracorpus- 
 cular "ring-forms" of the quotidian aestivo-autumnal plasmodium, and a few 
 crescents {gametes). The intracorpuscular plasmodia were very small, rather 
 dimly outlined, actively amoeboid, and corpuscules showing double infection 
 were numerous. The infected corpuscles were smaller than normal, dark 
 green in color, and often crenated. No pigmented forms were observed. 
 
 The gametes were remarkable because of their plump appearance and 
 small size; while the male and female organisms could be distinguished, both 
 were much more plump than the gametes of the tertian aestivo-autumnal 
 Plasmodium. They contained perfectly motionless, almost black t pigment, 
 in the form of short rods; their protoplasm had a peculiar refractive ground- 
 glass appearance, and in every instance a darker colored, greenish double out- 
 line was to be seen surrounding them. 
 
 Treatment. — Quinine in grm. 0.40 doses, given every four hours, caused 
 a disappearance of the fever in two days. 
 
 In this case the temperature chart is not as typical as in the other cases 
 cited, and is therefore more interesting. During the first two days of the illness 
 the temperature showed hardly any remission, but after that the remissions 
 occurred as usual. It is difficult to explain this by any other hypothesis than a 
 double infection at first, two groups of plasmodia reaching maturity within a 
 few hours of one another, one group afterward dying out. This explanation is 
 further strengthened by the fact that on the twenty-seventh, two paroxysms 
 occurred, and by the presence of gametes in the blood, thus showing that a 
 malarial infection must have existed in a latent condition for some time. Upon 
 the twenty-seventh, the last paroxysm occurred immedately after the remission 
 of the first. As a whole, however, the chart is a fairly typical one of quotidian 
 aestivo-autumnal fever, and illustrates the value of the microscopical examina- 
 tion of the blood, as this case resembled so closely a case of typhoid fever that it 
 was so diagnosed by every physician who saw it, and even the microscopical 
 
200 
 
 THE AESTIVCHAUTUMNAL MALARIAL FEVERS. 
 
 
 
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THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 201 
 
 examination was considered as only showing a malarial complication until the 
 rapid disappearance of the fever under quinine proved conclusively the malarial 
 nature of the infection. 
 
 Case IV. Chart 9. — R. S. This patient, a soldier, had been in the service 
 for thirteen years, during which time he had enjoyed good health. He had had 
 a slight cough at times during the past two years, but there were no physical 
 signs and the sputum was negative for Bacillus tuberculosis. While in Tampa, 
 Florida, in 1898, he suffered from chills, occurring every day, but this attack 
 ended after four days, and he went with his regiment to Santiago. He remained 
 there until January, 1899, and suffered from several attacks of malaria, being 
 unfit for duty for about six weeks in all. He arrived at the hospital at Fortress 
 Monroe on January 23, 1899. While in the hospital he developed a quotidian 
 temperature with slight chilly sensations, rarely a distinct chill, which was con- 
 sidered for a while to be due to tuberculosis. At the time of the paroxysms he 
 complained of headache, pain in the back and limbs, and slight nausea. He 
 had no distinct sweats. 
 
 Physical Examination. — Patient somewhat emaciated and very anaemic; 
 skin bronzed and rather moist; tongue flabby and coated; spleen enlarged; 
 heart and lungs normal; abdomen rather tender; pulse full and rapid. 
 
 Examination of the Blood. — The blood contained numerous ring-forms 
 of the quotidian aestivo-autumnal plasmodium and a few gametes (crescents) . 
 In several examinations only two pigmented plasmodia were seen. 
 
 The ring-forms were similar in appearance to those already described, 
 being minute in size and always perfectly round. The pigmented forms were 
 circular in shape, more sharply outlined than the "rings," and the pigment 
 consisted of one black dot situated in the center of the parasite. 
 
 The infected corpuscles were very dark green in color. The gametes were 
 small and very plump and presented a double outline. An intracorpuscular 
 crescent was observed during one examination. 
 
 Treatment. — Quinine in doses of grm. 0.40 every four hours reduced the 
 temperature promptly. 
 
 The temperature curve in this case is remarkable for its regularity, and 
 because of its resemblance to the temperature curve often observed in pulmonary 
 tuberculosis. This resemblance, together with an acute bronchitis which was 
 present, led to the case being considered one of phthisis until a microscopical 
 examination and the blood cleared up the diagnosis, and quinine cured the 
 infection. It will be observed that the temperature fell below normal after 
 each paroxysm. » 
 
 Case V. Chart 10. — C. S. The patient went with his regiment to Santi- 
 ago in August, 1898. He was there about three weeks when he was taken sud- 
 denly ill with "fainting spells," as he expressed it. He was taken to the hos- 
 pital and there suffered from severe headache, slight chills, and nausea and 
 night sweats. Was in the hospital about two weeks and was then returned to 
 duty, but had several relapses, the last one occurring about five weeks before 
 
202 
 
 THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 
 
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THE AESTTVO-AUTUMNAL MALARIAL FEVERS. 203 
 
 arrival at the Fortress Monroe hospital where he arrived on December 11, 1898, 
 and where I first saw him. While at the latter hospital he suffered from two 
 attacks of fever attended with chilly sentsations, severe headache, and nausea. 
 
 Physical Examination. — Patient somewhat emaciated and very anaemic: 
 skin yellow; tongue flabby and coated; heart and lungs normal; spleen not ap- 
 preciably enlarged; liver enlarged; abdomen distended, but not tender; bowels 
 constipated. 
 
 Examination or the Blood. — The blood contained a few typical "ring- 
 forms" of the quotidian aestivo-autumnal plasmodium, the "ring" being small, 
 circular in shape, actively amoeboid at times, and unpigmented. Pigmented 
 forms were also numerous. These were more sharply defined than the "ring- 
 forms," were less than one-fourth the size of the infected red corpuscle, and the 
 pigment occurred as a single dot, situated at the center or one side of the para- 
 site. The pigment was perfectly motionless and almost black in color. No 
 amoeboid motion was noticed in the pigmented forms and the infected corpusles 
 were always shrunken and crenated, and many "brassy" cells were observed. 
 
 Treatment. — Quinine in doses of grm. 0.40 every four hours soon reduced 
 the temperature to normal. 
 
 The temperature chart in this case is that of a typical quotidian aestivo- 
 autumnal infection, the paroxysms occurring regularly, and the chart resembling 
 that of a double tertian infection. From the study of a large number of cases 
 of this type of malaria, of which the five cases given are fair examples, the con- 
 clusion is inevitable that there occurs a type of aestivo-autumnal malarial in- 
 fection, characterized by quotidian paroxysms, and by the occurrence in the 
 blood of a specific plasmodium which completes its cycle of development in 
 man in approximately 24 hours. In blood secured by puncture of the spleen 
 all stages in the development of this plasmodium may be studied, and each 
 stage differs markedly from the corresponding stage of the tertian aestivo- 
 autumnal plasmodium. I have not been able to demonstrate the existence of 
 an unpigmented quotidian plasmodium, as described by Mannaberg, Manson, 
 and others. 
 
 Cases of Tertian Aestivo-autumnal Malaria. 
 
 In the chapters which have preceded this one I have called attention to 
 the fact that the majority of cases of aestivo-autumnal fever present paroxysms 
 occurring, approximately, every 48 hours. These tertian paroxysms are 
 peculiar in that while they occur every other day, each paroxysm is prolonged 
 so that it lasts considerably over 24 hours, and often almost 48 hours. This 
 type of malarial fever is further characterized by a peculiar temperature curve, 
 which was first described by Marchiafava and Bignami, and which shows the 
 following characteristics: a rapid and sudden rise, a stage of slight remissions, 
 a pseudocrisis, a precritical rise, during which the temperature generally 
 reaches a higher point than it had previously, and, lastly, the true crisis, in 
 which the temperature rapidly falls to normal or below. 
 
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 THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 
 
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THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 205 
 
 This peculiar temperature curve is presented in all uncomplicated cases 
 of tertian aestivo-autumnal malaria, where quinine has not been administered. 
 In cases infected with two groups of plasmodia sporulating at different times 
 or by the simple tertian or quartan plasmodium or, again, by both the quotidian 
 and tertian aestivo-autumnal plasmodia, this peculiar temperature curve will 
 not be observed, nor will it be in cases which have received insufficient doses of 
 quinine or quinine at long intervals of time. 
 
 In order, then, to secure a typical temperature chart of tertian aestivo- 
 autumnal fever, we must have a patient infected with a single group of plasmodia 
 and must withhold quinine for several days. It is safe to say that nearly all 
 of the confusion existing to-day regarding the types of aestivo-autumnal 
 malaria is due to one or two factors; infection with more than one species of 
 plasmodium or with more than one group of plasmodia, and the improper and 
 untimely use of quinine. The first factor can only be eliminated by the 
 microscopical examination of the blood, and the second only by an earnest 
 scientific spirit upon the part of the physician, so strong that he will be willing 
 to withhold quinine long enough to secure a proper knowledge of the nature 
 of the disease which he is called upon to treat. Medicine to-day has reached 
 the stage where the so-called diagnostic terms "intermittent" and "remittent" 
 malarial fevers are of little exact meaning, and an earnest effort should be 
 made to substitute for them, in medical nomenclature, the more scientific 
 terms, tertian and quartan malaria, and quotidian and tertian aestivo-autumnal 
 malaria. 
 
 The following cases are selected from a large number because they are 
 typical of tertian aestivo-autumnal malarial fever, and I believe that they 
 conclusively demonstrate the existence of this variety of aestivo-autumnal fever. 
 
 Case I. Chart n. — S. C. Age 23. The patient arrived at Santiago, 
 Cuba, in August, 1898. On September 20, 1898, he was taken sick with 
 a chill, which was followed by a high temperature. He had chills every other 
 day for several days, and suffered from nausea and vomiting, severe headache 
 and pains in the legs, and drenching perspiration. He had several attacks 
 during the next two months and was finally sent to the Simpson General Hospital, 
 where he arrived upon December 11, 1898. Upon December 17, he had a 
 rise of temperature accompanied by chilly sensations. This paroxysm was 
 succeeded by three others, all accompanied by chilly feelings, severe headache 
 and backache, nausea, and great nervous prostration. 
 
 Physical Examination. — Patient somewhat emaciated; skin yellowish; 
 mucous membranes pale; cheeks flushed; eyes bright; tongue broad and 
 coated; heart and lungs normal; abdomen rather tender; spleen slightly enlarged; 
 bowels constipated; marked mental depression and general debility. 
 
 Examination of the Blood. — The blood was examined at frequent 
 intervals and numerous "ring-forms," pigmented rings, and larger pigmented 
 forms of the tertian aestivo-autumnal plasmodium were found. No segmenting 
 forms were observed. The "ring-forms" were larger than those of the quotidian 
 
206 
 
 THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 
 
THE AESTIVO-AUTUMNAL MALAEIAL FEVERS. 2C] 
 
 aestivo-autumnal plasmodium, being about one-fourth the size of the infected 
 red cell, irregular in shape, most of them presenting an enlargement at some 
 portion of the periphery, thus causing the so-called "signet-ring" appearance. 
 They were refractive and sharply outlined, with clear protoplasm, and having 
 a sluggish amoeboid motion. The "ring-form" was sometimes lost during the 
 movement of the organism, a clear, circular, hyaline disk resulting. The infected 
 red corpuscles, while more greenish in color than the uninfected cells, was not 
 nearly as much altered in appearance as in the quotidian infections, and was 
 seldom crenated. 
 
 The pigmented rings and larger pigmented bodies were present in small 
 numbers. The "rings" showed a few fine pigment granules, generally in 
 the dilated portion of the ring, and these granules were often in rather rapid 
 motion. These pigmented rings still showed considerable amoeboid motion. 
 
 The pigmented bodies larger than the "ring-forms" were sharply defined, 
 the protoplasm being refractive and finely granular in appearance. The 
 pigment was in the form of fine reddish-brown granules, and possessed a 
 marked vibratory motion. These plasmodia were about one-half the size 
 of the infected red corpuscle, and some of them still showed a slight amoeboid 
 motility. 
 
 Treatment. — Quinine in doses of grm. 0.40 every four hours, reduced the 
 temperature in two days, and its continued use resulted in recovery. 
 
 A consideration of the temperature chart in this case shows it to be a 
 beautiful illustration of the peculiar temperature curve in this type of malarial 
 fever. Quinine was withheld until the occurrence of the fourth paroxysm. 
 It will be seen that the paroxysms occurred at intervals of approximately 
 48 hours, and that the temperature lasted from 36 to 40 hours, and the chart 
 shows well the various characteristics of the curve already mentioned. Taking 
 the paroxysm of the twenty-first, for example, we see beautifully illustrated 
 the rise, the period of slight remissions, the pseudocrisis, the precritical rise, 
 in which the temperature reaches the highest point, and, lastly, the crisis, in 
 which the temperature rapidly fell to nearly normal. The intervals between 
 the paroxysms were short, and two of the paroxysms were accompanied by 
 chills. As a general rule, the temperature goes to normal or below, during 
 the intervals, but in this case it did not always do so. 
 
 Case II. Chart 12. — P. R. H., Age 21. Patient arrived in Cuba 
 on December 17, 1898. Was taken sick March 13, 1899, with severe pain in 
 the head, chill, high fever, and nausea and vomiting. Was supposed to be 
 suffering from typhoid fever, but felt better after a week in the hospital and 
 was up and about. On April 6, the day before he boarded the steamer on his way 
 to Fortress Monroe, the fever returned, accompanied by the same symptoms, 
 He arrived at the Simpson Hospital upon April 12. He had four chills after 
 arrival, occurring every other day, but not very severe, accompanied by nausea 
 and vomiting, headache, and pain in the back and legs. 
 
 Physical Examination. — Patient looks very ill. Greatly emaciated; 
 
208 
 
 THE AESTIV0-A1 TUMNAL MALARIAL FEVERS. 
 
 H 
 
THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 2Q(J 
 
 skin yellow; face congested and eyes bright; tongue broad and coated with a 
 yellow fur; pulse rather weak and very rapid; heart and lungs normal; spleen 
 slightly enlarged; liver normal; abdomen rather tender; bowels constipated. 
 
 Examination of tfie Blood. — The blocd was examined at frequent 
 intervals and always showed "ring-forms" and pigmented ring-forms of the 
 tertian aestivo-autumnal plasmodium, similar in every respect to those described 
 in the preceding case. No segmenting forms or crescents were found in the 
 peripheral blood. The parasites were most numerous just before the 
 paroxysms. 
 
 Treatment. — Quinine, grm. 0.50 every six hours. Recovery. 
 
 The temperature chart in this case is a typical one of tertian aestivo- 
 autumnal fever. It will be seen that there were four paroxysms in all, and that 
 each paroxysm showed the characteristic temperature curve, although the 
 paroxysm of the twenty-third is slightly atypical, in that after the pseudo- 
 crisis there occurred a slight remission before the final rise and crisis. In no 
 other malarial fever will a temperature chart like this be observed, and it is 
 actually diagnostic of the type of infection which it occurs in. 
 
 Case III. Chart 13. — A. H. H. The patient, while in Santiago, suffered 
 from malarial fever, having chills nearly every other day, accompanied by 
 high fever, severe headache and backache, and nausea. He arrived at Fortress 
 Monroe on January 23, 1899, and after admission to hospital had several 
 paroxysms of fever, accompanied by chilly feelings, but no distinct chill; severe 
 headache and backache, some nausea, and general muscular pain. 
 
 Physical Examination. — The patient does not look very sick. There is 
 some anaemia; the tongue is coated; the heart, lungs, and liver are apparently 
 normal. The spleen is enlarged, reaching half-way to the umbilicus. There is 
 much mental depression. 
 
 Examination of the Blood. — The blood was examined frequently and 
 numerous pigmented and unpigmented tertian aestivo-autumnal plasmodia 
 were found, most numerous just before or some time after the paroxysm. No 
 sporulating parasites were observed. 
 
 Treatment. — Quinine, grm. 0.40 every four hours. Recovery. 
 
 In this case the temperature chart is again typical of tertian aestivo-autum- 
 nal infections, and would easily be recognized as such upon simple inspection. 
 The occurrence of the paroxysm upon every third day; the length of the indi- 
 vidual paroxysm; the peculiar curve exhibited — all prove conclusively the type 
 of malarial fever present, even without the aid afforded by the microscope in 
 detecting the characteristic plasmodium. 
 
 Case IV. Chart 14.— S. The patient arrived at Santiago, Cuba, in 
 August, 1898. He was there about two weeks when he was taken suddenly ill, 
 having a chill, high fever, nausea and vomiting, and great mental depression. 
 Chills recurred every other day and were always accompanied by intense 
 headache and fever. Arrived at the Simpson U. S. Army General Hospital on 
 December 11, 1898, and on the sixteenth, had chilly sensations and a rise of 
 14 
 
2IO 
 
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 211 
 
212 THE AESTIVO-AUTUMXAL MALARIAL FEVERS. 
 
 temperature. He had two paroxysms after this, accompanied by fever, intense 
 headache, nausea, general muscular pain, and mental depression. 
 
 Physical Examination. — Patient anaemic and listless. Skin slightly 
 yellow, tongue slightly coated; heart, lungs, and liver apparently normal. 
 Spleen not appreciably enlarged. Bowels constipated. Pulse full and 
 regular. 
 
 Examination of the Blood. — Numerous examinations of the blood were 
 made and pigmented and unpigmented forms of the tertian aestivo-autumnal 
 Plasmodium were found, and several segmenting forms were observed in the 
 peripheral blocd. The pigmented and unpigmented ring-forms have already 
 been described under Case I. The large pigmented parasites were nearly 
 half as large as the infected red corpuscle, and contained numerous fine granules 
 of pigment, generally collected near the center of the organism. The parasites 
 were very sharply defined and very refractive. In some of the pigmented forms 
 the pigment was collected in a solid block at the center of the organism, and 
 faint radial striations could be made out dividing the parasite into several 
 segments. 
 
 The segmenting forms observed appeared to be extracorpuscular, and con- 
 sisted of blocks of pigment with ten or more minute oval spores arranged about 
 them. 
 
 Treatment. — Quinine, grm. 0.40 every four hours. Recovery. 
 
 The temperature chart in this case is interesting in that each of the par- 
 oxysms presents a modification of the typical aestivo-autumnal curve. In the 
 first paroyxsm there is no stage of slight remissions, there being a rapid initial 
 rise and almost immediately a pseudocrisis, in which the temperature reached 
 normal; this was immediately succeeded by the precritical rise and followed 
 by the crisis. In the second paroxysm there is also no stage of slight remis- 
 sions, but the pseudocrisis is more normal and the precritical rise more 
 gradual. The third paroxysm is marked by a well-defined stage of slight 
 remissions, but the pseudocrisis is almost absent. 
 
 Such slight modifications as these are very common in the temperature 
 curve of tertian aestivo-autumnal fever, but they do not in the least affect the 
 general character of the curve nor cause a moment's doubt as to the nature of a 
 case showing such a temperature curve as is here presented. Such curves are 
 uniquely characteristic of the tertian aestivo-autumnal infections. 
 
 Case V. Chart 15. — C. C. Age 25. Arrived at Santiago, Cuba, in 
 August, 1898. Was there about one month, when he had a sharp chill followed 
 by a high temperature. Chills occurred for a while every other day, but later 
 became irregular. They were always followed by a high temperature. He 
 was admitted to the hospital there five different times, each apparent recovery 
 from the fever being followed by a relapse as soon as he returned to duty. 
 During the paroxysms he suffered from headache, very severe in character; 
 severe muscular pains; nausea and vomiting. He arrived at the Simpson 
 Hospital on December 11, 1898. Had chilly sensations and a headache on the 
 
THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 
 
 213 
 
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214 THE AESTIVO-AUTUMNAL MALARIAL FEVERS. 
 
 fifteenth, followed by a rise in temperature. He had three slight paroxysms 
 afterward, accompanied by chilly sensations. 
 
 Physical Examination. — Patient emaciated and anaemic. Skin yellow, 
 tongue flabby and coated. Heart and lungs normal. Spleen greatly enlarged, 
 reaching nearly to the umbilicus. Liver dullness normal. Bowels constipated. 
 .Abdomen tender. 
 
 Examination of the Blood. — The blood in this case showed pigmented 
 "ring-forms" of the aestivo-autumnal plasmodium and numerous gametes 
 (crescents). The ring-forms were similar to those described as occurring in 
 Case I. The gametes, both male and female, were very much more slender 
 and much larger than those of the quotidian aestivo-autumnal plasmodium, 
 and contained a much greater amount of pigment of a more reddish color. 
 The double outline was less commonly observed, but the protoplasm was 
 much more refractive. 
 
 In this case the temperature chart is not as typical as the preceding ones, 
 but it is typical of the more chronic forms of tertian aestivo-autumnal infection. 
 The paroxysms occur every 48 hours, but it is noticeable that the range of 
 temperature is not as high in this case and that there seems to be a tendency 
 toward a spontaneous decline of the infection. The chart is curious in that 
 there seems to be a reversal of the ordinary temperature curve, the highest 
 temperature being reached during the initial rise; but even in this chart the 
 temperature curve is, on the whole, so characteristic that a diagnosis of tertian 
 aestivo-autumnal fever could easily be made from an inspection of it 
 
 From the cases of quotidian and tertian aestivo-autumnal malarial fever 
 I have here considered it will be seen that a differentiation of the two types 
 cannot be made from a consideration of the clinical symptoms except that in 
 the quotidian form the chill or chilly sensations occur every 24 hours, while 
 in the tertian form they occur every 48 hours. A consideration of the tem- 
 perature charts, however, shows such a marked difference in the temperature 
 curves that we must admit that we are dealing with two distinct types of malarial 
 infection. The quotidian aestivo-autumnal type presents a simple intermittent 
 temperature curve, indistinguishable from that of a double tertian infection, 
 while the tertian aestivo-autumnal infections present a most peculiar and 
 characteristic temperature curve, entirely different from that shown in any 
 other type of malarial infection and diagnostic in itself. When to this is added 
 the fact that each form is due to a specific plasmodium, one sporulating in 
 24 hours, the other in 48 hours, the evidence is complete that there occur two 
 forms of aestivo-autumnal malarial fever, the tertian and quotidian, as first 
 described by Marchiafava and Bignami. 
 
 In the study of these infections it is absolutely necessary that the tempera- 
 ture be recorded every three or four hours, as, in many cases, a morning and 
 evening record of the temperature will give but little information regarding the 
 actual range of the fever. 
 
CHAPTER III. 
 The Pernicious Forms of the Malarial Fevers. 
 
 The term "pernicious" as used in the nomenclature of malaria indicates 
 infections in which some one symptom or group of symptoms so preponderate 
 as to color the clinical picture and threaten the life of the patient. Used in 
 this sense, the term is of value in clinical work, but unfortunately some writers 
 have considered the pernicious forms of malaria as disease entities and have 
 used the term to designate certain infections, especially the aestivo-autumnal 
 fevers. With these writers pernicious malarial fevers mean the aestivo- 
 autumnal infections and the use of the term becomes essential in designating 
 this group of fevers. A classification based upon the severity of the symptoms 
 present in any given disease is unscientific and confusing, and is especially 
 so in the malarial infections, which are due to different species of plasmodia. 
 Mannaberg says, regarding the classification of malaria into pernicious and 
 benign forms: "We search pathology in vain for an analogy. As far as I 
 know, there is no other disease, though it runs its course sometimes smoothly and 
 without prognostic danger, again under the severest and most threatening 
 symptoms, for which a division into benign and pernicious had been made. 
 If we were to follow out this division, we should speak of a benign typhoid 
 fever when the disease was mild, of a pernicious typhoid fever when, in its 
 evolution, dangerous symptoms arose. There would be, in addition, an endless 
 series of sub-divisions, depending on whether the dangerous symptoms proceeded 
 from one or another organ." This criticism of Mannaberg's is just, but 
 while the term should not be used to designate disease entities, it is of value 
 as a convenient clinical term in designating malarial infections of great severity 
 and in which certain symptoms arise which serve to distinguish them from 
 the ordinary type of infection. The term cannot be considered accurate, 
 as what shall be considered pernicious symptoms will always depend upon the 
 opinion of the physician, and this will, of course, vary greatly in individual 
 instances. 
 
 It should be distinctly understood that there is no species of plasmodium 
 which produces only pernicious forms of malaria, but that the same species 
 which causes the mildest infections is also capable of causing rapidly fatal 
 forms. Any of the species of malarial plasmodia may give rise to pernicious 
 symptoms, but the vast majority of fatal cases of malarial fever are due to the 
 tertian aestivo-autumnal plasmodium, the next most frequent parasite being 
 the quotidian aestivo-autumnal plasmodium. As the greater number of fatal 
 cases of malaria occur in patients infected with the aestivo-autumnal plasmodia, 
 
 215 
 
2l6 THE PERNICIOUS MALARIAL FEVERS. 
 
 it is very important to remember that there is always an element of danger in 
 these cases, in that they may at any time develop pernicious symptoms which 
 may cause the death of the patient. 
 
 The great majority of pernicious attacks of malaria occur in temperate 
 regions in the late summer and in autumn and are rare, while in the tropics 
 they occur throughout the year and are very common. The frequency of 
 occurrence of such infections, as given by various authors, varies greatly, 
 depending upon the locality in which the observer was working, the season of 
 the year in which the observations were made, and the number of cases of 
 malarial infection observed. Thus Borius, in Senegal, in ioo cases of aestivo- 
 autumnal malaria, observed 4.1 per cent, of pernicious cases; Laveran, in 
 Algiers, a proportion of 1 pernicious case to 35 others, and A. Plehn, in the 
 Kamerun, a proportion of one pernicious case to eight in which the symptoms 
 were benign. In temperate regions the proportion is nil in some localities and 
 very small in almost all regions in which the aestivo-autumnal infections occur 
 but rarely. In my own experience, embracing the study of several thousand 
 cases of malaria contracted in Cuba and the Philippine Islands, the proportion 
 of pernicious cases has not been over 1 to 100, but most of these infections were 
 treated promptly with quinine, which, of course, resulted in a smaller number 
 of pernicious attacks. 
 
 As a rule, pernicious symptoms develop only after repeated attacks of 
 the infection, although I have seen more than one instance in which the patient 
 was struck down, as by lightning, with a pernicious attack of malaria, but in 
 which no history of a previous infection could be obtained. However, the 
 great majority of pernicious attacks occur in persons who have suffered repeatedly 
 from malarial paroxysms which have not been properly treated, and the 
 pernicious symptoms often develop, in such cases, during an apparently mild 
 paroxysm. 
 
 The Causes of Perniciousness. — Why do certain cases of malarial infec- 
 tion develop pernicious and fatal symptoms ? In answer we must admit that 
 our knowledge is, as yet, incomplete, but individual susceptibility to the in- 
 fection; certain preexisting diseases of the viscera; external conditions, as 
 regards locality, exposure, and poverty; and the species and number of the 
 infecting plasmodia, all undoubtedly help to explain the occurrence of such 
 cases. 
 
 Some individuals appear to be very susceptible to the malarial poison and 
 always suffer from pernicious attacks, while, on the other hand, an individual 
 but little affected usually may suddenly develop pernicious symptoms. Alco- 
 holics, and those weakened by disease, exposure, and lack of proper food, are es- 
 pecially apt to suffer from pernicious attacks of malaria. I have repeatedly 
 observed the occurrence of pernicious symptoms in soldiers who have been 
 exposed for too long a time to the tropical sun, and some of the most severe 
 cases of cerebral pernicious malaria that I have observed have developed sud- 
 denly in soldiers upon the march in the tropics. Europeans are said to suffer 
 
THE PERNICIOUS MALARIAL FEVERS. 217 
 
 more frequently from pernicious attacks than natives, and while this is gener- 
 ally true, there are exceptions, as at Camp Stotsenburg, in the Philippines, 
 where pernicious cases were more common among the natives than among our 
 soldiers in the proportion of four to one. 
 
 As has been stated, the species of Plasmodium is of importance, as most 
 pernicious attacks are due to the aestivo-autumnal plasmodia, especially the 
 tertian form. However, we now have the records of many cases of pernicious 
 malaria caused by the simple tertian and the quartan plasmodium, and the 
 statement of Mannaberg that these organisms cannot cause pernicious symp- 
 toms can no longer be accepted. In the tropics the aestivo-autumnal infections 
 are more apt to become pernicious than in temperate regions, probably because 
 of the debility and anaemia so common in tropical regions, and the climatic 
 conditions there present. 
 
 The number of plasmodia present in any given case must have great influ- 
 ence in the production of pernicious symptoms, and it has been definitely 
 proven that in pernicious infections the plasmodia are always more numerous 
 than they are in mild infections. The increased number of plasmodia is not, 
 by any means, manifest in an examination of the peripheral blood, for in the 
 aestivo-autumnal infections, which furnish the majority of pernicious cases, 
 the plasmodia are frequently small in number in the peripheral blood, 
 but occur in immense numbers in the viscera, especially in the brain and the 
 spleen. Thus we can place but little dependence upon the number of plasmodia 
 observed in the peripheral blood as indicating the severity of the infection in 
 many instances, but in such cases a splenic puncture will demonstrate innumer- 
 able plasmodia to be present in that organ. I recall a case of fatal aestivo- 
 autumnal infection in which the examination of the peripheral blood resulted in 
 finding only three or four plasmodia after half an hour's search, but at autopsy 
 smears from the brain and the spleen showed so many plasmodia that it was 
 almost impossible to find an uninfected red corpuscle. In the cerebral types 
 of pernicious malaria the capillaries of the brain are always found crowded 
 with plasmodia, although the examination of the peripheral blood may have 
 shown but few plasmodia. 
 
 Although we have no reliable data at present concerning the malarial 
 toxin, it is but reasonable to suppose that a more powerful toxin is elaborated 
 in the pernicious infections, or better, perhaps, that a greater amount is pro- 
 duced because of the increase in the number of plasmodia. 
 
 The situation of the plasmodia has certainly something to do with the pro- 
 duction of pernicious symptoms. Bastianelli and Bignami have carefully 
 studied this subject, and make the following distinctions as regards distribution 
 of the plasmodia and the symptoms produced by them: 
 
 "1. Cases in which the number of parasites is most abundant, yes, enor- 
 mous, in the brain, while all the organs are less uniformly invaded. These 
 are the commonest forms of pernicious malaria, and are usually accompanied by 
 coma. 
 
2l8 THE PERNICIOUS MALARIAL FEVERS. 
 
 "There are some cases in this category in which the number of parasites 
 in the blood of the finger, of the spleen, of the bone-marrow, etc., is enormous, 
 while the number in the brain is scanty. Clinically, the absence of cerebral phe- 
 nomena is noted. 
 
 "2. Cases in which the number of organisms is absolutely and relatively 
 scanty in the bone-marrow, the spleen, and in the liver, while they may be rela- 
 tively few in the blood of the finger, and yet other organs are crowded with them. 
 Among these the following localizations are to be made out: 
 
 "a. The brain and the meninges are filled with parasites, either in sporula- 
 tion or in all their stages of development. Clinically, there are cerebral phe- 
 nomena. 
 
 "b. The stomach and intestines are chiefly invaded. In these organs the 
 mature forms of the parasites are usually found; these are the cases of pernicious 
 fever which present clinically intestinal phenomena." 
 
 Some authorities have endeavored to prove that the increased fever ob- 
 served in many cases of pernicious malaria is responsible for the occurrence 
 of the pernicious symptoms, but this is disproven by the fact that many 
 cases of pernicious malaria do not prevent any increase in fever as usually 
 observed in malarial infections, and some cases occur in which the fever is 
 so slight as to hardly attract attention. 
 
 Classification of Pernicious Fevers. — The pernicious forms of malaria 
 may be classified in three ways, i.e., from the species of plasmodium causing 
 them, as tertian, quartan, and aestivo-autumnal pernicious infections; from the 
 character of the temperature curve, as tertian, quartan, remittent and larval 
 infections; and from the most prominent symptoms present. Under the latter 
 classification we may have comatose, delirious, tetanic, eclamptic, hemiplegia, 
 dysenteric, choleraic, algid, cardialgic, hemorrhagic, pneumonic, bilious, and 
 tvphoidal pernicious fevers. 
 
 I shall describe the more important forms, using the terms applied to them 
 because of their most prominent symptoms, but it must be remembered that 
 these forms are not disease entities, and are classified in this manner only for 
 purposes of clinical description. 
 
 Comatose Pernicious Form. — This is the most common form of perni- 
 cious malarial fever, and occurs in two ways, either as a sudden attack of coma 
 or a gradually developing comatose condition during a paroxysm of fever. 
 
 The sudden development of coma is rare and, unless at once recognized 
 and treated, invariably fatal. In this form the patient, who has generally 
 suffered from repeated attacks of malaria and who has not felt well for some 
 time, is suddenly stricken with profound coma, falls to the ground, and in 
 fatal cases does not again regain consciousness. This form is apt to be mistaken 
 for apoplexy or sun-stroke. The face is suffused, the pupils contracted, the 
 pulse at first full and bounding, later soft, rapicl, and thready, the respirations 
 hurried and sometimes stertorous. The temperature is irregular, seldom 
 reaching 103 F., and is often subnormal. Death generally occurs within 
 two days. 
 
THE PERNICIOUS MALARIAL FEVERS. 2IQ 
 
 The most common form of comatose malaria is that in which coma develops 
 more or less gradually during an attack of the fever. The symptomatology 
 of the attack is the same as in the ordinary paroxysm, but the nervous symp- 
 toms, such as restlessness and delirium, may be more marked. As a rule, 
 the patient is restless and mentally depressed. Following this there develops 
 a tendency to somnolence, which deepens into stupor and finally coma. Uncon- 
 sciousness is complete, the patient lying perfectly quiet, or there may be restless 
 movements of the arms and legs. The skin is often somewhat icteric in hue, 
 and hot and dry; the pupils are generally equally contracted, but may be unequal 
 or equally dilated. The icteric hue, which is often present in the conjunctivae, 
 has led to a diagnosis of yellow fever in infected regions. The face may be 
 cyanotic, but in old infections it is generally pale. Slight spasms of the muscles 
 of the face are not infrequent. The tongue is tremulous, dry, and thickly 
 coated, and slight hemorrhages into the skin are sometimes observed. 
 There may be hemiplegia or total paralysis. The patellar reflex may be 
 absent or slightly increased. The respirations are generally slow and quiet, 
 but may be rapid, irregular, or stertorous. The Cheyne-Stokes type of 
 respiration is sometimes observed. The pulse is generally slow, full, and 
 incompressible at first, but becomes rapid and weak as the paroxysm progresses. 
 The faeces and urine are passed involuntarily toward the last, and retention of 
 urine may occur. In cases having a fatal termination, the pulse becomes 
 thready, rapid, and irregular; the respirations intermittent, labored, and 
 shallow; the skin pale and bedewed with a cold perspiration; the features pale, 
 shrunken, apparently emaciated, and death occurs by collapse. In cases 
 which recover, the temperature falls, accompanied by perspiration and the 
 consciousness is slowly regained, but in many of these cases the improvement 
 is only apparent and the patient relapses in the course of a few hours into a 
 second paroxysm, and perhaps into a third, which usually results fatally. 
 Between the paroxysms the mental condition is one of torpor or great mental 
 depression, accompanied by severe headache. The duration of the coma is 
 variable, lasting from a few hours to three or four days, but it generally does 
 not persist longer than 24 to 26 hours. 
 
 As regards the course of the temperature in this form of malaria, it may 
 be stated that it is irregular. Some patients have a high fever throughout, 
 between 103 and io4°F., while in others the temperature may remain slightly 
 above normal, or may be subnormal most of the time. In fatal cases the 
 fever, if present, declines, as a rule, some hours before death, but it may ascend. 
 Manson cites temperatures of no° and 112 F. before death. 
 
 As an illustration of how low the temperature may run the following 
 temperature record of a fatal case of quotidian aestivo-autumnal fever, of 
 the comatose type, is of interest. This case was under my personal observation 
 and was in the person of a soldier who had returned from the Philippine 
 Islands infected with malaria. 
 
220 the pernicious malarial fevers. 
 
 Temperature Record. 
 
 July 15, a. m., 98. 4 F.; p. m., ioi° F. 
 
 July 16, a. m., Q9 F.; p. m., 99. 6° F. 
 
 July 17, A. m., 9S F.; p. m., 97. 8° F. 
 
 July 18, a. m., 96. 4 F.; p. m., 98 F. 
 
 July 19, A. M., 100. 2 F.; p. m., 98 F. 
 
 July 20, A. M., 103 F.; p. m., Died. 
 
 In this case the disease was not recognized by the attending physician 
 until a few hours before death, when a blood examination was asked for, 
 and large numbers of quotidian aestivo-autumnal plasmodia were found. 
 
 Other Pernicious Forms of Malaria in Which Nervous Symptoms 
 Predominate. — Besides the comatose form of pernicious malaria there are 
 other forms in which nervous symptoms predominate. Among these may 
 be mentioned the delirious form, in which the patient has hallucinations, 
 followed by violent excitement; the eclamptic form, which is common in children, 
 in which the symptoms are similar to those of cerebrospinal meningitis, there 
 being vomiting, headache, fever, pain in the back of the neck, convulsions, 
 and coma; the hemiplegia form, characterized by hemiplegia; the paraplegic 
 form, characterized by paraplegia; and the amaurotic form, in which, after the 
 comatose symptoms have subsided, complete blindness may result. Among 
 the most infrequent forms of pernicious malaria may be mentioned the tetanic 
 form, characterized by trismus, convulsions, opisthotonos, and delirium, 
 and the ataxic form, cases of which have been very thoroughly studied by 
 Torti and Angelini. 
 
 In all cerebral types of pernicious malaria there may be present slight 
 deviation of the eye-balls and slight convulsions, clonic in character, of the 
 extremities. Epileptiform convulsions occur but rarely in adults, but are not 
 uncommon in children. At Camp Stotsenburg almost every case of pernicious 
 malaria that I observed among the native children was accompanied by 
 epileptiform convulsions. 
 
 The Bulbar Form of Pernicious Malaria. — A rare form of pernicious 
 malaria, associated with symptoms of bulbar paralysis has been studied by 
 Marchiafava, Bignami, and Bastianelli. Marchiafava thus graphically 
 describes the symptomatology of this form of the disease. "The chief symp- 
 toms are difficulty in articulation, which may even reach anarthria, a weak 
 and nasal voice, inferior facial paralysis often of one side only, a half-open mouth 
 from which drops the saliva, a pendent lower lip, a dry and only slightly 
 movable tongue, difficult or abolished deglutition. With these symptoms there 
 are sometimes associated disturbances of equilibrium which recall the staggering 
 gait of cerebellar disease. In a case of relapse Bastianelli and Bignami 
 noticed an unsteadiness of gait as in drunkenness, diminution of strength of 
 the left side, right facial paralysis, deviation of the tongue to the left, difficulty 
 in speaking, nasal voice, grave prostration and apathy." 
 
THE PERNICIOUS MALARIAL FEVERS. 221 
 
 The symptoms in these cases, under proper treatment, do not persist for 
 a longer period than two weeks, as a general ride. 
 
 The Paralytic Forms. — Malarial infections in which either hemiplegia 
 or paraplegia occur are rare, and I have observed only one case in which 
 hemiplegia was present. Landouzy has added much to our knowledge of 
 such infections, and in his Thesis de Paris, of 1880, has collected 12 cases 
 of hemiplegia occurring during malarial infection, of which eight were accom- 
 panied by aphasia. An intermittent form of paralysis has been described 
 occurring with the paroxysms, and remitting afterward, but it is probable that 
 the majority of these cases were hysterical in character. 
 
 The Algid Form.— In certain regions of the Southern and Middle States 
 and in other localities there occur pernicious forms of malaria known as algid 
 forms. The symptoms develop after one or more ordinary paroxysms or they 
 may be the primary symptoms. The characteristic condition is one of extreme 
 collapse attended by profuse perspiration, the temperature at the same time 
 being more or less elevated, although in some cases the temperature is sub- 
 normal. Patients suffering from this form of malarial infection present a 
 characteristic countenance, the cheeks being drawn and pinched, the eyes 
 sunken, the nostrils dilated and the skin bedewed with perspiration. The 
 entire body is cold, the skin cyanotic and bathed with a cold sweat. The lips 
 and finger-nails are intensely cyanotic. The tongue is tremulous, dry, and 
 coated with a dirty white fur. The pulse is rapid, thready, and easily, com- 
 pressible, and generally more or less intermittent; the heart sounds are muffled 
 and the second sound almost inaudible, and as death approaches the pulse 
 becomes imperceptible; the respirations are irregular, superficial in character, 
 and labored; the muscular weakness is extreme, while the mental condition of 
 the patient is one of apathy to his surroundings and indifference as to his condi- 
 tion. These symptoms rarely last over a few hours, death generally resulting. 
 This is one of the most pernicious types of malarial infection and one which 
 is most resistant to treatment. Such cases have been described by Laveran, 
 Thayer, Marchiafava, Bignami, Osier, and Sternberg. In one case observed by 
 the writer in the person of a soldier who contracted aestivo-autumnal fever in 
 Cuba, algid symptoms developed and death occurred in six hours despite all 
 therapeutic aid. He had suffered from several paroxysms previously, none of 
 which were of great severity and had been easily controlled by quinine. His 
 blood showed numerous tertian aestivo-autumnal plasmcdia. 
 
 The Choleraic Form. — Certain cases of aestivo-autumnal infection 
 present symptoms very closely simulating those of Asiatic cholera. It is not rare 
 to observe cases of malaria accompanied by more or less diarrhoea, but in cases 
 presenting the choleraic symptoms the stools suddenly become watery, very 
 profuse, and numerous; they may be blood- or bile-stained, or almost colorless, 
 and may contain mucus in small flakes, thus resembling the rice-water stool of 
 cholera. The profuse diarrhoea lends to collapse, the face becoming pinched, 
 the eyes sunken, the skin cold and clammy, and cyanotic in appearance. The 
 
22 2 THE PERNICIOUS MALARIAL FEVERS. 
 
 pulse and respiration become greatly weakened, and the patient, in a husky or 
 tremulous voice, complains of severe cramps in the abdomen and thighs and 
 intense thirst; he is greatly worried over his condition, and there is great mental 
 depression. Death is the usual result in untreated cases, but where proper 
 therapeutic measures are employed, the majority of the cases will recover. 
 The temperature in the choleraic form is generally elevated. It is rarely that 
 the choleraic symptoms recur, but when they do the result is almost invariably 
 fatal. 
 
 This form of pernicious aestivo-autumnal fever simulates cholera so closely 
 that the differentiation is very difficult, especially in countries where cholera is 
 endemic or epidemic. The recognition of such cases is of great importance 
 and can only be assured by the microscopical examination of the blood. Major 
 Chamberlain, of the U. S. Army, has recently reported a most interesting case 
 of choleraic pernicious fever, in which the symptoms were indistinguishable 
 from those of cholera. 
 
 The Cardialgic Form. — This form of pernicious malarial fever is com- 
 paratively rare, and is generally associated in classification with the gastralgic 
 form. The prominent symptoms are severe, agonizing pain in the epigastrium 
 or over the cardiac region, and the vomiting of matter tinged with blood. Hic- 
 cough is often a distressing symptom, and severe hematemesis may occur. 
 These symptoms occur during the febrile paroxysm. The patient presents an 
 anxious countenance, a dry, glazed tongue, brilliant eyes, a retracted abdomen, 
 cold extremities, hurried respiration, and a rapid, weak pulse; he suffers in- 
 tense pain, and either groans or calls out under the torture which he is enduring. 
 In fatal cases collapse occurs, accompanied by the symptoms of the algid form. 
 
 Laveran, Colin, and Haspel have described cases of the cardialgic and 
 gastralgic forms of pernicious malaria. I have seen but one case conforming to 
 this type. The patient was a soldier, 22 years of age, who had suffered from 
 repeated attacks of malaria in the Philippine Islands. During the paroxysm in 
 which I observed him he had most intense pain over the left nipple and the 
 epigastrium, which radiated to the vertebral column and down the thigh; the 
 pain was so intense that screams were forced from him. He repeatedly vomited 
 blood-stained fluid and suffered greatly from hiccough. His temperature 
 reached 103. 4 F., his pulse was very rapid and thready, his extremities cold, 
 and he complained of great prostration and was very anxious regarding his 
 condition. Under repeated hypodermics of quinine his condition gradually 
 improved and he eventually recovered. 
 
 The Dysenteric Form. — A considerable proportion of patients suffering 
 from aestivo-autumnal malaria present symptoms of dysentery, consisting in 
 frequent mucoid and bloody stools, tenesmus, colicky pain in the abdomen, and 
 progressive emaciation. Scheube observed such cases in Japan and describes 
 the malarial paroxysms as accompanied by the usual symptoms of acute dysen- 
 tery. At the U. S. Army General Hospital at the Presidio of San Francisco, 
 Cal., a very large proportion of cases of malaria, chiefly of the aestivo-autumnal 
 
THE PERNICIOUS MALARIAL FEVERS. 223 
 
 variety, presented dysenteric symptoms. In fact, 65 per cent, of cases of un- 
 recognized malaria (before a blood examination) observed there were diagnosed 
 either as diarrhoea or dysentery. This proves how commonly dysenteric 
 symptoms are produced by malarial infection, and it is undoubtedly the fact 
 that in tropical regions a certain proportion of cases diagnosed as dysentery 
 are in reality the dysenteric form of malarial infection. 
 
 There exists a chronic form of malarial infection characterized by the 
 symptoms usually observed in chronic dysentery, the patient suffering from 
 attacks of diarrhoea, pain in the abdomen, muscular weakness, and loss of flesh 
 and strength. This condition I have often observed in soldiers and it is always 
 cure by the persistent use of quinine. The proper administration of this drug in 
 multitudes of cases supposed to be dysenteric nature, until this was disproven by 
 the microscope, has always resulted, in my experience, in the disappearance 
 of the symptoms and a return to health. There is no doubt in my mind 
 that there not only exists an acute, and sometimes fatal form of pernicious 
 malaria, characterized by dysenteric symptoms, but that there is a form of 
 malaria, more chronic in character, which is common in the tropics, which is 
 characterized by repeated attacks of diarrhoea, dysenteric in type, and which 
 is generally diagnosed by the practitioner as a mild form of dysentery. 
 
 The Hemorrhagic Form.— Marchiafava and Laveran have described 
 cases of pernicious malarial fever characterized by severe hemorrhages into the 
 skin and mucous membrane, as well as the occurrence of hematemesis, epistaxis, 
 and hemoptysis. These symptoms may be so severe as to cause death. Another 
 group of cases occurs in which the hemorrhages occur within the viscera, 
 especially the lungs, and some of the pneumonic malarial infections are doubt- 
 less explained in this way. The temperature is extreme in most of these cases, 
 which are undoubtedly very rare. Epistaxis even of quite severe character, is 
 not, however, a very rare symptom in attacks of aestivo-autumnal malaria, for I 
 have observed a large number of such cases. 
 
 The Pneumonic Form. — This form of pernicious malaria must be care- 
 fully distinguished from pneumonia which occurs as a complication of 
 malaria. To Baccelli we owe the demonstration of a class of pernicious 
 malarial fevers which, in their symptomatology, simulate lobar pneumonia. 
 The chief symptoms are cough, pain in the side, dyspnoea, and the expectora- 
 tion of blood-stained sputum. The onset does not differ from an ordinary 
 paroxysm, but sometimes during the attack the lung symptoms mentioned 
 develop suddenly, and the case looks clinically like a case of lobar pneumonia. 
 It will be noticed, however, that the temperature curve is intermittent, and that 
 during the afebrile periods the symptoms disappear as a rule. Percussion shows 
 dullness over the affected lung, generally the lower lobe of one or both lungs, 
 and auscultation coarse, sibilant rales. The condition is not a true pneumonia, 
 but is due to the congestion brought about by the localization of the plasmodia 
 in the capillaries of the lungs and the consequent plugging of certain circulatory 
 areas. 
 
224 THE PERXICIorS MALARIAL FEVERS. 
 
 I have observed several cases in which the symptoms so closely simulated 
 lobar pneumonia that without the microscope they would have undoubtedly been 
 considered as slightly atypical instances of that disease. The chart which is 
 here given (Chart C) is a good illustration of the temperature in these cases, and 
 is from a case regarded as pneumonia, because of the clinical symptoms, until a 
 microscopical examination of the blood showed numerous tertian aestivo-autum- 
 nal plasmodia and the administration of quinine quickly cured the infection. 
 
 The following case for which I am indebted to Lt. Col. Charles Richard, 
 Medical Corps, U. S. Army, is an interesting example of this form of malaria. 
 "The patient, a soldier, gave no history of a previous malarial attack. He had 
 suffered for some days from fever, but had no chills. Had much pain in the 
 chest, a cough with expectoration, and some vomiting. The maximum tem- 
 perature was 104 F., but there was no regularity in the curve. The man 
 looked very sick and was the picture of lobar pneumonia. Physical examina- 
 tion showed a general bronchitis. The spleen could be felt below the ribs. 
 The examination of the blood showed numerous "ring-forms" of the aestivo- 
 autumnal parasites, and treatment with quinine resulted in recovery." 
 
 Scheube has observed cases of pneumonic malaria in Japan and has no 
 hesitation in claiming that they are due to the localization of the plasmodia in 
 the lungs, and if we consider the frequency with which these organisms are found 
 localized in other organs, as the brain, and the connection clearly established 
 between such localization and the symptoms produced, we must admit that 
 there is no reason to doubt that the symptoms observed in this type of ma- 
 laria are due to the plasmodia. Microscopic study of sections of the lung 
 from fatal cases of malaria conclusively prove that, in rare instances, the plas- 
 modia occur in immense numbers in the capillaries of the lung, and that the 
 lesions produced are sufficient to excite symptoms simulating those of lobar 
 pneumonia. 
 
 The Bilious Form ("Subcontinua bilosa"). — Certain cases of malarial 
 infection present a symptom-complex in which jaundice and the vomiting of 
 bile-stained fluid are most prominent. These cases have long been known 
 under the term of "bilious remittent fever." The attack is generally character- 
 ized in the beginning by well-marked malaria paroxysms, but the temperature 
 soon becomes more or less remittent or continuous. Marked jaundice ap- 
 pears and severe vomiting is present, the matter vomited being greatly bile- 
 stained. Epistaxis is common, and hematemesis often occurs. Delirium may 
 be present or there may be a condition of semi-coma or even coma. The pa- 
 tient often complains of severe pain in the epigastrium and hiccough is one 
 of the most common symptoms. The temperature curve in well-marked cases 
 is generally remittent or almost continuous, somewhat resembling that of 
 typhoid fever. If untreated, this form of the disease is almost invariably 
 fatal, but if properly treated recovery is generally the result. 
 
 Of the very rare forms of pernicious malaria may be mentioned the syncopal 
 form, first described by Sternberg, in which syncope occurs upon exertion dur- 
 
THE PERNICIOUS MALARIAL FEVERS. 
 
 22^ 
 
 15 
 
226 THE PERNICIOUS MALARIAL FEVERS. 
 
 ing the decline of the fever; the diaphoretic form, characterized by the oc- 
 currence of very profuse sweating, so severe as to produce collapse and death; 
 the exanthematous form, characterized by the occurrence of a scarlatiniform 
 rash upon the skin during the paroxysms, followed by desquamation; the 
 pleuritic form, in which intermittent attacks of sharp, lancinating pain occur in 
 the side, and, lastly, pernicious infections without fever, which have been de- 
 scribed by Pampoukis, who considers such infections much more dangerous 
 than those in which the temperature is high. 
 
 Examination of the Blood in Pernicious Malaria. — The examination of 
 the blood during an attack of pernicious malarial fever will almost invariably 
 result in the demonstration of large numbers of malarial plasmodia, whatever 
 species may be concerned in the etiology of the infection. In no other forms of 
 malaria are the plasmodia so numerous in the peripheral blood as in pernicious 
 attacks, and often a single microscopic field will contain from ten to twenty 
 infected corpuscles. 
 
 The findings in the blood vary in many cases with the period of time in 
 which the examination is made, but as most pernicious infections are due to 
 multiple group infection, the examination will show the presence of plasmodia 
 undergoing various stages of development. In the case of regularly intermittent 
 aestivo-autumnal pernicious infections, if the blood be examined at the acme of 
 the paroxysm, the plasmodia present will be mostly of the unpigmented variety, 
 w r hile if the blood be examined during the intermission or one or two hours 
 before the beginning of the paroxysm, the pigmented forms of the Plasmo- 
 dium will be found. At whatever time the blood is examined, however, it 
 will be found that the plasmodia are all approximately in the same stage of 
 development. 
 
 On the other hand, if the blood of cases suffering from pernicious aestivo- 
 autumnal fever, in which the temperature curve is irregular or almost con- 
 tinuous, be examined, it will be found that both pigmented and unpigmented 
 plasmodia will be present, at whatever period the blood be examined. These 
 remarks apply also to pernicious cases due to the tertian and quartan plasmodia, 
 save that in these two forms of infection the sporulating stage will be found in 
 peripheral blood. As I have shown, the presence of a few organisms in the 
 peripheral blood in aestivo-autumnal infections is not always evidence of a 
 mild infection, as multitudes of plasmodia may be localized in the viscera, and 
 the infection may be of a very deadly nature. 
 
 The aestivo-autumnal pernicious fevers present themselves in so many 
 disguises, and exhibit so many atypical symptoms, that even the most acute 
 clinical diagnostician may be entirely deceived regarding these cases. The 
 microscopical examination of the blood should never be neglected in the diag- 
 nosis of any form of malarial infection, and certainly not in pernicious cases in 
 which the life of the patient is threatened and every moment is precious. The 
 blood examination consumes but little time, is absolutely conclusive in its results, 
 and may save the life of the patient. The fact should never be forgotten that 
 
THE PERNICIOUS MALARIAL FEVERS. 227 
 
 the aestivo-autumnal fevers may readily become pernicious, and that the longer 
 a malarial infection remains unrecognized the greater are the chances for the 
 development of pernicious symptoms, and, therefore, the greater the danger of 
 the patient. Ignorance of the use of the microscope is no excuse for an omis- 
 sion which may cost a human life. 
 
 In illustration of this I have in mind the case of a soldier believed to be 
 suffering from acute catarrhal jaundice. His symptoms upon entering the 
 hospital were so typical of this condition that the physician in charge delayed 
 the request for a blocd examination for several days. The patient finally 
 lapsed into a semi-comatose condition and a blood examination was then 
 requested. The blood was found to be literally loaded with quotidian aestivo- 
 autumnal plasmodia, and, while the most energetic treatment was at once in- 
 stituted, despite all that could be done the patient died in a few hours. Without 
 doubt this man's life could have been saved had the blood been examined earlier, 
 before the intense malarial intoxication had occurred. In another case the 
 patient lay in coma for three days before a blood examination was requested, 
 upon the supposition that he was suffering from some brain lesion, and here 
 again death occurred because the malarial condition was not determined in 
 time. The only safety against mistakes of this character in regions in which 
 malaria is endemic or in the case of patients coming from malarial localities is 
 a careful microscopical examination of the blood. 
 
CHAPTER IV. 
 
 Latent Malaria; Masked Malaria; Recurrent Malaria; Etiology of Latency 
 and Recurrence; Intracorpuscular Conjugation of the Malarial Plasmodia. 
 
 Latent Malarial Infection. — In the study of the malarial fevers one is 
 much impressed by the fact that a considerable proportion of patients showing 
 some form of the plasmodia in the blood present no symptoms of the infection, 
 and these cases are of great importance from an epidemiological standpoint. 
 In such patients the infection is latent, a latent malarial infection being one in 
 which the plasmodia may be demonstrated to be present in the blood, but in 
 which no clinical symptoms of the disease of sufficient gravity to attract atten- 
 tion are to be observed. The term should not be confined to those instances in 
 which no symptoms of malaria have ever been present, for if the plasmodia be 
 present in the blood during the afebrile period in recurrent cases, the disease is 
 as truly latent during that period as before the initial attack. In many latent 
 infections some complicating disease may be present, and this is almost invari- 
 ably true of latent malarial infections discovered in hospital practice. It is 
 obvious that all cases of latent malarial infection are a great source of danger to 
 others in localities where the Anophelinae are present. 
 
 The material upon which the observations and conclusions detailed in 
 this chapter are based consists of 1,653 cases of malarial infection, 1,267 °f 
 which were observed at the U. S. Army General Hospital, Presidio, of San 
 Francisco, in American soldiers returning from service in the Philippine Islands, 
 and 386 cases studied at Camp Stotsenburg, in the Philippine Islands. Of the 
 latter cases 248 occurred in Americans and 138 in Filipinos. Besides the cases 
 mentioned a considerable portion of the data regarding latency and recurrence 
 has been obtained from the observation of malarial infections contracted by 
 American soldiers while in Cuba, and studied at the Simpson U. S. Army General 
 Hospital, Fortress Monroe, and at Camp Columbia, near Havana, Cuba. 
 Of the 1,653 cases of malaria upon which the statistics of this chapter are based, 
 424, or a little over 25 per cent., were latent infections. Of these 307 were in 
 American soldiers, while 115 occurred in natives of the Philippine Islands. 
 
 As regards the species of plasmodium present in the blood, the 424 cases 
 were divided as follows: 
 
 Tertian, no 
 
 Quartan, 8 
 
 Tertian aestivo-autumnal, 272 
 
 Quotidian aestivo-autumnal, 25 
 
 Combined tertian and tertian aestivo-autumnal, 7 
 Combined tertian and quotidian aestivo-autum- 
 nal, 2 
 
 424 
 228 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 22C) 
 
 In order to understand the significance of the above table it will be neces- 
 sary to consider the latent infections of Americans and of natives of the Philip- 
 pines separately. 
 
 Latent Infections in Americans. — The latent infections of Americans, as 
 regards the species of plasmodium present, were divided as follows: 
 
 Tertian, 81 
 
 Quartan, o 
 
 Tertian aestivo-autumnal, 199 
 
 Quotidian aestivo-autumnal, 21 
 
 Combined tertian and tertian aestivo-autumnal, 4 
 Combined tertian and quotidian aestivo-autum- 
 nal, 2 
 
 3°7 
 
 The 307 latent cases observed in Americans occurred, with but few ex- 
 ceptions, in soldiers invalided home from the Philippines. As is evident, the 
 aestivo-autumnal plasmodia are much more frequently encountered in latent 
 cases than any other species, 220 of the 307 latent infections in Americans being 
 due to either the tertian or quotidian aestivo-autumnal plasmodium. The 
 occurrence of so large a proportion of aestivo-autumnal infections is not due to 
 any peculiarity in the type of plasmodia other than that the aestivo-autumnal 
 organisms are much more resistant to quinine than the other species, and for 
 that reason more latent infections with these plasmodia are found in the class of 
 patients examined, who had probably all taken quinine at one time or another. 
 It is also true that in the Philippines, as in other tropical countries, the aestivo- 
 autumnal fevers are more prevalent than tertian or quartan fevers. 
 
 The fact that aestivo-autumnal infections are particularly apt to exist in a 
 latent form is of importance, as the diagnosis of such an infection may prevent a 
 sudden pernicious attack; and it is also important from an epidemiological 
 standpoint, as an individual thus harboring the plasmodia is, or may become, a 
 source of infection to the community in which he is living. It is thus evident 
 that the blood of every individual returning from a malarial region should be 
 examined, both as a safeguard to himself and to the community in which he may 
 be residing. 
 
 Frequency of Latent Infection in Americans. — Of the 1,297 cases of 
 malaria studied in Americans, 307 or nearly 24 per cent., were latent infections. 
 It should be remembered that in all of these cases there were absolutely no 
 symptoms of malaria present, and had it not been for the examination of the 
 blood these men might have remained sources of infection for weeks or months. 
 
 As showing the frequency of latent malarial infections and the importance 
 of their recognition, I quote the following from a report upon latent and masked 
 infections by the writer, published in American Medicine, in 1904: 
 
 In August, 1902, Company H, 16th Infantry, U. S. Army, returned to San 
 Francisco from the Philippines, having served in the Cagayan Valley, a notori- 
 
23O LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 ously malarial region in those islands. On August 16, 1902, this company, out 
 of a total strength of some 60 men, had 14 men in hospital suffering from mala- 
 rial infection, all having had chills since arrival in the United States. On ac- 
 count of this large proportion of infected men, I believed that it would be 
 advisable to make a blood examination of the entire company, and accordingly, 
 on August 17, I examined the blood of every man on duty in Company H, with 
 the following results: Of the 47 men who were doing duty, including the officers, 
 I found that 27 presented some form of malarial parasite in their blood. Of 
 these 27 cases, 25 were infected with the aestivo-autumnal plasmodia; 13 show- 
 ing gametes (crescents) of the tertian aestivo-autumnal species; 10 showing 
 crescents and ring-forms of the same species; two showing crescents and ring- 
 forms of the quotidian aestivo-autumnal plasmodium; and two showing nearly 
 full-grown forms of the simple tertian plasmodium. Thus of a total strength of 
 60 men, 41, which includes those sick in hospital, showed some form of malaria 
 infection, while 27, without presenting any symptoms of malaria, showed 
 parasites in the blood. 
 
 A study of the blood findings in this company is of great significance, not 
 only as showing the importance of a blood examination in persons returning 
 from the tropics, but because, in most instances, the gametes of the aestivo- 
 autumnal plasmodia, the most dangerous of the malarial parasites, are the 
 forms present. As the gametes, or crescents, are the forms which undergo 
 development within the mosquito it is evident that these men could infect 
 mosquitoes of the genus Anopheles wherever they might go. In this way 
 localities hitherto free from this dreaded type of malaria might become infected. 
 
 Latent Malarial Infection Complicating Other Diseases. — A very 
 large number of latent malarial infections in Americans occur as complications 
 of some other disease process, and it is important that the malarial factor in 
 such cases be recognized and removed. As an illustration of the frequency of 
 this condition I have compiled the following table, giving the original diagnosis 
 in 106 cases in which a latent malarial infection was found to exist. In nearly 
 all of these cases the removal of the malarial complication resulted in improve- 
 ment of the health of the patient. 
 
 Diagonisis 
 
 Number of cases 
 
 Chronic dysentery 
 
 Chronic diarrhoea 
 
 Pulmonary tuberculosis 
 
 Fractures and wounds 
 
 Chronic gastritis 
 
 Amoebic dysentery 
 
 Chronic indigestion 
 
 Hernia 
 
 Otitis media I 3 
 
 15 
 
 20 
 
 3 
 
 1 1 
 8 
 
 J S 
 3 
 3 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 23I 
 
 Diagnosis 
 
 Number of cases 
 
 Acute melancholia 
 
 Rheumatism 
 
 Syphilis 
 
 Insanity 
 
 Paralysis 
 
 Acute dementia 
 
 Convalescent from operation 
 
 Arthritis formans 
 
 Retinitis 
 
 Varicocele 
 
 Tachycardia 
 
 Uncinariasis 
 
 Diabetes mellitus 
 
 Paraplegia 
 
 Acute endocarditis 
 
 Hemorrhoids 
 
 Adenitis, cervical 
 
 to6 
 
 A consideration of some of the data given in the above table is of interest. 
 
 In 15 cases of chronic dysentery, non-amoebic in type, a latent malarial 
 infection was discovered. All of these patients gave a history of having suffered 
 from malaria in the Philippines, but of not having had any symptoms of the 
 disease since arrival in the United States. The much controverted statement 
 that there exists a form of dysentery due to the localization of the malarial 
 plasmodia in the capillaries of the intestine is of interest in connection with these 
 cases, as treatment of the malarial infection resulted in every case in marked 
 improvement of the dysenteric condition and ultimately in complete recovery, so 
 that it is probable that some of these cases were entirely malarial in character. 
 From personal observation I know that some aestivo-autumnal infections are 
 accompanied by a bloody diarrhoea, and it is my belief that many cases diag- 
 nosed as dysentery in tropical countries are due to the invasion of the intestines 
 by the malarial plasmodia or to the action of the malarial poison. The same 
 remarks apply to the 20 cases of chronic diarrhoea in which a latent malarial 
 infection was discovered. 
 
 In 15 cases of amoebic dysentery a latent malarial infection was observed. 
 In these cases Entamoeba histolytica was present in the faeces and one of the 
 species of plasmodia in the blood. 
 
 In nine cases of fractures and two of bolo wounds an examination of the 
 blood showed the presence of malarial plasmodia, although no symptoms of 
 such infection were noticed. This was also true in one case convalescent from 
 operation. 
 
232 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 Latent Infection in Natives of the Philippine Islands. — I have already 
 noted the results of various observers in the examination of the blood of native 
 races in tropical countries, and have shown that latent infection is very common 
 in certain localities among the native population. The following observations 
 upon the latent infections of the natives of the Philippines, made at Camp 
 Stotsenburg, are in agreement with those of other observers and prove that the 
 Filipino, like other tropical races, suffers from malarial infections in early 
 childhood, but, unlike some native races, does not establish any marked im- 
 munity in adult life. 
 
 Frequency of Latent Infection in Filipinos. — During five months in 
 which I was stationed at Camp Stotsenburg I observed 386 cases of malaria in 
 which I was able to demonstrate the parasites in the peripheral blood. Of 
 these, 248 occurred in Americans and 138 in Filipinos. As regards the type of 
 infection, 98 were infected with the tertian plasmodium, of which 63 were 
 Americans and 35 natives; eight with the quartan plasmodium, of which 2 were 
 Americans and 6 natives; and 272 with the aestivo-autumnal plasmodia, 
 183 being Americans and 89 natives. Of the aestivo-autumnal infections, 
 258 were due to the tertian aestivo-autumnal plasmodium and 14 to the 
 quotidian variety. All of the latent infections, 115 in number, occurred in 
 Filipinos. 
 
 It appeared probable to me in considering the malarial situation at this 
 post that the natives living in the barrios in close proximity were the principal 
 source of infection, as the sanitary conditions in the post proper were such as to 
 prohibit the belief that much malarial infection could originate there, while 
 breeding-places of mosquitoes abounded in the barrios and mosquitoes belong- 
 ing to the Anophelinae were much more numerous in them than at the post. 
 The barrios were constantly visited by the soldiers, especially at night,- and the 
 conditions for the spread of both human and mosquito infection were ideal. In 
 order to determine how large a proportion of the native population of the bar- 
 rios was infected, I made blood examinations of as many natives as possible, 
 living within two miles of the post. The result proved beyond question that 
 the origin of malarial infection at Camp Stotsenburg was to be found very 
 largely in the natives living in the immediate vicinity, and that any efforts to 
 limit the spread of the disease must take this condition into account. In a con- 
 siderable number of the cases of latent infection, even in the youngest children, 
 a history of previous attacks of fever could be obtained, but in none of them 
 were any symptoms of malaria present at the time of the examination of the 
 blood. In all, the blood of 225 Filipinos was examined, of which 115, or 51.1 
 per cent., showed a latent malarial infection. 
 
 This percentage of latent malarial infection should not be regarded as 
 typical of all localities in the Philippines, for many localities are free from 
 malaria, while in others the malarial index is low. Routine blocd examina- 
 tions of the natives of a tropical country will give much valuable information as 
 to the malarial endemicity of the locality, and such examinations should be 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 233 
 
 made before permanent military posts or civilian residences are established in 
 the tropics. 
 
 Of the 115 latent infections discovered, the tertian plasmodium was 
 present in 29, the quartan in six, and the aestivo-autumnal in 77; of the latter, 
 73 were due to the tertian aestivo-autumnal plasmodium, and four to the 
 quotidian aestivo-autumnal plasmodium. There were three combined infec- 
 tions with the tertian and the tertian aestivo-autumnal plasmodia. 
 
 Latent Infection in the Adult Natives. — I was able to examine the blood 
 of but 45 adults, of whom 28, or 62.2 per cent, were infected; of these, five 
 infections were due to the tertian plasmodium, and 23 to the tertian aestivo- 
 autumnal plasmodium. It is very probable that a further study of the blood of 
 a greater number of adults would materially reduce this great percentage of 
 infections, but from the results obtained, it is evident that the adult Filipino is 
 more often infected than the negro in Africa or the native of India. It is more 
 than probable that the adult Filipino possesses little or no immunity to malaria, 
 despite the fact that in malarial localities such adults have, from childhood, 
 suffered from repeated attacks of the disease. I have notes upon several adults, 
 who, within two years, were admitted to the hospital from 8 to 16 times with 
 malarial infections. The reason for this lack of immunity of the adult Filipino 
 to malarial infection is difficult to understand, but I believe that there is no 
 question but that it does exist to a marked degree even in the most malarial 
 localities. 
 
 Latent Infection in Native Children. — Of the 180 children whose blood 
 I examined, 87 or 48.3 per cent., showed the presence of the malarial plasmodia. 
 Of these latent infections, 34 were due to the tertian plasmodium, six to the 
 quartan, and 44 to the aestivo-autumnal species. Of the latter, 40 were due to 
 the tertian aestivo-autumnal species and four to the quotidian. There were 
 three combined infections with the tertian and tertian aestivo-autumnal plasmo- 
 dia. The infections in children diminished in number with advancing age. 
 Thus, between the ages of one month and five years, among 40 children, 79 per 
 cent, were infected; between 5 and 10 years, 37 per cent.; and between 10 and 15 
 years, 24.5 per cent. These results agree with those of Koch, Stephens and 
 Christophers, James, and others, who invariably found that the younger the 
 child, the more susceptible it was to malaria. 
 
 The percentage of latent infections in children varies considerably in the 
 different barrios in which the examinations were made. For instance, in the 
 town of Mabalacat, 25 school children between the ages of 5 and 10 years were 
 examined, of whom seven, or 28 per cent., were found infected; while of children 
 between 10 and 15 years of age, 35 were examined; of whom seven, or 20 per 
 cent., were infected. In the town of Dolores, 11 school children between the 
 ages of 5 and 10 years were examined, of whom seven, or 63.6 per cent., w r ere 
 infected; while of 13 children between 10 and 15 years of age, four, or nearly 31 
 per cent., were infected. 
 
 Family Infection. — Not only do the barrios differ in the ratio of malarial 
 
2 34 
 
 LATENT. MASKED AND RECURRENT MALARIAL FEVERS. 
 
 individuals to those in health, but certain portions of the barrios are most ma- 
 larious, while other portions are almost free from infection. It was also 
 observed that malaria in these barrios was very largely a family disease, 
 certain families suffering severely, while others were free from infection. The 
 following table illustrates the family character of malarial infection, being 
 compiled from the data obtained in one barrio where all of the families resided. 
 
 Family 
 
 No. members 
 
 No. infected 
 
 Type of infection 
 
 i 
 
 4 
 
 2 
 
 i aes-autumn. i ter. 
 
 2 
 
 3 
 
 2 
 
 2 aes-autumn. 
 
 3 
 
 4 
 
 2 
 
 i aes-autumn. i ter. 
 
 4 
 
 5 
 
 4 
 
 2 aes-autumn. i ter. 
 i quartan. 
 
 5 
 
 4 
 
 2 
 
 2 aes-autumn. 
 
 6 
 
 3 
 
 2 
 
 2 aes-autumn. 
 
 7 
 
 4 
 
 3 
 
 2 aes-autumn. i ter. 
 
 8 
 
 3 
 
 2 
 
 i aes-autumn. i ter. 
 
 9 
 
 3 
 
 2 
 
 2 tertian. 
 
 IO 
 
 6 
 
 4 
 
 2 aes-autumn. 2 ter. 
 
 In considering this table it should be remembered that all these infections 
 were latent in character, and I have repeatedly observed families in which every 
 member was suffering from a malarial infection, either latent or active. Family 
 No. 4 in the above table is of special interest because, of its five members, one 
 was suffering from a severe attack of tertian malaria at the time I made the ex- 
 amination, while of the other four, two presented aestivo-autumnal, one the 
 quartan, and the other the tertian plasmodium in the blood, so that in this one 
 family all the species of the malarial plasmodium couldbe studied. 
 
 The pathology of latent malarial infection has already been considered in 
 the chapter devoted to the special pathology of the malarial infections. 
 
 Practical Deductions. — From the facts given above, I believe that 
 it is obvious that latent malarial infections are of much importance from 
 both epidemiological and clinical standpoints; it is certainly true that latent 
 infections are a great source of malarial disease, and in the tropics, the latent 
 infection of the native is undoubtedly the principal source of infection of the 
 white man. The importance of an examination of the blood of the native 
 population of any given locality cannot be overestimated in the fight against 
 malaria. This is especially true in the tropics, for only from the results of such 
 an examination can the endemic areas of malaria be found and guarded against. 
 Only to one who has attempted it, can the almost hopeless task of exterminating 
 mosquitoes in tropical regions be appreciated, and, in fact, in many localities it 
 is impossible of accomplishment. This being so, it is apparent that it is useless 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 ! 35 
 
 to rid a locality of malaria, if it is impossible to eliminate the mosquito, unless 
 the infection is first stopped in the native, and in the tropics it appears to me 
 that the greatest hope of success is combating malaria lies in the treatment of 
 the latent infections of the natives. 
 
 Masked Malarial Fever.— Cases of malarial infection in which the 
 symptoms are masked by those of some other disease or in which the symptoms 
 closely resemble those of other diseases are known as masked infections. In 
 such cases malarial symptoms are present, but they are overshadowed by the 
 symptoms of the complicating disease. Such cases are common and should 
 be carefully distinguished from those instances of latent infection occurring 
 during other disease processes. In the latent cases no symptoms of malaria 
 are present, while symptoms are present in the masked cases. The following 
 table shows the diagnosis in 91 cases of masked malaria in all of which the 
 symptoms of the disease diagnosed masked those of the malarial infection. 
 
 Disease 
 
 No. cases masked 
 
 Chronic dysentery . . . . 
 
 Chronic diarrhoea 
 
 Pulmonary tuberculosis 
 Amoebic dysentery . . . . 
 
 Acute bronchitis 
 
 Rheumatism 
 
 Measles 
 
 Typhoid fever 
 
 Pneumonia 
 
 Abscess of the liver .... 
 
 Furunculosis 
 
 Diabetes mellitus 
 
 Gonorrhoea 
 
 Cellulitis 
 
 Appendicitis 
 
 45 
 
 5 
 
 9* 
 
 The instances in which the malarial symptoms so closely simulate those 
 of some other disease are also numerous, and it may truly be said that malaria 
 may simulate almost any disease so closely that only a microscopical examina- 
 tion of the blood will enable us to make a diagnosis. As a rule, however, the 
 periodical nature of the attacks will raise a suspicion of their malarial nature. 
 It should also be remembered that in the older literature of malaria many 
 conditions were classed under masked malaria which were not malarial in 
 nature and which would have been correctly diagnosed had the plasmodia been 
 discovered at the time they were described. No case should be considered as 
 one of masked malaria, unless a blood examination has shown the presence of 
 
236 
 
 LATENT, MASKED AND RECURRENT MALARIAL FEVERS, 
 
 the malarial plasmodium. Among the most common atypical symptoms of 
 malaria which are often considered as being due to some other disease may be 
 mentioned various neuralgic affections, periodical in type, especially of the 
 fifth nerve, the intercostal nerves, and of the occipital region; convulsions 
 especially common in malarial attacks in children; various nervous conditions, 
 as insomnia, delirium, melancholia, mania, and dizziness; and certain of the 
 infectious diseases, may be so closely simulated by malaria as to be almost 
 indistinguishable, especially typhoid, pneumonia, yellow fever, cerebrospinal 
 meningitis, and pulmonary tuberculosis. 
 
 The following table of 96 cases of masked malaria in which the diagnosis 
 as made before the malarial nature of the condition was discovered is given, well 
 illustrates how frequently malaria simulates other disease processes, and 
 how valuable a microscopical examination of the blood is in the diagnosis of 
 disease. In all of these cases, the symptoms present were sufficiently typical 
 of the disease diagnosed as to render the diagnosis justifiable, and in all, treat- 
 ment with quinine caused a rapid disappearance of the symptoms. 
 
 Diagnosis 
 
 No. of cases 
 
 Neuralgia, facial 
 
 Chronic dysentery 
 
 Chronic diarrhoea 
 
 Pulmonary tuberculosis . 
 
 Acute bronchitis 
 
 Pneumonia, lobar 
 
 Appendicitis 
 
 Peritonitis 
 
 Insolation 
 
 Syphilis 
 
 Melancholia 
 
 Insanity 
 
 Rheumatism, muscular . 
 
 Typhoid fever 
 
 Malta fever 
 
 Anaemia 
 
 Acute catarrhal jaundice 
 
 Yellow fever 
 
 Cerebrospinal meningitis 
 
 3 
 
 15 
 
 6 
 
 5 
 4 
 3 
 
 4 
 2 
 
 4 
 10 
 
 6 
 20 
 
 96 
 
 It is not necessary to consider this table in detail, but I would call attention 
 to the fact that in most of these cases the infection was due to the aestivo-autum- 
 nal plasmodium, and that most of them had been insufficiently treated with 
 quinine, which, no doubt, had much to do with the atypical nature of the 
 symptoms. The confusion of malarial infection with typhoid, Malta fever, 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 237 
 
 and tuberculosis is of frequent occurrence and has much to justify it, as the 
 symptoms of malarial fever of aestivo-autumnal type, often very closely simulated 
 those of any one of these diseases. 
 
 At first sight it would seem almost impossible that a diagnosis of lobar 
 pneumonia would be made in a case of malarial fever. I have already described 
 the occurrence of cases of malaria so closely simulating lobar pneumonia that 
 without the microscope a differential diagnosis could not be made, and believe 
 that the two following clinical histories amply illustrate how closely the symp- 
 toms of a malarial infection may simulate those of lobar pneumonia. 
 
 I am indebted for the notes of Case I to Dr. Edmund Barry, formerly of 
 the United States Army. 
 
 Case I. — W. D. C. Patient was admitted to the hospital from the Presidio 
 of San Francisco, with a transfer slip diagnosis of lobar pneumonia. On admis- 
 sion the patient was somewhat emaciated; his mental condition was apathetic; 
 tongue coated, and bowels constipated; he complained of chilliness most of the 
 time. The. spleen was enlarged considerably and tender. Soon after admission 
 he had a severe chill and became delirious, his temperature reaching 106. 2° F. 
 There was marked difficulty in breathing and severe pain in the side. An ex- 
 amination of the lungs showed marked friction sounds over the middle lobe of 
 the right lung, and dullness over the same area. Patient remained slightly 
 delirious for five days and during this time the physical signs of pneumonia 
 increased, marked dullness developing over the lower lobe. Respirations 
 were rapid, exceeding 50, and the pulse very weak. He coughed considerably, 
 but there was no expectoration. At the end of five days the blood was examined 
 and numerous "ring forms" of the tertian aestivo-autumnal plasmodium were 
 found. Immediately upon receipt of the laboratory report, quinine was admin- 
 istered, and in two days the patient was so much better that he was able to sit up 
 and was about within four days. 
 
 I personally examined this patient during the period in which he was 
 considered to be suffering from pneumonia, and his symptoms were typical 
 of that disease. His temperature curve was atypical, however, showing marked 
 remissions. (See Chart C.) 
 
 Case II. — C. S. The patient was admitted to the hospital with a diagnosis 
 of acute lobar pneumonia of the lower lobe, right lung, and at the time of admis- 
 sion was in a comatose state. After recovery the following history was obtained: 
 The illness began with a soreness in the chest and expectoration, slightly blood- 
 tinged. Just before admission he had a severe chill, accompanied by pain in 
 both sides of the chest, and at this time he spat up considerable blood. The 
 pain was very distressing on deep inspiration. At the time of admission his 
 respirations were 40; pulse 100; and temperature 104 F. 
 
 An examination of his lungs showed increased vesicular breathing, almost 
 bronchial in character; increased vocal fremitus; and numerous crepitant rales 
 over the right lung and lower lobe of the left. Both lower lobes were dull upon 
 percussion. The spleen was very much enlarged and there was slight enlarge- 
 ment of the liver. He was admitted to hospital Jan. 20, and a blood examination 
 was made the next day. The blood showed numerous full-grown tertian plas- 
 
238 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 modia and a few "ring-forms" of the quotidian aestivo-autumnal plasmodium. 
 Before the blood examination was made the diagnosis of pneumonia was con- 
 curred in by the attending surgeon, and treatment for that condition insti- 
 tuted. On receipt of the report from the laboratory, quinine was administered, 
 which was followed by a rapid improvement in the patient's condition, the tem- 
 perature falling from 104 F. to 96 F. The administration of quinine was con- 
 tinued and rapid recovery ensued. 
 
 In this case we have a clear history of the outset of what was apparently 
 true lobar pneumonia, the symptoms agreeing in every way with those usually 
 observed in that disease. There was pain in the side, chill, high temperature 
 expectoration of blood-stained sputum, and the physical signs which are 
 considered so characteristic of lobar pneumonia, yet two days' treatment with 
 quinine brought the temperature to normal, all of the symptoms disappeared, 
 and the patient was up and about within a week. Such cases as these prove 
 that the localization of the malarial plasmodia within the capillaries of the 
 lungs is capable of producing true pneumonic symptoms. 
 
 In rare instances a malarial infection will simulate appendicitis or peri- 
 tonitis so closely as to render the diagnosis impossible clinically. The following 
 case is of special interest, as it demonstrated how closely malarial infection may 
 simulate appendicitis. 
 
 The patient was an officer of the U. S. Army who was transferred to the 
 Army General Hospital at San Francisco with a diagnosis of suspected appen- 
 dicitis, transfer being made with a view to operation if the diagnosis was verified. 
 He gave a history of having had intermittent malarial attacks in the Philippines 
 which did not necessitate admission to sick report. He had not been feeling 
 well for some time, and on the day before admission to the hospital he had. an 
 attack of pain in the region of the ascending colon. Upon admission he com- 
 plained of pain in this region, at times very severe ; his tongue was coated ; 
 bowels regular; and his pulse and temperature about normal. A blood count 
 was made and a slight leucocytosis was found. Physical examination showed 
 no rigidity of the muscular wall, but he complained of pain in the right iliac 
 region on pressure, and after careful examination, operation the next morning 
 was determined upon. That evening he had a slight chill and his temperature 
 rose to 104 F. An examination of the blood was made and numerous hyaline 
 forms of the tertian aestivo-autumnal plasmodium were found. Quinine was 
 promptly administered, which resulted at once in a fall of temperature, and 
 continued administrations in complete recovery. In this case an operation 
 would undoubtedly have been performed in the morning for a condition essen- 
 tially malarial in character. 
 
 It is obvious that the recognition of these cases of latent and masked malarial 
 fever is of the greatest importance, as in the latent infections we are thus able 
 to cure the disease before any annoying or dangerous symptoms appear, and 
 in the masked cases we are able to remove the malarial element in those cases 
 in which other disease symptoms mask the malaria, or discover and treat the 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 239 
 
 true cause of disease in those cases in which the malarial symptoms resemble 
 those of other infections. 
 
 Duration of Latent and Masked Malarial Infections. — The length of 
 time during which a latent infection may exist is uncertain, but it is probable 
 that in many cases it may be for weeks or months. I recall one case in which 
 the aestivo-autumnal plasmodia were found in the blood for six weeks before 
 a paroxysm occurred, and I have observed many cases in which the plasmodia 
 were demonstrated in the blood for from seven to fourteen days before the 
 appearance of clinical symptoms. 
 
 The masked cases may continue for weeks where the infection is not of 
 a pernicious character or death may occur within a few days. 
 
 It should always be borne in mind that most latent and masked infections 
 are caused by the aestivo-autumnal plasmodia and that such infections are 
 especially liable to develop pernicious symptoms; that the clinical symptoms 
 in many of these cases are absolutely unreliable, so far as diagnosis goes; and 
 that in all diseases occurring in malarial regions a microscopical examination 
 of the blood should never be omitted. 
 
 Recurrent Malarial Infections. 
 
 It is probably a fact that with very few exceptions (and these most vigorously 
 treated with quinine) every primary malarial attack is followed by one or more 
 relapses or recurrences. By recurrences I mean the appearance of symptoms 
 due to the same group of parasites causing the original infection, and not to a 
 reinfection by another group. So common are recurrences in malaria that 
 a prevalent belief is that "once a victim of malaria, always a sufferer from 
 the disease"; while this belief is unfounded, recurrences often do persist for 
 months, and sometimes, although very rarely, for years. They are most 
 common and persistent in the aestivo-autumnal infections, as would be expected 
 from the greater resistance of these infections to treatment. 
 
 To the clinician the time elapsing between the initial attack and the 
 recurrences is one of the greatest interest, while to the investigator the etiology 
 of recurrences and the modus operandi have proven a fruitful field for controversy 
 and, from the very nature of the problem, of theoretical deduction. 
 
 Time of Recurrence. — Authorities differ somewhat as to the time of 
 recurrence in the different types of malarial infection, and when we consider 
 the difficulty of ruling out reinfections, especially in those who reside in a 
 malarial locality, the slight difference in the time as given by various observers 
 is indeed surprising. In malarious regions it is obviously impossible, in many 
 instances, to be sure that the reappearance of symptoms is not due to reinfection, 
 unless a different species of plasmodium be present than that found during the 
 initial attack. As a basis for the computation of the time of recurrence, Celli 
 reckons "as recurrent every case of fever which repeats itself in the same 
 
240 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 individual from the July of one year to the end of June of the following year, 
 or during all the cycle of the same yearly epidemic." While, of course, errors 
 are bound to occur with this method of computing recurrences, Celli believes, 
 and I think justly, that for practical purposes it is as perfect as is possible under 
 the circumstances. I have used this method in compiling the table of recurrences 
 which follows, but have taken the further precausion of selecting only those 
 cases which I am reasonably sure could not have become reinfected. 
 
 Bonus, an investigator working in Senegal, found that recurrences took 
 place preferably upon the seventh, fourteenth, twenty-first and twenty-eighth 
 day after the initial attack. Of 226 cases, 128 relapsed, and of these 18 relapsed 
 upon the seventh day, 64 on the fourteenth, 31 on the twenty- first, and nine on 
 the twenty-eighth day. Ninety-eight cases relapsed irregularly on the ninth, 
 tenth, sixteenth, and twentieth days. All of the cases took quinine at the time 
 of the attack. Barudel from his observations, concludes that quotidian fever 
 most frequently relapses upon the seventh day, tertian upon the fourteenth, and 
 quartan upon the twentieth. 
 
 Mariotti-Bianchi concludes that benign tertian infections relapse between 
 the fifth and eighteenth days after infection, while aestivo-autumnal fevers 
 relapse between five and twenty-one days, but frequently between five and 
 nine days after the initial attack. 
 
 Zieman found that in West Africa aestivo-autumnal infections relapsed 
 between nine and twelve days after the primary attack, which, as he points out, 
 is practically the same as the incubation period. 
 
 Werlhof, from his experience, decides that tertian infections relapse most 
 frequently in the second, and quartan in the third week, while Duden claims 
 that on the east coast of Africa, quotidian fever relapses almost invariably upon 
 the seventh day. 
 
 Authentic recurrences after long intervals of time are rare, but such cases 
 unquestionably occur. Thayer relates an interesting example and Mariotti- 
 Bianchi observed in tertian infections recurrences between three and thirteen 
 months, and in aestivo-autumnal fevers, between four and eight months apart. 
 V. Leyden observed a recurrence of a malarial infection three years after the 
 initial attack, and Schilling has observed recurrences after eight and a half 
 months and after two and a half years. As regards recurrences after such long 
 intervals as two or three years I agree with Mannaberg that the evidence is not 
 sufficient to prove undeniably that the so-called recurrences were not reinfections, 
 and such cases appear to me to be very doubtful. 
 
 The following table of recurrences in aestivo-autumnal and tertian malaria 
 are prepared from carefully selected cases in which reinfection was considered 
 at least very improbable, and which, I believe, may be considered as portray- 
 ing the exact length of time occurring between the relapses in these types of 
 malarial fevers. The patients were all American soldiers observed in hospital 
 and thoroughly treated with quinine during the active symptoms, while most 
 of them received prophylactic doses of quinine once a week, which undoubtedly 
 delayed somewhat the relapses in the men so treated. 
 
 Aestivo-autumnal Tertian Recurrences. — Time of the Various Recur- 
 rences in 55 cases of Tertian Aestivo-autumnal Malarial Infection. 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 241 
 
 Initial attack 
 
 Oct. 
 
 Nov. 
 
 Feb. 
 
 Nov. 
 
 Mar. 
 
 Dec. 
 
 Jan. 
 
 Feb. 
 
 Dec. 
 
 Feb. 
 
 Feb. 
 
 Dec. 
 
 Mar. 
 
 Nov. 
 
 Nov. 
 
 Feb. 
 
 Oct. 
 
 Aug. 
 
 Mar. 
 
 Feb. 
 
 Dec. 
 
 Jan. 
 
 Jan. 
 
 Oct. 
 
 Nov. 
 
 Mar. 
 
 Feb. 
 
 Dec. 
 
 Oct. 
 
 Jan. 
 
 Jan. 
 
 Jan. 
 
 Jan. 
 
 Oct. 
 
 Jan. 
 
 Oct. 
 
 Jan. 
 
 Oct. 
 
 Feb. 
 
 Aug. 
 
 Nov. 
 
 Sept. 
 
 Oct. 
 
 Oct. 
 
 Aug. 
 
 Sept. 
 
 Oct. 
 
 12 
 19 
 
 3° 
 
 8 
 
 24 
 
 12 
 
 24 
 
 6 
 
 6 
 
 25 
 1 
 29 
 14 
 4 
 3° 
 29 
 
 17 
 4 
 3° 
 26 
 1 1 
 
 29 
 
 17 
 
 1 
 
 19 
 20 
 
 J 9 
 19 
 18 
 
 25 
 
 2 1 
 30 
 13 
 27 
 
 17 
 
 13 
 6 
 
 3 1 
 
 First 
 recurrence 
 
 10 days 
 12 days 
 1 5 days 
 
 18 days 
 
 19 days 
 
 19 days 
 
 20 days 
 20 days 
 20 days 
 20 days 
 
 20 days 
 
 2 1 days 
 
 22 days 
 22 days 
 24 days 
 24 days 
 24 days 
 24 days 
 
 24 days 
 
 25 days 
 
 26 days 
 26 days 
 
 26 days 
 
 27 days 
 27 days 
 
 27 days 
 
 28 days 
 
 28 days 
 
 29 days 
 
 30 days 
 30 days 
 30 days 
 
 32 days 
 
 33 days 
 
 34 days 
 34 days 
 34 days 
 36 days 
 36 days 
 36 days 
 36 days 
 3 7 days 
 38 days 
 38 days 
 38 days 
 
 41 days 
 
 42 days 
 
 Second 
 recurrence 
 
 30 days 
 
 20 days 
 30 days 
 20 days 
 
 60 days 
 
 20 days 
 48 days 
 33 days 
 
 20 days 
 16 days 
 26 days 
 
 16 days 
 36 days 
 48 days 
 22 days 
 
 52 days 
 2 1 days 
 28 days 
 48 days 
 
 30 days 
 
 26 days 
 40 days 
 50 days 
 26 days 
 56 days 
 66 days 
 3 5 days 
 
 Third Fourth Fifth 
 recurrence ; recurrence recurrence 
 
 36 days 
 
 30 days 
 30 days 
 
 38 days 
 
 20 days 
 30 days 
 90 days 
 
 20 days 
 1 5 days 
 
 90 days 
 
 17 days 
 
 49 days 
 
 20 days 
 
 30 days 
 
 90 days 
 
 2 1 days 
 
 30 days 
 
242 
 
 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 Case 
 
 No. 
 
 Initial 
 
 attack 
 
 First 
 recurrence 
 
 Second 
 recurrence 
 
 Third 
 recurrence 
 
 Fourth 
 recurrence 
 
 Fifth 
 recurrence 
 
 4S 
 
 Jan. 
 
 Nov. 
 
 Dec. 
 
 Feb. 
 
 Oct. 
 
 Jan. 
 
 June 
 
 Mar. 
 
 1 
 
 3 
 
 7- 
 
 24 
 
 24 
 
 1S 
 
 14 
 3 
 
 4 5 .lays 
 46 days 
 40 days 
 
 50 days 
 
 51 days 
 61 days 
 64 days 
 80 days 
 
 30 days 
 2 r days 
 
 
 
 
 49 
 
 
 
 
 SO 
 
 
 
 51 
 
 24 days 
 39 days 
 
 1 56 days 
 66 days 
 
 120 days 
 
 41 days 
 
 
 
 52 
 
 
 
 S3 
 
 
 
 54 
 5 5 
 
 14 days 
 96 days 
 
 20 days 
 
 20 days 
 
 
 
 
 A consideration of this table shows that the first relapse in tertian aestivo- 
 autumnal malaria occurred at periods varying from 10 up to 80 days; in none 
 of the cases did a relapse occur before 10 days after the initial infection, which 
 does not agree with the results obtained by Mariotti-Bianchi and Zieman, 
 who found that this type of malarial infection relapsed most frequently in from 
 5 to 20, and 9 to 12 days, respectively. The administration of quinine in many 
 of these cases probably delayed the relapse, but even so, it will be noticed that 
 the great majority of the cases did not relapse until after the twenty-fourth day. 
 Taken in periods of ten days, an analysis of the table shows that six cases 
 recurred between the tenth and twentieth days; 23 between the twentieth and 
 thirtieth; 16 between the thirtieth and fortieth; five between the fortieth and 
 fiftieth; and the remainder at periods later than the fiftieth day from the initial 
 attack. The greatest number of relapses occurred between the twentieth and 
 thirtieth days, namely, 23, and almost as many between the thirtieth and fortieth 
 days, namely, 16. Of single days, five cases recurred upon the twentieth day; 
 five upon the twenty-fourth day; four upon the thirty-sixth day; and three upon 
 the twenty-sixth, twenty-seventh, thirtieth, thirty-fourth, and thirty-eighth 
 days after the initial attack. 
 
 In most instances secondary relapses occurred at longer intervals than 
 the primary one, although numerous exceptions to this rule will be noticed 
 in the table. 
 
 The statement that the longer the infection lasts the longer becomes the 
 interval between relapses is not borne out in this series of cases, if the majority 
 of the cases be taken into account. Thus in Case 16, relapses occurred at 
 periods of 20, 38, and 30 days; in Case 21, at periods of 26, 36, 30, 90, and 30 
 days; in Case 27, at periods of 28, 21, 20, and 21 days; in Case 37, at periods 
 of 34, 26, and 17 days; in Case 51, at periods of 50, 24, and 41 days; and in 
 Case 54, at periods of 64, 66, 14, 20, and 20 days. 
 
 Of the 55 cases, 36 had two relapses; 14, three relapses; 4, four relapses; 
 and 2, five relapses. This well illustrates the persistency of aestivo-autumnal 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 243 
 
 infections, and their resistance to treatment, unless the treatment be continued 
 for a long period of time. 
 
 A most interesting feature of the aestivo-autumnal cases is the fact that 
 21 of them suffered from at least two relapses when the prim ary relapse occurred 
 as long as 27 days after the initial attack. In the benign tertian infections 
 not a single secondary relapse occurred after the twenty-sixth day. In the 
 aestivo-autumnal infections it will also be noticed that no security against 
 future recurrences is apparent when the primary relapse occurs after a long 
 period of time from the acute attack, whereas in the benign tertian infections 
 one can almost rest assured that secondary relapses will not occur if the primary 
 relapse occurs a month after the initial attack of fever. 
 
 Tertian Recurrences. — The following table gives the data concerning 
 recurrences in 18 cases of benign tertian malaria. The number is small, but 
 while my records contain data covering hundreds of tertian malarial infections, 
 in only 18 cases can I be sure of genuine recurrence. The vast majority 
 of tertian cases, if properly treated, do not recur, and very many of them recover 
 spontaneously, although in such cases recurrence is much more common, and, 
 indeed, may be stated to be the rule. 
 
 Table of Recurrences in 18 Cases of Tertian Malarial Infection. 
 
 Case 
 No. 
 
 Initial 
 
 attack 
 
 First 
 recurrence 
 
 Second 
 recurrence 
 
 Third 
 recurrence 
 
 Fourth 
 recurrence 
 
 Fifth 
 recurrence 
 
 1 
 
 Nov. 2 
 Aug. 4 
 Aug. 28 
 Nov. 6 
 Jan. 17 
 Nov. 23 
 Oct. 6 
 Sept. 17 
 Aug. 27 
 Feb. 12 
 Jan. 17 
 July 20 
 May 3 
 Nov. 1 
 Sept. 22 
 Sept. 1 
 Dec. 13 
 Sept. 22 
 
 16 days 
 
 18 days 
 
 19 days 
 
 20 days 
 
 20 days 
 
 21 days 
 
 2 1 days 
 
 2 1 days 
 
 22 days 
 22 days 
 27 days 
 30 days 
 30 days 
 30 days 
 
 33 days 
 
 3 7 days 
 38 days 
 41 days 
 
 2 1 days 
 20 days 
 30 days 
 24 days 
 32 days 
 20 days 
 30 days 
 
 22 days 
 36 days 
 18 days 
 
 
 
 
 2 
 
 
 
 
 3 
 4 
 
 26 days 
 
 46 days 
 
 
 
 5 
 6 
 
 30 days 
 26 days 
 
 24 days 
 
 
 7 
 
 
 
 8 
 
 27 days 
 
 
 
 9 
 
 
 
 10 
 1 1 
 
 16 days 
 
 27 days 
 
 
 12 
 
 
 
 
 
 13 
 
 
 
 
 
 I 4 
 
 
 
 
 
 15 
 
 
 
 
 
 16 
 
 
 
 
 
 17 
 
 
 
 
 
 18 
 
 
 
 
 
 
 
 
 
 
 A consideration of this table shows that tertian relapses occurred at periods 
 of from 16 to 41 days; the shortest period after the initial attack was 16 days, 
 
244 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 while Mariotti-Bianchi found that recurrences in benign tertian appeared as 
 early as live days and not later than iS. Of the 18 cases, relapse occurred in i 
 in 16 days; in i in 18 days; in i in 19 days; in 2 in 20 days; in 3 in 21 days; 
 in 2 in 22 days; in 1 in 27 days; in 3 in 30 days; in 1 in ^^ days; in 1 in 37 days; 
 in 1 in 38 days, and in 1 in 41 days. Secondary relapses occurred in 10 cases; 
 a third relapse in six cases; a fourth in three cases; and a fifth in one case. 
 No secondary relapse occurred if the primary relapse occurred more than 22 
 days after the initial attack, and, therefore, in tertian infections we may say 
 that if a relapse does not occur within a month after the initial attack there 
 is practically no danger of future recurrences. 
 
 A study of the two tables given enables us to conclude that in aestivo- 
 autumnal tertian infections, relapses occur most frequently between the twen- 
 tienth and fortieth days after the initial attack, and in benign tertian infections 
 between the fifteenth and twenty-second days ; during these periods of relapse 
 as they may be termed, quinine should be given in full therapeutic doses, and 
 increased to the point of cinchonism at the appearance of the first symptoms 
 indicative of a malarial attack. It should be remembered that quinine was 
 given in prophylactic doses, once a week, to nearly all the cases quoted in the 
 tables, and thus the occurrence of the relapses was undoubtedly delayed some- 
 what, which accounts for the difference in my results and those of others who 
 have studied the subject in cases uninfluenced by quinine. 
 
 Etiology of Recurrences and Latency. Intracorpuscular Conjuga- 
 tion. — The etiology of recurrent and that of latent, malarial infection should be 
 considered together, as an explanation of the one would necessarily explain the 
 other, since the infection must be latent in the system during the periods be- 
 tween the recurrences. Many investigators have endeavored to explain recur- 
 rence in malarial infections, but almost all of our knowledge of these subjects 
 is theoretical and incapable of proof. It is evident that the plasmodia must 
 exist in some form in the body during the intervals in which no symptoms are 
 present, and I have already shown, in considering the pathology of latent in- 
 fection, that plasmodia may be demonstrated in the spleen of patients who have 
 died from some other disease and in whom no symptoms of malarial infection 
 were ever present; these plasmodia did not differ in appearance from those 
 observed in the peripheral blood in acute malarial attacks, and, furthermore, 
 were undergoing normal schizogony within that organ, but in numbers insuffi- 
 cient to produce clinical symptoms. In such cases it may be urged that after a 
 certain period of multiplication the plasmodia become numerous enough to 
 produce symptoms of malarial infection, and thus a relapse may follow. While 
 this is undoubtedly true in some instances, it will hardly account for long- 
 interval relapses, for it is impossible to believe that the plasmodia of malaria 
 continue to grow and multiply for weeks, and even months, within the body of 
 man without becoming numerous enough to produce clinical symptoms. 
 
 To overcome this objection, Bignami considers that the plasmodium 
 exists in some latent form, perhaps encapsulated, in the spleen or other inter- 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 245 
 
 nal organ, which may not be rendered visible with our present staining methods, 
 and which, resting as a spore, is only set free under certain favorable conditions, 
 the nature of which we are ignorant. 
 
 Celli, in discussing this subject says, "How are these recurrences explained? 
 It is difficult to say; perhaps they depend on forms resulting from sexual multi- 
 plication that remain in some viscera — possibly the bone-marrow — and, from 
 time to time, invading anew the blood, give rise to new generations of the 
 asexual cycle." 
 
 Recently Schaudinn, in an excellent study of Plasmodium vivax, stated 
 that recurrences are due to parthenogenesis of the macrogametes which are not 
 fertilized by the micro gametes, and remain in the blood of the human host. 
 After a certain period of time these macrogametes liberate schizonts which pene- 
 trate the erythrocytes, undergo schizogony, and thus produce a relapse. This 
 process is completed in from 9 to 1:2 days, and, according to Zieman and 
 Mariotti-Bianchi, agrees with the period in which relapses are most frequent. 
 Schaudinn's observations have never been confirmed and it is difficult to under- 
 stand how such a process explains relapses occurring at irregular intervals as 
 shown in the tables given, where it is obvious that no regularity is present in the 
 development of either the primary relapse or of those succeeding it. How can 
 the parthenogenesis of the macro gamete, which must occur in a cyclical manner, 
 be the cause of relapses occurring all the way from 16 to 80 days after the 
 initial attack of fever ? I cannot confirm Schaudinn's results in this direction, 
 and believe, with Celli, that the cause of relapse in malarial infection is a 
 resistant form of the plasmodium which is capable of remaining unchanged in 
 the human body for considerable periods of time, and which, under favorable 
 conditions, undergoes development, thus giving rise to the symptoms which are 
 the evidence of a recurrence. I have been so fortunate as to be able to devote 
 much study to a form of development of the malarial plasmodia within man, 
 which is evidently asexual in its nature, and which results in the production of a 
 form of the parasite which I believe is the cause of latent and recurrent infections. 
 To this process I have given the name "intracorpuscular conjugation,' as it 
 consists essentially in the conjugation of two malarial plasmodia within the 
 infected red blood-corpuscle. 
 
 The Process of Intracorpuscular Conjugation. — In December, 1905, 
 I described a process of conjugation in the malarial plasmodia taking place 
 within the infected red cells. This process had been described previously by 
 Ewing, who considered it of rare occurrence and of comparatively little signifi- 
 cance. He noted that the process occurred in only a certain proportion of the 
 cases studied by him and that it occurs in the first generations of the infection. 
 He says: "It seems probable that conjugation occurs in the first generations of 
 infection, and becomes less frequent as the disease progresses, the infection in 
 the human host thereby tending to limit itself." The material for my own 
 studies upon this subject consisted of nearly 300 cases of malaria presenting 
 clinical symptoms, observed at the U. S. Army General Hospital Presidio, of 
 
246 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 San Francisco, Cal., together with over 100 cases of latent infection observed at 
 the same place; a series of 75 latent cases in Filipino children studied at Camp 
 Stotsenburg, and 96 cases of acute infection observed at that post and in 
 Manila; together with acute infections observed at Fort Leavenworth, Kansas. 
 As a result of my studies, which cover a period of nearly seven years, I have 
 become convinced that intracorpuscular conjugation is not an accidental oc- 
 currence of no essential importance in the life history of the malarial plasmodia, 
 but is a process which is most essential and one that occurs invariably in all 
 acute infections in which quinine has not been given at such a stage as to pre- 
 vent its occurrence. In this process I believe we have the true explanation of 
 latency and recurrence, and that where it does not occur the malarial infection 
 disappears. 
 
 Morphology of Intracorpuscular Conjugation. — This form of conjuga- 
 tion always occurs between two. young hayaline ring-forms and is always 
 completed before the formation of pigment begins. The process may be divided 
 for convenience of description into three stages: In the first stage, or stage 
 of protoplasmic union, the two young hyaline ring-forms, situated within a red 
 corpuscle, are seen to be in contact, and careful examination demonstrates 
 that at the point of contact there is a direct union of the protoplasm; in stained 
 specimens it will be noted that the nuclear chromatin of the two parasites is 
 separated at this stage and that union begins in the protoplasm of the plasmodia. 
 In this stage the chromatin masses may be situated at any portion of the per- 
 iphery of the two "rings," but they are very rarely seen in apposition at this 
 time. I have been unable to detect any differences in the appearance of the 
 two conjugating bodies, for while one may occasionally be a little larger than 
 the other, this is not so as a rule, and the chromatin masses are always of the 
 same size. 
 
 In the second stage, which may be designated as the stage of complete 
 protoplasmic union, the chromatin masses, still distinct, become situated in 
 the protoplasm of one organism, formed by the gradual union of the protoplasm 
 of the two; the chromatin masses may be opposite one another or at any 
 portion of the periphery of the organism, sometimes almost in apposition. 
 The complete union of the protoplasm of the two plasmodia results in a more 
 or less perfect "ring-shaped" organism, slightly larger than either of the 
 original plasmodia, containing two masses of chromatin, surrounded by achro- 
 matic substance. 
 
 The third stage of the process, or stage of chromatic union, is characterized 
 by the union of the two masses of chromatin, one large mass resulting. In 
 many cases a very minute granule of chromatin is extruded from the Plas- 
 modium before the chromatin union is complete. In stained specimens 
 the plasmodium resulting from this form of conjugation is larger than other 
 unpigmented plasmodia, and consists of a mass of protoplasm staining a 
 brilliant blue with Wright's stain, enclosing a very large and bright mass of 
 chromatin, surrounded by an unstained area. The resulting organism grows 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 247 
 
 rapidly, develops much pigment, and when fully grown, entirely fills the red 
 cells containing it, and eventually becomes free in the blood plasma. 
 
 Briefly stated, then, intracorpuscular conjugation consists in the complete 
 and permanent union of two unpigmented plasmodia within the red blood- 
 corpuscle. It is absolutely necessary, apparently, to the maintenance of 
 malarial infection in man, and in those instances in which it does not occur, 
 the plasmodia undergo asexual sporulation for a limited time and then perish, 
 thus causing spontaneous recovery. It is present most frequently in those cases 
 in which the clinical symptoms are most severe, and is present in all varieties 
 of malarial infection, whether caused by the tertian, quartan, or aestivo- 
 autumnal plasmodia, although most easily observed in the aestivo-autumnal 
 infections. 
 
 The Significance of the Process of Conjugation in the Protozoa in 
 General. — In order to understand the significance of intracorpuscular conjuga- 
 tion as it occurs in the malarial plasmodia, it is necessary to review briefly 
 the significance of this process as it occurs in the Protozoa in general. It may 
 be stated that conjugation has been observed at some stage in the life-history 
 of individuals belonging to all the classes of the Protozoa. In the Rhizopoda, 
 the Flagellata, the Sporozoa and the Infusoria organisms are found in which the 
 process of conjugation occurs and in which it has been thoroughly studied. 
 The morphological changes occurring in intracorpuscular conjugation of 
 the malarial plasmodia are similar to those occurring in the conjugation of 
 other protozoan organisms, and it is reasonable to believe that the significance 
 of the process is also similar. We already know that the plasmodia of malaria 
 undergo sexual conjugation during their development within the mosquito and 
 that this is absolutely essential to sporulation or the formation of the sporo- 
 zoites. However, in contradistinction to the form of conjugation just described 
 as intracorpuscular conjugation, the conjugating organisms are sexually 
 differentiated in the sporogony of the malarial plasmodia. In the mosquito, 
 as regards the malarial plasmodia, conjugation is a fertilizing process per se, 
 while intracorpuscular conjugation simply stimulates the organism to renewed 
 activity and to the formation of a resisting form of the parasite. 
 
 The process of conjugation in the Protozoa was first observed and de- 
 scribed by O. E. Muller. His work was confirmed by Balbiani, who claimed 
 that certain of the Protozoa not only reproduced by simple division but also 
 by conjugation, the latter being a sexual act leading to the formation of the 
 young parasites. It is to Biitschli that we owe the corrected interpretation of 
 conjugation in the Protozoa. He observed that continued reproduction of 
 many of these organisms by simple division led eventually to the exhaustion 
 of the capability of division, and thus to the death of the organisms. He, 
 therefore, regarded the process of conjugation as intended to bring about 
 . rejuvenescence of the nearly exhausted individuals of a generation of organisms. 
 Englemann confirmed the interpretation of Biitschli, and to-day his definition 
 of the process is accepted by all zoologists. Briefly defined, conjugation is a 
 
248 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 process intended to bring about a restoration of former reproductive activity 
 in exhausted organisms, this result being secured by a rejuvenescence of the 
 vital activities of the organism. 
 
 Calkins, in discussing this subject says: "The various conjugation phe- 
 nomena seen in the Protozoa seem to show that each cycle starts with a certain 
 potential of vitality which is gradually exhausted in the vegetable activities 
 of the long line of individuals formed by simple division or by spore formation." 
 It is to rescue such generations of organisms that conjugation occurs, but it 
 also leads, in many instances, to the production of resting and resistant forms 
 of the Protozoa. That it is not a reproductive act in many of the Protozoa is 
 shown by the fact that the time consumed in conjugation is sufficient for repro- 
 duction by simple division to occur many times; this is well illustrated in those 
 Protozoa in which a resting stage succeeds conjugation. 
 
 In reviewing the phenomena of conjugation in the Protozoa we find that 
 in many of them, after the union of the conjugants, a resting or zygote stage 
 results, which possesses greater resistance to injurious influences than the 
 original organisms, and in which they remain latent, so to speak, no further 
 development occurring until conditions are favorable for the existence of the 
 original parasites. 
 
 The conjugation of a protozoon within its intermediate host is purely 
 sexual in nature and is followed at once by reproduction. Such a type of con- 
 jugation should be clearly distinguished from that in which there is a union of 
 two individuals followed by a period of inactivity or a zygote stage. The sexual 
 type occurring in an intermediate host is well illustrated in the conjugation of 
 the micro- and macrogametes of the malarial plasmodia within the mosquito's 
 stomach, while intracorpuscular conjugation of the same organisms is a typical 
 example of asexual conjugation. It is apparent, therefore, that asexual con- 
 jugation is not a reproductive act, but one intended to preserve the function of 
 reproduction in a race of organisms threatened with extinction by repeated 
 division, or intended to evolve a resistant form of the organism when conditions 
 are unfavorable for reproduction in the ordinary way. 
 
 The Relation of Intracorpuscular Conjugation to Latent and Recur- 
 rent Malarial Infections. — Having thus briefly reviewed the significance of 
 conjugation in Protozoa in general, we are in a position to consider the signifi- 
 cance of that peculiar form of conjugation in the malarial plasmodia which I 
 have called intracorpuscular conjugation. The conjugation of malarial 
 plasmodia within the infected red blood-corpuscle is asexual, it being impossible 
 to detect any constant difference in the appearance of the two conjugants. It 
 occurs between two hyaline plasmodia and is completed, so far as can be seen, by 
 the permanent union of both protoplasm and nucleus. It occurs whenever the 
 generations of plasmodia are in danger of perishing from repeated sporulation 
 in the usual manner; it is therefore most frequently observed during the latter 
 part of the acute attacks, instead of before the appearance of clinical symptoms. 
 As I have stated, conjugation occurs in many if not almost all organisms, when 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 249 
 
 unfavorable conditions arise, such as exhaustion from repeated division, in- 
 sufficient nutriment, or the presence of conditions in the environment that are 
 unfavorable to growth in the usual manner; it has also been shown that under 
 such conditions a resting or zygote stage succeeds conjugation, in which the usual 
 vital activities of the organism are wholly or in part suspended until the condi- 
 tions again become favorable, when the vital activities are resumed and repro- 
 duction occurs as before. 
 
 If we consider carefully the phenomena of intracorpuscular conjugation as 
 seen in the malarial plasmodia it is evident that they conform to those observed 
 during conjugation in many of the Protozoa, and that, if there is any value in 
 analogy, the conditions leading to the process and its significance are similar. 
 Considered in this way, I believe that intracorpuscular conjugation is easily 
 explained, and that the theory of the etiology of latency and recurrence which 
 follows and which is based upon this process is one that is worthy of careful 
 study and one that is well supported by the known significance of conjugation 
 in other protozoan organisms. Intracorpuscular conjugation in malaria occurs 
 after a series of reproductions by spore-formation, during which time the initial 
 potential energy of the race of plasmodia has gradually declined; during this 
 same period the clinical symptoms of malaria have been present, and the en- 
 vironment of the plasmodia rendered unfavorable, perhaps by the administra- 
 tion of drugs, such as quinine; as a consequence, decreased ability to reproduce 
 by spore -formation leads to intracorpuscular conjugation, and the formation of 
 a resistant form of the plasmodium; the process occurs within the red blood- 
 corpuscle, because only here can nutriment be obtained for further development. 
 
 When conjugation is completed by the permanent union of the protoplasm 
 and nucleus of the two conjugants, growth occurs at the expense of the red 
 corpuscle, until finally the entire cell is destroyed, as in schizogony, and the 
 spherical pigmented organism is liberated; this form now, in all probability, 
 becomes encysted and enters upon a resting or zygote stage, and it is more than 
 probable that it is this stage that was considered by Schaudinn as a macro gamete 
 which by parthenogenesis gives rise to recurrences. The large pigmented 
 bodies are found in the peripheral blood in tertian and quartan infections at 
 any time after their formation, but are seldom seen in the peripheral blood 
 in aestivo-autumnal infections, being found in the spleen and bone-marrow. 
 They are difficult to distinguish from the macrogametes in tertian and quartan 
 fevers, although they are larger and contain less pigment and a greater amount 
 of chromatin, while in aestivo-autumnal infections they are distinguished from 
 the gametes by the absence of the crescentic shape. 
 
 This stage is probably more resistant to injurious influences, such as 
 quinine, than other forms of the plasmodia, and may continue unharmed in 
 one of the internal organs, as in the spleen, or the bone-marrow, for long periods 
 of time. When conditions are favorable the cyst (for, as has been stated, the 
 organism is probably encysted) ruptures, and liberates a generation of spores 
 which have developed within it; these young plasmodia penetrate the red 
 
250 LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 
 
 blood-corpuscles and undergo schizogony in the usual manner. Latency is 
 thus rendered possible by the resistance of the resting or zygote stage, and recur- 
 rences are due to the liberation of the young plasmodia which have developed in 
 the resting form, and their subsequent sporulation within the red corpuscles. 
 In cases in which this form of conjugation exists, numerous large pig- 
 mented plasmodia are present, both within and external to the red corpuscles, 
 which show no evidence at any time of segmentation or flagellation; in these the 
 pigment is small in amount and distributed throughout the protoplasm in an 
 irregular manner, in the form of very fine granules. In aestivo-autumnal infec- 
 tions these bodies are seen only in the blood obtained by splenic puncture, and 
 they are absent in cases in which this form of conjugation is absent. These 
 bodies probably become encysted and situated in some internal organ or in 
 the bone-marrow. The growth of the conjugating form within the red cell is 
 rapid until the destruction of the cell and the liberation of the organism; it 
 then enters upon the resting stage and the duration of this stage probably 
 varies with conditions present, but I believe lasts for several days at least. 
 
 Reasoning from analogy, this stage must continue for some time, for, 
 as has been shown by Biitschli, Maupas, and Hertwig, in the Protozoa, the two 
 conjugating organisms might by simple division give rise to many generations 
 during the time occupied in conjugation, and this is true of every organism in 
 which asexual conjugation occurs, so far as I know. It would, indeed, be 
 strange if the malarial plasmodia were exceptions to so general a rule, and 
 therefore it follows that the resting stage must continue for several days, 
 and that intracorpuscular conjugation, admitting that it produces this form of 
 the plasmodia, is the most probable cause of latency and recurrence. The 
 periods of time between relapses, which vary somewhat, but are remarkably 
 uniform when quinine has not been administered, are explained by the time 
 consumed in the completion of the process, of intracorpuscular conjugation, 
 and the development of the young plasmodia within the encysted zygote 
 while the marked irregularity in the period between relapses after quinine has 
 been administered, is explained by the liberation of the young plasmodia only 
 when the environment becomes favorable, i.e., when the quinine has been 
 discontinued, the quantity administered decreased, or when absorption of the 
 drug fails to occur. We thus see relapses quickly follow the discontinuance of 
 quinine in all malarial regions, and Celli, in his suggestion that relapses may 
 depend upon forms which remain inert in some viscera, stated what is in all 
 probability the true explanation of recurrences in malaria, the inert sexual 
 bodies of Celli being the zygote or resting form of the plasmodia, produced by 
 intracorpuscular conjugation. That such a latent or resting form of the malaria 
 plasmodia is present somewhere in the body in malarial infection, is proven by 
 the fact that the withdrawal of quinine in cases which have been taking it 
 for weeks is often promptly followed by a relapse, and the reappearance of 
 the plasmodia in the peripheral blood; it is impossible to believe that normal 
 schizogony has occurred in such instances for weeks, even when quinine has 
 
LATENT, MASKED AND RECURRENT MALARIAL FEVERS. 25 1 
 
 been administered in large doses, without producing symptoms, and while, 
 as I have already shown, in discussing the pathology of latent infections, 
 schizogony does occur within the spleen without symptoms being produced, 
 it should be remembered that in the patients in which this was observed no 
 quinine was being administered, and symptoms would probably have soon 
 appeared had the patients lived. The administration of quinine, even in very 
 moderate doses, has a very marked effect upon intracorpuscular conjugation 
 as observed in the peripheral blood, the conjugating plasmodia disappearing, 
 perhaps collecting in the spleen or bone-marrow, while in those cases in which 
 the process has not appeared it is never observed, if quinine be administered 
 promptly. This fact again is a strong argument in favor of the view that this 
 form of the plasmodia is the cause of recurrences, for it is well known that pri- 
 mary cases of malaria thoroughly and promptly treated with quinine seldom 
 relapse, while those which have been treated improperly or in which the in- 
 fection has lasted for several days are almost sure to suffer from one or more 
 relapses. 
 
 The large pigmented forms which result from conjugation show no 
 morphological changes after the administration of quinine, and it is evident 
 that this drug has no effect upon this form of plasmodia. 
 
 It should be remembered that the list of the Protozoa in which the life 
 cycle has been followed through an intermediate host is not very large, and, 
 therefore, our knowledge of the exact details of asexual and sexual conjugation 
 in any single organism, at all stages of its development, is very limited. Among 
 the Haemoflagellates recent research has confined the presence of asexual and 
 sexual conjugation in the life cycle of Trypanosoma lewisi; asexual conjugation 
 occurring in the blood of the rat has been studied in this organism by Bradford 
 and Plimmer, Doflein, and Stassano; and the researches of Prowazek prove 
 that sexual conjugation occurs in an intermediate host. This observer found 
 that Trypanosoma lewisi undergoes a portion of its life cycle within the rat 
 louse, Haematopinus spinulosum; after reaching the mid-gut of the louse, 
 reduction occurs in the nucleus, and male and femate gametocytes are formed, 
 which can be easily distinguished; sexual conjugation between these forms 
 follows, the zygote becomes an ookinete and this eventually results in a single 
 trypanosome, which again infects the rat and reproduces as usual. 
 
 From the researches of the investigators mentioned, it is evident that in 
 Trypanosoma lewisi asexual conjugation occurs in the blood of the rat and 
 sexual conjugation in the mid-gut of the rat louse, and it is probable that 
 further research will demonstrate that asexual conjugation is constantly 
 present in those Protozoa which require an intermediate host for the completion 
 of their life cycle, sexual conjugation occurring within the intermediate host, 
 and asexual conjugation within the definitive host. 
 
CHAPTER V. 
 
 Subcontinued or Remittent Malarial Fevers; Mixed Malarial Infection; Chronic 
 Malarial Infection and Malarial Cachexia; Spontaneous Recovery. 
 
 Any of the malarial fevers may become irregular or remittent in character 
 as regards the temperature, but the aestivo-autumnal infections are especially 
 prone to present irregularities in the fever, which in many instances are very 
 confusing. A malarial fever may become continuous, irregular, or remittent 
 in various ways, the principal of which are: anticipation or retardation of the 
 paroxysm; infection with more than one group of plasmodia or with more 
 than one species; and insufficient treatment with quinine. In most of these 
 infections, especially those due to the aestivo-autumnal plasmodia, it is very 
 seldom possible to demonstrate the entire schizogony in the blood, but in those 
 cases which are caused by mixed infections with more than one species of 
 Plasmodium, the species present may be easily demonstrated. It is these 
 forms of malaria which are so often confused with other diseases, such as 
 typhoid fever, in regions where malarial infections are rare. 
 
 Subcontinuous Fevers Due to the Tertian Plasmodium (Plasmodium 
 Vivax). — While the great majority of benign tertian fevers are regularly inter- 
 mittent in type, it is not so very unusual to observe irregular or even subcon- 
 tinued forms of tertian infection. Thayer and Hewetson describe a case of 
 tertian infection in which the diagnosis of typhoid fever was made and I have 
 seen a few cases in which the temperature curve was slightly remittent and the 
 cases were at first regarded as typhoid fever. Such cases are rare, it being much 
 more common to observe tertian cases in which a double infection is present and 
 in which the paroxysms are prolonged, thus resulting in a very atypical tempera- 
 ture curve. In these cases the temperature curve may show an almost con- 
 tinuous fever or it may resemble very closely that of a tertian aestivo-autumnal 
 infection. 
 
 An examination of the blood in cases of irregular or subcontinued tertain 
 fever generally shows numerous plasmodia in various stages of development. 
 
 The symptoms of the subcontinued form do not differ in character from 
 those usually observed in tertian infections, except that they are apt to be more 
 severe and in some cases resemble closely those of typhoid fever. 
 
 Subcontinuous Fevers Due to the Quartan Plasmodium (Plasmodium 
 Malariae). — Irregular and subcontinued fevers due to the quartan Plasmo- 
 dium are so rare as to be of little practical importance. I have observed but one 
 case of quartan fever in which the fever was of the subcontinued type, and 
 Marchiafava and Bignami state that while they have seen a few cases of ir- 
 
 252 
 
OTHER VARIETIES OF THE MALARIAL FEVERS. 253 
 
 regularly intermittent quartan fever they have never observed one showing a 
 continuous fever, although Antolisei and Feletti describe such cases. In the 
 case observed by myself the blood showed quartan plasmodia in all stages of 
 development and the symptoms were very suggestive of typhoid fever. 
 
 Subcontinued Fevers Due to the Aestivo-autumnal Plasmodia 
 (Plasmodium Falciparum and Plasmodium Falciparum QuotidianumJ.— 
 The vast majority of irregular and subcontinued malarial fevers are caused 
 by the aestivo-autumnal plasmodia, for in this variety of malarial infection 
 the development of the life cycle of the plasmodia is more apt to be atypical, 
 and multiple and mixed infections are observed more frequently I agree with 
 Marchiafava and Bignami in prefering the term "subcontinuous" to the terms 
 "remittent" and "continuous" so frequently used in connection with these 
 fevers. I have already mentioned the various ways in which a malarial in- 
 fection may become continuous or remittent, but will briefly recapitulate here, 
 as it is in the aestivo-autumnal infections that these causes are most frequently 
 operative: 
 
 1. The paroxysms may be prolonged so that they overlap each other, thus 
 causing a more or less continuous temperature curve. 
 
 2. The paroxysms may anticipate, one beginning before the preceding one 
 ends. 
 
 3. The paroxysms may be duplicated. 
 
 4. There may be a mixed infection with the quotidian and tertian aestivo- 
 autumnal plasmodia or with the benign tertian or the quartan plasmodium. 
 
 5. Quinine may be administered in such doses as to cause the temperature 
 curve to become atypical without curing the infection. 
 
 Subcontinued aestivo-autumnal infections may begin as such, which is 
 frequently the case, or they may gradually develop during a typical attack of 
 either the tertian or quotidian infection. When developing in the latter manner 
 they are generally easy of recognition, but when an aestivo-autumnal infection 
 begins as a subcontinued fever, it is often impossible to recognize it without an 
 examination of the blood, and, if the plasmodia are present in but small num- 
 bers, repeated examinations of the blood will have to be made. To depend 
 upon clinical symptoms in the diagnosis of subcontinued aestivo-autumnal 
 malaria is to attempt the impossible in most instances, and if there is one thing 
 in the medical history of this country which should teach the profession the 
 folly of attempting to diagnose the malarial fevers by the symptoms alone it is 
 the experience of our armies in the camps throughout the South in 1898 and 
 the experience of the British army in South Africa during the Boer War. 
 
 Symptoms. — The symptoms of the subcontinuous aestivo-autumnal 
 fevers vary considerably in different cases, and various types have been described, 
 as the typhoidal, the pneumonic, and the bilious, but such a classification is 
 loose and unscientific and undeserving of consideration. It is but rarely that 
 a case of subcontinued or remittent aestivo-autumnal fever is observed for a 
 period of time sufficient to gain an adequate idea of its symptoms and course, 
 
254 OTHER VARIETIES OF THK MALARIAL II VERS. 
 
 as quinine is generally given at the beginning of the attack and the disease ar- 
 rested. In those cases I have observed the symptoms have varied, but on the 
 whole resembled those of typhoid fever very closely at some time in the course 
 of the disease. The prodromal symptoms are generally weakness and malaise, 
 headache, dull pains in the muscles of the trunk and extremities, and loss of 
 appetite. The attack usually begins with slight chilly sensations, a distinct 
 chill being observed but rarely. The patient's appearance is often very sug- 
 gestive of early typhoid, the face being flushed, the eyes brilliant, the conjunc- 
 tivae congested, the mucous membranes hyperaemic, and the skin hot and dry. 
 Severe headache is present and pain in the muscles of the back and legs; the 
 patient is very nervous and restless, sleeping poorly and waking with a start, and 
 there may be slight delirium. The tongue is dry and coated and may resemble 
 very closely the tongue of typhoid, while nausea and vomiting are present and 
 diarrhoea is a frequent symptom. The pulse is rapid and dicrotic in character, 
 while the respirations are hurried and very often superficial. There is often 
 present marked tenderness over the abdomen, and the spleen is enlarged and 
 tender upon pressure. 
 
 In those cases which most closely simulate typhoid fever — the so-called 
 "typhoid pernicious malarial fever" — the resemblance is indeed startling — epis- 
 taxis, roseolar eruption, gurgling and tenderness in the right iliac fossa, the 
 cerebral symptoms and the headache, all being present in addition to the symp- 
 toms enumerated. Before the discovery of the malarial plasmodia such cases 
 caused much confusion, but there is no difficulty in diagnosing them to-day by the 
 aid of the microscope. It is to this class of cases that the term "typho-malarial 
 fever" has been applied by some observers, but the microscope has definitely 
 proven the falsity of this appellation, and we know that there is no such disease 
 entity as typho-malarial fever, although there may be a mixed infection with 
 typhoid and any of the malarial fevers. 
 
 The temperature curve in the subcontinued aestivo-autumnal fevers is 
 very variable, but there may usually be traced slight intermissions corresponding 
 to the termination of the paroxysms. In some cases, however, the curve much 
 resembles that of typhoid fever, there being slight daily remissions; this is es- 
 pecially true of the subcontinued fevers due to the quotidian plasmodium. 
 The chart shown is fairly typical of such a fever. (Chart No. 16.) 
 
 The duration of the subcontinued or remittent fevers may be several 
 weeks, but usually spontaneous recovery or death occurs within three weeks. 
 If properly treated, the symptoms are easily controlled within a week, although 
 in very rare instances the plasmodia may be very resistant to quinine and persist 
 for eight or ten days. An examination of the blood, if carefully made and 
 repeated, if necessary, will invariably demonstrate one or perhaps both of the 
 aestivo-autumnal stages of development. Very rarely a sporulating organism 
 may be seen in the peripheral blood. 
 
 The point of greatest importance to remember regarding subcontinued 
 forms of malaria is that these infections pursue a more or less continuous or 
 
OTHER VARIETIES OF THE MALARIAL FEVERS. 
 
256 OTHER VARIETIES OF THE MALARIAL FEVERS. 
 
 remittent course as regards the temperature, resembling typhoid fever or 
 other febrile processes clinically, and that the only way of quickly diagnosing 
 them is by the microscopical examination of the blood. These fevers are apt 
 to become pernicious at any time, and death may occur suddenly, so that a 
 prompt diagnosis and proper treatment is of the very greatest importance. 
 
 Mixed Malarial Infections. — Any of the species of the malarial plasmodia 
 may occur together, thus causing what is known as a mixed or combined 
 infection. Such infections are very common in some localities and are rare 
 in others, as would be expected. In those localities in which more than one 
 type of malaria is common, mixed infections are common, while in those in 
 which only one type of infection occurs, they will be absent or very rarely 
 occur as imported cases. 
 
 In 2,803 cases of malaria occurring in soldiers who contracted their infection 
 in Cuba and in the Philippines, I observed but 61 cases of mixed infection, 
 of which 51 were combined tertian and tertian aestivo-autumnal infections; 
 nine combined tertian and quotidian aestivo-autumnal infections; and one 
 a combined tertian and quartan infection. This is a very small percentage 
 of mixed infections, but is explainable by the fact that in most of the localities 
 in which these men had been, the aestivo-autumnal infections were practically 
 the only infections present, and thus the men did not become infected with 
 the other varieties. In mixed infections the temperature chart is apt to be 
 irregular or remittent, but very often one type of plasmodium may so predomi- 
 nate in numbers that the infection will present the characteristic symptoms 
 caused by that organism. Thus we may have combined infection with 
 aestivo-autumnal and tertian plasmodia in which the aestivo-autumnal plasmo- 
 dia are so much more numerous than the tertian, that the case will present the 
 symptoms of an aestivo-autumnal infection. As would be expected, some 
 very peculiar temperature charts are observed in these mixed infections, and 
 the symptoms are often so anomalous that a diagnosis cannot be made without 
 the aid of the microscope. 
 
 Chart No. 17 is a beautiful illustration of a case in which there existed 
 a combined infection with the tertian and the tertian aestivo-autumnal plasmo- 
 dium and in which the aestivo-autumnal and tertian paroxysms occurred 
 independently of one another. This is the only instance of the kind I have 
 ever observed and I believe that this chart is unique in the literature of the 
 malarial fevers. A blood examination in this case demonstrated the presence of 
 both species of plasmodium, and the life cycle of the tertian plasmodium could 
 be easily followed in the peripheral blood and correpsonded with the chart. 
 
 The Symptoms of Chronic Malarial Infection and Malarial Cachexia. 
 — I have already described the pathology of chronic malarial infection and 
 malarial cachexia and have spoken of the changes occurring in the blood in such 
 infections. 
 
 In patients who have suffered from repeated attacks of malarial fever, 
 which have not been properly treated, there develops a peculiar condition, the 
 
OTHER VARIETIES OF THE MALARIAL FEVERS. 
 
 257 
 
 H 
 
 H 
 
 O 
 
 17 
 
258 OTHER VARIETIES OF THE MALARIAL FEVERS. 
 
 most characteristic symptoms of which are a more or less severe anemia and a 
 greatly enlarged spleen. This so-called malarial cachexia is most frequently 
 observed in tropical regions in which the aestivo-autumnal infections are 
 endemic and least frequently in localities in which only tertian fevers are 
 present. It is especially apt to develop after latent and masked infections, 
 which have gone untreated because unrecognized. 
 
 While malarial cachexia is a common condition in natives of tropical 
 regions, and in Europeans who have long resided in such regions, it is by no 
 means as common as many writers would lead us to believe. Since the dis- 
 covery that kala-azar is a distinct disease, for instance, it has become necessary 
 to revise our conceptions of the pathology and symptomatology of malarial 
 cachexia, for kala-azar was long believed to be a chronic malarial infection 
 and many of our classical descriptions of that condition were based upon the 
 symptoms and pathology of kala-azar. We now know that the enlargement 
 of ihe spleen, which is used by some authorities as an index of malarial endem- 
 icity, can no longer be so used in India, for this is one of the constant and one of 
 the most important symptoms of kala-azar. We should be careful, then, in 
 making a diagnosis of malarial cachexia, remembering that other tropical 
 diseases produce symptoms resembling very closely those present in chronic 
 malarial infection, and that some of our most important symptoms may be 
 due to an unrecognized condition, as was the case with kala-azar. 
 
 Chronic malarial infection is characterized, as a rule, by repeated attacks 
 of fever and the gradual development of anaemia and an enlarged spleen. The 
 patients suffering from malarial cachexia present a peculiar yellowish or grayish 
 hue of the skin, or an earthy pallor, while the mucous membranes are very 
 pale, due to the anaemia which is invariably present. There is a loss of 
 appetite, diarrhoea, dyspnoea, emaciation, and a general condition of nervous 
 exhaustion. Between the febrile attacks the temperature may be normal, 
 but generally shows a slight rise toward evening; it seldom reaches 102 F. 
 The condition is especially frequent in children living in tropical localities. 
 It should be remembered that in many instances repeated attacks of malaria 
 do not produce the symptoms of malarial cachexia, and this is well illustrated 
 in our soldiers, hundreds of whom have suffered from numerous attacks of 
 malaria, but who have never developed the symptoms of cachexia, being, between 
 the attacks, in vigorous health and presenting no anaemia of consequence. 
 In many patients suffering from malarial cachexia, epistaxis and hemorrhages 
 into the mucous membranes are common symptoms, due to the hydraemic 
 condition of the blood, while in others albuminuria, oedema, and nephritis are 
 frequently observed. 
 
 The anaemia which is present in malarial cachexia partakes of the character 
 of a secondary anaemia, the red cells being reduced to 2,000,000 or less per 
 cubic millimeter, while there is a marked increase in the large mononuclear 
 leucocytes and a corresponding decrease in the haemoglobin. In some instances 
 the blood becomes so impoverished that a recurrent attack of the fever may 
 
OTHER VARIETIES OF THE MALARIAL FEVERS. 259 
 
 prove fatal, if the pla?modia are numerous, because of the added acute de- 
 struction of the red corpuscles, and after such an attack a pernicious form of 
 anaemia may develop. In such cases the blood findings differ from those of 
 primary pernicious anaemia in the absence of nucleated red cells and the slight 
 degree of poikilocytosis. 
 
 Enlargement of the spleen is a common condition in malarial cachexia, but 
 not an invariable one. I have observed many cases of chronic malarial in- 
 fection in which the spleen was but little, if any, enlarged. In old cases the 
 organ may be enormously enlarged, reaching as low as the crest of the ilium, but 
 as a rule it does not extend more than 4 to 8 cm. below the border of the ribs. 
 It is firm and not painful upon palpation. The liver is usually enlarged and 
 pain is often complained of over the hypochondria. 
 
 Neuralgic affections have long been considered by some observers to be due 
 to malarial poisoning, but I believe that it is only occasionally that malaria is the 
 cause of neuralgia. The long-continued malarial infection renders these 
 patients especially liable to acute infectious diseases and slight injuries are 
 often attended by suppuration, phlegmonous inflammation, or haemorrhage. 
 
 Marchiafava and Bignami state that it has never been their experience to 
 observe in patients suffering from malarial cachexia grave infections with many 
 parasites in the blood, but that there are always a few parasites and very little 
 melanaemia. I agree with them in this and would impress upon the student of 
 this subject that malarial cachexia cannot always be determined by a causal 
 examination of the blood, as the plasraodia will not be present in any number 
 except when acute symptoms are present and in many cases melanaemia may be 
 absent. 
 
 Spontaneous Recovery. — By spontaneous recovery we mean the disap- 
 pearance of a malarial infection without the intervention of medicines; in 
 other words, the cure of the infection by the infected individual. In the pre- 
 quinine days this was the way in which most malarial infections were cured, and, 
 as often happens, the physician received the credit due to Nature. To what, 
 then, when spontaneous recovery occurs, is it due? We are unable to answer 
 this question exactly, but some deductions may be drawn from the examination 
 of the blood in such cases, and the known facts regarding. the defensive agencies 
 of the human body. 
 
 The examination of the blood in cases which are undergoing spontaneous 
 recovery shows a gradual diminution in the number of the plasmodia present as 
 improvement occurs in the condition of the patient. Together with this diminu- 
 tion, which is progressive, there occur certain degenerative changes in the 
 plasmodia, such as vacuolation and fragmentation, and numerous pigmented 
 leucococytes, macrophages, and much free pigment appears in the blood. 
 Many times, in cases undergoing spontaneous recovery, the entire life cycle of 
 the plasmodium may be observed in the blood, in tertian and quartan fever, but 
 the organisms are so few in number that no symptoms of the infection are 
 observed. 
 
260 OTHER VARIETIES OF THE MALARIAL FEVERS. 
 
 Metchnikofi and his adherents have laid much stress upon the relation of 
 phagocytosis to spontaneous recovery, and although it is doubtless a factor in 
 the production of spontaneous recovery in malaria, there are other factors 
 present which arc doubtless of as great importance. It must, I think, be 
 admitted that the phagocytes, by destroying numerous plasmodia, and removing 
 from the blood large quantities of pigment and excrementitious matter, greatly 
 help in producing. recovery from the infection, but phagocytosis per se is not the 
 sole cause of spontaneous recovery, which is undoubtedly due to several factors, 
 some of which are active in one case and some in another. 
 
 According as we are followers of Ehrlich's or of Metchnikoff 's theory of im- 
 munity, we may explain differently the occurrence of spontaneous recovery in 
 malaria, but I believe that both theories should be applied in this instance, as 
 it is obvious that strict adherence to one does injustice to the other, and that 
 both present valuable evidence helping us to understand the process under dis- 
 cussion. For instance, there can be no question but that in malaria the phe- 
 nomenon known as phagocytosis is of immense importance in the production 
 of spontaneous recovery, and to entirely ignore it in favor of Ehrlich's views' 
 would be both unjust and unscientific. For this reason I have endeavored to 
 view this subject from a somewhat broader standpoint than is usual, and in 
 doing so I have been inevitably led to include both Ehrlich's and Metchnikoff's 
 theories in the explanation of the process. 
 
 I believe that spontaneous recovery in malaria may be brought about by the 
 following factors: 
 
 i. The presence in the blood serum of antiplasmodial and antitoxic 
 principles, preexistent in the serum or liberated by phagolysis of leucocytes, or 
 both. 
 
 2. Absorption of the malarial toxin or toxins by the leucocyte. 
 
 3. Formation and excretion of antiplasmodial and antitoxic materials by 
 the leucocytes. 
 
 4. Phagocytosis. 
 
 5. Inability to produce the "latent phase of the plasmodium" which may 
 depend upon any of the above factors or may be due to other causes. 
 
 6. A partial natural immunity, dependent upon the factors discussed in 
 the chapter dealing with Immunity. 
 
 In addition to the factors enumerated and which are of prime importance 
 in the production of spontaneous recovery, there are secondary factors which 
 are active in assisdng the natural body defenses, such as good nursing, good 
 food, rest and quiet, and the prevention of reinfection. 
 
 It is certainly most probable that there are present in the blood serum in 
 malaria certain antiplasmodial and antitoxic substances which serve to over- 
 come the infection, and that other substances of this nature are evolved during 
 the progress of the disease. The degenerative changes observed in the 
 plasmodia during spontaneous recovery are indicative of the existence of such 
 bodies, and while Mannaberg believes that the fever present is detrimental to 
 
OTHER VARIETIES OF THE MALARIAL FEVERS. 261 
 
 the growth of the parasites, this can hardly be so, for often the cases showing 
 the highest temperatures present large numbers of plasmodia, all of them in 
 normal condition; Marchiafava leans to the theory that in malaria, as in bacterial 
 diseases, the parasite gradually loses its virulence, but in opposition to this it 
 may be urged that the cause of malaria is not a bacterium, but belongs to the 
 animal kingdom, and that there is no evidence of such a diminution in virulence, 
 and even in the case of bacteria a diminution in virulence does not cause de- 
 generative changes in the organism. If, then, neither the fever nor diminished 
 virulence can result in degeneration of the plasmodia, it is, I believe, justifiable 
 to conclude that it is due to antiplasmodial substances existing either pre- 
 formed in the blood serum or produced in reply to the stimulation of the 
 plasmodia. The antiplasmodial bodies which produce degeneration and frag- 
 mentation of the plasmodia probably consist of plasmodicidal and plasmodilytic 
 bodies. 
 
 In addition to antiplasmodial bodies it is evident that antitoxic bodies 
 are present in many instances and thus are explained those cases in which 
 numerous plasmodia may develop for weeks without the appearance of 
 symptoms and those cases in which repeated infection has resulted in very slight 
 symptoms only, even though many plasmodia are present in the blood. The 
 origin of these antiplasmodial and antitoxic bodies is unknown, but according 
 to Metchnikoff may be the leucocytes or, according to Ehrlich, of indefinite 
 origin, being found only in the serum. 
 
 Phagocytosis has already been discussed, but it is evidently of great impor- 
 tance in the production of spontaneous recovery. The malarial plasmodia, 
 whether living or dead, are engulfed by the phagocytic cells and destroyed, 
 and though in many cases there exists an apparent decrease in the leucocytes 
 in the peripheral blood in malaria, we must remember that there is an increase 
 in the large mononuclear leucocyte, and that, after all, the decrease may be 
 only apparent, the greater number of the leucocytes being collected in the internal 
 organs, where they are acting as phagocytes. There is much anatomical evi- 
 dence in favor of this view, for in sections of the spleen and the bone-marrow, 
 the phagocytic cells are present in immense numbers in cases dying of 
 pernicious malaria. 
 
 The process of intracorpuscular conjugation, or, rather, its absence, is 
 of great importance in the production of spontaneous recovery. Unless the 
 resistant form produced by conjugation is present, the malarial infection will 
 disappear in time as the initial potential energy of the race of plasmodia will 
 become exhausted after a series of reproductions. When, therefore, for any 
 reason, intracorpuscular conjugation does not occur during a malarial infection, 
 spontaneous recovery must necessarily follow after a certain period of time. 
 
 I have already considered the factors at work in the production of immunity 
 and, where the immunity is only partial, these factors are of importance in the 
 explanation of the cause of spontaneous recovery. 
 
 Often, however, spontaneous recovery is thought to have occurred when, 
 
262 OTHER VARIETIES OF THE MALARIAL FEVERS. 
 
 in reality, it has not. The fever may disappear, together with many or all 
 of the clinical symptoms, only to be followed in a week or ten days by a relapse. 
 Often also after spontaneous recovery is thought to have occurred, an examina- 
 tion of the blood will demonstrate the presence of a few plasmodia, and these 
 may persist for weeks without causing any noticeable symptoms. Again, the 
 plasmodia may entirely disappear from the peripheral blood, but may be found 
 in numbers in the blood obtained by splenic puncture. In aestivo-autumnal 
 infections especially we should be very careful to draw a sharp distinction 
 between apparent and real recovery, and I am convinced, after a large experience 
 with these fevers, that it is impossible to say with certainty when a patient is 
 cured, for relapses occur so frequently that a guarded statement concerning 
 cure is always advisable. 
 
 Literature upon the Symptomatology of Malaria, Latent and Masked Malaria, 
 Recurrences and Intracorpuscular Conjugation. 
 
 The Symptomatology of Malaria. 
 
 The monographs upon Malaria already quoted. 
 1836. Maillot. Traite - des fievres intermittentes. Paris. 
 1882. Sorel. Recherches de la glycosurie d. les paludiques. Bui. d. 1. Accad. 
 
 de Med., ii, p. 5. 
 1882. Range. Paludisme et Diabete, Archiv. d. med. navale, p. 36. 
 
 1888. Mosse. Recherches sur l'excretion urinaire apres les aeces de fievres 
 intermittentes. Revue de med., viii, p. 944. 
 
 1889. Kelsch and Kiener. Maladies des pays chauds. Paris. 
 
 1892. Bowie. Spontaneous Rupture of the Spleen in Ague. The Lancet, 
 Sept. 17. 
 
 1895. De Brun. Etude sue le pneumo-paludisme, etc. Revue de Med., v, No. 
 1 1. 
 
 1896. Laveran. Paludisme. In Traite de Mddecine et de therapeutique, vol. 
 iii. Paris. 
 
 1896. Plehn, A. Beitrage zur Kentniss der tropischen Malaria in Kamerun 
 Berlin. 
 
 1897. Pasminik. Ueber malariapsychosen. Wien. med. Woch., Nos. 12-13. 
 1897. Osler. Malarial Fevers. In Allbut's System of Medicine, vol. ii, 
 
 London. 
 
 1897. Marchoux. Le paludisms ay Senegal. Ann. d l'institut Pasteur. 
 
 1898. Yarr. Malarial Affections of the Eye. Jour, of Trop. Med., Sept., p. 43. 
 1898. Rem-Picci. Sulle lesioni renali nella infezione malarica, II, Policlin. 
 
 Nos. 5-6. 
 1898. Thayer, W. S. On Nephritis of Malarial Origin. Am. Jour. Med. 
 Sciences, Nov. and Dec. 
 
 1898. Campbell. Malarial Peripheral Neuritis. Jour. Trop. Med., i, No. 5. 
 
 1899. Kipp. On Malarial Keratitis. N. Y. Med. Record, August. 
 
 1900. Spiller. A Case of Malaria Presenting the Symptoms of Disseminated 
 Sclerosis. Am. Jour. Med. Sciences, December. 
 
 1900. Osler. A Case of Multiple Gangrene in Malarial Fever. Bull. Johns 
 Hopkins Hospital. 
 
 1901. Bell, J. Malarial Coma. The Lancet, p. 527. 
 
OTHER VARIETIES OF THE MALARIAL FEVERS. 263 
 
 1 90 1. Cardamantis and Kanellis. Les troubles Psychiques dans le paludisme 
 Prog. Med. 
 
 1901. Daniels. Enlarged Spleens and Malaria. Thompson Yates Labora- 
 tory Reports, vol. iii, Part 2, p. 177. 
 
 1902. Mathis. Trois eas de polyne"vrites palustres. Revue de Med., xxii, 
 p. 105. 
 
 1903. Burns, W. B. Malarial Dysentery. Jour. Am. Med. Assoc., vol. xli, 
 No. 4, p. 246. 
 
 1903. Glogner. Ueber Darmerkrankungen bei Malaria. Virch. Archiv. Bd. 
 clxxi, Heft 2. 
 
 Literature upon Latency, Recurrences, and Intracorpuscular 
 
 Conjugation. 
 
 The monographs upon Malaria already quoted. 
 
 1900. Koch. Deutsch med. Wochenschrift, xxvi, p. 733. 
 
 1901. Bassett-Smith. Jour. Trop. Med., iv, No. 11, p. 178. 
 1901. Glogner. Virch. Archiv., clxvi, No. 1, p. 171. 
 
 1 90 1. Plehn, A. Weiteres iiber Malaria, Immunitat und Latenzperiode. 
 
 1 901. Stephens and Christophers. Rep. Malarial Com. Royal Soc, 3d ser., 
 p. 6. 
 
 1902. James. Scien. Mem. Officers Med. San. Depts. Govt. India, New Se- 
 ries, No. 2. 
 
 1902. Caccini. The Duration of the Latency of Malaria after Primary Infec- 
 tion, etc., Jour Trop. Med., Apr. 15, p. 119; May 1, p. 13; May 15, p. 
 151; June 1, p. 172; June 15, p. 186. 
 
 1903. Craig, C. F. American Med., vi, p. 145; ibid., 1904, viii, p. 757 ; ibid., 1905, 
 x, pp. 982, 1029. 
 
 1903. Schilling. Ein Malariarezidivn, etc., Deutsche med. Wochenschr., No. 10. 
 
 1903. Mariotti-Bianchi. Reforma med. Rome, xix, p. 313. 
 
 1903. Schaudinn. Arb. a.d. kaiserl. Gesundheitsamte, xix, p. 169. 
 
 1903. Ewing. Clinical Pathology of the Blood. New York, p. 454. 
 
 1904. Strasser and Wolf. Ueber Malariarezidiv., Blatter fur klinische 
 Hydrotherapie, No. 3. 
 
 1906. Zieman. Handbuch der Tropenkrankheiten, Mense. Leipzig. 
 
 1906. Craig, C. F. Latent Malarial Infection and Intracorpuscular Conjuga- 
 tion. Philippine Jour, of Science, i, p. 523. 
 
 1907. Craig, C. F. A Study of Latent and Recurrent Malarial Infection and 
 the Significance of Intracorpuscular Conjugation in the Malarial Plas- 
 modia. Jour, of Infectious Diseases, vol. iv, No. 1, Jan. 1, pp. 108—140. 
 
PART IV. 
 
 THE SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF THE 
 
 MALARIAL FEVERS. 
 
CHAPTER I. 
 
 The Sequelae of the Malarial Fevers. 
 
 If we consider the lesions produced by malarial infections in the blood and 
 viscera in pernicious cases and the extensive changes occurring in the blood in 
 all instances of malarial infection, we can easily understand the reason for 
 the occurrence of many grave sequelae of these infections. Properly 
 speaking, the sequelae of a disease are those affections developing after the 
 disease itself has ceased and which are due to poisons generated during the 
 course of the disease. The toxins elaborated during the development of the 
 malarial plasmodia within man may give rise to certain conditions which 
 develop coincident with or after the malarial infection has ceased, and these 
 must be regarded as sequelae of the disease. It is not always easy to differen- 
 tiate sequelae from complications, for in many instances a certain morbid proc- 
 ess will develop during an attack of malaria and it will be impossible to say 
 whether or not it is the result of the malarial infection or is simply a complica- 
 tion of the disease. In such instances we must depend upon a careful clinical 
 survey of the case and the recorded experience of others in deciding the question. 
 
 The sequelae of malaria affect almost every organ and tissue in the body 
 and will be considered under the following headings: Sequelae affecting the 
 Nervous System, the Circulatory System, the Digestive System, the Genito- 
 urinary System, the Glandular System, and the Organs of Special Sense. 
 
 1. Sequelae Observed in the Nervous System. — Sequelae are not in- 
 frequently observed in the nervous system due to the blocking of the brain 
 capillaries by the malarial plasmodia or their products or to certain toxins 
 produced by the plasmodia, and are especially numerous following the aestivo- 
 autumnal infections. In many instances the conditions are evanescent in 
 character, but in others they may persist for months. Such a case I recall, in 
 which a paresis of one side of the face developed during an aestivo-autumnal 
 attack, which persisted for two months after the disease was apparently cured. 
 
 Not uncommonly, after severe malarial attacks, the mind appears to be 
 sluggish and inactive, memory being very defective, and sometimes an almost 
 stuporous condition may be present. While focal neuroses are uncommon in 
 my experience, they are described by many observers as of frequent occurrence. 
 Thus Mannaberg describes cases of hemiplegis, aphasia, paraplegia and mono- 
 plegias. Sensation may be diminished or there may be marked hyperasthesia. 
 Boinet and Salabert report a case of motor aphasia, which continued a month 
 after the malarial infection was cured, and from which recovery finally ensued. 
 Vincent reports an interesting case in which there was paralysis of the extensors 
 
 267 
 
268 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 of the right hand and aphasia following malaria, while Sacchi reports cases of 
 amaurosis and loss of the sense of taste and smell. I have observed two cases 
 in which aphasia was present, but both recovered. 
 
 Affections of the spinal cord are very rare as sequelae of the malarial 
 fevers. Paraplegia is the most common form observed, accompanied by 
 either loss of sensation or hyperasthesia. I have observed one case in which 
 there was a paraplegia, with partial paralysis of the rectum and bladder. 
 Marchiafava and Bignami describe cases in which the symptoms were those 
 of bulbar paralysis. 
 
 It is probable that some of the cases reported as suffering from setpielae of 
 malaria affecting the spinal cord have been instances of infection with other 
 diseases, as beriberi and syphilis. In tropical regions especially, where both 
 malarial infections and beriberi are present, this mistake is very likely to 
 occur. 
 
 A condition almost indistinguishable from multiple sclerosis has been 
 described by Torti, Angelini, Bignami and Bastianelli and Canalis, as occurring 
 after attacks of aestivo-autumnal malaria. In these cases the symptoms disap- 
 peared after treatment with quinine, but relapses occurred in some of them. 
 Kahler and Pick describe an ataxic condition, or pseudotabes, occurring as a 
 sequela of malaria. 
 
 Affections of the peripheral nerves are not uncommon, and many observers 
 have reported cases of neuritis following the malarial fevers. Boinet and 
 Salabert report a case in which there was atrophy of the muscles, diminution of 
 the tendon reflex, and neuritis. Multiple neuritis has been described as follow- 
 ing aestivo-autumnal malaria by Gowers, Raymond, and Jourdan. Glogner has 
 studied very exhaustively several cases of polyneuritis following malarial fever, 
 the symptoms consisting of severe pain in the lower extremities, increased by 
 pressure; formication; motor weakness in the legs; partial or total loss of the 
 deep reflexes; partial or total loss of response to electrical stimulation, and 
 oedema. His observations have been confirmed by those of Chiarini and 
 Bardellini, in Rome, and there can be no doubt that polyneuritis may be a 
 sequel of the malarial infections. 
 
 Bastianelli, Bignami, and Chiarini have described cases in which symp- 
 toms similar to those of electric chorea or "Dubini's disease" followed aestivo- 
 autumnal malarial infections. 
 
 Neuralgia is a common sequelae of malaria infections, although it should be 
 added that it is not as common as is generally supposed. Many cases of so- 
 called" malarial neuralgias" have in reality no connection with malaria, and 
 the name is used as a cloak for ignorance of the etiology of the affection. The 
 regions most frequently affected by true malarial neuralgia are the face and the 
 lumbar region. I have observed one case of severe intercostal neuralgia follow- 
 ing aestivo-autumnal infection, one case of severe abdominal neuralgia, and one 
 case of very severe sciatica following a tertian aestivo-autumnal attack. In all 
 of these cases continued treatment with quinine resulted in recovery. 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 269 
 
 Neurasthenia not infrequently is observed following attacks of malaria, 
 and in our soldiers many instances of this condition were observed during the 
 Philippine insurrection. While it is true that hardship, anxiety, home- 
 sickness, and the depressing influences of a tropical climate had a great in- 
 fluence in the production of these cases, it must be admitted that there were 
 numerous instances in which the condition did not develop until after repeated 
 attacks of malaria, and that the continued and vigorous use of quinine resulted 
 in the recovery of most of them. 
 
 Melancholia, mania, and delusional insanity occur as sequelae of the 
 malarial infections. Manson, Segard, and Pasminik, as well as other observers, 
 have described cases of insanity following malaria, uncomplicated by heredity 
 or alcohol. Pasminik in 5,400 cases of malaria observed mental disturbances in 
 to6 cases. Melancholia and delusional insanity are the most common forms 
 occurring as sequelae of malaria, and the duration of the cases varies from less 
 than a week to six months or more. In very many cases the mental depression 
 occurring with and following the paroxysms is very great, and it is a very com- 
 mon occurrence for patients who have suffered from malaria to complain for 
 weeks afterward of suffering from "the blues" or of ill-defined forebodings; an 
 exaggeration of this condition becomes melancholia which I have found to be 
 the most common mental disturbance following malaria. I have observed 
 many cases of slight melancholia in soldiers in the Philippines and returning 
 therefrom, which were undoubtedly due to repeated malarial infection, generally 
 of the aestivo-autumnal type, and it has been remarkable how quickly the con- 
 dition disappeared under the proper administration of quinine. I have also 
 seen cases of mania and delusional insanity following malaria in which there 
 can be no question that the condition was due to the malarial infection. 
 
 Persistent insomnia often occurs after malarial infection, especially among 
 Europeans who are residing in the tropics, and it is sometimes very resistant to 
 treatment. 
 
 2. Sequelae Observed in the Circulatory System. — It may be said 
 with truth that malaria has but little effect upon the heart and blood-vessels. 
 Lancereaux has endeavored, without success, to prove that acute endocarditis 
 may be caused by malaria, and he and Huchard claim that chronic arteritis is 
 often of malarial origin. Their arguments are illogical and they furnish no con- 
 vincing proof of the truth of their assertions. It is certainly a fact that no such 
 sequelae have been described by those who have studied malarial infections in 
 tropical regions and it is evident that if such sequelae were present they would 
 have been reported by many different observers. When these diseases occur 
 with malarial infections they are complications and not sequelae. 
 
 3. Sequelae Observed in the Digestive System.— As a result of the 
 localization of the plasmodia in the mucous membrane of the stomach or in- 
 testine, a true acute or chronic ulcerative enteritis may result, and, very rarely, 
 the formation of gastric ulcers. Parotitis has been described by Lancisi, but I 
 have never observed a case. Mannaberg describes haemorrhage from the 
 
2 JO SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 bowels in malarial cachexia, and Pensuti reports one case in which there was 
 atrophy of the mucous membrane of the stomach. From the results of a large 
 number of autopsies upon patients dying of chronic dysentery, most of whom 
 had suffered previously from malarial infection, I am very much inclined to 
 doubt the occurrence of such cases as that described by Pensuti, as even in the 
 cases autopsied, which were certainly very liable to such changes, atrophy of the 
 mucous membrane of the stomach was not common. 
 
 I have already noted the occurrence of dysenteric symptoms in many cases 
 of malarial infection and following such infections. It is my belief that dysen- 
 teric symptoms are often due to the localization of the plasmodia in the mucous 
 membrane of the intestine, and that in rare instances chronic dysentery may be 
 a sequela of such infections. 
 
 4. Sequelae Observed in the Genito-urinary System. — Albuminuria 
 is of very common occurrence along with and following malarial infections, 
 especially of the aestivo-autumnal type. As a rule, it is a complication of 
 malaria rather than a sequela, but I have seen several cases in which a persistent 
 albuminuria resulted from malarial infection, no other renal symptoms being 
 present. Rem-Picci has contributed much to our knowledge of this subject, 
 and he divides the albuminurias into the febrile, which occur with the malarial 
 paroxysms, or follow them at once, and the postmalarial, which persist after the 
 malarial attack and occur in malarial cachexia. 
 
 Nephritis both in an acute and chronic form may occur as a sequela of 
 malaria, especially after aestivo-autumnal infections. That even chronic 
 nephritis may be induced by repeated malarial attacks has long been believed 
 by such observers as Rosenstein, B artels, Laveran, Herz, McLean, and Kelsch 
 and Kiener. The latter authorities describe two forms of kidney affections 
 following malarial infection, one characterized by a congested kidney, the other 
 by an atrophic kidney. They describe two forms of nephritis, the glomerular 
 and the granular. The glomerular form is divided into acute and chronic, the 
 first developing during or immediately after the acute malarial infection, the 
 second during chronic infection. The clinical symptoms are those of acute 
 and chronic parenchymatous nephritis. The granular form is also divided into 
 acute and chronic, the first developing in patients who have suffered from 
 numerous relapses of malaria, the clinical symptoms being those of subacute 
 and chronic interstitial nephritis. 
 
 Rem-Picci, in his exhaustive and most valuable study of nephritis following 
 malaria, divides the condition into acute and chronic forms, the first developing 
 either during or after the malarial infection, the second developing insidiously 
 after the malarial attack. The acute form may be severe or slight in character 
 and varies in duration. As a rule, the prognosis is good. He finds that it is 
 most common in aestivo-autumnal infections in autumn or winter, and in young 
 rather than in old people. The chronic form is a true interstitial nephritis, 
 which may develop without a previous acute attack. It is much more rare than 
 is the acute form. 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 2 h Jl 
 
 Thayer, in a valuable study of malarial nephritis, states that of 112 cases of 
 acute nephritis observed in the Johns Hopkins Hospital, 21, or 18.7 per cent., 
 were of malarial origin. He observed four cases of chronic nephritis following 
 malarial infection in 1,832 patients suffering from malaria, and in 758 cases of 
 malarial fever treated in the wards of the hospital he found that 17.5 per cent, 
 presented casts of the urinary tubules in the urine. He found that nephritis 
 was much more common in aestivo-autumnal infections than in either tertian 
 or quartan, occurring in 4.7 per cent, of aestivo-autumnal infections as com- 
 pared with only 2.3 per cent, of all other infections combined. 
 
 From personal observation I believe that some form of nephritis follows 
 aestivo-autumnal infection in at least 3 per cent, of all cases, but that it does not 
 follow tertian or quartan infections except in rare instances, not over 0.5 of 1 
 per cent, of my tertian and quartan cases showing nephritis as a sequela. In all 
 fatal cases of malaria some form of nephritis will invariably be found. Nephri- 
 tis following malaria may be divided into subacute parenchymatous, chronic 
 parenchymatous, and chronic interstitial forms, and these forms do not differ in 
 their symptomatology from such conditions as observed when occurring alone or 
 as a complication or sequelae of other diseases. The chronic forms may 
 develop insidiously, but the subacute form is always preceded by an acute 
 attack. Amyloid degeneration may occur in certain cases of parenchymatous 
 nephritis. 
 
 From my own observations I would say that casts of the urinary tubules 
 occur in 25 per cent, of the cases of aestivo-autumnal malaria, and in 5 per cent, 
 of all cases of benign tertian and quartan malaria, but that only a comparatively 
 small number of these cases develop nephritis. 
 
 Polyuria is a frequent sequela of the malarial fevers, especially of the 
 aestivo-autumnal variety, transient as a rule, but in some cases very persistent. 
 I have observed a large number of cases of polyuria following malarial infection, 
 and in some instances the condition was very marked. In one case the amount 
 of urine passed during the 24 hours varied from 20,000 to 25,000 cubic centi- 
 meters, and this condition existed for several weeks. 
 
 Glycosuria is a very rare sequela of aestivo-autumnal infection, so rare that 
 there is good reason to doubt its occurrence. Marchiafava and Bignami re- 
 port a case in which glycosuria developed during malarial cachexia, but there is 
 no proof that the condition was due to malaria. 
 
 5. Sequelae Observed in the Glandular System. 
 
 The Liver. — In cases which have suffered from repeated attacks of 
 malaria, especially the aestivo-autumnal fevers, a condition known as hyper- 
 trophic malarial hepatitis develops, characterized by enlargement of the organ, 
 the perilobular tissue being increased, and the capillaries markedly dilated. 
 This condition, however, does not cause much disturbance in the functional 
 activity of the organ, and no clinical symptoms are present which are 
 characteristic. 
 
 Typical atrophic cirrhosis of the liver is, I believe, very rarely the result of 
 
2-J2 SEQUELAE, COMPLICATION'S, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 malarial infection. Many observers differ upon this point, but there is no 
 evidence sufficient to prove that cirrhosis is often the result of such infection. 
 It is, of course, present in some cases, but generally occurs as a complication due 
 to some other cause. That this is so is evidenced by the fact that cirrhosis of the 
 liver is no more common in intensely malarial regions than it is in immune 
 districts. 
 
 The Spleen. — I have already mentioned the enlargement of the spleen 
 occurring in patients who have suffered from repeated malarial attacks, and to 
 this enlargement are due certain other interesting sequelae of malarial in- 
 fection, such as floating spleen and rupture of the organ. 
 
 In rare instances the enlarged spleen, by its weight, sinks into the abdominal 
 cavity, the ligaments holding it in place become stretched, and the organ can be 
 felt as a movable mass through the abdominal walls. The condition is known 
 as wandering or floating spleen. The symptoms are pain upon movement, a 
 feeling of weight in the abdomen, and reflex disturbances, such as headache, 
 nausea, and vomiting. 
 
 In acute or subacute infections the spleen is generally very soft and 
 friable, and rarely this leads to rupture of the organ. This result may be 
 induced by blows, falls, retching in vomiting, or sudden movements of the 
 body. The capsule may be lacerated or there may be a slight tear in one 
 region. Laceration of the capsule only occurs when the rupture is due to 
 violence. The symptoms are sharp, lancinating pain in the left side, and the 
 usual signs of collapse due to hemorrhage. Death may occur almost in- 
 stantly, or a day or two may pass before the fatal ending, depending entirely 
 upon the extent of the laceration and the consequent hemorrhage. I have 
 observed two cases of rupture of the spleen and one case has been reported to 
 me by Captain Banta, of the Medical Corps of the U. S. Army. The occur- 
 rence of abscess of the spleen has been reported, following malarial infection, 
 by Laveran and other observers. Fassina has collected seven cases in the liter- 
 ature and saw two himself. Without doubt such abscesses have resulted from 
 bacterial invasion, although the malarial infection may have produced condi- 
 tions favoring the infection. The symptoms have been pain, swelling, the 
 formation of a tumor, fever, and diarrhoea. Rupture of the abscess may 
 occur. 
 
 Lymphatic Glands. — Martin and Bodnar describe enlargement and sub- 
 acute inflammation of the lymphatic glands as sequelae of chronic malarial in- 
 fection, accompanied by intermittent or remittent fever. I have never observed 
 such cases, and believe that they may have been confused with cases of climatic 
 bubo, glandular fever, or syphilis. It should also be remembered that in 
 infected regions, sleeping sickness, in its early stages, and kala-azar might 
 easily be considered as chronic malarial conditions and the enlargement of the 
 glands present in these diseases be regarded as of malarial origin. 
 
 Orchitis and epididymitis have been described as sequelae of malaria by 
 Berthelon, Martin, Magnin, and others, but a careful examination is sufficient 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 273 
 
 to prove that many of these cases are based upon untrustworthy evidence, 
 although I believe that a case such as that reported by Zieman, in which no 
 other cause could be demonstrated and the malarial plasmodia were found 
 in the blood, proves that such a condition may very rarely occur. The cases 
 reported in which there is good reason to believe that the cause was really ma- 
 larial presented a remittent fever, with enlargement of the testicles and the 
 epididymis, and some pain and inflammatory swelling; the symptoms were 
 easily controlled by quinine, but the enlargement lasted in some of the cases 
 for months. 
 
 6. Sequelae Observed in the Organs of Special Sense. 
 
 The Eye. — Affections of the eye are not uncommon as sequelae of malarial 
 infections, especially in the tropics and following aestivo-autumnal infections. 
 I shall mention briefly the most important. 
 
 Amaurosis. — In severe malarial attacks amaurosis sometimes occurs 
 during the attack, but it also occurs as a sequela. One of the first instances 
 of this kind was reported by Jacobi, in 1868, and Chiarini has since reported 
 several cases in which there was optic neuritis. The more chronic condition 
 may be followed by partial or total loss of vision by reason of atrophy of the 
 optic nerve. 
 
 Retino choroiditis has been described by Poncet as occurring in chronic 
 malarial infections, and Guarnieri has given in detail the pathological lesions 
 observed in such cases. He found that the retinal capillaries contained red 
 corpuscles entirely, many of them containing pigmented plasmodia. In the 
 choroid he found the larger vessels filled with pigmented leucocytes and 
 many of the leucocytes contained parasite-infected red corpuscles. 
 
 Keratitis. — In 120 cases of malaria observed in the United States, Kipp 
 found keratitis to be present, and Poncet, and Sedan and Levrier have seen 
 similar cases. 
 
 Vitreous Humor. — Bull reports 17 cases in which haemorrhage had oc- 
 curred into the vitreous humor, and Seely and, later, Sulzer, described serous 
 engorgement of the vitreous followed by almost total blindness. The lesion 
 consists in a serous infiltration of the vitreous, and is seen as a whitish cloudiness 
 of that body. In one of Seely's cases recovery occurred under quinine. 
 
 Suppurative choroiditis is described in one case by Pennoff, terminating in 
 destruction of the eye. 
 
 Paralysis of the power of accommodation has been noted by Bull as the 
 result of malarial infection, and spasm of the accommodation by Stilling. 
 
 The Ear. — Certain affections of the ear have been ascribed to malaria, but 
 only a few can be regarded as really due to the malarial infection. Intermittent 
 otalgia occurs as an expression of chronic malarial infection and is relieved in 
 such cases by quinine. Frank, Politzer, and De Rossi have recorded cases of 
 this character; intermittent attacks of deafness due to lesions of the internal ear 
 or the auditory nerve brought about by malarial infection have been reported by 
 Bar, Wolff, and Ferreri, but there is always, in such cases, the possibility that 
 18 
 
2J4 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 the deafness was really due to quinine, although some of the cases described by 
 these observers were undoubtedly due to the malarial infection. 
 
 Labyrinthine vertigo occurs as the result of malarial poisoning and has been 
 very carefully studied by Ferreri. In one case the patient, who had suffered 
 from slight symptoms of aural trouble for some time, had an attack of fever and 
 some time afterward an attack of deafness, ringing in the ears, and vertigo of so 
 severe a type that he fell; this was followed by three similar attacks and the 
 examination of his blood showed the presence of aestivo-autumnal plasmodia. 
 Treatment with quinine cured the condition in two months. 
 
 The cases of suppurative otitis media mentioned by Liel, Hotz, and De 
 Rossi, cannot be considered as due to malarial infection, for the malarial 
 plasmodia are not pyogenic organisms and there is no well authenticated in- 
 stance upon record of any suppurative process due to these parasites. 
 
 The special senses of taste and smell are not affected by malarial infection. 
 
 Miscellaneous Sequelae. — Pigmentation of the skin is a very common 
 result of malarial infection, and in some instances is so marked as to closely 
 simulate Addison's disease. It is probable that much of the pigmentation of 
 the skin following malaria of Europeans in the tropics is as much due to the 
 tropical sunlight as to the malarial infection, for it is a common experience 
 to observe decided pigmentation of the skin brought about by residence in a 
 tropical country. 
 
 Gangrene. — Fischer and Sarda have reported severe cases of dry gangrene 
 following intense malarial infection, but such a condition must be very rare. 
 
 The changes observed in the subjects of malarial cachexia have already 
 been considered. 
 
 Postmalarial Anaemia. — An anaemia, pernicious in character, and 
 presenting the same blood findings as are found in cases of primary pernicious 
 anaemia, occurs very rarely as a sequela of malarial infection. I have observed 
 but one such case, but in this case the findings in the blood were exactly similar 
 to those found in primary pernicious anaemia and I believe that the condition 
 was the direct result of malarial infection. 
 
 In the aestivo-autumnal forms of malaria the anaemia produced by 
 repeated attacks may be very severe and very persistent. In the tertian and 
 quartan fevers the regeneration of the blood is very rapid as compared with the 
 aestivo-autumnal fevers, and in the latter the number of red blood-corpuscles 
 may reach a very low level. I remember several cases in which the number of 
 red cells was not over 900,000 per cubic millimeter, and one in which the blood- 
 count showed but 497,000 red corpuscles per cubic millimeter. I have already 
 discussed the anaemia following the malarial infections, especially that of 
 pernicious character, and will not reconsider the subject here. 
 
 In reviewing the subject of the sequelae of the malarial fevers I have in- 
 cluded only those sequelae which are of importance and which occur with 
 enough frequency to merit description. There are many sequelae which have 
 been reported from time to time, by various authors, which I have not spoken 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL LEVERS. 2?5 
 of, partly because they are of such rare occurrence as to },, r f 
 
 fever, it does not ^ w Si, "dt "to thT I f* ", ^ ° f """^ 
 careful in our conclusions reg^ng th e elfe fZ "f ™ ^ '" "' 
 ditions following the malariaf fevers ^ ^ ^^"^ a " d con " 
 
 
 II 
 
CHAPTER II. 
 
 The Complications of the Malarial Fevers. 
 
 The malarial fevers may be complicated by or associated with many 
 other diseases, and in some instances it would appear that the malarial infection 
 is responsible for certain of the complications, but the old theory, first advocated 
 by Boudin, that all malarial complications were due to the malarial poison, has 
 long since been abandoned. The malarial plasmodia are not the cause of a 
 lobar or bronchopneumonia complicating malaria nor of a typhoid which may 
 be coexistent with it; in each case the complicating disease is due to its specific 
 organism, and though the course and clinical symptoms of either disease may be 
 more or less altered by their association, yet their etiology remains unchanged. 
 In other words, there is no such thing as a typical lobar pneumonia due alone to 
 the malarial plasmodia or a peculiar form of typhoid fever caused by these 
 organisms. 
 
 Of the many diseases which may complicate the various forms of malaria, 
 and especially the aestivo-autumnal infections (for these infections, being more 
 severe in character than the tertian and quartan, are more apt to be accompanied 
 by complications), the following may be mentioned: 
 
 Complications Observed in the Nervous System. — Coincident with the 
 malarial fevers there may occur attacks of acute mania, such cases having been 
 described by Yanarris, but this complication is very rare. Hysteria is a com- 
 mon complication in nervous women, and even in men, and, as in hysterical 
 attacks in general, the symptoms vary greatly in character and severity. 
 Paraplegia and hemiplegia may rarely complicate these fevers, and neuroses of 
 various kinds are not uncommon. Meningitis may occur as a complication. 
 
 Complications Observed in the Respiratory System. — The most com- 
 mon complication observed in the respiratory system is acute bronchitis. A mild 
 form of this affection is observed in very many cases of malaria, probably due 
 to the infection per se, but not infrequently a severe form of bronchitis will 
 complicate our malarial cases and may persist for weeks after the infection has 
 disappeared. 
 
 Both lobar and lobular pneumonia occur as complications of the malarial 
 fevers, the first being by no means a rare complication. Early observers held 
 that the pneumonia sometimes accompanying malaria was directly due to the 
 malarial plasmodia, but recent investigations have conclusively shown that these 
 organisms are unable to produce a true pneumonitis. The pneumonic symp- 
 toms which appear in certain cases are undoubtedly due to the localization of 
 the plasmodia in the lungs, and I have already described the form of pernicious 
 
 276 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 277 
 
 malaria in which the symptoms are chiefly referred to the lung and are practi- 
 cally identical with those of lobar pneumonia, but a microscopical exami- 
 nation of sections of the lung in such cases shows that the lesions present differ 
 considerably from typical of lobar pneumonia. 
 
 Lobar pneumonia may complicate the malarial fevers at any time, and may 
 develop suddenly or insidiously. In some instances the course of the disease 
 is similar to that in a patient in whom no malarial infection is present, while 
 in others, the course of the pneumonia is interrupted by chills and exacerbations 
 of fever due to the malarial infection. The pneumonic symptoms may mask 
 the malaria, or vice versa. The prognosis in pneumonia complicating the 
 aestivo-autumnal fevers is very grave, Ascoli placing the mortality as high as 
 60 to 78 per cent, in patients who have suffered from repeated attacks of malaria. 
 Death may occur from thirty-six to seventy-two hours from the initiation of the 
 pneumonic symptoms. 
 
 Broncho-pneumonia or lobular pneumonia occurs as a complication less 
 frequently than lobar pneumonia and resembles in its pathology the form 
 produced by the plasmodia more closely than does lobar pneumonia. Clini- 
 cally, the two conditions (typical lobular pneumonia and the form produced by 
 the plasmodia) cannot be distinguished. 
 
 In cases of pneumonia complicating malaria which recover, the convales- 
 cence is generally verj slow, resolution being greatly delayed. An empyema 
 may result in rare instances. Not rarely the affected portions of the lung become 
 fibroid, and a chronic fibroid pneumonia results, or bronchiectasis may occur. 
 
 Pneumonic septicaemia has been described by Bignami, Marchiafava, 
 and Nazari as complicating malaria. This condition appears in patients 
 suffering from long-continued malarial infection who have developed pneumonia, 
 and has only been observed in aestivo-autumnal infections. 
 
 In malarial patients in whom pneumonia has occurred as a complication, 
 the latter disease is very apt to terminate in delayed resolution; a typhoid state, 
 followed by death; pneumococcic septicaemia or induration. All of these 
 terminations are frequent in patients who present the symptoms of malarial 
 cachexia. 
 
 Pleurisy has been reported by Hertz as a complication of the malarial fevers, 
 but it is a very rare one. 
 
 Tuberculosis. — The old belief that tuberculosis and malaria were 
 antagonistic and that they seldom occurred together has been proven false, and 
 we now know that both diseases are very commonly associated and that fatal 
 cases of malaria may occur in patients suffering from tuberculosis. Marchia- 
 fava claims that "if the malarial infection attacks organisms affected by 
 tuberculosis, the latter is not arrested, but acquires a tendency to spread, and 
 produces miliary tuberculosis." This statement is interesting and in my 
 experience true, for I have repeatedly observed miliary tuberculosis in malarial 
 subjects, and the number of instances of miliary tuberculosis discovered at 
 autopsy in patients who were also the victims of severe malarial infections, has, 
 
278 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARLA.L FEVERS. 
 
 in my experience, been remarkable. I have repeatedly seen cases diagnosed as 
 pulmonary tuberculosis in which there were physical signs of cavity formation 
 and consolidation, and which later developed severe malarial infection. At 
 autopsy, besides the presence of cavities and large areas of consolidation, a 
 severe miliary tuberculosis was found, thus proving, I believe, the truth of 
 Marchiafava's contention, that malarial infection in the subjects of tuberculosis 
 stimulates the formation of miliary tubercles. The same authority claims 
 that, unlike other cachexias, malarial cachexia does not predispose to tubercu- 
 losis. In view of the effect of malarial infection upon existing tuberculosis, it 
 is obvious that such infection should be promptly recognized and eliminated. 
 
 If quinine be administered to a patient suffering from any of the compli- 
 cations mentioned, it will be followed by the cessation of the malarial symptoms, 
 and the complicating process will run its usual course. 
 
 Complications Observed in the Circulatory System. — Any of the 
 organic diseases of the heart may complicate a malarial infection, and in severe 
 aestivo-autumnal infections the prognosis may be exceedingly grave. Acute 
 endocarditis may occur as a complication, but is never due to malarial infections, 
 as has been claimed by Lancereaux. The ulcerative form of endocarditis may 
 occur following a pneumonic complication. A systolic murmur is often present 
 in severe malarial infections, and functional disorders are very common. A 
 slow pulse during convalescence is very frequently observed, sometimes counting 
 but forty beats to the minute. 
 
 Complications Observed in the Genito-urinary System. — The most 
 common complication observed in the genito-urinary system isnepJiritis. While 
 albuminuria is very common, it can hardly be called a complication, as it is un- 
 doubtedly due to the malarial infection and is so common as to constitute a 
 symptom of the disease. Thus Thayer, in 691 cases of malaria, found albu- 
 minuria in 321 instances, or 46.4 per cent. In my own experience I have found 
 albuminuria in at least 50 per cent, of all cases. It is most frequently observed 
 in aestivo-autumnal infections; thus Thayer found that in tertian and quartan 
 infections it occurred in 38.6 per cent, of all cases, while in aestivo-autumnal 
 infections it occurred in 58.3 per cent, of all cases. My own figures confirm 
 those of Thayer as regards tertian and quartan infections, but I have found 
 that at least 65 per cent, of aestivo-autumnal infections show albumin in the 
 urine and that the condition is always present in fatal malarial infections. 
 
 Some form of nephritis occurred as a complication in at least 4 per cent, of 
 the aestivo-autumnal cases I have observed, and in one-half of 1 per cent, of 
 tertian and quartan infections. Very often the nephritis is an acute one, due 
 directly to the malarial infection, as is proven by the disappearance of the condi- 
 tion after the cessation of the malarial attack, but not infrequently a chronic or 
 subacute nephritis, already existing, complicates the malarial infection, and in 
 such cases the prognosis is often grave. Thayer states that among 1,832 cases 
 of malarial fever observed at the Johns Hopkins Hospital, acute nephritis was 
 present in 26 instances, in all but three instances undoubtedly due to the ma- 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 279 
 
 larial infection. Of these cases four died, one from the malaria] infection, the 
 others as the result of the nephritis. It will thus be seen that this complication 
 is sometimes a fatal one and that in the majority of instances it is caused by the 
 malarial infection. A further discussion of nephritis as a result of malarial 
 infection will be found in the chapter dealing with the sequelae of the malarial 
 fevers. 
 
 Orchitis and epididymitis may occur as complications of the malarial fevers, 
 but a history of gonorrhoea is usually to be obtained. These complications are 
 especially common among soldiers, and neither condition appears to be ag- 
 gravated by the malarial plasmodia. In some cases of epididymitis the tem- 
 perature chart is rendered atypical because of the fever accompanying the 
 genital condition. The cases of orchitis described by Maural, Calmette, 
 Schmidt, and others are open to serious question, as being due to malarial 
 infection, although very rarely such a condition may occur. 
 
 Gangrene of the penis, the scrotum, and the labia has been described by 
 Mannaberg as complicating or following malarial infection. These conditions 
 might easily occur as complications, but I believe that it is very doubtful if they 
 occurred as the result of malarial infection. 
 
 Complications Observed in the Gastrointestinal Tract. — The most 
 frequent and important disease of the gastrointestinal tract complicating 
 malaria is dysentery, either amoebic or specific, or some form of enteritis. In 
 patients returning to temperate regions from the tropics where either specific or 
 amoebic dysentery is epidemic or endemic, it is very common to observe the 
 coexistence of these diseases with malaria. In the case of soldiers returning 
 from the Philippine Islands, as observed at the U. S. Army General Hospital 
 at San Francisco, over 65 per cent, showing malarial plasmodia were also 
 suffering from either chronic specific dysentery or amoebic dysentery. Of these 
 cases 25 per cent, were suffering from amoebic dysentery, as shown by the 
 presence of Entamoeba histolytica in the faeces. The combination of these two 
 protozoan infections, malaria and amoebic dysentery, is very common in the 
 Philippine Islands, and the malarial infection appears to aggravate the dysen- 
 teric condition. When malaria is complicated by dysentery, or vice versa, the 
 dysenteric symptoms are aggravated, and the prognosis is much worse than 
 when either disease occurs alone. The symptoms of malaria are often masked 
 by those of dysentery, or the malarial infection may be latent. The administra- 
 tion of quinine in patients suffering from malaria complicated by dysentery, not 
 only removes the malarial infection, but, in the majority of instances, markedly 
 benefits the dysentery condition, and a return to health is more rapid. The 
 explanation of this fact is not hard to find. We know from pathological studies 
 that the mucous membrane of the intestine is generally invaded by the malarial 
 plasmodia, which invasion must necessarily injure the vitality of the tissues; 
 removal of the plasmodia by quinine aids the tissues in regaining their normal 
 vitality, and thus indirectly improves the dysenteric condition. 
 
 In a certain proportion of patients suffering from malarial infection in 
 
280 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARLA.L FEVERS. 
 
 which dysenteric symptoms are present, the latter symptoms are undoubtedly 
 due to the localization of the plasmodia within the capillaries of the intestine, 
 as I have already shown, and in such patients the administration of quinine 
 is rapidly followed by complete recovery. 
 
 Typhoid Fever. — The complication of malarial infection by typhoid 
 fever is a most important and interesting one, which will be fully considered in 
 the following chapter. 
 
 Cholera may complicate malaria, and such instances have been described 
 by Bastianelli and Sternberg. I have autopsied several Filipinos who had 
 died of cholera in whom the spleen showed evidence of malarial infection, but I 
 have never observed a case clinically in which cholera and malaria coexisted. 
 There is no reason to doubt, however, that cholera complicates malaria fre- 
 quently during widespread cholera epidemics. 
 
 Acute Infections Complicating Malaria. — Almost all of the acute 
 infectious diseases have been reported as complicating malaria. Smallpox, 
 measles, diphtheria, Malta fever, erysipelas, acute articular rheumatism, and 
 streptococcic septicaemia have all been observed during malarial attacks, and it 
 is probable that such cases occur much more frequently than we have supposed 
 in regions in which malaria is prevalent. 
 
 Miscellaneous. — To Sternberg and to Kelsch and Kiener we owe the 
 knowledge that insolation is a frequent complication of the malarial fevers, 
 and that it often aids in the production of a pernicious attack. Exposure to 
 the sun's rays in a person debilitated by repeated malarial paroxysms is very apt 
 to be followed by sunstroke, and it is well known that such exposure is very 
 efficient in bringing out the symptoms of malaria in cases in which the infection 
 is latent. I have often observed that a drill in the tropics is followed by the 
 admission to the military hospital of many cases suffering from malaria, develop- 
 ing, in those so exposed, during or immediately after the drill, and in m\ ex- 
 perience more than one pernicious attack of malaria was preceded by pro- 
 longed exposure to the rays of the tropical sun. It is now generally admitted 
 that an individual who has suffered from repeated attacks of malaria is much 
 more sensitive to the sun's rays than one who has not, and that insolation is very 
 apt to occur in such cases. 
 
 Puerperal women who have suffered from attacks of malaria are more 
 liable to complications, such as puerperal fever, hemorrhages, and abortion, than 
 are those free from such infection, because of the anaemia invariably present, 
 and the lowered vitality of the tissues. Abortion complicates malarial infection 
 frequently in regions where the aestivo-autumnal fevers are prevalent, and it 
 has long been known that abortion is much more frequent in malarial countries 
 than in others. Thus Weatherley, who has given this subject careful study, 
 found that in the East Indies as many as 46.6 per cent, of pregnant women 
 aborted, while in England only 3.56 per cent, aborted. Of course these figures 
 are likely to be only approximate, but they demonstrate the fact that in malarial 
 regions abortion occurs much more frequently than in immune localities. 
 
SEQUELAE, CONPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 281 
 
 In the tropics the malarial infections may be complicated by infe< tion 
 with any of the animal parasites so commonly found in such regions. A 
 combined infection of malaria and Anchylostoma duodenalis or Necator ameri- 
 canns is frequently observed, and is always a serious condition, as both parasites 
 produce anaemia. Combined infections of malaria and fdariasis have been 
 reported several times and are probably of a very common occurrence in regions 
 where filariasis is prevalent. Infections with Schistosoma haematobium and 
 Paragonimus westermanii sometimes complicate the malarial fevers and greatly 
 delay recovery from the malarial infection. I have already discussed the 
 frequent association of the malarial plasmodia and Entamoeba histolytica and 
 called attention to the importance of recognizing this complication. 
 
 Of other diseases which may complicate the malarial fevers may be men- 
 tioned diabetes mellitus, sciatica, tonsillitis, parotitis, and various skin diseases. 
 Any of the chronic diseases affecting the viscera may complicate the malarial 
 fevers and in many instances render the prognosis very grave. 
 
 Malaria as a Puerperal and Postoperative Complication. — A malarial 
 paroxysm often follows parturition in women who have become infected, and 
 pernicious symptoms may develop in such cases unless the infection is promptly 
 treated. It is also well known that a latent malarial infection is often made 
 manifest by an operation or by trauma, and in malarial regions many post- 
 operative fevers are malarial even though quinine may have been administered 
 in small doses as a prophylactic. In fevers arising during the puerperium and 
 following wounds and operations it should always be remembered that a micro- 
 scopical examination of the blood is indicated, especially in malarial regions or 
 in patients who have resided in such localities; such an examination will often 
 remove a load of anxiety from the mind of the obstetrician or surgeon, and 
 frequently result in the saving of the life of the patient. 
 
 Literature upon the Sequelae and Complications of the Malarial Fevers. 
 
 1856. Morehead. Clinical Researches on Diseases in India. London. 
 
 1857. Griesinger. Infections Krankheiten. Virchow's Handbuch der spec. 
 Path. u. Therapie. 
 
 1868. Jacobi. Zwei verschiedene Falle von Neuritis optica. Archiv. f. 
 
 Opthal., 14, p. 149. 
 1875. B artels. Krankheiten des Harnapparates. Ziemssens Handbuch 
 der spec. Path., vol. ix. 
 
 1877. Bull. American Journal Medical Sciences, p. 413. 
 
 1878. Poncet. Retino choroidite palustre. Annal. oculistique, Maj^. 
 
 1879. Bodnar. Ueber Bubo malaricus. Pester med-chir. Presse, No. 47 
 1879. Levrier. Accidents oculaires dans les fievres intermittentes. Thesis 
 
 d. Paris. 
 1879. Kahler and Pick. Beitrage zur Pathologie und pathol. Anatomie des 
 
 Centralnervensystem. Leipzig, p. 61. 
 1882. Fayrer. On the Climate and Fevers of India. London. 
 1882. Kelsch and Kiener. Les alterations paludeennes des reins. Archiv. 
 
 de Physiologie normale et pathologique. 
 
282 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 1883. Maurel. Traite des maladies paludeennes a la Guyane. Paris. 
 
 1885. Seely. A Second Case of Serous Effusion into the Vitreous Humor, etc., 
 Proc. Amer. Oph. Society. 
 
 1SS6. Petit and Verneuil. Asphyxie locale et gangrene palustres. Rev. 
 de chirurgie, No. 3. 
 
 1886. Hertz. Malariainfectionen. Ziemssen's Handbuch. d. spec. Pathologie 
 u. Therapie, Leipzig. 
 
 18S6. Schmidt. Observations d'orchite paiudeenne. Arehiv. de med. et 
 
 pharm. Mil.,' No. S. 
 18S6. Rosenstein. Pathologie und Therapie der Nieren-krankheiten, 3d. 
 
 Ed., Berlin. 
 1886. Segard. Rapport medical de la Creuse a Madagascar. Arch. d. med. 
 
 navale, 46, p. 5. 
 
 1886. Berthelon. Orchites paludeennes primitives. Arch, de med. et de 
 phar., mil., October. 
 
 1887. Berthelon. Ann. des mal. org. gen.-urin., p. 312. 
 
 1887. Charvot. Etude clinique sur l'orchite paiudeenne. Bull, et mem. de la 
 
 Soc. de chir., p. 597. 
 1887. Magnin. Sull' orchite d'origine palustre. Gaz. med. Ital. Lombard, 
 
 No. 42. 
 
 1887. Canalis. Etude sur un cas de sclerose en plaques, etc. Gaz. hebd. de 
 Med., p. 554. 
 
 1888. Sacchi. Sulla paralisi da malaria. Neurol. Centralbl. No. 7, p. 634. 
 18S9. Kipp. Further Observations of Malarial Keratitis. N. Y. Med. Record, 
 
 August. 
 
 1889. Martin. Aerztliche Erfahrungen iiber die Malaria der Tropenlander, 
 Berlin. 
 
 1889. Fassina. Des abces de la rate dans les maladies infectieuses, etc., Thesis 
 de Paris, No. 230. 
 
 1889. Kelsch and Kiener. Maladies des pays chauds. Paris. 
 
 1890. MacNamara. Malarial Neuritis and Neuroretinitis. Brit. Med. Jour., 
 P- 54o. 
 
 1890. Schellong. Die Malaria Kranheiten in Kaiser Wilhelms Land. Berlin 
 
 1890. Sulser. Klin. Monatsblatter fur Augenheilkunde. 
 
 1891. Lancereaux. Du Paludisme. Bull, med., p. 959. 
 
 1 89 1. Marchiafava and Bignami. Malaria. Twentieth Century Practice, 
 vol. xix, New York. 
 
 1892. Torti and Angelini. Infezione malarica cronica coi sintorni della 
 sclerosi a plache. Bull, della Soc. Lancisiana. 
 
 1892. Raynaud. Troubles oculaires de la malairia. Thesis de Paris, No. 166. 
 1894. Boinet and Salabert. Les troubles moteurs dans 1'impaludisme. IX 
 
 Internat Med. Congress. Rome, vol. iii, p. 82. 
 1896. Vallin. Bull, de l'acad. d. med., xxxv, p. 366. 
 1896. Metin. Un cas. de polynevrite d'origine paiudeenne. Arch. d. med. 
 
 navale, No. 66. 
 1896. Grocco. A Proposito dell' emoglobinuria da chinina nei malarici. 
 
 Arehiv. ital. di clin. med., p. 716. 
 
 1896. Senator. Erkrankungen der Nieren. Nothnagles Treatise. Vienna. 
 
 1897. Pasminik. Ueber Malariapsychosen. Wiener med. Wochenschrift, 
 
 P- 5*7- 
 
 1898. Thayer. On Nephritis of Malarial Origin. Trans. Assoc. Am. Phys. 
 
 1899. Edmonds. Malaria and Pregnancy. Brit. Med. Jour., Apr. 29, p, 1023. 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 283 
 
 1902. Daniels. Notes on Malaria and Other Tropical Diseases. Brit. Guinea 
 
 Med. Ann., No. 1, p. 40. 
 1902. Bernheim. Tuberculose et paludisme. Rev. internationale de la tuber- 
 
 culose, p. 894. 
 
 1902. Davidson. Carcinoma and Malaria. Brit. Med. Jour., vol. i, p. 77. 
 
 1903. Moore, J. T. Postoperative Malaria, etc., N. Y. Med. Record, vol. lxiii, 
 p. 291. 
 
 1905. Tsuzuki. Ueber die Sekundare Infektion mit Frankelschen Pneumo- 
 kokken bei Malariakranken. (Malariapneumonie.) Archiv. f. Schiffs- u. 
 Tropen-Hyg., Bd. ix, p. 442. 
 
 T905. Mannaberg. Malaria. Nothnagel's Practice. English Trans, Phil. 
 
 1907. Craig, C. F. The Malarial Fevers, in Osier's "Modern Medicine," 
 vol. i, Philadelphia. 
 
CHAPTER III. 
 
 Coincident Typhoid and Malarial Infection. 
 
 The simultaneous occurrence of typhoid and malarial fever is a subject 
 of much interest to investigators, and one which has given rise to much contro- 
 versy, and has evoked many varying opinions from eminent authorities. Dur- 
 ing the war of the Rebellion a great number of cases of fever were observed 
 which did not answer to the typical characteristics of either typhoid fever or the 
 malarial fevers, and Woodward, a Major Surgeon of the Union Army, designated 
 such fevers as "typho-malarial" fever, a classification accepted by the Army 
 authorities. From July i, 1862, until June 30, 1866, there were reported to the 
 Surgeon-General's office 57,400 cases of typho-malarial fever, with 5,360 
 deaths. Woodward, in thus designating these fevers, never intended that the 
 name"should indicate a disease entity, but a hybrid condition, brought about by 
 the combination of typhoid and malarial infection, and differing clinically 
 from either of these diseases. Thus, in a paper read before the International 
 Medical Congress at Philadelphia, in 1876, he stated: 
 
 "I never meant this term (typho-malaria) to represent a specific type of 
 fever, but intended it to designate all the many-faced brood of hybrid forms 
 resulting from the combined influence of the causes of malarial fever and of enteric 
 fever." 
 
 Again. he says: 
 
 "And this brings me at length to answer the question, Is typho-malarial 
 fever a special type of fever? and I reply unhestitatingly that it is not. I, at 
 least, am free from the blame of that error, if anyone has fallen into it." 
 
 Unfortunately, many practitioners did fall into the error of regarding 
 typho-malarial fever as a distinct disease and the term soon became of common 
 diagnostic use, and was the cause of great confusion in the study of the con- 
 tinued fevers. Too often it was employed to cover ignorance of the condition 
 present and even to-day a diagnosis of typho-malarial fever is not infrequently 
 made in long-continued fevers in which uncertainty exists as to the exact nature 
 of the infection. For this reason the term should be abandoned, for research 
 has demonstrated that while typhoid fever may be complicated by malaria, and 
 vice versa, there is no reason for applying a special name to the combination, 
 and clinically the cases do not present any characteristic group of symptoms. 
 
 While a great number of coincident infections with typhoid and malarial 
 fever have been reported in the literature of medicine, very few have been 
 studied scientifically, and since the discovery of the plasmodia of malaria and 
 
 284 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 285 
 
 the Widal test there have been but a small number of cases reported in which 
 the diagnosis was rendered certain by the use of laboratory methods. 
 
 Historical. — Prior to the use of the Widal test in the diagnosis of typhoid 
 fever numerous observers had reported cases in which the malarial plasmodia 
 were found in the blood and in which, after the disappearance of these organisms, 
 the fever persisted and presented the symptoms of typhoid. Laveran was 
 probably the first to mention such cases, describing two, in one of which inter- 
 mittent fever occurred during convalescence from typhoid, and another in which 
 the malarial fever preceded and followed the typhoid. Kinyoun described 
 several cases in 1899, dividing them into those in which the malarial symptoms 
 predominated and those in which the symptoms of typhoid were most prominent. 
 Other cases have been reported by Thompson, Osier, and Vincent. While 
 most of these cases were undoubtedly instances of coincident typhoid and 
 malarial infection, and the malarial plasmodia were demonstrated in the blood 
 of the patients, in none of them was the Widal test applied, nor were the typhoid 
 bacilli separated from the excreta, so that an element of doubt exists regarding 
 some of the cases. 
 
 The only cases in which we can be sure that such a coincident infection 
 occurs are those in which one of the malarial plasmodia can be demonstrated 
 in the blood, and at the same time some substantial proof of the existence of 
 typhoid, as the separation of the bacilli from the blood, rose spots, or excreta, or 
 a positive reaction to the Widal test, can be shown to exist. Applying such tests 
 the number of cases of coincident typhoid and malarial infection which have 
 been reported are surprisingly few, and I believe that while the combination of 
 these diseases is much more common than the number of cases reported would 
 lead us to believe, still the condition is a rare one when we consider the chances 
 of such infections in localities in which both diseases are prevalent. 
 
 Frequency of Occurrence. — The researches of Lyons and of Reed, 
 Vaughn, and Shakespeare prove that coincident typhoid and malarial infection 
 is of rare occurrence. Lyons, in 1900, collected all of the cases of coincident 
 typhoid and malaria on record in which the plasmodia were found in the blood 
 and sufficient proof existed that typhoid fever was present, and found that 
 they only numbered 29 in all. In the classical report upon the "Spread of 
 Typhoid Fever in the United States Military Camps during the Spanish War 
 of 1898" by Reed, Vaughn, and Shakespeare, which included data up to 1904, 
 there are collected 95 cases in which these diseases coexisted, but only 12 are 
 reported as occurring during the active stage of the typhoid fever. Curry, who 
 examined the blood of hundreds of cases of typhoid during the same war found 
 only one case in which malaria occurred during the active symptoms of typhoid, 
 and Ewing, at Montauk Point, observed no case in which such infection occurred, 
 although he saw many cases of typhoid develop malaria during convalescence. 
 As the result of his observations he concludes that typhoid and malaria are 
 incompatible, the malarial symptoms apparently being held in abeyance by 
 the coexisting typhoid infection. Da Costa reports three cases of coexistent 
 
286 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARLAL FEVERS. 
 
 typhoid and malaria, Muehleck, live cases, and Witherington, three cases in 
 which the malaria was coincident with the active symptoms of typhoid. 
 
 In my own experience, covering the observation of hundreds of cases of 
 typhoid fever, and thousands of malarial infection, I have seen but ten instances 
 of coincident typhoid and malarial infection. It should be understood that 
 I regard as coincident infections only those in which the malarial paroxysms 
 occur during the active symptoms of typhoid and not during convalescence. 
 It is not at all uncommon to observe the occurrence of malarial paroxysms 
 during convalescence from typhoid or preceding that disease, but such instances 
 cannot be considered as true examples of coincident infection. 
 
 From the data given it is evident that coincident infections with typhoid 
 and malaria are rare, and that while cases do occur, their number is insignificant 
 when compared to the number of cases of typhoid and malaria observed in the 
 endemic areas of these diseases. There is, I believe, good reason for think- 
 ing that there does exist a certain amount of incompatibility between the two 
 infections, for it is frequently observed that when typhoid develops in a patient 
 suffering from malarial fever, the malarial symptoms disappear, as well as the 
 Plasmodia from the peripheral blood, and only reappear during convalescence 
 from the typhoid. 
 
 Species of Malarial Plasmodium Present. — Any of the species of 
 malarial plasmodia may be present in coincident typhoid and malarial infection, 
 but Plasmodium vivax has been most frequently observed. In 44 cases collected 
 by Reed, Vaughn, and Shakespeare, the tertian plasmodium occurred in 22 
 the aestivo-autumnal in 12, the tertian and aestivo-autumnal in 9, and the 
 quartan in one, a case reported by the writer. In the 10 cases observed by 
 myself, six were infected with the tertian aestivo-autumnal plasmodium, three 
 with the tertian plasmodium, and one with the quartan plasmodium. 
 
 Symptomatology. — It may be stated that there are no characteristic 
 symptoms of coincident malarial and typhoid infection, every case differing 
 somewhat in this respect. The occurrence of the malarial complication is 
 generally evidenced by a chill, but in the aestivo-autumnal infections the chill 
 may be absent, the patient complaining only of slight chilly sensations. The 
 fever may show a sudden exacerbation and in some instances every malarial 
 paroxysm may be clearly seen upon the temperature chart, owing to the sudden 
 rise in the temperature curve. This is beautifully illustrated in the chart given 
 of coincident typhoid and quartan malaria and also in that illustrating a 
 coincident typhoid and aestivo-autumnal infection. Paroxysms-of chill, fever, 
 and sweating, occurring during an attack of typhoid are very significant of a 
 malarial complication, but such paroxysms occur in typhod from other causes, 
 and we cannot, therefore, base our diagnosis upon them. The abdominal 
 symptoms are generally increased during the malarial infection, and this is 
 also true of the symptoms connected with the nervous system. The headache 
 is very severe and delirium is almost invariable present, even in those cases 
 in which it was absent befpre the appearance of the malarial paroxysm. In 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 287 
 
 general, it may be stated that all the symptoms of typhoid are increased in 
 severity and there are added to them the symptoms commonly observed in a 
 malarial paroxysm. 
 
 When malaria occurs during convalescence from typhoid it is generally 
 manifested by chills, fever, and sweats, and the temperature curve is charac- 
 teristic of the type of malaria which may be present. It should be remembered, 
 however, that paroxysms of chill, fever and sweating are sometimes observed 
 at the onset of typhoid and during convalescence from that disease, so that the 
 occurrence of such paroxysms does not always mean the presence of a malarial 
 infection. 
 
 The effort which has been made to ascribe to cases of so-called "typho- 
 malarial fever" a more or less definite and characteristic symptomatology has 
 resulted in failure, and the most that we can say as to the symptomatology 
 of these coincident infections is that the symptoms present are those commonly 
 present in both diseases, but in these cases combined, thus giving rise to 
 atypical clinical pictures, in which sometimes the typhoid symptoms predomi- 
 nate and sometimes those of the malarial infection. 
 
 Illustrative Cases. — The following cases of coincident typhoid and ma- 
 larial infection were observed in soldiers of the U. S. Army, and are typical of 
 all similar cases I have studied. In these patients the malarial paroxysms 
 were present during the active symptoms of typhoid fever, and although the 
 symptomatology may have been slightly altered by the administration of 
 quinine, the malarial infection was present for a sufficient length of time to 
 profoundly alter the course of the typhoid, and to give to the temperature chart 
 characteristics of a malarial infection. 
 
 Coincident Typhoid and Quartan Malarial Fevers.— The following 
 case was observed at the Sternberg IT. S. Army General Hospital, Chickamauga 
 Park, Ga., in 1898, and is, so far as I know, the only case recorded of coincident 
 typhoid and quartan malarial infection. The patient was a Southern physician 
 who had suffered previously from repeated attacks of malarial fever, but had 
 been free from the disease during the time he was at the Park. The clinical 
 history which follows is compiled from my own observation and from informa- 
 tion furnished me by Acting Assistant Surgeon Barnhardt, U. S. Army, who 
 was in attendance upon the patient during the latter portion of his illness and 
 until his removal to another hospital. 
 
 Clinical History. — D. R. P. had suffered from September 29 to October 5, 
 from general malaise, constipation, and headache, with an evening temperature 
 of from 101 F. to 102 F. Although feeling ill he did not take to his bed until 
 October 5, when he was admitted to the hospital, complaining of severe headache 
 and great nervousness. The previous evening he had had a slight chill. On 
 admission he presented the following clinical symptoms: Gurgling and tender- 
 ness in the right iliac fossa; a dry, hot skin; brilliant eyes, with injected con- 
 junctivae; and a typical typhoid tongue. The typhoid symptoms gradually 
 increased, and he developed tympanites, epistaxis, rose spots, extreme restless- 
 ness, and a slight bronchitis. 
 
288 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARLAL FEVERS. 
 
 October 12, or about the twelfth day of the fever, his blood was tested for 
 the Widal reaction and found positive, the reaction being marked; he also 
 showed the diazo-reaction in his urine The patient had never had typhoid 
 fever previously. 
 
 Upon Obctober 15, the morning temperature had fallen to ioo° F.,and 
 his general condition appeared much improved, but later in the day he had a 
 slight chill and the temperature rose to 103.4° F. The attending physician 
 thought little'of the chill, as, by evening, the temperature had fallen to ioi° F., 
 and for the succeeding two days ranged between ioo° F. and 102° F. October 
 18, however, just 72 hours after the first chill, a second and more severe chill 
 occurred, the temperature rising to 104° F. 
 
 At this time I was called upon to examine the blood, and found the quartan 
 malarial Plasmodium present in large numbers. The blood examinations are 
 detailed below. At the time of the first blood examination the patient's general 
 condition was markedly altered for the worse, and he suffered from general 
 muscular pains, severe in character, a weak, irregular pulse, and was very weak 
 and tremulous. 
 
 From October iS to October 21 his temperature ranged between 98. 8° 
 to 1 00. 6° F. The administration of quinine in small doses (5 grains night and 
 morning) was begun upon October 18. Upon October 21, a third paroxysm oc- 
 curred, but was delayed somewhat (probably by the quinine), so that it extended 
 into the 2 2d, the acme of the fever being reached at 4 a. m. of that day. This 
 paroxysm was very severe, the chill lasting thirty minutes, and the temperature 
 rising from 99. 2° F. to 104.6° F. A fourth paroxysm occurred upon October 25, 
 the quinine, for some reason, having been stopped upon the 23d. A fifth paroxysm 
 occurred upon October 28, after which quinine in large doses (10 grains every 
 four hours) was given. Upon October 31, a very slight chill occurred, with a 
 rise of temperature to only 102° F. 
 
 From this time on the patient had no further paroxysms and his tempera- 
 ture gradually reached normal. The convalescence was very slow. During 
 the malarial complication the patient's condition was that of a desperately sick 
 man, and none of the surgeons who saw him entertained any hopes of his 
 recovery. He became greatly emaciated and very anaemic, and was delirious 
 much of the time. During the entire time his blood showed numerous quartan 
 Plasmodia, corresponding in their development with the time of the paroxysms. 
 The blood always gave a marked Widal reaction whenever tested. 
 
 The following is a brief summary of the results of the examination of the 
 blood in this case. 
 
 The blood was first examined at the time of the second chill, when numerous 
 full-grown and segmenting quartan plasmodia were found. Examinations 
 were made every day, and plasmodia were always demonstrated without 
 difficulty. The last Plasmodium observed in the blood was a full-grown quartan 
 organism, upon October 31. 
 
 A record of four days, which follows, shows the average findings for that 
 period throughout the course of the malarial fever. 
 
 October 18. — Chill. Large numbers of full-grown organisms; a few segment- 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 289 
 
 ing plasmodia; a few fragmenting bodies; and a few extracellular and hyaline 
 bodies. 
 
 October 19. — Numerous hyaline, unpigmented plasmodia; a few pigmented; 
 and one fragmenting body. 
 
 October 20. — Many half-grown and nearly three-quarters grown, pigmented 
 quartan plasmodia, a few vacuolated. 
 
 October 21. — Many full-grown plasmodia; several segmenting bodies; and 
 fragmenting and extracellular bodies. 
 
 A careful study of the clinical chart (Chart No. 17.5) in this case is of great 
 interest. Up to October 15, the twenty-second day of the typhoid, the course of 
 the fever had been typical, and the temperature had begun to decline gradually, as 
 is characteristic of the disease. On the fifteenth, following the chill, the tempera- 
 ture rose, but instead of falling to normal or below, which is characteristic of the 
 decline of ordinary malarial fevers, it fell only to the point previously held by the 
 original disease. From that time a gradual decline took place in the tempera- 
 ture until the second chill, upon October 18, when the fever rose from 99. 4 F. 
 to io4°F., but fell in the course of four hours to 99 F. If, now, we discard the 
 rises in temperature due to the malarial infection, we will observe that the 
 course of the temperature is that of a typical declining typhoid, which holds 
 true up to the twenty-fourth, when the temperature between the malarial 
 jDaroxysms became very irregular. Prior to the twenty-fourth the temperature 
 curve illustrated most instructively how these two diseases, which existed 
 together, influenced the temperature chart. The malarial paroxysms occurred, 
 but did not materially influence the course of the typhoid temperature, which 
 gradually declined just as it does in uncomplicated cases, while the temper- 
 ature of the malarial paroxysms was also typical of that observed in ordinary 
 quartan infections. This observation conclusively proves that a malarial in- 
 fection may occur during the active course of typhoid and that each fever 
 preserves its characteristic temperature curve. 
 
 The irregularity of the temperature curve after the twenty-fourth may be 
 explained by the development of severe hypostatic congestion, and the extreme 
 state of nervous excitability from which the patient suffered. Naturally of a 
 very nervous disposition, he was passing through a very severe attack of typhoid 
 fever, only to be set back and exhausted by the severe chills and high fever 
 which accompanied the malarial infection; he became extremely nervous and 
 discouraged, and so changed in appearance that one would recognize at a glance 
 the terrific, strain under which he was struggling. He came to look forward 
 with the utmost dread to the chills; and this intensely nervous condition, taken 
 with the hypostatic congestion, undoubtedly explains the irregularity of the 
 temperature toward the latter part of his disease. It may be possible that 
 there was a multiple infection with the quartan plasmodia, but the blood findings 
 would appear to preclude this. 
 
 It will be observed that the fever was very resistant to small doses of 
 quinine, but that large doses of this drug reduced it very promptly. The 
 19 
 
290 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 
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292 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARLA.L FEVERS. 
 
 patient was convalescent when I lost sight of him, but I have since learned that 
 he died of pneumonia several weeks later. This case is of especial interest 
 because the type of malaria present was the quartan variety, a form very rare 
 even in malarial localities in the United States. 
 
 The two following cases of combined typhoid and aestivo-autumnal ma- 
 larial fever are fairly typical of such infections and occurred in soldiers of the 
 U. S. Army. 
 
 Case I. — S. J. Colored. Was admitted to the hospital suffering from 
 typhoid fever and presenting the usual signs and symptoms of that disease. 
 Date of admission, March 16, 1899. Had been sick for two weeks before ad- 
 mission, but had had no chills. Upon the seventeenth of March he had a chill 
 and his temperature rose to 104. 4 F. He suffered from headache, backache, 
 and nausea. Physical examination showed an enlarged spleen ; tender abdomen ; 
 hot, dry skin; and suffused and brilliant eyes. An examination was made of 
 his blood and numerous "ring-forms" of the tertian aestivo-autumnal Plasmo- 
 dium were found, every microscopic field showing one or more. Quinine was 
 at once administered, but as the temperature did not decline the Widal test was 
 made and a marked reaction was obtained. All of the typical symptoms of 
 typhoid fever was present, and the course of the disease, after the malarial 
 complication was eliminated by quinine, was that of a gradually declining 
 typhoid. 
 
 In this case it will be observed that the malarial complication occurred 
 during the acute stage of the typhoid, and a study of the chart (Chart No. 18) 
 will demonstrate how little the malaria affected the course of the typhoid, and 
 that but for the microscope the diagnosis of the malarial infection could hardly 
 have been made. 
 
 Case II. — This case, observed at the U. S. Army General Hospital, 
 Presidio of San Francisco, Cal., occurred in the practice of Captain Bevans, 
 Medical Corps, and I am indebted to him for the clinical notes upon the case, 
 which are given in his own words. 
 
 "Corporal R. M. Co. K, 29th U. S. V. Inft. Aged 21, born in Tennessee, 
 was admitted on October 3, 1899. The man lived in his native State until 
 enlistment in the Fourth Tennessee Volunteer Infantry in the fall of 1898. 
 He then served in Cuba, and during his first service had a few light chills,, 
 which continued after his return home and until his reenlistment in August 
 1899. The chills appeared again at Fort McPherson, where he stayed about a 
 month, and continued irregularly up to the time of his present sickness. En- 
 route to the Presidio, where he arrived October 1, he was confined to his bed 
 with headache, light chills, and general malaise. He had not, previous to that 
 time, been on sick report. After three days in quarters in camp he was sent to 
 the General Hospital. As he was brought into the ward he appeared pale, 
 emaciated, and cold. His temperature was 102. 4 F., respiration 22, and pulse 
 94. His tongue was coated, the abdomen tender, the liver and spleen some- 
 what enlarged. His mental condition was dazed. By October 7 rose spots had 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 293 
 
 developed and he was in an active delirium. He had involuntary passages of 
 urine and faeces. Light chills occurred daily after the sixth. On the eleventh 
 the chill was prolonged and severe. Malarial parasites were first found in the 
 blood upon that day. Quinine was then administered in large doses and the 
 last chill was observed two days later. Delirium continued until the twenty- 
 fifth. The temperature curve and symptoms after the thirteenth were those of 
 typhoid fever. The temperature reached normal on the twenty-ninth, and 
 slow convalescence has taken place." 
 
 Captain Bevans asked me to examine the blood in this case upon the 
 fourth of October, and also to make a Widal test, but both examinations were 
 negative, and it was not until the eleventh that I was able to demonstrate the 
 Plasmodia in the blood and the Widal test was not positive until after the tem- 
 perature had become normal. The late appearance of the positive reaction to 
 the Widal test is of interest, as in other cases of coincident typhoid and malarial 
 infection the response to the Widal test has always been prompt. Upon the 
 eleventh of October numerous "ring-forms" of the tertian aestivo-autumnal 
 Plasmodium were found in the blood, which soon disappeared after the ad- 
 ministration of quinine. The chart in this case is not given as it is not typical 
 of anything but an ordinary typhoid with a sudden rise of temperature marking 
 the occurrence of the malarial paroxysm. 
 
 From the examples of coincident typhoid and malarial fever which have 
 been given it is evident that Woodward's definition of typho-malarial fever as a 
 hybrid disease presenting certain characteristic symptoms is not borne out, for 
 there was nothing in any of these cases which would differentiate them from 
 ordinary typhoid with the exception of the occurrence of chills, but chills also 
 occur in typhoid uncomplicated with malaria, and where septic infection 
 exists. I think it may be stated with truth that no one of the symptoms de- 
 scribed by Woodward as characteristic of typho-malarial fever has been proven 
 by recent research to be so, and Dock, in an excellent discussion of this sub- 
 ject, in which he gives the conclusions of years of study, states that "we find 
 that the belief in a characteristic disease composed of typhoid and malarial 
 elements is not based on sufficient evidence," and with this statement I am fully 
 in accord. 
 
 The prognosis in cases of coincident typhoid and malarial infection is 
 always grave and it is the concensus of opinion of all who have observed such 
 cases that during the malarial paroxysms the patient appears to lose ground 
 rapidly, and that the occurrence of malarial infection during an attack of 
 typhoid appears to increase the severity of the symptoms of that disease. 
 
 The recognition of these cases is of great importance, especially in regions 
 in which the aestivo-autumnal fevers are prevalent, but it should be remem- 
 bered that such recognition is only possible by the use of the microscope, and 
 quinine should never be administered to a patient suffering from typhoid fever, 
 presenting atypical symptoms, unless the malarial plasmodia can be demon- 
 strated in the blood, for while the administration of this drug is always beneficial 
 
294 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 295 
 
296 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 in malaria, it is always harmful in typhoid. Thayer has very aptly discussed 
 this point as follows: 
 
 "The mere use of the term typho-malarial fever has indicated to many the 
 advisability of the administration of quinine, and not infrequently this drug is 
 used for days and for weeks in cases of uncomplicated typhoid fever in doses 
 which cannot but be injurious to the patient. This is a matter of really grave 
 importance. It is one of the positions in which the physician actually has done 
 and does do, to-day, really serious harm to his patient. There is no excuse for 
 cinchonizing an individual with continuous fever who, after three or four days, 
 shows no change in the symptoms, while the blood is free from malarial 
 parasites." 
 
 This statement of Thayer's has been borne out in my own experience for I 
 have more than once observed cases in which the attending physician had ad- 
 ministered quinine in doses of from 40 to 60 grains, for four weeks, in typical 
 attacks of typhoid fever, under the impression that the disease was really typho- 
 malarial fever or remittent malaria. Such treatment is nothing less than 
 criminal and cannot be too strongly condemned. The use of the term "typho- 
 malaria" should be entirely discarded in medical nomenclature, for its retention 
 will lead inevitably to the extensive use of quinine in atypical cases of typhoid 
 fever. 
 
 Osier's dictum, that any continued fever which resists the use of quinine 
 for over five days is not malarial in character, has been proven by every experi- 
 enced practitioner in malarial localities to be true, and I am convinced that the 
 vast majority of malarial fevers are checked or markedly affected by this drug 
 within three days of its administration, and that it is folly to continue giving 
 quinine in fevers which resist its action for more than five days. 
 
 While it is the testimony of all practitioners who have had much to do with 
 the malarial fevers that the above statement is true, it is still all too common to 
 observe the indiscriminate and continued use of this drug in typhoid fever, often 
 to the great injury of the patient. A microscopical examination of the blood 
 would obviate this mistake, and quinine should never be administered in 
 typhoid fever unless such an examination demonstrates the presence of malarial 
 Plasmodia. 
 
 Literature upon Coincident Typhoid and Malarial Infection. 
 
 1863. Woodward. Outline of the Chief Camp Diseases of the United States 
 Armies, as Observed During the Present War. Philadelphia. 
 
 1864. Levick. Miasmatic Typhoid Fever. The American Jour. Med. Sciences, 
 April. 
 
 1867. Bartholow. Camp Fevers. Memoirs of the United States Sanitary 
 Commission, New York. 
 
 1870. The Medical and Surgical History of the War of the Rebellion. Wash- 
 ington. Part r, vol. i. 
 
 1875. Cochran. Typho-malarial Fever. Trans. Med. Assoc. State of Alabama, 
 28th session, Note B. I. 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 297 
 
 876. Woodward. Typho-malarial Fever: Is it a Special Type of Fever? 
 
 Trans. International Med. Congress, Philadelphia. 
 888. Cahn. De la marche de la fievre typhoid chez les paludeens. Thesis 
 
 de Paris. 
 890. Kinyoun. Enteromalarial Fever. Abstract of Sanitary Reports 
 
 Marine Hospital Bureau, vol. v. 
 892. Gancel. Etude sur la fievre typho-palustre. Arch. Med. et Pharmacy, 
 
 Milit, Paris. 
 892. Young. Typho-malarial Fever, so-called. Med. and Surg. Reporter, 
 
 vol. lxvii. 
 
 894. Thompson. Notes on the Observations of Malarial Organisms in Con- 
 nection with Enteric Fever. Trans. Assoc. Amer. Phys., vol. ix. 
 
 895. Osler. Chills in Typhoid Fever. University Med. Magazine, Novem- 
 ber. 
 
 89 5. Vincent. Sur la symptomatology et la nature de la fievre typhopalustre. 
 Le Mercredi Medical, December 4, vol. vi. 
 
 897. Da Costa. The Coexistence of Typhoid and Malarial Infection. Inter- 
 national Clinics, Seventh Series, vol. ii. 
 
 897. Osler. The Diagnosis of Malarial Fever. The Med. News, March 6. 
 
 898. Cardamantis and Canellis. Etude clinique sur le typhisme, sur la 
 fievre continue paludeenne et sur la fievre typho-malarienne. Le 
 Progres Medicale, March 26, April 23 and 30. 
 
 899. Lyon. Combined Typhoid and Malarial Infection. Amer. Jour. Med. 
 Sciences, January. 
 
 Dock. Typho-malarial Fever, So-called. N. Y. Medical Jour., Feb. 25. 
 Ewing. Preliminary Report on the Results of Blood Examinations at 
 Camp Wikoff, etc., N. Y. Med. Jour., Jan. 28 and Feb. 4. 
 Craig, C. F. Report of a Case of Combined Typhoid and Quartan 
 Malarial Fevers. Philadelphia Med. Jour., June 17. 
 Muehleck. Philadelphia Med. Jour., May 20, 1899, p. 11 16. 
 
 1900. Bevans. A Case of Mixed Typhoid and Malarial Fevers. N. Y. Med. 
 
 Jour. Feb. 10. 
 1902. Rho. Annals Med. Navale, 1902. 
 1904. Reed, Vaughn and Shakespeare. Rep. on Origin and Spread of 
 
 Typhoid Fever, etc. U. S. Gov't Printing Office, p. 645 
 
CHAPTER IV. 
 
 The Prognosis of the Malarial Fevers. 
 
 If one were to draw his deductions concerning the prognosis of the malarial 
 fevers from the vital statistics of the cities and towns of the United States, he 
 could not but conclude that the prognosis in these fevers is very bad, for the 
 number of deaths ascribed to malaria in such statistics is very great. In speak- 
 ing of this Osier calls attention to the fact that while in temperate climates it 
 is well known that the prognosis in malaria is most favorable, still the vital 
 statistics in some of our large cities show a greater death rate for malaria than 
 for typhoid fever. He says: 
 
 "In the United States Census Report of 1890, which covers the six preceding 
 years, the deaths from malarial fever in New York and Brooklyn were more 
 numerous than from typhoid fever. In both these cities it is notorious that a 
 death from malarial fever is a great rarity. No more than three or four cases 
 occur each year in the entire hospital practice of the city of New York." 
 
 Nothing could illustrate more forcibly the immense importance of a 
 scientific diagnosis of malarial fevers by an examination of the blood than does 
 this quotation, and the condition of ignorance of the true nature of malaria 
 which it portrays is a reproach to American medicine. 
 
 General Factors Influencing Prognosis. — Certain general factors 
 should be taken into consideration in estimating the prognosis of the malarial 
 fevers, the chief of which are locality, race, age, occupation, and physical and 
 social condition of the patient. 
 
 Locality. — In certain localities the prognosis of malaria is much more 
 grave than it is in others. In the tropics the prognosis of all varieties of ma- 
 larial fever is more grave than it is in temperate regions, this being true of the 
 aestivo-autumnal infections as well as of the quartan and tertian infections. 
 Again, in certain regions in the tropics the aestivo-autumnal fevers are much 
 more fatal than in others. For instance, these fevers are more fatal in Santiago, 
 Cuba, than they are in Havana, although the climate is practically the same. 
 The prognosis of malaria in the tropics should always be guarded, for here we 
 meet with most of the pernicious types of fever, and the aestivo-autumnal 
 infections occur in most cases, and in them the prognosis is always grave. 
 
 Race. — The negro and many native races in the tropics enjoy a relative 
 immunity to the effects of the malarial plasmodia, acquired through repeated 
 attacks during childhood and early youth; but in regions in which only the 
 aestivo-autumnal fevers are present, while an immunity may be present against 
 them, exposure in another locality to tertian or quartan infection may result in 
 
 298 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 299 
 
 severe attacks of these forms and the prognosis in individual cases may be grave. 
 As a general rule, it may be stated that in adult natives, living in infected regions, 
 the prognosis of malaria is good, even severe infections being rapidly recovered 
 from. 
 
 Age. — The prognosis is most grave at the extremes of life. In very young 
 infants and in the aged the prognosis of the aestivo-autumnal fevers is always 
 very grave. 
 
 Occupation. — Certain occupations, by decreasing the resisting powers of 
 the individual, render the prognosis of malaria very grave, especially if the 
 aestivo-autumnal infections be present. All occupations leading to anaemia, 
 loss of muscular strength, and deficient nutrition, increase the gravity of the 
 prognosis in the malarial fevers. 
 
 Physical and Social Condition of the Patient. — It is obvious that the 
 prognosis in patients suffering from organic disease or severe functional disorders 
 will be more grave than in the case of those who have previously been in good 
 health, and in individuals weakened by long-continued disease or by severe 
 attacks of other acute fevers the prognosis, especially in aestivo-autumnal 
 infections, is always grave. 
 
 The social condition of the patient has much to do with the severity of 
 a malarial attack and markedly influences prognosis. The prognosis in the 
 well-to-do is always more favorable than in the poor, both because the physical 
 condition of the first class is better, as a rule, than that of the second, and because 
 in the first class the disease is at once treated, while in the second, because of 
 the fear of expense, a physician is not called, and repeated attacks may occur 
 before treatment is instituted. The prognosis in the case of laborers who have 
 been exposed to repeated malarial infection and in soldiers serving in tropical 
 climates is always grave, as has been conclusively proven in the case of laborers 
 upon the Panama Canal and in our soldiers in Cuba and the Philippine Islands. 
 While intelligent treatment has, in the vast majority of cases, prevented a fatal 
 termination of the acute attack, the debility and anaemia occasioned by repeated 
 recurrences have often induced a state of chronic invalidism, and in many cases 
 death has eventually resulted. In considering in detail the prognosis in the 
 malarial fevers, I shall discuss the prognosis in each variety of infection sepa- 
 rately, as by doing so we can arrive at a more just conception of the prognosis 
 as it is affected by the occurrence of certain symptoms. 
 
 Tertian and Quartan Infections. — The prognosis in cases of uncompli- 
 cated tertian and quartan malarial infection is good, but it should be remembered 
 that fatal cases of both these forms of malaria have been reported, and in 
 tropical regions the prognosis in the quartan infections, especially, should be 
 guarded, as very often these infections are resistant to treatment, recur fre- 
 quently, and may assume pernicious forms at any time. 
 
 Quotidian Aestivo-autumnal Malaria. — The prognosis in cases of 
 quotidian aestivo-autumnal fever, provided they are not pernicious in 
 character and treatment is begun promptly, is always favorable so far as im- 
 
300 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARL4.L FEVERS. 
 
 mediate danger to life is concerned. If, however, treatment is not persisted in 
 for several weeks after the symptoms have disappeared, relapses almost invari- 
 ably occur, producing marked anaemia and debility, and in such cases the prog- 
 nosis should be more guarded. Several times I have observed fatal cases of 
 anaemia following attacks of this form of malarial fever, in one case the red 
 blood-corpuscles falling to 400,000 per cubic millimeter before death. 
 
 In cases which are unrecognized or improperly treated the prognosis is 
 grave. Repeated relapses, together with the complications which may arise, 
 render a favorable prognosis as to ultimate cure impossible. When complica- 
 tions, such as pneumonia, nephritis, dysentery, and severe nervous conditions, 
 accompany the paroxysms the prognosis is grave and should be very guarded. 
 
 In all infections with the quotidian aestivo-autumnal plasmodium the prog- 
 nosis given should be influenced by the fact that pernicious symptoms are apt 
 to develop at any time. 
 
 Tertian Aestivo-autumnal Malaria. — In uncomplicated cases of tertian 
 aestivo-autumnal fever, properly treated, the prognosis is good. If, however, 
 the patient has suffered from previous attacks and is greatly debilitated by 
 them the prognosis is much more grave, as such infections are often very 
 resistant to treatment. This heightened resistance is probably due to dimin- 
 ished ability to absorb quinine or to a more resistant form of the plasmodium. 
 In cases in which grave complications, such as nephritis and cardiac disease 
 are present, the prognosis should be guarded, and often depends quite largely 
 upon the nature and severity of the complication. In untreated cases of 
 tertian aestivo-autumnal malaria the prognosis is grave, and the liability of this 
 form of infection to develop pernicious symptoms should always be considered 
 in giving a prognosis. While formerly I considered that the prognosis in 
 tertian aestivo-autumnal fever was more favorable than in the quotidian form, 
 further observation has led me to believe that very little difference exists 
 between the two forms as regards prognosis. While a greater number of 
 pernicious cases, in which the result has been fatal, have been found to be 
 infected with the tertian aestivo-autumnal plasmodium, I cannot help but 
 believe that this is largely due to the more frequent occurrence of the tertian 
 infections, and that further investigation will demonstrate that the quotidian 
 plasmodium produces as severe infections as does the tertian species. 
 
 The Pernicious Forms of Malarial Fever. — As I have already stated, 
 pernicious forms of malaria may be produced by any of the species of malarial 
 Plasmodia, although the vast majority of such forms are due to the aestivo- 
 autumnal plasmodia. Whatever the species concerned in their etiology, the 
 prognosis is practically the same, and depends more upon the character of the 
 symptoms produced than upon the species of plasmodium present. 
 
 The prognosis in the pernicious cases varies with the number of paroxysms 
 which have occurred and the clinical character of the attack. If the patient 
 is first seen after having suffered from one or more pernicious paroxysms, the 
 prognosis is very grave although, if treatment be rigorously instituted, not 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 3OI 
 
 hopeless. If seen during the first paroxysm, the prognosis is grave, and 
 treatment should be at once instituted. In such cases a fatal paroxysm may 
 follow, even after the most energetic treatment. 
 
 The Cerebral Pernicious Forms. — The prognosis is very grave in those 
 forms of pernicious malaria which exhibit cerebral symptoms. This is espe- 
 cially true of the comatose form in which the prognosis is always most grave. A 
 large number of such cases recover with proper treatment, but this form furnishes 
 the greater number of cases of fatal pernicious malarial fever. The forms 
 characterized by delirium and acute maniacal attacks also are of grave prognosis. 
 Untreated, the cerebral forms of pernicious malaria are almost invariably fatal. 
 
 The Algid Form. — The prognosis in the algid form is almost as grave as it 
 is in the cerebral forms, and such cases, if untreated, are usually fatal. Prompt 
 treatment will save many, but not a few terminate fatally despite all treat- 
 ment. The prognosis as to ultimate recovery in the algid form is unfavorable, 
 as convalescence is slow, the patient greatly weakened, and relapses are apt to 
 occur. 
 
 The Choleraic Form. — The prognosis in this form is very grave and 
 Marchiafava and Bignami believe that this form ranks next to the cerebral 
 forms in fatality. 
 
 The Dysenteric Form. — The prognosis in the dysenteric form of aestivo- 
 autumnal fever is grave, and I have observed several cases which resulted 
 fatally despite all treatment, but only where treatment was delayed for several 
 days after the onset of the symptoms. The prognosis in these cases should de- 
 pend largely upon the severity of the dysenteric symptoms and the degree of 
 anaemia present. The paroxysms are apt to be hidden by the intestinal 
 phenomena, and the malarial element thus remains long undetected before 
 treatment is instituted. Death is usually the result of exhaustion and anemia 
 in these cases. If treatment be promptly instituted most cases of dysenteric 
 pernicious fever will recover, but an irritable condition of the bowels persists 
 for some time afterward. 
 
 The Pneumonic Form. — In the pneumonic form the prognosis is always 
 grave and, if untreated, a large proportion of such cases terminate fatally. 
 This form is so rare that it is difficult to estimate the relative gravity of it and 
 the other forms of pernicious malaria, but I believe that untreated it is a very 
 fatal form of malaria. 
 
 Other Pernicious Forms. — The prognosis in the other pernicious forms 
 of malarial fever, as the diaphoretic, cardialgic, haemorrhagic, and the forms 
 characterized by convulsions and paralysis, is always grave, and these cases 
 demand immediate treatment. 
 
 Prognosis in Irregular and Sub-continued Fevers. — The prognosis in 
 the irregular and sub-continued malarial fevers differs, of course, with the 
 severity of the symptoms present, but it is always more grave than in the 
 regularly intermittent fevers, but less so than in the pernicious forms. As these 
 infections are very apt to be considered of non-malarial nature, they may have 
 
3<D2 SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 
 
 persisted for some time before treatment is instituted, and this, of course, renders 
 the prognosis more grave than it would otherwise be. Most of these cases, 
 however, recover promptly under the proper administration of quinine. 
 
 Prognosis in Complicated Cases of Malaria. — The prognosis in cases of 
 malarial fever attended by important complications is that of the type of 
 malaria present and the added complication. It is always more grave than in 
 uncomplicated cases. Among the complications which render the prognosis 
 very grave may be mentioned pneumonia, the infectious fevers, tuberculosis, 
 sunstroke, and typhoid fever. 
 
 Prognosis of the Sequelae of Malaria. — As a general rule, it may be 
 stated that the prognosis of the sequelae of the malarial fevers is good, recovery 
 usually occurring within a few weeks or months. The most important of the 
 sequelae will be considered in detail. 
 
 Nervous and Mental Sequelae. — The prognosis in the various nervous 
 and mental sequelae is good and recovery usually occurs within a few weeks, even 
 in cases in which paralysis has followed a malarial attack. Insanity, occurring 
 as a sequela of malaria, does not generally persist for more than six months, 
 although there may be impairment of the mental faculties for a long time after- 
 ward. The condition of melancholia, so often observed following severe 
 malarial attacks, especially in our soldiers serving in the Philippines, is quickly 
 recovered from under the persistent use of quinine, and upon a change of 
 station to the United States. 
 
 Nephritis. — The majority of cases of nephritis occurring with, or following 
 the malarial fevers are rapidly recovered from and the prognosis is good. A 
 few cases become subacute or chronic, and in rare instances the acute nephritis 
 occurring as a complication terminates fatally. 
 
 Postmalarial Anaemia. — The various types of anaemia occurring as 
 sequelae of the malarial fevers have already been described, and it may be said 
 that the prognosis depends entirely upon the character of the anaemia. In 
 simple anaemia following malaria the prognosis is generally good, the blood 
 regaining the normal number of red corpuscles after a period of days, weeks, or, 
 in the more severe secondary forms, months. This recovery often occurs in 
 cases in which the red corpuscles have been very seriously reduced in number, 
 and I have observed cases in which, after repeated attacks of aestivo-autumnal 
 fever, the red blood count was less than 1,000,000 per cubic millimeter, but in 
 which a return to normal was observed within a month. As a rule, in the more 
 severe cases of secondary anaemia the red cells increase in number rapidly until 
 they reach 2,000,000 per cubic millimeter, after which the increase is very slow, 
 and it may be months before the normal number of red cells is attained. 
 
 The prognosis in those cases in which the anaemia following malaria 
 assumes the pernicious type is always most grave, death usually resulting within 
 a few months. 
 
 Malarial Cachexia. — In cases of malarial cachexia in which a change of 
 climate is possible, the prognosis, under suitable treatment is excellent, but in 
 
SEQUELAE, COMPLICATIONS, AND PROGNOSIS OF MALARIAL FEVERS. 303 
 
 those cases which are unable to leave the locality in which they have contracted 
 their infection the prognosis is always grave as to ultimate recovery, and such 
 patients usually succumb to some intercurrent disease to which they are ren- 
 dered less resistant because of the weakened condition brought about by the 
 long-continued malarial poisoning. 
 
 In estimating the prognosis in the malarial fevers it is usually possible, in 
 all but the pernicious forms, to give a favorable prognosis as to immediate 
 recovery from the malarial attack, but the physician should always give a 
 guarded prognosis as to ultimate cure, unless he can be satisfied that the 
 patient will pursue faithfully an extended treatment with quinine. Relapses 
 are sure to occur, especially in the aestivo-autumnal infections, unless quinine 
 is given for weeks after the first paroxysm, and very often a change of climate 
 is found necessary before the infection can be overcome. One of the most 
 discouraging features of the aestivo-autumnal fevers is the extreme tenacity of 
 these infections, and it is a great mistake for the physician to assure the patient 
 that he is cured because the administration of quinine has resulted in the cessa- 
 tion of the symptoms of an acute attack. The physician who does not insist 
 upon his malarial patients persisting in the use of quinine for weeks after 
 the disappearance of the acute symptoms fails in his duty to the patient and to 
 himself. 
 
 In the prognosis of the malarial fevers the following axiom should never 
 be forgotten: The prognosis in all cases of aestivo-autumnal malaria is 
 grave, because pernicious symptoms may arise at any time during their course. 
 
PART V. 
 
 THE DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF THE 
 MALARIAL FEVERS. 
 
CHAPTER I. 
 
 The Laboratory Diagnosis of the Malarial Fevers; Staining Methods; Exami- 
 nation of the Blood; Examination of Malarial Mosquitoes. 
 
 The diagnosis of the malarial fevers may be considered from two stand- 
 points: the diagnosis by laboratory methods and the diagnosis from the clinical 
 character of the fevers. As I have tried to make plain, it is only in the most 
 typical cases of malarial fever that we are able to arrive at a diagnosis from the 
 clinical symptoms alone, and therefore that the diagnosis of malaria, and 
 especially of the type of malaria, should always rest upon the results of a blood 
 examination. 
 
 The importance of the use of laboratory methods in the diagnosis of the 
 malarial fevers cannot be too strongly emphasized, and when we remember 
 that the technic is not difficult, requires but a few moments of time, and but a 
 very small amount of laboratory apparatus, it is evident that there is no excuse 
 for the neglect of this method of diagnosis. The plea, so often urged by the 
 busy practitioner, that he has not the time, can be seldom urged truthfully, and 
 when true is no excuse, as it is possible, in most regions, to secure the services of 
 some one who is familiar with methods of blood examination and who has the 
 time to devote a few moments to the study of the blood of a suspected case. I 
 have seen so much misery result from the neglect of blood examinations in fever 
 cases, even the death of the patient in some instances, that I feel that I cannot 
 urge too strongly the vital importance of such examinations in all cases of fever. 
 I believe that the time will come when it will be considered malpractice to 
 neglect the blood examination in fever cases, and that he who loses a patient 
 from malaria and has not recognized the disease because of the neglect of a 
 blood examination will be amenable to the law. 
 
 The examination of the blood is the quickest and most reliable method of 
 diagnosing any of the varieties of malarial fever, and in those cases, which are 
 numerous, in which the clinical symptoms are atypical, the diagnosis must rest 
 upon the result of a blood examination. The therapeutic test by the adminis- 
 tration of quinine, urged by some writers, is unsatisfactory, for while the fever, 
 if malarial, will succumb to the drug, there is no surety that malaria was the 
 disease present, for every fever which declines after the administration of this 
 drug is not malarial in nature. Our vital statistics are burdened with hundreds 
 of cases of fevers diagnosed as malarial because quinine reduced them or they 
 disappeared spontaneously, and it is evident that we can never be sure of the 
 variety of malaria present when we employ quinine as a diagnostic aid to the 
 exclusion of the blood examination. Again, the continued use of quinine is 
 
 307 
 
308 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 often injurious to the patient, as has been noted in the discussion of typho- 
 malarial fever, and to keep a typhoid patient cinchonized for weeks, under the 
 impression that the fever is due to malaria, when a few moments' examination 
 of the blood would definitely decide the question, is hardly less than 
 criminal. 
 
 As a rule, one examination of the blood, if carefully made, will be found 
 sufficient ; but if . a negative result is obtained in a suspected case, repeated 
 examinations should be made at intervals, for in some cases so few plasmodia 
 are present in the blood that such repeated examinations are necessary in order 
 to demonstrate them. The statement so often made that cases of malaria occur 
 in which it is impossible to demonstrate plasmodia in the blood, while it may be 
 true, has not proven so in my experience. From personal observation, I believe 
 that such cases must be very, very rare and so mild in character that it would 
 be impossible to recognize them clinically. I have yet to observe a case of 
 malarial fever severe enough to cause clinical symptoms in which it was im- 
 possible to demonstrate plasmodia in the peripheral blood, if repeated examina- 
 tions were made. On the other hand, I have records of hundreds of cases of 
 very mild and latent infections, in which plasmodia were found in the per- 
 ipheral blood. 
 
 The general factors to be considered in arriving at a suppositional diagnosis 
 of malaria are the following: The season of the year; the locality, as to whether 
 it is malarious; the location of the dwelling of the patient; the history of previous 
 attacks of fever; the presence of Anophelinae; the periodicity of the fever; the 
 chances of infection; the age of the patient, if we are dealing with natives of the 
 tropics; the presence of the signs of malaria cachexia or of anaemia; and the 
 occurrence of similar fevers in other members of the household. 
 
 The microscopical diagnosis of the malarial fevers depends upon the find- 
 ing of the plasmodia in the blood or the presence in the same fluid of pigmented 
 leucocytes. The finding of free pigment is also conclusive of malarial infection, 
 past or present, but it is often impossible to distinguish such pigment from 
 extraneous substances, and a diagnosis based upon the presence of free pig- 
 ment alone is always open to question. The endeavor to diagnose malaria by 
 a differential blood count has not resulted in success, as a similar differential 
 count is found in other acute fevers. 
 
 The Examination of the Blood. 
 
 The blood may be examined in the fresh condition or various staining 
 methods may be employed which render the plasmodia easier of detection than 
 they are in fresh preparations. Where it is desired to study the movements and 
 vital phenomena of the plasmodia the use of fresh preparations is necessary, but 
 since the development of the Romanowsky staining method and its modifications, 
 the examination of stained specimens is far better in diagnosis, both because the 
 plasmodia are more easily seen and because there is less chance of mistaking 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 309 
 
 other objects for them. The use of one of the chromatin stains is also neces- 
 sary when we desire to study the exact structure of the malarial plasmodia. 
 
 Apparatus. — The apparatus necessary in making a blood examination for 
 malaria is very simple and can easily be transported to the bedside of the 
 patient, if that be necessary. A good compound microscope, with a 1/12 inch 
 oil immersion lens; microscopic cover-glasses and slides; two or three medicine 
 droppers; a bottle of staining solution, and a bottle of distilled water are all 
 that is necessary to enable us to make the most exact examination of the blood 
 for malaria. The 1/12 oil immersion lens is absolutely essential, for while the 
 larger forms of the tertian and quartan plasmodia, and the gametes, or crescents, 
 of the aestivo-autumnal fevers may be seen with a lens as low as a 1/6 inch, 
 the small hyaline ring-forms can only be well seen when the 1/12 lens is used. 
 It is a great mistake to undertake the microscopic diagnosis of malaria without 
 a 1/12 inch oil immersion lens. An Abbe condenser is, of course, an essential 
 portion of the microscope, and, if possible, the microscope should be equipped 
 with a mechanical stage, for the use of such a stage increases the chance of 
 finding the plasmodia very greatly, and this fact, together with the infinitely 
 greater ease of manipulation, and the satisfaction of knowing that the same 
 portion of the specimen has not been looked over twice, is worth far more to the 
 observer than the slight additional cost of such a stage. 
 
 Objects Which maybe Mistaken for Plasmodia. — There is no one thing 
 more essential to success in recognizing the malarial plasmodia in the blood 
 than a practical knowledge of the microscopical appearance of both fresh and 
 stained specimens of normal and pathological blood. He who supposes that 
 he has only to look into his microscope at a specimen of blood in order to find 
 the plasmodia, without having had previous experience in blood examinations, 
 will invariably be disappointed, and will either give up the search in disgust or 
 mistake some artefact or other object for the malarial plasmodium. Success 
 might possibly attend the search of such a tyro in the case of the large, fully 
 developed forms of the quartan or tertian plasmodium, but never when the 
 hyaline "ring-forms" of the aestivo-autumnal plasmodia are alone present. 
 The use of a good chromatin stain has done much to enable the less experi- 
 enced observer to recognize these organisms, and for this reason the use of 
 stained specimens in diagnosis is preferable to the examination of the fresh 
 blood. 
 
 In fresh specimens of blood the following objects may be mistaken for 
 malarial plasmodia: 
 
 Crenations. — These occur if the blood be exposed long to the air in mak- 
 ing ; the specimen or if the slide or cover-glass be not clean, and are confusing 
 to an inexperienced observer if they be looked down upon directly, as they thus 
 appear as round, rather haline bodies within the red corpuscles, but they have no 
 ring-like outline, and when focussed upon appear alternately as light and dark 
 areas. 
 
 Retraction of the haemoglobin from the edge of the red cell is often 
 
3IO DL\GXOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 observed at some point on the periphery of the cell, giving rise to small areas 
 devoid of haemoglobin, but they have no amoeboid motion, and when focussed 
 upon often present a reddish refraction about the edge. Cracks in the haemo- 
 globin are similar in appearance and are generally easily differentiated from 
 Plasmodia. 
 
 Vacuoles. — There is no more deceiving object in the blood than a small 
 vacuole within the red corpuscle. Sometimes, especially if the border of the 
 vacuole alters in shape, the resemblance to the hyaline disk-form of the aestivo- 
 autumnal plasmodia is well-nigh perfect. I have time and again had such 
 vacuoles shown to me for plasmodia by experienced microscopists who had 
 had but little practice with malarial blood. The greater refraction of the 
 vacuole, its less opaque character, and the fact that vacuoles "open out" or 
 grow larger and smaller as focussed upon, should distinguish them from any 
 of the stages of growth of the malarial plasmodia. 
 
 Areas devoid of haemoglobin or "eye spots" as they have been termed 
 by some observers, occur within the red cells frequently in diseases, such as 
 typhoid fever, tuberculosis, pneumonia, and the acute infectious diseases, 
 and are also observed in normal blood. They may be situated at any portion 
 of the corpuscle, and may be round, spindle-shaped, oval, or ring-shaped, and 
 hyaline in appearance. Many of them, especially the oval and spindle-shaped 
 areas contain a darker dot at the center, which resembles pigment. These 
 bodies have been several times described as new parasites and sometimes their 
 superficial resemblance to the ring-forms of the malarial plasmodia is striking, 
 but the absence of ameboid movements, and the much greater degree of refrac- 
 tion should serve to differentiate them from the plasmodia. 
 
 Platelets. — Occasionally a blood platelet, if superimposed upon a red 
 blood-corpuscle, will resemble slightly a malarial plasmodium, but upon 
 focussing it will be observed that there is a great difference in the level of the 
 two objects and that the platelet is less opaque and less refractive than the 
 malarial plasmodia. 
 
 Haemokonien or blood-dust may sometimes be mistaken for plasmodia, 
 especially when the small active granules lodge upon a red cell, but a little 
 practice will soon suffice to differentiate these bodies. 
 
 Granules derived from broken-down leucocytes sometimes resemble small 
 plasmodia when they rest upon the red corpuscles, but their size, the absence 
 of amoeboid motion and their less hyaline appearance easily serve to distinguish 
 them. 
 
 Other objects which may cause trouble to the beginner are grains of dirt 
 which may be mistaken for pigment; the normal lighter colored center of the 
 red corpuscles, especially marked in persons suffering from anaemia; cocci or 
 bacteria in the blood; and flaws or dirt upon the slide or cover-glass. 
 
 In stained specimens the objects most apt to be mistaken for plasmodia 
 are the blood plates, especially when, as often occurs, they are observed with 
 the red corpuscles. They may be distinguished by their smaller size (as a rule) 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 3II 
 
 and the minuteness of their chromatin granules, as well as the absence of the 
 distinct blue protoplasm observed in the malarial plasmotlia. 
 
 Bacteria upon the red cells; Yeasts, and extraneous matter, which may 
 be stained, are all sometimes mistaken for plasmodia, but a very little experience 
 in the examination of stained specimens of blood will render such mistakes 
 impossible. Flaws upon the slide, in which the stain may settle, sometimes 
 resemble extracellular plasmodia, but careful examination will demonstrate 
 their nature. 
 
 The flagellated plasmodia are simulated by certain erythrocytes under- 
 going degeneration, in which long, slender, active protoplasmic pseudopodia 
 are observed projecting from the periphery of the misshapen red cell.' These 
 bodies may be distinguished from the flagellated plasmodia by the greenish 
 color due to the haemoglobin of the red cell and by the absence of pigment. 
 
 5678 
 
 Fig. 23. — Appearances in the Red Blood-corpuscles which have been mistaken for Plasmodia 
 1, Crenations; 2, Vacuoles; 3, Areas devoid of haemoglobin; 4, Blood plates; 5, Blood dust; 
 6, Bacteria of various kinds; 7, Yeast cells; 8, Free pigment granules. 
 
 The crescents or gametes of the aestivo-autumnal plasmodia are frequently 
 confused with folded red cells, which have a crescentic outline, but such cells 
 may be easily differentiated from the plasmodia by their green color and the 
 absence of pigment. 
 
 Preparation of Blood Specimens. — The following procedure is recom- 
 mended if it be desired to procure fresh specimens of blood for examination. 
 The patient's ear lobe, or the tip of the finger, is carefully cleaned with alcohol, 
 dried thoroughly, a slight puncture made with a lancet or needle, and the 
 first drop or two of blood allowed to flow away. A small drop is then taken 
 upon a slide which has been carefully cleaned and a cover-glass dropped gently 
 upon it. If the cover-glass is thin, and the drop of blood on the slide small, the 
 blood will spread evenly and quickly, but if it does not, very slight pressure upon 
 the cover-glass will suffice to spread the blood and will do no harm. If upon 
 examination it is found that the blood-cells are in clumps or rouleaux, the prep- 
 aration should be discarded and one obtained in which the red cells are spread 
 singly and evenly over the field. The preparation of the specimen should take 
 as little time as possible, as exposure of the blood to the air crenates the red cells 
 and thus renders it difficult to find the plasmodia. A little practice will enable 
 
312 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 one to secure suitable specimens very quickly. The specimens should be 
 examined as soon as possible, but if carefully wrapped in tissue-paper can be 
 carried in the pocket for several hours without much danger of changes occurring 
 which will obscure the plasmodia, and if the specimens be ringed with vaseline 
 they will keep well for as long as twelve hours. The ear is preferable to the 
 finger for obtaining the blood, especially in children, as there is less pain, and 
 the patient cannot watch the operator during the procedure. At least half an 
 hour should be spent upon the examination of the specimen before it is considered 
 negative, and more than one specimen should be examined when a negative 
 result is obtained. For the examination of certain phenomena in the life 
 cycle of the malarial plasmodia, such as exflagellation, the use of fresh specimens 
 of blood is essential, but with our improved methods of staining, better results 
 in diagnosis will be arrived at, by the majority of physicians, if stained specimens 
 be used, provided some practice has been had in distinguishing these organisms 
 in such preparations. 
 
 Preparation of Stained Specimens. — The preparation of blood smears 
 for staining is so simple that it is remarkable to read in many of our works 
 upon diagnosis the elaborate methods advocated for making blood smears, some 
 of them involving the use of special apparatus. All that is necessary in the 
 way of apparatus are two microscopic slides and a needle with which to make 
 the puncture in the ear or finger. After washing the ear as described and 
 allowing a drop or two of the blood to flow away, a small drop is caught upon 
 the end of one slide and the edge of the other slide applied to it, when the blood 
 will spread along the applied edge. As soon as this occurs, draw the edge 
 of the slide gently along the surface of the slide upon which is the drop of blood, 
 and a thin even smear will result. This is allowed to dry and is then ready for 
 staining. Good smears may be obtained by spreading the blood over the slide 
 with the needle, but the smears so obtained are apt to be thicker than when 
 the edge of the slide is used. 
 
 Staining Methods.— Many methods have been devised for staining the 
 plasmodia of malaria, but prior to the description in 1890, by Romanowsky, of 
 his staining method, the results obtained were unsatisfactory from a diagnostic 
 standpoint as well as from a morphological one. In Romanowsky's method, 
 however, the staining reactions of the plasmodia were so distinctive that they 
 could hardly be mistaken for other objects, and thus the method was generally 
 adopted in the diagnosis of the parasites of malaria. Various modifications of 
 the method have been evolved, many of them superior to the original and 
 easier of application. The success of the Romanowsky stain and all of its 
 modifications depends upon the fact that when a solution of methylene blue is 
 acted upon by sodium carbonate or some other alkaline reagent, methylene 
 azure and methylene violet result, being formed in the solution. When these 
 bodies are in turn acted upon by a solution of eosin, certain bodies result which 
 have the power of staining the nuclear chromatin an intense red, hence the 
 name "chromatin stains" applied to these staining methods. In old poly- 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 313 
 
 chrome methylene blue solutions these staining bodies are present, but they can 
 be quickly produced in fresh solutions if certain procedures are followed. I 
 shall describe here only those staining methods which I have personally found 
 satisfactory, merely mentioning those which have been used by various ob- 
 servers, but which have not proven generally useful. 
 
 Wright's Stain. — In my own work I have found Wright's stain, as modified 
 by Oliver, most satisfactory, and at the present time I use this stain to the ex- 
 clusion of all others. In over 10 years' experience I have always found this 
 stain reliable when properly made and when the right ingredients were 
 used. It should be remembered that this stain depends for its efficiency upon 
 chemically pure ingredients and the substitution of others will always result in 
 disappointment. 
 
 Chemicals Used in Preparation of Wright's Stain. — The following 
 chemicals are used in preparing Wright's stain: 1. Methylene blue (Grubler'sj. 
 2. Eosin. Yellow. Water soluble (Grubler's). 3. Methylic alcohol (Merck's 
 reagent). 
 
 Method of Preparation. — The stain I use is prepared as follows: Add 
 0.5 gm. of sodium bicarbonate to 100 c.c. of distilled water, dissolve thoroughly, 
 and add 1 gm. of methylene blue (Grubler); heat the mixture for one hour in 
 an Arnold sterilizer or other steam sterilizer, after the steam is up. After heat- 
 ing allow the solution to cool. Make a 1 to 1,000 solution of yellow aqueous 
 eosin (Grubler) and add this, while stirring, to the cooled mythylene blue 
 solution, in about the proportion of 500 c.c. of the eosin solution to 75 c.c. of the 
 methylene blue solution. This should be done in a white dish of some kind, 
 in order that the precipitate that forms as the eosin solution is added may be 
 easily seen. The proportion of eosin solution added to the methylene blue 
 solution will vary in different batches of the stain, but the eosin solution should 
 always be added until a well-marked precipitate follows after stirring. A marked 
 metallic scum will appear upon the surface of the mixture at the time the eosin 
 solution is in sufficient quantity and this may be used as an indicator, but if no 
 precipitate is present when the metallic scum appears the eosin solution should 
 be added until it appears. The mixture should then be allowed to stand for 
 fifteen or twenty minutes, and then filtered through one small filter-paper, the 
 precipitate saved, dried in a hot-air oven, removed from the filter-paper, and 
 used in making the staining solution. The precipitate, which is a fine powder, 
 greenish in color, will keep well and can be used as stock material for months. 
 
 The staining solution is prepared as follows: Take 0.3 gm. of the powdered 
 precipitate and add it to 100 c.c. of pure methylic alcohol (Merck's reagent), 
 filter, and to 80 c.c. of the filtrate add 20 c.c. of the methylic alcohol, or if more 
 than 80 c.c. be left after filtration, enough to bring the entire amount up to 
 100 c c. The staining solution is now ready for use and will keep unim- 
 paired for weeks. 
 
 Method of Use. — To stain, add a few drops of the staining solution to the 
 blood smear prepared in the manner directed, and let stand for from two to four 
 
314 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 minutes. This fixes the specimen. Then add enough distilled water to cause 
 a slight metallic scum to form upon the surface of the preparation; let stand for 
 from three to five minutes, wash in running distilled water, and examine when 
 dry. The washing in distilled water is important, as by it the precipitate formed 
 during the staining process is removed, and it should be continued until the 
 specimen is a delicate shade of pink or pinkish-brown. If it is desired to pre- 
 serve the specimen, do not mount in Canada balsam, but preserve the slide 
 without the addition of a cover-glass. 
 
 Prepared and used in the manner described, it will be found that Wright's 
 stain is always reliable and can be depended upon to give the most beautiful 
 pictures of stained malarial plasmodia. 1 have had but little success with this 
 stain as prepared by manufacturing chemists, and would strongly advise that 
 the stain be made by the one using it, and that only the ingredients mentioned 
 be used in its manufacture. None of the other modifications of Romanowsky's 
 stain, such as Leishman's, Nocht's or Jenner's can compare with this stain, in 
 my opinion, as regards ease of manipulation and the results obtained. 
 
 The Staining Reactions of the Blood With Wright's Stain. — In 
 specimens of blood properly stained with Wright's stain, the red blood-corpus- 
 cles are stained a brownish-pink or a light pink, while the various leucocytes 
 are stained as follows: the polynuclear leucocytes present a light red nucleus 
 with unstained protoplasm except for light pink granules which are generally 
 present within the protoplasm; the mononuclears and lymphocytes have a dark 
 ruby-red or violet nucleus, very sharply defined, while the protoplasm is stained 
 a light blue; the eosinophiles have a deep violet nucleus and the granules are 
 stained a pale red, in the coarsely granular variety, a brilliant red; the mast cells 
 have dark purplish-black granules, and a dark red nucleus; the blood plates 
 stain a bright ruby-red, with, in most instances, a well marked, pale lilac margin. 
 
 The staining reactions of the malarial plasmodia when Wright's stain is 
 used have already been thoroughly described in the section dealing with the 
 morphology of the plasmodia. It may be repeated here, however, that the 
 protoplasm of the plasmodia stains a robin's egg-blue, the vesicular portion of 
 the nucleus remains unstained, while the chromatin of the nucleus stains a 
 beautiful ruby-red. 
 
 Other Methods of Staining the Malarial Plasmodia. — Among the 
 other methods in use for staining the malarial plasmodia the following are the 
 most important and useful: 
 
 Romanowsky's Method. — Two solutions are used: Sol. 1. Methylene blue 
 (Grubler), 1 part. Sodium carbonate, 1.5 part. Water, 100 parts. Sol. 2. 
 Eosin, yellow aqueous (Grubler) 1 part. Water, 1000 parts. Solution 1 
 should be mixed and kept in an incubator for several days or in the sun-light, 
 until a distinct purple tinge develops, and solution 2 should be kept in the dark. 
 
 The staining solution is made by mixing 5 c.c. of each solution with 95 c.c. 
 of water and then adding the methylene blue solution to the eosin solution in 
 the proportion of one part of the former to two parts of the latter. The stain 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 315 
 
 should be allowed to act for at least fifteen minutes and the best specimens are 
 obtained after from one to two hours. After staining, the smears should be 
 thoroughly washed in running distilled water. The staining reactions are 
 similar to those obtained with the Wright stain. 
 
 Leishman's Method. — This method is a favorite one in England, but I 
 have not secured as good results with it as with Wright's method, although 
 it is an excellent stain for the plasmodia. The method of preparing this stain 
 is as follows. 
 
 1. Make a 1 per cent, solution of Grubler's medicinal blue in distilled 
 water made alkalein by the addition of 0.5 per cent, of sodium carbonate. 
 Heat for 12 hours at 65 C. in an oven and allow to stand for 10 days at room 
 temperature before using. 
 
 2. Prepare a 1 to 1000 solution of eosin (Grubler's extra B. A.). 
 
 3. Equal volumes of these two solutions are mixed in an open dish and 
 allowed to stand for from 6 to 1 2 hours, during which time the mixture should 
 be stirred at intervals. 
 
 4. Collect the precipitate that results upon one small filter-paper and wash 
 with distilled water until the washings are colorless or a pale blue; the precipitate 
 is then dried and powdered. 
 
 5. To make the staining fluid, dissolve 0.15 gm. of the powder in 1,000 c.c. 
 of Merck's methylic alcohol (reagent). 
 
 The method of using the staining solution is similar to that of Wright's, a 
 little of the stain being added to the smear, allowed to remain for two to three 
 minutes, when distilled water is added until a slight metallic scum appears upon 
 the surface; the specimen is then stained for five more minutes, and washed in 
 running distilled water. After washing, Leishman recommends that the stained 
 smears be allowed to soak in distilled water for one minute, claiming that this 
 intensifies the chromatin stain, removes deposits, and changes the color of the 
 red blood-corpuscles to a delicate pink. If this be done the smears will be 
 free from any precipitate. The staining reactions are the same as with Wright's 
 stain. 
 
 Nocht's Method. — The following method, advocated by Nocht, is said 
 by Ewing to be excellent for staining the malarial plasmodia, but I have not 
 found it as satisfactory as Wright's stain. The following solutions are used: 
 
 1. To 30 c.c. of polychrome methylene blue (Grubler) add five drops of a 
 3 per cent, solution of acetic acid (U. S. P., 23 P er cent.). 
 
 2. Make a saturated solution of methylene blue (Grubler) dissolving the 
 powder by gentle heat in water. This solution should be kept for at least 
 a week before it is used. 
 
 3. Make a 1 per cent, solution in water of yellow aqueous eosin (Grubler). 
 The staining solution is prepared as follows: 
 
 To 10 c.c. of water add four drops of the eosin solution, six drops of the 
 polychrome methylene blue, and 2 drops of the 1 per cent, methylene blue 
 solution, mixing well. 
 
6 
 
 1 6 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 The stain is used as follows: 
 
 The blood smears are fixed by absolute alcohol for five minutes or by heat, 
 stained for two hours or more with the staining solution, in a moist chamber, 
 washed in distilled water, and examined. The best result is obtained after six 
 or more hours' staining. 
 
 According to Nocht, the two methylene blue solutions may be replaced by 
 a i per cent, solution of Ehrlich's rectified methylene blue to which has been 
 added a few drops of a half of i per cent, solution of sodium hydrate, the 
 mixture having been heated for a few days in an incubator at 50 C. When 
 this solution is used the method of staining consists in adding two or three 
 drops of the eosin solution to 2 c.c. of water, and to this adding, drop by drop, 
 the methylene blue solution, until the red color of the eosin solution had nearly 
 disappeared. The results are not as good as when the original method is used. 
 With this stain the staining reactions are similar to those obtained by Wright's 
 stain. 
 
 Plehn's Method. — The following method, advocated by Plehn, is some- 
 times useful, but the chromatin staining is uncertain. 
 
 The following solution is used: 
 
 Concentrated aqueous solution of methylene blue (Grubler), 60 parts. 
 
 One-half per cent. sol. of eosin in 75 per cent, alcohol, 20 parts. 
 
 Distilled water, 40 parts. 
 
 Twenty per cent, solution of sodium hydrate, 12 drops. 
 
 The blood smears are fixed in absolute alcohol for five minutes, stained in 
 the above solution for from five to ten minutes, washed in water, and examined. 
 Marino's Stain. — This stain, somewhat more complicated in technic 
 than Wright's, but which gives excellent results when carefully prepared and 
 used, is as follows: 
 
 Sol. I. Methylene blue (Grubler's), 0.5 gm. 
 
 Azure blue, 0.5 gm. 
 
 Water, 100.0 c.c. 
 
 Sodium bicarbonate, 0.5 per cent, sol., 10. o c.c. 
 
 This solution is kept in the incubator at 73 C. for from two to four daysj 
 or heated to 6o° C. for six hours. 
 
 Sol. II. A 0.2 per cent, solution of aqueous eosin (Grubler's). The 
 eosin solution is added to the methylene blue solution until a well-marked 
 precipitate occurs, which is collected by filtration, dried, and used as stock 
 material. 
 
 The staining solution is made by adding 0.4 gm. of the methylene-azure 
 powder, obtained by filtration, to 20 c.c. of pure methylic alcohol, and is used 
 as follows: 
 
 The blood smears are covered with the staining solution, the number of 
 drops required to do so being recorded. After the stain has been allowed 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 3 I 7 
 
 to act for three or four minutes, double the number of drops of an aqueous 
 solution of eosin, containing 0.05 gm. of eosin to 1,000 c.c. of water are added, 
 and left on for from two to three minutes. The smears are then thoroughly 
 washed in distilled water and examined at once. 
 
 Giemsa's Stain. — This stain, so useful in staining Treponema pallidum 
 and Treponema pertenuis, is also a valuable stain for the plasmodia of malaria, 
 but its method of preparation is so complicated and requires so much care that, 
 while the results obtained by it are reliable, it is not as available for general use 
 as is the more simple Wright's method. It is also very prone to overstain and 
 to undergo changes with age which render it useless for the staining of the 
 malarial parasites. The stain is prepared as follows: 
 
 In preparing the stain and using it the utmost care should be taken that 
 everything is chemically clean and that none of the dishes or implements used 
 are moist, and that they are absolutely free from acid. The dishes should all 
 be sterilized before using and thus rendered free from bacterial contamination. 
 
 Preparation of Stock Staining Solution.— Weigh out the following: 
 
 Azure II-eosin, 3.0 grams. 
 Azure II, 0.8 gram. 
 
 Dissolve these, with constant shaking, in chemically pure glycerine (250 c.c.) 
 at a temperature of 6o° C. After solution is complete add 250 c.c. of absolute 
 methyl alcohol (Kaulbaum I) previously heated to 6o° C. This mixture is 
 shaken well, allowed to stand at room temperature for 24 hours, and then 
 filtered into a chemically clean, sterilized air-tight stock bottle. During the 
 filtration the funnel must be covered with an inverted watch-glass to protect 
 the hydroscopic fluid from moisture. 
 
 The stain should always be protected from the sunlight. 
 
 The method of using this stain is as follows: 
 
 For structures such as spirochaetes, the Treponema, and the malarial 
 plasmodia proceed as follows: 
 
 1. Make thin, even smears of the material to be examined upon fat-free 
 cover-slips or slides. 
 
 2. Dry in the air and fix for twenty minutes in absolute ethyl alcohol. 
 
 3. Blot off the alcohol with smooth, closely woven, white filter-paper. 
 
 4. Stain with the following solution: 
 
 Stock solution, 10 drops 
 Distilled water, 10 c.c. 
 
 One per cent. sol. potass, carb. 1 or 2 drops to each 10 c.c. of the mixture 
 of distilled water and stock solution. 
 
 If the malarial plasmodia are to be stained, the staining solution should be 
 allowed to act for from 5 to 10 minutes, but if the treponema is to be stained it 
 should be at least an hour before the stain is removed. 
 
 5. Wash the stained smears in running distilled water, air dry, and examine 
 
318 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 at once. With this stain the protoplasm of the plasmodium colors a very dark 
 blue, the vesicular part of the nucleus remains unstained, and the chromatin 
 takes a very dark red, almost black color. 
 
 Staining of Flagellated Parasites.— The flagellated forms of the mala- 
 rial plasmodia may be stained by any of the methods mentioned, Wright's 
 stain being especially serviceable. A patient should be selected in which 
 gametes are numerous, and the blood should be exposed a short time to the air 
 after securing it on the slide, or the slide may be breathed upon to hasten 
 exflagellation. The smear should be thick and should be allowed to dry 
 slowly. The technic of staining is the same as for the other forms of plasmo- 
 dia, but it is well to allow the stain to act longer after the water has been added. 
 
 Bodies in Stained Specimens Which may be Mistaken for Plasmodia. 
 — To one who has had much experience in the examination of stained specimens 
 of malarial blood, where any of the chromatin stains have been used, the mistake 
 of confusing any stage of growth of the plasmodia with artefacts, granules of 
 dirt, or other objects, is impossible, for the staining reactions of the plasmodia 
 are very distinctive, and a comparatively little practice will enable one to 
 recognize the stained organisms without any difficulty. Certain objects may be 
 mistaken in stained specimens for plasmodia by those unused to studying such 
 preparations, the most important of which are the following: 
 
 i. Flaws in the slide in which a portion of the stain may collect. If these 
 be situated beneath a red blood-corpuscle they may resemble a poorly stained 
 Plasmodium, but upon focussing it will be observed that they are situated at a 
 different level than the red cell and thus they may be easily distinguished. 
 
 2. Blood platelets, especially if lying upon the red blood-corpuscles, as 
 frequently happens, are commonly mistaken for plasmodia by those unaccus- 
 tomed to stained preparations. They are differentiated by the lack of a blue- 
 stained protoplasm and the bright ruby-red mass of chromatin, the chromatin 
 of the blood plate being darker in color, irregular in outline, and more granular 
 in appearance. Most blood plates are surrounded by a well-marked bluish 
 limiting membrane, especially well observed when the plate is lying free in the 
 plasma. Sometimes the blood plates are collected in crescentic masses and 
 might be mistaken for crescents, but a little study should served to obviate such 
 mistakes. 
 
 3. Vacuoles, in which some of the stain has been retained, may occur in 
 the red blood-cells, but may be easily distinguished from the plasmodia by the 
 absence of the blue protoplasm and the red chromatin. 
 
 4. Leucocytes have been mistaken for stained malarial plasmodia, but such 
 a mistake could only be made by the merest tyro in blood examinations. 
 Among other objects which might be confused with the plasmodia in stained 
 specimens may be mentioned particles of dirt of extraneous origin, yeast cells 
 and other micro-organisms, degenerated leucocytes, neucleated red cells, and 
 basophilia of the red corpuscle. It is obvious that an acquaintance with the 
 appearance of both normal and diseased blood in stained specimens will make 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 3IQ 
 
 such mistakes impossible, and, as I have stated, a knowledge of the micro- 
 scopic appearance of normal blood, in both fresh and stained preparations, is 
 absolutely essential to one who expects to study the malarial plasmodia or to 
 make microscopic examinations of blood for diagnostic purposes. 
 
 The Microscopic Diagnosis of the Species of Malarial Plasmodia. — 
 The species of malarial plasmodia may be differentiated in both fresh and 
 stained specimens of blood, and in making such a differentiation two factors 
 should be borne in mind, i.e., the character of the infected red corpuscle and the 
 character of the parasite infecting it. I have already described in detail the 
 characteristics of the various species of plasmodia and the changes occurring 
 in the infected red cell in the chapter dealing with the morphology of the plasmo- 
 dia, but for convenience I shall here give a brief summary of the distinctive 
 features of the plasmodia which may be used in diagnosing the species present 
 in any given case. 
 
 Tertian Plasmodium. — The red cell infected with Plasmodium vivax is 
 invariably enlarged, even during the earliest stage of growth of the parasite, and 
 after the occurrence of pigment the red cell is markedly larger than the unin- 
 fected cells and is lighter green in color. The occurrence of Schuffner's dots is 
 characteristic of tertian infection. The youngest "ring-forms" are larger, more 
 veil-like in appearance, and more noticeably amoeboid than are the "ring- 
 forms" of any other species. The pigment when developed is in finer, lighter 
 brown granules than in the other species, and is much more actively motile. 
 The organism after the development of pigment and until within a few hours of 
 segmentation is actively amoeboid, thus leading to an irregularity in shape that 
 is characteristic. When fully developed the organism fills the entire red cell, 
 which is greatly enlarged, often twice to three times the size of a normal red cell. 
 
 In stained specimens the youngest tertian "rings" are with difficulty dis- 
 tinguished from those of other species, but with the development of pigment, 
 the larger size of the red cell and the irregular shape of the organism serves to 
 distinguish it from the other species. At all stages it is larger than any of the 
 other plasmodia at a corresponding stage, and the pigment is distributed through- 
 out the protoplasm instead of collected in clumps as in the other species. 
 
 Quartan Plasmodium. — The infected red cell in quartan infection, or 
 infection with Plasmodium malariae, is unchanged or slightly smaller than 
 normal and slightly more greenish in color. The young "rings" are smaller 
 than the tertian "rings," more refractive, regular in shape, and generally 
 contain a little pigment. The larger forms are more refractive, regular in 
 shape, being oval or spherical, and the pigment is in larger, darker brown 
 granules than in the tertian plasmodium, and is collected about the periphery of 
 the organism. The segments number from 8 to 12, while in the tertian form the 
 segments number from 12 to 24. At no stage of development is the infected 
 cell enlarged. 
 
 In stained specimens this species is distinguished by the non-enlargement 
 of the red cell, the fact that when fully developed the organism fills the entire 
 
320 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 cell; the character of the pigment; the more deeply staining chromatin, which 
 is present in larger amount; and the number of the segments. The absence of 
 Schuffner's dots is also a distinguishing point. 
 
 The Aestivo-autumnal Plasmodl^. — The red cells infected with 
 Plasmodium falciparum and Plasmodium falciparum quotidianum are always 
 smaller than the uninfected red cells, and much darker green in color. In 
 infections with these plasmodia the so-called ''brassy corpuscles" occur, and 
 only in such infections. At every stage of development of the plasmodia the 
 infected red cell is smaller than normal, and is generally somewhat irregular 
 in shape. In these infections only the "ring-forms" and the young pigmented 
 bodies are found in the peripheral blood in the vast majority of cases. The 
 red cell is never entirely fdled by either of these plasmodia, generally not more 
 than one-half of the cell being occupied when the parasites are fully developed. 
 The occurrence of crescents is diagnostic of aestivo-autumnal infections. A 
 diagnosis of aestivo-autumnal infection may be made when repeated examina- 
 tions of the blood never show any but hyaline "ring-forms" and small pigmented 
 forms to be present, for in tertian and quartan infections the larger develop- 
 mental forms will be present as well as sporulating bodies. 
 
 The terian aestivo-autumnal plasmodium is differentiated from the 
 quotidian by its larger size, the occurrence of several granules of lighter brown 
 pigment; its less refractive outline; greater amoeboid motion; and by the fact 
 that the tertian crescents are more slender, both male and female, than are the 
 quotidian, and contain a greater amount of pigment. They are also smaller. 
 
 For a more extended discussion of the differential features of the malarial 
 plasmodia the reader is referred to the chapter treating of the morphology of 
 the plasmodia (Chapter II). 
 
 Demonstration of Plasmodia in Sections of Tissue. — It is often desir- 
 able to demonstrate the plasmodia in the organs of fatal cases of malaria, and 
 this may be done by taking smears of the organic pulp, and staining as with 
 blood smears, or by sectioning the invaded organs and then staining. In 
 most instances, where it is desired to simply prove or disprove the existence 
 of a malarial infection, all that is necessary is to make a few smears of the splenic 
 pulp by simply drawing the microscopic slide across the cut surface of the 
 organ and then staining with Wright's stain. Where it is desired, however, to 
 demonstrate the exact situation of the plasmodia in the tissues, it is necessary 
 to section the invaded organs, and to stain the section with some suitable 
 solution. The following method I have found satisfactory: 
 
 The tissue is cut into small blocks not over 3 mm. in diameter, and then 
 passed through 50, 65, 75, and 90 per cent, alcohol, and finally absolute alcohol, 
 allowing about three hours in each alcohol. The tissue should then be washed 
 and left for two hours in chloroform, after which it is embedded in paraffin at 
 a temperature which will just keep the paraffin in a fluid state. The tissue 
 should remain in the paraffin bath for about six hours, and then the paraffin 
 allowed to harden around it, after which sections may be cut with any good 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 7> 21 
 
 microtome, the sections to be as thin as possible, as only in very thin sections 
 will the plasmodia show to advantage when stained. 
 
 For staining Delafield's haematoxylin is very useful, as is methylene 
 blue and Giemsa's stain. It is difficult to secure good results with any of 
 the modifications of the Romanowsky method, although I have seen fairly 
 good staining with the Wright stain. 
 
 The technic of staining the sections is as follows: 
 
 The section is removed from the microtome and placed upon a slide which 
 has smeared upon its surface a little egg-albumin water. The section is then 
 successively washed in xylol to remove the paraffin in 95 per cent, and 
 absolute alcohol and water; and stained with haematoxylin and eosin, thionin, 
 or Wright's stain. The stain should be allowed to remain for from ten minutes 
 to an hour, then washed off with alcohol, and the sections cleared in oil of clove. 
 They are then mounted in balsam, and are ready for examination. Care should 
 be taken in dehydrating with alcohol that all the water is removed, and if it is 
 found that in order to do this too much stain is removed, the alcohol should be 
 blotted off and the section covered with oil of clove, which will complete the 
 dehydration without removing so much of the stain. Care should be taken 
 that during no stage of the staining the sections become dry. In sections of 
 tissue properly stained the plasmodia show well, but appear much smaller than 
 in stained smears or in fresh blood specimens, owing to the shrinkage brought 
 about by the hardening and embedding processes. In sections the chromatin 
 staining is very seldom well defined, and the infected corpuscles do not show 
 distinctly, the plasmodia appearing to lie free within the capillaries. The 
 parasites are most numerous in the smaller capillaries and are scarce in the 
 large vessels. In the smaller vessels the plasmodia occur chiefly along the walls 
 of the vessel, very few being observed toward the center, but in the minute 
 capillaries the plasmodia occur in masses which often occlude them. The 
 plasmodia are often at different stages of development or they may be prac- 
 tically all in one stage of their life cycle. In aestivo-autumnal infections it is 
 common to find the capillaries of the brain and of the spleen filled with spherical 
 pigmented plasmodia of the same size and appearance. In all cases of perni- 
 cious malaria or cases suspected to be such smears of the brain and of the 
 spleen, as well as of the bone-marrow, should be stained and examined, and in 
 addition sections of the brain and spleen should be made. 
 
 The Diagnostic Value of Free Pigment and Pigmented Leucocytes. — 
 The presence of free pigment in the blood is characteristic of malarial infection, 
 but, unfortunately, is of little diagnostic value, as such pigment is so easily 
 simulated by particles of dirt, artefacts, and other matter that it is generally 
 impossible to be sure of the diagnosis of malarial pigment. It is, therefore, 
 unjustifiable to make a diagnosis of malaria, because material resembling 
 malarial pigment is observed free in the blood plasma. Wlien, however, the 
 pigment is observed enclosed in mono- or polynuclear leucocytes; when it is of 
 a characteristic golden-brown or blackish color; and when several pigmented 
 
6~- 
 
 DIAGXOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 leucocytes are observed in two or more smears, carefully prepared, we are 
 justified in making a diagnosis of malarial infection, either past or present ; but 
 under such circumstances it is impossible to diagnose the variety of malarial 
 infection present. The pigment is generally observed in the large mono- 
 nuclear leucocytes, but in my experience it has not been rare to observe pigment 
 in the polynuclear leucocytes. To one who has had experience in the examina- 
 tion of malarial blood the pigmented leucocyte is easy of recognition and is 
 always indicative of a malarial infection. 
 
 The Diagnostic Significance of Blood Counts. — I have already men- 
 tioned the increase of large mononuclears in chronic malarial infections and in 
 infections in which several relapses have occurred. This mononuclear in- 
 crease is believed by Rodgers to be of diagnostic importance, but I am unable 
 to agree with him that such an increase is diagnostic of malarial infection. A 
 similar increase is observed in other acute fevers as well as in chronic infections. 
 Thus in dengue one of the most characteristic blood pictures is a mononuclear 
 increase, while in kala-azar the same condition occurs. I consider it very unsafe 
 to base a diagnosis of malaria upon the differential blood count, and I believe 
 that further research will show that a mononuclear increase is observed in most 
 infections due to the Protozoa. 
 
 Agglutination Test in Diagnosis. — It has been demonstrated by La 
 Monaco and Panichi that the blood serum of patients suffering from malarial 
 fever possesses agglutinative power over the blood of healthy individuals, 
 while Stephens and Christophers have noted the agglutination of malarial 
 sporozoites by malarial blood. This subject is of great scientific interest, as it 
 would indicate the presence of specific precipitins or agglutinins in malarial 
 blood, but the agglutination test is of no practical value at present in the diagno- 
 sis of malarial infection. 
 
 The laboratory diagnosis of malarial infection rests upon the finding of 
 the plasmodia or of pigmented leucocytes in either fresh or stained specimens 
 of blood or in smears or sections of tissue from a suspected case. The best 
 time for the examination of the blood in tertian and quartan cases is a few hours 
 before the chill or at the time of the chill, while in aestivo-autumnal infections 
 the best time for blood examination is a few hours before the expected paroxysm. 
 In the latter class of cases it is not unusual to find that the time of onset of the 
 paroxysm cannot be foretold, and in such instances the blood should be re- 
 peatedly examined, at hourly intervals, until several smears have been looked 
 over, and thus a negative result assured, as not infrequently the plasmodia are 
 very few in number in the peripheral blood and only by repeated examinations 
 will their presence be demonstrated. 
 
 Puncture of Spleen. — I have never found puncture of the spleen necessary 
 from a diagnostic standpoint, and I would earnestly advise against this pro- 
 cedure for such a purpose. The operation is always dangerous where the spleen 
 is enlarged and softened, and it should only be undertaken by one skilled in the 
 technic and under the most careful precautions as regards asepsis and guard- 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 323 
 
 ing against haemorrhage. The spleen should never be punctured unless it 
 reaches well below the border of the ribs, as otherwise there is great danger 
 that the capsule will be torn by the needle coming in contact with the ribs 
 during inspiration, for it is almost impossible to guard against more or less 
 movement of the organ during the pain of the puncture. 
 
 The Examination of the Malarial Mosquitoes. 
 
 It is essential to the student of malaria that he be able to recognize the 
 malarial mosquitoes, and that he possess enough knowledge of their habits to be 
 able to rear them and thus be enabled to procure specimens for experimental 
 purposes. In this section I shall give briefly the most important diagnostic 
 features which serve to distinguish the Anophelinae from other mosquitoes, 
 features which are easily learned and a knowledge of which will enable any one, 
 who cares to take the time, to recognize the presence of malarial mosquitoes; 
 general directions will also be given concerning the rearing of these insects 
 and the methods of using them in experimental work. 
 
 Fig. 24. — Diagram of Typical Anophelina. 
 
 A, Proboscis; B, palpi; C, Cylpeus; D, eye; E, occiput; F, prothoracic lobe; G, mesothorax; 
 H, scutellum; I, metathorax; J, abdominal segments; K, halter; L, legs; M, wing; N, antenna. 
 (Modified from Theobald.) 
 
 Diagnosis of Malarial Mosquitoes. — The Anophelinae, or malarial 
 mosquitoes, are easily differentiated from other mosquitoes by certain well 
 marked characteristics of the adult insect, which may be summarized as follows: 
 
 1. The Relative Length of the Palpi and the Proboscis. — In the 
 Anophelinae the palpi of the female are as long as the proboscis, while in 
 the female Culicinae the palpi are short, stubby structures. An examination 
 of the palpi and proboscis of any mosquito will, therefore, enable one to say 
 
324 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 whether it belongs to the Anophelinae or the Culicinae. In the males of both 
 the Anophelinae and the Culicinae the palpi are long and plumose, being 
 covered with delicate hairs, giving a plume-like appearance. 
 
 2. The Angle of the Proboscis with the Body. — In the Anophelinae 
 the proboscis does not form an angle with the rest of the body, but continues in 
 a direct line with it, thus differing from Culex, Stcgomyia, and Taenio- 
 rhynchus, in which the proboscis forms a distinct angle with the rest of the body. 
 This characteristic gives mosquitoes belonging to the Anophelinae a peculiar 
 "business-like" appearance, the entire insect resembling a boring instrument. 
 
 3. The Attitude when Resting Upon a Surface. — Mosquitoes belong- 
 ing to the Anophelinae, when resting upon a flat surface, such as a wall, form a 
 distinct angle with the surface, the insect resting upon the first two pairs of legs, 
 the last pair floating in the air or held out straight behind it. In many instances 
 the angle maintained by the insect is almost a right angle, and the body 
 is always on a line with the probosis. The position assumed by other mos- 
 quitoes, as Culex, is well described as "hunch-backed," the tail approaching 
 the resting surface, while the thorax is distinctly higher than any other portion of 
 the body, thus giving the "hunched" appearance. Certain mosquitoes rest 
 with the body parallel to the resting surface, but the Anophelinae alone form a 
 distanct angle with it. One species belonging to the Anophelinae, Myzomyia 
 culicifacies Giles, rests with its body parallel to the resting surface, thus resem- 
 bling a Culex, but this is the only exception so far discovered to the general rule 
 noted (see Fig. 20). 
 
 4. Most of the Anophelinae have Spotted Wings, but this is also true 
 of at least a few other mosquitoes. However, for practical purposes, mosqui- 
 toes having distinctly spotted wings may be classed as Anophelinae. For 
 species determination the reader is referred to the generic table given, and to 
 Theobald's classic work upon these insects. 
 
 The ova of the Anophelinae may be distinguished by the fact that they lie 
 separately upon the water, or, at most, are only connected by the ends, while 
 the ova of Culex occur in boat-shaped masses. The ova of the Anophelinae are 
 also provided with lateral air-cells or "floats," which are characteristic. The 
 larvae of all Anophelines are easily distinguished from those of Culex by the 
 absence of a respiratory siphon, so that when they are at the surface of the 
 water they are obliged to lie nearly parallel to it, while Culex hangs head down- 
 ward at an acute angle with the surface of the water. The larvae of the Anophe- 
 linae have smaller heads in proportion to the body than other mosquito larvae, 
 and they move in a much more jerky manner when rising to the surface of the 
 water (see Fig. 18). 
 
 The Collection of Ova, Larvae, and Adult Mosquitoes. — The ova of the 
 Anophelinae may be collected along the edges of small natural pools, but they 
 are detected with difficulty, and a much more satisfactory method of obtaining 
 them is to catch a number of the mature insects, confine them in jars containing 
 water, and collect the ova from the surface of the water for examination. 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 325 
 
 The larvae of the Anophelinae may be collected from the edges of small 
 puddles, shallow pools, and slowly running streams, by muddying the water, 
 when the larvae, if present, may be clearly distinguished by reason of their 
 grayish color, and can be easily removed by aid of a small dipper. The adult 
 insects may be captured at night by placing a lamp so that a portion of a wall is 
 but slightly lighted, upon which the mosquitoes will gather, and from which they 
 may be captured by aid of a test-tube having a large mouth, or of small straight 
 glass cylinders, closed at one end. Cotton should be used to close the open end 
 of the cylinder or tube. If it is desired to kill the mosquitoes as they are col- 
 lected, a cyanide bottle may be used, or a little cotton saturated with chloro- 
 form may be placed at the bottom of the test tube or cylinder. When it is 
 desired to collect mosquitoes for rearing or for experimental work the test-tube 
 or cylinder should be gently placed over the insect, as it rests upon the wall, and 
 then gently moved across the surface of the wall, when the insect will fly to the 
 closed end, and the tube may then be sealed with the cotton stopper. The best 
 places to search for the adult Anopheles is in the dark corners of rooms; under 
 surfaces of tables and sinks; in closets; and about the base-boards of rooms not 
 exposed to sunlight. In regions in which these insects are common a search of 
 such localities will always result in finding many specimens. 
 
 To Kill and Mount Mosquitoes. — Mosquitoes may be killed by exposing 
 them to tobacco smoke, the fumes of chloroform, or by using a cyanide bottle 
 in their capture. If chloroform is used be careful not to wet the insect, as 
 by so doing the scales are removed from the wings and thus a distinguishing 
 feature, useful in the differentiation of species, is lost. In order to properly 
 mount mosquitoes for purposes of preservation the following apparatus is nec- 
 essary: Cardboard, preferably white; entomological pins and forceps, the 
 pins being large and small (No 20) ; and glass specimen tubes and corks. 
 
 A disk, slightly smaller than the diameter of the specimen tube, is cut from 
 the cardboard, and a fine entomological pin is pushed through the center of 
 the disk for about two-thirds its length. The mosquito is placed upon its 
 back upon a piece of white paper, and transfixed with the fine entomological 
 pin which has attached to it the paper disk, the pin entering the insect at the 
 center of the under surface of the thorax, and emerging as close to the center of 
 the dorsum of the thorax as possible, where it should extend for about a milli- 
 meter. The entire specimen is now mounted by transfixing the edge of the 
 paper disk with a coarse entomological pin or a common pin in a direction 
 opposite that of the fine pin, for three-quarters of its length, the point being 
 pushed into the cork of the specimen tube upon its inner side (see Fig. 25). 
 
 To Dissect Mosquitoes. — In order to make good dissections of the Anophe- 
 linae for the purpose of detecting malarial infection or for studying the develop- 
 ment of the plasmodia within these insects the following apparatus is necessary: 
 Microscopic slides and cover-glasses; fine dissecting needles, mounted in handles; 
 a good dissecting microscope, and some normal salt solution. A compound 
 microscope with high-power lenses is, of course, necessary for studying the 
 
26 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 development of the plasmodia. The portions of the mosquito of greatest 
 interest to the student of malaria are the salivary glands and the mid-gut or 
 stomach. 
 
 To Dissect the Salivary Glaxps. — While in most works upon mosquitoes 
 it is said to be a simple procedure to dissect out the salivary glands, it will be 
 found in practice that it is indeed a very difficult task to secure perfect specimens 
 of these glands, although it is comparatively easy to secure portions of the glands 
 sufficiently perfect to allow of demonstrating the sporozoites. The glands are 
 situated within the thorax, lying ventrally, commencing at 
 the posterior portion of the neck and ending at the level of 
 the first pair of legs. The simplest way of securing them 
 for study is to cover the insect with salt solution and place 
 it so that the head is toward the dissecting hand. While 
 the needle of the left hand steadies the thorax, the needle 
 of the right hand makes traction upon the head, separating 
 it gently from the body. If the operation has been suc- 
 cessful it will be observed that a little white bit of tissue 
 has been extracted from the thorax with the head, and 
 upon examination with the microscope it will be observed 
 that in this bit of tissue lie the salivary glands, which 
 may now be separated from the head and carefully 
 studied. The glands may also be isolated by making an 
 antero-posterior cut in the ventral portion of the thorax 
 and a connecting cut at right angles with it, and then sep- 
 arating the glands from the portion of thorax removed by 
 teasing gently in salt solution, but this method almost 
 always results in mutilation of the glands. 
 
 In order to determine the presence of malarial sporo- 
 zoites the glands are pressed, upon firmly enough to 
 rupture them, when the sporozoites, if present, will be 
 liberated in the salt solution. A one-sixth lens should be 
 used for the examination and as little light as possible. 
 The sporozoites appear as fine, hyaline, curved rods, having more or less active 
 motion in some instances, lying free in the salt solution or in large numbers 
 within the cells of the salivary glands. They measure about 14^ in length, 
 and about 2^ in width. They may be permanently preserved by making thin 
 films of the salt solution containing them upon glass slides, and drying and 
 staining with Wright's stain, as described for blood films. For the study of 
 the morphological structure of the sporozoites a one-twelfth lens is essential. 
 In stained specimens the sporozoites are fusiform in shape, consisting of blue 
 stained protoplasm having a mass of red chromatin at the center or distributed 
 along it in the form of a narrow ribbon or thread. 
 
 To Dissect the Mid-intestine or Stomach. — The dissection of the 
 mid-intestine of the mosquito is essential if we are to study the development 
 
 Fig. 25. — Method of 
 Mounting and Pre- 
 serving Mosquitoes. 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. • 327 
 
 of the malarial plasmodia within this insect, and with a little practice it is easily 
 accomplished. The insect, from which the wings and legs have been removed 
 by dissecting forceps, is moistened with a little alcohol and then immersed in 
 the salt solution upon a glass slide, a dark background being employed to 
 facilitate the dissection. Placing the insect upon its back, the left-hand needle 
 is used to steady it, while with the right a nick is made in the chitin on 
 either side as near the posterior end as is possible; the left-hand needle is now 
 placed firmly upon the thorax, and the right upon the end of the abdomen 
 and gentle traction exerted, when between the separating abdominal segments 
 a white mass of viscera will be observed; the traction is continued until it 
 is possible to separate easily the anterior end of the mid-gut, which consists of 
 an anterior tubular portion and a posterior saccular portion, lying at the level of 
 the fifth and sixth abdominal segments, and which is the portion in which 
 zygotes will be found if the mosquito is infected. If it is found that this portion 
 of the mid-gut contains blood, the specimen should be discarded, unless it be 
 desired to study exflagellation, as the zygotes cannot be distinguished easily 
 in the mid-gut when undigested blood is present. In examining mosquitoes 
 for malarial infection it should be remembered that only a comparatively 
 few of the insects collected will prove to be infected and therefore several insects 
 should be examined before a negative report is of value. 
 
 Demonstration of Zygotes. — The specimen of the mid-gut or stomach 
 should be examined with both a one-sixth and a one-twelfth lens, the larger 
 zygotes being easily visible with a one-sixth lens, while for the detection of the 
 earlier stages a one-twelfth lens is necessary. Any granule resembling malarial 
 pigment should be carefully inspected, as by so doing the zygotes are most 
 quickly discovered, even in the earliest stage of development. The earliest 
 stage is an oval or spherical body, about 8// in diameter, containing pigment,. 
 the character of which varies with the species of the plasmodium, the aestivo- 
 autumnal zygotes having black pigment collected in a clump; the tertian, yellow- 
 ish or brown pigment collected in delicate strands; and the quartan, coarse 
 dark brown pigment collected in a large clump. As development advances, the 
 species of the zygote becomes indistinguishable, and each organism is surrounded 
 by a well-developed cyst wall, within which the sporoblasts are developed. At 
 a later period of development the sporozoites may be observed packing the 
 cysts, which have become so large as to be visible with a two-thirds inch lens, 
 while the sporozoites are easily seen with a one-sixth lens. The pigment disap- 
 pears in many of the zygotes as development proceeds, but many contain black 
 clumps of material, which probably represents residual pigment, or parasitic 
 infection. 
 
 To Section Mosquitoes. — The following method, advocated by Stephens 
 and Christophers and given in their own words, is an excellent one when it 
 is desired to section infected mosquitoes for purposes of study and demon- 
 stration. 
 
 1. Select Anophelines free from blood and kill by chloroform vapor. 
 
o 
 
 28 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 2. Fix in (a) acetic alcohol for 5 or 10 minutes (glacial acetic acid one 
 part, absolute alcohol, six parts, chloroform, three parts); wash in absolute 
 alcohol till free from acid (it is often advisable, especially with thick flies, to 
 nick the chitin at some unessential part in order to allow penetration of the 
 fixative), or (b) sublimate alcohol, or (c) absolute alcohol, 15 minutes. 
 
 3. Place in 1 per cent, celloidin for a day and in 3 per cent, celloidin for 
 another clay. These times may with advantage be increased, but sometimes 
 a few hours only suffice. (The solution of celloidin is made by dissolving dry 
 chips in 50 per cent, alcohol and then in a day or so adding 50 c.c. of ether. 
 
 4. Transfer to cedar- wood oil, and when the mosquito sinks transfer to 
 
 5. Paraffin for half to one hour, and then section and strain. 
 
 To Rear Mosquitoes. — Many species of Anopheles are reared with great 
 difficulty under artificial conditions, but others breed well in confinement. The 
 more nearly we imitate nature in the surroundings of our rearing cages for 
 mosquitoes, the greater will be our success in rearing these insects. Cages 
 built of light wood and covered with fine wire gauze are suitable and each 
 should contain a vessel of water. Glass jars containing water and vegetable 
 material make good breeding-places , and pieces of large bambo "sawed off some 
 distance from the joints have been used with great success by many investi- 
 gators. When jars or other open-mouthed receptacles are used the open end 
 should be covered with gauze. 
 
 A goodly number of mosquitoes should be captured, both males and 
 females, and liberated in the breeding receptacle, which should be placed in a 
 shaded part of the room or in a closet. The males soon die, but the females 
 will, many of them, lay their eggs, and in due time the larvae will appear. The 
 insects may be fed by placing small pieces of banana within the cages or by 
 laying slices of banana upon the gauze covering the jar or other breeding place. 
 Dead insects should be removed each morning, and, with care, adult insects may 
 be kept for many days in this manner. If it is desired to breed out the larvae 
 they should be removed from the cage and placed in a jar of water exposed to 
 light but not to excessive heat. The insects live longer in glass jars than in 
 gauze cages, as a general rule. 
 
 Feeding Experiments. — When mosquitoes are required for feeding 
 experiments they should be removed from the breeding jar and transferred to a 
 glass jar having a wide neck covered with cotton gauze, where they should be 
 kept for at least three days without food. It is better to use mosquitoes bred out 
 from the larvae in such experiments, as they are sure to be free from infection, 
 and will bite readily 48 hours after birth. At least 25 mosquitoes should be 
 used in each feedng experiment, in two jars. A patient is selected whose 
 blood contains gametes, and, after dark, allowed to place his arm over the 
 gauze covered neck of the jars. Biting is hastened by washing the arm in warm 
 water just before the experiment. The insects usually bite within half an 
 hour, but it will be found that some of them require a longer time to bite and 
 that some will not bite. It is well to wait for an hour before ceasing the ex- 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 329 
 
 periment, thus allowing the insects plenty of time. The jar should be labeled 
 with the time and date of biting, and the insects dissected at various intervals 
 after the first twenty-four hours if it is desired to follow the development of 
 the plasmodia, or kept for twelve days before allowing them to bite if we 
 desire to transmit malaria experimentally. 
 
 The Diagnosis of Malarial Regions. — Before establishing residences or 
 permanent military camps or posts in the tropics or in regions in which mos- 
 quitoes capable of transmitting malaria abound, it is of the greatest importance 
 that the presence or absence of the malarial fevers be determined and in the ex- 
 amination of the blood of the natives, and the mosquitoes, as to the presence of 
 malarial infection, we possess methods which enable us to make a malarial 
 survey of any locality. 
 
 A map of the locality should be obtained and there should be marked upon 
 it the location of the breeding-places of mosquitoes and the species found in each 
 breedery, also whether any of the insects examined were found to be infected 
 with plasmodia; the dwellings of any individuals found infected with malaria 
 during the blood examination of the natives should be indicated upon the map, 
 and thus the relation of the breeding-places of the mosquitoes to such infections 
 will be clearly shown. The map should also show the ratio of infected indivi- 
 duals and of infected mosquitoes, and the most dangerously infected localities. 
 The work of a few days in the examination of the blood of the natives, the 
 dissection of mosquitoes, and the search for the breeding-places of these insects 
 will result in a most valuable mass of data enabling one to judge of the advisa- 
 bility of locating in the region examined. Such a preliminary survey of the 
 malarial endemicity of localities is of the very greatest sanitary importance in 
 the selection of camp sites of a permanent nature or sites for permanent military 
 posts in the tropics and in the malarial regions of the temperate zones. 
 
CHAPTER II. 
 
 The Clinical Diagnosis of the Malarial Fevers; The Differential 
 Diagnosis of the Malarial Fevers. 
 
 As I have stated the diagnosis of malarial infection, without the aid of 
 laboratory assistance, is often impossible, and still more frequently is it impos- 
 sible to diagnose the variety of infection present. In uncomplicated and single 
 tertian and quartan infections a diagnosis may be reached by the study of the 
 temperature chart, the regularly recurring paroxysms of fever being sufficient to 
 establish the type of infection present, but in many cases of both tertian and 
 quartan malaria the temperature chart is misleading, the paroxysms occurring 
 at irregular intervals, thus causing an irregular temperature curve. It is in the 
 aestivo-autumnal infections, however, that we most frequently find it impos- 
 sible to arrive at a diagnosis without the aid of the microscope, for these in- 
 fections occur in so many atypical forms that the diagnosis from clinical 
 symptoms alone is seldom easy and very frequently impossible. The micro- 
 scopical examination of the blood is the only infallible method of arriving at a 
 diagnosis and should never be neglected. The therapeutic test by quinine, i.e., 
 the administration of the drug in suspected cases, has been lauded as a means of 
 diagnosis, but the malarial fevers are not the only fevers that are influenced by 
 this drug, and it is illogical to regard every fever that declines after the ad- 
 ministration of quinine as malarial. Added to the worthlessness of the 
 quinine test as a diagnostic test of malaria, it is dangerous to rely upon this 
 drug in diagnosis, for it is usually given by the mouth in such instances 
 and it is well known that many pernicious infections are very resistant to 
 quinine when so administered. In this way the diagnosis may be delayed until 
 the patient is in grave danger or even moribund. While it is undoubtedly true, 
 as stated by Osier, that any fever which resists the action of quinine properly 
 administered for over four or five days is not malarial in character, it is foolish 
 to wait so long to establish our diagnosis when a few moments' examination of 
 the blood will enable us to reach the same conclusion. 
 
 Certain factors are of value in arriving at a suppositional diagnosis of 
 malarial fever, among the most important of which may be mentioned the time 
 of occurrence of the disease; the character of the locality in which the patient 
 is resident or from which he has come; the location of the dwelling-house in 
 relation to water and thus to possible breeding-places of mosquitoes; the history 
 of previous attacks; the periodicity of the attacks; the species of mosquitoes 
 present; and the occurrence of similar fevers in other members of the family. 
 
 Diagnosis of the Various Forms of Malarial Fever. — A differential 
 
 33° 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 33 1 
 
 diagnosis of the various types of malarial infection is most quickly and scientifi- 
 cally made by an examination of the blood. In this way the entire life cycle 
 of the tertian and quartan plasmodium may be studied, and the aestivo- 
 autumnal plasmodia easily differentiated. Where, however, an examination 
 of the blood is impracticable, clinical symptoms have to be relied upon to 
 determine the type of infection and in a limited proportion of cases such 
 symptoms are sufficient. 
 
 Tertian Infection. — The temperature range in uncomplicated cases of 
 tertian infection is so typical that a temperature chart is often all that is needed 
 to enable us to make the diagnosis. The occurrence of a definite paroxysm, 
 accompanied by chill, fever, and sweating, every 48 hours, is generally sufficient 
 to prove the type of malaria present, but certain cases are indistinguishable 
 clinically from mild tertian aestivo-autumnal infections, while if double tertian 
 infections be present or small doses of quinine have been administered, it 
 becomes impossible to distinguish the type of infection present without the aid 
 of the microscope. 
 
 Quartan Infection.- — In uncomplicated cases of quartan infection the 
 temperature chart is absolutely characteristic. The occurrence of a paroxysm 
 of chill, fever, and sweating every seventy-two hours is absolutely characteristic 
 of quartan malarial infection and we may safely make a diagnosis of such 
 infection under such conditions, but double and triple infections occur in which 
 the temperature chart is untrustworthy, and in these we have to depend upon the 
 microscope in diagnosing the type of malaria present. 
 
 Quotidian Aestivo-atumnal Infection. — When an aestivo-autumnal 
 infection is known to be present, the diagnosis of the quotidian form from the 
 tertian is comparatively easily made, because of the usual occurrence of a distinct 
 chill in the quotidian form and the character of the temperature curve. The 
 differential diagnosis of this type from a double tertian or triple quartan infec- 
 tion is, however, impossible without the aid of the microscope. 
 
 Tertian Aestivo-autumnal Infection. — While the diagnosis of the 
 tertian type of aestivo-autumnal fever from the clinical symptoms alone is very 
 often impossible, there not infrequently occur cases in which this form of 
 malarial infection may be diagnosed from the temperature chart alone. I have 
 already described the peculiar range of the temperature in tertian aestivo- 
 autumnal infection when uncomplicated, and a chart showing this peculiar 
 curve, which is not found in any other fever, is absolutely diagnostic, provided 
 the temperature be taken at least every four hours. It is obviously illogical, 
 however, to wait several days until such a typical chart is obtained, when an 
 examination of the blood upon the very first day will clear up the diagnosis. 
 In tertian aestivo-autumnal fever the chill is, as a rule, either absent or very 
 slight, and the general symptoms of no value in making a differential diagnosis, 
 aside from the temperature. 
 
 Pernicious Infections. — These infections, usually due to the aestivo- 
 autumnal plasmodia, are easily diagnosed from the benign fevers by the 
 
332 DIAGNOSIS, PROPHYLAXIS. AND TREATMENT OF MALARIAL FEVERS. 
 
 character and severity of the symptoms, which have already been described. 
 From other disease processes they can very seldom be diagnosed without the 
 aid of the microscope, and it is safe to say that hundreds of lives have been 
 sacrificed to malaria which could have been saved had an examination of the 
 blood been made in the endeavor to arrive at a diagnosis. In all cases in which 
 a suspicion of malaria exists, and especially in those cases presenting pernicious 
 symptoms, the first thought of the diagnostician should be the microscopical 
 examination of the blood. 
 
 I have noted the most important differential features of the various types 
 of malaria, but I would impress upon the reader the vital importance of an 
 examination of the blood in the diagnosis of malaria. The data we possess 
 regarding the occurrence of malarial fevers in various localities, and the type 
 of infection present, are almost worthless, because the cases have been diagnosed 
 upon clinical symptoms, the examination of the blood being neglected, 
 and the obsolete classification of the malarial fevers, so often observed in the 
 vital statistics of the public services, is directly due to the constant endeavor 
 to diagnose malaria by clinical symptoms instead of by the examination of 
 the blood. The absurdity, for instance, of a classification of malarial fevers 
 based upon the intermittency or remittency of the temperature curve is evident 
 at once to one who has had even a limited experience with these fevers, and such 
 classifications are a reproach to scientific medicine. Aside, however, from this 
 aspect of the subject, the life of many patients depends upon the quick recogni- 
 tion of the malarial infection, and this is only possible through the microscopical 
 examination of the blood. 
 
 The Differential Diagnosis of the Malarial Fevers. 
 
 The differential diagnosis of the malarial fevers from other diseases is 
 only possible, in many instances, by an examination of the blood, and this 
 should never be neglected when we are called to see a fever in malarial localities 
 or in an individual returning from such a locality. The difficulty of a differential 
 diagnosis by aid of clinical symptoms alone is especially great in the case of 
 the aestivo-autumnal infections in which the occurrence of atypical symptoms 
 are common and in which pernicious symptoms occur which simulate those 
 present in other specific diseases. The following diseases not infrequently have 
 to be differentiated' from malarial fever, and most of them are sometimes so 
 closely simulated by malaria that the differential diagnosis has to be made by 
 the microscope. 
 
 Typhoid Fever. — Perhaps no other disease has been so often mistaken for 
 malaria as has typhoid, and if there is anything in the history of medicine which 
 proves the futility of attempting to diagnose the malarial fevers by clinical 
 symptoms alone, it is the experience of our surgeons in the war with Spain. 
 When one has seen, as the writer has, hundreds of cases of severe typhoid 
 diagnosed as remittent malaria and treated accordingly, one is inevitably 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 333 
 
 forced to the conclusion that the diagnosis of the malarial fevers by means of 
 clinical symptoms alone is, to say the least, attended with great difficulty, and 
 places the patient in peril of his life in many instances. At least three-fourths 
 of the fevers occurring in our Southern camps during 1898 and diagnosed as 
 "remittent malarial fever" were, in reality, typhoid, as shown by the examina- 
 tion of the blood and the Widal test. Clinically, the confusion of these two 
 diseases has much to justify it. It is probable that a typical tertian or quartan 
 malaria is never suspected to be typhoid, or vice versa, but in the more irregular 
 aestivo-autumnal infections this mistake has often been made. This is so 
 because many cases of aestivo-autumnal malaria present the same sympto- 
 matology, at least in part, as typhoid, and without an examination of the blood 
 it is impossible to arrive at a diagnosis. The mistake, however, of considering a 
 typhoid infection as one of malaria after the administration of quinine for over 
 five days without result is, it appears to me, inexcusable, yet I have observed 
 scores of cases of typhoid given large doses of quinine for weeks under the 
 impression that they were suffering from malarial infection, and in supposedly 
 malarial regions almost every typhoid patient is drenched with quinine simply 
 because of the neglect of the blood examination. 
 
 The differential diagnosis depends upon the microscopical examination of 
 the blood, the Widal test, and the therapeutic test by quinine. If the plasmodia 
 are present in the blood and the Widal test is negative, the diagnosis is at once 
 established; if the Widal be positive and there is no history of a previous at- 
 tack of typhoid, we are dealing with a combined infection, but it should be 
 remembered that such infections are very rare, and a careful inquiry should be 
 made concerning the previous occurrence of a continued fever; if the Widal test 
 be positive and no plasmodia are present, after repeated examinations, the case 
 is one of typhoid; while if neither the plasmodia be present nor a positive Widal 
 can be secured after repeated trials, the fever must be due to some other in- 
 fection. If a blood examination is impossible and a Widal test cannot be made, 
 the administration of quinine for three or four days will clear up the diagnosis, 
 as if the case is malarial the quinine will reduce the temperature within five 
 days, if properly administered. During the defervescence of the fever in typhoid 
 the temperature may become intermittent, the curve resembling that of a 
 double tertian or quotidian aestivo-autumnal infection. (Chart No. 19.) 
 Chills may also occur at this time, during the onset, or at any time during the 
 course of the disease; thus further increasing the resemblance to malaria, and in 
 such cases a diagnosis is often made of " typho-malarial" fever. Any diagnosis 
 of malarial fever under such circumstances is utterly worthless unless confirmed 
 by a blood examination. With the Widal test, and the improved methods we 
 . possess of staining the malarial plasmodia it is inexcusable to-day to fail in 
 differentiating the malarial fevers from typhoid fever. 
 
 Yellow Fever. — In regions in which both malaria and yellow fever are 
 endemic the differentiation of these diseases is often exceedingly difficult with- 
 out a blood examination, and pernicious cases of aestivo-autumnal fever are not 
 
[34 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 
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DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 335 
 
 infrequently mistaken for yellow fever. This is especially true of the so-called 
 bilious remittent and haemorrhagic forms of pernicious malaria, in which the 
 yellow tint of the skin, the congested eyes, the flushed cheeks, the severe vomit- 
 ing, often of black fluid resembling the dreaded "black vomit," the high tem- 
 perature, and the not infrequent occurrence of albumin in the urine, form a 
 clinical picture closely resembling that of yellow fever. A patient presenting 
 such a picture in a yellow fever region is almost always thought to be suffering 
 from that disease, and in such cases the examination of the blood is of the very 
 greatest importance. 
 
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 of interest and importance, as kala-azar was for years considered a chronic 
 form of malarial infection, and only with the discovery of the Leishmania- 
 donavani was the distinction recognized and the differentiation of the two 
 diseases made possible. In kala-azar we have an enlarged spleen, anaemia, 
 an irregular temperature curve similar to that of many cases of aestivo-aulum- 
 nal malaria; and an examination of the blood will alone enable us to be sure of 
 our diagnosis. 
 
 Dengue. — The malarial fevers may be confused with dengue fever, but in 
 the latter disease the more severe character of the muscular pains and the 
 occurrence of an eruption will, in most cases, serve to distinguish the two. An 
 examination of the blood is often necessary, however, and should never be 
 neglected. 
 
 Malta Fever. — In regions in which Malta fever occurs there is often much 
 difficulty in differentiation between this disease and the more atypical forms of 
 the aestivo-autumnal fevers. An examination of the blood will at once demon- 
 strate the plasmodia if malarial infection be present, and a positive reaction will 
 be obtained from the blood with the agglutination test with Micrococcus meli- 
 tensis, if Malta fever be present. 
 
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 taken for malaria may be mentioned puerperal fever, which has already been 
 discussed; septicaemia and pyaemia, in which the chills, occurring at regular 
 intervals, followed by fever and sweating, often produce a picture very suggestive 
 of malarial fever; pyelitis attended by chills and fever; the early stages of the 
 eruptive fevers; relapsing fever, in which the demonstration of the spirochaetae 
 in the blood is sufficient to establish the diagnosis, and trypanosomiasis , which 
 depends for its diagnosis upon the demonstration in the blood of Trypanosoma 
 gambiense. All of these conditions may be easily differentiated from the 
 malarial fevers by a careful microscopical examination of the blood. 
 
 Tuberculosis. — Many cases of tuberculosis, especially if complicated by 
 a streptococcus infection, exhibit a temperature curve closely resembling that of 
 a double tertian or a quotidian aestivo-autumnal infection, and there may also be 
 daily chills or chilly sensations, while the patient presents the anaemia and the 
 facies so often observed in long-continued malarial infections. There is no 
 enlargement of the spleen, however, and an examination of the chest will show 
 
56 
 
 6 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 
 
 
 
 
 
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DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 337 
 
 lesions not found in malaria. The examination of the blood for the malarial 
 Plasmodia and of the sputum for Bacillus tuberculosis will definitely establish 
 the diagnosis. Not very rarely cases of tuberculosis are complicated by some 
 form of malarial infection, and thus an examination of the blood is of great 
 importance, as the discovery of the malarial infection and its removal will 
 greatly benefit the patient. Such cases are usually stumbled upon accidentally 
 while examining the blood of tubercular patients for leucocytosis, but it should 
 be a routine practice, in malarial regions, to examine the blood of all tubercular 
 patients, presenting chills and a temperature above ioo° F., for the malarial 
 Plasmodia. (Chart No. 20.) 
 
 Hepatic Abscess. — In regions where amoebic dysentery is endemic, cer- 
 tain patients suffering from hepatic abscess due to the amoebae may present 
 symptoms which closely simulate those of malarial fever; thus, there may be 
 chills occurring at daily intervals, and a temperature curve, which, while that of 
 sepsis, very closely simulates that of some of the forms of aestivo-autumnal 
 malaria. The chief clinical points in favor of hepatic abscess are enlarge- 
 ment of the liver and tenderness over the hepatic region, while the spleen is not 
 enlarged; the occurrence of very profuse perspiration, independently of the 
 decline of the fever, and the history of dysentery. An examination of the blood 
 will establish the diagnosis of malaria by the finding of the plasmodia, while in 
 those cases in which the symptoms are suggestive of a chronic malarial infection, 
 the absence of plasmodia or pigmented leucocytes and the presence of a leuco- 
 cytosis would point to the presence of hepatic abscess. I have observed more 
 than one case in which autopsy showed the presence of multiple abscesses in 
 the liver of patients diagnosed and treated for malaria, so that this mistake 
 is one that is frequently made and one that should be carefully guarded 
 against. 
 
 Ulcerative Endocarditis. — The temperature curve in ulcerative endocar- 
 ditis often resembles that of a quotidian malaria, while there may be present 
 paroxysms of chill, fever, and sweating. Dock has published a very interesting 
 case of this kind, the chart of which is here reproduced. (Chart No. 21.) 
 Examination of the heart will generally suffice to determine the nature of such 
 cases, and if not, an examination of the blood will generally settle the question 
 at once. 
 
 Dysentery. — As has been shown, malarial infection may occur with 
 dysentery, and the removal of the malarial element in a large proportion of such 
 cases results in a rapid improvement in the dysenteric symptoms and their final 
 disappearance. In view of this fact, i.e., that malarial infection is capable of 
 producing the clinical symptoms of dysentery, it is important that we be able to 
 differentiate between these cases and true cases of dysentery, either amoebic 
 or specific. The examination of the blood and of the faeces should quickly enable 
 us to differentiate dysentery and the malarial fevers, and such an examination 
 is most useful also in that it will often result in demonstrating a combination of 
 the two diseases. 
 
00 
 
 8 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
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DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 339 
 
 Cerebral Apoplexy. — The differential diagnosis between cerebral apoplexy 
 and some forms of pernicious malaria, such as the comatose form, is often 
 extremely difficult without a blood examination. Cerebral pernicious malaria 
 is often manifested by coma, stertorous breathing, loss of reflexes, and other 
 symptoms which so closely simulate apoplexy that a clinical diagnosis is almost 
 impossible. The main clinical points to be relied upon in differentiating the 
 two are the high fever in malaria, although this is not constant; the age of the 
 patient, and the presence of splenic enlargement if the cause be malarial. An 
 examination of the blood should be made at once in all cases of sudden loss of 
 consciousness in malarial regions. 
 
 Sunstroke. — In tropical or subtropical regions certain cases of pernicious 
 malaria very closely simulate sunstroke. I have already described such cases 
 and have spoken of the fact that heat very often aggravates or brings on severe 
 malarial paroxysms. It is therefore necessary that we be sure that an apparent 
 case of sunstroke is not in reality a case of pernicious malarial fever, and a 
 microscopic examination of the blood is our only means of assuring ourselves 
 of this fact. I can recall three instances in which men were brought to the 
 hospital supposed to be suffering from sunstroke, whose blood, when examined, 
 was found to be teeming with malarial plasmodia. The history of no previous 
 attacks of malaria; the lack of anaemia; and the absence of splenic enlarge- 
 ment will aid us in arriving at a diagnosis of sunstroke, but an examination of 
 the blood should never be neglected. 
 
 Among other disease processes which may be confused with malaria may be 
 mentioned cholera, in which the diagnosis rests upon a blood examination; 
 disease of the gall-bladder and bile-ducts, if suppurative; lobar and lobular 
 pneumonia; WeiVs disease; purpura haemorrhagica, anduraemia. A microscopi- 
 cal examination of the blood will suffice to differentiate the malarial fevers from 
 any of these conditions. 
 
 Leukaemia. — In very rare instances the malarial fevers may be confused 
 with leukaemia, as in the latter disease chills and fever frequently occur, and 
 more or less anaemia is present. Very rarely leukaemia is complicated by 
 malaria and a microscopical examination of the blood will result in a diagnosis of 
 both diseases. I have records of a most interesting case of this kind in the 
 person of a young soldier who entered the hospital for the first time, suffering 
 from a chill and a temperature of 103 F. The blood was sent to the laboratory 
 for examination for malaria, and was found to present the typical picture of 
 myeloid leukaemia, but upon a hasty examination no malarial plasmodia were 
 found. However, a blood count showing 1,520,000 leucocytes per cu. mm. and 
 only 410,000 red cells per cu. mm. indicated a more careful examination of the 
 blood, which resulted in finding numerous tertian plasmodia, thus proving that 
 the symptoms present were indeed malarial in character, and that the patient 
 was in addition suffering from leukaemia, which had not been suspected. The 
 spleen in this case reached to the umbilicus, but had never occasioned the man 
 any trouble. The very great reduction in the red corpuscles is of interest, being 
 
34° DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 produced by the combined action of the leukaemia and the plasmodia. The 
 
 elimination of the malarial infection resulted in a rise of the red blood count to 
 over 2,000,000 cells per cu. mm. 
 
 It is from the study of such cases as this that we realize the importance of a 
 blood examination in every febrile condition, and with the improvement in our 
 microscopical methods, the reduction in the cost of microscopes, and the op- 
 portunities given every physician to master the technic of blood examinations, 
 it may be truly said that he who to-day loses a patient from malarial fever be- 
 cause of inability to recognize the disease, bears upon his shoulders a heavy 
 weight of responsibility which no regret will lessen. 
 
 Literature upon the Laboratory and Clinical Diagnosis of the Malarial Fevers. 
 Literature upon Staining Methods. 
 
 1888. Chenzinsky Lehre liber den Microorganismus des Malaria- fiebers. 
 
 Centralbl. f. Bakt. Referat. iii, No. 15, p. 457. 
 1 89 1. Romano wsky. Zur Frage der Parisitologie u. Therapie der Malaria. 
 
 St. Peters. Med. Woch., Nos. 34 and 35. 
 
 1897. M anson, P. A. Method of Staining the Malaria Flagellated Organism. 
 Brit. Med. Jour., vol. ii, p. 68. 
 
 1898. Nocht. Zur Farbung des Malariaparasites. Centralbl. f. Bakt., Bd. 
 xxiv, No. 1, p. 8. 
 
 1898. Zieman, H. Eine Methode der Doppelfarbung bei Flagellaten, etc. 
 Centralbl. f. Bakt., Bd. xxiv, No. 25, p. 945. 
 
 1898. Idem. Ueber Malaria und andere Blutparasiten. Jena. 
 
 1899. Nocht. Farbung der Malariaparasiten. Centralbl. f. Bakt., Bd. xxv, 
 No. 1, p. 17. 
 
 1901. Ewing. Malarial Parasitology. Jour. Exper. Med., vol. v, No. 5, 429. 
 
 1902. Giemsa. Farbenmethoden fiir Malariaparasiten. Centralbl. f. Bakt., 
 Bd. xxxii, No. 4, p. 307. 
 
 1902. Craig, C. F. A New Method of Staining the Malarial Parasites, etc. 
 N. Y. Med. Jour., Sept. 13. 
 
 1902. Wright, J. H. A Rapid Method for the Differential Staining of Blood 
 Films and Malarial Parasites. Jour, of Med. Research, vol. vii, No. 1. 
 
 1903. Laveran. Procede de coloration des Protozoaires parasites du sang. 
 Compt rendus. de la Soc. de Biol., March 7. 
 
 1904. Leishman. Notes on Romanowsky Staining. Jour. R. A. Med. Corps, 
 vol. ii, p. 669. 
 
 1904. Idem. Deep Chromatin Staining in Malaria. The Lancet, Mar. 19, 
 p. 801. 
 
 1904. Giemsa. Meine Methylenazur-Methylenblau-Eosin Farbenmethode. 
 Centralbl. f. Bakt., Bd. xxxvii, No. 2, p. 308. 
 
 1905. Harris, H. F. A Modification of the Romanowsky Stain. Centralbl. 
 f. Bakt., Bd. xxxix, No. 2. 
 
 1904. Plehn, A. Schnellfarbung und Schnittfarbung nach Romanowsky. 
 Arch. f. Schiffs- und Tropenhyg, Bd viii, Heft 2. 
 
 1905. Leishman. A Method of Producing Chromatin Staining in Sections. 
 Jour, of Hygiene, vol. iv, No. 3. 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 34I 
 
 General Literature upon Diagnosis. 
 
 1899. Curry, J. J. On the Value of Blood Examinations in the Diagnosis of 
 Camp Fevers. Boston Med. and Surg. Jour., vol. cxii, p. 513. 
 
 1900. Kronecker. Die "Kala-azar" in der vorderindischen Provinz Assam. 
 Archiv. f. Schiffs- und Tropenhyg, Bd. iv, No. 4, p. 220. 
 
 1900. Manson, P. The Diagnosis of Malaria, etc. The Lancet, vol. i, p. 1377. 
 
 1901. Grixoni. L'agglutinazione del sangue malarico. Gazz. degl. Osped. e 
 delle cliniche, Anno xxii, No. 57. 
 
 1900. Stephens and Christophers. The Agglutination of Sporozoites. Roy. 
 Soc. Rep. on Malaria, 3d Series. 
 
 1 90 1. Rogers, L. Note on Serum Reactions and the Temperature Curve 
 in Chronic Malaria, including Kala-azar. Ind. Med. Gaz., p. 377. 
 
 1 90 1. Idem. The Diagnostic Value of the Variations in the Leucocytes and 
 other Blood Changes. Brit. Med. Jour., April 5, p. 827. 
 
 1901. La Monaco e Panichi. Agglutination of the Blood in Malaria. II 
 policlinico, vol. viii. 
 
 1 90 1. Crespin. Diagnostic entre la malaria et la fievre jaune, etc. Bull, de 
 medicine sanitaire maritime. 
 
 1902. La Monaco e Panichi. Agglutination of Malarial Blood. Second Note. 
 Reforma Medica, Nos. 33-35. 
 
 1903. Laveran. Pseudo-hematozoaires endoglobulaires. Compt. rendus de 
 la Soc. Biologie, No. 14. 
 
 1903. Craig, C. F. Malarial Infections: Their Parasitology, Symptomatology, 
 Diagnosis and Treatment. International Clinics, Oct, 1903, p. 1. 
 
 1904. Klemperer. Ueber Fieber bei Syphilis der Leber. Zeitschr. f. klin. 
 Med., Bd. Iv. 
 
 1904. Powell, A. The Blood Examination of Three Thousand Four Hundred 
 
 Cases of Febrile Disease in Bombay. Ind. Med. Gaz., Nos. 2 and 3. 
 1904. Hunt, W. J. Interesting Cases of Malaria which Simulated Appendicitis. 
 
 N. Y. State. Jour, of Med., vol. iv. 
 1904. Capograssi, A. Valore diagnostico del potere agglutinante del siero 
 
 del sangue di malarici sui globuli rossi. Atti. della Soc, per gli Studi 
 
 della Malaria, p. 65. 
 
 1907. Daniels. Laboratory Studies in Tropical Medicine. London. 
 
 1908. Stephens and Christophers. The Practical Study of Malaria and 
 other Blood Parasites. London. 
 
CHAPTER III. 
 The Prophylaxis of the Malarial Fevers. 
 
 The subject of prophylaxis in the malarial fevers is of the very greatest 
 importance, for these fevers are preventable, and since the discovery of the 
 Plasmodia and the method of the transmission of these parasites by the mosquito, 
 we are in a position to control the spread of fevers of malarial origin. Until 
 recently we were ignorant of the source of the infection in malaria and could do 
 but little toward prevention, but we now know the etiological factors concerned 
 in the production of the malarial fevers and their method of transmission, and 
 we also know that proper methods of prophylaxis have already resulted in the 
 disappearance of the infection from numerous localities. It is not too much to 
 believe that, in time, the malarial fevers will be as rare as are now some of the 
 acute infectious fevers, provided we maintain and extend the present prophy- 
 lactic methods in use against this class of fevers. 
 
 Man and mosquitoes are, so far as we know, the only sources of malarial 
 infection, and the mosquitoes have to become infected from man; it therefore 
 follows that if it were possible to destroy all mosquitoes capable of transmitting 
 malaria or to destroy, all plasmodia infecting man, we would be able to cause 
 the disappearance of these fevers, but as this is impossible, we must depend in 
 prophylaxis on methods directed both toward the destruction of the mosquito 
 and the destruction of the plasmodia, remembering that while it will be 
 given us in many instances practically to rid certain localities of malaria, in 
 many others the most that we can hope for, because of local conditions, is a 
 distinct reduction in the number of cases. The success of malarial prophylaxis 
 is very largely a question of local conditions and the assistance given by the 
 local and governmental authorities. 
 
 The prophylactic methods at present in use against malaria consist in: 
 
 i. The prevention of the development of the plasmodia in man and the 
 destruction of the plasmodia in infected individuals. Both these aims are 
 accomplished by the administration of quinine, i. e., quinine prophylaxis. 
 
 2. Destruction of the mosquitoes transmitting malaria. 
 
 3. Protection of man from the bites of mosquitoes. 
 
 4. Education of the public regarding malarial prophylaxis. 
 
 In order to be most successful all of the methods mentioned should be 
 employed in prophylaxis, although in certain localities it may be found possible 
 to achieve success by attention only to mosquito destruction or to quinine 
 prophylaxis, while in others we may have to rely chiefly upon quinine pro- 
 phylaxis because of the manifest impossibility of destroying the breeding- 
 
 342 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 343 
 
 places of mosquitoes. If possible, however, we should employ all of the methods 
 of prophylaxis mentioned, as -by so doing we will more quickly attain a successful 
 result. 
 
 1. The Destruction of the Plasmodia. — It is obvious that if we can 
 destroy the plasmodia in infected individuals or prevent their development 
 we will be successful in preventing malaria, as it will be impossible for mosqui- 
 toes biting such individuals to become infected. This fact is the basis of quinine 
 propyhlaxis, which consists in the administration of the drug to all individuals 
 harboring the plasmodia and to all individuals exposed to the bites of mosquitoes 
 belonging to the Anophelina. We know that quinine is capable of destroying 
 the malarial plasmodia in the blood of man and that it is most effective in the 
 younger stages of development of these parasites, but that in all stages, with the 
 exception of the gametes, it is capable of interfering with the life cycle in the 
 human body and eventually destroying it. The fact that quinine has, so far 
 as we know, no effect upon the crescentic gametes of the aestivo-autumnal 
 infections, and probably none upon the gametes of tertian and quartan infec- 
 tions, renders quinine prophylaxis uncertain and makes it essential that we also 
 direct our methods toward the destruction of the mosquito. 
 
 The advocates of quinine prophylaxis, such as Koch, have claimed that 
 by this method alone it is possible to rid a community of malaria, but prac- 
 tically this can only be true in very exceptional localities, where the universal 
 use of the drug can be enforced. That such enforcement would eventually 
 render the occurrence of malaria impossible is undoubtedly true, as the develop- 
 ment of the sporozoites inoculated by mosquitoes would be rendered impossible 
 by the prophylactic dose of quinine, and no new mosquitoes could become 
 infected. In addition, those already infected would be harmless. As a matter 
 of fact, however, such results could only be obtained by the administration of 
 quinine for a long period of time to every individual in the infected locality, 
 and the prophylactic use of the drug would have to be continued indefinitely, 
 for as long as Anopheles mosquitoes are present so long is there danger of the 
 spread of malarial infection from imported cases of the disease. While it 
 is unwise, as has been shown by experience, to depend wholly upon quinine 
 prophylaxis, it is a fact that the use of the drug in this manner is of the greatest 
 value and should never be neglected. This method has now been tried for 
 years and the data on hand concerning its efficiency prove conclusively that 
 it is of prime importance in the prevention of the malarial fevers. 
 
 The authorities differ as to the dose of quinine to be administered in 
 prophylaxis and the best time for its administration. Koch believes in using 
 1 gm. (15 grains) administered upon every eighth and ninth day; Laveran, 
 0.4 to 0.6 gm. every 12 days; A. Plehn, 1 gm.once a week; Laborde, 0.1 to 0.3 gm. 
 daily; and Zieman advocates 1 gm. given upon every fourth day. The method 
 recommended by Koch has been adopted by many observers. He claims to 
 have secured better results by it than by any other method, and at Stephensort, 
 New Guinea, he claims that he was able to entirely rid the place of malaria by 
 
344 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 his method alone. Frosch, in Istria, found that whereas 16 per cent, of the 
 inhabitants were infected before the use of Koch's method (407 infections), 
 one year after the initiation of the method there were only 1 7 new infections, and 
 a year after that there were none. Gosio, in Toskano, Italy, reports a decrease 
 in the malarial morbidity from 47 per cent, to 12 per cent, with this method alone 
 after two years' trial. In South Africa, Vagedes began Koch's method in the 
 summer, the fever-free season. As a result he found a great decrease in the 
 number of cases of malaria during the next malarial season. Thus, in Tutara, 
 where the previous year, before the use of Koch's method, there had been a 
 morbidity of 75 per cent., this season there was a morbidity of only 7 per cent.; 
 in Kanas, previous year a morbidity of 30 per cent., this year none; in Franz- 
 fontain, previous year a morbidity of 75 per cent., this year only 9 per cent. 
 
 Other authorities have not secured as good results with this method as 
 with the daily administration of quinine in smaller doses or administered in 
 larger doses at more frequent intervals. Ollwig has shown that in uncivilized 
 communities, such as Dutch East Africa, such a method as Koch's is impracti- 
 cable as it is impossible to administer quinine to all of the inhabitants, or even 
 to all who harbor the malarial plasmodia. Zieman considers the method use- 
 ful but not to be depended upon alone, and this opinion is also held by Manson 
 and A. Plehn. In considering the results attained by those who advocate the 
 method of Koch, it should be remembered that the percentage of malarial 
 infections varies very greatly, even in badly infected regions, from year to year, 
 and also that the success of the method depends upon how many of the inhabi- 
 tants of a given locality have the resistant gametes in their blood, and the 
 number and species of the Anophelinae present. 
 
 Zieman recommends the administration of quinine as a prophylactic in 
 doses of 1 gram every fourth day, and if quinine be disagreeable in its effects 
 that euquinine in doses of 1 gram be substituted. He has shown that by the 
 use of this method not only is the number of new infections greatly reduced, 
 but that haemoglobinuria is not so apt to occur in those taking the quinine as 
 it is in those who have not taken the drug. Zieman does not believe that in 
 regions where pernicious forms of malaria occur Koch's method is sufficient, 
 as he claims that the dose of quinine is too small if given only upon the eighth 
 and ninth days. 
 
 Duncan, from his experience in the prophylactic use of quinine in large mili- 
 tary commands, concludes that quinine, in daily doses of 0.2 grm. to 0.6 grm., 
 reduces the admissions to hospital from malaria over one-half, and in regions 
 where only tertian and quartan infections are found, I have demonstrated that 
 daily doses of 0.15 grm. of quinine are sufficient to prevent malarial infection in 
 the vast majority of instances. At Camp Stotsenburg, in the Philippine 
 Islands, where nearly 36 per cent, of the command, a regiment of cavalry, 
 entered the hospital with malaria during the malarial season, I recommended 
 the prophylactic use of quinine, the drug being administered every seventh day 
 in doses of 1 grm. This method was used for several months and resulted in a 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 345 
 
 diminution of over two-thirds in the malarial infections entering the hospital. 
 At this post every other prophylactic method was used previously to the use of 
 the quinine, such as destruction of mosquitoes, use of mosquito bars, etc., but 
 only when to these methods was added the prophylactic use of quinine did we 
 secure the fullest measure of success in combating malaria. Since using the 
 method of quinine porphylaxis I have found that the best results are secured 
 by administering the drug in doses of 0.6 grm. (10 grains) upon retiring, every 
 third, sixth, and ninth days for two weeks, and then the same amount upon 
 every fifth day thereafter. The object of giving the drug- more frequently for a 
 period of two weeks is to destroy any plasmodia that might have been present 
 at the time the quinine prophylaxis is instituted. 
 
 The most important contribution to the subject of quinine prophylaxis 
 has been given us by Celli, as the result of the work of the Italian Society for 
 the Study of Malaria. He states that in Italy it has been found prac- 
 tically impossible to prevent recurrences in all malarial infections, and that, 
 therefore, it is necessary to prevent the malarial infection itself. In order to 
 do this he relies mostly upon quinine prophylaxis, although all the other methods 
 of prophylaxis are used faithfully by the society. As the result of their ex- 
 perience he believes in the daily administration of quinine as a prophylactic, 
 in average doses — 0.4 gm. of the bisulphate, hydrochlorate, or bihydrochlorate 
 to adults; 0.2 gm. of the same salts for children, or 0.3 gm. of the tannate of 
 quinine, in all cases compounded with sweet chocolate, thus disguising the 
 bitter nauseating taste. Where the malarial infections are of very severe char- 
 acter he recommends the daily administration of 0.5 to 0.6 gm. Celli says: 
 "He who takes quinine every day, and therefore has always a supply of 
 quinine in the blood stream, can undergo with impunity inoculations of blood 
 full of malarial parasites, and can expose himself with little or no danger to 
 the bites of infected mosquitoes." 
 
 He also says: " The unanimous agreement of both the doctors and patients 
 during these last years have convinced us more and more that this daily quinine 
 treatment diminishes notably the recurrences, causes the perniciousness to dis- 
 appear, prevents cachexia, and very frequently the primary infections, and at 
 least renders the fevers milder and more readily curable by simply increasing 
 the quinine for a few days to the therapeutic dose and then returning to the 
 prophylactic dose." 
 
 "Hence it is that from the Agro Romano, where we made our first experi- 
 ments, the daily use of quinine, which is as necessary as daily bread in the dis- 
 tricts and months of malaria, has to-day extended to every malarious province of 
 Italy, and it is extending more and more among the rural populations, the State 
 employes living along the railways, and in the army. Thus in Italy (where we 
 have employed it from 1899), Algeria, and Russia it has been proved to be the 
 most suitable method for guaranteeing health and the power of work to man 
 even in the most desolate malarious regions." 
 
 These eloquent words of Celli speak conclusively of the value of quinine 
 
546 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 prophylaxis in malaria, but it is only because the Government supported 
 the Italian Society by the state issue and sale of quinine that such results 
 have been possible. Thus in Italy the state sells quinine to those who can 
 afford to pay for it, at the minimum price; workers of every kind have quinine 
 issued to them gratuitously for the treatment of malaria, at the expense of their 
 employers; workers of every kind have quinine issued to them gratuitously for 
 prophylaxis, at the expense of the State; and, finally, the poor have quinine 
 given them gratuitously. As Celli says, these laws conflicted with many private 
 interests, but were, nevertheless, enforced, and to-day Italy has the honor of 
 pointing out to the world the proper legislative control of a disease that has 
 made her lands barren in the past and has destroyed countless thousands 
 of her inhabitants. 
 
 The following table, given by Celli, illustrates the results obtained by 
 quinine prophylaxis in Italy, and also demonstrates that the state has profited 
 not only by the saving of the lives of thousands of its citizens, but also finan- 
 cially. It should be stated that the profit made by the state from the sale of 
 quinine is expended in the prevention of malaria in other ways, as in drainage 
 works, etc. 
 
 State Quinine and Mortality from Malaria. 
 
 Consumption of state quinine 
 
 Mortality from malaria 
 
 Net profit of ad- 
 
 
 
 
 
 ministration 
 
 
 
 
 
 of state quinine 
 
 Financial year 
 
 Kilograms sold 
 
 Solar year 
 
 Deaths 
 
 in lire 
 
 1895 
 
 
 
 189S 
 
 16464 
 
 
 
 1896 
 
 
 
 1896 
 
 14071 
 
 
 
 1897 
 
 
 
 1897 
 
 11947 
 
 
 
 1898 
 
 
 
 1898 
 
 11378 
 
 
 
 1899 
 
 
 
 1899 
 
 1081 1 
 
 
 
 190c 
 
 
 
 1900 
 
 15865 
 
 
 
 1901 
 
 
 
 1901 
 
 13861 
 
 
 
 1902-3 
 
 2242 
 
 1902 
 
 9908 
 
 34270 
 
 1903-4 
 
 7 2 34 
 
 1903 
 
 8513 
 
 183039 
 
 1904-5 
 
 14071 
 
 1904 
 
 8501 
 
 183382 
 
 1905-6 
 
 18712 
 
 1905 
 
 7838 
 
 293395 
 
 1906-7 
 
 20723 
 
 1906 
 
 4871 
 
 462290 
 
 The above table shows that while from 1895 to 1902 an average of 13,000 
 individuals died annually in Italy from the malarial fevers, since the introduc- 
 tion of quinine prophylaxis in 1902 the mortality has steadily declined until in 
 1906 it was less than 5,000 per annum. Who can doubt the efficacy of this 
 method of prophylaxis when such evidence as this is presented and how small 
 any pecuniary out-lay would be, placed beside the thousands of lives which 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 347 
 
 have been saved by the free distribution of quinine in Italy. It is, however, 
 cheering to observe that the state has profited financially through the sale of the 
 drug to those able to buy, and that in reality thousands of lives have been saved 
 at actually no expense to the state. The experience of Italy well illustrates 
 the fact that no state can stand to lose financially by caring for the health of its 
 inhabitants. 
 
 Celli claims that the issue of quinine in 1905 saved no less than 7,500 lives, 
 and he states that of 59,340 persons taking daily doses of four centigrams of 
 quinine, only 5.8 per cent, developed malaria, including both initial infections 
 and relapses. In the south of Italy, where malaria is most severe, the per- 
 centage of infections has been reduced from 80 per cent, to 18 per cent. 
 
 Bettinetti, in the commune of Milan, used daily doses in 3,453 cases, of 
 whom only 4 per cent, developed malaria, and Brignoni and Algona found that 
 by using as small a daily dose as 20 centigrams they were able to prevent in- 
 fection in most of those experimented upon. Thus of 80 persons who took this 
 daily dose none developed malaria, while of 175 who took the same dose at ir- 
 regular intervals, 13 developed the fever. Of 50 individuals who did not take 
 any quinine, 31 developed malarial infections. From the evidence adduced I 
 believe that it is impossible to deny that quinine prophylaxis in malaria is of the 
 greatest value, but it should be remembered that we cannot depend upon this 
 method alone, except in very exceptional instances, and even those who have 
 used it most extensively have also used the other prophylactic methods known to 
 be of service, such as destruction of the mosquitoes, protection from mosquito 
 bites by screening, isolation of malarial cases, and avoidance of notoriously 
 infected regions. It is not too much to say, however, that unless quinine 
 prophylaxis is used we will not be successful in our efforts at prophylaxis in 
 most localities, and therefore this method should never be neglected. 
 
 2. Destruction of Mosquitoes. — One of the most valuable prophylactic 
 measures we possess against malaria is the destruction of the insect which 
 transmits the disease, i.e., the mosquito, and in suitable localities this measure 
 may in itself be sufficient to rid the locality of malarial infection. Generally, 
 however, it will be found that it is practically impossible to entirely rid a locality 
 of mosquitoes, and while we should do our utmost in this direction, we will have 
 to depend also upon other prophylactic measures if we expect to achieve success 
 in our endeavors. Only to one who has attempted it can the almost hopeless 
 task of exterminating mosquitoes in many regions, especially in the tropics, be 
 appreciated, and in many localities it is impossible of accomplishment. This 
 being so, it is evidently useless to expect to rid a locality of malaria from 
 which the mosquitoes cannot be eliminated, unless the infection is first 
 stopped among the inhabitants; and it appears to me that the greatest hope of 
 success in combating malaria in such localities lies in the distribution of quinine 
 to the inhabitants. On the other hand, it has been proven in a few instances that 
 the destruction of the mosquito alone was sufficient to cause a practical disap- 
 pearance of malaria. 
 
1901 
 
 1902 
 
 1903 
 
 1904 
 
 i9°S 
 
 1990 
 
 1548 
 
 214 
 
 9° 
 
 37 
 
 348 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 The success of mosquito extermination depends entirely upon local con- 
 ditions as regards terrain, the size of the infected territory, and climatic changes. 
 
 As examples of the success attending the destruction of mosquitoes in the 
 prophylaxis of malaria may be mentioned the following: 
 
 At Ismailia, a town of 6000 inhabitants, upon the Suez Canal, the pro- 
 phylaxis of malaria was undertaken in 1902, by the destruction of mosquitoes. 
 In 1900 there had been over 2,000 cases of malaria in Ismailia and the results 
 attending mosquito destruction are seen from the following figures: 
 
 Years, 1900 
 
 Cases, 2250 
 
 At the beginning of 1906 Ismailia was declared to be free from malarial 
 infection, and Pressat, who has reported these results, claims that he was able to 
 effect the greater part of the work, as regards destruction of the mosquitoes, by 
 a mosquito brigade of only four men. Quinine prophylaxia was used also at 
 Ismailia. 
 
 The effects of mosquito destruction upon malaria is brilliantly illustrated 
 by the campaign against these insects carried on at Klang and Port Swettenham, 
 in the Federated Malay States, by Watson and Travers, and reported by them 
 and by Ronald Ross. The following figures show the diminution in malaria 
 after mosquito prophylaxis was instituted. 
 
 Years, 
 Cases, 
 
 The mosquito campaign was commenced in 1902. 
 
 The results achieved by Col. Gorgas, of the U. S. Army, in exterminating 
 the mosquitoes of Havana will always stand as a monument to the efficiency of 
 this method of prophylaxis against yellow fever and malaria, as is shown by the 
 following figures, the mosquito campaign commencing in 1900: 
 
 Years, 1895 1896 1987 1898 1899 1900 1901 1902 1903 
 
 YellowFever, 552 1385 745 128 122 302 500 
 
 Malaria, 206 450 811 1907 909 325 151 77 51 
 
 The results secured upon the Isthmus of Panama will be discussed later. 
 
 Mosquitoes may be destroyed in the larval and the adult stage, and by 
 chemical, physical, and biological methods. 
 
 tj( Chemical methods are efficient in all stages of development of the insect, 
 and many substances have been experimented with in the hope of obtaining one 
 which would prove efficacious, being at the same time cheap and easily obtained. 
 Howard, in 1892, published the result of his work upon the destruction of 
 mosquito larvae by sprinkling a thin layer of kerosene upon the surface of the 
 water in which they breed. This method acts mechanically by preventing the 
 larvae from reaching the air when they attempt to breathe, but it also is capable 
 of killing the adult mosquito when in the act of depositing her eggs. It is 
 
 1901 
 
 1902 
 
 1903 
 
 1904 
 
 ^05 
 
 610 
 
 199 
 
 69 
 
 3 2 
 
 23 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 349 
 
 especially applicable to collections of water which cannot be drained and which 
 are not of great extent. The quantity of kerosene used is approximately one 
 ounce (30 gms.) to every 15 square feet of surface, but enough should be used to 
 entirely cover the surface of the water. The application does not need to be 
 renewed more than once a month in most instances, although I believe that it 
 would be better to renew the application at least every three weeks. This 
 method has been very extensively used in all parts of the words with very great 
 success, and it is invaluable in rendering artificial collections of water harmless, 
 as well as water in fire buckets and other receptacles which would prove to be 
 breeding places for mosquitoes. 
 
 Many other chemical substances are capable of killing the larvae, such as 
 sulphurous oxide, permanganate of potassium, hydrochloric acid, sulphate of 
 iron or copper, corrosive sublimate, formalin, cresol, certain aniline dyes, and coal 
 tar. Celli has experimented very extensively with various chemical agents and 
 has found that larvicide and gallol, two aniline dyes, are very efficient, the first 
 killing the larvae in 24 hours if added to the water in the proportion of 0.00015 
 parts per mille, the second in the same time in the proportion of 0.0125 parts per 
 mille. These dyes are not poisonous to man or to animals, and if added to the 
 water in larger amount will kill the larvae in twelve hours. He believes that 
 these substances are superior to kerosene and that they deserve a more extended 
 use. 
 
 The powder of the unexpanded flowers of the chrysanthemum, or pyreth- 
 rum powder, is a very efficient larvicidal substance and is easily soluble in 
 water. 
 
 Of all the chemical agents mentioned the only ones of practical interest 
 are pyrethrum powder, the aniline dyes, larvicide and gallol, and petroleum. 
 Of these the most widely used has been petroleum and it is also the cheapest and 
 probably the most generally practical, although I believe that the aniline dyes 
 should be given a more extended trial. It is of great importance to inspect the 
 pools which have been treated with petroleum at least every week, and see that 
 the film of oil remains constant, as it is very apt to become displaced by currents 
 created by winds and by the movements of aquatic animals. It will not in- 
 frequently be found impossible, in tropical regions especially, to make a very 
 extended use of petroleum in the destruction of mosquito larvae, and in such 
 regions, because of the luxuriant jungle growth, it is often impossible to even 
 locate the breeding-places of the mosquitoes which abound. The experience of 
 James, at Mian Mir, in India, where despite the most careful oiling and drain- 
 age, the Anopheles still continued to breed, is an example of the ill success which 
 will attend our efforts in not a few localities. 
 
 The destruction of the adult mosquito is possible by means of many 
 chemical substances, such as the fumes of burning pyrethrum powder, tobacco 
 smoke, sulphur dioxide, eucalyptus, larvicide, and pitch, or by odors such as 
 those from the essential oil of turpentine, camphor, musk, menthol, and nutmeg. 
 These substances are many of them useful in houses at night, being burned or 
 
350 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 exposed when the mosquitoes begin to appear. Thus pyrethrum powder or 
 tobacco may be burned early in the evening in the living-rooms and bed-rooms 
 and thus the insects present many be destroyed and many prevented from 
 entering by the odor of these substances. The most powerful of the fumes are 
 those from tobacco, which kill mosquitoes instantly, while pyrethrum powder 
 produces death in five minutes. Sulphur dioxide is the most powerful of the 
 gases, producing death instantly, and is easily generated by burning sulphur; 
 it is much used for the destruction of mosquitoes in the holds of ships and in 
 buildings which can be closed tightly and kept so for a sufficient period to allow 
 thorough disinfection as regards mosquitoes. This agent is not a suitable one 
 for household use because of the irritating character of the gas. Celli has ex- 
 perimented, in company with Casigrandi, upon a large number of chemical 
 substances which may be used in the destruction of the adult mosquito, and the 
 following table is compiled from their report. 
 
 Action of Culicidal Substances on Adult Mosquitoes of the Genus 
 
 Anopheles. 
 
 Substances used 
 
 Time in .which death occurred 
 
 Apparent 
 
 Real 
 
 I. Gases. 
 
 Sulphur dioxide 
 
 Hydrogen sulphide 
 
 Ammonia 
 
 Illuminating gas 
 
 Formaldehyde 
 
 77. Fumes. 
 
 Of tobacco 
 
 Of larvicide 
 
 Of pyrethrum powder 
 
 Of valerian root 
 
 Of fresh leaves of eucalyptus 
 
 III. Odors. 
 
 Of oil of turpentine 
 
 Of iodoform 
 
 Of menthol 
 
 Of nutmeg 
 
 Of musk 
 
 Of camphor 
 
 Instantly 
 Instantly 
 
 i m. 
 
 i m. 
 
 2 m. 
 
 Instantly 
 Instantly 
 
 5 m. 
 
 5 m. 
 3 m.-s m. 
 
 i m. 
 io m. 
 io m. 
 io m. 
 
 o m. 
 
 4 m.-s m. 
 
 i m. 
 i m. 
 
 2 m. 
 
 2 m. 
 
 io m.-i 5 m. 
 
 i m.— 3 m. 
 
 5 m - 
 i hr. 
 
 2 hr. 
 
 3 hr - 
 
 i m. 
 40 m. 
 
 4 5 m - 
 2 hr 
 3 hr. 
 4 hr.— s hi. 
 
 The great objection to the use of any of these substances is the fact that 
 in order to be efficient the air of the room has to be saturated and only a few of 
 them are available for habitual use on this account, as most of them are too 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 35 1 
 
 disagreeable to enable one with any comfort to remain in a room in which the 
 air is saturated. Celli found a powder composed of larvicide, the unexpanded 
 flowers of the chrysanthemum, and valerian root to be less disagreeable and 
 more efficient than any other chemical substance for the destruction of the 
 adult insect, one to two tablespoonfuls burned in the room in the evening 
 stupefying the mosquitoes until morning. 
 
 The biological means available for the destruction of mosquitoes consist 
 in the use of fish which will devour the larvae, the use of insects which will 
 devour the adult mosquito, and the introduction into the breeding-places of 
 vegetable organisms capable of destroying the larvae and nymphae. All of these 
 methods have been used, but it must be said with but little success. The intro- 
 duction of fish into certain reservoirs from which the water was used for drinking 
 purposes, but which abounded with mosquito larvae, has been tried with partial 
 success, the fish used being the German carp or the common little stickle-backs. 
 The rearing of dragon flies, which destroy the mosquito in both the larval 
 and adult stage, in ponds filled with larvae, has been suggested and tried, but 
 with very little success. Galli-Valerio and de Jongh, in their experiments 
 upon animals or plants that kill or impede the development of mosquitoes, 
 found that Triton cristatus was very efficient in destroying the larvae, and that 
 cultures of Aspergillus niger. and Aspergillus glaucus when added to water 
 containing the larvae quickly destroyed them. They tried the latter method 
 with success upon natural collections of water, and it would appear that this 
 method merits attention and experiment. 
 
 The physical means available for the destruction of mosquitoes and their 
 larvae consist in the destruction of the breeding-places by drainiage, filling 
 in of low land, and removal of shelter for the insects. The most important 
 of all methods of destroying the mosquito larvae is that by drainage of the breed- 
 ing-places, and this is a method which can be applied over very large areas of 
 country in which malaria is endemic, and which has been proven to be of the 
 greatest service in the fight against these fevers. To secure results, however, 
 in the drainage of malarial localities we must have the support of the local and 
 often also of the state authorities, for this method of prophylaxis calls for the 
 expenditure of large sums of money in many instances, and to secure them the 
 consent of the state is essential. In many regions in which malaria is endemic 
 in its most virulent form, drainage is feasible and can be carried out with but 
 little trouble, although the expense involved is often apparently prohibitory, 
 but as Celli says, "such methods for the destruction of the mosquitoes, while 
 experimentally soluble, will only be practically so when economic interests 
 demand it." Where drainage is impossible the breeding-places of mosquitoes 
 may be filled in with sand or loam, and it is always important in malarious 
 localities to fill up all areas of depression in the surface of the land that cannot 
 be adequately drained. Swampy areas, if not too large, may thus be filled in 
 and one of the greatest sources of mosquitoes eliminated. The success that has 
 attended the campaign against the mosquito upon the Isthmus of Panama is 
 
352 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARLAL FEVERS. 
 
 due very largely to drainage and the filling in of depressions which would serve 
 as breeding-places for the insects. 
 
 Another most important method of destroying mosquitoes is the removal, 
 so far as possible, of all shelter such as is afforded them by jungles, long grass, 
 luxuriant vegetation, and decaying vegetable matter along the edges of streams. 
 The clearing of tropical jungles for a distance of at least a mile from inhabited 
 districts; the removal of high grass from about residences; the clearing of the 
 water of small streams are all of importance in the prophylaxis of malaria. At 
 Camp Stotsenburg, P. I., it was invariably noted that mosquitoes increased 
 greatly in number whenever the grass about the post was allowed to grow to 
 any length, and that a coincident increase occurred in the number of malarial 
 infections. The cutting of the grass was followed at once by a marked diminu- 
 tion in the number of mosquitoes and in the cases of malaria. At one time, 
 on account of the lack of facilities, the grass was allowed to grow for weeks and 
 the mosquitoes became so numerous as to be almost unbearable while the 
 number of cases of malaria admitted to the hospital became alarming. The 
 change brought about by the mowing of the grass was remarkable and proved 
 conclusively the great danger of affording shelter to the mosquito. 
 
 Besides the methods mentioned the formation of mosquito brigades, as 
 suggested by Ross, is of the greatest service in limiting malarial infection. 
 The brigades consist of a certain number of men, the number varying with the 
 ground to be covered, whose business it is to inspect the premises of every 
 individual in a locality and destroy the larvae in the small breeding-places 
 which harbor the Anopheles, such as domestic water receptacles, water butts, 
 and tanks; the removal of small puddles in streets and yards as well as empty 
 tins, jars, broken bottles, or anything in which water may collect and in which 
 mosquitoes may breed. In the formation of such brigades the area to be covered 
 such as a town or city, is divided into districts, to each district being assigned an 
 overseer and a number of men, whose entire time is occupied in searching for, 
 and destroying the breeding-places of mosquitoes. Methods similar to this 
 were employed in Havana by Colonel Gorgas, and resulted in the almost 
 total disappearance of the yellow fever mosquito from that city. 
 
 Garden wells and water barrels and tanks, being prolific sources of mosqui- 
 toes, should be covered with wire netting, thus preventing the laying of the eggs 
 and the development of the larvae. If this is not practicable the surface of the 
 water, if not used for drinking purposes, should be covered with petroleum. 
 
 The results obtained by Colonel Gorgas, of the Medical Corps of the U. S. 
 Army, in the prevention of yellow fever and malaria upon the Isthmus of 
 Panama by the use of the physical methods of destroying mosquitoes just 
 mentioned, prove conclusively the value of such methods in the prophylaxis 
 of malaria. As is well known, the Isthmus of Panama has for centuries been 
 notorious for the prevalence of yellow fever and the most pernicious forms of 
 malaria, and during the days of the French control of the Isthmian canal, 
 work was rendered difficult, and many times impossible, by reason of the great 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 353 
 
 mortality of the laborers employed in digging the canal. How different has been 
 the history of the American "occupation" of the Isthmus of Panama. To-day 
 the canal is being built, and it is being built with a smaller sick rate than the 
 normal one of many European and American cities, and this great difference 
 is due entirely to the destruction of mosquitoes and modern sanitation. No 
 greater object lesson exists to-day of the beneficent results of sanitary science 
 than the Panama Canal. The following data illustrates what has been 
 accomplished in the prevention of yellow fever and malaria upon the Isthmus 
 of Panama. 
 
 As regards yellow fever the cities of Panama and Colon, once hot-beds 
 of this disease, have been entirely free from this fever for years, and this is 
 true also of the Canal Zone. As regards the malarial fevers, the following 
 table, given by Colonel Gorgas, illustrates the decrease in these fevers: 
 
 Year. 
 
 Force 
 Employed. 
 
 No. Cases 
 Admitted. 
 
 No. Cases per 
 Thousand. 
 
 No. Deaths. 
 
 No. Deaths per 
 Thousand. 
 
 1905 
 1906 
 1907 
 1908 
 
 16511 
 26705 
 39344 
 43890 
 
 8496 
 21938 
 16709 
 
 12372 
 
 5i4 
 821 
 424 
 282 
 
 92 
 199 
 138 
 
 59 
 
 5-57 
 7-45 
 3-5 1 
 i-34 
 
 From this table it will be seen that despite the fact that the force employed 
 upon the Isthmus is constantly increasing the number of cases of malaria is 
 steadily decreasing. These results have been achieved by screening, destroy- 
 ing the breeding places of mosquitoes, the prophylactic use of quinine, and 
 oiling where drainage was impracticable. 
 
 3. Protection of Man from the Bites of Mosquitoes. — One of the 
 most valuable methods of malarial prophylaxis is the protection of individuals 
 from the bites of Anopheles. This protection applies not only to uninfected 
 persons, but is especially important in the case of those suffering from these 
 fevers. Such protection may be secured by the use of screening about houses, 
 head nets, mosquito bars, certain substances placed upon the skin, the isola- 
 tion of patients suffering from malaria, and, of course, by the methods of 
 mosquito destruction which I have already described. 
 
 Isolation of Malarial Patients in screened rooms is of the greatest 
 importance from a prophylactic standpoint, and yet how seldom we see this 
 precaution taken even in regions in which the malarial fevers are endemic and 
 severe. We have seen that the mosquito is necessary as an intermediate host 
 in the life history of the malarial plasmodia and that the mosquito becomes 
 infected by biting an individual suffering from malarial disease. From this 
 it is obvious that if we can place the infected individual in a position where the 
 mosquitoes cannot gain access to him the transmission of the infection will 
 23 
 
354 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 be impossible. Theoretically, if every individual infected with malaria could 
 be screened from mosquitoes for a sufficient period of time these fevers would 
 disappear, but practically the infection is of such a nature that even when no 
 symptoms are present the plasmodia may be present in the blood and thus the 
 mosquitoes may become infected. In aestivo-autumnal infections the cres- 
 centic form of the plasmodia (gamete), the very form intended to undergo its 
 life cycle in the mosquito is very frequently present in the blood when no 
 symptoms of malaria are noticeable, so that it is obvious that we cannot in this 
 way entirely prevent malaria, but in the light of our present knowledge the 
 malarial fevers should be regarded as infectious and the patient strictly isolated 
 in a screened room, and he who neglects to thus protect the uninfected is guilty 
 of gross negligence. Not only is this isolation of importance to those surround- 
 ing the patient, but also to himself, for if he his not protected from mosquitoes 
 he is constantly exposed to reinfection by the bites of these insects. This form 
 of prophylaxis should never be neglected in any locality, but is especially 
 important in regions were the pernicious forms of malaria are prevalent. 
 
 In addition to isolation of the malarial patient, segregation of the natives 
 in tropical regions has been suggested by Ross and Stephens as a measure of 
 great value in the prevention of malarial infection among the foreign European 
 population. I have already shown how frequent is latent malarial infection 
 in natives of malarial localities and how often the disease is masked by other 
 symptoms. By segregation of the natives we at once remove a common source 
 of infection in the person of the natives suffering from a latent infection, and 
 also protect the European from the effects of the filthy habits of the native 
 population. The suggestion of Ross and Stephens that the European quarter 
 should not be placed, as is common, in the midst of the native village or city in 
 malarious localities, but should be situated at some distance, is an excellent 
 one, for it is often impossible to secure proper hygienic conditions if we be forced 
 to live among a native population. Unfortunately, for business reasons, it 
 is generally impossible to do much in the way of segregation of the native, 
 although the method is applicable in the establishment of military posts and 
 camps. 
 
 The screening of all dwelling-houses in malarial regions is a measure 
 which has resulted in infinite good as regards the prophylaxis of malaria, 
 and one that should be insisted upon by every sanitarian. The screening used 
 should be of copper wire if possible, containing n wires to 2 cm. of surface. 
 The use of wire screening other than copper is more expensive in the end, as 
 such screening quickly rusts and becomes useless. If other screens be used 
 the netting should be covered with two coats of good paint. The experiments 
 of Sambon and Low, repeated by many others, prove conclusively that even in 
 the most malarious regions the infection may be escaped by living in properly 
 screened houses. Sbacchi has shown that, in the case of the employee's of the 
 Sicula Occidentale Railway in Italy, those protected by living in mosquito-proof 
 houses suffered but little from malaria, while those not so protected developed 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 355 
 
 the disease in almost every case. Of 641 persons living in screened habitations, 
 only 4.8 per cent, developed malaria, which corresponds to the results obtained 
 by quinine prophylaxis, and it is probable that had both methods been used the 
 malarial percentage would have been almost nil. The barracks of troops 
 serving in malarial localities should be carefully screened, for this will not only 
 protect them from malaria, but also from yellow fever and dengue. The 
 latter disease has been proved by Graham and Ashburn and myself to be 
 transmitted by Culex fatigans , and our work has been confirmed by Phelan and 
 Nichols, so that screening of the barracks of troops or dwelling-houses in infected 
 localities offers a large measure of protection against the malarial fevers, yellow 
 fever, dengue, and filiariasis. Probably no one sanitary measure which can be 
 accomplished at so little cost is productive of so much good and protects 
 against so many diseases as does the screening of buildings against mosquitoes. 
 
 In conjunction with the screening of houses and barracks the use of the 
 mosquito bar for the bed, and the head net and gloves for wear when obliged 
 to be out at night, are very valuable prophylactic measures. In houses or 
 barracks which are not screened, the use of the mosquito bar for the bed should 
 never be neglected, and it is also well to provide a small mosquito-proof com- 
 partment, either in a room or upon the porch, for use in the late afternoon and 
 evening. The use of the mosquito bar has very greatly reduced the number of 
 cases of malaria in our posts in the Philippines and Cuba, but strict attention 
 must be paid to the enforcement of the use of this bar in military commands, as 
 the soldier generally dislikes to sleep under it on account of the heat. An 
 inspection of the barracks at night after the men have retired will generally 
 demonstrate that many of the men are not using the bar or that it is improperly 
 used, and such inspections are necessary if we are to secure good results from 
 this method of prophylaxis. When mosquito bars are used they should be 
 large enough to be suspended several feet above the bed, and should be placed 
 in position and tucked beneath the mattress early in the evening, and examined 
 before retiring in order to see that mosquitoes have not gained an entrance. 
 The mosquito bar for protection of the bed is an absolute necessity in malarial 
 regions, and should always be carried by the traveler in such regions. To 
 neglect its use is to invite infection. 
 
 By the use of the methods mentioned for the protection of man from the 
 bites of the Anophelinae, especially by the screening of barracks, Procaccini, in 
 Sardinia, reduced the number of cases of malaria among the troops from 70 
 per cent, to 57 per cent., in one season, and later the percentage was reduced 
 to less than 20 per cent. In Formosa, Tzuzuki protected 115 soldiers by 
 screening their barracks from Sept. 2 1 to Dec. 8, and not a case of malaria de- 
 veloped, while in the same time among 717 soldiers not so protected there devel- 
 oped 251 malarial infections. Head nets were used during the day and the 
 men were confined to the barracks after dark. 
 
 This experiment of Tzuzuki's shows what may be accomplished by a 
 rigid enforcement of the use of screens in the prophylaxis of malaria, but it 
 
356 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 is doubtful if our soldiers would consent to being confined to their barracks 
 as did the Japanese. Nevertheless, great good may be accomplished by as 
 rigid an enforcement as possible of the use of the mosquito bar, and in the 
 tropics and in all malarial localities our military barracks should be thoroughly 
 screened. 
 
 The use of punkas and of electric fans is of service in keeping mosquitoes 
 away by keeping the air in motion, while the burning of pyrethrum powder or 
 larvicide is efficient in small rooms, stupefying the insects so that they are 
 unable to bite. Everyone who has lived in malarial regions is aware of the 
 protection afforded one when smoking a cigar or pipe, a protection which 
 really constitutes the strongest argument for the use of tobacco in the tropics. 
 
 A limited amount of protection is afforded against mosquito bites by ap- 
 plications to the skin of such substances as oil of citronella, oil of eucalyptus, 
 camphor, and petroleum, or covering the skin with bland ointments, which 
 prevent the mosquito from biting by reason of mechanical interference. Mense 
 recommends a solution of quinine and glycerine, i-iooo rubbed upon the skin, 
 as an efficient protective. All of these substances are more or less unpleasant 
 and the protection afforded is evanescent, so that they are really of but little 
 practical value in the prophylaxis of malaria. 
 
 4. Education of the Public Regarding Malarial Prophylaxis. — As so 
 many of our best methods of prophylaxis against malaria are dependent upon 
 the public support, because of their financial and social aspects, it is essential 
 that for their success, the public be informed as to their nature and what is 
 expected to be accomplished by their use. In Italy this has been accomplished 
 by the Society for the Study of Malaria to such an extent that there is probably 
 no one so ignorant in that country as to doubt the efficiency of the methods 
 already instituted for the suppression of malaria, or who does not know why 
 they were instituted, and how they are proving successful. The example of 
 Italy may well be followed by every state in which malaria is endemic, for only 
 by educating the public can we hope to fight a winning battle against these 
 infections. Thus the education of the public is a powerful means of prophylaxis 
 against malaria, for upon the response of the public, both financially and 
 socially, must we depend for the sinews of war. 
 
 Besides the more important prophylactic measures which have been 
 mentioned, there are certain measures which may be taken by the individual 
 which will assist in protecting him from malaria. Fatigue, exposure to rain and 
 to the sun, excessive indulgence in alcoholics, and excesses of every kind should 
 be avoided in malarial regions, for these all deplete the natural resisting powers 
 of the individual and render him more liable to infection. In traveling, the 
 season of the year in which the malarial fevers are most prevalent should not be 
 selected, if possible, and the journeys should be made in the daytime. In the 
 selection of camp sites and sites for building, high, well-drained land should be 
 chosen, and the vicinity of swamps and collections of water carefully avoided. 
 The drinking-water should always be boiled, for, while malaria is not transmitted 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 357 
 
 by water, this measure may prevent other diseases which would so weaken the 
 individual as to render him an easy prey to infection. The prophylactic use of 
 quinine and the use of a mosquito net at night should never be neglected by the 
 traveler in malarial regions. 
 
 General Summary. — The methods which have been found serviceable in 
 the prophylaxis of malaria may be briefly summarized as follows: 
 
 1. The prophylactic use of quinine, in daily doses of from 0.12 to 0.30 gm. 
 (2 to 5 grains), according to the severity of the malarial infection in the locality 
 in which this method of prophylaxis is practiced. The administration of 
 quinine to all natives, both infected and uninfected, is a most valuable measure, 
 but requires governmental control, which, in many places, we are unable to 
 secure. 
 
 2. The destruction of the breeding-places of mosquitoes by drainage and 
 filling in, and the destruction of the insects by other methods which have been 
 described. 
 
 3. Protection of man from the bite of mosquitoes, secured by screening all 
 buildings in which he lives or works; the use of mosquito bars; head nets, and 
 gloves; and of various fumes and applications to the skin. 
 
 4. The avoidance of all excesses and of exposure of the person to rains, 
 the tropical sun, and to physical hardships. 
 
 5. The education of the public to the importance of the prevention of the 
 malarial fevers. 
 
 6. The segregation of the natives in malarial regions; a simple and very 
 efficient measure, but one that can be carried out only in rare instances because 
 of political, business, and social reasons. 
 
 The method of prophylaxis suggested by Kuhn, which consists in produc- 
 ing immunity to malaria by the injection of horse serum from horses immunized 
 to "horse pest" is, at the present time, of no practical importance. While he 
 claims that the injection of such serum kills the plasmodia and produces im- 
 munity, his results have not been confirmed, and it is very problematical if they 
 will be in the future. 
 
 The Existence of the Plasmodia Outside Man and the Mosquito. — As 
 to whether the plasmodia of malaria may exist in any form outside of man and 
 the mosquito our knowledge is very limited, but such as it is it would appear to 
 prove that the parasites cannot so exist. Schaudinn has demonstrated that the 
 sporozoites are very delicate, degenerating when placed in water, or in blood 
 serum removed from the human body, and his experiments would appear to 
 prove that malaria cannot be transmitted by water containing mosquitoes 
 infected with the malarial plasmodia. More work should be done along this 
 line, however, before we can be sure that malaria is not transmitted save by the 
 mosquito. 
 
 So far as we know, the plasmodia of malaria do not occur in any of the 
 lower animals, although plasmodia have been found in bats and monkeys which 
 very closely resemble the human parasites in morphology. Dionisi has de- 
 
358 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 scribed three species occurring in bats, but they may be easily differentiated 
 from those occurring in man. Koch found a plasmodium in monkeys which 
 resembles somewhat Plasm odium vivax of man, but this organism could not be 
 transmitted to man nor could human malaria be transmitted to monkeys. 
 Richard, Di Mattei, Fischer, and Koch have all endeavored to transmit the 
 malaria of man to monkeys, but without success. Koch has demonstrated that 
 it is impossible even in the case of the anthropomorphic apes; he experimented 
 upon three orang-outangs and three Hylobatcs agilis, injecting both the blood of 
 patients suffering from tertian and from aestivo-autumnal malaria, but without 
 being able to produce the slightest symptom of infection, while the blood of 
 these animals remained free of the plasmodia. It would appear, therefore, 
 that the conclusion is justified that the plasmodia of human malaria are found 
 only in the blood of man and in mosquitoes belonging to the Anophelinae. The 
 success attending the methods of prophylaxis which have been described is 
 additional proof that in our fight against malaria we have only to deal with man 
 and the mosquito. 
 
 Literature upon the Prophylaxis of the Malarial Fevers. 
 
 j88t. Jilek. Ueber das Verhalten der Malariafieber in Pola. Wien. k.k. 
 Hof- u. Staatsdruckerei. 
 
 1887. Plehn, A. Zur Prophylaxe der Malaria. Berl. klin. Wochenschrift, 
 No. 39, p. 733. 
 
 1896. Laborde. L'action preventiv de la quinine dans le paludisme. Bull, 
 de l'acad. de Medicine. 
 
 1899. Buchanan, W.J. The Value of Prophylactic Issues of Cinchona Prepa- 
 rations. Jour. Trop. Med., March, p. 201. 
 
 1899. Celli and Casigrandi. Ueber die Vernichtung der Mosquitos. Cen- 
 tralbl. f. Bakt., Bd. xxvi, No. 13, p. 396. 
 
 1900. Idem. Epidemiologic und Prophylaxis des Malaria, etc. Berl. klin. Woch- 
 enschrift, No. 6, p. 113; No. 7, p. 142. 
 
 1900. Grassi. Erster summarischer Bericht iiber die Versuche zur Verhutung 
 
 der Malaria, etc., Centralbl. f. Bakt., Bd. xxviii, p. 535. 
 1900. Mense, C. Chininglycerin und andere auiizere Mittelgegen Muckenstiche 
 
 und Malaria. Archiv. f. Schiffs- u. Tropenhyg., Bd. iv, No. 1, p. 14. 
 1900. Plehn, F. Die neusten Untersuchungen iiber Malariaprophylaxe in 
 
 Italien und ihre tropenhygienische Bedeutung. Archiv. f. Schiffs- u. 
 
 Tropenhyg , Bd. iv, p. 339. 
 
 1900. Procaccini. Ricerche profilattische contri le malaria instituite nella 
 costa Sarda. Annali di Medicina Navale, Anno xi, xii. 
 
 1 90 1. Celli. Die neue Prophylaxis der Malaria. Archiv. f. Hygiene, Bd. xi, 
 P- 235. 
 
 1902' Gorgas, W. C. Mosquito Work in Havana. Medical Record, vol. xix, 
 No. 7. 
 
 1902. Laveran. L'assainissement de la Corse. Presse medicale, No. 8. 
 1902. Ross, R. The War Against Mosquitoes. Indian Med. Gaz. No. 1, p. 35. 
 1902. Idem. Mosquito Brigades and How to Organize Them. London. 
 1902. Schoo. Wat kan er aan Prophylaxis der Malaria in Nederland getaan 
 
 worden. Nederlandsch Tijdschrift V. Geneeskunde, No. 17. 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 359 
 
 1902. Tzuzuki. Ueber die Verwendbarkeit des Moskito-Drahtgazeschutzes 
 in den Malaria-gegenden der Tropen. Archiv. f. Tropenhyg. Bd. vi, No. 
 1, p. 1. 
 
 1903. Celli. Zur Prophylaxe der Malaria. Hyg. Rundschau, No. 20, p. 
 1017. 
 
 1903. Idem. Die neue Malariaprophylaxis in Latium. Centralbl. f. Bakt. 
 
 Abst., Bd. xxviii, p. 696. 
 1903. Idem. Die Malaria in Italien in 1902. Archiv. f. Hygiene, Bd. xlviii, 
 
 No. 3. 
 1903. Christophers. The Prevention of Malaria in Tropical Africa. Thompson 
 
 Yates Lab. Reports, vol. iii, p. 169. 
 1903. Dutton, E. J. Report of the Malaria Expedition to the Gambia, 1902. 
 
 Thompson Yates Lab. Reports, vol. v, No. 1. 
 1903. Frosch, P. Die Malariabekampfung in Brioni (Istrien). Zeitschr. f. 
 
 Hyg., Bd. vliii, Heft 1. 
 1903. Gosio, B. Die Behampfung der Malaria der Toscano. Zeitschr. f. Hyg., 
 
 Bd. xliii, Heft 1. 
 1903. Ollwig. Die Bekampfung der Malaria. Zeitschr. f. Hyg., Bd. vliii, 
 
 Heft 1. 
 1903. Stephens and Christophers. Report to the Malarial Commit. Royal 
 
 Soc, 8th Series. 
 
 1903. Vagedes. Die Malaria unserer Kolonieen im Lichte der Kochschen 
 Forschung. a. d. Festschrift zum sechzigsten Geburtstage von Robert 
 Koch. 
 
 1904. James. Report of the Malarial Committe of Royal Society, Series 8. 
 1904. James. The Causation and Prevention of Malarial Fevers. Lancet, 
 
 Jan. 30, p. 307. 
 1904. Editorial. The Success of Mosquito Destruction Operations. Brit. 
 
 Med. Jour., No. 2281, p. 631. 
 1904. Schaudinn, F. Die Malaria in dem Dorfe "St. Michele de Leuse" 
 
 in Istrien, etc., Arc. a. d. Kaiserl. Gesundheitsamte, Bd. xxi, Heft 3. 
 1904. Ed. Sergent and Et. Sergent. Versuch einer Malariabekampfung. 
 
 Annales de l'lnstitut. Pasteur, Feb. Referat. 
 1904. Idem. Campagne antipaludique en Algerie (1903). Annalea de l'ln- 
 stitut. Pasteur, vol. xviii, p. 64. 
 1904. Stephens, J. W. The Antimalarial Operations at Mian-Mir. Lancet, 
 
 vol. clxvi, p. 637. 
 1904. Idem. The Prophylaxis of Malaria. Lancet, vol. clxvi, p. 611. 
 1904. Zieman, H. Ueber Chininprophylaxe in Kamerun. Archiv. f. Schiffs- u. 
 
 Tropenhyg., Bd. viii, p. 329. 
 1906. Zieman, H. Malaria. Handbuch der Tropenkrankheiten, Mense. 
 
 Leipzig. 
 1906. Brignone, G., and Algona, V. Prophylactic Use of Quinine. Atti 
 
 della Soc. per gli Studi della Malaria. 
 1906. Bettinetti. Prophylactic Use of Quinine. Ibid. 
 1906. Celli. Prophylactic Use of Quinine. Ibid. 
 1906. Sbacchi. Prophylaxis by Wire Gauze. Ibid. 
 
 1906. Galli-Valerio and de Jongh. Life History of Mosquitoes. Ibid. 
 
 1907. Craig, C. F. The Malarial Fevers. Osier's Modern Medicine, vol. 1, 
 Philadelphia. 
 
 1908. Ross, R. The Prevention of Malaria in British Possessions, Egypt, 
 and Parts of America. Jour. Royal Army. Med. Corps, vol. x, No. 2, p. 
 i55- 
 
CHAPTER IV. 
 
 The Treatment of the Malarial Fevers. 
 
 For the treatment of the malarial fevers medicine possesses one of its 
 few true specifics, i.e., quinine, and by quinine is meant all of the derivatives 
 of cinchona bark. This bark was introduced into Europe in 1640 by the 
 Countess del Cinchon, who had been treated with it in South America, where 
 it had been used for many years in the treatment of malarial fevers by the 
 natives. In 1820, Pelletier and Caventou discovered the alkaloids quinine 
 and cinchonine in the bark, and in 1852, quinidine was isolated. When 
 properly administered quinine will invariably destroy the malarial plasmodia, 
 and Osier has well said that "the physician who at this day cannot treat 
 malarial fever successfully with quinine, should abandon the practice of 
 medicine." 
 
 While there are rare instances in which the drug appears to be powerless 
 to limit the course of a malarial infection, a careful study of such cases will 
 invariably show that it has been administered improperly. For instance: 
 Certain individuals are unable apparently to absorb quinine through the 
 intestinal tract, but in such indivduals the hypodermic use of the drug will 
 result in a cure of the infection. The successful treatment of malaria by quinine 
 depends wholly upon the proper administration of the drug. 
 
 Historical. — The history of the discovery of the efficiency of cinchona 
 bark in malaria and its introduction into Europe is of much interest and is well 
 told by Markham, in his book entitled "A Memoir of the Lady Ana de Osorio, 
 Countess of Cinchon," published in London in 1874. Regarding the discovery 
 of the value of the drug, Markham, says: "In 1638 the Countess of Cinchon, 
 the wife of the Viceroy of Peru, lay very ill with tertian fever at Lima, the 
 capitol city. The news was carried to Canizares, then Corregidor of Loxa, 
 a town among the Andes, in the present Ecuador. Though the natives of Peru 
 were unacquainted with the curative power of the bark, those of the more 
 northern-lying countries appreciated its worth, and from them Canizares 
 obtained the secret. He therefore sent a parcel of it to the vice-queen. Her 
 physician, de Vega, agreed to its employment, and she recovered in a short 
 time. In 1640 the Countess returned to Spain and carried with her a large 
 quantity of the precious bark, which she distributed about her native place in 
 the vicinity of Madrid. De Vega followed and brought likewise a large amount 
 of the bark to Spain, which he sold at Madrid for a hundred orrales a pound. 
 The Countess employed the bark so extensively that for a long time it bore the 
 name 'Countess's Powder' (Pulvis comitissae)." 
 
 360 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 361 
 
 Although the value of the bark was proven beyond doubt, it was many years 
 before it was used in general practice. The bigotry of the learned of the day 
 refused audience to a remedy discovered by savages, and those using it were 
 even subjected to religious persecution. About the latter half of the seventh 
 century the bark was adopted by the Jesuits and was used by them in the treat- 
 ment of fevers, being known at that time as Jesuits' bark, but "it had still to 
 encounter the sneers of the learned and the hate of bigots, and it was not until 
 an English quack succeeded in curing by its means men of high rank that 
 fashion broke down the prejudices which reason could not remove." 1 
 
 Medicinal Treatment. — It is essential that every case of malarial fever 
 be thoroughly treated with the specific, quinine, both from a therapeutic and 
 prophylactic standpoint. The mild intermittent malarial infections, such as 
 the tertian and quartan, tend toward spontaneous recovery, but while this is 
 true in many instances, it should be remembered that even these infections may 
 become malignant, and even if they do not, the occurrence of repeated par- 
 oxysms results in a diminution of the vitality of the patient, as is evidenced by 
 the anaemia which invariably accompanies such repeated attacks. Added to 
 this we have the important fact that every malarial patient is a source of infection 
 to others unless the plasmodia be rendered harmless, so that we must admit 
 that every malarial infection, no matter how mild in character, should be 
 treated medicinally and not be left for nature to cure. 
 
 In considering this portion of our subject it may, for convenience, be 
 divided as follows: 
 
 1. The action of quinine upon the malarial plasmodia. 
 
 2. Choice of preparation. 
 
 3. Time of administration. 
 
 4. Methods of administration. 
 
 5. The amount to be administered. 
 
 6. Contraindications and substitutes. 
 
 1. The Action of Quinine upon the Malarial Plasmodia. — That quinine 
 is a specific in the malarial fevers is proven by its action upon the malarial 
 plasmodia. The drug exerts its beneficial action upon malarial infections by 
 directly destroying the plasmodia, a fact first proven by Binz in the case of 
 some other protozoa, and repeatedly confirmed by other investigators as regards 
 the malarial plasmodia. 
 
 Although a considerable amount of research has been devoted to the 
 action of quinine upon the plasmodia of malaria, reference to the reports of the 
 various investigators who have been so engaged reveals the fact that much 
 confusion still exists regarding the exact effect of this drug upon the plasmodia, 
 and, therefore, the best time for its administration in the treatment of the 
 malarial fevers. This is well illustrated in the following quotation from 
 Manson 2 who, in speaking of the action of the drug, says: 
 
 1 National Dispensatory, 5th Ed., p. 1352. 
 
 2 Tropica] Diseases, 4th Ed., p. 124. 
 
362 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 "In what way quinine acts has not yet been satisfactorily explained. Some, 
 reasoning from the toxic influence this drug exerts on many kinds of free amoebae, 
 say that it acts in malaria in the same way; that is, as a direct poison to the 
 parasite. They support this view by pointing to the degenerative changes, as 
 evidenced by imperfect staining reaction, exhibited by such parasites as persist in 
 the blood after administration of quinine has been commenced. Others main- 
 tain that it acts in stimulating the phagocytes, the natural enemies of the para- 
 site. Some experimentalists, allege, on the other hand, that it paralyses the 
 white corpuscles. • It is said by some to be most effective against the free 
 spores and the very young intracorpuscular forms, but inoperative against the 
 more mature parasites; hence they advocate giving it early in the parasitic cycle. 
 Others, on the contrary, maintain that it is operative only on the large intra- 
 corpuscular forms, and therefore advocate its use at a late stage of the cycle." 
 
 Much confusion which exists regarding the action of the drug upon the 
 Plasmodia is due, I believe, to the staining methods employed by various 
 observers, many of which were imperfect, and to the interpretations arrived 
 at from them. In my own work I have used the modified Wright's stain 
 already described, by which method the chromatin of the nucleus of the parasite 
 stains a brilliant red, the protoplasm a robin's-egg blue, while the vesicular 
 portion of the nucleus remains unstained. The method is uniform in its results 
 and in the great number of specimens examined the morphology of the plasmodia 
 after the administration of quinine was always the same for the various periods 
 in the life cycle of the organisms. 
 
 While stationed at Camp Stotsenburg, P. I., in 1905, where all varieties of 
 the malarial fevers were prevalent, I spent several weeks in studying the effect 
 of quinine upon the malarial plasmodia, in order to determine, if possible, the 
 actual effect of the drug upon the various species of plasmodia, and therefore 
 the best time to administer quinine in treating the malarial fevers. The conclu- 
 sions arrived at are the result of the examinations of a very large number of 
 both fresh and stained specimens of blood after the administration of quinine 
 was begun, and they represent, I believe, the exact action of the drug upon 
 the various species of malarial plasmodia in all stages of their human life cycle. 
 
 Historical. — Before considering the results of my studies, the following 
 historical summary is of interest: Binz, in 1867, was the first to interpret the 
 curative action of quinine in malaria as being due to its effect directly upon the 
 cause of the disease, which he concluded to be some low form of animal life. 
 In support of his position he instanced the effect of solutions of the drug upon 
 many species of infusoria. In 1881 Laveran demonstrated that a 1-1000 solu- 
 tion of quinine caused the immediate cessation of the movements of the plas- 
 modia when added to a preparation of malarial blood under the microscope and 
 asserted that "it is because it destroys the parasite that quinine causes the 
 disappearance of the manifestations of paludism." 
 
 The Tertian Plasmodium. — Golgi claimed that the action of quinine was 
 most marked upon the tertian Plasmodium, even the adult forms being affected 
 by it. His studies were made upon fresh blood and the changes produced by the 
 drug, as described by him, consisted in a shrinkage of the parasites, while the 
 protoplasm became coarsely granular and opaque. The segmenting parasites 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 363 
 
 were shrunken and contained numerous pigment masses and a smaller number 
 of spores. 
 
 Romanowsky, using his admirable staining method, found that in the 
 young intracellular tertian parasites the drug caused a disappearance of the 
 vesicular portion of the nucleus, while the chromatin stained less intensely. 
 The adult parasites showed more marked changes, becoming round in shape, 
 while the pigment was distributed throughout the organisms or else collected 
 about the periphery; the protoplasm stained uniformly; the chromatin was re- 
 duced in amount, stained less intensely and the vesicular portion of the nucleus 
 had disappeared. He found that in the sporulating bodies the segments stained 
 uniformly, the nucleus slightly, while the unstained area was absent. 
 
 Mannaberg studied both fresh and stained specimens of blood. In the for- 
 mer he found that amoeboid motion became lessened, and that several hours 
 after the administration of the drug fragmentation occurred. In the full-grown 
 forms the pigment became immotile, while the protoplasm became more refrac- 
 tive and homogeneous. In stained preparations he claimed that quinine causes 
 the chromatin to lose its power of staining and in the segmenting forms most 
 of the segments contained no chromatin. Zieman found that when quinine is 
 administered during apyrexia, the parasites become fragmented, but the chroma- 
 tin remains normal in appearance, while if the drug be given at the time of 
 fission this process is not hindered, even the chromatin dividing as usual. 
 
 The Quartan Plasmodium. — Antolisei, from his observations, concludes that 
 the adult quartan plasmodium is not affected by quinine, development and 
 sporulation occurring as usual; but in the attack following the administration of 
 the drug, the young intracellular forms occur in much smaller numbers. 
 
 Golgi agrees with Antolisei, but found that the effect of the drug upon 
 the young parasites varies, many being killed, while others were hindered in their 
 development, which produced irregularities in the type of fever. He claims that 
 the drug does not affect the adult quartan parasite. 
 
 Mannaberg found that the changes observed in the quartan plasmodia after 
 the administration of quinine were the same as those observed in the tertian 
 Plasmodium. 
 
 The Aestivo-autumnal Plasmodia. — Baccelli observed that in aestivo- 
 autumnal infections quinine produced an increase in the amoeboid movements, 
 and that the plasmodia disappeared from the blood without any degenerative 
 changes being apparent. 
 
 Marchiafava and Bignami, after a careful study of this subject, determined 
 that quinine caused the young plasmodia to leave the infected corpuscle, and that 
 staining showed no evidence of morphological change after the administration 
 of the drug. They state that development is hindered, however, as shown 
 by the non-development of pigment, thus proving that nourishment is hindered. 
 These authors believe that quinine not only acts directly upon the plasmodia, 
 but also modifies the erythrocyte in such a way that it becomes impossible for the 
 Plasmodium to develop within it. In conclusion they say: "Quinine acts upon 
 the malarial parasites in that phase of their life history in which they are nour- 
 ished and develop." 
 
 La Monaco and Panichi claim that the resistance of the plasmodia to 
 quinine is greatest during the apyrexial period, and least at the approach of 
 and during the pyrexial. In their experiments they found that the effect of the 
 quinine varies with the strength of the solution employed, weak solutions causing 
 swelling of the parasites and stimulating amoeboid motion; medium solutions 
 greatly stimulating movement, resulting in the extrusion of the plasmodium frcm 
 the erythrocytes; while strong solutions caused contraction and death. 
 
364 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 Cappogrossi concludes that the exit of the plasmodium from the erythrocyte 
 is not the result of the specific action of quinine, but is purely physical, being due 
 to the hypotonicity of the quinine solution. He claims that quinine in an iso- 
 tonic solution of sodium chloride does not cause the plasmodia to leave the ery- 
 throcytes, but results in loss of motility, while the protoplasm becomes more 
 opaque and tinted with haemoglobin. 
 
 Personal Observations. — In considering the action of quinine upon the 
 malarial plasmodia I shall describe the changes occurring in each species, in 
 both fresh and stained specimens of blood. 
 
 Plasmodium Vivax (Tertian Plasmodium). — The action of quinine upon 
 the tertian plasmodium is evident in fresh blood specimens during every stage 
 of the life cycle in man except immediately before sporulation. The changes 
 produced by the drug consist chiefly in a granular degeneration of the proto- 
 plasm and fragmentation, the latter being most common in the nearly full- 
 grown parasites. To these changes should be added a great diminution in the 
 amount of pigment in the developing forms, thus showing a marked disturbance 
 in the nutritive functions of the organisms. 
 
 The effect of the drug varies with the time of administration and the dose, 
 but it is effective upon all but the segmenting bodies, and therefore is curative 
 whenever given, whether in one large dose just before sporulation or in divided 
 doses. 
 
 If quinine is administered when the young intracorpuscular plasmodia are 
 present the changes produced by it are an increase in amoeboid motion, followed 
 in an hour by a decrease and finally by complete cessation; an increase in the 
 refractive quality of the protoplasm; and finally granular degeneration of this 
 portion of the plasmodium. During the stage of stimulation, the amoeboid 
 motion may become very active, the pseudopodia being projected so swiftly 
 that it becomes almost impossible to follow the process. After the cessation of 
 motion the young plasmodia become "ring-shaped" or spherical, and much 
 more sharply outlined than is the normal tertian plasmodium. At this stage of 
 growth no shrinkage of the organisms was observed as described by Golgi. 
 
 If now the blood be examined at regular intervals, the quinine being 
 continued, it will be found that the plasmodia diminished greatly in number up 
 to the time of sporulation, proving that at every stage of their growth quinine is 
 capable of destroying them. Although this is so, a considerable number 
 succeed in developing and finally reproduce by sporulation, but, as will be shown 
 in studying stained specimens, even these more fortunate organisms develop 
 atypically, as the majority of the spores are sterile and incapable of further 
 development. 
 
 In those plasmodia which perish prior to sporulation, quinine causes 
 fragmentation, and eventually complete degeneration. Such fragmented para- 
 sites are very numerous in specimens of blood from tertian infections after the 
 administration of quinine, and in those instances in which the drug has been 
 given after pigment formation, fragmentation is the most common form of 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 365 
 
 degeneration, but is always preceded by increased motility and by an increased 
 refractive index. Numerous erthrocytes are observed containing plasmodia 
 which are fragmented, the fragments containing pigment in most instances. 
 The pigment may be motile or immotile, and is collected in the form of rather 
 large blocks or masses. The protoplasm of the fragmented organism is al- 
 ways more refractive than that of the normal tertian plasmodium, and generally 
 appears coarsely or finely granular. In many instances the fragmented para- 
 sites are extruded in whole or in part from the red blood-corpuscles and thus 
 become free in the plasma, from which they quickly disappear, and in tertian 
 infections after the administration of quinine it is very common to find many 
 free degenerated plasmodia in the blood. Fragmentation of the tertian Plasmo- 
 dium due to quinine occurs at every stage in the human life cycle of the organism 
 up to the sporulating form, but in the latter bodies I have never observed any 
 evidence of this process. 
 
 While fragmentation of the plasmodia is very often the result of the action 
 of quinine upon these parasites, it does not invariably occur, for many of the 
 plasmodia present certain changes which do not eventuate in fragmentation. 
 These changes consist in a marked shrinkage in the size of the organism, loss of 
 motility of the pigment, and increase in the refractive index, together with 
 granular degeneration of the protoplasm. 
 
 Upon the fully developed tertian plasmodium prior to the beginning of 
 sporulation, quinine exerts a marked action, causing a shrinkage of the organism, 
 and a markedly granular appearance of the protoplasm, while the pigment be- 
 comes immotile, and is collected in large clumps throughout the protoplasm or 
 is distributed about the periphery in small masses. Fragmentation may occur, 
 but it is not as common as in the younger pigmented forms. 
 
 When quinine is administered just at the beginning of sporulation it 
 produces no morphologic changes in the plasmodia, but if it has been present 
 during the period of growth of the plasmodia it will be found that the sporulating 
 bodies, which have evidently partially resisted the action of the drug, are smaller, 
 appear more refractive than normal, while the number of spores is reduced. 
 
 There can be no doubt that quinine is very fatal to the young spores 
 resulting from segmentation, while they are yet free in the blood plasma, but it 
 is not fatal to all of them, for in every case careful examination will demonstrate 
 that some escape, penetrate the erythrocytes, and undergo more or less complete 
 development. This can be demonstrated even in those cases of tertian malaria 
 which do not present clinical symptoms of the infection, i.e., the latent cases. 
 
 From the changes which have been described it is evident that if quinine is 
 administered when the blood contains the young intracellular plasmodia of ter- 
 tian malaria it produces death in a certain number, while others are able to 
 develop more or less perfectly, but are undoubtedly injured during every stage 
 of their growth if the drug be given at regular intervals. This injury may 
 result in death at a later period of development or by atypical development. 
 If sporulation occurs, the spores are reduced in number, and. as will be shown in 
 
6 
 
 66 DIAGNOSIS, PROPHYLAXIS. AND TREATMENT OF MALARIAL FEVERS. 
 
 the description of the stained specimens, most of them are sterile. Upon al 
 forms of the pigmented tertian plasmodium until the beginning of sporulation 
 quinine has a marked action, causing either fragmentation, shrinkage in size, 
 or granular degeneration of the organism. The effect of the quinine upon all 
 stages of growth of the plasmodium is most marked when it is administered in 
 divided doses at regular intervals of time, thus keeping the blood supplied with 
 it. If given just prior to the expected chill, in one large dose, the majority of 
 the young plasmodia are destroyed while free in the blood plasma, but those 
 which escape and develop present but little evidence of the action of the drug, as 
 would be expected, for the blood is free from quinine for several hours before the 
 administration of the next dose. 
 
 In stained specimens of blood containing the tertian plasmodium the ac- 
 tion of quinine is very clearly demonstrated. The modification of Wright's 
 method already described was used invariably, and invariably the same mor- 
 phological changes were observed after the administration of this drug. From 
 my observations I have been able to confirm many of Romanowsky's published 
 results, but I have been unable to demonstrate that the chromatin of any of the 
 species of plasmodia loses its staining properties, but, rather, I have found that 
 this important portion of the nucleus stains even more intensely than normal, 
 but that the brilliant red color is replaced by a very dark violet or almost black. 
 While this is true it was invariably observed that the unstained portion of the 
 nucleus had disappeared, and in those plasmodia which continued the develop- 
 mental cycle, the chromatin had either failed to divide or divided imperfectly, 
 many of the spores showing no chromatin, as described by Mannaberg. The 
 statement of Zieman that the chromatin remains normal in appearance and 
 divides as usual can only be true of those cases in which the quinine is ad- 
 ministered just before sporulation, for if this drug be given during the formation 
 of pigment the vast majority of the plasmodia which live to sporulate present 
 either no evidence of division of the chromatin or division is imperfect, only a 
 few of the spores showing any chromatin. 
 
 In order to study the morphologic changes occurring in the tertian plas- 
 modia as the result of the administration of quinine it is necessary that the drug 
 be given in divided doses to single tertian infections, the first dose just before 
 sporulation; specimens of blood should then be taken at intervals of three 
 hours and immediately stained. Given just before sporulation and repeated at 
 intervals of every three hours, the quinine acts upon the plasmodia not only 
 while free in the plasma, but also upon every stage of their life cycle in man, and 
 it is thus possible to study the morphologic changes produced by quinine in 
 every stage of the development of these organisms. 
 
 The young, unpigmented "ring-forms" stain very intensely after the ad- 
 ministration of quinine, the protoplasm a much darker blue than normal, while 
 the chromatin stains a very dark crimson, often almost black. Besides the in- 
 crease in the intensity of the stain, the loss of the unstained area about the 
 chromatin (the vesicular portion of the nucleus) is very noticeable, and con- 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 367 
 
 stitutes a most important evidence of the injurious action of the drug upon these 
 parasites. 
 
 In tertian plasmodia a little further advanced in development, the staining 
 reactions are the same as for the "ring-forms," but the increased motility of the 
 plasmodia is shown in the great number and "bizarre" arrangement of the 
 pseudopodia. Fragmentation is observed even before the formation of pig- 
 ment, some of the unpigmented plasmodia being broken up into deeply stained 
 portions, the chromatin lying in one of these portions or free near the periphery 
 of the red cell. 
 
 After the formation of pigment, and especially after the plasmodia are from 
 one-half to three-quarters grown, the evidence of fragmentation and extrusion 
 of the chromatin becomes more marked. Many of the erythrocytes contained 
 deep blue portions of protoplasm, the chromatin lying free within the red cor- 
 puscle. The latter is frequently situated at the extreme periphery of the red 
 cell or even partly outside of it. At this stage numerous extracellular plasmodia 
 are observed, either undergoing fragmentation or other forms of degeneration. 
 Many of the fragments are entirely devoid of pigment, staining a deep uniform 
 blue throughout, while some may be almost filled with blocks and granules of 
 pigment. The vesicular portion of the nucleus is always absent, nor is there any 
 evidence of an increase in the amount of chromatin which is so noticeable in the 
 normal plasmodium when at this stage of development. If fragmentation be 
 absent, the protoplasm of the plasmodium stains a very dark blue and the 
 chromatin a dark violet or almost black. The pigment is generally collected 
 about the periphery of the plasmodium. In many instances the chromatin is 
 situated at the extreme periphery of the parasite or may lie partly or wholly out- 
 side of it within the erythrocyte, proving that quinine possesses the power of 
 causing extrusion of the chromatin, thus rendering the plasmodium sterile. 
 
 Together with absence of the vesicular portion of the nucleus there is 
 seldom any evidence of increase in the amount of chromatin and of division of 
 the latter. 
 
 In fully developed tertian plasmodia fragmentation frequently occurs, 
 many of the fragmented parasites being free from chromatin, but the character- 
 istic change at this period of development in those plasmodia in w T hich frag- 
 mentati:n is absent, as shown by stained specimens, lies in the fact that although 
 the chromatin may be present and stains an intense violet, it has increased but 
 little or not at all in amount, and division is either absent or imperfect, only two 
 or three small masses being present, which lie close together near the periphery 
 of the organism. In tertian plasmodia which have not been acted upon by 
 quinine, and have reached this stage of development, the chromatin has always 
 greatly increased in amount and is found divided into numerous masses which 
 are scattered throughout the protoplasm. The morphology of the plasmodia at 
 this stage of their growth indicates clearly that quinine prevents an increase in 
 amount of chromatin and either hinders division or prevents it altogether. 
 
 At this stage the protoplasm of the plasmodium stains a deep blue and the 
 
368 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 pigment is collected about the periphery in blocks or granules, or more rarely, 
 distributed throughout the protoplasm in the form of fine granules or small 
 clumps. The vasicular portion of the nucleus is always absent. 
 
 Those plasmodia which sporulate after having been exposed to the action 
 of quinine throughout their entire cycle of development present very marked 
 morphological evidences of the injurious action of the drug, in stained prepara- 
 tions. While sporulation may not be entirely prevented the majority of the 
 spores are devoid of chromatin, and are undoubtedly sterile. The spores are 
 also greatly decreased in number and may be distorted in shape, while in 
 those which show the presence of chromatin the latter is in the form of minute 
 irregular masses, very distinct from the compact spherical mass observed in 
 normal parasites. Very often sporulating bodies are observed in which only 
 two or three of the spores possess chromatin; in such spores the protoplasm 
 stains a deep blue, the chromatin almost black, and there is no evidence of the 
 vesicular portion of the nucleus. Associated with the chromatin containing 
 spores are from six to eight, or perhaps more, deeply stained spores devoid of 
 chromatin. In the sporulating plasmodia, the pigment, instead of being 
 collected in a dense compact mass, as is the rule in the normal tertian Plas- 
 modium, is reduced in amount, and scattered in small clumps or granules 
 between the spores. 
 
 From the changes demonstrated in stained specimens of tertian plasmodia 
 after the administration of quinine it is evident that this drug, administered in 
 divided doses, exercises a markedly injurious effect upon every stage in the 
 human life cycle of this organism, either causing the death of the parasite at 
 some period of its development or preventing normal sporulation by restrain- 
 ing the production and division of the chromatin prior to segmentation. The 
 death of the organism is evidenced by fragmentation or extrusion of the chroma- 
 tin, while the effect upon sporulation is shown by the lessened production of 
 this substance, the limited division of the chromatin present, and the number of 
 spores which are devoid of this essential portion of the nucleus. The loss of 
 the vesicular portion of the nucleus is probably responsible for the changes 
 which are observed. 
 
 If quinine is administered in one large dose just prior to segmentation and 
 the dose is not repeated, the changes produced are the same in kind as those 
 described, but a very large number of the plasmodia escape entirely or are but 
 little injured. When given in this way segmentation occurs as usual, and both 
 the sporulating bodies and the individual spores appear normal. 
 
 Plasmodium Malariae (the Quartan Plasmodium). — The changes 
 produced by quinine in the quartan plasmodium, as shown by both fresh and 
 stained preparations of blood, are practically the same as those described for 
 the tertian plasmodium, and I cannot agree with Antolisei and Golgi that upon 
 the adult quartan plasmodium quinine has no effect. In the young intracellular 
 forms development is hindered or stopped, there being the same initial stimula- 
 tion of amoeboid movement, while in the older forms fragmentation and degen- 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 369 
 
 eration occur as frequently as in the tertian plasmodium. I have not been able 
 to observe any difference, so far as morphologic evidence goes, in the effect of 
 quinine upon the tertian and quartan plasmodia, although it is undoubtedly 
 true that because of greater resistance to the drug, a larger number of quartan 
 plasmodia escape destruction at the time of sporulation. As in the tertian 
 infections, the effect of the drug is most apparent when it is administered in 
 divided doses at regular intervals. 
 
 Plasmodium Falciparum. Plasmodium Falciparum Quotidianum 
 (The Tertian and Quotidian Aestivo-autumnal Plasmodia). — As the effect 
 of quinine is the same upon both species of aestivo-autumnal plasmodia, 
 I shall consider them together. As stated in the historical summary, 
 Marchiafava and Bignami found that in fresh specimens, after the administra- 
 tion of quinine, the plasmodia assumed a discoid form and left the erythrocytes, 
 while the motility was normal or increased. While I have been able to confirm 
 the occurrence of the discoid shape, I have not been able to confirm their ob- 
 servations regarding the exit of the plasmodia from the red cells. The follow- 
 ing observations are based upon the study of the action of quinine upon both 
 fresh and stained specimens of blood containing the aestivo-autumnal plas- 
 modia, including every form of the organisms except the fully developed 
 pigmented bodies and the sporulating bodies. 
 
 In fresh specimens, a few hours after the administration of quinine in 
 divided doses, the time varying with the rate of absorption of the drug, the 
 hyaline "ring-forms" become much more refractive and sharply cut than 
 normal while the amoeboid motion is always greatly stimulated. In most 
 instances, the "ring-forms," owing to the great increase in the activity of the 
 amoeboid motion, lose their distinctive form, becoming discoid or assuming 
 irregular shapes, and not infrequently change their position in the red corpuscle 
 very rapidly, occupying the same portion of the cell only a few seconds at a 
 time, but I have never observed their exit from the red corpuscle. 
 
 Upon the larger pigmented forms, and pigmented "rings" quinine appears 
 to have less effect, the only change observed in fresh specimens being an 
 increase in the refractive index, while the outline of the plasmodia becomes 
 more sharply defined. I have not observed degeneration by fragmentation in 
 the aestivo-autumnal plasmodia, although it is so common in the tertian and 
 quartan parasites. 
 
 In stained specimens the results of my observations are opposed to those 
 of Marchiafava and Bignami, who claim that no morphologic changes occur in 
 these plasmodia after the administration of quinine, and that the unpigmented 
 parasites do not become pigmented after its administration. I have repeatedly 
 observed pigmented forms of both the tertian and quotidian aestivo-autumnal 
 plasmodia develop after quinine had been administered for as long as three 
 days, while the morphologic changes produced, though not so marked, are 
 similar to those observed in the tertian and quartan plasmodia. 
 
 In the "ring-forms," which are most easily studied, the staining capacity 
 24 
 
370 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 of both the protoplasm and the chromatin is increased, but the unstained area 
 surrounding the chromatin disappears. A large number of the " ring-forms" 
 may appear normal, but careful examination will demonstrate that most of 
 them show the loss of the vesicular portion of the nucleus and that the "rings" 
 are distorted in shape owing to the increased amoeboid motion. In a few 
 instances I have observed the separation of the chromatin from the body of the 
 Plasmodia, thus proving that extrusion had occurred. I have never observed 
 fragmentation of the "ring-forms." 
 
 The changes produced in the young pigmented forms of the aestivo-autum- 
 nal plasmodia, as shown in stained preparations, are similar in every respect 
 to those occurring in the tertian and quartan plasmodia, consisting in frag- 
 mentation, loss of the vesicular portion of the nucleus and extrusion of the 
 chromatin. 
 
 Effect of Quinine upon Gametes and upon Intracorpuscular Conjuga- 
 tion. — No morphological changes occur in the gametes (crescents) of the 
 aestivo-autumnal plasmodia so far as can be observed in both fresh and stained 
 preparations, and Marchiafava, Gualdi, and Martirano have proven that the 
 crescents are not destroyed by quinine and that they are still capable of under- 
 going development wathin the mosquito, after quinine has been administered, 
 for long periods of time. Crescents, however, do not appear if quinine be 
 thoroughly given during the first attack of an aestivo-autumnal infection, a 
 fact well known to every student of the aestivo-autumnal fevers. 
 
 As regards the effect of quinine upon the tertian gametes, Schoo, in Holland, 
 has demonstrated that quinine prevents the development of the tertian gamete 
 in the mosquito; his experiments follow: 
 
 A case of tertian fever was bitten by a large number of Anopheles, all 
 becoming infected. One gm. of quinine was then administered for three days, 
 and 1 6 Anopheles allowed to bite, none becoming infected. 
 
 A case of tertian malaria was bitten by 10 Anopheles during the afebrile 
 period, of which eight became infected. Four hours before the chill he was 
 given i gm. of quinine, and six hours afterward was bitten by nine Anopheles, 
 of which none became infected. 
 
 Upon the quartan gametes we possess no evidence showing that quinine 
 is capable of preventing their development in the mosquito. 
 
 In both tertian and quartan infection the prompt administration of quinine 
 during the first attack of fever will prevent the development of the gametes. 
 
 Upon intracorpuscular conjugation quinine has a fatal influence, for, after 
 the administration of this drug, conjugating plasmodia entirely disappear from 
 the peripheral blood and do not reappear unless the administration has been 
 stopped, and then only after an interval of days or even weeks. Even in those 
 instances in which the drug is given in such small doses as to injure but slightly 
 the developing plasmodia, the conjugating organisms quickly disappear, and 
 as the process of conjugation is undoubtedly intended to assist in maintaining 
 malarial infection, the marked action of quinine upon it offers another explana- 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 37 1 
 
 tion of the efficiency of the drug in curing these fevers if it be properly given 
 during the initial attack. 
 
 From the evidence submitted I believe that it is an incontrovertible fact 
 that quinine is a true specific for the malarial fevers, acting directly upon the 
 Plasmodia causing these fevers, during every stage of their human life cycle, 
 except the presegmenting stage, and that its persistent administration will 
 invariably result in the cure of any malarial infection, provided the drug be 
 properly administered. 
 
 2. Choice of Preparation. — Of the eighteen or more salts of quinine 
 which have been used in the treatment of the malarial fevers, but a very limited 
 number are deserving of attention, in that they are of practical use. The most 
 useful are the sulphate and the bihydrochloride or bimuriate of quinine. Of 
 these two salts the bihydrochloride is the more soluble, being dissolved in the 
 proportion of 1 part to .96 parts of water, while the sulphate is only soluble in 
 1 to 800 parts of water. Of the two salts the sulphate is the more used, as it 
 is much cheaper and can be procured more easily. The following table of the 
 chief salts of quinine and their solubility will prove useful to the therapeutist, 
 but practically it will be found that the sulphate is most useful in the vast 
 majority of our cases of malarial fever. 
 
 Salt 
 
 Alkaloid 
 
 in salt 
 
 73 
 
 5 
 
 % 
 
 81 
 
 8 
 
 % 
 
 72 
 
 
 
 % 
 
 76 
 
 6 % 
 
 60 
 
 
 
 % 
 
 59 
 
 1 
 
 % 
 
 76 
 
 2 
 
 % 
 
 73 
 
 
 
 % 
 
 78 
 
 2 
 
 % 
 
 70 
 
 1 
 
 % 
 
 69 
 
 4 
 
 % 
 
 20 
 
 
 
 % 
 
 Solubility in cold water 
 
 Sulphate 
 
 Hydrochloride 
 Bihydrochloride 
 Hydrobromide 
 Bihydrobromide 
 
 Bisulphate 
 
 Phosphate 
 
 Valerianate .... 
 
 Lactate 
 
 Salicylate 
 
 Arseniate 
 
 Tannate 
 
 In 800 parts. 
 
 In 40 parts. 
 
 In .96 parts. 
 
 In 45 parts. 
 
 In 7 parts. 
 
 In 11 parts. 
 
 In 420 parts. 
 
 In 120 parts. 
 
 In 10 parts. 
 
 In 225 parts. 
 
 Very slightly soluble. 
 
 Very slightly soluble. 
 
 For hypodermic use the bihydrochloride or bimuriate of quinine is most 
 commonly employed, but the bihydrobromide, the lactate, and the bichloride 
 of quinine and urea may also be used for hypodermic injection. 
 
 3. Time of Administration. — The time of administration of quinine in 
 malarial infections has been the subject of much discussion, but from what 
 we know of the action of the drug upon the malarial plasmodia it is difficult 
 to see why this should be so. As I have shown, the drug acts upon every stage 
 in the development of all the species of plasmodia except the presegmenting 
 
3 7 2 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 stage and therefore it is evident that if the blood constantly contains the drug 
 the best effects will be secured. Those who advocate the administration of 
 quinine in one large dose just before the expected paroxysm, trusting that all of 
 the newly developed spores will thus be killed, lose sight of this fact, and also 
 of the fact that many of the spores escape when the drug is thus administered. 
 While in tertian and quartan infections, in which the paroxysms occur at regular 
 intervals, good results may be obtained by giving the quinine in one large dose 
 during the decline in the temperature, in aestivo-autumnal infections and in 
 irregular tertian and quartan infections the best results are obtained when the 
 drug is given in divided doses at regular intervals, and I have found from 
 personal experience that the latter method of administration is preferable in 
 all cases of malarial infection. 
 
 It is not necessary to discuss here the many contributions to the literature 
 of malaria dealing with this subject, but those interested should consult the 
 valuable paper of Dock which contains a summary of the opinions of various 
 writers upon the administration of quinine in malaria. From the studies 
 of the action of this drug upon the plasmodia it is evident that in order to secure 
 the best therapeutic results the drug should be present in the blood continually, 
 and therefore it should be administered in divided doses at regular intervals of 
 time. Given in divided doses at regular intervals the blood constantly contains 
 a sufficient quantity to practically stop the development of the plasmodia which 
 have succeeded in escaping it while free in the blood plasma, and recovery is 
 thereby hastened. 
 
 The practice of giving quinine in the manner mentioned is not only justi- 
 fied by the morphologic changes observed in the plasmodia, but its value is 
 proven by practical experience. Manson recommends the administration of 
 quinine in divided doses, and many tropical practitioners have found that this 
 is the most successful method of administration. I have at present the records 
 of over 2,000 malarial cases (mostly in the person of soldiers of our army, 
 returning from the Philippines and serving in the Philippines), including 
 tertian, quartan, and aestivo-autumnal infections, in which quinine was 
 administered in doses of 0.50 gm. every three hours until from 1.50 to 2.00 gms. 
 were taken, and in all of these cases recovery was prompt and occurred more 
 quickly than in similar cases in which one large dose of the drug was adminis- 
 tered prior to sporulation. In the tertian cases it was very rarely that a second 
 chill occurred after the beginning of the administration of the drug, although 
 in about 20 per cent, of the cases a rise of a temperature was noted upon the 
 day of the expected paroxysm. In the quartan cases a second paroxysm 
 never occurred after the beginning of the administration of quinine in this way; 
 while in the aestivo-autumnal cases, which comprised nearly two-thirds of 
 the total number of cases, the temperature, except in two pernicious cases, 
 reached normal in from two to three days and recovery followed. It is in the 
 latter type of malarial infection that the administration of quinine in divided 
 doses is especially efficient, for in this type it is generally impossible to tell the 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 373 
 
 exact time of the ensuing paroxysm, and thus it is impossible to attack the 
 Plasmodia while they are free in the blood plasma by the administration of one 
 large dose of the drug. In these infections it is necessary to give quinine in 
 divided doses of from 0.30 to 0.60 gm. (5 to 10 grains) at intervals of four to six 
 hours until the temperature reaches normal, and to increase the number of 
 doses if experience shows that the quantity advised is insufficient. When the 
 temperature reaches normal the quinine should be administered in one large 
 dose at bedtime or in smaller divided doses during the twenty-four hours. 
 In pernicious and irregular forms of the malarial fevers, especially if due to the 
 aestivo-autumnal plasmodia, the administration of the drug should not be 
 delayed, but it should be given hypodermically in doses of 1 gm. (15 grains), 
 repeated in three hours if necessary. 
 
 In tertian and quartain infections the drug should preferably be given in 
 divided doses, but nearly as good results will be secured if it be administered in 
 one large dose during the decline in the temperature or at the end of pyrexia. 
 Given in this way the next paroxysm will be prevented in the majority of the 
 cases as the drug has thus been brought in contact with the free spores upon 
 which it acts most vigorously. In all such cases the sulphate administered 
 in solution or in capsules will be found the cheapest and most efficient prepara- 
 tion. Quinine should not be discontinued, even in the mildest cases of malaria, 
 after apparent recovery, but should be given in doses of from 0.30 to 0.60 gm. 
 ( 5 to 10 grains) daily for at least a week and once a week in doses of 0.60 gm. 
 (10 grains) for at least two months afterward. Unless some such plan is 
 adopted recurrences are bound to occur and may lead to chronic malarial 
 cachexia. 
 
 4. Methods of Administration. — Quinine may be administered by the 
 mouth, by the rectum, intravenously, and hypodermically. Inunctions through 
 the skin have been practised in rare instances, but are of little practical impor- 
 tance. In the vast majority of cases of malarial infection the administration 
 of quinine by the mouth will be found the most practicable method of using the 
 drug. 
 
 Administration by the Mouth.— There are comparatively few cases in 
 which quinine cannot be administered by the mouth. In pernicious cases, in 
 patients who appear to be unable to absorb the drug from the stomach, and 
 in those very rare instances in which the drug so deranges the stomach as to 
 produce grave symptoms of poisoning, quinine will have to be administered in 
 some other way, but in the vast majority of our cases of malaria the drug may 
 be given by the mouth. When administered in this way quinine may be given 
 in the form of pills, tablets, wafers, capsules, and solutions. The drug should 
 never be given in pill or tablet form unless we can be sure that these are 
 readily soluble, and in most instances it will be found that the pills and tablets of 
 quinine ordinarily found in drug houses are very insoluble, and therefore the 
 use of the drug in these forms should be avoided if possible. The best form 
 in which to administer quinine is in solution, but on account of the intensely 
 
374 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 bitter taste this method is often inapplicable, and then we should administer 
 it in capsules or in wafers. I have found from experience that to secure good 
 results in the treatment of malaria quinine should never be administered in the 
 form of pills or tablets, and that the best results are secured when it is adminis- 
 tered in solution. 
 
 When solutions are used, the sulphate is most frequently employed, a drop 
 of dilute hydrochloric or sulphuric acid being added for every 0.065 (g ram ) °f the 
 drug. The bitter' taste of the solution may be partially disguised by the addi- 
 tion of verba santa, or a chocolate syrup, to the solution. For children and for 
 those who are very easily nauseated by the bitter taste of quinine, the adminis- 
 tration of the drug in the form of chocolate troches containing the tannate of 
 quinine is indicated, and in Italy the combination of chocolate with quinine has 
 been adopted by the Government as the most palatable method of dispensing 
 the drug to children and is the form in which the quinine issued by the Govern- 
 ment is always dispensed. 
 
 Administration by the Rectum. — The administration of quinine through the 
 rectum has been advocated by some authorities, but will be found most unsatis- 
 factory in practice. This method is recommended in children, but is much more 
 disagreeable to them than the administration of the drug by the mouth in the 
 form of a cholcolate syrup containing it or chocolate troches containing the 
 tannate. By the rectum absorption is very slow, a much larger dose of the drug 
 has to be given, and rectal irritability and pain is almost certain to occur. 
 When the drug is given in this way the dose should be one-half again as much 
 as when given by the mouth, and should be prepared in the form of a rectal sup- 
 pository. If given in solution by the rectum an enema of 150 to 250 c.c. of 
 sterile salt solution should be given containing the dose of the drug, with from 
 five to ten drops of tincture of opium added. 
 
 Cutaneous Inunctions. — Feuchtwanger and Rasch have advocated 
 cutaneous inunctions of quinine in children, but this method is only mentioned 
 to be condemned, as the absorption of the drug is so slow that but little can be 
 expected from this form of administration in well marked cases of malaria, and 
 we possess so many other and better methods of administration in this class of 
 patients that cutaneous inunctions are undeserving of consideration. The 
 chocolate tablets containing tannate of quinine will be found the easiest method 
 of administering this drug to children, but it should be remembered that the 
 tannate is very slowly absorbed and that the dose should be twice that of the 
 sulphate. 
 
 Administration by the Hypodermic Syringe Subcutaneously.— In the 
 pernicious forms of the malarial fevers and in those cases in which, for any 
 reason, the drug cannot be administered by the mouth, the hypodermic injec- 
 tion subcutaneously of the more soluble salts of quinine, such as the bihydro- 
 chloride, the bihydrobromide, and the bichloride of quinine and urea is indi- 
 cated. When these cannot be secured the bisulphate, which is soluble in n 
 parts of water, may be employed for hypodermic injection. The following 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL EEVERS. 375 
 
 solution I have found most useful in treating malaria by the hypodermic in- 
 jection of quinine: 
 
 B Hydrochloride of quinine, 5 gm. (gr. lxxv) 
 Distilled water, add 10 gm. (3iiss) 
 
 In this solution 1 c.c. (15 m.) contains 0.5 gm. (grs. viiss) of quinine. 
 
 In giving hypodermic injections of quinine the utmost care should be taken 
 that everything used in the operation, as well as the skin of the patient is sterile, 
 as abscesses and extensive necrosis of the skin is apt to occur, and even tetanus 
 may develop after the use of a dirty syringe or a septic solution. The syringe 
 used should be, if possible, constructed entirely of glass, with the exception, of 
 course, of the needle, and should be boiled for 15 minutes before use. The 
 quinine should be placed in sealed glass tubes and sterilized in a hot-air chamber. 
 The skin over the region to be injected, preferably the back or buttock, is 
 thoroughly cleaned with soap and water, then scrubbed with ether, and 
 finally with alcohol, and the injection should be made deep into the subcutane- 
 ous tissues, as otherwise necrosis of the skin is of frequent occurrence. The 
 intramuscular method of injection is best. If the materials used in the opera- 
 tion are sterile, abscess formation will not occur, but despite our greatest care 
 there is generally much discomfort and pain following the injections and a con- 
 siderable amount of induration frequently occurs about the site of the injection. 
 
 Owing to the possibility of abscess formation and the pain and discom- 
 fort arising from the injections, this method of administration of quinine should 
 not be used save in cases in which it is essential to secure the effect of the drug 
 rapidly, as when pernicious symptoms develop and where, for any reason, such 
 as unconsciousness or inability to retain the quinine, it is impossible to give the 
 drug by the mouth. The tendency of many practitioners in late years to 
 administer quinine hypodermically in most of their cases of malaria is to be 
 deplored, for it is but rarely that the drug cannot be administered with good 
 results by the mouth. 
 
 After injecting the quinine solution the wound made by the syringe needle 
 should be carefully washed with alcohol and sealed with a collodion dressing. 
 The dose of the drug hypodermically is 0.5 gm. (gr. viiss), repeated every four 
 hours if necessary. 
 
 Intramuscular Injection. — Koch advocates the intramuscular injection 
 of quinine in cases of recurrent malaria and in severe cases of aestivo-autumnal 
 infection, even though pernicious symptoms be absent. He states that the 
 dose required is less than one-half that by the mouth and that the infection is 
 cured more quickly and recurrences are less apt to occur. 
 
 The gluteal muscles are used for intramuscular injections, and the solution 
 used is the same as for hypodermic injection, the same precautions being used as 
 regards the prevention of injection. Maurer and Schiiffer use the bimuriate of 
 quinine in equal parts of water and glycerine for intramuscular injection, and 
 claim that with this solution there is but little danger of abscess formation. 
 
376 DIAGNOSIS, PROPHYLAXIS. AND TREATMENT OF MALARIAL TEVERS. 
 
 Intravenous Injection of Quinine. — To Baccelli we owe this method of 
 administering quinine. It is indicated whenever we desire the most prompt 
 effect of the drug, as in comatose cases; pernicious cases after one pernicious 
 paroxysm has been succeeded by another; when the patient's strength is rapidly 
 failing; or when other treatment has proved unavailing. Marchiafava and 
 Bignami urge the value of this method especially in the algid forms of pernicious 
 malaria. The following solution will be found most uesful when it is desired to 
 give the drug intravenously: 
 
 Bihydrochloride of quinine, 1 gm. (grs. xv) 
 
 Chloride of Sodium, °-°75 (grs. iss) 
 
 Distilled water, 10 gm. (oiiss) 
 
 This solution should be perfectly clear and the entire amount is to be in- 
 jected, the fluid being Luke-warm. In injecting, the veins of the forearm are 
 made prominent by a circular tourniquet and one of the most prominent selected 
 for the injection. The same precautions are observed regarding asepsis as 
 described already, and the needle is introduced from below upward into the 
 lumen of the vein. The injection is made slowly and when the entire amount is 
 injected the site of puncture is sealed with collodion. Extreme care must be 
 taken that no air is introduced into the vein, and that the needle is sterile, as well 
 as the solution. The dose may be repeated if necessary. By this method the 
 mortality of the pernicious malarial fevers has been markedly reduced and it 
 should always be adopted in those cases which have resisted other forms of 
 treatment or which require the immediate effect of quinine. Baccelli states that 
 whereas before the use of intravenous injections of quinine the mortality in those 
 cases of pernicious malaria treated by the hypodermic method of administration 
 was 17 per cent., with his method the mortality has been reduced to less than 
 6 per cent., and his conclusions are confirmed by those of many other observers. 
 
 5. The Amount of Quinine to be Administered. — There is no doubt 
 that we err more often upon the side of excess in the administration of 
 quinine than vice versa, and in most cases of malaria too much of the drug is 
 usually given. It is not uncommon to observe the use of from 5 to 6 grammes 
 of the drug during the 24 hours, even in the mildest cases of tertian and quartan 
 fever, and a general impression appears to prevail in the profession that the 
 malarial fevers require massive doses of quinine in their treatment. The 
 employment of the large amount mentioned above is entirely unnecessary 
 and simply makes the patient more miserable while undergoing treatment. 
 It should be remembered that it is as much the manner in which the quinine 
 is administered as it is the dose, which counts in the treatment of malaria, 
 and that the use of over 40 grains of quinine in the 24 hours is never necessary, 
 even in the treatment of the most severe infection. From personal experience 
 I believe that 2 grammes (30 grains) of quinine, administered in divided doses 
 each 24 hours, is amply sufficient to cure any ordinary case of aestivo- 
 autumnal infection, while in tertian and quartan infections a single dose of 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 377 
 
 i gramme (15 grains) will prevent the next paroxysm, and the same amount, 
 administered in divided doses during the 24 hours, will eventually cure the 
 infection. In my experience with the aestivo-autumnal infections I have 
 yet to see a single case in which treatment was begun in time that did not 
 recover in a few days when treated with 2 grammes of quinine during the 24 
 hours, and I have seen scores recover rapidly when but 1.3 grammes (xx grains) 
 of the drug was administered during the 24 hours. 
 
 When the drug is used hypodermically a dose of 0.5 gm., or 7 1/2 grains, 
 should be administered and repeated, if necessary, until about 1.5 gm. (grs. 24) 
 have been injected. Some very severe cases may require more than this amount, 
 but they will be rare, and in such instances the intravenous methods of adminis- 
 tration should be adopted. 
 
 As soon as the active symptoms of the paroxysm have subsided the dose 
 of quinine may be gradually diminished, but the drug should be used for 
 several weeks thereafter, as otherwise recurrences are bound to occur in the 
 majority of cases. I have found the following doses of quinine efficient in 
 curing most of the malarial infections with which I have come in contact, and 
 it is rarely that the doses as given will need to be increased. 
 
 In tertian and quartan infections, in which the paroxysms occur at regular 
 intervals, namely, in single infections, the attack may be promptly cured by 
 the administration of 1 to 2 gms. (15 to 30 grains) of quinine by the mouth 
 during the decline of the temperature, and the dose repeated upon the following 
 day, or (and I have found this method preferable) the same amount of quinine 
 is given in 0.32 gm. (5 grains) doses every four hours until 1 to 2 gms. are given 
 and the active symptoms disappear. For a period of at least one month 
 the drug should be given in gradually decreasing doses, thus preventing a 
 recurrence. In cases of tertian and quartan infection in which, because of 
 double or mixed infections, it is impossible to foretell the time of the paroxysm, 
 quinine should be administered as in aestivo-autumnal infections. 
 
 In aestivo-autumnal infections quinine should be given by the mouth in 
 doses of 0.32 gm. (grs. 5) every four hours until the active symptoms dis- 
 appear and every five or six hours afterward for a period of three days. During 
 the next week the drug should be administered in doses of 1 gm. (15 grains) 
 at bedtime on every other day, and for at least two months thereafter 
 upon the evening of every sixth day. If the drug be thus administered a 
 definite cure of the vast majority of the aestivo-autumnal infections may be 
 predicted. In cases showing pernicious symptoms quinine should always be 
 given hypodermically. 
 
 One of the most serious mistakes made in the treatment of the malarial 
 fevers is the abandonment of quinine after the disappearance of the active 
 symptoms, and this mistake is responsible for recurrences and the continuation 
 of malarial infection in many localities. The malarial infections are resistant 
 to treatment, especially the aestivo-autumnal fevers, and while a few days' 
 treatment with quinine will cause the disappearance of the symptoms, a limited 
 
378 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 number of the plasmodia may escape, and multiplying gradually, will cause 
 a recurrence of the infection. In all malarial infections, and especially in the 
 aestivo-autumnal fevers, quinine should be administered in the manner suggested 
 for several weeks after all evidence of the infection has disappeared, and only 
 by so doing can we be sure that recurrences will not occur. This is a lesson which 
 the physician in malarial localities seems to have hardly appreciated as yet, 
 and it is most important, both from a therapeutic and prophylactic standpoint. 
 
 In view of the researches of Ehrlich and Browning upon the production 
 of strains of trypanosomes resistant to certain drugs which are usually cura- 
 tive, this resistance being produced by insufficient dosage of the drug, and 
 followed by relapses of the injection, it would appear that a similar resistance 
 to quinine may be acquired by the malarial plasmodia, and this may explain 
 the cases of malarial infection characterized by numerous relapses and resis- 
 tance to this drug. Reasoning from analogy it is reasonable to believe that 
 the malarial plasmodia, like the trypanosomes, may become resistant to certain 
 chemicals which ordinarily are fatal to them. 
 
 Quinine should never be administered during the height of a malarial 
 paroxysm, except in pernicious cases, as the drug will greatly increase the 
 discomfort of the patient, and can be as well given during the decline in the 
 temperature, when it will prove practically as effectual, as if given during the 
 height of the fever. This is a point of some importance in the treatment of 
 malaria in children and in nervous individuals, in whom I have observed violent 
 maniacal delirium follow the administration of large doses of quinine at the 
 height of the paroxysm. In the treatment of malaria in children under one 
 year of age 0.032 to 0.065 g m - (§ rs - i ss to i) f° r a dose is sufficient, the dose to be 
 repeated as in the adult. In older children the drug is better borne and should 
 be used, without hesitation, in large doses in pernicious attacks. 
 
 6. Contradictions to, and Substitutes for Quinine. — In rare instances 
 the administration of quinine is contraindicated in malarial fever because the 
 drug produces such dangerous symptoms that it cannot safely be used. It has 
 been the experience of most physicians that many patients suffering from 
 these fevers protest against the use of the drug, claiming that they are unable 
 to take it because of the dangerous symptoms produced in their case. In most 
 instances it will be found that these patients can take quinine, and that the 
 belief that they cannot is founded upon nothing more than a vivid imagination. 
 If the physician be firm in insisting upon the use of the drug most of these 
 patients will be found able to take large doses with no more than the usual 
 disagreeable effects. Idiosyncrasy to quinine, however, does exist in certain 
 individuals, and therefore some substitute for the drug must be administered. 
 
 In nearly all individuals the use of moderately large doses of quinine 
 produce unpleasant symptoms, such as tinnitus aurium, vertigo, confusion of 
 thought, slight deafness, or congestion of the cerebral blood-vessels and headache. 
 In very susceptible persons these symptoms may be produced by very small 
 doses of the drug, and I have observed one case, a delicate girl of 18 years of 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 379 
 
 age, in which 1 /4 of a grain of sulphate of quinine produced the above symptoms- 
 Such symptoms, however, do not contraindicate the use of quinine, but when 
 amaurosis, total deafness, syncope, dyspnoea, alarming irregularily of the 
 heart, haematuria, and severe bleeding from the bowels and mucous membrane 
 occur, the quinine should be discontinued and one of the substitutes to be 
 mentioned should be administered. The question of the production of haemo- 
 globinuria by quinine will be fully discussed in the section upon haemoglobinuric 
 fever, but it may be stated here that very rarely quinine does produce haemo- 
 globinuria and that in cases in which there is a history of such a condition 
 following its administration, the drug should not be used. 
 
 Certain eruptions of the skin sometimes follow the use of quinine, even in 
 small doses, the most common of which are erythema and urticaria, the latter, in 
 some instances, being very severe. Extensive desquamation of the epidermis is 
 rarely observed, one case coming to my attention peeling so extensively that 
 practically the entire epidermis of the body was replaced. Almost perfect casts 
 of the hands and feet, composed of epidermis, were obtained in this case, and in 
 several other cases I have observed considerable desquamation following the use 
 of this drug. 
 
 F. Plehn has described a condition which he has called "quinine fever" 
 occurring in those who have taken the drug for long periods of time, and he 
 believes that it is due to the destruction of the red blood-corpuscles by the drug 
 and the consequent absorption of toxic substances. While such a form of fever 
 may occur in certain localities, and among certain races, it must be very rare, as 
 in thousands of cases of malaria observed in the United States, Cuba, and the 
 Philippine Islands, I have never observed the occurrence of this form of fever. 
 
 The use of quinine in the treatment of malaria during pregnancy deserves 
 attention. It is an undoubted fact that in women who abort easily this drug is 
 capable, in considerable doses, of producing miscarriage, but it is also true that 
 repeated malarial paroxysms will lead to the same result, and I believe that 
 miscarriage is more apt to occur if the malarial infection remains untreated. 
 In pregnant women the drug should be carefully administered in the smallest 
 efficient dose, but it should be administered if a malarial infection be present. 
 In the event of pernicious symptoms developing the treatment should be the 
 same as in any pernicious case of malaria, for the prospective mother's life is 
 endangered, and we are justified in disregarding that of the child. 
 
 Substitutes for Quinine. — The substitutes for quinine which have been 
 recommended from time to time comprise preparations of the drug which are 
 less toxic than the ordinary salts, and other drugs which have been found to be 
 beneficial in the treatment of malaria. It may be stated with truth that none 
 of them are as efficient as the salts of quinine and on account of their cost, in 
 many instances, are of very limited use in practice. The following are the more 
 important substitutes, but I have never found it absolutely necessary to employ 
 any of them. 
 
 Among the other derivatives of cinchona bark may be mentioned chincho- 
 
o 
 
 So DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 nine, chinchonidine, quinidin, and quinoidia, all of which have been used in the 
 treatment of the malarial fevers, but as the symptoms attending their use are 
 similar to those produced by quinine and as they are very much less efficacious, 
 they have never enjoyed the confidence of the profession in the treatment of 
 malaria. 
 
 Euchinin, an ethyl carbonate of quinine, is a tasteless preparation, and 
 has been extensively used in malaria by Nikastro, Celli, di Mattei, and Sylvain. 
 It has to be given in larger doses than quinine and is apt to produce deafness 
 and derangement of vision. St. George Gray and Mori consider it a very 
 valuable addition to our therapeutic resources in the treatment of malaria. The 
 dose is a little less than twice that of quinine. Personally, I have had no ex- 
 perience with this preparation, and it is too costly for general use. 
 
 Salochinin, or salicylate of quinine, has been recommended by some 
 writers, and Kunst commends very highly a preparation known as Aristoclrin 
 which is administered in doses one-half as large again as quinine. 
 
 Methylene blue has been used quite extensively in the treatment of ma- 
 laria, and was first advocated by Guttman and Ehrlich, whose attention was 
 drawn to it by the observations of Celli and Guarnieri, who proved that the 
 malarial plasmodia could be stained by this agent while still in the circula- 
 tion. I have used this drug but seldom and have found it unreliable. In rare 
 instances it will effect a cure, but it is not to be compared to the salts of quinine 
 in efficiency. Marchiafava and Bignami believe that this drug is worse than 
 useless, as it may produce strangury, albuminuria, and diarrhoea. When 
 administered, only the medicinal methylene blue should be used, and it may be 
 given in capsules in doses of 0.13 gm. to 0.2 gm. (grs. ii-iii) every four hours. 
 It is well to add a little powdered nutmeg to the dose given as this tends to 
 prevent strangury, and warning should always be given that the urine will be 
 colored blue by the drug. This drug has been found efficient in tertian in- 
 fections by Thayer, Kunst and Ivanoff, but in quartan, and especially in the 
 astivo-autumnal infections it has not proven of much value. It is always less 
 efficient than the salts of quinine. 
 
 Phenocoll. — The hydrochlorate of phenocoll, a derivative of phenacetin, 
 has been investigated by numerous observers, notably Albertoni, Pucci, Novi, 
 Anconi, and F. Plehn. The general concensus of opinion is that, while this 
 drug is sometimes useful in the mildest tertian and quartan fevers, it cannot be 
 depended upon in the treatment of the aestivo-autumnal infections, and that it is 
 not free from injurious effects, as symptoms of collapse have followed its use in 
 therapeutic doses. The dose is from 1 to 3 grams (grs. xvi to lv) during the 
 24 hours. 
 
 Various arsenical preparations have been recommended as substitutes 
 for quinine in the treatment of acute malaria, but I have never observed that 
 arsenic had any effect whatever upon the course of a malarial infection, and 
 I agree with Manson that "the place for arsenic is not as a substitute for 
 quinine during fever, but as a blood restorer after fever." 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 381 
 
 From the summary given of the substitutes for quinine it will be observed 
 that they are comparatively few in number and that all of them have been found 
 to be less efficient in the treatment of malaria. In very rare instances it may be 
 found necessary to employ one of them, but I have found that practically all 
 cases of malarial infection may be treated by quinine, provided it is properly 
 administered, and I have yet to see a single case in which quinine, if given early 
 enough, did not succeed in curing the infection. 
 
 General Treatment and Treatment of Special Conditions. 
 
 General Treatment. — All malarial patients should be confined to the bed 
 during the active symptoms of the disease, and after the active symptoms have 
 subsided in the aestivo-autumnal cases it is well to insist upon the patient 
 remaining in bed for two or three days. The bowels should be thoroughly 
 evacuated, preferably by a cathartic dose of calomel or of magnesium sulphate. 
 During the acute stages symptomatic treatment should be adopted; thus in the 
 cold stage, warm drinks, with the application of external heat in some form, are 
 indicated; while in the warm stage, baths of tepid or cold water or an alcohol 
 sponge will be found very beneficial. The ice-pack or bath should always be 
 used in hyperpyrexia. Antipyretics, such as acetanilide or phenacetine, should 
 never be used during a paroxysm of malarial fever, as they never do any good 
 and may do much harm. If vomiting be exhausting, the nervous symptoms 
 pronounced, or pain be excessive, a hypodermic of morphia is allowable, but 
 this drug should not be used if it is possible to avoid it. Subnormal tempera- 
 ture is best combated by hot baths, strong coffee, and massage, while severe 
 headache is often greatly relieved by the ice-cap. Should cardiac weakness be 
 present, suitable stimulants should be administered, the most useful being 
 strychnine, atropine, and brandy; if the weakness is extreme these should be 
 administered hypodermically. While the treatment of special symptoms arising 
 during the malarial paroxysm is of great importance,, it should be remembered 
 that all other treatment is useless unless quinine be administered, so far as 
 curing the infection is concerned, and that the prompt and proper administra- 
 tion of this drug will alone, in many instances, cause the disappearance of all 
 alarming symptoms. It should always be our aim to administer quinine at 
 once in every patient known to have malarial fever. 
 
 During the attack the food should be liquid in character, consisting largely 
 of milk, broths, and thin gruels. The drink should be water or lemonade, the 
 latter especially being greatly relished by most patients, and Tomassi-Crudelli 
 has observed a marked improvement in cases in which the juice of the lemon 
 was administered during the attack and convalescence. As the active symp- 
 toms abate the regular diet may be gradually resumed, and during convales- 
 cence a nutritious diet is necessary. 
 
 Convalescence. — The convalescence from malarial infections which have 
 been properly treated is usually rapid, except in the severe aestivo-autumnal 
 
382 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 infections, when convalescence may be very slow. During convalescence 
 besides the administration of quinine in the manner already described, the use 
 of some form of iron and of arsenic is advisable, on account of the anaemia 
 invariably present. Bland's pill and Fowler's solution are excellent, or other 
 well-tried preparations of these drugs may be used. The diet should be 
 generous and nutritious, sufficient outdoor exercise should be insisted upon, 
 and precautions taken to avoid reinfection. In all cases, where it is possible, 
 a change of climate to a high, dry region, known to be non-malarious, should be 
 urged, as this will do more for the patient than any other therapeutic measure. 
 Bitter tonics are often very useful in stimulating appetite and digestion, and 
 the use of some good mineral water, laxative in action, is indicated, especially 
 in female patients. 
 
 Treatment of Special Conditions. 
 
 Pernicious Fevers. — In all malarial infections presenting pernicious 
 symptoms our first thought must be to get a sufficient dose of quinine into contact 
 with the plasmodia at once, and for this reason the drug should be administered 
 by the hypodermic syringe in the dosage already mentioned. After this has 
 been done the case should be treated symptomatically, but a thorough action 
 of the bowels should be secured by the use of calomel. If the case be one of 
 the bilious remittent type the vomiting may be stopped or allayed by an emetic 
 dose of ipecac or mustard water followed by large doses of subgallate or sub- 
 nitrate of bismuth; mustard plasters over the epigastrium, the sucking of 
 cracked ice, and the hypodermic injection of small doses of morphia are often 
 efficient in allaying the vomiting. Symptoms of collapse should be treated as 
 already described. In choleraic cases opium is indicated and the intravenous 
 injection of normal salt solution. If coma be present, the bladder and intestine 
 should be thoroughly emptied and quinine administered intravenously. Where 
 there is intense congestion of the cerebral vessels and acute delirium, bleeding 
 may be performed with advantage in robust subjects, but this is contraindicated 
 when marked anaemia is present. Hyperpyrexia should be promptly treated 
 by immersion in the cold bath until the temperature is reduced. It is well 
 to give always the cold bath if the temperature by the mouth reaches 106 F., 
 and to remove the patient from the bath when the temperature has been reduced 
 to 102 F. or 102. 5 F. If the temperature begins to rise again the bath should 
 be repeated if it reaches 104 F. In algid forms of pernicious malaria injection 
 of salt solution, external heat applied by means of hot-water bottles and warm 
 blankets, and the free use of alcoholic stimulants is indicated. 
 
 Malarial Cachexia (Chronic Malarial Infection). — The treatment 
 of chronic malarial poisoning or malarial cachexia consists in the use of those 
 drugs which build up the blood, the employment of hygienic measures, and 
 the use of quinine in proper doses at regular intervals. It may be stated with 
 truth that the treatment of this condition is generally unsatisfactory if the 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 383 
 
 patient remain in the locality in which he contracted his infection, or if he live 
 in a locality in which he is continually exposed to reinfection. While 
 various remedial measures may be pursued under such conditions, it will 
 often be found that little result will follow unless a change in climate be secured, 
 and thus we should always, in such cases, counsel a change to a high and dry, 
 non-malarial region, and in the case of patients living in the tropics, a change to 
 a temperate region. The chief drugs used in the treatment of this condition 
 are arsenic, iron, and quinine. 
 
 Arsenic is best used in the form of Fowler's solution, commencing with 
 4 drops after each meal, and increasing 1 drop every three days, until from 12 
 to 15 drops are taken three times a day. If symptoms occur at anytime 
 indicating that the physiological limit to the use of the drug has been exceeded, 
 the treatment should be interrupted for a few days, and resumed with the same 
 dose which was being taken just prior to the occurrence of the unfavorable 
 symptoms. There can be no doubt that arsenic has some effect upon the 
 Plasmodia of malaria, as Gautier has shown that it produces fragmentation of 
 the protoplasm of the gametocytes and Durham claims that this form of the 
 Plasmodia is destroyed by the drug. From this it would appear that arsenic 
 might be of great value in the prophylaxis of malaria, although we have no data 
 which indicate that it is of much value in this direction. 
 
 Iron in some form, such as Basham's mixture or the Blaud pill, is of 
 undoubted value in the treatment of malarial cachexia, stimulating the blood- 
 forming organs and thus repairing the damage done to the blood by the plasmodia. 
 
 Grassi has recommended a combination of quinine, arsenic, and iron, 
 known as esanophele in the treatment of both acute and chronic malaria 
 and in malarial prophylaxis, claiming that better results are obtained with this 
 mixture than with any of the drugs when used alone. The preparation is 
 made in the form of pills or in solution. Schaudinn used this combination in 
 chronic malaria showing recurrences and in latent infections with good results, 
 but in aestivo-autumnal infections and in the malarial infections of the tropics, 
 better results are obtained in the treatment of acute malarial attacks by the use 
 of solutions of quinine alone. In malarial cachexia the esanophele pills are 
 very useful, especially in the treatment of children. The formulae of the 
 esanophele pill is as follows: 
 
 Quinine bimuriaticum, 0.1 grm. 
 
 Acid arsenosum, 0.001 grm. 
 
 Ferrum citricum, 0.3 grm. 
 
 Ext. amara, 0.15 grm. 
 
 Each pill to contain the above. 
 
 Dosage: Children, 3 to 6 years, 1 pill at 6 A. m. and 1 pill at 6 P* M. 
 7 to 14 years, 2 pills at 6 A. m. and 1 pill at 6 P. M. 
 Adults, 2 pills at 5 A. m., 2 at 8 a. m. and 1 at 6 p. m. 
 
384 DIAGNOSIS, PROPHYLAXIS, AM) TREATMENT OF MALARIAL FEVERS. 
 
 In children from 1 to two years of age the following solution, known as 
 Esanophele Solution No 1 is given: 
 
 Each teaspoonful contains, Quin. bimuriate, 0.12 gm.; Arsenous acid 
 0.0003 gm.; Ferrum citricum, 0.03 gm.; an d Ext. amara, 0.1. A teaspoonful, 
 or 5 c.c, is given at 6 A. M., 9 A. M. and 12 noon for 15 days. 
 
 In children from 7 to 12 months of age, Esanophele Solution No. 2 is 
 recommended, each teaspoonful containing; Quin. bimuriate, 0.1 gm. ; Arsenous 
 acid, 0.0002 gm.; Ferrum citricum, 0.013 g m -; an d Ext. amara, 0.1 g. A 
 teaspoonful is given at 7 a. m. and at 10 a. m. for 15 days. I have had no experi- 
 ence with this mixture, but it would appear from the evidence of those who 
 have used it that it is valuable in the treatment of malarial cachexia and in 
 latent malaria in the inhabitants of malarial localities. 
 
 Warburg's Tincture has been used very extensively in the treatment of 
 chronic malaria, but I have never seen much benefit follow its use in the few 
 cases in which I have employed it, although many practitioners in the tropics 
 consider it an invaluable mixture in the treatment of malaria. I believe that 
 where it does do good it is entirely due to the quinine which it contains, and it is 
 a well-known fact that the formula of the original Warburg's tincture has been 
 lost and that the preparations in the market are filled with inert drugs, pos- 
 sessing, so far as we know, no therapeutic use whatever. Some authors claim 
 that they have seen this preparation succeed in curing malaria where quinine 
 alone has failed, but it is very doubtful if a careful study of such instances would 
 establish the truth of this statement. I have, from personal experience, arrived 
 at the conclusion that Warburg's tincture is of little use in the treatment of acute 
 malarial infections, but that it may have a place in the treatment of chronic 
 infections where active symptoms are not present and in the mild latent in- 
 fections so common among the inhabitants of malarial localities. 
 
 Patients suffering from chronic malarial infection should be clothed 
 warmly, should avoid exposure to either cold or heat, should live quietly, and 
 eat plenty of nourishing food. The great importance of a change of climate has 
 already been mentioned, but such patients should be very careful about exposing 
 themselves to cold winds or to dampness, as much exposure is very apt to be 
 followed by a recurrence of active symptoms. In patients going from the 
 tropics to a temperate locality it is especially important that chilling be 
 avoided and that quinine be taken during the sea voyage or land journey and 
 for weeks after arriving at their destination. There is nothing more commonly 
 observed than acute attacks of malaria occurring after arrival in a temperate 
 climate in those who have suffered from malaria in the tropics Such attacks 
 could be avoided by the daily administration of quinine. 
 
 Treatment with the Roentgen Rays — The effect of the A' -rays upon, 
 certain protozoa has been thoroughly studied by Schaudinn and his results offer 
 no hope that the treatment of malaria by this means will ever result in practical 
 benefit, as the exposures are so long as to endanger the patient. That pro- 
 longed exposure to the A-ray will ultimately destroy, or at least so injure the 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 385 
 
 Plasmodia as to render them harmless, has been proven, but the method is not 
 at present capable of practical application. 
 
 Serum Therapy. — That the serum therapy of malaria will ever be of 
 practical utility is open to very serious question, and the results so far obtained 
 are of more interest to the bacteriologist and protozoologist than they are to the 
 physician. A curative serum would hardly become popular, as we possess in 
 quinine a specific for the malarial fevers, but a prophylactic serum would cer- 
 tainly be a great boon to mankind. Up to the present, however, such a serum 
 has not been obtained, and it is very doubtful if it ever will be. Several investi- 
 gators have studied this phase of malarial therapy, and some of their results 
 are deserving of mention. Kuhn, for instance, has endeavored to use the 
 serum of horses immunized to the South African horse sickness in the treatment 
 of malaria. This disease, according to Laveran, is due to a protozoon, Babesia 
 equi, and Kuhn considers that the horse sickness is similar to human malaria, is 
 produced by a similar parasite, and that the serum of an immunized horse 
 should, therefore, prove specific in the treatment of human malaria. He and 
 Hovorka tried this method of treatment in 13 cases of tertian malaria, 16 cases 
 of quartan, and 14 cases of pernicious malaria; in the quartan cases it was use- 
 less, but in the tertian and pernicious cases it appeared to have a very feeble 
 curative action. These results have not been confirmed and there are so 
 many objections that might be raised to the technic of the method practised 
 and the interpretation of the results that we are forced to conclude that 
 Kuhn's method is of no value in the treatment or prophylaxis of malaria. 
 
 The investigations of Major J. H. Ford, of the Medical Corps of the U. S. 
 Army, are of interest in that they suggest that further study of this subject may 
 result in a specific serum therapy for the malarial fevers. He endeavored to 
 secure an antitoxic serum by inoculating rabbits, monkeys, and goats with 
 blood containing the plasmodia of human malaria. His conclusions regarding 
 his work with Plasmodium vivax are as follows: 
 
 "From the cases recorded it would appear that the successive inoculations 
 of monkeys or goats with blood containing Plasmodium vivax gives rise in those 
 animals to an antitoxin which, when injected in adequate dosage into human 
 beings, may be followed by disappearance of the parasites from the circulation 
 and disappearance of the symptoms of malaria. This agent has no apparent 
 influence on infections caused by a variety of the malarial parasite other than 
 that from which it was developed." 
 
 In a personal letter to the writer Ford states that his further work upon 
 this subject appears to indicate that an immunity to the various species of 
 plasmodia cannot be produced by the use of serum from the animals experi- 
 mented with, but suggests that the serum may prove of value in the differentia- 
 tion of species. While of some value in the treatment of malaria, according to 
 Ford, the serum is not as efficient as quinine, and therefore is of no practical 
 value in the treatment of these fevers. Ford's work yet awaits confirmation, 
 and it would appear that further research in this direction is needed before the 
 theory can be accepted as proven that immunity to any of the species of human 
 25 
 
386 DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 
 
 Plasmodia can be obtained by using the serum of animals which have been 
 inoculated with them or that in such animals an antitoxin develops which can 
 be used in the treatment of human malaria. . 
 
 Literature upon the Treatment of the Malarial Fevers. 
 
 1867. Binz. Ceoitralblatt. f. med. Wiss, p. 308. 
 
 1S70. Bixz. Ueber die antipyretische Wirkung von Chinin und Alkohol. 
 
 Vircli. Archiv, Bd. xli, pp. 23-24. 
 'S01. Ehrlich and Guttman. Ueber die Wirkung des Methylenblau bei 
 
 Malaria. Berl. klin. Wochenschr., No. 39. 
 1892. Golgi. Action de la quinine sur les parasites malariques, etc. Rendi- 
 
 conte del R. Instituto Lombardo, Series II, vol. xxv, Fasc. 3 and 5. 
 1892. Idem. Ueber die Wirkung des Chininsauf die Malaria-parasiten. Deutsch. 
 
 med. Wochenschr., No. 29, p. 613; No. 30, p. 685; No. 3 1, p. 707 ; No. 32, 
 
 p. 729. 
 1S94. Binz. Unsere jetzige Kenntnis von der Malaria fieberhirtung durch 
 
 Chinin. Centralbl. f. d. med. Wissensch., No. 20. 
 
 1895. Rasch. Ueber das China und die Krankheiten im Konigreich Siam. 
 Virchow's Archiv, vol. cxl, No. 2, p. 327. 
 
 1896. Feuchtwanger. Die Behandlung der Malaria in Kindesalter. Therap. 
 Monatsch., August, p. 439. 
 
 1898. Plehn, A. Die bisher und dem sog. Euchinin gemachten Erfahrungen. 
 
 Arch. f. Schiffs- und Tropenhyg., Bd. ii, No. 4, p. 234. 
 1898. Leukowicz. Ueber Phenocoll, Analgen, Chinopyrin und Euchinin 
 
 als antimalarische Mittel. Wien. klin. Wochenschr., No. 41. 
 1898. Gray, St. George. Euchinin in Malaria. Brit. Med. Jour., Feb. 26, 
 
 P- 551- 
 
 1898. Zieman. Ueber Malaria and anderer Blut-parasiten. Jena. 
 
 1899. Dock. Quinine in Malaria. Jour. Am. Med. Assoc, July 29. 
 
 1900. Grassi. Primo resoconto sommario dell' experimento contro la Malaria 
 fatto nei Dintorni di Pesto. Revista Medica, Anno viii, No. 9. 
 
 1900. Gros. Paludisme et Quin. Bull de la. Soc. de Med. de Gand., Sep- 
 tember. 
 
 1900. Ivanoff. Ueber die Behandlung der Malaria mit Methylenblau. Ge- 
 neesh. Tijdschr. v. Nederl. Indie., vol. xli, p. 493. 
 
 1 90 1. Rose, A. Methylene Blue in Malarial Disease. New York Med. Jour., 
 vol. xi, No. 9. 
 
 1901. Kunst, J. J. Die Behandlung der Malaria mit Anilinblau. Deutsch. 
 
 med. Wochenschr., Therap. Beil., No. 5. 
 1 90 1. Atkinson and Long. Methylene Blue in the Treatment of Malignant 
 
 Malarial Fever. The Lancet, May 16. 
 1 90 1. Kleine. Ueber die Resorption von Chininsalzen. Zeitschr. f. Hyg., 
 
 etc., Bd. xxxviii, No. 3, p. 458. 
 1 90 1 Braddon, W. J. Note on the Rapid Cure of Tropical Fevers. Jour. 
 
 Trop. Med., June 1, p. 185. 
 1901. Bluenchen. Zur Technik und Verwendbarkeit subcutaner Chinin- 
 
 injektionen. Deutsch. med. Wochenschr., No. 17. 
 1 90 1. La Monaco and Panichi. Die Wirkung der antiperiodischen Heilmit- 
 
 tel auf den Malariaparasiten. Untersuchungen zur Naturlehre des 
 
 Menschen and der Tiere, Bd. xvii, p. 22. 
 
DIAGNOSIS, PROPHYLAXIS, AND TREATMENT OF MALARIAL FEVERS. 387 
 
 1901. Gualdi and Martirano. L'azione della chinina sulle semilune. An- 
 
 nali d'lgiene sperimentale e Policlinico. 
 1 90 1. Capogrossi. Intorno all' azione della chinina sui parasiti della malaria. 
 
 II Policlinico, December. 
 1 90 1. Kuhn, P. Ueber eine Impfung gegen Malaria. Arch. f. Schiffs- und 
 
 Tropenhyg., Bd. v, No. 9, p. 283. 
 
 1 90 1. Craig. The Aestivo-autumnal Malarial Fevers. New York. 
 
 1902. Gautier. Sur un traitement specifique tres puissant des fievres palus- 
 tres. comptes rend, hebdomadaires. II, Paris. 
 
 1902. Hovorka. Ueber Impfung gegen Malaria mit dem Kuhn'schen Serum 
 in Bosnien. Wiener med. Presse, No. 71. 
 
 1902. King, A. F. A. A New Factor in the Etiology of Malarial Fever, Indi- 
 cating New Methods of Treatment. Am. Jour. Med. Sciences, Feb. 
 
 1902. Borrow, H. P. W. Malaria Treated by the Hypodermic Injection of 
 Quinine. Brit. Med. Jour., Jan. 25, p. 201. 
 
 1902. Kolosvary. Ueber die Wirkung eines neuen geschmacklosen Chinin- 
 praparates, des Salochinins, auf die Malaria. Die Heilkunde, Septem- 
 ber. 
 
 1903. Sylvaine. L'Euchinin et sa valeur therapeutique. Arch. f. Schiffs- 
 u. Tropenhyg., Bd. vii, No. 2, p. 85. 
 
 Nuastro. Ueber Euchinin. Gaz. med. Lombardo, Anno lxiii, No. 3. 
 Baum, H. Das Aristochinein Ersatzmittel des Chinins. Die Heilkunde, 
 May. 
 
 Schaudinn, F. Ueber den Einfluss der Rontgenstrahlen auf Protozoen. 
 Arch. f. d. gesamte Physiol., Bd. lxxvii. 
 
 Masucci. L'arrenal nell' infezione malarica. Annali di Med. Navale, 
 ix, vol. i, p. 299. 
 
 Ford, J. H. The Antitoxin Treatment of Tertain Malarial Infections. 
 Med. Record, vol. lxvi, No. 26. 
 
 Mariani. L'assorbmiento e l'eliminazione della chinina, etc., Atti della 
 Societa per gli Studi della malaria, p. 211. 
 
 Kunst, J. J. Ueber die Behandlung Malariakranker mit Aristochen. 
 Archiv. f. Schiffs- und Tropenhyg., Bd. viii, No. 3, p. 126. 
 Craig. The Malarial Fevers. Osier's "Modern Medicine," vol. i, p. 442, 
 Philadelphia. 
 
 1903 
 1903 
 
 1903 
 
 1903 
 
 1904 
 
 1904 
 
 1904 
 
 1907 
 
PART VI. 
 
 HAEMOGLOBINURIC FEVER. 
 
HAEMOGLOBINURIC FEVER. 
 
 Synonyms. — Black-water fever; Bilious remittent fever; Bilious haema- 
 turic fever; Melanuric fever; Haematuric fever; Malarial haematuria; Haemo- 
 globinuria. German: Schwarzwasser fieber. French: Fievre bilieuse haemo- 
 globinurique ; Fievre haematurique; Fievre malanurique. Italian: Febbre 
 emoglobinurica. 
 
 Definition. — An acute febrile disease, occurring in tropical and subtropical 
 regions, and characterized by fever, bilious vomiting, jaundice, and haemo- 
 globinuria. 
 
 Believing as I do that haemoglobinuric fever has no etiological connec- 
 tion with the malarial fevers, it would seem somewhat out of place to consider 
 this condition in a work devoted to the malarial fevers and to the protozoa of 
 the blood, but as the disease most frequently occurs in malarial regions, and 
 very often in the subjects of malarial infection, I have thought it wise to give 
 a concise description of haemoglobinuric fever, including the most recent views 
 regarding its etiology. 
 
 Like kala-azar, this disease has long been considered as due to malarial 
 infection, but the more we inquire into its etiology, its distribution, symptoma- 
 tology, and pathology, the more must we become convinced that the malarial 
 nature of the condition is far from certain, and that the evidence points to 
 its being a separate disease entity, in all probability caused by a hitherto undis- 
 covered organism. At the present time the question as to the etiology of this 
 fever is still undecided, but I believe that it is wise to abandon the malarial 
 hypothesis and endeavor to study the disease without being biased by precon- 
 ceived ideas as to its malarial nature. There is no more important problem 
 awaiting solution in tropical medicine than the etiology of haemoglobinuric 
 fever. 
 
 Historical. — We owe our first knowledge of haemoglobinuric fever to the 
 French naval surgeons, Dutrouleau, Berenger-Feraud, Corre, and le Roy 
 de Mericourt, who studied it in the natives of Madagascar and the surrounding 
 islands, as well as in Guinea and the West Indies. Their descriptions were 
 published during the latter portion of the nineteenth century, and since then a 
 voluminous literature has accumulated dealing with this subject. The researches 
 of Marchiafava and Bignami, Mannaberg, Koch, Stephens and Christophers, 
 Thayer, Manson, the brothers Plehn, and Cardamantis have added greatly 
 to our knowledge within recent years, and the disease is now being studied by 
 numerous investigators in all parts of the world. The first cases reported in 
 this country were those of Cummings, in Louisiana, in 1859. 
 
 Geographical Distribution. — The geographical distribution of haemo- 
 
 39 1 
 
39 2 HAEMOGLOBINURIC FEVER. 
 
 globinuric fever is very wide, and it is an important fact, as regards etiology, 
 that this fever, while most common in malarial localities, also occurs in regions 
 which are free from malaria, while in many of the most severely infected malarial 
 regions the disease does not occur except in the form of imported cases. 
 
 In North America haemoglobinuric fever occurs in almost all of the 
 Southern States, having been reported from Virginia, North Carolina, South 
 Carolina, Georgia, Florida, Louisiana, Texas, Arkansas, Mississippi, Alabama, 
 and Tennessee. It is commonly observed in some localities in most of these 
 States, but has been investigated but little as to its frequency and mortality. 
 
 In Central America the fever occurs upon the Isthmus of Panama, in 
 Honduras, Nicaragua, Costa Rica, and along the entire coast-line. 
 
 In South America the disease occurs in Venezuela, Guiana, the Argentine 
 Republic, and Brazil, always along the coast-line and in swampy areas. 
 
 In the West Indies, black-water fever occurs in Cuba, Martinique, 
 Guadeloupe, Trinidad and some of the smaller islands belonging to this group. 
 In Europe and Asia Minor the disease is most prevalent in Sardinia, 
 Sicily, and Greece, but it is also found in Italy, Russia, Turkey, in the Caucasus, 
 and along the banks of the Danube. In Palestine it occurs in limited localities. 
 In India there is good evidence for the belief that the disease is of recent 
 importation, for it is only since 1885, according to Manson, that it has been 
 described as occurring in Hindustan or the East. At present it has been ob- 
 served in the Madras Presidency, in the Punjab, along the Ganges, around 
 Bombay, and in Assam and Burmah. The Malay Peninsula, Cochin-China, 
 Siam, and Southern China are all infected with haemoglobinuric fever. 
 
 In the East Indies, haemoglobinuric fever has been reported from Sumatra 
 Java, the Celebes, the Bismarck Archipelago, and New Guinea. It is very 
 rare in the Philippine Islands, only a few cases having been reported, and it is 
 probable that these were imported or were suffering from a haemoglobinuria 
 induced by other causes. 
 
 In Africa this disease has been most thoroughly studied and there it is 
 most prevalent. From the earliest explorations of that continent black-water 
 fever has been one of the most dreaded foes of the white man and one of the 
 greatest obstacles to the opening up of the country. It is not found in all parts of 
 Africa, but is especially deadly along the West Coast and along the Congo and 
 the deltas of the Niger and Gambia rivers. In Sierra Leone, Cameroon, Nigeria, 
 and along the Gold Coast black-water fever is a veritable curse. It occurs also 
 along the East Coast, in British, German, and Portuguese East Africa and in 
 the Congo Free State. It occurs in British Central Africa, in Uganda, the 
 Soudan, and Algeria. Egypt is free from this disease. It occurs also in Mada- 
 gascar and in Mauritius, Reunion, Bourbon, and the Comoro Islands. Cases 
 have been reported from Formosa. 
 
 From this summary of the geographical distribution of haemoglobinuric 
 fever it is evident that while the disease does occur in many regions in which the 
 malarial fevers are endemic, it also occurs in others in which malaria is rare or 
 
HAEMOGLOBINURIC FEVER. 
 
 393 
 
 absent, and that it does not occur in many regions which are intensely malarial. 
 Thus certain parts of Japan are badly infected with malaria, but black-water 
 fever has never been reported as occurring there. In the Philippines, where I 
 served in a most intensely infected region as regards malaria, I never observed 
 a single case of haemoglobinuria, and it may be stated as a fact that haemoglo- 
 binuric fever is so rare in these islands as to be a medical curiosity, despite the 
 fact that all forms of malaria are extremely common throughout the islands, 
 many of them being of pernicious character. There is good reason to doubt, 
 indeed, if a single case of genuine haemoglobinuric fever has ever been observed 
 in the Philippine Islands. 
 
 Some authorities endeavor to explain the absence of haemoglobinuric fever 
 in malarial regions by claiming that it is frequent only where there is a large 
 amount of latent infection, but there are many observations upon record which 
 negative such a contention. ' Thus, at Camp Stotsenburg, in the Philippines, 
 the ratio of latent infection (or children and adults showing plasmodia in the 
 blood without symptoms) was very high, yet a case of haemoglobinuric fever 
 has never been observed in that locality. 
 
 The disease is limited, as regards its endemicity, to low-lying coast-lines, 
 and swampy regions situated near the coast. This, of course, suggests the 
 transmission of the disease by mosquitoes, and also its relation to malaria. 
 
 As regards seasonal prevalence, it may be stated that in the United States 
 the disease is most prevalent in the late summer and in autumn, while in 
 tropical regions it is most prevalent following the end of the rainy season. 
 
 Epidemics of black-water fever have been reported by Masterman, Wenyon, 
 and Plehn, but such epidemics are very rare, and occur only when unsanitary 
 conditions, such as overcrowding and exposure, are present. 
 
 Frequency of Occurrence.— On account of the lack of sufficient data it 
 is very difficult to arrive at a true conception of the frequency of the occurrence 
 of haemoglobinuric fever, but it is an undoubted fact that it is a rare disease 
 when compared to the malarial fevers, which, by many, are considered to stand 
 in etiological relationship to it, for in many regions in which the malarial fevers 
 are very numerous, black-water fever is unknown or is so rare as to occasion 
 surprise when a case occurs. The following table, compiled from Deaderick's 
 excellent resume of this fever, will serve to illustrate the frequency of this disease 
 as observed by various authors: 
 
 Observer 
 
 Place Time 
 
 No. of cases 
 
 Brown 
 
 British Honduras . . . 
 
 Panama 
 
 Porto Empedoclo . . . 
 
 India 
 
 Cameroon 
 
 i year 3 
 
 8 months 20 
 
 1 2 years 17 
 
 Gorgas 
 
 Moscato 
 
 Seal 
 
 Doering 
 
 7 years 
 
 9 months 
 
 6 
 
 40 
 
 
 
394 HAEMOGLOBINURIC FEVER. 
 
 As regards the relative frequency of the malarial fevers and haemoglobin- 
 uric fever in localities where both occur, the following data is of interest: 
 Pampoukis, in Greece, observed 34,937 cases of malaria, of which 0.7 per cent, 
 presented haemoglobinuria; Burot and Lagrand, five out of 599 fatal cases of 
 malaria ; Ipscher, in Cameroon, observed 285 cases of malaria in one year, and 20 
 cases of haemoglobinuric fever; Sims saw over a hundred cases of haemoglobin- 
 uria in 20 years' practice in the Congo region, but during that time saw 
 thousands of case's of malaria. Burot and Legrand saw 31 fatal cases of 
 haemoglobinuric fever in Senegal and the Soudan and 155 deaths from the 
 malarial fevers, while Davidson states that in Nossi Be the proportion of black- 
 water cases to malaria was as 1 is to 14. 
 
 The statistics given above apply only to those regions in which haemo- 
 globinuric fever is most prevalent, but if we take those localities in which the 
 malarial fevers are prevalent and in which black-water fever is rare, the relative 
 proportion will be very greatly reduced. In my own experience, covering 10 
 years' observation of the malarial fevers, during which time I have studied 
 nearly six thousand cases of malaria, I have observed haemoglobinuria but 
 once, and then the condition was not at all typical of haemoglobinuric fever. 
 All of these cases were observed in Cuba or in the Philippines, or in the United 
 States in the persons of soldiers returning from those countries. When we take 
 into consideration that most of the patients were white men, susceptible to 
 haemoglobinuric fever and all suffering from malaria, I regard it as evi- 
 dent that haemoglobinuric fever is not due to the malarial plasmodia, but to 
 some other cause. 
 
 Predisposing Causes. — All ages and both sexes are susceptible to this 
 disease, but it is said to be most frequently observed in the middle aged, and in 
 those debilitated by preexisting disease. A previous attack of malaria is said 
 by many authorities to be absolutely necessary in order that haemoglobinuric 
 fever develop, and some have gone so far as to claim that there is no case upon 
 record of the occurrence of this disease in an individual who had never suffered 
 from a malarial infection. As a matter of fact, there are numerous instances 
 of persons who had never had malaria developing haemoglobinuric fever, and 
 Manson 1 says: black- water fever frequently attacks people who previously 
 had never had a single paroxysm of intermittent fever." It is but natural that 
 the two diseases should occur in the same individual frequently, in regions in 
 which both are endemic. 
 
 Length of residence appears to have an important influence upon the liability 
 to haemoglobinuric fever in many instances, but that a long residence in the 
 infected locality is unnecessary is shown by the experience of such observers 
 as Plehn, Ritchie, Cardamantis, Daniels, and Lynch and Scott, who all report 
 instances of perfectly healthy individuals being attacked within two to three 
 months after reaching the infected territory, and before there was any evidence 
 
 1 Tropical Diseases, 4th Ed., London. 
 
HAEMOGLOBINURIC FEVER. 395 
 
 of a malarial infection. Manson states that he has been frequently informed 
 by officers of the African colonial service that they were suddenly attacked by 
 black-water fever while in perfect health, and Daniels states that a malarial 
 history is denied by a goodly proportion of the sufferers from black water unless 
 they have resided for over a year in the infected region. 
 
 As regards race, haemoglobinuric fever chiefly attacks the whites, but the 
 negro is not immune as a race. In localities in which the fever is endemic 
 the negro, if present, undoubtedly develops an immunity against the disease, 
 but numerous observers have seen instances of infection in negroes. F. Plehn 
 reports an epidemic occurring among the negroes in the Cameroon, and it 
 has been repeatedly observed that negroes introduced into an infected region 
 from an uninfected one, are susceptible to the disease. Chinese are said to be 
 almost as susceptible as the white man, but Daniels claims that the native of 
 India is only one-fourth as susceptible as is the European. 
 
 Change of Residence is often followed by a recurrence of haemoglobinuria 
 in those who have suffered from the disease, or may be the exciting cause of 
 the primary attack, especially if the change be an abrupt one as regards climate 
 or altitude. Recurrences are frequently observed and are generally brought 
 about by exposure, change of climate, or removal from a low to a high altitude. 
 Patients returning from the tropics to England or America sometimes develop 
 haemoglobinuria after arrival. 
 
 Among the other predisposing causes of an attack of haemoglobinuric 
 fever may be mentioned exposure and fatigue, traumatism, excessive venery, 
 and alcoholic excesses. Haig believes that the uric acid diathesis strongly 
 predisposes to haemoglobinuria, but there is no experimental evidence favor- 
 ing his view. 
 
 Etiology. — The cause of haemoglobinuric fever is unknown, but there are 
 three chief hypotheses regarding its etiology, each supported by some evidence 
 of value, and each ardently believed in by its advocates. These are: that 
 it is due to malarial infection; that it is due to quinine; and that it is a specific 
 disease. All of these theories have been investigated, and the advocates of 
 all are able to point to evidence favoring their claims, but I believe that a 
 careful study of this vexed question by an unprejudiced observer must result 
 in the conviction that the specific theory of the etiology of the disease is correct, 
 and that haemoglobinuric fever is a disease sui generis, caused by a hitherto 
 undiscovered organism, probably of protozoal nature. 
 
 The Malarial Theory. — This theory of the causation of the fever is sup- 
 ported by many eminent students of malaria, notably by Stephens, Plehn, and 
 Mannaberg. The advocates of this theory claim that the distribution of the 
 disease; the presence in a large proportion of the cases of malarial plasmodia; 
 the fact that in most cases a previous history of malarial infection can be obtained ; 
 the blood findings apart from the plasmodia, and the fact that the disease affects 
 those who have resided for some time in the infected region, all point to its 
 malarial origin. It is well to consider each of these points separately and by 
 
39^ HAEMOGLOBINURIC FEVER. 
 
 so doing I believe that the conclusion will be that not one of them can be 
 considered as proving that black-water fever is malarial in origin. 
 
 The distribution of the disease I have already referred to and have shown 
 that in many malarial regions haemoglobinuric fever is unknown, although 
 these regions are badly infected with the most severe forms of malaria, such 
 as the aestivo-autumnal. In the Philippines, where pernicious cases of 
 malaria are not uncommon and where the mortality from malaria in 1902, 
 according to the census of the Philippines Islands, was 26.8 per cent, of all 
 deaths, there being during that year 118,476, deaths from these fevers, or 17 per 
 thousand, not a single death is reported from haemoglobinuric fever, and this 
 is true of many other malarial localities. The fact that black-water fever has 
 been reported from regions in which malaria is unknown also serves to show 
 how little we can depend upon the distribution of a disease in considering its 
 etiology. Many other acute infectious diseases are most common in regions 
 infected with malaria, but because this is so we do not at once conclude that they 
 must therefore be due to malarial poisoning. 
 
 The presence of malarial Plasmodia in the blood of a large proportion of 
 patients suffering from haemoglobinuric fever is considered by many as proving 
 its malarial origin, but many other conditions occur in malarial regions which 
 no one would consider for a moment as being due to malaria, but in which 
 malarial plasmodia are found in the blood. 
 
 It is but natural that, in an intensely malarial district, patients suffering 
 from haemoglobinuric fever should present plasmodia in their blood, and the 
 fact that the latter fever is most prevalent in malarial districts does not prove 
 that it is due to malaria, but that it depends for its spread upon factors which 
 also favor the transmission of the malarial fevers. As regards the frequency of the 
 occurrence of malarial plasmodia in the peripheral blood of black-water fever 
 patients, I have collected 273 cases reported in the literature, of which 109, or 
 nearly 40 per cent, showed malarial plasmodia in the blood. Stephens and 
 Christophers and Mannaberg have shown that the number of plasmodia in the 
 blood varies with the time of examination, 95 per cent, of patients showing them 
 the day before the attack, 60 to 70 per cent, showing them the day of the attack, 
 and 17 to 20 per cent, showing them the day after the attack. This fact has 
 been used in the endeavor to discount the proofs of the absence of plasmodia in 
 haemoglobinuric fever, but there are scores of cases upon record in which the 
 blood was examined both before, during, and after the attack, and no plasmodia 
 were ever found. If the fever is due to the presence of plasmodia, why is it 
 that in case after case these organisms are not found though repeated and careful 
 search is made for them, the spleen having been punctured in some cases with 
 a negative result? 
 
 It appears to me most illogical to claim, that because a large proportion of 
 patients suffering from haemoglobinuric fever show malarial plasmodia in their 
 blood, the disease must necessarily be due to them. Take, for example, 
 infection with ankylostoma. This parasite is most common also in malarial 
 
HAEMOGLOBIN URIC FEVER. 397 
 
 regions, because such regions are most favorable to its development. It also 
 will be found present in a vast majority of patients suffering from malaria in 
 such regions, yet we do not for a moment believe that ankylostomiasis must 
 therefore be due to malaria, for in this instance we have demonstrated that it is 
 due to a definite parasite. In haemoglobinuric fever, unfortunately, the 
 parasite has not been discovered, and so it is easier to consider it of malarial 
 origin, because the two diseases frequently coexist. In India for years kala- 
 azar was considered of malarial origin, and it was not until the discovery of 
 Leishmania-donovani that this notion was abandoned. Such an experience 
 should serve as a warning to us in our conceptions of the etiology of haemo- 
 globinuric fever. 
 
 A previous history of malarial infection is undoubtedly to be obtained in 
 most of our cases of haemoglobinuric fever' but here again the reason is not far 
 to seek. The occurrence of the disease most frequently in malarial localities 
 makes it inevitable that most patients suffering from it should have previously 
 suffered from malaria or may be suffering from that infection at the time they 
 develop haemoglobinuria. From what we know of black-water fever it is 
 evident that, compared with malaria, it is a rare disease, and it therefore happens 
 that most patients residing long enough in a locality to develop black-water 
 fever have already suffered from malaria. It has been asserted by the most 
 ardent advocates of the malarial origin of haemoglobinuric fever that not a 
 single case is on record of the outbreak of this disease in a patient who had not 
 previously suffered from malaria, but such an assertion can only be made by 
 one who is little acquainted with the literature, for numerous cases are reported 
 in which haemoglobinuric fever developed in perfectly healthy individuals 
 within two or three months after reaching the infected locality and in whom 
 there had never been any symptoms of malaria. Such cases have been reported 
 by Manson, Cardamantis, Plehn, Ritchie, Daniels, and many other observers. 
 
 The blood examination in cases of haemoglobinuric fever generally demon- 
 strates an increase in the large mononuclear leucocytes, and frequently the 
 presence of pigmented mononuclear cells. This fact has been used as a weighty 
 argument by the believers in the malarial origin of the fever, as similar results 
 are found in malaria. However, it is of little real value as an argument, for a 
 large mononuclear increase is observed in several other diseases due to the 
 protozoa, as kala-azar and trypanosomiasis, while the pigmented leucocytes 
 are present in patients who have suffered from malaria, even after symptoms of 
 infection have been absent for weeks. While the presence of pigmented 
 leucocytes may indicate that at some time the patient has suffered from 
 malarial infection, it certainly is very poor proof that an attack of haemo- 
 globinuric fever is due to malaria. 
 
 The relation of long residence in an infected locality to the malarial origin of 
 the fever has already been mentioned. It is sufficient to repeat that while 
 most cases occur only after the first twelve months of residence, many have been 
 reported in which the disease appeared within two to three months after enter- 
 
398 HAEMOGLOBIN URIC FEVER. 
 
 ing the infected territory and in perfectly healthy individuals, thus proving 
 that long residence is not essential to the development of the disease. That 
 most of the cases develop after a residence of a year or more would appear to 
 indicate that the disease is one of long incubation or, and this is more probable, 
 due to an organism which is seldom met with or which requires certain peculiar 
 conditions favorable for its development before infection occurs. Recently a 
 number of authors have claimed that while the plasmodia of malaria have no 
 direct etiological relationship to haemoglobinuric fever, malarial infection is, 
 nevertheless, a necessary predisposing cause, bringing about certain conditions 
 in the blood and tissues necessary for the existence of the parasite causing the 
 fever. While these theories are interesting, they simply beg the question, and 
 1 believe are of little value as working hypotheses, for, as shown, haemoglobin- 
 uric fever does occur where there has been no malarial infection, and, there- 
 fore, we are justified in believing that it is not caused by the malarial plasmodia 
 or dependent upon the changes produced in man by infection with these 
 parasites. 
 
 The Quinine Theory. — Many observers, while denying that malaria is 
 responsible for the appearance of haemoglobinuria, believe that this fever is 
 produced in certain susceptible individuals by the administration of quinine. 
 In 1858, Veratas, a Greek physician, suggested this explanation of the occur- 
 rence of haemoglobinuria, and in 1874, Tomaselli, of Italy, reported in favor 
 of this theory, and it has since been accepted by many practitioners in malarial 
 localities. When Koch gave it the support of his great authority, the scientific 
 world believed that at last the etiology of the disease was explained, but even 
 Koch does not state that quinine is the sole cause of the fever. As a matter of 
 fact, many cases of black-water fever have been reported in which no quinine had 
 been taken previously to the attack, and Cardamantis has reported no less 
 than 32 cases in Europeans who had never taken a dose of quinine. It is true, 
 however, that very rarely the administration of quinine has been followed by 
 the appearance of haemoglobinuria, but it is very doubtful if the symptoms, 
 beyond the occurrence of blood in the urine, were those of black-water fever. I 
 have seen two cases in which quinine caused haemoglobinuria, even when given 
 in small doses, but there were no symptoms in the least suggestive of haemoglo- 
 binuric fever. That quinine has been administered in most cases of haemoglo- 
 binuric fever prior to the outbreak of the disease is due to the fact that as the 
 disease occurs so frequently in malarial localities the drug has been given to 
 combat malarial infection. It is certainly illogical to claim, because quinine 
 has been administered to a patient suffering from malaria and who afterward 
 develops haemoglobinuric fever, that the drug is the cause of the disease. 
 In many regions quinine is given as a prophylactic to practically the whole 
 population, but because this is so must we believe that the cases of black-water 
 fever which may occur are due to this drug ? How can we explain upon such a 
 hypothesis the absence of haemoglobinuric fever in regions such as the Philip- 
 pine Islands, where malaria is common and quinine is given very extensively ? 
 
HAEMOGLOBINURIC FEVER. 399 
 
 If we take into consideration also that quinine is given in many other in- 
 fections without producing haemoglobinuric fever; that it is used with good 
 results in the treatment of the disease itself, when a malarial complication is 
 present; that there exists no relation between the amount of the quinine given 
 and the severity of the disease; and that even in those who have suffered from 
 an attack of the fever apparently produced by quinine, the use of the drug 
 afterward is harmless; I believe that we must admit that quinine is not the 
 cause of black-water fever. 
 
 The Specific Theory. — Recently the theory that haemoglobinuric fever is 
 a distinct disease, produced by a specific parasite, probably protozoal in nature, 
 has been gaining ground, and I believe that ultimately this theory will be found 
 correct. The most ardent advocates of the specific nature of the disease are 
 Manson, Sambon, Rho, and Blanchard, while numerous other investigators 
 believe that only by admitting the specific nature of the disease can we explain 
 the apparent contradictions inherent in the other theories. Manson 1 says: 
 "I have long entertained the idea that too much has been taken for granted in 
 relegating black-water fever to malaria, and thereby ignoring its possible 
 individuality as a separate disease; an individuality strongly suggested not 
 only by the symptomatology, but also by epidemiology and analogy." The 
 resemblance of the disease to paroxysmal haemoglobinuria and the occurrence 
 of a somewhat similar disease in cattle, known as Texas fever, forcibly suggests 
 that haemoglobinuric fever is a distinct disease, and that it may be due to a 
 protozoon closely allied to the parasite of Texas fever, Babesia bigemina. The 
 discovery of other parasites in animals belonging to this genus, some of them 
 very small, is of importance in the consideration of this disease, for it is not at all 
 improbable that black-water fever may be due to a babesia or allied organism 
 so small as to escape our present microscopic lenses, or it may prove to be 
 actually ultramicroscopic in size. Certain it is that the distribution of the 
 disease, its epidemiology and symptomatology, and its resemblance to other 
 protozoal diseases, would appear to justify us in regarding it as probably 
 due to a protozoon, and in view of the fact that neither the malarial theory 
 nor the theory that the disease is due to quinine has been proven, that it is wise 
 to consider the etiology of this disease as still unsolved. 
 
 Pathology. — The pathology of haemoglobinuric fever is but little char- 
 acteristic, if we do not take into consideration the condition of the urine. The 
 principal changes are found in the kidneys, blood and urine, the other organs, 
 save for the changes brought about by preexistent or existing malarial infection, 
 showing little change of importance. 
 
 The Kidneys. — The kidneys are always congested and present the evi- 
 dences of acute venous congestion or acute nephritis. The capsule is not 
 adherent, the cortex is thickened, the intertubular capillaries much congested, 
 and the general appearance of the section that of an acute tubular nephritis. 
 Microscopical examination shows marked epithelial desquamation in the 
 1 Ibid. 
 
400 HAEMOGLOBINURIC' FEVER. 
 
 tubules, congested Malpighian tufts, and congested capillaries. If the patient 
 dies after three or four weeks the kidneys present the lesions of a subacute 
 parenchymatous nephritis. In instances where a malarial infection compli- 
 cates the haemoglobinuria, the sections of the kidneys may show melanin within 
 the capillaries or enclosed within the cells. In almost every instance the cells 
 within the tubules contain a considerable amount of yellow pigment, derived 
 from the broken-down red corpuscles. 
 
 The Spleen.— Except in patients who have suffered from malarial infection 
 few pathological lesions are observed in the spleen in fatal cases, beyond en- 
 largement, congestion, and decrease in consistency. In fact the spleen is that 
 usually observed in acute infectious fevers, and does not contain malarial 
 pigment unless preexistent malarial infection has occurred. A large 
 amount of yellow pigment is generally present, due to the destruction of the 
 red cells. 
 
 The Liver. — The liver is enlarged, decreased in consistence, and usually of 
 a yellowish color. Sections show albuminoid degeneration of the liver cells, 
 and haemosiderin is common in the degenerated cells. There may be marked 
 congestion of the capillaries, and it is not uncommon to observe areas of focal 
 necrosis in the region of the intralobular vein. Melanin is not present except in 
 patients suffering from coincident malarial infection. 
 
 The Brain. — The brain shows no pathological lesions which are character- 
 istic, and only in patients having a coincident malarial infection is pigment or 
 parasites observed in this organ. The total absence of pigment in the brain in 
 many fatal cases of black-water fever is very suggestive of the lack of relation of 
 malaria to this fever, for in almost every fatal case of malaria it is not difficult 
 to demonstrate plasmodia, and especially pigment, in the capillaries of the 
 brain. 
 
 Bone-Marrow. — No changes of importance occur in the bone-marrow. 
 If malarial infection is present or the patient has suffered from repeated attacks 
 of malaria, the changes are those observed in that disease which have already 
 been described. 
 
 The Blood. — The blood looks yellowish or yellowish-red in color, and is 
 less viscid than normal. Haemoglobinaemia or cholaemia may be present, but 
 in many cases haemoglobinaemia is not present. Microscopically the blood- 
 cells appear normal in size and shape, but are generally paler than normal. 
 The presence of malarial plasmodia in the blood of haemoglobinuric fever has 
 already been discussed, and it may be stated that in many cases they are not 
 present at any time during the disease or preceding it, and that when they are 
 present it simply means a coincident malarial infection. Neither is melanin 
 present in the blood in uncomplicated cases of haemoglobinuric fever. During 
 the early symptoms of the fever there may be a marked leucocytosis, but later 
 in the disease the polynuclear cells are decreased, and there is a marked in- 
 crease in the large mononuclear leucocytes, a fact on which great stress is laid 
 by the advocates of the malarial nature of the disease. As we have shown, 
 
HAEMOGLOBINURIC FEVER. 4OI 
 
 this mononuclear increase is present in other protozoal diseases, and therefore 
 cannot be considered as characteristic of black-water fever. 
 
 The Urine. — The color of the urine is usually a dark cherry red, but it is 
 sometimes necessary to use the spectroscope to detect the presence of haemoglo- 
 bin ; in such instances the color is a light brownish-yellow. The reaction is alka- 
 line, the specific gravity low, and there is generally a large amount of sediment, 
 which, upon being examined, is found to consist of yellowish granular matter, 
 numerous hyaline and haemoglobin casts, and a very few red blood-corpuscles. 
 The granular material is evidently composed mostly of the detritus of degen- 
 erated red blood-corpuscles, and as haematuria is not a characteristic of the 
 disease, this explains the very few red corpuscles which are present in the urine. 
 Crystals of haemotoidin occur in sparse numbers in the sediment. The bile- 
 pigments, may be present ; but are not commonly observed. Albumin is 
 always present in large amount, mostly in the form of serum-globulin, which is 
 derived from the blood. The spectroscopic examination of the urine shows 
 the characteristic spectrum of oxyhaemoglobin and, in some instances, of 
 methaemoglobin. 
 
 Period of Incubation. — The period of incubation in haemoglobinuric 
 fever is unknown. From the observations of Scott, in Africa, it would appear 
 that the fever may occur after a period of eight days from exposure in the 
 infected territory, but it is probable that the period of incubation is a very 
 variable one, for we know that recurrences take place at long intervals, even of 
 months. Manson mentions cases in which the disease appeared for the first 
 time in Europeans who had been absent from the infected localities for months, 
 so that it would appear that, as in the malarial fevers, black-water fever has a 
 very uncertain period of incubation. 
 
 Symptomatology. — In almost every case the disease begins suddenly with 
 a chill, after which the temperature rises rapidly to 103 F. or higher. The 
 chill is generally severe, but may be so slight as to be hardly noticeable. The 
 usual symptoms of fever are present, such as malaise, pain in the muscles and 
 articulations, loss of appetite, and mental depression. Later in the attack the 
 pain is more severe in the lumbar region and over the liver and spleen, while 
 in many instances severe bladder pain is complained of. After the symptoms 
 are well pronounced there is marked desire to pass the urine which presents 
 the characteristic brownish-red color of "black-water." The fever may be 
 intermittent, remittent, or almost continuous in type, and jaundice slowly 
 develops in many instances. Tympanites is a common symptom and pain 
 over the stomach is often elicited upon pressure. In favorable attacks there 
 is bilious vomiting, but it is not so excessive and so long continued as it is in 
 cases which go on to a fatal termination. In not a few instances bilious vomit- 
 ing is absent, so that this symptom cannot be said to be characteristic of 
 haemoglobinuric fever. The termination of the attack in patients who recover 
 is usually by crisis, the temperature receding, accompanied by profuse perspira- 
 tion, while the haemoglobinuria disappears. Great prostration is often observed 
 26 
 
402 HAEMOGLOBINURIC FEVER. 
 
 after an attack of haemoglobinuric fever, and convalescence may be much 
 delayed by recurrences of the haemoglobinuria and fever or by the recurrence 
 of the fever alone. The haemoglobinuria may last only for an hour or two in 
 mild cases or may persist at intervals for weeks. As the haemoglobinuria 
 disappears, the urine, which may have been greatly decreased in quantity at 
 the height of the attack, becomes lighter in color, greater in quantity, and is 
 passed with less discomfort to the patient. The acute attack may last only 
 a day or may be prolonged over several days. Diarrhoea is common, but 
 constipation is frequently observed. 
 
 In fatal cases the temperature may go to 104 F. or higher; there is severe 
 and prolonged bilious vomiting; bilious diarrhoea; great pain in the loins and 
 the epigastric region; and a gradually developing somnolence which deepens 
 into a fatal coma. In some instances the symptoms are those of uraemia, 
 due to total suppression of the urine or to the development of nephritis, while in 
 others the fatal symptoms are those of severe haemorrhage, or death may 
 occur from hyperpyrexia or the typhoid state may develop. A marked decrease 
 in the total quantity of urine passed in twenty-four hours is always an un- 
 favorable symptom. 
 
 The following clinical facts are of importance in the symptomatology of 
 haemoglobinuric fever; the temperature is not in any way characteristic of the 
 disease; haemoglobinuria is constant, but unless accompanied by the other 
 symptoms, such as fever, vomiting, and jaundice, cannot be considered as 
 peculiar to this disease; the vomiting of bile-stained material is so commonly 
 observed as to be an important confirmatory symptom, but alone is of no value; 
 the microscopic character of the sediment in haemoglobinuric fever is not 
 characteristic, as the same elements are found in haemoglobinuria due to other 
 causes; the development and persistence of jaundice is very characteristic 
 when accompanied by other symptoms. 
 
 The physical signs during an attack of haemoglobinuric fever consist in 
 an enlargement of the spleen and liver and a jaundiced condition of the sclerae 
 and skin. A systolic murmur is not infrequently heard, haemic in character, 
 and not transmitted. A bronchitis may be present or there may be evidence of 
 congestion and oedema of the lungs. Anaemia is generally marked when the 
 blood count is made during the attack, but counts made after the symptoms 
 have disappeared do not show as severe a degree of anaemia as one would 
 expect from the obvious destruction of the red cells. 
 
 In malarial localities an attack of haemoglobinuric fever is often compli- 
 cated by a coincident attack of malaria, and it is certain that many of the symp- 
 toms of black-water fever, which have become almost classic in our text-books 
 upon the subject, were in reality those of malaria, and it is very probable that a 
 more careful study of our cases will result in proving that haemoglobinuric 
 fever has a definite and characteristic symptomatology which will enable us to 
 recognize it as having no connection with the malarial fevers and peculiar unto 
 itself. At the present time the subject, both from an aetiological and clinical 
 
HAEMOGLOBINURIC FEVER. 403 
 
 standpoint, is in a far from satisfactory condition and is one of the most 
 important of all tropical problems in medicine. 
 
 Complications and Sequelae. — These are few in number, nephritis 
 being the most common of the sequelae, and malaria of the complications. 
 Anaemia is a frequent sequela, but is rapidly recovered from under proper 
 treatment. Parotitis, neuraligia, pleurisy, endocarditis, and severe chronic 
 enteritis have been reported as sequelae of the fever. 
 
 Prognosis. — The prognosis is always grave, the mortality varying from 
 10 to 30 per cent. The mortality varies in different localities and in different 
 years, being sometimes very low and sometimes appalling, even as high as 95 
 per cent., but there is good reason to believe that the disease has often been 
 confused with yellow fever, and that thus the mortality has been overestimated, 
 especially in our Southern States. Some attacks are so mild as hardly to be 
 recognized, but in the majority of cases the prognosis should be guarded. 
 Unfavorable prognostic signs are decrease in the quantity of urine, excessive 
 vomiting, continued hiccough, and somnolence. Plehn has reported cases 
 in which sudden death has occurred from thrombus formation in the large 
 vessels or the heart. 
 
 Diagnosis. — Of the diseases which may be confused with haemoglobinuric 
 fever may be mentioned yellow fever, paroxysmal haemoglobinuria, pernicious 
 malaria of bilious remittent type, and Weil's disease. 
 
 Yellow fever may easily be confused with haemoglobinuric fever by one 
 who has had little acquaintance with either disease, but if it is remembered 
 that in yellow fever the icterus does not begin until the third or fourth day; 
 that haemoglobinuria is absent; that albuminuria occurs from the second to the 
 fourth day ; and that the temperature is characteristic, it is not difficult to make 
 a differential diagnosis. The diagnosis from paroxysmal haemoglobinuria in a 
 region where both diseases occur is most difficult, and may be impossible, 
 but in the majority of cases the greater severity of the symptoms in haemo- 
 globinuric fever will serve to distinguish it. Pernicious malarial fever, of the 
 bilious remittent type, may be confused with haemoglobinuric fever, but the 
 presence of the plasmodia until quinine is administered, the prompt subsidence 
 of the infection under quinine treatment, and the absence of haemoglobinuria, 
 should serve to enable us to diagnose the malarial nature of the malady. Weil's 
 disease might be mistaken for haemoglobinuric fever, but haemoglobinuria is 
 not present; the urine, if affected, containing multitudes of erythrocytes. 
 
 I have mentioned the rare occurrence of haemoglobinuria following the 
 administration of quinine in malarial patients. This condition may be easily 
 differentiated from haemoglobinuric fever by the absence of acute symptoms, 
 the occurrence of the condition in localities known to be free from "black water" 
 and in patients who have never been exposed to the latter disease, and the prompt 
 disappearance of the haemoglobinuria upon ceasing the administration of 
 quinine. 
 
 Prophylaxis. — It is difficult to lay down rules regarding the prophylaxis 
 
40-| HAEMOGLOBINURIC FEVER. 
 
 of a disease when we are unacquainted with its cause and the method of its 
 transmission, but we have good reason to believe that the measures taken for 
 the prophylaxis of malaria are also quite efficient in the prophylaxis of this 
 disease. This fact has been used as an argument in favor of the malarial origin 
 of black-water fever, but it is simply an argument in favor of the insect trans- 
 mission of the disease and of its protozoal nature. That the methods adopted 
 in the prophylaxis of malaria are also efficient in the prophylaxis of haemoglo- 
 binuric fever is merely a coincidence, just as protection from the mosquito is 
 efficient in the prophylaxis of filariasis and dengue as well as in malaria. 
 
 A. Plehn, in Cameroon, has found that the prophylaxis of malaria there 
 has not only resulted in a reduction in the number of malarial infections, but 
 also in the number of cases of haemoglobinuric fever, the morbidity of malaria 
 being lowered one-half, while that of black-water fever was reduced one-fourth, 
 and Moffatt has reported similar results. It is therefore recommended that 
 in regions infected with haemoglobinuric fever the utmost precautions be 
 taken regarding protection from the bites of insects and that prophylactic 
 doses of quinine be administered. 
 
 Treatment. — The treatment of haemoglobinuric fever is at the present 
 time most unsatisfactory because of the divergent opinions held by observers 
 regarding the use of quinine in this disease. It would be unprofitable here to 
 review in extenso the arguments for and against the use of this drug in haemo- 
 globinuric fever, for the question is still far from settled, and statistics are 
 quoted by both parties favorable to their contentions. The association of 
 haemoglobinuria with malaria and the fact that haemoglobinuria may be 
 produced by quinine is responsible for the difference in opinion regarding the 
 use of the drug in treatment. As I have shown, haemoglobinuric fever occurs 
 without coexisting or preexisting malaria and in patients who have never 
 taken a dose of quinine, so that it appears that the question is simply as to 
 whether quinine is beneficial in haemoglobinuric fever or whether it is of no 
 value. I believe that there is little evidence that indicates that quinine, in 
 uncomplicated cases of haemoglobinuric fever, is of any value, and it may well 
 be that the use of this drug in large doses renders the blood more susceptible 
 to the action of the parasite causing haemoglobinuria. When, however, the 
 haemoglobinuric fever is complicated by a malarial infection, as shown by the 
 presence of the plasmodia in the blood, quinine should be given in doses suf- 
 ficient to cure the malarial complication, but it should not be given unless the 
 plasmodia can be found. As showing the very slight difference between the 
 mortality when quinine is administered and when it is not, the following data, 
 collected by Deaderick are of interest. Of 328 cases treated with quinine, 
 
 56 died, a mortality of 17 per cent., while of 374 cases treated without quinine, 
 
 57 died, a mortality of 15.2 per cent. Unfortunately, we are ignorant as to 
 how many of these cases were positive for the malarial plasmodia, but I believe 
 that the results as given indicate that it makes but little difference in the 
 mortality of haemoglobinuric fever whether quinine be administered or not, 
 
HAEMOGLOBINURIC FEVER. 405 
 
 and as in rare instances quinine is capable of producing haemoglobinuria, it 
 is better to abstain from the use of the drug unless the malarial plasmodia are 
 found in the blood, when, of course, it is indicated not as a therapeutic agent in 
 the treatment of haemoglobinuric fever, but as a specific against the coincident 
 malarial infection. 
 
 The following rules governing the administration of quinine in haemo- 
 globinuric fever will be found valuable as a guide to the use of the drug in 
 this disease: 
 
 1 . In all cases showing the plasmodia of malaria in the blood, quinine should 
 be administered in doses sufficient to cure the existing malarial complication. 
 
 2. In all cases which do not show the presence of the malarial plasmodia 
 during the first day of the attack, quinine should be withheld, as most of these 
 cases are uncomplicated, and there is no reason to believe that quinine is of 
 any value in the treatment of uncomplicated haemoglobinuric fever. 
 
 3. In cases of haemoglobinuria arising during the administration of quinine 
 in proven malarial infections, the administration of the drug should be discon- 
 tinued for a day or two, and entirely if malarial plasmodia do not again appear 
 in the blood. 
 
 4. If haemoglobinuric fever develop during an attack of malaria which 
 is already being treated by quinine, but in which the plasmodia can still be 
 demonstrated in the blood, quinine should be administered until the plasmodia 
 disappear. 
 
 From the above recommendations it is evident that the administration of 
 quinine in haemoglobinuric fever depends entirely upon the presence of the 
 malarial plasmodia, and the drug should never be administered in this disease 
 unless these organisms be present. Quinine is of no use whatever in the treat- 
 ment of haemoglobinuric fever per se, and a very careful examination of the 
 blood should be made for the plasmodia before it is administered. I regard 
 it as conclusively proven that quinine is harmful in haemoglobinuric fever 
 unless the disease is complicated by malarial infection, and this would ap- 
 pear to be a strong proof of the lack of relationship between the two 
 diseases. 
 
 General Treatment. — The patient suffering from haemoglobinuric fever 
 should be confined to bed in even the mildest infections, the body should be 
 kept warm, and warm drinks will be found most useful in maintaining the 
 bodily heat. The bowels should be opened by a dose of calomel or by mag- 
 nesium sulphate, and if there be evidence of suppression of urine, diuretics, such 
 as potassium citrate, should be freely administered, hot fomentations applied 
 over the region of the kidneys, and an exclusive milk diet enforced. If vomit- 
 ing be slight, liquid nourishment may be given at short intervals, but in cases in 
 which the vomiting is severe nutrient enemeta should be given, and enemata of 
 salt solution should be administered at intervals of four hours. If the enemata 
 are not retained, the salt solution should be injected into the subcutaneous 
 tissue of the breast or of the loins. The use of morphine in this disease requires 
 
406 HAEMOGLOBINURIC FEVER. 
 
 great caution and the drug should never be administered when it can be 
 avoided. 
 
 The use of stimulants is indicated in most cases, but no form of alcohol 
 should be employed in the treatment of haemoglobinuric fever. Strychnine, 
 digitalis, strophanthus and the aromatic spirits of ammonia are all useful, and 
 the inhalation of oxygen is warmly advocated by Plehn. 
 
 The treatment by chloroform, advised by Quennec, has proven of value in 
 some instances, but as it was combined with quinine it is impossible to say how 
 efficacious it really is in uncomplicated cases of haemoglobinuric fever. He 
 uses the following mixture: Chloroform, 6 gms.; gum arabic, 8 gms. ; simple 
 syrup, 250 gms. The entire quantity is taken every 24 hours, a sip being taken 
 every 10 or 15 minutes. He claims for the treatment that it controls vomiting, 
 diminishes albuminuria, and increases the quantity of the urine. The Stern- 
 berg treatment of yellow fever, by a mixture of bichloride of mercury and 
 sodium bicarbonate, has been used by some practitioners with good results. 
 The method of Vincent, who uses calcium chloride, a well-known antihemolysin, 
 is deserving of consideration in the treatment of this disease, as it is founded 
 upon sound scientific principles. The drug is given in doses of from 4 to 6 
 grammes per day by the mouth, or from 1 to 2 grammes hypodermically, 
 during the acute symptoms, and in every case in which it has been administered 
 the results have been such as to indicate that it is more nearly a specific than 
 any remedy so far used in the treatment of this disease. 
 
 The fever seldom requires treatment, as the temperature is not excessive 
 and does not last many days, but in cases in which there is hyperpyrexia spong- 
 ing with tepid water and alcohol is generally sufficient; vomiting, often most 
 distressing, may be benefited by mustard plasters over the epigastrium, the 
 sucking of cracked ice, the drinking of carbonated beverages, and, as a last 
 resource, the hypodermic injection of morphine. Champagne is permissible 
 in cases in which the vomiting is severe, the strength exhausted, and no food can 
 be retained by the stomach. It should be given in small quantities, frequently 
 repeated. During convalescence the diet should be light but nutritious, the 
 patient should be warned against overexertion and the use of alcoholics, and 
 every measure should be taken to avoid mental worry and nervous excitement. 
 If possible, the patient should leave the infected locality and never return to it, 
 for longer residence will very often result in recurrences of the haemoglobinuric 
 attack. 
 
 From what has been said of the treatment of haemoglobinuric fever it is 
 evident that as yet we have discovered no specific for the disease, and that 
 the treatment is wholly empirical, due to our ignorance of the exact etiological 
 factor. If, as is held by many, haemoglobinuric fever is due to the malarial 
 Plasmodia, why is it that treatment with quinine is not successful, and if, as 
 others hold, it is due to quinine, how is it that the continuation of the use of this 
 drug in treatment does not lead to a fatal result in the majority of cases? The 
 truth is that quinine is beneficial in haemoglobinuric fever just so long as 
 
HAEMOGLOBINURIC FEVER. 407 
 
 malarial plasmodia are found in the blood, thus proving that the malaria 
 infection is merely a coincidence, for the drug is absolutely useless in those 
 cases of haemoglobinuric fever in which no malarial plasmodia can be demon- 
 strated. The only conclusion possible to an unprejudiced student after care- 
 fully considering the epidemiology, symptomatology, and therapeutics of 
 haemoglobinuric fever is that neither malaria nor quinine have anything to do 
 with its etiology, but that it is caused by some parasite, hitherto undiscovered, 
 in all probability belonging to the Protozoa. 
 
 Literature upon Haemoglobinuric Fever. 
 
 1861. Dutrouleau. Traite des maladies des Europeans dans les pays chauds. 
 
 Paris. 
 1874. Berenger-Feraud. De la fievre bilieuse melanurique des pays chauds. 
 
 Paris. 
 
 1878. Idem. De la fievre bilieuse inflammatoire aus Antilles et dans l'Amerique 
 tropicale, etc. Paris. 
 
 1879. Idem. Note sur deux cas de fievre melanurique. Archiv. de Med. navale. 
 1887. Loeff, Van Der. Monatsblatter f. praktische Dermatologie. 
 
 1889. Rossoni. Studi clinici sulle emoglobinurie. Milan. 
 
 1892. Baccelli. Ueber einen Fall von nicht paroxysmaler Hamoglobinurie. 
 Verhandlungen des Congresses fur innere Medicin zu Wiesbaden. 
 
 1893. Davidson. Hygiene and Dieases of Warm Climates. London. 
 
 1893. Bastianelli and Bignami. Sulle emoglobinurie da malaria. Bull, 
 della Soc. Lancisiana. 
 
 1894. Studel. Die perniciose Malaria in Deutsch Ostafrika. Leipsic. 
 
 1894. Pfeiffer, L. Die Protozoen als Krankheitserreger. Jena. 
 
 1895. Murri. Sull' intossicazione da chinino. II Policlinico. 
 
 1895. Kuchel. Ueber Schwarzwasserfieber, etc. Deutsch. med. Wochenschr., 
 1895. 
 
 1896. Bastianelli. Le emoglobinurie da malaria secondo i recenti studi. 
 Annali di Medicina navale, 1896. 
 
 1896 Berthier, A. Pathogenie et traitement de l'haemoglobinurie paludeenne. 
 Archiv. de medecine experimentale, 1896. 
 
 1896. Manson. British Medical Journal, vol. i, p. 257. Also Trans. Epidemi- 
 ological Society, vol. xii, 1892-93. 
 
 1897. Tomaselli. La intossicazione chinica el infezione malarica. Catania. 
 
 1898. Plehn, F. Die Kamerun Kiiste. Berlin. 
 
 1899. Crosse. Black-water Fever. London. 
 
 1900. Marchiafava and Bignami. Malaria, in Twentienth Century Practice, 
 No. 19, New York. 
 
 1900. Marchoux. Rapport au congres de Paris, 1900. 
 
 1 90 1. Daniels. Reports to the Malaria Committee of the Royal Society, 
 5th Series. 
 
 1 90 1. Thayer. Lectures upon the Malarial Fevers. New York. 
 
 1902. Celli. Archives Italian Soc. de Biologie, p. 211. 
 
 1903. Plehn, A. Archiv. f. Schiffs- und Tropenhyg., Bd. vii, p. 541 and p. 270. 
 1903. Stephens. Thompson- Yates Laboratory Reports, vol. v, Part i, p. 217. 
 
 1906. Cassigrandi. Atti della Soc. per gli Studi della Malaria, p. 115. 
 
 1907. Stephens, J. W. W. Black-water Fever. System of Medicine, Allbutt 
 and Rolleston, vol. ii, Part ii, p. 289, London. 
 
408 HAEMOGLOBINURIC FEVER. 
 
 1907. Idem. Black-water Fever. Osier's "Modern Medicine," vol. i, p. 449. 
 1007 Daniels. Laboratory Studies in Tropical Medicine. Second Edition, 
 London and Philadelphia. 
 
 1907. Manson. Tropical Diseases. Fourth Edition. London and New York. 
 
 1908. Stephens and Christophers. The Practical Study of Malaria and 
 other Blood Parasites. London. 
 
 1 90S. Plehn, A. The Cause, Prevention, and Treatment of Haemoglobinuric 
 Fever in Warm Countries. Jour, of Tropical Med. and Hyg., vol. xi, 
 Xo. 19, p. 294. 
 
 1 90S. Deaderick, W. H. Haemoglobinuric Fevers. Memphis Med. Monthly, 
 Dec, 1907, and March, 1908. 
 See also the treatises upon "Malaria" by Kelsch and Kiener, Laveran, Man- 
 
 naberg, and Celli. 
 
PART VII. 
 
 THE BLOOD PROTOZOA OF MAN. 
 
Plate IV 
 
 -. 
 
 2 3 
 
 10 
 
 • 
 
 *;• 
 
 7 8 9 
 
 
 •••• 
 
 • 
 
 " & \ 
 
 •l7 ■ 
 
 i& 18 
 
 ? £ & 
 
 * 
 
 t & 
 
 4 
 
 5 V 
 
 o 
 
 7 
 
 6 
 
 
 8 
 
 C. F. CRAIG, DEL. 
 
EXPLANATION OF PLATE IV. 
 
 Leishmania donovani. Leishman-Donovan Bodies. Stained with Wright's 
 Stain. 
 
 i to 10. Various forms of Leishmania donovani, the protoplasm stained 
 blue, the chromatin, red. 
 
 10. Matrix containing several Leishmania donovani. 
 
 1 1 . Large endothelial cell containing many Leishmania donovani. 
 
 12 to 34. Various cultural forms of Leishmania donovani. Many of these 
 forms show division into two parasites. 
 
 34. A so-called "rosette" formed by cultural forms of Leishmania donovani. 
 Fig. A. Trypanosoma gambiense, stained with Wright's stain. 
 Fig. B. Spirochceta duttoni, stained with Wright's stain. 
 
 1. Spirochasta showing peculiar out-growths along its course, containing 
 chromatin. 
 
 2. Spirochasta undergoing longitudinal division. 
 
 3. Spirochasta undergoing transverse division. 
 
 Fig. C. Various forms of Histoplasma capsulatum. (After Darling.) 
 
 In all of these figures the red equals chromatin and the blue, protoplasm. 
 
CHAPTER I. 
 The Leishman-Donovan Bodies. Leishmania-donovani. 
 
 Since their discovery, the Leishman-Donovan bodies, or Leishmania-dono 
 vani, have proven of the greatest interest to students of protozoology and 
 tropical medicine, and have been accepted as the cause of a form of tropical 
 splenomegaly, commonly known as kala-azar or "dum-dum fever." Wright's 
 discovery of a similar organism in tropical ulcer (Delhi boil) and the discovery 
 of Pianese and Nicolle in infantile splenic anaemia of a parasite indistinguish- 
 able morphologically from these organisms has awakened renewed interest in 
 the subject, and would appear to indicate that parasites belonging to the genus 
 Leishmania are more widely distributed than we had supposed and that they 
 constitute a most important factor in the etiology of disease. 
 
 While it is far more common to find Leishmania-donovani in the liver and 
 spleen than in the blood, it is true that they may be demonstrated in the per- 
 ipheral blood, and, therefore, have to be considered in any discussion of the 
 protozoa of the blood. 
 
 Historical. — The form of tropical splenomegaly known as kala-azar has 
 long been studied in India, where it was first described, and is a unique illustra- 
 tion of the fallibility of medical opinion and deduction. Clarke first called the 
 attention of medical men to kala-azar in 1882, when he studied it in Assam, and 
 states that the disease was recognized in 1869. For many years it was regarded 
 as a persistent form of malaria, or malarial cachexia, and it was not until the 
 discovery of the Leishmania-donovani that the theory of the malarial nature of 
 this malady was abandoned, although many other theories had developed 
 regarding its etiology. Thus, Giles, after careful study, announced in 1889 
 that malaria had nothing to do with the etiology of kala-azar, but that the 
 disease was due to Anchylostoma duodenale, as most of the patients suffering 
 from the disease showed ova of this worm in their faeces. Bentley, in 1903, 
 regarded kala-azar as a severe form of Malta fever; while in 1896, Leonard 
 Rogers, and in 1898, Ronald Ross, considered the disease as malarial in nature, 
 Rogers claiming that it was a fatal form of malarial fever, while Ross con- 
 sidered it as malarial fever complicated by some secondary infection. Manson 
 was one of the first to suggest that kala-azar was a disease entity, due to some 
 undiscovered parasite, probably a trypanosoma, and it is interesting to observe 
 how closely this careful investigator guessed at the truth. 
 
 To Leishman belongs the credit of first observing and describing, in a 
 soldier of the English Army, the true parasite of kala-azar. In 1900 he had 
 observed in the splenic pulp obtained at autopsy from a soldier who had died of 
 
 411 
 
41^ THE BLOOD PROTOZOA OF MAX. 
 
 kala-azar small round or oval bodies, possessing a large and small chromatin 
 mass; at that time he did not call attention to them, but later, having found 
 similar bodies in the blood of a rat infected with the parasite of nagana, he 
 published a paper (in 1903) calling attention to the matter, and suggesting that 
 the bodies observed by him in the splenic pulp of the soldier might be degenera- 
 tive forms of a trypanosoma. In the same year Donovan found the same 
 parasite in splenic smears Obtained at autopsy and in blood from the spleen 
 obtained during life, and their presence was quickly confirmed by Marchand 
 and Manson in patients suffering from kala-azar. The results obtained by the 
 investigators mentioned awakened great interest in the subject and during the 
 next few years the fact was definitely demonstrated that patients suffering from 
 this disease invariably present within their viscera, and often in the peripheral 
 blood, the parasite described by Leishman and Donovan, and at the present 
 time this parasite is accepted as the cause of the disease. That it is the cause 
 has not been absolutely proven, but the fact that it is found always and only in 
 patients afflicted with this fever is, I believe, sufficient to prove that it stands in 
 etiological relationship to kala-azar. 
 
 Geographical Distribution. — For years it was thought that kala-azar 
 was a disease peculiar to India, but after the discovery of the parasite it was 
 found that the disease was widely distributed throughout the Orient and every 
 year the geographical distribution of this organism is added to by investigators. 
 At first localized in certain regions in India, it has gradually spread until at the 
 present time it is a veritable scourge in various regions of that country and is 
 said to be still spreading. 
 
 It is common in Ceylon and Burma, and has been found in China, in 
 Arabia, Egypt, the Soudan, Algeria, Tunis, and in other parts of Africa. 
 Although it has been carefully searched for in the Philippine Islands, it has not 
 as yet been demonstrated there. The occurrence, however, of a form of 
 tropical splenomegaly in these islands is suggestive, and further research may 
 show that Leishmania-donovani is the etiological factor in some of these cases. 
 While serving on the U. S. Army Board for the Study of Tropical Diseases in 
 the Philippine Islands, Ashburn and I repeatedly examined the splenic pulp 
 from a native suffering from splenomegaly accompanied by attacks of fever, but 
 were not able to find the Leishman-Donovan bodies, although hours were 
 spent in the search and many splenic punctures were performed. While in 
 this case the condition was obviously not due to Leishmania-donovani, it is 
 possible that it may be the etiological factor in some of the cases of enlarged 
 spleen not infrequently observed, and the subject should be given careful 
 study. 
 
 Biological Position. — The biological position of the Leishman-Donovan 
 parasite has occasioned much controversy, and it is impossible to classify this 
 organism permanently until we know every point regarding its morphology and 
 life history. At the present time a provisional classification has been agreed 
 upon, in which the Leishman-Donovan body is placed in the genus Leishmania 
 
THE BLOOD PROTOZOA OF MAN. 413 
 
 and species donovani, the proper name for the organism being Leishmania- 
 donovani. 
 
 Leishman considered the organisms as degenerated forms of a trypanosoma, 
 but later investigations have shown that trypanosoma forms are never found in 
 the human body, and while the development of flagellated forms in cultures 
 might appear to confirm Leishman's theory, the flagellated forms are distinct 
 morphologically from any known trypanosoma. Laveran, Mesnil, and Donovan 
 regard the parasite as a Piroplasma, as they have seen forms which they have 
 interpreted to be intracellular in the red blood-corpuscle, and Laveran named it 
 " ' Piroplasma-donovani. ,} The existence of forms occurring within the red blood- 
 corpuscles is very doubtful and the further fact that the organism possesses two 
 clumps of chromatin and that, in cultures, flagellate forms develop, definitely 
 place it in some other genus. Rodgers places it in the genus Herpetomonas and 
 Birt thinks that it may be the gregariniform stage of a Herpetomonas because of 
 its resemblance to the small ovoid forms of Crithidia fasciculata. Ross, who 
 considers it a distinct form of protozoa, suggested placing it in a new genus, 
 Leishmania, and named it Leishmania-donovani, and until we know more of its 
 life history it is considered wise by most protozoologists to adopt the classifica- 
 tion suggested by Ross. 
 
 The discovery by Wright, of Boston, of a similar parasite in tropical 
 ulcer, and by Pianese and Nicolle in infantile splenic anaemia, has added 
 two more members to the genus Leishmania; the organism associated with 
 tropical ulcer being called Leishmania tropica, while that associated with 
 infantile splenic anaemia is known as Leishmania infantum. 
 
 The Morphology of Leishmania-donovani. — The morphology of 
 Leishmania-donovani in the human body and in cultures varies so widely that it 
 is necessary to consider each separately. The flagellate forms observed in 
 cultures have never been observed in the peripheral blood or in smears from 
 any of the organs of the body, so that it is evident that the flagellate stage of 
 growth is extracorporeal, and probably occurs within some insect, as will be 
 shown later in considering the very interesting work of Patton. 
 
 Morphology in Man. — The parasite consists essentially of a small mass 
 of protoplasm surrounded by a limiting membrane, and enclosing two chromatin 
 clumps, one considerably larger than the other. The organisms vary some- 
 what in size, measuring from 2 to 4 microns in length by 1.5 to 2 microns in 
 breadth. 
 
 In shape the Leishman-Donovan bodies are generally oval, but may be 
 elongated slightly or perfectly spherical. Pyriform organisms are observed 
 and led to the classification of the organism as a pyroplasma, but it is probable 
 that most, if not all, of the organisms presenting a pyriform shape are so 
 distorted in the process of making the smear. In the fresh preparations 
 the organism is never observed to change its shape, thus indicating that it 
 does not possess amoeboid motility. 
 
 The limiting membrane is well defined in the fresh specimen, but in stained 
 
414 THE BLOOD PROTOZOA OF MAN. 
 
 preparations it is commonly dim or may appear absent, although in deeply 
 stained specimens it may be very well defined as a bluish, clearly cut membrane 
 surrounding the almost unstained and vacuolated protoplasm. It does not 
 contain any trace of chromatin. 
 
 The protoplasm, in fresh specimens, appears homogeneous and refractive. 
 It does not stain well and appears vacuolated in stained specimens, the chroma- 
 tin masses appearing to lie in a large vacuole surrounded by the limiting 
 membrane. The' protoplasm, when stained by any of the modifications of the 
 Romanowsky stain, appears faintly bluish in color in well-stained specimens, 
 the color being most marked around the periphery of the organism just within 
 the limiting membrane. 
 
 The two chromatin masses lie within the cytoplasm, one, the larger, being 
 situated at the center or near the periphery, while the smaller mass is situated 
 opposite the larger, near the periphery of the parasite. In rare instances 
 these two masses of chromatin are joined together by a bluish-stained portion 
 of cytoplasm. The larger chromatin mass, or nucleus, is generally oval in 
 shape, although not infrequently it is perfectly spherical, and stains a dull 
 red or pink, much less intense in color than the staining of the smaller mass. 
 Manson and others believe that the nucleus, prior to division, moves toward the 
 periphery, and becomes elongated, and it is certain that when the nucleus is 
 situated at the center of the parasite it is always oval or spherical in shape, 
 and that the elongated forms are only observed at the periphery. The smaller 
 chromatin mass (centrosome or blepharoplast) is generally rod-shaped, and 
 stains a very intense scarlet with the Romanowsky stains, sometimes appearing 
 almost black. It is situated opposite the nucleus, and the rod may point 
 toward the latter or lie at any angle to it; this body exhibits no distinct 
 structure, staining evenly throughout and appearing like a bacillus. Chris- 
 tophers and James have observed a tail-like prolongation of the chromatic 
 substance of the blepharoplast, extending from it at right angles to its long axis, 
 the significance of which has not yet been determined. 
 
 In smears from the liver and spleen the parasites may occur free, lying 
 singly or in groups, or they are observed within the endothelial cells in large 
 numbers, or lying in masses in a granular faintly stained matrix, the re- 
 mains of the degenerated cell. In man Leishmania-donovani are intracellular 
 organisms, invading the endothelial cells of the organs and only appearing free 
 in the blood plasma or the juices of the organs after they have been liberated 
 by the destruction of the host cell. The parasite invades the protoplasm of the 
 host cell and apparently multiplies within it, causing great enlargement and 
 ultimate destruction of the nucleus and degeneration of the entire cell. In the 
 peripheral blood and in smears of the various organs, multitudes of these 
 parasites may be observed within phagocytes, which undoubtedly play a very 
 important part in their destruction within man. In the irregular masses of 
 granular substance already mentioned the parasites may occur in very large 
 numbers, and I have counted in one such matrix over three hundred parasites. 
 
THE BLOOD PROTOZOA OF MAN. 415 
 
 It is not uncommon to observe atypical parasites in these granular masses, 
 in which either the nucleus or blepharoplast is missing and the limiting 
 membrane remains unstained. 
 
 Manson and Low, who have contributed valuable studies upon the morph- 
 ology of the Leishman-Donovan body, distinguish several types of the organism 
 in stained films, and as their description applies to what is usually observed in 
 smears made from the liver or spleen, I give it in their own words: 
 
 "In the stained films we recognize the following: 
 
 "1. Oat-shaped, oval, and circular bodies, clearly defined in outline, 
 stained a faint blue, and having a rather large and deeply stained, usually 
 spherical nucleus, lying against the capsule about the middle of the parasite, 
 and a still more deeply stained, short, bacillus-like body on the opposite side 
 of the capsule, but directed, as a rule, but not invariably, toward the nucleus 
 at various angles. In a few instances this bacillus-like centrosome, if so we 
 may call it, is represented by a point." 
 
 2. "Similar and generally rather larger bodies with the nucleus larger and 
 less deeply stained or with the nucleus spread out as a deeply stained layer 
 on the inside of the capsule, and in the usual position, that is, vis-a-vis to the 
 centrosome. In the latter type of parasite, with the exception of the nucleus 
 and centrosome, the contents of the capsule are very faintly stained." 
 
 3. "The foregoing bodies in association with a faintly staining and slightly 
 granular substance, which may be either regularly disposed around them or 
 attached to one side of them as a roundish or flocculent irregular mass." 
 
 4. "Two of the oval bodies closely applied to each other, one of the bodies 
 being smaller than the other. Occasionally in these twin bodies their respective 
 nuclei and centrosomes are disposed symmetrically." 
 
 The last named form of parasite is a dividing form or one in which division 
 is complete. The arrangement of the centrosome as a single small dot of 
 chromatin is not uncommon in the large collections of parasites within a 
 granular matrix, and very often, in such instances, it is impossible to distinguish 
 all of the morphological features which have been described as characteristic 
 of the Leishman-Donovan body. 
 
 The morphology of the forms undergoing division will be considered in 
 speaking of the methods of multiplication of these parasites. (See Plate IV.) 
 
 Morphology in Cultures. — In 1904, Leonard Rogers, of the Indian 
 Medical Service, first succeeded in cultivating the Leishman-Donovan bodies, 
 and proved that in such cultures true flagellated bodies developed which, 
 on account of their resemblance to the trypanosomatidae, were described by 
 him as trypanosomes, and so regarded until further culture experiments 
 definitely proved that they were not morphologically identical with any known 
 form of trypanosoma. 
 
 The first morphological change observed in the parasite in cultures is a 
 considerable enlargement of the nucleus (macronucleus), the chromatin at the 
 same time becoming less compact and staining less intensely; coincidently with 
 
416 THE BLOOD PROTOZOA OF MAN. 
 
 the enlargement of the nucleus the protoplasm apparently increases in amount 
 and the entire organism becomes larger; the centrosome (micronucleus) does 
 not enlarge, and remains unchanged throughout the entire process of flagella- 
 tion. After the changes described the organism undergoes division by simple 
 fission at least twice, the resulting bodies being round or oval in shape and pos- 
 sessing the same morphology as when observed in man. 
 
 After this preliminary division has been completed there appears in the 
 protoplasm a vacuole which contains an eosin staining substance, called by 
 Rogers the "eosin-spot," which is always situated near the blepharoplast 
 (micronucleus). The parasite now becomes elongated and ovoid in shape, one 
 end being more narrow than the other, and the blephoroplast and eosin con- 
 taining vacuole become situated at one end of the body of the organism, gen- 
 erally the more pointed extremity. After attaining this position the eosin 
 vacuole enlarges and finally reaches the surface of the body, where it appears to 
 liberate a fringe-like structure which eventually becomes a flagellum. This, 
 when fully developed, is seen to arise from the blepharoplast (micronucleus) 
 as in the trypanosomes. No undulating membrane ever develops, nor is there 
 any approximation of the blepharoplast and nucleus at any stage in the process 
 of flagellar formation. After the liberation and development of the flagellum 
 the entire organism elongates, the extremity furthest away from the blepharo- 
 plast becoming narrow and pointed, while that from which the flagellum arises 
 is more rounded in appearance; the nucleus is situated toward the non-flagel- 
 lated extremity in some instances but is central in the majority of the parasites. 
 
 The flagellated forms, the development of which has just been described, 
 divide into spirillar-like forms, division being preceded by the appearance of 
 chromatin granules, which are arranged in pairs throughout the protoplasm. 
 The division of the flagellate forms occurs longitudinally and, according to 
 Leishman, more than two spirillar-like organisms result from such division, 
 but Rogers describes an equal division of the organism into two spirillar-like 
 forms. According to Rogers, the blepharoplast (micronucleus) and flagellum 
 first divide, followed by the division of the nucleus, and the longitudinal split- 
 ting of the body into two equal portions, each of which repeats the process of 
 division within a short time. This rapid division results in the formation of 
 rosettes in which the flagella point toward the center of the rosette. It will be 
 observed that, according to Roger's description, the flagellum of each organism 
 is already formed when division is complete, while, according to Leishman, 
 the flagellum is developed after division, which has resulted in the formation of 
 several individuals. Minchin also states that the process of division would 
 appear to be "a process of markedly unequal longitudinal fission." As< a 
 matter of fact, both forms of division occur, equal longitudinal division being 
 most commonly observed; but not infrequently an organism may be observed 
 in which the splitting off of the minute spirillar-like forms described by 
 Leishman is occurring. The latter forms are at first devoid of a flagellum, 
 but one is developed rapidly and the organism becomes very actively motile. 
 
THE BLOOD PROTOZOA OF MAN. 
 
 417 
 
 The forms resulting from equal longitudinal division are at first pear-shaped 
 and broad, but soon elongate and become actively motile, much more so than 
 were the parent bodies at the time of division; the blepharoplast, from which 
 arises the flagellum, is situated anteriorly, while the nucleus is at or near the 
 center of the body. After the formation of the flagellated forms no further 
 development occurs in cultures, and the organisms soon perish. The 
 flagellated forms of the Leishman-Donovan body appear in cultures between 
 the third and sixth day after inoculating the culture media. 
 
 hit utu-uJ 
 
 M 
 
 Fig. 26. — Leishmania donovani. (After Leishman.) 
 1-3, Kala-azar parasites as observed in man. At 3 is seen a large mononuclear cell contain- 
 ing four parasites; 4-14, Leishmania donovani as observed in cultures (cultural forms). At 
 12 and 13 are seen parasites dividing into the spirochaete forms described by Leishman. 
 
 Multiplication. — In man, Leishmania-donovani multiplies in two ways: by 
 simple fission, binary in character, and by multiple fission. In the former the 
 nucleus first divides into two, quickly followed by the division of the blepharo- 
 plast (micronucleus) into two portions, after which the body of the parasite 
 divides longitudinally into two equal portions, each of which contains a nucleus 
 27 
 
418 THE BLOOD PROTOZOA OF MAN. 
 
 and a blepharoplast. When multiple fission occurs, the parasite becomes 
 nearly twice as large as normal, the nucleus and blepharoplast divide into 
 three, four or more equal portions, and the protoplasm shows lines of cleavage 
 surrounding each pair of chromatin masses, the nucleus and blepharoplast. 
 In this way the multiplying organism resembles somewhat a malarial rosette, 
 but may be easily distinguished by observing that each segment consists of a 
 mass of protoplasm, and two chromatin masses, one larger than the other, and 
 placed opposite one another, the smaller being rod-shaped. The organisms 
 resulting from this mode of multiplication are much smaller than the parent 
 organism and are sometimes so minute as to require very careful examination in 
 order to demonstrate them. 
 
 The multiplication of the parasites in cultures has already been described, 
 and, as will be shown, Patton has demonstrated a similar method of multiplica- 
 tion in the stomach of a certain species of bed-bug. 
 
 Cultivation. — -Until 1904 nothing was known regarding the extracorporeal 
 existence of the Leishman-Donovan body, but in that year Rodgers was suc- 
 cessful in demonstrating that this organism can be cultivated outside of man 
 and that its developmental cycle comprised not only the forms observed in the 
 infected patient, but that it also possessed a flagellate stage which only developed 
 when the organism was removed from the blood or organs of its host. The 
 further researches of Patton, which would appear to prove that the same forms 
 occur in the stomach of the bed-bug, indicate that this insect is the transmitting 
 agent of the disease, and that the flagellate forms, as in malaria, only develop 
 within an intermediate host. Rogers' cultivation experiments were promptly 
 repeated and confirmed by other investigators, notably Christophers, Leishman, 
 Chatterjee, Statham and Patton. I have already described the development 
 of the Leishman-Dononan bodies in cultures and will here discuss briefly the 
 method most successful in cultivation. 
 
 Rogers first endeavored to grow the parasites by adding to blood ob- 
 tained by splenic puncture from kala-azar patients, about 1 c.c. of sterile salt 
 solution containing 5 to 10 per cent, of sodium citrate, and incubating at blood 
 temperature, but he found that by this method the parasites were quickly 
 destroyed and that no development occurred. Using the same method, and 
 incubating at 27 C, he found that the parasites lived for several days and 
 that evidences of division occurred, but no flagellate bodies appeared. However, 
 upon incubation at 22 C. he found that the parasites multiplied very rapidly 
 and that the characteristic flagellate forms developed within from three to six 
 days. 
 
 The following procedure will be found to result in success if carefully 
 carried out: Prepare some normal salt solution and to it add about 8 per 
 cent, of sodium citrate, dissolving thoroughly; if the resulting solution is not 
 acid in reaction it should be made very slightly so by the addition of citric 
 acid, after which it is sterilized. Several test-tubes of small caliber should be 
 sterilized after stopping them with cotton wool, and a reliable glass syringe, to 
 
THE BLOOD PROTOZOA OF MAN. 419 
 
 be used in securing the blood, should be sterilized along with the other materials. 
 A patient suffering from kala-azar, in whom numbers of the parasites have 
 been demonstrated by microscopic examination of smears from the liver, is 
 selected, and the liver punctured, using the sterile syringe and observing the 
 most careful precautions regarding the sterilization of the skin and of the hands 
 of the operator. About 1 c.c. of blood, or more if the blood flow freely, is 
 withdrawn and about half placed in one culture tube, the remainder in another, 
 and to each tube about 1 c.c. of the citrate solution is added. If the organisms 
 are not very numerous it is preferable to add all of the blood to 1 c.c. of the 
 citrate solution in one tube. After gently shaking together the blood and the 
 citrate solution the tubes are placed in an incubator at 22 C. (in most countries 
 where kala-azar occurs an ice incubator will be necessary) and the preparation 
 examined daily, care being taken not to infect the tubes, as such infection 
 inevitably results in the destruction of the Leishman-Donovan bodies. 
 
 Rogers calls attention to the following important points which should 
 be most carefully regarded if we are to expect success with the culture of 
 Leishmania-donovani: 1. The temperature used for incubation should be 
 from 20 to 22 C, as very marked development never occurs above 25 C. 
 According to him, an exposure for even a short time to a temperature above 
 25 C. results in the destruction of the parasites in the culture. The minimum 
 temperature at which the organisms can develop is about 17 ° C. 
 
 2. The mixture of blood and citrate solution must be sterile except for 
 the Leishmania-donovani, for he found that whenever the cultures became 
 contaminated with other organisms the parasites quickly degenerated and 
 disappeared. All bacteria are inimical to successful cultivation, but Rodgers 
 found that the staphylococci especially were most fatal to the Leishman- 
 Donovan bodies in cultures. 
 
 3. The medium should have a slightly acid reaction, the acidity being 
 secured by the addition to the infected citrated blood solution of a drop or 
 two of a weak citric acid solution. Rogers found that after thus modifying 
 the culture media the flagellated forms appeared more rapidly and in far greater 
 numbers, and that the development was much more uniform, the flagellates 
 appearing about the third day. 
 
 On account of the danger attending splenic puncture, it is preferable to 
 puncture the liver in order to obtain material for culture. 
 
 Transmission and Pathogenicity. — Aside from the forms observed by 
 Patton in a species of bed-bug, no phases in the development, under natural 
 conditions, of Leishmania-donovani outside the human body have been 
 observed, nor have we any direct experimental evidence that this parasite will 
 produce kala-azar upon being inoculated in man. It is very probable that 
 certain forms of the organisms occur in natural conditions which have not as 
 yet been observed, and that the infective stage may be so different in its 
 morphology from the known developmental stages as to render its recognition 
 impossible. The observations of Patton, of the Indian Medical Service, would 
 
420 THE BLOOD PROTOZOA OF MAN. 
 
 appear to indicate that the parasite is transmitted by the bed-bug, and while his 
 observations have not been confirmed, I believe that he has shown that the 
 parasite can undergo development within an insect and that this method of 
 transmission is the most probable one in every respect. 
 
 The development in cultures of flagellated forms; the fact that develop- 
 ment occurred best in cultures at a temperature between 20 C. and 22 C, 
 and that the medium should be acid in reaction, as well as certain well-known 
 epidemiological peculiarities, suggested to Rogers and his co-workers that the 
 parasite of kala-azar was transmitted to man by a biting tick or insect. Rogers 
 endeavored to discover the organism in the bodies of bed-bugs, examining no 
 less than 200 bugs, but was unsuccessful. Christophers obtained negative 
 results from his examinations of moscpiitoes and ticks, and the work of a few 
 other investigators was equally unsuccessful in demonstrating the parasite 
 within the body of the insects. In 1907, Patton published a preliminary 
 note describing the results obtained by him in infecting a species of bed-bug 
 with Leishmania-donovani by feeding experiments, in which he claimed that in 
 the stomach of the infected bugs there occurred forms similar to those observed 
 in cultures. Patton has continued his researches in this direction and has, I 
 believe, proven that in bed-bugs allowed to suck the blood of kala-azar patients 
 and kept at a temperature of 22 C. or thereabouts, flagellated forms develop 
 like those observed in cultures and that the entire process of development 
 has been observed in blood within the stomach of the insect. In a postscript 
 to his original paper Patton states " Since w y riting the above I have found in the 
 bed-bug (Cimex macrocepJialus) all the intermediate stages of development 
 and numerous fully developed flagellates similar to those seen in cultures 
 of splenic blood,'' and in a letter to Rogers, quoted by the latter in his work, 
 "Fevers in the Tropics," he says: "There is no shadow of doubt that the 
 bed-bug transmits the disease." The bed-bug in which Patton was successful 
 in following the development of the flagellated stage of Leishmania-donovani is 
 Cimex rotundatus Signoret {Cimex macrocephalatns Fieber). 
 
 While further observation will probably confirm Patton's work, it should 
 be noted that much still remains to be done before we possess a clear under- 
 standing of the exact method of transmission of this disease, and it is especially 
 important that the question of the hereditary transmission of the infection to 
 bed-bugs be determined. 
 
 Distribution of the Leishman-Donovan Bodies in Man. — These 
 parasites may be found in almost every organ of the body, but are most numerous 
 in the spleen, bone-marrow, and liver. The pathology of kala-azar and the 
 distribution of the parasites in the body has been thoroughly worked out by 
 Leishman, Marchand, Statham, Christophers, Ledingham, and Manson, 
 and the occurrence of the parasites in the blood has been studied especially 
 by Laveran, Statham, Christophers, Rogers, Donovan, and James. From 
 the observations of these investigators it has been proven that Leishmania- 
 donovani is generally found within the cytoplasm of mononuclear cells, very 
 
THE BLOOD PROTOZOA OF MAN. 421 
 
 seldom being observed free in the tissues or in the blood. The occurrence of 
 numerous parasites within the mononuclear cells appears to have no injurious 
 action until the entire cytoplasm is filled with them, when the nucleus is pushed 
 to one side and the cell eventually ruptures; that the cell itself has no injurious 
 action upon the parasite is evidenced by the fact that fission occurs, as is 
 shown by the presence in most of the cells of divisional forms in all stages of 
 division. The nature of the mononuclear cells and their origin has been shown 
 by the studies of Christophers, who has proven that they are endothelial in 
 character, and originate from the walls of the capillaries and lymphatics. In 
 other words, they are the same cells which act as "macrophages" in malaria, 
 but in the case of the kala-azar parasite the macrophage is unable to destroy 
 the organism, as it does in malaria. Christophers has shown that these cells, 
 crowded with Leishmania-donovani, are most common in the spleen and in the 
 bone-marrow, but they have also been found in the liver, mesenteric glands, 
 intestinal ulcers, lungs, kidneys, in the lymphatic glands, in the arachnoid, and 
 in ulcerations of the skin and skin eruptions in kala-azar patients. In fact, the 
 parasite may be said to invade the endothelial cells of the capillaries and the 
 lymphatics in almost every portion of the body, but especially in the spleen, bone- 
 marrow, and liver. 
 
 Leishman considers that the parasite, after invading the body, is taken up 
 by the endothelial cells, as these cells are well known as active phagocytes, but 
 it would appear more probable that the parasites themselves invade the endothe- 
 lial cells, as it would seem that they multiply in man only within these cells. 
 However this may be, it is proven that the Leishman-Donovan body is an 
 intracellular parasite whose host cell is the endothelial cell of the blood-vessels 
 and lymphatics. 
 
 After multiplication of the parasite has progressed for a certain time the 
 cytoplasm of the cell becomes filled with young organisms, which distend the 
 host cell and eventually cause its separation from the wall of the blood-vessel or 
 lymphatic. The infected cell then ruptures or degenerates and the young 
 parasites are again taken up by endothelial cells or actually invade them, when 
 the process of division, detachment of the endothelial cell, and liberation of the 
 parasites is repeated. The infection is spread through the body by the presence 
 in the blood and lymph of free parasites and infected leucocytes, the larger of 
 which lodge in the capillaries of various organs; the granular matrix in which 
 hundreds of the parasites are commonly observed embedded is undoubtedly 
 the degenerated cytoplasm of the endothelial cell invaded by the organism. 
 
 In the spleen, which is greatly enlarged, a microscopical examination shows 
 the sinuses filled with multitudes of mononuclear cells containing Leishmania- 
 donovani; the infected cells vary in size and are much more numerous in some 
 portions of the sections than in others, while the Malpighian corpuscles are 
 generally free from the infection. In the liver the entire process of infection of 
 the endothelial cell and its subsequent detachment from the wall of the capillary 
 may be easily studied, the walls of the portal capillaries being covered with cells 
 
422 
 
 THE BLOOD PROTOZOA OF MAN. 
 
 containing parasites, the cells being in various stages of detachment from the 
 vessel wall. The hepatic capillaries also contain many large mononuclear cells 
 filled with parasites. In the bone-marrow there occur multitudes of infected 
 mononuclears, showing parasites in all stages of division. In the kidney the 
 endothelial cells showing infection are those of the smallest capillaries, especially 
 those of the glomerular tufts, and the parasites have never been demonstrated 
 in the epithelial cells of the tubules. The parasites have never been found in 
 the urine. 
 
 The Blood in Kala-azar. — The observations of Donovan, Christophers, 
 James, Laveran, and others show conclusively that the Leishman-Donovan 
 bodies occur in the peripheral blood and that in many cases it is possible to find 
 
 Fig. 27. — Leishmania donovani contained within a large endothelial cell. (Note the large 
 
 number of the parasites.) Photomicrograph from a splenic smear of a patient suffering from 
 
 kala-azar, kindly sent the author by Dr. Leishman, X 1000. 
 
 them in this fluid. Donovan has reported finding the parasites in 75 per cent, of 
 his cases in the peripheral blood while, according to Rogers, Patton was able to 
 find them by a blood examination in even a larger proportion of advanced cases. 
 In the peripheral blood the parasites occur within the leucocytes, chiefly the 
 polynuclears and large mononuclears. Laveran and Mesnil and Donovan have 
 reported the occurrence of the parasite within the red blood-corpuscles, but 
 their observations have not been confirmed, and it is probable that parasites 
 lying upon but not within the red corpuscles were really observed by these in- 
 vestigators, as numerous workers have reported instances of this character. It 
 has been found that the parasites appear in the blood most frequently during 
 the latter stages of the disease and that repeated examinations of the blood in 
 
THE BLOOD PROTOZOA OF MAN. 423 
 
 new infections almost invariably result negatively so far as the presence of the 
 parasite is concerned. 
 
 Certain changes are produced in the blood by Leishmania-donovani which 
 are of interest and importance from a diagnostic standpoint. In advanced 
 cases there is marked anaemia, the red blood count being reduced to from 
 2,500,000 to 2,000,000 per cu. mm. the haemoglobin being reduced in propor- 
 tion, while there is a marked leucopenia, the white cells numbering from 1,000 
 to 5,000 per cu. mm. The most characteristic change observed, aside from the 
 very marked leucopenia, is a reduction in the number of the polynuclears and 
 eosinophiles, and a large increase in the relative proportions of the large mono- 
 nuclears and lymphocytes. The increase in large mononuclears is of greatest 
 importance from a diagnostic standpoint, according to Rogers, but it should be 
 remembered that an increase occurs in these cells in malaria, trypanosomiasis, 
 and other diseases, so that it cannot be considered peculiar to kala-azar. 
 
 Elimination of the Parasites. — It may be said that nothing is known 
 with certainty regarding the elimination of Leishmania-donovani from the body. 
 They have never been demonstrated in any of the excretions, and the situation 
 of the parasites in the endothelial cells of the capillaries in the kidneys, and their 
 absence from the renal epithelium or the cells of the tubules is almost certain 
 proof that they are not eliminated through the kidneys. The occurrence of 
 the parasites in the intestinal ulcers and in eruptions and ulcerations of the skin 
 suggest that they may be eliminated in the faeces or through the skin, but they 
 have never been found in the faeces, and as the ulcerations of the skin are not of 
 constant occurrence it is not probable that the parasites are naturally eliminated 
 in this manner. When haemorrhages occur, which are not infrequently 
 observed in this disease, the parasites may be found in the blood, and it may be 
 that this is one method of elimination. The bites of insects furnish the most 
 probable method by which the parasites leave man, and the observations of 
 Patton, already referred to, would appear to indicate that the bed-bug is the 
 intermediate host of Leishmania-donovani. 
 
 Demonstration of Leishmania-donovani. — As the diagnosis of kala- 
 azar rests upon the recognition of Leishmania-donovani in the blood or tissues, 
 the methods available for its demonstration require careful consideration. 
 The parasite is most easily recognized in stained specimens, and for staining the 
 method of Wright, of Leishman, and the Giemsa stain, described in the section 
 upon malaria, are suitable. Wright's stain is very satisfactory and I believe will 
 be found most useful, but Leishman's method is excellent and is the one which 
 has been most frequently employed for the demonstration of this organism. 
 The Giemsa stain gives good results, but is more complicated and requires 
 greater care in order to secure good specimens. 
 
 The organisms may be demonstrated in stained smears secured from the 
 spleen or liver by puncture or in smears of the peripheral blood. On account 
 of the danger of splenic puncture, the specimen should be preferably obtained 
 from the liver, the utmost precautions being exercised as regards asepsis of the 
 
424 THE BLOOD PROTOZOA OF MAN. 
 
 skin, the instrument used, and the hands of the operator. The abdomen should 
 be tightly supported by a bandage and the patient cautioned against jumping 
 when he feels the sting of the needle; the latter should be a long hypodermic 
 needle having a very sharp point and not too fine a caliber. It should be 
 remembered that it is not necessary to secure much of the material for examina- 
 tion and that if we secure only blood the examination will probably result 
 negatively, as it is the pulp of the liver or spleen which will give the best results 
 in examination. 
 
 The examination of the peripheral blood should be made in every suspected 
 case, but it is only in those showing high fever or in advanced cases that we can 
 expect to find the parasite. A one-twelfth inch immersion lens should be used 
 and every leucocyte carefully examined, and several hundred should be inspected 
 before the result is recorded as negative. The examination of the peripheral 
 blood will generally result in the demonstration of the parasite in advanced 
 cases when there is high temperature, but little can be expected from it in the 
 early stages of the disease, and thus it cannot be relied upon as a method of 
 diagnosis in such cases. To facilitate the finding of the parasites in the periph- 
 eral blood, from i to 5 c.c. of blood may be taken from a vein, added to a centri- 
 fuge tube containing a little sodium citrate solution to prevent clotting, and 
 thoroughly centrifuged, after which specimens are prepared from the upper 
 portion of the layer of cells. Leishman recommends this method, but Rogers 
 states that he has not been able to demonstrate the organism by its use. It 
 deserves a more extended trial. The presence in leucocytes or mononuclear 
 (endothelial) cells of bodies possessing a capsule, a spherical or oval mass of 
 chromatin, and a rod-like, much smaller, chromatin mass, the entire organism 
 being about the size of a blood platelet, is conclusive as to the presence of Leish- 
 man ia dcnovani, when such cells are obtained frcm the organs or peripheral 
 blood of patients suffering from fever. 
 
 Leishmania tropica and Leishmania infantum. — Because of their mor- 
 phological resemblance to Leishmania-dcnovani, it is necessary to mention briefly 
 two other organisms occurring in man belonging to the genus Leishmania; i.e., 
 Leishmania tropica, discovered by Wright in the granulation tissue cells of 
 oriental sore (tropical ulcer) and Leishmania infantum, discovered in infants 
 suffering from splenic anaemia by Pianese and Nicolle. Morphologically, 
 these organisms are indistinguishable from the Leishman-Donovan body, but 
 that they are distinct species is proven by the pathological lesions produced by 
 them. 
 
 Nicolle, in 1908, produced splenic anaemia in dogs by inoculating them 
 with tissue from cases of splenic anaemia, and cultivated the organisms from 
 the experimental animals on blood-agar, flagellate forms developing in the 
 cultures like those of the Leishman-Donovan body. He was not able to re- 
 produce the disease by inoculation of these cultures, but Novy in the same year 
 was successful in producing the disease in a dog by the inoculation of cultures 
 containing numerous flagellate forms obtained from Nicolle. The results 
 
THE BLOOD PROTOZOA OF MAN. 425 
 
 obtained by Novy prove beyond question that the flagellate forms of Leishmania 
 infantum, when inoculated into dogs, produce a disease identical with infantile 
 splenic anaemia, and that the forms found in the dog's tissues are morphologic- 
 ally indistinguishable from the forms of Leishmania-donovani observed in man. 
 His results also prove that the flagellate forms revert to forms usually observed 
 in man, and that these forms, when cultivated, develop typical flagella, as he was 
 able to show that in cultures of the infected dog's blood made from the spleen, 
 liver and bone-marrow there developed "enormously rich cultures of the 
 typical flagellate forms." The importance of the work of Novy in its relation 
 to the life history of Leishmania donovani cannot be over-estimated, and it will 
 indeed be surprising if, with the light which his studies have thrown upon the 
 subject, we are unable to solve the problem of the transmission of tropical 
 spleno-megaly or kala-azar. 
 
 Literature upon the Leishman-Donovan Bodies. Leishmania-donovani. 
 
 1897. Rogers, Leonard. Report on Kala-azar. 
 
 1898. Giles. The Etiology of Kala-azar. Ind. Med. Gaz., p. 1. 
 
 1899. Ross, Ronald. Report on the Nature of Kala-azar. 
 
 1899. Rogers, Leonard. The Diagnostic and Prognostic Value of the Leu- 
 
 copenia of Cachexial Fever and Kala-azar. Brit. Med. Jour., Apr. 1. 
 1902. Bentley. Epidemic Malta Fever in Assam, etc. Ind. Med. Gaz., p. 379. 
 
 1902. Rogers, Leonard. Note on the Serum-reactions and the Temperature 
 Curve in Chronic Malaria, including Kala-azar. Ind. Med. Gaz., p. 377. 
 
 1903. Leishman. On the Probability of the Occurrence of Trypanosomiasis 
 in India. Brit. Med. Jour., vol. i, p. 1252; vol. ii, p. 1376. 
 
 1903. Ross, Ronald. Note on the Bodies Recently Described by Leishman 
 
 and Donovan. Brit. Med. Jour., vol. ii, p. 1261 and 1401, Nos. 2237 
 
 and 2239. 
 1903. Ross, R. A New Parasite of Man. Thompson- Yates Lab. Reports, vol. 
 
 v, p. 79. 
 1903. Donovan. On the Possibility of the Occurrence of Trypanosomiasis 
 
 in India. Brit. Med. Jour., vol. ii, p. 59. 
 1903. Wright, J. H. Protozoa in a Case of Tropical Ulcer (Delhi Boil). The 
 
 Jour, of Med. Research, vol. x, No. 3, p. 472. 
 
 1903. Laveran et Mesnil. Sur un protozoaire noveau (Piroplasma Donovani) 
 parasite d'une fievre de l'lnde. Compt. Rend. Acad, des Sci, Paris, T. 
 137, No. 33, pp. 957-961. 
 
 1904. Leishman. The Nature of the Leishman-Donovan Body. Brit. Med. 
 Jour., vol. ii, No. 2270, p. 29. 
 
 1904. Idem. Discussion on the Leishman-Donovan Body. Brit. Med. Jour., 
 vol. ii, No. 2281, p. 642. 
 
 1904. Idem. Note on the Nature of the Parasites Found in Tropical Spleno- 
 megaly. Brit. Med. Jour., vol. i, p. 303. 
 
 1904. Leishman. Notes upon the Further Investigation of the Parasites of 
 Kala-azar and Delhi Boil. Jour. R. A. Med. Corps, vol. iii, p. 287. 
 
 1904. Idem. A Method of Producing Chromatin Staining in Sections. Jour, of 
 Hyg., vol. iv, No. 3, p. 434. 
 
 1904. Manson and Low. The Leishman-Donovan Body. Brit. Med. Jour., 
 vol. i, p. 1251. 
 
426 THE BLOOD PROTOZOA OF MAN. 
 
 1904. Idem. The Leishman- Donovan Body and Tropical Splenomegaly. Brit. 
 
 Med. Jour., vol. i, p. 183. 
 1904. McFarland, J. The Leishman-Donovan Blood Parasites. American 
 
 Medicine, vol. vii, No. 23, p. 888. 
 1904. Rogers, Leonard, Cachexial Fever in India Associated with Cunning- 
 ham- Leishman-Donovan Bodies. Brit. Med. Jour., vol. i, p. 645. 
 1004. Idem. Leishman-Donovan Bodies in "Malarial Cachexia" and Kala- 
 
 azar. Brit. Med. Jour., vol. i, p. 1249. 
 1904. Idem. Preliminary Note on the Development of Trypanosoma in Cul- 
 tures of the Cunningham-Leishman-Donovan Bodies of Cachexial Fever 
 
 and Kala-azar. Lancet, vol. ii, July, 23. 
 1904. Idem. On the Development of Flagellated Organisms (trypanosomes) 
 
 from the spleen protozoic parasites of Cachexial Fevers and Kala-azar. 
 
 Quart. Jour. Mocro. Sci., vol. xlviii, Part iii, November. 
 1904. Donovan, C. Human Piroplasmosis. Lancet, vol. ii, p. 744, and Brit. 
 
 Med. Jour., vol. i, p. 651. 
 1904. Idem. Piroplasmosis. A History of the Discovery of the Donovan 
 
 Bodies in Madras. Ind. Med. Gaz., p. 321. 
 1904. Christophers, S. R. A Preliminary Report upon a Parasite Found in 
 
 Persons Suffering from Enlargement of the Spleen in India. Sci. Men. 
 
 Med. and San. Depts. Govt, of India, N. S., N. 8, Calcutta. 
 1904. Idem. On a Parasite found in Persons suffering from Enlargement of the 
 
 Spleen in India. Sci. Mem Med. and San. Depts., Govt, of India, No. 2. 
 1904. Idem. Tropical Splenomegaly and Oriental Sore. Brit. Med. Jour., vol. 
 
 ", P- 655. 
 1904. Phillips, L. Note on the Occurrence of the Leishman-Donovan Body 
 
 in Arabia and Egypt. Brit. Med. Jour., vol. ii , p. 657. 
 1904. Castellani, A. Leishmania Donovani in Ceylon. Brit. Med. Jour., 
 
 vol. ii, p. 656. 
 1904. Bentley, A. A Short Note on the Parasite of Kala-azar. Ind. Med. 
 
 Gaz., p. 81. 
 1904. Idem. Notes upon Kala-azar and the New Parasite. Brit. Med. Jour., 
 
 vol. ii, p. 453. 
 1904. Laveran. Piroplasma donovani en Tunisis d'apres nue observation 
 
 de Cathoire. Bull, de l'Acad. de Med. Seance des 22 Mars. 
 1904. Laveran et Mesnil. Nouvelles observations sur Piroplasma donovani 
 
 Compt. Rend. Acad. des. Sci., Tome 138, p. 187. 
 1904. Blanchard, R. Note Critique sur les corpuscles de Leishman. Rev. 
 
 de Med. et d'hyg tropicales, p. 37. 
 1904. Neave, S. Leishmania donovani in the Soudan. Brit. Med. Jour., 
 
 vol. i, p. 12 52. 
 1904. Ruata, G. R. Kala-azar or Tropical Splenomegaly. Jour of Trop. Med., 
 
 Nov. 15, p. 350. 
 
 1904. Chatterjee, G. C. Development of the Flagellated Stage of Leishman- 
 Donovan Bodies. Lancet, vol. ii. 
 
 1905. Idem. The Cultivation of Trypanosoma out of the Leishman-Dono- 
 van Body by the Method of Capt. L. Rodgers. Lancet, vol. i, p. 16. 
 
 1905. Rogers, L. The Conditions affecting the Development of Flagellated 
 Organisms from Leishman-Donovan Bodies, and Their Bearing upon the 
 Probable Mode of Infection. Lancet, vol. i, p. 1848. 
 
 1905. Statham, J. B. C. Preliminary Note on the Cultivation of the Leishman 
 Body. Jour. R. A. Med. Corps, vol. iv, January. 
 
THE BLOOD PROTOZOA OF MAN. 427 
 
 1905. Idem. A case of Kala-azar. Jour. R. A. Med. Corps, vol. v, Aug. and 
 
 Sept. 
 1905. Christophers, S. R. On a Parasite Found in Persons Suffering From 
 
 Enlargement of the Spleen in India. Third Report. 
 1905. James, S. P. On Kala-azar, Malaria, and Malarial Cachexia. Sci, 
 
 Mem. Officers Med. and San. Depts. Govt. India, N. S., No. 19. 
 1905. Leishman and Statham. The Development of the Leishman Body 
 
 in Cultivation. Jour. R. A. Med. Corps, vol. iv, March. 
 1905. Manson, Sir P. Notes on Two Cases of Febrile Tropical Splenomegaly, 
 
 etc., Brit. Med. Jour., Nov. 11. 
 1905. Rogers, L. The Diagnostic and Prognostic Value of the Leucopenia 
 
 of Cachexial Fever and Kala-azar. Brit. Med. Jour., April 1. 
 
 1905. Childe, L. F. The First Case of Leishman- Donovan Disease in a Euro- 
 pean in Bombay. Ind. Med. Gaz., p. 447. 
 
 1906. Rogers, L. Further Work on the Development of the Herpetomonas 
 of Kala-azar and Cachexial Fever from Leishman-Donovan Bodies. 
 Proc. Royal Society, vol. lxxvii, p. 284. 
 
 1907. Idem. Milroy Lectures on Kala-azar. Abstracts in Brit. Med. Jour., 
 vol. i, and Lancet, vol. i. 
 
 1907. Patton, W. S. Preliminary Report on the Development of the Leish- 
 man-Donovan Body in the Bed-bug. Sci. Mem. Med. and San. Depts. 
 Govt, of India, N. S., No. 27. 
 
 1907. Leishman. Kala-azar, in System of Medicine, Allbutt and Rolleston, 
 vol. ii, Part ii, p. 226, London. Also article on Kala-azar, in Memse's 
 " Handbuch der Tropenkrankheiten," Bandiii, Halbbandii, Leipzig, 1906. 
 
 1907. Manson, Sir P. Kala-azar, in "Tropical Diseases," 4th Ed., p. 178, 
 London and New York. 
 
 1908. Lyons, I. P. Kala-azar, in Osier's "Modern Medicine," vol. iv, Phila- 
 delphia, p. 770. 
 
 1908. Rogers, L. Fevers in the Tropics, p. 31, London. 
 
CHAPTER II. 
 
 Trypanosoma Gambiense (Trypanosoma Ugandense). 
 
 Trypanosoma gambiense is a protozoan parasite of the blood, occurring 
 in Africa, and causing the peculiar disease known as "sleeping sickness." 
 In the early stages of the disease the parasite is found in the blood and lym- 
 phatic glands, and, after the development of typical symptoms, in the cerebro- 
 spinal fluid as well as in the blood and the lymphatic glands. 
 
 Trypanosomes are probably the most widely distributed of all protozoan 
 parasites, being found in mammals, birds, reptiles, batrachians, fishes, and 
 insects. To Valentin, of Berne, belongs the credit of the discovery of the 
 trypanosomes, a species of which he found in the blood of trout, but it was 
 not until Dutton's discovery of a trypanosome in the blood of man in 1901 and 
 the subsequent work of Castellani, Bruce, and Nabarro, proving this organism 
 to be the cause of sleeping sickness, that the trypanosomes were considered of 
 importance in human pathology. 
 
 Historical. — In 1841, Valentin discovered and described the first trypano- 
 some, a parasite of the trout (Salmo fario), and his discovery was followed by 
 papers relating to similar organisms, found in the blood of the frog, by Grube 
 and Gluge (1842-1843), the former author first applying the generic term 
 "trypanosoma" to these organisms. In 1845, Gros found a trypanosome 
 in the blood of the field mouse and mole, and in 1850, Chaussat, and in 1871, 
 Ray Lankester, discovered trypanosomes in the blood of batrachians. Interest 
 in these organisms was renewed in 1871, by Lewis, who found that a trypano- 
 some was a common parasite of the blood of rats in India, and his observations 
 were very soon confirmed by workers in other parts of the world, All of the 
 trypanosomes discovered up to and including Lewis's trypanosome, were non- 
 pathogenic, but in 1880, Evans discovered a trypanosome in the blood of 
 horses suffering from "surra," which he proved experimentally to be the cause 
 of that disease. The discovery of Evans was followed in 1894 by that of Rouget, 
 who found another trypanosome in the blood of a horse suffering from dourine 
 (mal du coit); of Bruce, of the trypanosoma of nagana; of Elmassion, of the 
 trypanosome of mal de caderas; and of Theiler, of the trypanosoma of galziekte 
 or gall-sickness of cattle in the Transvaal. 
 
 Until 1902, the date of the discovery of the trypanosome of Theiler, it was 
 supposed that the trypanosomes were parasites of the lower animals only, but 
 the observations of Dutton and Todd and of Castellani, Bruce and Nabarro, in 
 1902 and 1903, conclusively proved that there occurred in man a pathogenic 
 
 428 
 
THE BLOOD PROTOZOA OF MAN. 429 
 
 trypanosome of the greatest importance because of the fatal disease of which it 
 was the etiological factor. 
 
 The trypanosome of man is the cause of sleeping sickness, a disease first 
 described by Winterbottom in 1803 as occurring among the negroes along the 
 West Coast of Africa. On account of its peculiar symptoms this disease has 
 always attracted a great deal of attention, and many efforts were made to de- 
 termine its etiological organism, many bacteria having been described as con- 
 cerned in its production. Marchoux, Bettencourt, and Castellani were among 
 the most earnest students of the disease and all described some bacterium as the 
 causative factor. Manson for a long time considered that sleeping sickness was 
 due to Filaria perstans, because this organism was met with so often in the blood 
 of those suffering from the disease, but the fact that Filaria perstans occurs in 
 many regions where sleeping sickness is unknown and that many victims of 
 sleeping sickness are not infected with this parasite, conclusively proved that 
 the filaria had no relation to the disease. 
 
 In 1 901, Forde observed, in the blood of a European in the hospital at 
 Bathurst, Gambia, minute, actively motile, worm-like bodies, the nature of 
 which he was unable to determine, but Dutton, who examined the blood of the 
 same patient in December, 1901, recognized the bodies as trypanosomes, and 
 gave the name Trypanosoma gambiense to the organism. The occurrence of 
 this organism in the blood of certain patients suffering from fever was con- 
 firmed by Dutton and Todd, Manson, Broden, Brumpt, and Baker in 1903, 
 and Maxwell-Adams in the same year suggested that the organism might be 
 the cause of sleeping sickness. 
 
 In 1903, Castellani, while engaged in examining the cerebrospinal fluid of 
 negroes suffering from sleeping sickness, discovered that a large proportion of 
 them showed a trypanosome in this fluid, which he considered a different 
 species from Trypanosoma gambiense, and which he called Trypanosoma 
 ugandense, a name afterward amended to Trypanosoma castellani, by Kruse. 
 The discovery of Castellani was confirmed by Bruce and Nabarro at once; 
 they found the parasite in the cerebro-spinal fluid, in every one of thirty-eight 
 cases examined and in twelve of them in the peripheral blood. These authors 
 concluded, that the trypanosome was the cause of the disease, and their researches 
 were confirmed by Greig, Brumpt, Dutton, Todd, Broden, and Christy. 
 
 For some time the trypanosome found in sleeping sickness and that found 
 in patients suffering from irregular fever (Trypanosoma gambiense and Trypano- 
 soma ugandense) were thought to be different species, and Castellani stated 
 that well-marked morphological differences existed between them, but the 
 observations of Bruce, Nabarro, Greig, Dutton, Todd, and Christy proved 
 that, without doubt, the trypansoma found in sleeping sickness, and discovered 
 by Castellani, was identical with that found in fever cases, and discovered by 
 Dutton and Forde. The later observations of Thomas and Linton, Laveran, 
 Thomas and Breinl, and Gray and Tulloch upon the pathogenic lesions 
 caused in animals by these organisms confirm the observations based upon 
 
430 THE BLOOD PROTOZOA OF MAN. 
 
 morphology, and it is now generally accepted that Trypanosoma gambiense and 
 Trypanosoma ugandense are identical and that the organism should be known 
 as Trypanosoma gambiense. 
 
 The earliest symptoms of sleeping sickness are not those of lethargy, but 
 are characterized by fever, swelling of the lymphatic glands, and skin eruptions, 
 and it is during this stage that the trypanosomes are found in the peripheral 
 blood and in the gland juices, while they are found in the cerebrospinal fluid 
 only after the onset of the symptoms typical of sleeping sickness: languor, 
 gradually developing sleepiness, tremor, and coma. In other words, sleeping 
 sickness is merely the termination of trypanosoma infection or trypanosomiasis. 
 
 Geographical Distribution. — Trypanosoma gambiense is confined, as 
 regards its geographical distribution, to certain parts of Equatorial Africa. 
 It is found most frequently along the West Coast, in Gambia, Uganda, the 
 Congo basin, Sierra Leone, Liberia, Upper Guinea, the Ivory Coast, and 
 Yatenga. It is also found in South Angola (Wellman), the Upper Niger, 
 Lagos, Togo, the Cameroon (Ziemann), Angola, Portuguese West Africa, 
 French Congo, the Congo Free State, German East Africa (Ahlbory), and in 
 the Nile Valley. The parasite is found along the banks of lakes and rivers, 
 and the extension of commerce and means of travel in Africa has resulted in 
 the introduction of the parasite into many localities where, until quite recently, 
 it was unknown. The rapid extension of sleeping sickness throughout the 
 river valleys of Africa has become of the greatest economical importance, as the 
 disease is invariably fatal and has already caused the death of hundreds of 
 thousands of the natives of the infected regions. It is estimated that in Uganda 
 alone more than 100,000 deaths have occurred from infection with this parasite 
 during the six years from 1901 to 1907. 
 
 Biological Position. — There is no doubt regardng the biological 
 position of Trypanosoma gambiense. In 1843, Grube established the genus 
 Trypanosoma, in which he placed the trypanosome of the frog, and in which all 
 organisms possessing the morphology of a typical trypanosome must be placed. 
 As regards its generic position, therefore, Trypansoma gambiense is a member 
 of the genus Trypanosoma. As regards its relation to the Protozoa, in a 
 wider sense, it belongs to the Mastigophora, sub-class Flagellata, and family 
 Trypanosomatidae. 
 
 General Morphology of Trypanosomes. — It is necessary, in order to 
 understand thoroughly the structure of Trypanosoma gambiense, to consider in 
 detail the morphology of trypanosomes in general and their biological peculiari- 
 ties. Laveran and Mesnil, in their classical work upon the trypanosomes, 
 state that "Several mammalian trypanosomes resemble one another so closely 
 that it is impossible to distinguish them by their morphological characters alone. 
 This applies to the trypanosomes of nagana, surra, dourine, and sleeping 
 sickness." It will thus be seen that a study of the morphology of the trypano- 
 somes, as a class, is of importance in the study of any one species of trypano- 
 some, as in this way only can we interpret many structural phenomena observed 
 
THE BLOOD PROTOZOA OF MAN. 43 1 
 
 in isolated organisms or understand the significance of certain biological pro- 
 cesses which may only rarely be observed in the organism under consideration. 
 
 All typical trypanosomes are spindle-shaped, and possess a nucleus, a 
 centrosome or blepharoplast, and an undulating membrane which ends in a 
 flagellum. Among zoologists there is considerable discussion as to which end 
 of the trypanosome the flagellum arises from, the anterior or posterior. Laveran 
 and Mesnil consider the extremity from which the flagellum arises as the 
 anterior extremity, and this interpretation is accepted by most authorities, but 
 Woodcock, Sambon, Manson, and others, regard the flagellated extremity as 
 posterior. In order to avoid confusion it is better, as suggested by Minchin, 
 to distinguish the two extremities of the body of the trypanosome as the flagellar 
 and anti flagellar extremities, respectively. 
 
 A trypanosome presents for description a body, a nucleus, a blepharo- 
 plast, an undulating membrane, and a flagellum. 
 
 The body is more or less spindle-shaped in all but cultural forms, some 
 of which may be almost spherical. As, however, no one has yet succeeded 
 in cultivating Trypanosoma gambiense, the morphology of cultural forms 
 will not be considered in this summary of the general morphology of the 
 trypanosomes. Considerable variation exists as regards the shape of the 
 organism, even in individuals of the same species, and short, blunt-ended 
 forms occur together with slender, pointed organisms, in the same specimen 
 of blood. The shape of the organism may also differ according to the species 
 of animal which is infected. 
 
 The flagellar extremity of a trypanosome is generally longer and narrower 
 than the antiflagellar extremity, and may be pointed or slightly rounded. 
 A careful examination will demonstrate that in nearly every case it is continued 
 for a little distance along the flagellum, which thus does not start abruptly 
 from the body, but gradually, as a continuation of the undulating membrane 
 and the protoplasm of the body. 
 
 The antiflagellar extremity varies extremely in shape in various species, 
 in individuals of the same species, and in the blood of the same animal. Thus 
 it may be elongated and pointed, short and blunt, or hemispherical in shape, and 
 in Trypanosoma gambiense the variation is often very marked. 
 
 The protoplasm of trypanosomes stains a deep blue when Wright's method 
 is used and is composed apparently of fine granules; arranged in more or less 
 irregular masses. This arrangement of the granules causes an irregular 
 staining of the protoplasm, some areas appearing a deep blue, while others are 
 almost unstained. Chromatic granules are present in some organisms, staining 
 a deep violet, and irregularly distributed in the protoplasm. These granules 
 may be of some service in determining species, but cannot be greatly relied 
 upon for this purpose. The body is not surrounded by a definite membrane, 
 so far as we have been able to determine. The protoplasm surrounds the 
 nucleus and the blepharoplast, and may contain one or more vacuoles, especially 
 in degenerating organisms. 
 
432 THE BLOOD PROTOZOA OF MAN. 
 
 The nucleus, which stains a bright crimson or violet, with Wright's stain, or 
 any modification of the Romanowsky method, is known also as the macronucleus 
 or trophonucleus; it is much larger than the blepharoplast, is round or oval in 
 shape, and situated at or near the center of the body of the organism. In 
 T. lewisi it is situated in the flagellar end, and is of diagnostic importance. 
 The nucleus is composed of chromatin granules arranged compactly (the 
 granules varying in size), and connected by a dimly staining nuclear substance. 
 The nucleus divides amitotically. 
 
 The blepharoplast, also known as the mieronucleus, centrosome, or kincto- 
 nucleus, is very much smaller than the nucleus, and in most species of trypano- 
 somes is situated near the antiflagellar extremity. In trypanosomes undergoing 
 division the blepharoplast may be near the center of the organism, in close 
 relation to the nucleus, and in some species it is always situated in this region. 
 It generally consists of a small, compact mass of chromatin granules, staining 
 a deeper purple or red than the nucleus; spherical in shape; and surrounded by 
 a clear, unstained area, oval in shape, which resembles in appearance a vacuole. 
 It measures from 0.5 to 1 micron in diameter, and generally stains so intensely 
 that the separate granules of chromatin composing it are invisible. As it 
 usually lies near the antiflagellar or narrow extremity of the parasite, it often 
 appears to extend the entire width of the organism, but careful examination 
 will demonstrate that a narrow rim of protoplasm surrounds it, if the vacuole 
 mentioned be absent. The blepharoplast divides by simple fission. 
 
 The undulating membrane is a beautifully curved and delicate membrane 
 extending as a crest or ridge for a variable length along the body of the trypano- 
 some. It varies in length with the situation of the blepharoplast and, as in 
 most of the trypanosomes, this is near the antiflagellar extremity the undu- 
 lating membrane extends along the greater portion of the body. The structure 
 of this membrane appears similar to that of the protoplasm of the body, but its 
 border is thickened owing to the flagellum which forms it, together with the 
 protoplasm of the membrane. This membrane always arises opposite the 
 blepharoplast on the lateral surface of the body, and extends toward the 
 flagellar extremity, forming, in most instances, along with the flagellum, the 
 flagellar extremity of the trypanosome. The number of curves varies with 
 the species of trypanosome and in some species the undulating membrane 
 is thin and almost straight. The presence of striations in the undulating mem- 
 brane of -some trypanosomes has been reported by Prowazek and others, but 
 most mammalian trypanosomes do not present any very definite structure of 
 the membrane. 
 
 The flagellum arises from the blepharoplast, is continued along the border 
 of the undulating membrane, and in most trypanosomes extends for some 
 distance beyond the extremity of the body, or undulating membrane, as a 
 free flagellum. In organisms which show a vacuole lying in contact with the 
 blepharoplast the flagellum appears to arise from the border of this vacuole, 
 but in organisms showing no vacuole the flagellum is observed to arise directly 
 
THE BLOOD PROTOZOA OF MAN. 433 
 
 from the blepharoplast. Laveran and Mesnil divide the flagellum into three 
 portions: the root, that portion extending from the blepharoplast to the 
 commencement of the undulating membrane; the intermediate portion, running 
 along the edge of the undulating membrane; and the free portion, forming the 
 free flagellum of the trypanosome. The thickness of the flagellum varies 
 somewhat, it being thickest along the border of the undulating membrane and 
 thinnest at its origin and its free extremity. With any modification of the 
 Romanowsky stain it takes a dark red or purple color, exactly similar to 
 that of the blepharoplast, thus proving that the flagellum is composed of 
 chromatin. Longitudinal division of the flagellum occurs during multiplica- 
 tion of the parasite in most species of trypanosomes, the blepharoplast first 
 dividing, followed by the division of the flagellum along its entire length. 
 In some species only the blepharoplast divides and the root of the flagellum. 
 
 Morphology of Trypanosoma gambiense. — In fresh blood Trypano- 
 soma gambiense may be easily found with a 1/6 inch objective, appearing 
 as an active, spindle-shaped, colorless body, forcing its way among the corpuscles 
 or moving in a jerky manner across the field of the microscope. Its morphology 
 cannot be satisfactorily studied in fresh specimens, and for this purpose stained 
 preparations, using some modification of the Romanowsky stain, should be 
 employed. 
 
 Trypanosoma gambiense varies considerably in length, measuring from 
 16 to 30 microns long by 1.5 to 2.5 microns wide, the longest forms being 
 those which are undergoing division. The flagellum originates in the blepharo- 
 plast, forms the edge of the undulating membrane, and is continued as a free 
 flagellum which forms from one-quarter to nearly one-half the total length of 
 the organism. In rare instances there is no free flagellum, the protoplasm of 
 the body and of the undulating membrane extending and blending with the 
 flagellum for its entire length. 
 
 The nucleus is oval in shape, comparatively large, and situated near the 
 center of the body or slightly toward the antiflagellar extremity ; it stains deeply 
 with the chromatin stains. 
 
 The blepharoplast is situated at the antiflagellar extremity, stains a deep 
 purple, and is composed apparently of a single large dot of chromatin. An 
 unstained area generally surrounds the blepharoplast but according to Laveran 
 and Mesnil, this appearance is due to faulty technic in preparing the specimen, 
 and it is undoubtedly true that many of the trypanosomes do not present this 
 vacuole. The flagellum, in well stained specimens, is seen to arise from the 
 blepharoplast, being intimately connected with it at its origin. 
 
 The antiflagellar extremity of the trypanosome varies in shape, being 
 narrow and pointed sometimes, and sometimes rounded and broad. It is evi- 
 dent that the organism possesses the power of altering the shape of this ex- 
 tremity, and that many of the appearances presented in stained preparations 
 are caused by agonal movements of the parasite. 
 
 The flagellar extremity is generally pointed, the body being attenuated 
 28 
 
434 THE BLOOD PROTOZOA OF MAN. 
 
 gradually until it becomes blended with the undulating membrane and the 
 flagellum. 
 
 The protoplasm stains a delicate blue and contains chromatic granules, 
 which vary in shape, size, and number in individual organisms. 
 
 The description given applies to the average of parasites observed, but it 
 should be remembered that great variations occur in the morphology of this 
 trypanosome, as observed in stained specimens, some of them due to errors in 
 technic, and others representing stages in the development of the parasite, 
 with which, at present, we are unfamiliar. Thus we often observe long, 
 slender organisms and short, blunt ones in the same specimen; some that stain 
 well and others that stain with difficulty; some in which the nucleus is near the 
 center and others in which it is near the flagellar or antiflagellar extremity; 
 some in which the blepharoplast lies within a vacuole, and others in which the 
 vacuole is absent. Forms also occur without a free flagellum, and others in 
 which the undulating membrane is rudimentary or even absent, while the 
 nucleus and blepharoplast are situated in a nearly spherical body, in close con- 
 tact with one another. In some chromatic granules are absent while in others 
 they are present in great numbers and are of large size. Many trypanosomes 
 are observed undergoing degenerative changes, the protoplasm being filled 
 with vacuoles while the nucleus and blepharoplast either stain very faintly or 
 not at all, the free flagellum also being absent, and the portion forming the 
 border of the undulating membrane staining so faintly as to be almost invisible. 
 In most instances two distinct forms of Trypanosoma gambiense may be 
 distinguished in the blood: one, slender, and having a free flagellum of con- 
 siderable length; the other, short and broad, and having a short free flagellum. 
 According to the researches of Prowazek, Luhe, Zieman and Nocht, it is 
 probable that the long slender forms are males and the short, broad forms 
 females, while the forms which are intermediate are the so-called "indifferent 
 forms" which are not sexual in nature. 
 
 Multiplication. — In the blood of man Trypanosoma gambiense multiplies 
 by binary division, the blepharoplast first dividing into two, followed by the 
 nucleus, the flagellum, and the protoplasm of the body, so that eventually two 
 trypanosomes result. As it has been proven that some trypanosomes undergo 
 a sexual cycle of development in an intermediate host (a blood-sucking inverte- 
 brate in all the species so far investigated), it is probable that Trypanosoma 
 gambiense also has an intermediate host and that sexual multiplication occurs in 
 that host, but at the present time we are ignorant of the changes occurring 
 during such a cycle, although we know that the parasite is transmitted by 
 Glossina palpalis and others species belonging to the same genus. 
 
 It is not necessary to call attention here to the work of Prowazek on the 
 changes occurring in Tr. Icwisi in the stomach of the rat louse {Haematopimis 
 spinulosis) beyond stating that he was able not only to demonstrate various 
 stages of development of this trypanosome in the louse, but also to prove beyond 
 question that this louse is, in fact, the intermediate host of the trypanosome, 
 
THE BLOOD PROTOZOA OF MAN. 
 
 435 
 
 sexual forms being developed in the gut of the louse. However, while the inter- 
 mediate host of Tr. lewisi is undoubtedly the rat louse, we have no conclusive 
 evidence that Glossinapalpalis is the intermediate host of Trypanosoma gambiense. 
 The observations of Koch and Gray and Tulloch appeared for a while to 
 indicate that this trypanosome underwent sexual development in the stomach 
 of Gl. palpalis, but the careful work of Novy upon the trypanosomes of tsetse 
 flies proved beyond question that the trypanosomes studied by the investigators 
 mentioned were peculiar to tsetse flies and had no relation whatever to Trypano- 
 soma gambiense. In a later paper by Minchin, Gray, and Tulloch, these 
 authors say, " We are, therefore, now convinced from the results of these numer- 
 ous experiments that the trypanosomes found in the freshly caught flies have 
 nothing to do with sleeping sickness and are not developmental stages of Tr. 
 gambiense." These authors also found that flies infected with this trypano- 
 some were not infective after 48 hours, and while they describe sexual forms in 
 the fly they are the same that occur in blood films from man. At the present 
 
 a bo 
 
 Fig. 28. — Trypanosoma gambiense. 
 A, Trypanosoma gambiense, after Dutton. B, Trypanosoma gambiense, after Liihe. 
 C, Trypanosoma gambiense, after Liihe. 
 
 time, therefore, there is no evidence that the tsetse-fly is the intermediate host 
 of Trypanosoma gambiense, but that this insect transmits the infection directly, 
 no sexual cycle being necessary before the trypanosome becomes infective. 
 This does not, however, preclude the existence of a true intermediate host for 
 this trypanosome. The observations of Salvin-Moore and Breinl regarding a 
 resistant form of Trypanosoma gambiense which they observed in infected rats, 
 have not as yet been confirmed, but are worthy of further investigation. In 
 rats infected with Trypanosoma gambiense they observed in the lungs, bone- 
 marrow, and spleen, small round bodies, consisting of protoplasm and nucleus, 
 which they claim are derived from the trypanosomes. Under favorable condi- 
 tions typical trypanosomes develop from these bodies and multiply as usual. 
 The resistant forms only develop when the trypanosomes begin to disappear 
 from the peripheral blood of the rats. These observations are very suggestive 
 and may explain the persistence of trypanosome infection after treatment has 
 resulted in causing the disappearance of the parasites from the blood. 
 
436 THE BLOOD PROTOZOA OF MAN. 
 
 Cultivation. — Although Novy and MacNeal have succeeded in cultivating 
 certain trypanosomes upon artificial media, and their work has been confirmed 
 by numerous other investigators, the attempts at cultivation of Trypanosoma 
 gambiense, with the exception of the partial success of Gray and Tullock, have 
 met with failure. Novy and MacNeal have succeeded in cultivating Tr. 
 lewisi, Tr. brucei, and Tr. evansi, as well as other trypanosomes of less im- 
 portance, and it was hoped that by following their methods it would be possible 
 to cultivate the parasite of sleeping sickness, but little success has attended the 
 efforts of these who have endeavored to do so, for while it has been possible 
 to keep the parasite alive upon the artificial media used, multiplication oc- 
 curred in but one experiment, and subcultures could not be obtained. Thomas 
 and Breinl used chicken and veal infusion in their experiments, to which was 
 added 1 to 2 per cent, salt, 2.5 to 3.5 per cent, agar, and 1 to 1.5 per cent, pep- 
 tone. This medium was prepared and added in the proportion of two to one, or 
 three to two, to rabbit's or sheep's blood, the rabbit's blood being preferable. 
 In this medium the trypanosomes lived for from 10 to 40 days, and in one instance 
 living trypanosomes were found after 50 days, but there was no multiplication of 
 the organisms, and sub-cultures could not be obtained. 
 
 The experiments of Gray and Tulloch were more successful in that multi- 
 plication did occur in their tubes, but they also were unable to obtain sub- 
 cultures. They used the media of Novy and MacNeal (agar), adding to it three 
 times the volume of defibrinated blood from the dog. 
 
 In their culture tubes, inoculated from the blood of a white rat, which con- 
 tained many trypanosomes, there were found on the fifteenth day numerous 
 organisms, occurring singly and in groups, many of which were undergoing 
 division. The trypanosomes were longer and broader than those observed in 
 the blood of the rat and of man, and the blepharoplast was placed much closer 
 to the nucleus. After the twentieth day the trypanosomes disappeared from 
 the cultures, which became greatly contaminated by bacteria of various 
 kinds. 
 
 Laveran and Mesnil found that when Trypanosoma gambiense is placed in 
 horse serum or salt solution it remains alive for from five to six days and for 
 some time longer in blood agar. Tubes of rabbit's blood agar inoculated 
 with blood containing this organism showed living trypanosomes for 28 days 
 after inoculation when kept at a temperature of 22 C. They also observed 
 that division occurred upon such culture media and that the trypanosomes 
 were much larger than those observed in the blood of man. They were not 
 able to secure subcultures. 
 
 Biological Phenomena. — Trypanosoma gambiense, like all other organisms 
 of this class, shows no nutritive vacuoles, and therefore must nourish itself by 
 a process of osmosis. They do not feed upon the red blood-corpuscles nor 
 enter them, but haemoglobin appears to be essential to their growth upon 
 culture media, as proven by Novy and MacNeal's experiments. 
 
 They possess active motility, which varies in rapidity under certain 
 
THE BLOOD PROTOZOA OF MAN. 437 
 
 conditions. Cold evidently decreases motility very decidedly, and exposure 
 of the blood containing them to the air also lessens activity. The motility is 
 chiefly due to the undulating membrane and the flagellum, but the protoplasm 
 possesses contractility, which causes marked contraction of the body as well 
 as a form of amoeboid motion. The organism progresses either with the 
 flagellum forward or backward, but generally with the flagellum forward. 
 The flagellum possesses a lashing movement which is easily made out in the 
 more sluggish organisms, while the movement of the undulating membrane 
 consists in undulations in various directions. In the blood of man the trypano- 
 some often moves so rapidly that it is impossible to detect either the movement 
 of the flagellum or the undulating membrane. 
 
 Pathogenicity of Trypanosoma gambiense. — This trypanosome is 
 pathogenic for a large number of animals besides man. Its pathogenicity 
 varies considerably, due, as in all pathogenic trypanosomes, to conditions which 
 have not yet been thoroughly demonstrated. Its virulence depends upon the 
 race and species of animals inoculated, upon the orgin of the trypanosoma 
 inoculated, and upon successive passage through certain species of animals. 
 
 In monkeys, of which the Macacus and Cercopithecus are most susceptible, 
 the inoculation of blood containing Trypanosoma gambiense is followed some- 
 times by slight fever and the symptoms of a typical attack of sleeping sickness, 
 but more often the only symptoms noted are emaciation, anaemia, lowering of 
 the temperature, and a tendency to slumber. The trypanosomes may be 
 demonstrated in the blood and in the cerebrospinal fluid in those cases which 
 present marked cerebral symptoms. It is very probable that infection with 
 this trypanosome in the monkey is always fatal. The higher apes appear to 
 be more resistant to infection than the lower, but typical trypanosomiasis 
 has been produced in baboons by Thomas and Linton, Gray and Tulloch, and 
 Thomas and Breinl. Bruce, Nabarro, and Greig have observed typical lethargy 
 in the monkey weeks before death occurred. The period of incubation in 
 monkeys varies from 9 to 40 days, the average being 18 days. The duration 
 of the disease was usually seven months, but the animals may live over a year 
 after infection. 
 
 In dogs this organism, when inoculated, produces a chronic infection 
 varying in duration from two to nine months, as a rule. The period of incuba- 
 tion and the duration of the disease in the dog is very variously given by dif- 
 ferent investigators, thus proving that they worked with trypanosomes varying 
 greatly in virulence. The Uganda Commission found the incubation period 
 to be from two to five weeks in dogs, while Brump and Wurtz give the incuba- 
 tion period as 17 days; these authors state that the duration of the disease is 
 36 days, while Thomas and Linton give the duration as from three weeks to 
 nine months. 
 
 The symptoms are emaciation, anaemia, and a subnormal temperature 
 before death, although during the infection the temperature may be higher 
 than normal at intervals. The trypanosomes may be found in the blood in 
 
438 THE BLOOD PROTOZOA OF MAN. 
 
 small numbers. Gray and Tulloch found that around Lake Albert the dogs 
 were naturally infected with Trypanosoma gambiense. 
 
 This trypanosome is also infective to the jackal (Nabarro), cats, rabbits, 
 guinea-pigs, white rats, mice, jerboas (Laveran), marmots, goats, sheep, and 
 horses. Cattle are very resistant, but may be infected. In all of these animals 
 the infection runs a chronic course, and does not result fatally in the larger 
 mammals, as the sheep, horses, and cattle. In goats the infection may be a very 
 fatal one, as shown by the experiments of Thomas and Breinl. 
 
 Methods of Transmission. — It has been determined that Trypanosoma 
 gambiense is transmitted to man through the agency of biting flies belonging 
 to the genus Glassina. To Bruce and Nabarro we owe the first demonstra- 
 tion that Glossina palpalis is the chief agent in the transmission of the trypano- 
 some of sleeping sickness, for in August, 1903, these investigators reported a 
 successful infection of a Cercopithccus monkey by the bites of numerous flies 
 of this genus. A later report gives the results these authors obtained, in 
 conjunction with Greig (1903, November), in the experimental infection of 
 monkeys by the bites of infected Glosinna palpalis. These flies were allowed 
 to suck the blood of infected negroes and were then placed upon the monkeys, 
 and after an incubation period of about two months the trypanosomes were 
 demonstrated in the blood of the animals. They also proved that the flies were 
 able to infect monkeys 24 to 48 hours after biting the infected negro, but, as 
 has been stated, no developmental stages of the trypanosomes, indicating a 
 sexual cycle, have been found in the stomachs of the flies. The discovery of 
 the etiological relationship of this fly to sleeping sickness at once explained the 
 occurrence of the disease only in certain localities, for further investigation has 
 shown that sleeping sickness is found only where flies belonging to the genus 
 Glossina abound. 
 
 The discovery by Wellman, of a new species of Glossina, Gl. palpalis well- 
 mani Austen, in South Angola, and by Massey, in the Upper Congo, where 
 sleeping sickness occurs, indicates that this fly, as well as palpalis, is capable of 
 transmitting the trypanosome, and Nabarro and Greig have apparently proven 
 that Gl. pallidipes, Gl.fusca, and Gl. longipennis are able to convey Trypanosoma 
 gambiense from sick to healthy animals. 
 
 So far as we know, the infection is carried from the sick to the well by the 
 proboscis of the fly, as no evidence exists that the trypanosomes undergo any 
 development within the insect, and the fly is not infective after 48 hours. As 
 so many of the lower animals are susceptible to infection with this trypanosome, 
 which produces in most of them a chronic disease in which the organisms are 
 present in the blood for weeks or months, it is easy to understand how the 
 disease is maintained in localities where it is endemic, and how difficult it 
 has proven to rid a locality of the infection. 
 
 Distribution in Man. — In man Trypanosoma gambiense is found in the 
 blood, in the lymphatic glands, the cerebrospinal fluid, and in the various 
 organs, within the capillaries. The organism occurs in small numbers in the 
 
THE BLOOD PROTOZOA OF MAN. 439 
 
 blood, in larger numbers within the lymph glands, and in large numbers in the 
 cerebrospinal fluid in well-marked cases of sleeping sickness, after the develop- 
 ment of cerebral and spinal symptoms. In sections of the organs of patients 
 dying from this disease the trypanosomes are seldom found, but they have been 
 demonstrated in the spleen, the liver, the bone-marrow, and the lungs. 
 The pathological changes produced by infection with this parasite comprise 
 hypertrophy of the lymphatic glands, lesions in the meninges resembling those 
 of cerebrospinal meningitis, chronic inflammatory lesions of the lymphatics of 
 the central nervous system, and degeneration of the spinal cord. The pathogno- 
 monic lesion, according to Mott, to whom we owe our most exact knowledge of 
 the pathology of sleeping sickness, consists in "the universal perivascular cell- 
 infiltration of the central nervous system." He also states that the changes 
 observed in the nervous system are almost identical with those observed in 
 syphilis with the exception that in this disease the proliferative endarteritis 
 leading to thrombosis is absent, whereas it is common in syphilis. 
 
 Demonstration of Trypanosoma Gambiense. — The diagnosis of sleep- 
 ing sickness can be made by an examination of the blood, the cerebrospinal 
 fluid, and juice from the enlarged lymphatic glands. In all of these fluids the 
 trypanosomes occur, but they are said to be most easily demonstrated in the 
 juice obtained from the enlarged lymphatic glands of the cervical region. For 
 staining the modification of Wright's method which I use in staining malarial 
 blood is most useful, but any of the modifications of the Romanowsky stain, 
 such as Leishman's, Jenner's, or the Giemsa stain, may be used. 
 
 Examination of the Blood. — The blood may be examined either fresh or 
 stained. As the trypanosomes occur but in small numbers in the blood it 
 is better to make several smears for staining, as in this way more time can be 
 given to the examination, and a greater number of specimens examined at 
 leisure. It is generally better to use some method of centrifuging the blood as 
 the parasites are so few in number that many smears prepared in the ordinary 
 way will have to be examined before a trypanosome is encountered. 
 
 The method of examination recommended by Bruce and Nabarro is an 
 excellent one and is as follows: About 10 c.c. of blood is removed from a vein 
 and placed in a centrifuge tube containing a small amount of sodium citrate 
 solution and centrifuged for 10 minutes. The supernatant serum, the leucocyte 
 layer, and the upper portion of the red layer is pipetted off and again centrifuged 
 for ten minutes, after which the upper layer is pipetted off and centrifuged for 
 the same time. A small drop of the supernatant liquid so obtained is placed 
 upon a slide and examined as a fresh preparation, and if the trypanosomes are 
 not present in this a portion of the sediment should be examined, in which they 
 will surely be found if the case is one of sleeping sickness. An examination 
 should be made of each specimen before it is recentrifuged as the trypanosomes 
 may be found after once centrifuging only. Smears may be prepared from the 
 sediment and stained. 
 
 Examination of the Cerebrospinal Fluid. — In order to obtain the 
 
44° THE BLOOD PROTOZOA OF MAN. 
 
 cerebrospinal fluid for examination it is necessary to perform lumbar puncture. 
 The following method of performing this operation is that recommended by 
 Tuffier (L'Analgesie chirurgicale par voie rachidienne, Paris, 1901) as given in 
 Laveran and Mesnil's classical work upon "Trypanosomes and Trypano- 
 somiases," translated by Nabarro. 
 
 "Use a platinum-iridium needle (which can be sterilized easily) 8 centi- 
 meters (about 31/2 inches) long, fitted to'a hypodermic syringe. The external 
 diameter of the needle should be 1 millimeter, and the internal diameter o.O 
 millimeter; the point should be bevelled off very little. It is unnecessary to use 
 a general anaesthetic. The patient should sit up with the arms held in front. 
 The lumbar region is thoroughly washed and rendered aseptic. The iliac crests 
 are used as a guide, the transverse line joining their highest points crossing the 
 spine at the level of the fourth lumbar vertebra (spinous process). 
 
 " The left index finger being placed on this spinous process, the patient is told to 
 bend the head well forward. This serves to separate the laminae of the vertebrae 
 between which the needle has to pass. At the moment of inserting the needle 
 the patient must be warned that he is going to be pricked, and that he must 
 remain perfectly still and on no account straighten the back by sitting uprigh.1 . 
 The needle of the syringe, properly sterilized, is introduced at a point 1 centi-. 
 meter (about 1 / 2 an inch) from the middle line close up against the edge of the 
 index finger, which is kept on the spinous process. The point of the needle is 
 directed slightly toward the middle line and upward, and when it enters the 
 subdural space it is distinctly felt that there is no longer any resistance. A 
 clear liquid immediately wells up into the needle and can be collected in a tube, 
 or a syringe can be fitted to the needle." 
 
 Nabarro recommends slight aspiration if the needle becomes clogged and 
 states than in sleeping sickness the cerebrospinal fluid, on account of the 
 increased pressure in the spinal canal, often spurts out of the needle in a steady 
 stream and as much as 50 c.c. may be collected at one time. The administra- 
 tion of a general anaesthetic should, in most cases, be insisted upon, as the 
 operation is much easier when the anaesthetic is given, and both Nabarro and 
 Christy recommend chloroform. 
 
 In the cerebrospinal fluid the trypanosomes are generally few in number 
 and it is necessary to centrifuge the fluid for ten minutes and the sediment 
 should be examined fresh or stained preparations made, using one of the 
 chromatin stains. Nabarro states that in a few instances the trypanosomes 
 were so numerous that they were detected in the fluid before it was centrifuged, 
 but he also states that in other cases it was necessary to perform lumbar puncture 
 as many as four times before the parasite was discovered. It is probable that the 
 trypanosome is always present in the cerebrospinal fluid in every case of sleep- 
 ing sickness, but repeated examinations may have to be made in order to demon- 
 strate it. A certain periodicity appears to be present as regards the occurrence 
 of the trypanosomes in the cerebrospinal fluid, and they are never found there 
 in the earlier stages of trypanosomiasis, only appearing when the symptoms 
 characteristic of sleeping sickness appear. 
 
 In stained smears made from the cerebrospinal fluid the trypanosomes do 
 
THE BLOOD PROTOZOA OF MAN. 44 1 
 
 not appear well stained, and for this reason it is not advisable to stain such 
 organisms, but to examine them in the fresh fluid. 
 
 Examination of the Gland Juice. — The discovery by Greig and Gray 
 that the juice of the lymphatic glands in human trypanosomiasis contained the 
 trypanosomes in comparatively large numbers has proven of the greatest 
 service in diagnosis. These investigators, following a suggestion made by 
 Mott, examined the contents of the lymphatic glands in 15 cases of sleeping 
 sickness and found the trypanosomes in all of them, and that the organisms 
 were much more numerous than in either the blood or the cerebrospinal fluid. 
 They also found the organisms in the lymphatic glands of patients suffering 
 from trypanosomiasis in whom the symptoms of sleeping sickness had not 
 appeared. At first they excised the glands, but later found that this was not 
 necessary, one of the enlarged glands being punctured with the needle of a 
 hypodermic syringe and some of the juice of the gland aspirated into the 
 syringe, placed upon microscopic slides and examined at once or stained. The 
 cervical glands were fcund to cor. tain the orgarisms in greatest numbers, but 
 they were also demonstrated in the enlarged femcral and inguinal glands. 
 
 Nabarro gives the following directions regarding the technic of gland 
 puncture: 
 
 "Gland puncture is quite a simple operation, but it is necessary to attend 
 to a few details of technic. The syringe must be boiled before use, then washed 
 with a 'sterile salt solution, every trace of which should be got rid of before using 
 the syringe. After obtaining the drop of gland juice, the piston should be 
 allowed to return almost as far as it will, and then fixed with the finger, other- 
 wise much of the fluid aspirated would be lost in the body of the syringe. The 
 drop of fluid in the syringe must be pushed out by one sharp push of the piston 
 rather than by two or three movements, so as to avoid getting air bubbles in the 
 preparation. The drop is quickly covered with a cover-glass (care being taken 
 to avoid the minute piece of skin punched out by the needle) ringed with vase- 
 line, and examined at once (Todd)." 
 
 The observations of Greig and Gray have been confirmed by Dutton and 
 Todd, as well as many other investigators, and it is generally acknowledged 
 to-day that gland puncture is the best method of demonstrating Trypanosoma 
 gambiense in early cases of trypanosomiasis and also in those cases in which 
 the symptoms of sleeping sickness have already developed. It is especially in 
 the early cases of infection that this method is valuable, as in such patients the 
 trypanosomes are very scanty in the blood and absent from the cerebrospinal 
 fluid, but are often numerous in the gland juice. The posterior cervical glands 
 have given the best results, according to Nabarro (95 per cent.), the axillary, 
 the femoral, and the epitrochlear following in order. The trypanosomes 
 obtained in glandular juice stain better than those from the cerebrospinal 
 fluid, but not as well, in most instances, as those obtained from the blood. The 
 trypanosomes have also been found in pleural, peritoneal, and pericardial 
 exudates and in hydrocele fluid. 
 
442 THE BLOOD PROTOZOA OF MAN. 
 
 Staining. — For diagnostic purposes staining is not necessary if gland 
 juice or cerebrospinal fluid is to he examined, as the trypanosomes are easily 
 recognized by their active, wriggling movements and their peculiar spindle 
 shape. Examination of these fluids should be made with a i , 6 inch objective 
 and several specimens should be examined before a negative result is recorded. 
 The cerebrospinal fluid should be centrifuged if an examination of the uncentri- 
 fuged fluid is negative. In staining with Wright's or Leishman's stain the stain 
 should first be allowed to fix the preparation of blood or other substance for 
 five minutes, the water then added, and the stain allowed to act for from ten 
 to twenty minutes longer, the time being judged by the staining reactions as 
 observed after experimentation with several specimens. In well stained prepara- 
 tions the protoplasm of Trypanosoma gambiense should be colored a well- 
 marked blue, the nucleus a crimson or dark red, the blepharoplast a darker 
 red or brilliant violet, and the flagellum, from its origin at the blepharoplast, 
 along the edge of the undulating membrane and throughout its free portion 
 a dark red or violet, the undulating membrane being blue in color. Good 
 specimens can be secured only after a certain amount of experimentation, and 
 the beginner should not be discouraged if the first few specimens stained by 
 him do not show perfectly the morphology of the trypanosome. 
 
 Other Mammalian Trypanosomes. — For convenience in reference the 
 following list of the trypanosomes of most interest which infect mammals is 
 appended. 
 
 Trypanosoma lewisi. Kent. 1879. A parasite of rats, generally non- 
 pathogenic, but sometimes pathogenic. Discovered by Chaussat in 1850. 
 
 Trypanosoma evansi. Steel. 1885. A parasite of horses, mules, 
 elephants, camels, carabao (the Philippines) buffaloes and dogs. Produces in 
 horses and mules the disease known as "surra." Discovered by Evans in 1880. 
 
 Trypanosoma briicei. Plimmer and Bradford. 1899. A parasite of 
 horses and most of the game animals of Africa. Causes the disease known as 
 "nagana" in horses. Transmitted by the Glossing. Discovered by Bruce in 
 1895. 
 
 Trypanosoma equiperdum. Doflein. 1901. A parasite of horses and 
 donkeys, transmitted by coitus. It causes in these animals the disease known as 
 dourine, or " malady du coit." Discovered by Rouget in 1894. 
 
 Trypanosoma equinum. Voges. 1901. A parasite of horses, causing the 
 disease known as "mal de caderas." Discovered by Elmassian, in 1901. 
 
 Trypanosoma theileri. Laveran. Bruce. 1902. A parasite of cattle. 
 Produces in these animals the disease known as galziekte (gall sickness). 
 Discovered by Theiler in the Transvaal. 
 
 Trypanosoma dimorphon. Dutton and Todd. 1904. A parasite of 
 the horse and probably of sheep, cattle, antelopes, dogs, and pigs. Causes in 
 horses the disease known as Gambian horse disease. Discovered by Dutton 
 and Todd in 1902. 
 
THE BLOOD PROTOZOA OF MAN. 443 
 
 Literature upon Human Trypanosomiasis. 
 
 1803. Winterbottom. An Account of Native Africans in the Neighborhood 
 
 of Sierra Leone. London. 
 1899. Mott, W. F. The Changes in the Central Nervous System of Two Cases 
 
 of Negro Lethargy. Brit. Med. Jour., December 16. 
 1902. Dutton, J. E. Preliminary Note upon a Trypanosome Occurring in the 
 
 Blood of Man. Thomp. -Yates. Lab. Rep., vol. iv, p. 453. 
 1902. Warrington, W. B. A Note on the Condition of the Central Nervous 
 
 System in a Case of African Lethargy. Brit. Med. Jour., Sept. 27, p. 929. 
 
 1902. Forde, R. M. Some Clinical Notes on a European Patient in whose 
 Blood a Trypanosoma was Observed. Jour. Trop. Med., Sept. 1, 261. 
 
 1903. Castellani, A. Presence of Trypanosoma in Sleeping Sickness. Rep. 
 Sleeping Sickness Commis., Roy. Soc, No. 1, p. 3. 
 
 1903. Idem. Researches in the Etiology of Sleeping Sickness. Jour, of Tropical 
 
 Medicine, June 1, p. 167. 
 1903. Idem. Adult Forms and Developmental Forms of the Trypanosome 
 
 Found in Sleeping Sickness. Rep. Sleeping Sickness Commis., Roy. 
 
 Soc, No. 2, p. 9. 
 1903. Idem. Some Observations on the Morphology of the Trypanosoma 
 
 Found in Sleeping Sickness. Brit. Med. Jour., vol. ii, No. 20, p. 2216. 
 1903. Bruce and Nabarro. Reports of the Sleeping Sickness Commission, 
 
 Royal Society, No. 1, p. 11. 
 1903. Idem. Further Report on Sleeping Sickness in Uganda. Ibid., No. 4. 
 1903. Christy, C. The Epidemiology and Etiology of Sleeping Sickness in 
 
 Equatorial Africa. Rep. Ibid., No. 3. 
 1903. Boyce, Ross, and Sherrington. The History of the Discovery of 
 
 Trypanosomiasis in Man. Lancet, vol. ii, p. 21. 
 1903. Manson, Sir P. Trypanosomiasis on the Congo. Jour. Trop. Med., 
 
 March 16, p. 85. 
 1903. Rabinowitsch and Kempner. Die Trypanosomen in der Menschen- und 
 
 Tierpathologie, etc. Centralbl. f. Bakt. Orig., Bd. xxxiv, No. 8, p. 804; 
 
 Jour. Trop. Med., Dec. 15, p. 389. 
 1903. Sambon. Sleeping Sickness in the Light of Recent Knowledge. Jour. 
 
 Trop. Med., July 1, p. 201, vol. vi, No. 13. 
 1903. Dutton and Todd. Researches on Trypanosomiasis in West Africa. 
 
 Brit. Med. Jour., vol. ii, Sept. 19, p. 650. 
 
 1903. Novy and McNeal. The Cultivation of Trypanosoma Brucei. Jour, 
 of Am. Med. Assoc, Nov. 21, p. 1266. 
 
 1904. Blanchard, R. Arch, de Parisitologie, vol. ix, No. 4, p. 573. 
 
 1904. Dutton, Todd, and Christy. Reports of the Trypanosomiasis Expe- 
 dition to the Congo. 1 903-1 904. Liverpool School of Tropical Med., 
 Mem. xii. 
 
 1904. Chatterjee, G. C. Notes on a Few Cases of Trypanosomiasis in Man. 
 Lancet, vol. xii, No. 3. 
 
 1904. Christy, C. Sleeping Sickness (Trypanosomiasis). Brit. Med. Jour., 
 vol. ii, p. 26. 
 
 1904. Greig and Gray. Note on the Lymphatic Glands in Sleeping Sickness. 
 Lancet, 4, vi. 
 
 1904. Low and Mott. Examination of Tissues in Case of Sleeping Sickness 
 in a European. Brit. Med. Jour., 30, iv. 
 
 1904. Sambon, L. W. The Elucidation of Sleeping Sickness. Jour. Trop. 
 Med., vol. vii, No. 4, p. 61. 
 
444 TII E BLOOD PROTOZOA OF MAX. 
 
 igo4. SAMBON, L. W. The Transmission of Sleeping Sickness by Flies of the 
 
 genus Glossina. Brit. Med. Jour., vol. i. No. 2255, p. 696. 
 1004. Thomas and Linton. Lancet, May 14, p. 1337. 
 
 1004. Nabarro. Epidemiological Society. Lancet, Jan. 23. 
 1U04. Laveran, C. R. Acad. Sciences, Apr. 5. 
 
 1Q04. Brumpt and Wtjrtz. Soc. de Biol., March 26, p. 567. 
 
 [904. Christy, C. One Hundred and Four Lumbar Punctures. Thompson- 
 
 Yates and Johnson Lab. Reports, vol. vi, p. 57. 
 11105. Gray and Tullocii. The Multiplication of T. gambiense in the Alimen- 
 tary Canal of Glossina Palpalis. Rep. Sleeping Sickness Commis. Roy. 
 
 Soc, No. 6, p. 2S2. 
 [905. Greig and Gray. Continuation Report on Sleeping Sickness in Uganda. 
 
 Rep. Sleeping Sickness Commis. Roy. Soc, No. 6, p. 1. 
 [905. Plimmer. Proc. Roy. Soc, vol. v, No. 74, p. 388. 
 190$. Thomas and Breinl. Thompson- Yates and Johnson, Lab. Reports, 
 
 vol. vi, part ii, p. 93. 
 [905. Mott, F. W. Observations on the Brains of Men and Animals infected 
 
 with Various Forms of Trypanosomes. Proc. Roy. Soc, Ser. B, vol. 
 
 lxxvi, p. 235. 
 
 1905. Breinl, A. Thompson-Yates Lab. Reports, vol. vi, part ii, p. 66. 
 
 1005. Dutton and Todd. Thompson-Yates and Johnson Lab. Reports, vol. 
 vi, part ii, p. 97. 
 
 1906. Laveran, C. R. Acad. Sciences, vol. cxlii, p. 10O5. 
 
 1906. Wellman. Trypanosomiasis in Angola. Jour. Hygiene, vol. v, No. 6, 
 
 p. 237. (" Notes from Angola. ") 
 1906. Mott, F. W. Pathology of Trypanosomiasis. Rep. Sleeping Sickness 
 
 Commis. Roy. Soc, No. 7. 
 
 1906. Mole. The Lesions in the Lymphatic Glands in Human Trypanosomi- 
 asis. Liverpool School Tropical Med. Memoirs, 21, p. 69. 
 
 1907. Gray and Tulloch. Rep. Sleeping Sickness Commis. Roy. Soc, No. 
 
 8, P- 133- 
 
 1007. Minchin, Gray, and Tulloch. Glossina Palpalis in its Relation to 
 
 Trypanosoma gambiense and other Trypanosomes. Jour. Roy. Army 
 
 Med. Corps, p. 568. 
 1907. Manson, Sir P. Tropical Diseases. London, p. 150. 
 1907. Bruce, D. Trypanosomiasis. Osier's "Modern Medicine," vol. i, 
 
 p. 460, Philadelphia. 
 1907. Stephens, J. W. W. Trypanosomiasis. System of Medicine by Allbutt 
 
 and Rolleston, vol. ii, part ii, p. 207, London. 
 
 1906. Now, F. G. The Trypanosomes of Tsetse Flies. Jour. Infec. Dis., 
 vol. iii, No. 3, p. 394. 
 
 1907. Idem. Trypanosomes. Jour. Am. Med.. Assoc, vol. xlviii, Jan. 5-12. 
 
 1907. Laveran .Mesnil, and Nabarro. Trypanosomes and Trypanosomiasis. 
 London and Chicago. 
 
 1908. Stephens and Christophers. Practical Study of Malaria and Other 
 Blood Parasites, p. 313, London. 
 
 1908. Rogers, Leonard. Fevers in the Tropics, London, p. 90. 
 
 1908. Ward, H. B. "Protozoa" in Ref. Handbook Med. Sciences. Revised 
 Appendix, p. 643, New York. 
 
 1908. Martin and Leboeuf. The Microscopical Diagnosis of Human Trypano- 
 somiasis. Bull. Soc. Path, exot., t. i, p. 126. 
 
 1908. Idem. Glandular Enlargement in Sleeping Sickness, Ibid., p. 221. 
 
CHAPTER III. 
 
 The Spirochaetes; 1 Spirochaeta Recurrentis; Spirochaeta Duttoni; Spirochaeta 
 Carteri; Spirochaeta Novyi (Spiroschaudinnia). 
 
 The spirochaetae are parasites of the blood causing a group of relapsing 
 fevers endemic in certain localities. It was supposed for a long time that only 
 one spirochaeta, Spirochaeta recurrentis {Spirillum obermeieri) caused relapsing 
 fever, but the recent investigations of Novy and Knapp, Breinl and Todd, 
 Dutton, Prowazek, Carter, and others have definitely proven that there are at 
 least four species, each causing a peculiar form of relapsing fever, and each 
 apparently limited in geographical distribution. 
 
 Historical. — Relapsing fever has been known since the time of Hippocrates 
 but nothing was known of its etiological factor until Obermeier, in 1873, 
 described an organism occurring in the blood of patients suffering from the 
 disease, to which Cohn gave the name Spirillum obermeieri, but which had been 
 previously named Spirochaeta recurrentis by Lebert in 1874. Obermeier and 
 others proved that this organism produced the symptoms of relapsing fever in 
 animals, and observation has since demonstrated that the organism is invariably 
 present in the blood of cases of relapsing fever occurring in certain parts of 
 Europe, notably Russia and the Balkans. The occurrence of relapsing fever 
 in India, Africa, and in America, associated with similar organisms, led to 
 the belief that all cases of relapsing fever were due to this spirochaeta, but 
 Manson, Sambon, and Koch, in 1904 and 1905, suggested that on account 
 of geographical distribution, and clinical differences, there might be a group of 
 relapsing fevers due to specific organisms, and to Novy and Knapp we owe 
 the first definite demonstration that distinct morphological differences existed 
 between the spirochaetae. In a paper published in 1906 these authors, as the 
 result of their study of spirochaetae from Europe and Africa, concluded that 
 the spirochaeta of relapsing or tick fever of Africa is a distinct species, and 
 named it Spirillum duttoni, while they also state that the organism found in the 
 blood of relapsing fever in India is probably a distinct species. As will be seen 
 later, Novy and Knapp regarded all spirochaetae occurring in relapsing fever 
 in man as bacteria, belonging to the spirilli. The observations regarding the 
 African spirochaeta were soon confirmed and it is now generally admitted that 
 it is a distinct species. The investigations of Norris, Flournoy, Pappenheimer, 
 
 1 I have included these organisms among the blood protozoa provisionally, 
 as their exact biological position has not yet been definitely settled and because 
 they are blood parasites. Until it is proven that they are bacterial in nature 
 I believe that they should be regarded as belonging to the Protozoa. 
 
 445 
 
446 THE BLOOD PROTOZOA OF MAN. 
 
 and Novy and Knapp upon a spirochaeta found in the blood of relapsing fever 
 cases occurring in the United States resulted in showing that this organism was 
 probably a distinct species, and Uhlenhuth and Haendel proved by means of 
 agglutination reactions that the American spirochaeta is different from others, 
 and this organism is now known as Spirochaeta novyi. Further investigations 
 of the spirochaeta of Indian relapsing fever confirmed the belief of Novy and 
 Knapp that this also was a distinct species, and to it Mackie has given the 
 name "Spirochaeta carteri." As the result of these various studies of the 
 spirochaetae occurring in relapsing fever, we recognize at the present time the 
 four following species: 
 
 Spirochaeta rccurroitis. Lebert. 1874. Causing European relapsing 
 fever. 
 
 Spirochaeta duttoni. Now and Knapp. 1906. Causing African relapsing 
 fever. 
 
 Spirochaeta novyi. Schellach. 1907. Causing American relapsing fever. 
 
 Spirochaeta carteri. Mackie. 190S. Causing Indian relapsing fever. 
 
 Geographical Distribution. — The geographical distribution of the spiro- 
 chaetae is apparently limited as regards the different species, each species being 
 peculiar to the country in which it is found. The relapsing fever of Africa, 
 better known as "tick fever" is caused by Spirochaeta duttoni, and the geo- 
 graphical distribution of this organism is confined to the continent of Africa; 
 the same is true of the other species, Spirochaeta recurrentis being peculiar to 
 Europe, Spirochaeta novyi to America, and Spirochaeta carteri to Asia. 
 
 Biological Position. — The biological position of these organisms has 
 not been definitely determined, scientists being divided into two schools regard- 
 ing this question, one believing that they are protozoa, the other that they are 
 bacteria. It is actually impossible to state at the present writing which school 
 has the better of the argument, but the occurrence of longitudinal division, 
 which I believe has been demonstrated beyond question in these parasites, 
 would appear to prove their protozoal nature. It must be admitted, however, 
 that the evidence regarding their bacterial nature is very strong and that further 
 research may demonstrate that, in reality, they possess features common to 
 both the protozoa and the bacteria, forming, as it were, a connecting link 
 between animal and vegetable organisms. 
 
 For those who believe in the bacterial nature of these organisms they 
 must be regarded as spirilli, while for those who believe in their 'protozoan 
 origin they are placed in the genus "Spirochaetae." Recently some zoologists, 
 as Sambon and Ward, have created a new genus to include the parasites of the 
 relapsing fevers, the Spiroschaudinniae, but this classification has not been 
 generally adopted. 
 
 Until the publication of Schaudinn's paper upon Spirochaeta ziemanni, 
 the cause of relapsing fever, commonly known as Spirillum obermeieri, was 
 regarded as a bacterium, but his statement that in all probability all spirochaetes 
 would be found to be developmental stages of trypanosomes (which has proven 
 
THE BLOOD PROTOZOA OF MAN. 447 
 
 not to be the case) and the demonstration of chromatin and an undulating 
 membrane in some of the spirochaetae, caused investigators to study anew the 
 organisms concerned in the etiology of relapsing fever, with the result that their 
 bacterial nature was disputed. The type species of the spirochaetae, Spiro- 
 chaeta plicatilis, possesses a distinct undulating membrane and is devoid of 
 a flagellum, but many other members of the genus differ considerably in 
 morphology from this typical spirochaeta. The organisms concerned in the 
 etiology of relapsing fevers differ so markedly from a typical spirochaeta, as 
 described by Schaudinn, that I believe that they should be taken from that 
 genus and placed in a new one, that already adopted by Ward (Spiro- 
 schaudinnia) being available. 
 
 Novy and Knapp, who are ardent advocates of the bacterial nature of the 
 spirochaetes of relapsing fevers, believe that the following evidence is sufficient 
 to prove that they belong to the bacteria: transverse division; multiple flagella; 
 absence of a nucleus, undulating membrane and blepharoplast; resistance to 
 plasmolytic changes and to heat; and, finally, that active immunity is easily 
 obtained, which is not true of protozoal infections. 
 
 The evidence that these organisms are protozoal in nature, as believed 
 by Schaudinn, Prowazek, and other zoologists, consists in the occurrence of 
 longitudinal as well as transverse division; the presence of chromatin; the fact 
 that many organisms are twice as thick as others, these being the forms which 
 undergo longitudinal division; the method of natural transmission by an insect, 
 and through the egg of an insect; the reaction of the organisms to solutions of 
 sodium chloride and to solutions of saponin and the bile salts, and the demonstra- 
 tion of a minute mass of chromatin projecting from some portion of the organism. 
 It is evident that further research is needed before a definite conclusion can be 
 reached regarding the exact biological position of these parasites, but until this 
 is possible I believe that it is wise to regard them as belonging to the Protozoa. 
 
 Morphology of the Spirochaetae of the Relapsing Fevers. — In 
 describing the morphology of the spirochaetae causing the relapsing fevers of 
 man I shall describe each separately, concluding with a discussion of the 
 differential features of the various species. 
 
 Spirochaeta Recurrentis (Spirillum Obermeieri). — This parasite varies 
 in length from 19// to 29/i and in breadth from 0.3/z to 0.5 //, the number of 
 curves varying from four to eighteen, the organism being typically spiral in 
 shape, the curves marked and regular. The ends are pointed and, according 
 to Koch and Karlinsky, one or more flagella are present at each end, while 
 Manson states that the flagellum is present at only one of the extremities. 
 The observation of Fraenkel that the organism possesses numerous peritrichous 
 flagella is disputed by Prowazek and Schellach, who insist that the flagella seen 
 by Fraenkel were artefacts produced by the method of staining employed. 
 In specimens stained by any modification of the Romanowsky stain but little 
 structure can be distinguished, but in rare instances an irregular staining is 
 noticed, the body of the parasite containing minute, irregularly distributed 
 
448 THE BLOOD PROTOZOA OF MAN. 
 
 masses of substance taking the chromatin stain. An undulating membrane has 
 been described by Schaudinn and Leishman, but their observations concerning 
 this have not been confirmed. With Giesma's stain the organism presents 
 numerous deeply stained granules throughout its entire length, with the ex- 
 ception of the ilagellum. Both transverse and longitudinal division occurs, 
 transverse division being the most frequent method of reproduction, but the 
 occurrence of Y-shaped organisms, which can only be regarded as forms under- 
 going longitudinal division, prove that this method of reproduction, typical of 
 the Protozoa, occurs in this parasite. The presence of a terminal flagellum at 
 one extremity of the organism is evident in well-stained specimens. 
 
 In fresh specimens of blood this organism is very actively motile, passing 
 across the microscopic field so rapidly as to be hardly distinguishable, and this 
 rapid motility may be retained for days and even weeks after the blood has been 
 removed from the body, but sooner or later, the motion becomes more sluggish 
 and it is possible to study its characteristics. The active motion is due to cork- 
 screw-like movements of the parasite which enable it to progress rapidly, but as 
 the organisms become less motile this form of motion is succeeded by undula- 
 tory movements of the body, the resulting motion being slowly progressive. In 
 organisms which have been kept outside of the body for weeks, progressive 
 motion is lost, being succeeded by a swaying motion from side to side and 
 slight twitching movements of the body. Careful observation will demonstrate 
 that the extremities of the body possess the power of bending to almost an acute 
 angle, and organisms are observed in which the extremities are apparently 
 united, a perfect circle thus being formed. 
 
 Spirochaeta Duttoni (Spirillum Duttoni). — The disease due to this 
 parasite, or tick fever, was first described by Livingstone, but it was not until 
 the discovery of a spirochaeta in the blood of patients suffering from it, by Ross 
 and Milne, in 1904, and almost simultaneously by Dutton and Todd, that the 
 etiology of the disease was placed upon a scientific basis. It is probable that 
 this spirochaeta has been more thoroughly studied than any of this class of 
 organisms and yet the biological position of the organism is undetermined 
 and the morphological data variously interpreted by different observers. 
 
 In length Spirochaeta duttoni varies frcm 13^ to 45// and in width from 
 0.2/1 to o.4/t. Different authorities give very different measurements, Novy and 
 Knapp stating the length as 16/*; Dutton and Todd as 13/i to 43^; Ross as 
 45/i, and Schellach as 2411. It is probable that some of the longer measure- 
 ments were obtained by measuring two organisms attached end to end, as they 
 so frequently are. The morphology is similar to that of Spirochaeta recurrentis, 
 a flagellum being present at one end and the staining being irregular when 
 Giesma's stain is employed. Transverse and longitudinal division occurs, 
 transverse division being the usual method of reproduction. The motility of this 
 species is greater than that of any other species of spirochaetae found in man. 
 
 The observations of Dutton and Todd upon the morphology of this 
 organism and those of Schellach are especially important and demand atten- 
 
THE BLOOD PROTOZOA OF MAN. 449 
 
 tion. Dutton and Todd state that the organism is ribbon-shaped on transverse 
 section, and that it is composed of a central core staining a deep red, the chroma- 
 tin, and of a delicate periplastic sheath, staining light pink. Both extremites 
 are pointed, but one may be extended through the sheath as aflagellum, which 
 contains no chromatin. The chromatin may not stain as a solid core, but may 
 lie in irregular masses surrounded by unstained areas. Peritrichial flagella 
 were never observed. Many of the spirochaetae presented deeply stained knobs 
 or swellings, either situated at one end or laterally, some of them being separated 
 from the parent organism, but still attached by a very delicate pink-staining 
 thread. Most of these swellings stain uniformly red, but in some the protoplasm 
 is stained blue and contains deep red dots of chromatin. 
 
 Some of the organisms are thicker at one extremity than at the other and 
 these forms the authors believe to indicate a stage preceding longitudinal 
 division. The usual method of reproduction was found to be by transverse 
 division, but longitudinal division was frequently observed, being most common 
 toward the termination of the attack. Longitudinal division is preceded by 
 thickening of the organism which then splits, beginning at one end, thus pro- 
 ducing the Y-shaped forms frequently observed. In smears made from the 
 spleen, bone-marrow, and liver, the spirochaetae were frequently observed 
 coiled up into spherical masses, which become larger and irregular in shape as 
 the crisis approaches. Interesting changes were observed in some of these 
 organisms, consisting in encystment followed by disintegration of the body of 
 the parasite, the cyst being filled with granules showing the chromatin staining 
 reaction. They note the occurrence of minute, blue-stained bodies, containing 
 chromatin granules, and measuring from r/i to 3// in diameter, in the blood and 
 organs of infected animals, but are uncertain of the nature of such bodies. 
 These authors agree with Leishman that Spirochaeta duttoni possesses an 
 undulating membrane, stating that they have observed, both in the blood of 
 men and animals, and in blood from the alimentary canal of the tick, an un- 
 mistakable undulating membrane. To demonstrate it they recommend the 
 use of the highest powers and a very careful scrutiny of every organism. This 
 membrane extends the entire length of the body and some of the unstained 
 areas in the latter are due to the undulating membrane crossing the body. 
 
 Schellach observed the spirochaeta in the living state. He gives the 
 length as 24/i at the most, the width as 0.45//. The number of undulations as 
 8 to 12. A terminal flagellum was' demonstrated, but while' he obtained peri- 
 trichial flagella by Zettnow's method, he regards them as artefacts. Deep- 
 staining granules were noted in the protoplasm when Giemsa's method of stain- 
 ing was employed. He also described appearances suggesting longitudinal 
 division, but considers that the method of reproduction is always by transverse 
 division. While Dutton and Todd claim that the organism may occur both 
 within red and white blood-corpuscles, Schellach believes that the organisms 
 are not intracellular at any stage of development and that phagocytosis does not 
 occur. 
 
 2Q 
 
45° 
 
 THE BLOOD PROTOZOA OF MAN. 
 
 Breinl, Kinghorn, and Garrett could not demonstrate an undulating mem- 
 brane or a flagellum, but they describe refractile dots in the protoplasm. 
 
 The motility of Spirochacta duttoni is similar in character to that oi Spiro- 
 chaeta recurrentis, consisting in cork-screw motions, undulations, and a swaying 
 motion, but it is much more active than any of the other spirochaetae of man. 
 
 Spirochaeta novyi (Spirillum novyi). — This spirochaeta resembles in its 
 general morphological characters the organisms already described, but it is 
 shorter and more slender than the other spirochaetae of man. The organism 
 has been thoroughly studied by Norris, Novy, and Knapp and more recently 
 by Schellach. 
 
 Ai cording to Novy and Knapp, single cells of this organism measure from 
 lix to q« while Schellach gives the length as from 17/x to 20LI with 6 to 8 undula- 
 tions. The same author gives the width as 0.31//. A terminal flagellum has 
 been demonstrated by Novy, Knapp, and Schellach, and while peritrichial 
 iiagella have been described by Fraenkel and Zettnow, it is generally conceded 
 that these were artefacts produced by the method of staining. The organism 
 is actively motile, the same varieties of motion being observed as in the preced- 
 ing spirochaetae. Reproduction occurs by transverse division, but longitudinal 
 division occurs at certain intervals, typical dividing forms having been 
 observed. 
 
 Spirochaeta carteri (Spirillum carteri). — As described by Mackie, 
 Spirochaeta carteri measures from 12 11 to 16/i in length, by 00.3/i to 0.5/1 in 
 breadth, but forms are observed measuring from 7/1 to 8/j., while in infected lice 
 the spirochaetae may measure only 2ll to 3/* in length. Only in degenerative 
 forms has any trace of structure been discovered, the appearance of chromatin 
 dots being coincident with degeneration of the cytoplasm. A terminal flagel- 
 lum is demonstrable, but Mackie interprets this as the empty portion of the 
 sheath which surrounds the organism. Transverse division is the common 
 method of reproduction, but Mackie has observed organisms in the stomach of 
 the louse which were probably undergoing longitudinal division and con- 
 jugation. An undulating membrane has not been demonstrated. The 
 organism is motile, the movements being similar in character to those described 
 in the other spirochaetae of man. 
 
 From the descriptions of the spirochaetae given it will be observed that 
 their differentiation upon morphological grounds alone rests upon the size, the 
 number of undulations or curves, and the character of the curves. The follow- 
 ing table illustrates the variations in these particulars in the four species of 
 spirochaetae which infect man: 
 
 Length Max . 
 
 Width 
 
 No. of Curves 
 Shape of Curves 
 
 Sp. recurrentis 
 
 19/1 to 29/x 
 
 8 to 10 
 spiral 
 
 Sp. duttoni 
 
 I 2fJL to 24// 
 
 0.45/^ 
 8 to 12 
 open flexures 
 
 Sp. novyi 
 
 1-jjj. to 20/! 
 0.3 i/i 
 6 to 8 
 typical spirals 
 
 Sp. carteri 
 
 l6fl 
 0.50 ft 
 
 (?) 
 open flexures 
 
THE BLOOD PROTOZOA OF MAN. 45 1 
 
 Mackie considers that Sp. Carteri can be easily distinguished upon morpho- 
 logical grounds from Sp. novyi, the latter being shorter, staining less intensely, 
 and thinner and more delicate in contour; the American organism being 
 typically spiral in shape, the Asiatic having very shallow undulations, more open 
 in character. 
 
 Fortunately, we do not have to depend upon morphology in order to differ- 
 entiate the spirochaetae, for we possess in their reactions to immune sera and to 
 inoculation into various animals, a certain and easy method of distinguishing 
 them. 
 
 Cultivation of Spirochaetae. — Spirochaeta novyi is the only spirochaete 
 which has, at the present writing, been cultivated upon artificial media outside 
 of the human body. Novy and Knapp succeeded in cultivating the organisms 
 in collodiun sacs placed in the peritoneal cavity of white rats, and in this manner 
 they were able to carry the parasites through successive generations, multiplica- 
 tion being abundant. Their method was as follows: "Collodium sacs were 
 filled with uncoagulated rat's blood and after inoculation were placed at once in 
 the peritoneal cavity of a white rat. Three days later, on removal, the sacs 
 were found to contain active spirilla and in increased numbers. From the sacs 
 transplants were made to new ones and the result was equally satisfactory." 
 They transplanted their cultures every three or four days, using sacs containing 
 from 2.5 to 3 ex., and it was found that if the sacs were left in the perito- 
 neal cavity for seven days or over the spirochaetae decreased in number or 
 disappeared. 
 
 The spirochaetae of all of the relapsing fevers may be kept alive for days 
 and weeks in citrated blood at room temperature, but there is no evidence that 
 multiplication occurs, and transplants cannot be obtained. 
 
 The morphology of the spirochaetes in the collodium sacs did not differ 
 from that of the organisms in the blood, and, according to Novy and Knapp, 
 there was no evidence of a developmental cycle in their cultures similar to that 
 demonstrated in some of the protozoa. 
 
 Butler has recently shown that in citrated blood, kept in an ice-box at a 
 temperature of i5°C, Spirochaeta duttoni develops oval or round enlargements, 
 situated either at the extremities or laterally, which contain granules of chroma- 
 tin. The parent body degenerates after from two to three months, but the 
 enlargements retain the stain and become free in the plasma. Butler found 
 the same bodies upon spirochaetes in blood obtained from the stomach of 
 fleas allowed to feed upon infected rats. These bodies are the same as those 
 previously described by Dutton and Todd as occurring upon Spirochaeta duttoni 
 observed in the blood of infected rats. In our work upon Treponema pertenue and 
 Treponema pallidum, Ashburn and myself observed similar bodies attached to 
 both these organisms, and the fact that they are observed so frequently is very 
 suggestive that they have something to do with the reproduction of both spiro- 
 chaeta and treponema. 
 
 Pathogenicity. — The group of fevers caused by the spirochaetes described 
 
45 2 THE BLOOD PROTOZOA OF MAN. 
 
 are characterized by attacks of fever alternating with periods of normal tem- 
 perature. At the time of pyrexia the organisms are found in the peripheral 
 blood, but become less numerous during the decline in the fever, and after the 
 crisis they entirely disappear from the peripheral blood, although, as shown by 
 Breinl and Kinghorn, in the case of Spirochaeta duttoni, the blood is still infective 
 to susceptible animals. These parasites are pathogenic for some of the lower 
 animals, and the reaction of these animals to the inoculation of the different 
 species and the reaction of the organisms to immune sera form our most effi- 
 cient methods of differentiating the various species. 
 
 Spirochaeta recurrentis is pathogenic for man, monkeys, white rats, 
 tame rats, and mice. In monkeys the injection of blood containing this 
 organism is followed by severe fever, accompanied by relapses, and the parasite 
 is easily demonstrated in large numbers in the peripheral blood. White rats 
 and mice can only be infected by the inoculation of organisms which have first 
 been passed through the monkey, and antibodies are formed in the blood of 
 infected animals. To Uhlenhuth and Haendel and Fulleborn and Meyer we 
 owe much cf our knowledge of the pathogenic properties of this spirochaeta. 
 
 Spirochaeta duttoni is pathogenic for man, monkeys, white rats, common 
 rats, mice, guinea-pigs, rabbits, dogs, sheep, horses, and goats, while cats, 
 pigeons, and chickens are not susceptible. The researches of Breinl and 
 Kinghorn upon the pathogenicity of this organism are most valuable. They 
 found that the white rat is more susceptible to infection than is the monkey, 
 and that the parasite passes through the placenta, thus infecting the foetus. 
 They also determined that it passes through a Berkefeld filter fine enough to 
 retain B. prodigiosan. In their work the period of incubation varies from a 
 few hours in white rats to seven days in monkeys, and relapses occurred in most 
 of their experimental animals. (The occurrence of relapses at regular intervals 
 following infection with the spirochaetae is very significant of their protozoal 
 nature, as they indicate that the organism passes through a definite cycle of 
 development.) The disease in monkeys is not generally fatal, but in white 
 rats and guinea-pigs a fatal result is frequent. These observers also demon- 
 strated that the peripheral blood is infective during apyrexia, although the 
 spirochaeta cannot be found in it, which would appear to prove that during 
 apyrexia the parasite is present in the blood in some form which has not yet 
 been recognized. 
 
 Spirochaeta novyi is pathogenic for man, monkeys, white rats and mice, 
 and tame and wild rats. Novy and Knapp found that white mice were very 
 susceptible, and that the organisms occurred in their blood in immense numbers. 
 These observers found that rabbits and guinea-pigs could not be infected. 
 
 Spirochaeta carteri has been found by Mackie to be pathogenic for 
 white rats and mice, white rabbits, black rats, brown rats, and guinea-pigs. 
 Goats, dogs, cats, and pigeons are not susceptible. As with the other spiro- 
 chaetes, this organism is pathogenic to man and monkeys. The disease in 
 laboratory animals, except the monkey, is of slight character, and the organisms 
 
THE BLOOD PROTOZOA OF MAN. 453 
 
 occur in the blood in small numbers. Mackie found that the monkey could 
 be infected by scarification of the skin followed by the rubbing in of infected 
 blood; by feeding with blood containing the organisms, and by puncture of the 
 skin with a grooved needle containing the virtus. 
 
 Immunity. — From a diagnostic and therapeutic standpoint the question 
 of acquired immunity to infection with the various species of spirochaetae is of 
 great importance, but as yet an immune serum which can be used for the 
 treatment of human infections has not been produced, although Novy and 
 Knapp have cured infections in rats by the injection of immune blood. It is 
 a fact of prime importance in the differential diagnosis of the species of spiro- 
 chaetae that an animal which has suffered from an infection with one species is 
 immune to that species but not to the others, so that a differential diagnosis is 
 easily made by the use of immune animals. The occurrence of any of the 
 varieties of relapsing fever in man is followed by a period of immunity, and this 
 is also true of experimental infections in the lower animals, but the duration of 
 the immune period is not known and varies with the species of animal and the 
 species of spirochaeta producing the infection. 
 
 The immunity produced by Spirochaeta recurrentis is slight and transient 
 in character. Immune substances are produced in the blood of animals suffer- 
 ing from the infection, and blood serum containing them causes paralysis of 
 movement in this spirochaeta, but has no effect upon the other spirochaetae. 
 Metchnikoff 's theory that the disappearance of the spirochaetae from the blood 
 was due to phagocytosis occurring principally in the spleen has been disproven 
 by Tictin, Lamb, and Breinl and Kinghorn. 
 
 Breinl and Kinghorn, working with Spirochaeta duttoni, were unable to 
 produce immunity by immune serum or to cure the infection in animals by 
 'the use of such serum. Their conclusions are of great value and are given 
 practically verbatim: 
 
 i. "Immune serum, whether derived from horses, monkeys, or rats, has no 
 appreciable value either in preventing the occurrence of the attacks in suscep- 
 tible animals or in curing the disease once contracted. The incubation period 
 may be prolonged to a greater or less extent, but the inoculation of infected 
 blood is always followed by infection. 
 
 2. "Hyperimmune serum has no pronounced value in the treatment of the 
 disease in monkeys, does not prevent infection, but given in large doses markedly 
 lengthens the incubation period, and mitigates the course of the disease. 
 
 3. "In animals which have recovered from the infection there is a rel- 
 atively active immunity of comparatively long duration. 
 
 4. "We have been unable to produce passive immunity through the use 
 of immune serum. 
 
 5. "In animals from which the spleen has been removed, the spirochaetes 
 disappear from the peripheral circulation after the attack as promptly as in 
 normal animals, and relapses occur in the ordinary way." 
 
 These authors also proved that animals rendered immune to infection 
 
454 THE BLOOD PROTOZOA OF MAN. 
 
 with Spirochaeta duttoni, because of having recovered from such infection, 
 were not immune to Spirochaeta recurrentis, and that ticks fed upon infected 
 animals were able to transmit the infection immediately. 
 
 The immunity produced by infection with Spirochaeta novyi has been 
 carefully studied by Novy and Knapp, whose conclusions are here reproduced 
 in part: 
 
 i. "A powerful specific germicidal body is present in the decline and in 
 recovered blood,- notably in blood of hyperimmunized rats. An immunizing 
 body is also present and is probably distinct from the germicidal agent. 
 
 2. "Pfeiffer's phenomenon can be demonstrated in vitro and in vivo." 
 
 3. "Active immunity follows recovery from the infection. By successive 
 injections of spirillar blood this immunity can be increased to a remarkable 
 degree." 
 
 4. "Passive immunity can be imparted by injections of recovered or 
 hyperimmunized blood." 
 
 5. "Preventive inoculations can be successfully made in rats, mice, and 
 monkeys." 
 
 6. "Infected rats, mice, and monkeys can be promptly cured by injection 
 of hyperimmunized blood." 
 
 7. "Agglutination of spirilla occurs in vitro and in vivo under the influence 
 of recovered or hyperimmunized blood." 
 
 8. "The agglutination, germicidal, and immunizing properties of recovered 
 blood can be used in the sero-diagnosis of relapsing fever. Also for the identifi- 
 cation of spirilla." 
 
 From the results obtained by Novy and Knapp it is evident that this 
 organism differs very greatly from Spirochaeta duttoni in its effect upon animals, 
 for, as shown by Breinl and Kinghorn, the latter produces no immune serum 
 capable of preventing or curing an infection, while a very active immunizing 
 and curative serum is produced after infection with Spirochaeta novyi. 
 
 According to Mackie, the injection of blood from man and monkeys 
 containing Spirochaeta carteri into monkeys and goats is followed by a certain 
 degree of immunity, and the blood serum from these animals killed the spiro- 
 chaetes within fifteen seconds in a dilution of 1 in 20. 
 
 Methods of Transmission. — -It is now generally believed that all the 
 species of spirochaetae producing relapsing fever in man are transmitted through 
 the agency of insects, and, in the instance of the relapsing fever of Africa, or 
 "tick fever," this method of transmission has been definitely proven. 
 
 Spirochaeta recurrentis is believed to be transmitted by an insect, but we 
 possess no definite knowledge as to what insect is concerned, although the bed- 
 bug {Cimex lectularius) has been regarded by some observers as the transmitting 
 agent. As long ago as 1897, Tictin concluded, as the result of his experiments, 
 that this bug transmitted the disease. He allowed bed-bugs to suck the blood 
 from patients suffering from relapsing fever, then rubbed them up in a mortar 
 and inoculated them into monkeys, which afterward developed fever. His 
 
THE BLOOD PROTOZOA OF MAN. 455 
 
 experiments were obviously imperfect as regards technic and the more 
 recent negative experiments of Breinl and Kinghorn with these bugs and both 
 Spirochaeta recurrentis and Spirochaeta duttoni prove that the bed-bug does not 
 transmit these parasites to man. 
 
 The method of transmission of Spirochaeta duttoni has been definitely 
 ascertained. Dutton and Todd, working in the Congo valley, proved that 
 African tick fever is due to the organism that we now know as Spirochaeta 
 duttoni, and that it is transmitted to man by the bite of a tick, Ornithodorus 
 moubata, which had sucked the blood of infected individuals. These observers 
 also proved that the infection in the tick is hereditary, as the larvae hatched out 
 of the eggs of infected ticks were also capable of causing the disease. Their 
 observations were at once confirmed by Ross and Milne, and later by Breinl 
 and Kinghorn, and there can be no doubt but that this organism is conveyed to 
 man by the bites of infected ticks or their progeny. 
 
 Dutton and Todd have studied very carefully the morphological changes 
 occurring in Spirochaeta duttoni in the tick, Ornithodorus moubata. Many 
 degenerating forms are observed in the blood in the stomach of the tick after it 
 has bitten an infected animal, as well as all of the forms described as occurring 
 in the peripheral blood. In blood from the receptaculum, obtained 24 hours 
 after ingestion, they observed two distinct types of organism, one slender and 
 the other stout, while a third form was seen rarely, which was twice the usual 
 length and three times the usual breadth. The organisms were also observed 
 coiled up within erythrocytes, leucocytes, and within the cells lining the receptac- 
 ulum, while encysted forms were very common. Fragmentation of the chro- 
 matin was very marked and only a single granule is found in the encysted form. 
 At a later stage of development the granules are double, the parasite consisting 
 of a blue-stained mass of protoplasm containing many pairs of deep red granules. 
 They were not able to follow the further development of these bodies, but sug- 
 gest that they rupture, setting free the chromatin pairs, which eventually 
 develop into minute spirochaetes. In stained specimens they believe that they 
 have been able to trace the development of a single granule into a comma- 
 shaped clump of chromatin from which a small spirochaete developed. These, 
 observations have not been confirmed. 
 
 Koch studied the organisms in the stomach of the tick and was unable to 
 trace any cycle of development. He found that the spirochaetae disappeared 
 from the stomach in a few days and could then be found upon the surface of the 
 ovary, where multiplication occurred. Carter describes longitudinal division 
 as occurring in spirochaetes of this species in the eggs of ticks, but this observa- 
 tion still awaits confirmation. We do not know anything as yet regarding the 
 method of transmission to man of Spirochaeta novyi. 
 
 Mackie has endeavored to demonstrate the method of transmission of 
 Spirochaeta carteri, and his results would appear to indicate that the common 
 body louse (Pediculus corporis) is capable of transmitting this parasite to man. 
 He found that 14 per cent, of lice taken from a badly infected boy's ward, 2 
 
456 THE BLOOD PROTOZOA OF MAN. 
 
 per cent, from a slightly infected girl's ward, and 13 per cent of lice fed upon 
 infected patients, showed spirochaetes in the stomach blood and in the ovaries, 
 multiplication of the organisms having occurred in both stomach and ovaries. 
 He states that: "A fluid rich in active spirilla (spirochaetes) could be obtained 
 by gentle pressure on the heads of infected lice." Mackie also examined the 
 organs of Cimex rotundatus and found the spirochaetes present in the stomach 
 until the sixth day after feeding, but there was no evidence that they underwent 
 multiplication. He allowed bugs of this species, after biting infected monkeys, 
 to bite 10 healthy monkeys, but the disease appeared in only one of these 
 animals, and the infection in this case may have been due to other factors. 
 
 Distribution in Man. — The spirochaetes causing the relapsing fevers are 
 blood parasites and are found only in the blood plasma, as they are not intracel- 
 lular organisms. The observations of Dutton and Todd, which would indicate 
 that these organisms occur within the red blood-corpuscles and the leucocytes, 
 have not been confirmed, and their occurrence in these cells is probably acci- 
 dental. The organisms are also found in the capillaries of the various viscera 
 after death, but only in a few instances have they been reported as occurring 
 in the endothelial cells and the cells of the tissues. 
 
 The examination of the blood in relapsing fever is generally useless (so 
 far as demonstrating the parasite is concerned) during apyrexia, and even when 
 fever is present several stained preparations should be examined before the 
 result is regarded as negative. 
 
 Spirochaeta recurrentis is found only in the blood stream during the febrile 
 paroxysm, rapidly disappearing as the crisis approaches, and being entirely 
 absent from the peripheral circulation after the crisis occurs. 
 
 Spirochaeta didtoni also occurs only in the blood stream, but in smaller 
 numbers than the preceding parasite, and, according to Ross, they can only be 
 found during the relapse, being absent from the peripheral blood during the 
 primary attack. Dutton and Todd describe this parasite as occurring within 
 the erythrocytes but their occurrence in this situation is accidental. 
 
 Spirochaeta novyi and Spirochaeta carteri also occur only within the blood, 
 and in both infections the organisms can be easily demonstrated in the peripheral 
 blood during the febrile attack. In the internal organs the parasites occur 
 within the capillaries but not within the tissue cells. 
 
 While the parasites cannot be demonstrated in the peripheral blood during 
 the afebrile period, Dutton and Todd have shown, in the case of Spirochaeta 
 duttoni, that the apyrexial blood is infective, and Mackie has shown that the 
 apyrexial blood from monkeys infected with Spirochaeta carteri, produces in- 
 fection in other monkeys, so that it is more than probable that the spirochaetes 
 exist in the blood during apyrexia in some unrecognized form, as the examina- 
 tion of scores of blood films at this time always results negatively. We 
 possess no evidence sufficient to prove that any of the spirochaetes causing 
 relapsing fever in man are intracellular organisms, all of the observations 
 pointing to their being true parasites of the blood plasma. In this they differ 
 
THE BLOOD PROTOZOA OF MAN. 457 
 
 from Treponema pallidum and Treponema pertenue, closely related organisms, 
 which" are true tissue parasites. 
 
 Demonstration of Spirochaetae. — Spirochaeta recurrentis, Spirochaeta 
 novyi, and Spirochaeta carteri may be easily demonstrated in fresh blood 
 preparations from patients suffering from relapsing fever, provided the blood 
 be obtained during the febrile period, but after the crisis the parasites disappear, 
 and it is then useless to examine the blood. Spirochaeta duttoni may also be 
 demonstrated in the fresh blood specimens during the febrile period, but this 
 organism occurs in such small numbers that it is better to make blood smears 
 and stain them by some modification of the Romanowsky method. In fact, 
 in suspected cases of infection with any of the spirochaetes of relapsing fever 
 better results will be obtained by the examination of stained blood smears. If 
 it is desired to examine fresh blood the ear or finger should be pricked with a 
 sterilized needle and a rather large drop of blood be placed upon the microscopic 
 slide and immediately covered with a cover-glass. It is necessary that the blood 
 film be rather thick, as otherwise the organisms, being comparatively few in 
 number, might be overlooked. If it is desired to examine stained smears of 
 blood they should be made rather thick, and should be fixed and stained as 
 recommended in the section of this work dealing with the staining of the malarial 
 Plasmodia. Any modification of the Romanowsky stain may be employed, but 
 the Wright stain, used as recommended for the plasmodia, gives the best 
 results. In infections with Spirochaeta duttoni, and in other infections in which 
 the spirochaetes are few in number, it is often necessary to centrifuge the blood 
 and examine the sediment, either as a fresh preparation or stained in the same 
 manner as blood smears. The method of centrifugation is the same as recom- 
 mended for the demonstration of Trypanosoma gambiense. In both fresh and 
 stained specimens the spirochaetae are easily recognized, as no other object 
 occurs in the blood which in the least resembles them, with the exception of 
 the free flagella of the malarial plasmodia, and to one who has had any ex- 
 perience in the study of malarial blood, it is easy to differentiate the flagella 
 from the spirochaetes. 
 
 In order to differentiate the species of spirochaetae we must depend upon 
 their morphology, their action upon animals, and their reaction to immune 
 sera. I have already spoken of the differences in the morphology of the four 
 species described in man and have also noted for each species the animals 
 to which it is pathogenic. The most practical method of distinguishing species 
 is by the use of immune blood sera, for it has been found that the serum of an 
 animal which has suffered from infection with any one of the species has no 
 effect upon the other species when it is added to blood containing them, but that 
 it agglutinates the species to which the animal has been rendered partially im- 
 mune. Therefore, if we possess blood serum from animals which have been 
 infected with the four species, we are able to distinguish by the use of these sera 
 any doubtful species with which we are dealing. For instance: A spirochaeta is 
 found in the blood, but we are unable to distinguish the species from morphology 
 
458 THE BLOOD PROTOZOA OF MAN. 
 
 alone. The blood serum of animals infected with each of the four species of 
 spirochaetae is added to blood from the patient containing the spirochaeta, 
 and the preparation in which agglutination occurs contains the serum of the 
 animal immunized to the spirochaeta from the patient. Thus, if the spiro- 
 chaeta in the patient be Spirochaeta duttoni the preparation containing serum 
 from an animal which has passed through an infection with this species will 
 be the only one which will show agglutination of the patient's spirochaetes. 
 In this way it is possible to demonstrate with which species we have to deal in 
 cases in which morphology cannot be depended upon for such differentiation. 
 
 It is probable that further research will result in simpler methods of dif- 
 ferentiating species, for it must be confessed that the methods in which it is 
 necessary to use animals are too cumbersome and difficult of application to be 
 of much use to the general practitioner in the diagnosis of the relapsing fevers. 
 
 Literature upon the Spirochaetes of Relapsing Fever of Man. 
 
 1S73. Obermeier, O. Berl. klin. Wochenschrift, pp. 152-378-391-455. 
 1S80. Megnin. Les parasites et les Maladies parasitaires. Paris. 
 
 1898. Gabritschewsky, G. Beitrage zur Pathologie u. Serotherapie der 
 Spirochaten-Infektionen. Centralbl. f. Bakt., i, No. 23, p. 365. 
 
 1899. Bardach, J. Recherches sur la fievre re"currente. Ann. de l'lnst 
 Pasteur, No. 13, p. 365. 
 
 1901. Graham. Relapsing Fever in Sumatra. Jour. Trop. Med., vol. i, No. 6. 
 
 1902. Karlinski, J. Zur Aetiology des Recurrenstyphus. Centralbl. f. Bakt., 
 No. 1, p. 31. 
 
 1902. Christy, C. Spirillum Fever. Jour. Trop. Med., i, ii. 
 
 1903. Idem. Ornithodoros moubata and Tick Fever in Man. Brit. Med. Jour., 
 Sept. 19, p. 652. 
 
 1904. Idem. Tick Fever. Brit. Med. Jour., 24, xii, p. 1726. 
 
 1904. Powell. The Morphology of the Spirillum of Relapsing Fever. Brit. 
 
 Med. Jour., 30, iv, p. 1014. 
 1904. Ross and Milne. Tick Fever. Brit. Med. Jour., 26, xi, p. 1453. 
 1904. Cook. Relapsing Fever in Uganda. Jour. Throp. Med., January, p. 325. 
 
 1904. Novy and MacNeal. On the Filtration of Trypanosomes. Sixth Rep. 
 Michigan Acad. Sciences, p. 180. 
 
 1905. Dutton and Todd. The Nature of Tick Fever in the Eastern Part of 
 the Congo Free State, etc., Mem. xvii, Liverpool School of Tropical 
 Med., also Brit. Med. Jour., Nov., ii, p. 1259. 
 
 1905. Cropper. Spirillum Fever in Palestine. Brit. Med. Jour., 22, vii, p. 190. 
 1905. Low. Discussion on Tick Fever. Ibid., i, ii, p. 47. 
 1905. Wellman, F. C. Relapsing Fever. Amer. Med., No. 10, p. 151. 
 1905. Yale-Massey. Spirillosis in Portugese West- Africa. Jour. Trop. Med., 
 
 August. 
 1905. Borrel et Marchoux. Argas et spirilles. Compt. rend, de la Soc. 
 
 de Biol., 17 mars., 60, pp. 540-42. 
 1905. Schaudinn, F. Zur Kenntniss der Spirochaete pallida. Deutsche med. 
 
 Wochenschr., Oct. 31, p. 1665. 
 1905. Schaudinn-Hoffmann. Ibid. Arb. a. d. kaiserl. Gesundheitsamte, 22, 
 
 P- 527- 
 
THE BLOOD PROTOZOA OF MAN. 459 
 
 1904. Schaudinn, F. Generations- und Wirtswechsel bei Trypanosomen und 
 
 Spirochaete. Arb. a. d. kaiserl. Gesundheitsamte, 20, p. 387. 
 1906. Breinl and Kinghorn. Observations on the Animal Reactions of the 
 
 Spirochaeta of the African Tick Fever. Lancet, March jo, p. 668. 
 1906. Breinl, Kinghorn, and Garrett. Mem. Liverpool School Trop. Med., 
 
 No. 21. 
 1906. Now and Knapp. Studies on Spirillum Obermeieri and Related Or- 
 ganisms. Jour. Infec. Diseases, May, vol. iii, p. 291. 
 1906. Carlisle, R. D. Ibid., p. 233. 
 
 1906. Norris, Pappenheimer, and Flournoy. Ibid., p. 266. 
 1906. Ross, P. Tick Fever. Jour. Trop., Med., i, iii. 
 1906. Koch, Robert. Vorlaufige Mitteilungen iiber die Ergebnisse einer 
 
 Forschungsreise nach Ost- Africa. Deutsch. med. Wochenschr., Nov. 23, 
 
 p. 1865. 
 1906. Idem. Ueber afrikanischen Recurrens. Berl. klin. Wochenschr., Feb. 
 
 12, p. 185. 
 1906. Prowazek. Morphologische, etc., iiber Hulmerspirochaten Arb. a. d. 
 
 kaiserl. Gesundheitsamte, xviii, p. 554. 
 1906. Zettnow, E. Geisselnbei Huhner- und Recurrens-Spirochaten. Deutsche 
 
 med. Wochenschr., March 8, p. 376. 
 1906. Idem. Farbung und Teilung bei Spirochaten. Zeitschr. f. Hyg., Bd. 
 
 Hi, p. 485- 
 1906. Schilling. Ruckfallfieber. Hand. der. Tropen Krankheiten. Mense. 
 
 Bd. iii, Halbbd. ii. 
 1906. Now and Knapp. Spirochaete Obermeieri. Am. Jour. Med. Assoc, 
 
 January 13. 
 
 1906. Idem. The Cultivation of Spirillum Obermeieri. Jour. Am. Med. Assoc, 
 Dec. 29, vol. xlvii, p. 21 52. 
 
 1907. Fulleborn and Meyer. Med. Klinik, Apr. 28. 
 
 1907. Uhlenhuth and Haendel. Arb. a. d. kaiserl. Gesundheitsamte, 
 
 No. 26. 
 1907. Ross, Philip. Tick Fever. Allbutt and Rolleston's System of Medicine, 
 
 vol. ii, Part ii, p. 130. 
 1907. McCrae, T. Relapsing Fever. Osier's Modern Medicine, vol. ii, p. 245. 
 1907. Manson, Sir P. Relapsing Fever. Tropical Diseases, Fourth Ed., p. 
 
 171. 
 
 1907. Minchin. The Protozoa. Allbutt and Rolleston's System of Medicine, 
 vol. ii, Part ii, p. 42. 
 
 1908. Mackje. A Review of Recent Work on Spirillar Fevers. New York 
 Med. Jour., Aug. 22. Also Trans. Am. Soc Tropical Med., 1908 
 
 1908. Dutton and Todd. A Note on the Morphology of Spirochaeta duttoni. 
 Trans. Soc of Tropical Med. and Hyg., p. 52. 
 
 1908. Butler. U. S. Naval Med. Bull., vol. ii, No. 4, p. 1. 
 
 1908. Stephens and Christophers. Practical Study of Malaria and Blood- 
 parasites, 375. 
 
CHAPTER IV. 
 
 Histoplasma Capsulatum. 
 
 In December, 1905, Darling discovered a protozoan organism in the 
 endothelial cells of the lung, spleen, liver, and bone-marrow to which he gave 
 the name Histoplasma capsulation. While this parasite has not been found in 
 the peripheral blood, and while it is not, strictly speaking, a parasite of the 
 blood, the fact that it closely resembles in its morphology the Leishman- 
 Donovan bodies (Leishmania donovani) and that it is found within the endothe- 
 lial cells in smears from the liver, spleen, and bone-marrow is sufficient excuse 
 for a brief consideration of this interesting organism in any discussion of the 
 blood protozoa. The parasite has only been observed in three patients at 
 autopsy and has never been demonstrated in living individuals. All of the 
 cases have been observed by Darling upon the Isthmus of Panama, the most 
 important clinical symptoms being an irregular remittent temperature, spleno- 
 megaly, emaciation, and a marked leucopenia. The parasites were found in 
 the endothelial cells of the lymph and blood-vessels, and in necrotic areas and 
 granuloma-like growths in the intestine, the lymph nodes, the bone-marrow, 
 and the liver, spleen, and lungs. It has never been found free in the blood 
 plasma. A similar organism has been found by Darling in mucus from the 
 colon of a rat, but it is doubtful if the two are identical. 
 
 The following description of the parasite is given by Darling in his article 
 upon "Histoplasmosis" in "The Archives of Internal Medicine" for September, 
 1908. 
 
 "The bodies are round and oval. There is among the larger forms a 
 tendency toward an oval outline. A.n average-sized spherical body is 3 
 microns in diameter. The longer diameter of an oval body is 3.75 microns. 
 The bodies are always surrounded by a clear, refractile, achromatic zone or 
 capsule, giving the impression at once of an encysted protozoon. The body 
 does not stain homogeneously, but very irregularly, hardly any two parasites 
 looking exactly alike. The body consists of a deeply staining substance or 
 chromatin, a faintly staining substance staining light blue with polychrome 
 stains, and achromatic spaces. The deeply staining substance, or chromatin, 
 is practically always heaped up along one side or end of the body; sometimes it 
 consists of a single mass or several small masses of chromatin; sometimes it is 
 ring-shaped or occasionally extending along half of the periphery of the body, 
 being crescent-shaped. Occasionally a chromatin dot or very rarely a chroma- 
 tin rod will be seen near the larger chromatin body. This chromatin dot or 
 chromatin rod may sometimes be at the opposite end or side of the body. 
 
 460 
 
THE BLOOD PROTOZOA OF MAN. 46 1 
 
 There may be several such dots of chromatin. When there are several of good 
 size the bodies appear to be in a presegmenting stage. The faintly staining 
 blue substance takes up the rest of the space, excepting where there may be one 
 or two small achromatic zones, resembling the vacuoles of protozoa. These 
 vacuoles are irregularly disposed, being sometimes in the center and at other 
 times near the periphery of the body. The most striking thing about the 
 parasite is the extremely irregular way in which the staining substance (chroma- 
 tin) is disposed. This is in striking contrast with the appearance of the Leish- 
 man-Donovan body." 
 
 From the above description it is evident that the parasite discovered by 
 Darling is a protozoon, and that it does not answer in morphology to any of the 
 known protozoa, thus justifying him in placing it in a new genus. Flagellated 
 forms were observed in smears from the lung in one case, three organisms 
 being noticed, each having a single, short, thick fiagellum. As many as 300 
 of the parasites were observed in an alveolar epithelial cell of the lung, and 
 many cells contained from 10 to 100 parasites. The red blood-corpuscles were 
 never invaded. 
 
 The parasite is evidently very rare in Panama as only three cases of infec- 
 tion with it have been observed out of 33,000 admissions to the hospital at 
 Ancon in the Canal Zone. Nothing is known as to its method of transmission, 
 its endemic range or factors predisposing to infection. 
 
 The pathological lesions peculiar to infection with Histoplasma capsulatum 
 were disseminated hyaline pseudo-granulomata in the lungs; necrotic areas in 
 the liver, infiltrated by the parasites; enlargement of the spleen; and ulceration 
 of the ileum, jejunum, and colon. The ulceration in the intestine appeared to 
 be preceded by the formation of a circular, raised granuloma, which became 
 pigmented, and finally ulcerated, the ulcer measuring about 8 mm. in diameter. 
 It is significant that ulceration also occurs in the intestine in infection with 
 Leishmania donovani, and that both infections are accompanied by an irregular 
 fever and an enlarged spleen. 
 
 Literature upon Histoplasma Capsulatum. 
 
 1906. Darling, S. T. Jour. Am. Med. Assoc, xlvi, p. 1283. 
 
 1907. Idem. Histoplasmosis. Maryland Med. Jour., April. 
 
 1908. Idem. Histoplasmosis. A Fatal Infectious Disease Resembling Kala- 
 azar Found among Natives of Tropical America. Archiv. Internal 
 Med., September. 
 
LIBRARY OP run 
 
 ALUMNI ASSOCIATK 
 
 COLLEGE OF PHYSICIANS AND SU 
 COLUMBIA UNIVE 
 NRW YORK 
 
 INDEX OF AUTHORS 
 
 Abbott, 6, 13, 148, 160 
 
 Addison, 274 
 
 Agramonte, 63 
 
 Albertoni, 380 
 
 Algoni, 347, 359 
 
 Anconi, 380 
 
 Angelini, 102, 116, 175, 267, 282 
 
 Annett, Dutton, and Eliott, 97, 103, 114 
 
 Antolisei, 6, 20, 27, 53, 54, 83, 102, 144, 
 
 175- 363, 368 
 Antolisei and Angelini, 54, 83, 102, 116, 
 
 175 
 Argutinsky, 55 
 Arnstein, 138, 146 
 Ascoli, 277 
 
 Ashburn, 60, 63, 355, 412 
 Askanzy, 129 
 Avicenna, 4 
 
 Baccelli, 7, 12, 83, 102, 116, 144, 147, 
 
 223, 363, 376, 407 
 Baker, 429 
 Balbiani, 247 
 Banks, 74 
 Banta, 272 
 Bar, 273 
 Bardach, 458 
 Bardelini, 268 
 Barker, 134, 148, 160 
 Barry, 237 
 Bartels, 270, 281 
 Bartholow, 296 
 Barudel, 240 
 Bassett-Smith, 263 
 Bastianelli, 6, 7, 8, 13, 20, 32, 58, 59, 
 
 83, 86, 91, 117, 121, 122, 135, 
 
 137, 148, 220, 268, 407 
 Bastianelli and Bignami, 54, 77, 88, 
 
 116, 121, 135, 217, 268, 407 
 Baum, 387 
 
 Bein, 83, 102, 116, 121 
 Bell, 262 
 
 Bentley, 411, 425, 426 
 Benvenuti, 151 
 Berenger-Feraud, 391, 407 
 Bernasconi, 141 
 Bernheim, 283 
 Berthelon, 272, 282 
 Berthier, 407 
 Bettencourt, 429 
 Bettinetti, 347, 359 
 Bevans, 292, 297 
 Beyer, 145 
 
 Bignami, 6, 7, 8, 12, 13, 20, 32, 34, 
 57, 58, 59, 80, 83, 86, 88, 91, 
 92, 116, 117, 118, 1 2 j, 122, 
 128, 130, 134, 135, 136, 144, 
 147, 148, 160, 164, 166, 182, 
 220, 244, 268, 277 
 
 Bignami and Bastianelli, 54, 55, 268 
 
 Bignami and Dionisi, 164, 166 
 
 Billet, 122, 132, 147 
 
 Billings, 147 
 
 Binz, 362, 386 
 
 Birt, 413 
 
 Blanchard, 16, 70, 71, 72, 78, 399, 426, 
 
 443 
 Bleumchen, 386 
 Bloch, 129 
 Bloombergh, 155 
 Blumer, 92 
 Bodnar, 272, 281 
 Boinet and Salabert, 268, 282 
 Borius, 216, 240 
 Borrel and Marchoux, 458 
 Borrow, 387 
 Botazzi, 140, 143, 147 
 Botazzi and Pensuti, 140, 142, 143, 147 
 Boudin, 81, 102, 276 
 Bouzian, 121 
 Bowie, 262 
 Boyce, 443 
 
 Boyce, Ross, and Sherrington, 443 
 Braddon, 386 
 Bradford, 442 
 
 Bradford and Plimmer, 251, 442 
 Breinl, 435, 436, 437, 438, 444, 450 
 Breinl and Kinghorn, 452, 453, 454, 
 
 455. 459 
 Breinl, Kinghorn, and Garrett, 450, 
 
 452, 459 
 Breinl and Todd, 445 
 Brignoni, 347, 359 
 Broden, 429 
 Brousse, 143 
 Brown, 393 
 Brown, P. K., 147 
 Browning, 378 
 
 Bruce, 428, 429, 437, 438, 439, 442, 444 
 Bruce and Nabarro, 443 
 Brumpt, 429, 437 
 Brumpt and Wurtz, 444 
 Brunnhoff, 108 
 Buchanan, 122, 358 
 Bull, 273, 281 
 Burns, W. B., 263 
 
 463 
 
464 
 
 INDEX OF AUTHORS. 
 
 Burot, So, 394 
 Butler, 451, 459 
 Butschli, 247, 256 
 
 Cabot, 129 
 
 Caccini, 32, 121, 263 
 
 Cahn, 297 
 
 Calandrucio, 83, 116 
 
 Calkins, 248 
 
 Calmette, 279 
 
 Campbell, 262 
 
 Canalis, ^^, 34, 53, 268, 282 
 
 Cappogrossi, 341', 364, 387 
 
 Carbone, 139 
 
 Cardamantis and Canalis, 263, 297 
 
 Cardamantis, 391, 394, 397, 398 
 
 Carlisle, 459 
 
 Carroll, 63 
 
 Carter, 445, 455 
 
 Casigrandi, 350, 407 
 
 Castellani, 41 1, 426, 428, 429, 443 
 
 Caventou, 360 
 
 Celsus, 4, 12 
 
 Celli, 6, 7, 12, 13, 18, 22, 34, 74, So, 81, 
 82, 83, 94, 103, 109, 112, 114, 
 118, 122, 134, 138, 140, 145, 
 239, 240, 245, 250, 345, 346, 
 
 347- 349- 35°. 35*. 358, 359. 
 
 380, 407, 408 
 Celli and Casigrandi, 358 
 Celli and Guarnieri, 53 
 Celli and Sanfelice, 54 
 Chamberlain, 105, in, 178, 222 
 Charvot, 282 
 
 Chatterjee, 77, 418, 426, 443 
 Chaussat, 428, 442 
 Chenzinsky, 340 
 Chiarini, 268, 273 
 Chiarini and Bardellini, 268 
 Childe, 427 
 Christophers, 12, 41, 75, 97, 132, 147, 
 
 359, 414, 418, 420, 421, 422, 
 
 426, 427 
 Christy, 429, 440, 443, 444, 458 
 Ciarrochi, 102 
 Clarke, 411 
 Cochran, 296 
 Coffin, 155 
 Cohn, 445 
 Colin, 13, 138, 222 
 Colosanti, 142, 147 
 Columella, 4, 7, 12, 56 
 Cook, 458 
 Coronado, 92, 103 
 Corre, 391 
 
 Councilman, 6, 12, 32, 53, 148, 160 
 Craig, C. F., 12, 18, 55, 103, 122, 160, 
 
 166, 263, 283, 297, 340, 341, 
 
 359. 387 
 Crawley, 60 
 Crespin, 341 
 Cropper, 458 
 Crosse, 407 
 Cuboni, 6 
 Cummings, 391 
 Curry, 285, 341 
 
 Da Costa, 285, 297 
 
 Daniels, 70, 75, 77, 263, 2S3, 341, 394, 
 
 395. 397. 407, 408 
 Danilewsky, 14 
 Darling, 460, 461 
 Davidson, 82, 114, 283, 394, 407 
 Deaderick, 404, 40S 
 De Brun, 262 
 De Rossi, 273, 274 
 Di Mattei, 84, 102, 103, 116, 122, 358, 
 
 380 
 Dionisi, 115, 130, 131, 146, 164, 357 
 Dionisi and Bignami, 164 
 Dock, ft, 34, 54, 134, 147, 14S, 160, 292, 
 
 2 97. 337- 372 
 Doenng, 393 
 Doflein, 251, 442 
 Donne, 73 
 
 Donovan, 412, 413, 420, 422, 425, 426 
 Dubini, 268 
 Duchek, 121, 122 
 Duden, 240 
 Duncan, 344 
 Durham, 383 
 Dutrouleau, 391, 407 
 Dutton, 97, 114, 359, 428, 429, 441, 
 
 443. 44 5 
 Dutton and Todd, 428, 429, 441, 442, 
 
 443. 444, 448, 449. 45 1 . 455. 
 456, 458, 459 
 Dutton, Todd, and Christy, 443 
 
 Edmonds, 282 
 
 Ehrlich, 100, 260, 261, 378, 380, 386 
 
 Elting, 7, 83, 116, 122 
 
 Elliot, 97, 1 14 
 
 Elmassion, 428, 442 
 
 Englemann, 247 
 
 Ewing, J., 55, 129, 148, 160, 245, 263, 
 
 285, 297, 340 
 Evans, 428, 442 
 
 Fassina, 272, 282 
 
 Favre, 78 
 
 Fayrer, 13, 281 
 
 Feletti, 6, 35, 53 
 
 Felkin, 122 
 
 Felt, 78 
 
 Ferreri, 273, 274 
 
 Feuchtwanger, 374, 386 
 
 Finot, 175 
 
 Fischer, 274, 358 
 
 Fish, 129 
 
 Flexner, S., 144, 153 
 
 Flournoy, 445 
 
 Fliigge, 56 
 
 Ford, J., 385, 387 
 
 Forde, 429, 443 
 
 Fraenkel, 447, 450 
 
 Francis, 145 
 
 Frank, 273 
 
 Frerichs, 5, 138 
 
 Freund, 141 
 
 Frosch, 344, 359 
 
 Fuellborn and Meyer, 452, 459 
 
INDEX OF AUTHORS. 
 
 465 
 
 Gabritchewsky, 458 
 
 Galli-Valerio, 78, 351, 359 
 
 Gancel, 297 
 
 Garrett, 450 
 
 Gautier, 55, 383, 387 
 
 Gee, 141 
 
 Gerhardt, 7, 83, 102, 116 
 
 Giemsa, 317, 340, 423 
 
 Giles, 63, 69, 71, 78, 411, 425 
 
 Glogner, 147, 263, 268 
 
 Gluge, 428 
 
 Goeldi, 70 
 
 Golgi, 6, 13, 19, 26, 32, 35, 53, 134, 135. 
 
 144, 147, 362, 363, 364, 368, 386 
 Gorgas, 348, 352, 358, 393 
 Gosio, 344, 359 
 Gowers, 268 
 Grabham, 70 
 Graham, 63, 70, 355 
 Grassi, 6, 7, 8, 12, 13, 18, 55, 58, 59, 77, 
 
 86, 88, 91, 105, 117, 122, 358, 
 
 383, 386 
 Grassi, Bignami, and Bastianelli, 77, 
 
 135 , • 
 Grassi and Feletti, 3 5, 53 
 
 Grawisz, 129 
 
 Gray, 429, 435, 436, 437, 438, 44i- 443. 
 
 444 
 Gray, St. George, 380, 386 
 Gray and Tulloch, 429, 435, 444 
 Greig, 429, 437, 438, 441, 443, 444 
 Greig and Gray, 441, 443, 444 
 Griesinger, 175, 281 
 Grixoni, 341 
 Grocco, 282 
 Groff, 4 
 Gros, 386, 428 
 Grube, 428, 430 
 Gualdi, 83, 145, 370, 387 
 Gualdi and Antolisei, 83, 102, 116 
 Guarnieri, 22, 148, 160, 273, 380 
 Guttman, 380, 386 
 
 Haendel, 446, 452 
 
 Haig, 39s 
 
 Hamburger, 92 
 
 Harris, 340 
 
 Haspel, 222 
 
 Hertwig, 2 50 
 
 Hertz, 277, 282 
 
 Herz, 270 
 
 Hewettson, 12, 34, 113, 142, 171, 175 
 
 Hirsch, 113 
 
 Hirshberg, 75 
 
 Hippocrates, 4, 12 
 
 Horcicka, 142, 147 
 
 Hope, 97 
 
 Hotz, 274 
 
 Hovorka, 385, 387 
 
 Howard, 68, 78, 348 
 
 Huchard, 269 
 
 Hunt, 341 
 
 Iacoangelini, 142, 147 
 Ipscher, 394 
 Ivanoff, 380, 386 
 
 3° 
 
 Jackson, 32, 118, 122, 178 
 
 Jacobi, 273, 281 
 
 James, 32, 97, 233, 263, 349, 359, 414, 
 
 420, 422, 427 
 Jancso, 78, 109, 1 1 7 
 Jilek, 358 
 Jourdan, 268 
 
 Kahler and Pick, 268, 281 
 Karlinsky, 447, 458 
 Kelsch, 129, 130, 132, 138, 146, 160 
 Kelsch and Kiener, 12, 190, 262, 270, 
 
 280, 281, 282, 408 
 Kempner, 443 
 Kent, 442 
 
 Kieweit de Jonge, 142, 147, 351, 359 
 King, F. A., 7, 56, 387 
 Kmghorn, 450, 452, 453, 454, 455 
 Kinyoun, 285, 297 
 Kipp, 262, 273, 282 
 Klebs, 5, 13 
 Kleine, 386 
 Klemperer, 341 
 
 Knapp, 445, 446, 448, 450, 452, 454 
 Koch, 8, 56, 57, 60, 77, 93, 96, 97, 98, 
 
 102, 103, 114, 115, 175, 233, 
 
 263, 343. 357- 358, 375. 39 1 . 
 
 398, 435. 445. 447- 455. 459 
 Kolosvary, 387 
 Kronecker, 341 
 Kruse, 15, 54, 429 
 Kuchel, 407 
 Kuhn, 357, 385, 387 
 Kunst, 380, 386, 387 
 
 Labbe, 15, 54 
 
 Laborde, 343, 358 
 
 Lagrand, 394 
 
 Lamb, 453 
 
 La Monaco, 74, 322, 341, 363 
 
 La Monaco and Panichi, 322, 341, 363, 
 386 
 
 Lancereaux, 269, 278, 282 
 
 Lancisi, 5, 7, 13, 269 
 
 Landouzy, 221 
 
 Lankester, 428 
 
 Laveran, 6, 12, 13, 14, 54, 55, 56, 83, 
 122, 134, 138, 144, 148, 175. 
 190, 216, 221, 222, 223, 262, 
 270, 272, 285, 340, 341, 343. 
 358, 362, 408, 413, 420, 422", 
 425, 426, 429, 430, 438, 442, 
 
 444 
 Laveran and Mesnil, 430, 431, 432, 
 
 436, 440 
 Laveran, Mesnil, and Nabarro, 440, 444 
 Lazear, 55, 63 
 Lebert, 445, 446 
 Leboeuf, 444 
 Ledingham, 420 
 Leishman, 315, 340, 411, 412, 413, 416, 
 
 418, 420, 421, 424, 425, 427, 
 
 448 
 Leishman and Statham, 427 
 Lemoine, 143 
 Leukowicz, 386 
 
4 66 
 
 INDEX OF AUTHORS. 
 
 Levick, 296 
 
 Levrier, 273, 281 
 
 Lewis, 42S 
 
 Leyden, V., 240 
 
 Liel, 274 
 
 Linton, 429, 437, 444 
 
 Liston, 71, 73 
 
 Litter, 129 
 
 Livingstone, 448 
 
 Loeff, Van der, 407 
 
 Loew, 72, 73 
 
 Low, 89, 354, 41' 5, 425, 443, 458 
 
 Low and Mott, 443 
 
 Ludlow, C. S., 70, 74 
 
 Liihe, 16, 55, 434 
 
 Lutz, 70 
 
 Lynch and Scott, 394 
 
 Lyons, 285, 297, 427 
 
 MacCallum, 7, 55, 57, 77 
 
 Mackie, 446, 450, 451, 452, 453, 454, 
 
 455. 456, 459 
 
 MacNamara, 282 
 
 MacNeal, 436, 443 
 
 Magnin, 272, 282 
 
 Maillot, 175, 262 
 
 Mannaberg, 6, 12, 15, 32, 34, 54, 116, 
 122, 130, 142, 145, 171, 175, 
 190, 215, 217, 240, 260, 267, 
 269, 279, 283, 363, 366, 391, 
 395. 396, 408 
 
 Manson, P. Thorburn, 90 
 
 Manson, Sir P., 7, 32, 49, 55, 56, 57, 63, 
 77. 8 3. 86, 9°. I °3> IJ 5, JI 7. 
 269, 340, 341, 344, 361, 37 2 . 
 3 8 °. 39 1 . 394, 395, 397, 399, 
 407, 408, 411, 412, 414, 415, 
 420, 425, 427, 429, 431, 443, 
 
 444, 445, 447, 459 
 
 Manson and Low, 414 
 
 Marchand, 412, 420 
 
 Marchiafava, 6, 7, 12, 13, 14, 17, 32, 83, 
 86, 92, 106, 134, 135, 138, 144, 
 150, 220, 221, 223, 261, 277, 
 
 278, 379 
 Marchiafava and Bignami, 54, 80, 84, 
 94, 117, 118, 122, 128, 130, 
 148, 151, 170, 182, 184, 203, 
 214, 253, 259, 267, 271, 282, 
 
 363, 369, 376, 3 8o > 39 1 , 407 
 Marchiafava and Celli, 14, 32, 53, 134, 
 
 138 
 Marchoux, 57, 120, 262, 407, 429, 458 
 Mariani, 387 
 Marino, 316 
 Mariotti, 7, 83 
 Mariotti and Ciarrochi, 102 
 Mariotti-Bianchi, 122, 240, 242, 244, 
 
 245, 263 
 Markham, 360 
 Martin, 95, 272, 282 
 Martin and Leboeuf, 444 
 Martirano, 370, 387 
 Massey, 458 
 Masucci, 387 
 Mathis, 263 
 
 Maupas, 250 
 
 Maurel, 94, 279, 282 
 
 Maurer, 42, 55, 375 
 
 Maximow, 128 
 
 Maxwell- Adams, 429 
 
 Meckel, 5, 13, 138, 146 
 
 Megnin, 458 
 
 Meigs, 138 
 
 Mense, 356, 358 
 
 Meigen, 71, 73 
 
 Mericourt de, 391 
 
 Mesnil, 413, 422, 425, 426 
 
 Metchnikoff, 14, 100, 134, 135, 137, 
 
 260, 453 
 Metin, 282 
 Meyer, 452 
 Milne, 448, 455 
 Mmchin, 416, 431, 435, 459 
 Minchin, Gray, and Tulloch, 435, 444 
 Mitchell, 5, 13, 92 
 Moffatt, 404 
 Mole, 444 
 
 Monti, 148, 150, 160 
 Moore, 283 
 Morehead, 281 
 Mori, 380, 407 
 Morton, 5, 13 
 Moscato, 393 
 Mosse, 262 
 
 Mott, 439, 441, 443, 444 
 Muehleck, 281, 297 
 Midler, O. F., 247 
 McCrae, 459 
 McFarland, 426 
 McLean, 270 
 
 Nabarro, 428, 429, 438, 439, 440, 441, 
 
 444 
 Navarre, 118 
 Nazari, 277 
 Neave, 426 
 Neveu-Lemaire, 12 
 Nicolle, 411, 413, 424 
 Nikastro, 380 
 Nocht, 315, 340, 434 
 Norris, 445, 450 
 Norris, Pappenheimer, and Flournoy, 
 
 4 59 
 Nott, 7, 56 
 Novi, 380 
 
 Novy, 424, 425, 435, 444, 450 
 Novy and Knapp, 445, 446, 447, 448, 
 
 45°, 45 1 - 452, 453- 454, 459 
 Novy and MacNeal, 436, 443, 458 
 Nuastro, 387 
 Nuttall, 66, 77, 85 
 
 Obermeieri, 445, 458 
 Oliver, 313 
 Ollwig, 344, 359 
 
 Osier, 6, 13, 14, 27, 53, 134, 221, 262, 
 285, 296, 297, 298, 360 
 
 Palladius, 4, 13 
 Pampoukis, 394 
 Panichi, 116, 322, 341, 363, 386 
 
INDEX OF AUTHORS. 
 
 467 
 
 Panse, 98, 103 
 
 Pappenheimer, 445 
 
 Parker, 145 
 
 Pasminik, 262, 269, 282 
 
 Patton, 413, 418, 419, 420, 422, 423, 427 
 
 Pelletier, 360 
 
 Pennoff, 273 
 
 Pensuti, 140, 143, 147, 270 
 
 Pepper, 129 
 
 Peters, 123 
 
 Petit and Verneuil, 282 
 
 Pfeiffer, 56, 407 
 
 Phillips, 426 
 
 Pianese, 411, 413, 424 
 
 Pick, 268, 281 
 
 Plehn, A., 34, 74, 78, 95, roo, 103, 129, 
 147, 190, 216, 262, 263, 316, 
 340, 343. 344. 358, 3 8 6, 394, 
 395, 403, 404, 406, 408 
 
 Plehn, F., 188, 358, 379, 380, 395, 407 
 
 Plimmer, 251, 442, 444 
 
 Poch, 132 
 
 Politzer, 273 
 
 Poncet, 273, 281 
 
 Powell, 341, 458 
 
 Pressat, 348 
 
 Procaccini, 355, 358 
 
 Prowazek, 251, 432, 434, 445, 447, 459 
 
 Pucci, 380 
 
 Quennec, 406 
 Queriolo, 144 
 
 Rabinowitsch, 443 
 
 Rabinowitsch and Kempner, 443 
 
 Range, 262 
 
 Rasch, 374, 386 
 
 Raymond, 268 
 
 Raynaud, 282 
 
 Reed, W, 63, 144, 153, 285 
 
 Rem-Picci, 140, 141, 142, 147, 262, 270 
 
 Rho, 13, 297, 399 
 
 Richard, 6, 13, 144, 358 
 
 Richard, C, 224 
 
 Ritchie, 394, 397 
 
 Rogers, L., 49, 93, 132, 133, 147, 341, 
 411, 413, 415, 416, 418, 419, 
 420, 422, 423, 425, 426, 427, 
 
 444 
 Romanowsky, 22, 54, 128, 312, 314, 
 
 34°, 3 6 3, 366, 414 
 Roque, 143 
 Rose, 386 
 Rosenau, 145 
 Rosenbach, 92, 103 
 Rosenstein, 141, 270, 282 
 Ross, P., 448, 455, 456, 459 
 Ross, R., 7, 13, 18, 57, 77, 83, 86, 352, 
 
 354, 358, 359, 4ii, 413, 4i6, 
 
 424, 425 
 Ross and Milne, 448, 455, 458 
 Rossoni, 134, 146, 407 
 Rouget, 428, 442 
 Rowley, 55 
 
 Ruata, 426 
 
 Ruge, 41, 42, 54, ss 
 
 Sacchi, 268, 282 
 
 Sacharoff, 7, 13, 18, 54, 83, 84, 92, 102, 
 
 103 
 Salabert, 268 
 Salisbury, 5, 13 
 Salvin-Moore, 435 
 Sambon, 89, 90, 354, 399, 431, 443, 444, 
 
 445, 446 
 Sanfelice, 34, 54 
 Sarda, 274 
 Sbacchi, 354, 359 
 Schaudinn, F., 16, 19, 41, 42, 46, 55, 
 
 59, 78, 92, 121, 245, 249, 263, 
 
 357, 359, 383, 384, 387, 446, 
 
 447, 448, 458, 459 
 Schaudinn and Hoffman, 458 
 Schellach, 446, 447, 448, 449 
 Schellong, 12, 282 
 Scheube, 113, 222, 224 
 Schewiakoff, 60 
 Schilling, 240, 263, 459 
 Schmidt, 279, 282 
 Schoo, 358, 370 
 Schiiff er, 375 
 Schuffner, 26, 55, 78, 128 
 Schwalbe and Solley, 129 
 Scott, 394 
 Seal, 393 
 Sedan, 273 
 Seely, 273, 282 
 Segard, 269, 282 
 Senator, 282 
 Sereni, 121, 123 
 Sergent, 74, 78, 359 
 Shakespeare, 285 
 Sherrington, 443 
 Shipley, 66 
 Simms, 394 
 Smith, J. B., 78 
 Solley, 129 
 Sorel, 262 
 Spadoni, 80 
 Spiller, 262 
 Stassano, 251 
 
 Statham, 418, 420, 426, 427 
 Steel, 442 
 
 Stengel, White, and Pepper, 129 
 Stephens, 12, 41, 97, 354, 359, 395, 
 
 444 
 Stephens and Christophers, 41, 75 
 
 103, 114, 13 2 , !47, 2 33, 
 
 3 22 , 34i, 359, 39 1 , 396, 
 
 444, 4 59 
 Sternberg, G. M., 6, 13 
 
 280 
 Stilling, 273 
 Strachan, 103 
 Strasser and Wolf, 263 
 Studel, 407 
 Sulzer, 273, 282 
 Sydenham, 5, 13 
 Sylvaine, 380, 387 
 
 54, 11 
 
 4°7. 
 
 . 97, 
 263, 
 408, 
 
 8, 221, 
 
4 68 
 
 INDEX OF AUTHORS. 
 
 95. Io: 
 
 Thayer, W. S., 12, 34, 55, 77, 103, 106, 
 109, i2i, 122, 123, 134, 140, 
 144, 148, 160, 171, 22i, 262, 
 
 27I, 278, 282, 296, 2Q1, 380, 
 407 
 
 Thayer and Hewettson, 12, 113, 142, 
 
 171, 175, 252 
 Theiler, 428, 442 
 Theobald, 63, 65, 69, 70, 78 
 Thomas, 429, 436, 437, 438 
 Thomas and Breinl, 429, 437, 444 
 Thomas and Linton, 429, 437, 444 
 Thompson, 285, 297 
 Tictin, 453. 454 
 Todd, 429, 441, 442, 443, 444, 440, 451, 
 
 4 55. 4 56 
 Tomaselli, 398, 407 
 Tomassi-Crudelli, 5, 13, 8i 
 Torti, 5, 13, 268 
 Torti and Angelini, 282 
 Travers, 348 
 
 Tsuzuki, 73, 283, 353, 359 
 Tuffier, 440 
 
 Tulloch, 429, 435, 436, 437, 438, 444 
 Turk, 130 
 
 Uhlenhuth, 446 
 
 Uhlenhuth and Haendel, 416, 452, 450 
 
 Vagedes, 344, 359 
 
 Valentin, 428 
 
 Vallin, 282 
 
 Varro, 4, 7, 12, 56 
 
 Vaughn, V., 285 
 
 Veratas, 398 
 
 Verneuil, 282 
 
 Vincent, 80, 268, 285, 297, 406 
 
 Virchow, 5, 13, 138, 146 
 Vitruvius, 56 
 Voges, 442 
 
 Ward, H. B., 444, 440 
 
 Warrington, 443 
 
 Watson, 348 
 
 Weatherfey, 280 
 
 Welch, W. H., 144, 153 
 
 Wellman, 438, 444, 458 
 
 Werlhof, 240 
 
 White, 129 
 
 Whitmore, 74 
 
 Winslow, 122 
 
 Winterbottom, 429, 443 
 
 Witherington, 285 
 
 Woldert, 77 
 
 Wolf, 263 
 
 Wolff, 273 
 
 Woodcock, 43 1 
 
 Woodward, 284, 292, 296, 297 
 
 Wright, J. H., 22, 60, 313, 340, 366, 
 
 411, 413. 423, 424, 425 
 Wurtz, 437, 444 
 
 Yanarris, 276 
 Yarr, 262 
 Young, 297 
 
 Zeri, 83, 147 
 
 Zettnow, 449, 450, 459 
 
 Zieman, 12, 16, 54, 55, 74, 77, 78, 118, 
 
 121, 122, 123, I32, I42, I44, 
 147. 17 5. 240, 242, 245, 263, 
 
 340, 343. 344, 359, 363, 3^6, 
 3 86 > 434 
 
GENERAL INDEX 
 
 Abdomen, symptoms connected with, 
 
 279 
 Abortion, as complication, 280 
 Adrenal glands, pathology of, 152 
 Aestivo-autumnal malaria, 176 
 
 classification of parasites of, 15,31 
 
 frequency of occurrence of, 176 
 
 parasites of, 31, 39, 50 
 
 prodromal symptoms of, 180 
 
 prognosis of, 299, 300 
 
 recurrences in, 240 
 
 red corpuscles in, 39, 191 
 
 remittent forms of, 224 
 
 sub-continued forms of, 2 53 
 
 symptoms of, 180 
 
 temperature curve in, 180 
 
 typhoid and, 292 
 
 varieties of, 15, 180 
 Age as predisposing cause, 114 
 Agglutination test, 322 
 Air, transmission by, 79 
 Albuminuria, as sequel of, 270 
 
 complication of, 278 
 Algid malaria, 221 
 Altitude, as predisposing cause, 105 
 Amaurosis, as a sequela, 273 
 Amoebae, occurrence of, 279 
 Anaemia, malarial, 129, 274 
 
 in cachexia, 2 58 
 
 recovery from, 302 
 
 red corpuscles, in, 130 
 
 post-malarial, 274 
 
 prognosis of, 302 
 
 varieties of, 131 
 Anophelinae, 63 
 Anchylostoma duodenale, occurrence of, 
 
 281 
 Aphasia, 267 
 Apoplexy, symptoms suggesting, 218 
 
 differential diagnosis of, 332 
 Appendicitis, symptoms of, 190 
 
 differential diagnosis of, 332 
 Aristochin, 380 
 Arteritis as sequela, 269 
 
 Bacillus malarias, 5 
 
 Bacteria in malaria, 5 
 
 Band forms of parasites, 30 
 
 Bilious remittent fever, 224 
 
 Blood, examination of, 191, 308 
 artefacts in, 128, 309, 318 
 changes in red corpuscles, 25, 31, 
 39. 127 
 
 Blood, citrated cultures of, 93 
 
 examination of, in pernicious in- 
 fections, 220 
 general pathology of, 127 
 haemoglobin of, 128, 133 
 in aestivo-autumnal infections, 39, 
 
 191 
 in malarial cachexia, 274 
 inoculation of, 83, 115 
 in quartan infections, 31, 191 
 in tertian infections, 25, 191 
 leucocytes in, 127, 132, 322 
 segmenting forms in, 21, 24, 28, 
 
 37> 39 
 staining of, 128, 312 
 summary of changes in, 140 
 
 Bone-marrow, changes in, 156 
 
 Brain, pathology of, 148 
 blood-vessels of, 148 
 changes in nerve cells of, 149 
 endothelial cells in, 149 
 free pigment in, 149 
 free plasmodia in, 148 
 macrophages in, 149 
 pigmented leucocytes in, 149 
 segmentation of plasmodia in, 148 
 
 Bronchiectasis, 277 
 
 Bronchitis, acute, as complication, 
 189, 276 
 
 Cachexia, discussion of, 256 
 
 pathology of, 164 
 
 prognosis of, 302 
 
 symptoms of, 258 
 
 treatment of, 382 
 Cadaver, appearance of, 148 
 Cardiac weakness, 221 
 
 treatment of, 381 
 Cardialgic form, 222 
 Chagres fever, 10 
 Children, malaria in, 192 
 
 frequency of, in, 192 
 
 symptoms in, 192 
 Chills, 172 
 
 analysis of character of, 186 
 
 in aestivo-autumnal malaria. 180 
 
 in quartan malaria, 176 
 
 in tertian malaria, 172 
 Chinchonidin, 370 
 Chinchonin, 370 
 Cholera as a complication, 280 
 
 differential diagnosis from, 339 
 Choleraic form of malaria, 221 
 
 469 
 
47° 
 
 GENERAL LNDEX. 
 
 Chorea, occurrence of, 268 
 Chromatin, staining reactions of , 23, 30, 
 
 39 
 Circulatory system, sequela? in, 269 
 
 complications in, 278 
 Classification of plasmodia, 14 
 
 biological, 14 
 
 Blanchard's, 16 
 
 clinical, 169 
 
 Craig's, 17 
 
 Grassi and Feletti's, 15 
 
 Kruse's, 1 5 
 
 Labbe's, 1 5 
 
 Luhe's, 16 
 
 Mannaberg's, 1 5 
 
 Sacharoff 's, 1 5 
 
 Schaudinn's, 16 
 
 Thayer and Hewettson's, 15 
 
 Zieman's, 16 
 Climate, influence of, 85, 104 
 Collapse, treatment of, 381 
 Congenital malaria, 120 
 Conjugation, intracorpuscular, 244 
 
 effect of quinine on, 370 
 
 morphology of, 246 
 
 relation to latency and recurrences, 
 248 
 
 significance of, 247 
 
 spontaneous recovery and, 261 
 Constipation, occurrence of, 189 
 Convalescence, treatment of, 381 
 Coma, occurrence of, 218 
 Comatose pernicious malaria, 218 
 Complications, 276 
 
 abortion as, 280 
 
 acute specific diseases as, 280 
 
 animal parasites as, 281 
 
 in circulatory system, 278 
 
 in gastro-intestinal system, 279 
 
 in genito-urinary system, 278 
 
 in nervous system, 276 
 
 in respiratory system, 276 
 
 insolation as, 280 
 Corpuscles, red blood-, 25 
 
 artefacts in, 31, 39, 128, 309, 318 
 
 changes in, 25, 31, 39 
 
 haemoglobin in, 25, 31, 39 
 
 morphology of, 25,31 
 
 plasmodia in, number of, 36, 38 
 
 reduction of, 131, 274 
 Corpuscles, white, reduction in, 127 
 Country, malarial, 85 
 Crenations of red corpuscle, 36, 309 
 Crescents, development of, in man, 49 
 
 development of, in mosquito, 56 
 
 discovery of, 6, 32 
 
 distinction of tertian and quotid- 
 ian, 48 
 
 fertilization of, 49 
 
 proportion of cases showing, 49 
 Culicidae, 62 
 Cultivation of plasmodia, 92 
 
 Deafness from quinine, 378 
 
 as a sequela, 273 
 Delirium as a symptom, 191 
 
 Dengue, leucocytes in, 131 
 
 differential diagnosis of, 335 
 Diagnosis of quotidian form, 331 
 
 of tertian form, 331 
 
 of pernicious forms, 331 
 
 by clinical methods, 330 
 
 by laboratory methods, 307 
 Diagnosis, differential, 332 
 
 from acute specific diseases, 335 
 
 from apoplexy, 339 
 
 from cholera, 339 
 
 from dysentery, 337 
 
 from endocarditis, 337 
 
 from hepatic abscess, 337 
 
 from infections with other para- 
 sites, 319, 335 
 
 from insolation, 339 
 
 from leukaemia, 339 
 
 from purpura, 339 
 
 from tuberculosis, 335 
 
 from typhoid fever, 332 
 
 from yellow fever, 333 
 Diagnosis of malarial mosquitoes, 323 
 Diarrhoea, occurrence of, 189 
 Diazo reaction, occurrence of, 142 
 Digestive system, complications in, 279 
 
 sequela? in, 269 
 Diphtheria, occurrence of, 280 
 Dissection of mosquitoes, 325 
 Distribution, geographical, 8 
 
 factors influencing, 9 
 
 in Africa, 1 1 
 
 in Asia, 1 1 
 
 in Central America, 10 
 
 in Europe, 10 
 
 in North America, 9 
 
 in South America, 10 
 
 in West Indies, 10 
 Diabetes mellitus, occurrence of, 281 
 Diet in acute fever, 381 
 
 in convalescence, 381 
 Digestive system, complications in, 279 
 
 sequelae in, 269 
 Dysentery, occurrence of, 270, 279 
 
 differential diagnosis of, 337 
 Dysenteric malaria, 222 
 
 Ear, sequelae affecting, 273 
 Elevation and malaria, 105 
 Endemic malaria, 8 
 Entamoeba histolytica, occurrence of 
 
 279, 281 
 Endocarditis, as a complication, 278 
 
 as a sequela, 269 
 
 differential diagnosis of, 337 
 Enteritis, acute, as a symptom, 269 
 
 chronic, ulcerative, 269 
 Epidemic malaria, 9 
 Epididymitis, malarial, 272, 279 
 Epigastrium, pain in, 190 
 Epistaxis, occurrence of, 254 
 
 in malarial cachexia, 258 
 Erysipelas, occurrence of, 280 
 Erythrocytes, changes in, 25, 31, 39, 
 
 I2 7> 3°9. 3 l8 
 Esanophele, 383 
 
GENERAL INDEX. 
 
 471 
 
 Etiology, 3 
 
 Euchinin, 380 
 
 Eye, sequelae affecting, 273 
 
 Facial appearance, 188 
 Fever, etiology of, 144 
 
 cause of pernicious, 216 
 
 causes of variation in, 184 
 
 continuous, 252 
 
 crisis of, 182 
 
 diagnostic features of, 330 
 
 effect of quinine on, 184 
 
 in children, 192 
 
 incubation of, 115 
 
 latent, 161, 228 
 
 masked, 235 
 
 modifications of, 184 
 
 pseudocrisis of, 182 
 
 quartan, 176 
 
 puerperal, 280 
 
 remittent, 224 
 
 sub-continued, 253 
 
 tertian, 172 
 
 tertian aestivo-autumnal, 180 
 
 typho-malarial, 284 
 
 variations in, 184 
 
 Malta, 280 
 
 long-interval fevers, 171 
 
 recurrences of, 240 
 Filipinos, malaria in, 11, 283 
 
 filariasis in, 281 
 ' Flagellate forms, activity of, 43, 48 
 
 active form of, 42 
 
 degenera ion of, 44 
 
 development of, 43 
 
 discovery of, 6 
 
 methods of obtaining, 318 
 of staining, 318 
 
 origin of, 42, 44 
 
 passive form of, 43 
 
 pigment in, 43, 48 
 
 sexual nature of, 18, 42 
 
 significance of, 7, 18, 42 
 
 staining reactions of, 46, 48 
 
 varieties of, 42, 48 
 
 Gall-bladder, pathology of, 152 
 
 Gametes, nature of, 40 
 
 differentiation of, 41, 48 
 
 of quartan plasmodium, 48 
 
 of tertian plasmodium, 43, 45 
 
 of the aestivo-autumnal plasmodia, 
 
 . 48 
 Micro-, 43, 44, 46, 48, 51 
 Macro-, 43, 46, 48, 50, 52 
 development in man, 43 
 
 in mosquito, 56 
 relation to mosquito of, 42 
 staining reactions of, 45, 52 
 Gangrene, occurrence of, 274, 279 
 Gastralgia, occurrence of, 222 
 Gastro-intestinal tract, complications 
 in, 279 
 sequelas in, 269 
 
 Genito-urinary system, complications 
 in, 278 
 
 sequelae in, 270 
 Glands, lymphatic, in malaria, 272 
 
 in kala-azar, 272 
 
 in sleeping-sickness, 272 
 
 in spirochetosis, 272 
 
 in trypanosomiasis, 272 
 Glandular system, sequelae in, 271 
 Glycosuria, occurrence of, 2 7 1 
 
 Hcemato phylum malarice, 14 
 Hcemamceba prcecox, 16 
 quartance, 16 
 tertiance,, 16 
 Halteridium, 7 
 Haemoglobinuric fever, 391 
 blood in, 400 
 
 complications and sequelae of, 403 
 definition of, 391 
 diagnosis of, 403 
 epidemics of, 393 
 frequency of, 393 
 geographical distribution of, 391 
 history of, 391 
 incubation of, 401 
 malarial theory of, 395 
 pathology of, 399 
 predisposing causes of, 394 
 prognosis of, 403 
 prophylaxis of, 403 
 quinine in, 404 
 
 theory of, 398 
 race and, 395 
 recurrences of, 395 
 residence and, 394 
 seasonal prevalence of, 393 
 specific theory of, 399 
 symptoms of, 401 
 treatment of, 404 
 urine in, 401 
 Haemoglobin, reduction of, 133 
 
 retraction of, 128, 309 
 Haemorrhage, occurrence of, 223, 280 
 from the bowels, 223 
 in malarial cachexia, 258 
 in pernicious malaria, 223 
 Haemosiderin, origin, 139 
 
 character of, 139 
 Headache, in tertian fever, 191 
 
 in aestivo-autumnal fever, 191 
 in quartan fever, 191 
 Heart, pathology of, 151 
 sounds of, 171, 184 
 symptoms connected with, 269 
 Hemiplegia, occurrence of, 220, 267, 
 
 276 
 Hepatitis, occurrence of, 190 
 Herpes, occurrence of, 188 
 History of malaria, 3 
 
 periods of, 4 
 Hyalin stage of plasmodium, 20, 27, 35, 
 
 36 
 in aestivo-autumnal fever, 35, 37 
 in quartan fever, 27, 30 
 in tertian fever, 20, 23 
 
47 2 
 
 GENERAL INDEX. 
 
 Hyalin stage of Plasmodium, number 
 in infected cell, 36, 38 
 staining reactions of, 23, 30, 39 
 
 Hysteria, occurrence of, 276 
 
 Histo plasma capsulatum, 400 
 
 Immunity, natural, 93 
 
 absolute, acquired, 95 
 natural, 04 
 relative, 94 
 
 acquired, 95 
 
 cause of, in malaria, 101 
 
 congenital, 94 
 
 natives and, 95 
 
 racial, 95 
 
 relative, acquired, 95 
 
 theories of, 100 
 
 various forms of malaria and, 102 
 Incubation, period of, 1 1 5 
 
 after inoculation by the mosquito, 
 
 117 
 after inoculation of malarial blood, 
 
 XI 5 
 after natural infection, 117 
 
 cause of prolonged periods of, 120 
 
 prolonged periods of, 1 iq 
 Insanity, occurrence of, 269 
 Iritis, occurrence of, 273 
 Infection, latent malarial, 228 
 
 by air, 79 
 
 by inoculation, 83 
 
 by mosquitoes, 84 
 
 by water, 81 
 
 by winds, 81, 108 
 
 chronic, 256 
 
 combined, 284 
 
 family, 233 
 
 in adults, 233 
 
 in children, 192, 233 
 
 masked, 235 
 
 mixed, 2 56 
 Inoculation, direct infection by, 83 
 
 experiments in, 83, 118 
 
 experimental transmission by the 
 mosquito, 84 
 
 by malarial blood, 83 
 Insomnia, occurrence of, 269 
 Insolation, occurrence of, 280 
 
 differential diagnosis of, 339 
 Intestines, pathology of, 151 
 
 necrosis of, 152 
 
 Plasmodia in, 152 
 
 ulceration of, 1 52 
 
 Jaundice, occurrence of, 224, 253, 335 
 
 Kala-azar, cause of, 411 
 
 differential diagnosis of, 335 
 leucocytes in, 131 
 
 Keratitis, occurrence of, 273 
 
 Kerosene as a prophylactic, 349 
 
 Kidneys, tubules of, 1 56 
 
 general pathology of, 155 
 
 Latent malaria, 161, 228 
 as a complication, 230 
 
 Latent malaria, duration of, 239 
 etiology of, 244 
 frequency of, 229 
 pathology of, 161 
 Plasmodia in, 161, 228 
 types of infection in, 22S 
 Laverania malaria, 15, 16 
 Leishmania-donovani , 41 1 
 
 blood in infection with, 422 
 biological position of, 412 
 cultivation of, 418 
 demonstration of, 423 
 distribution in man of, 420 
 elimination of, 423 
 geographical distribution of, 412 
 history of, 411 
 morphology of, 413 
 
 in cultures, 415 
 multiplication of, 417 
 occurrence in blood of, 422 
 pathogenicity of, 420 
 transmission of, 419 
 Leishmania tropicum and Leishmania 
 
 infantum,, 424 
 Leucocytes, reduction of, 131 
 
 diagnostic value of pigmented, 32 1 
 differential count of, 132 
 Leucocytosis in malaria, 131 
 Leukaemia, differential diagnosis of, 339 
 Locality, relation of, to predisposition, 
 104 
 in prognosis, 298 
 Lungs, pathology of, 1 50 
 
 broncho-pneumonia of, 151 
 capillaries of, 151 
 free pigment in, 151 
 phagocytes in, 151 
 Plasmodia in, 151 
 Liver, pathology of, 152 
 capillaries in, 1 53 
 cirrhosis of, 153, 271 
 epithelium of, 1 53 
 focal necrosis in, 1 53 
 free pigment in, 1 53 
 Kupfer's cells in, 153 
 macrophages in, 1 53 
 phagocytes in, 153 
 Plasmodia in, 153 
 
 Macrogametes, 41, 43, 46, 48 
 Macrophages, 1 54 
 Malta fever, 280 
 
 differential diagnosis of, 335 
 Mania, occurrence of, 269, 276 
 Marshall's dots, 40 
 Masked malaria, 235 
 
 duration of, 239 
 Merozoites, of tertian malaria, 21, 24 
 
 of aestivo-autumnal tertian, 39 
 
 of quotidian, 37 
 
 of quartan malaria, 28, 30 
 Melancholia, occurrence of, 269 
 Melanaemia, occurrence of, 5, 137 
 
 of adrenal glands, 152 
 
 of brain, 149 
 
 of heart, 151 
 
GENERAL INDEX. 
 
 473 
 
 Melanaemia, of kidneys, 155 
 
 of liver, 153 
 
 of lungs, 151 
 
 of retina, 1 50 
 
 of spleen, 1 54 
 
 of stomach and intestines, 152 
 Melanin, origin of, 138 
 
 chemistry of, 139 
 
 distribution of, 139 
 Measles, occurrence of, 280 
 Memory, loss of, 267 
 Meningitis, occurrence of, 276 
 Mental sequelae, 267 
 
 prognosis of, 302 
 Methylene blue as remedy, 380 
 Microgametocytes, 41 
 
 of aestivo-autunal tertian, 51 
 
 of quotidian, 51 
 
 of quartan malaria, 48 
 
 of tertian malaria, 43, 46 
 Micro gametes, 41 
 
 of aestivo-autumnal tertian, 51 
 
 of quotidian, 51 
 
 of quartan malaria, 48 
 
 of tertian malaria, 44, 47 
 Micro-organisms, and malaria, 5 
 Mosquitoes, 63, 86 
 
 classification of, 70 
 
 collection of, 324 
 
 destruction of, 347 
 
 development of plasmodia in, 56, 
 86 
 
 diagnosis of malarial, 323 
 
 dissection of, 325 
 
 distribution of, 72 
 
 experimental infection by, 84 
 
 feeding of, 68, 323 
 
 flying distance of, 69 
 
 habits of, 68 
 
 hibernation of, 69 
 
 larvae of, 66 
 
 malarial, 73, 323 
 
 mounting of, 325 
 
 ova of, 66 
 
 percentage of infected, 74 
 
 period of incubation in, 117 
 
 protection from, 89 
 
 pupae of, 68 
 
 rearing of, 328 
 
 sectioning of, 327 
 
 species of, 73, 76 
 
 structure of, 63 
 
 Natives, immunity in, 233 
 
 examination of blood in, 232 
 
 latent infection in, 232 
 Nausea, as symptom, 189 
 Necator americanus, 281 
 Necrosis, focal, of liver, 1 53 
 
 of spleen, 155 
 Nephritis, as a symptom, 278 
 
 as a sequela, 270 
 Nervous system, complications in, 276 
 
 sequelae in, 267 
 Neuralgia, occurrence of, 268 
 Neurasthenia, occurrence of, 269 
 
 Neuritis, multiple, as a sequela, 268 
 Neuroses, occurrence of, 276 
 
 Occupation, in predisposition, 86, 114 
 
 in prognosis, 299 
 Oocyst, description of, 58 
 Ookinete, description of, 58 
 Orchitis, occurrence of, 272, 279 
 Oscillaria malaria, 14 
 Otalgia, occurrence of, 273 
 Otitis media, occurrence of, 274 
 
 Paralysis, bulbar, 220, 268 
 
 occurrence of, 220 
 Paragonimus westermanii, 281 
 Paraplegia, occurrence of, 221, 267, 276 
 Parasites, malarial, see Plasmodia. 
 Parotitis, occurrence of, 269, 281 
 Paroxysms, malarial, 171 
 
 in aestivo-autumnal tertian, 180 
 
 in quotidian, 182 
 
 in quartan malaria, 171 
 
 in tertian malaria, 171 
 Pathology of malaria, 127, 148 
 
 general, 127 
 
 of fever, 144 
 
 of kala-azar, 420 
 
 of latent malaria, 161 
 
 of malarial cachexia, 164 
 
 of spirochaetosis, 451 
 
 of trypanosomiasis, 437 
 
 special, 148 
 Pernicious malaria, 215 
 
 classification of, 218 
 
 definition of, 215 
 
 diagnosis of, 331 
 
 etiology of, 216 
 
 frequency of, 216 
 
 parasites concerned in, 215 
 
 prognosis of, 300 
 
 treatment of, 382 
 Pernicious malaria, forms of, 215 
 
 algid form, 221 
 
 amaurotic form, 220 
 
 ataxic form, 220 
 
 bilious form, 224 
 
 bulbar form, 220 
 
 cardialgic form, 222 
 
 choleraic form, 221 
 
 comatose form, 218 
 
 delirious form, 220 
 
 diaphoretic form, 226 
 
 dysenteric form, 222 
 
 eclamptic form, 220 
 
 exanthematous form, 226 
 
 gastralgic form, 222 
 
 hasmorrhagic form, 223 
 
 paralytic forms, 220 
 
 pleuritic form, 226 
 
 pneumonic form, 223 
 
 syncopal form, 224 
 
 tetanic form, 220 
 
 typhoid form, 218 
 Phagocytosis, cells concerned in, 134, 
 
 . J 35 
 
 significance of, 136 
 
474 
 
 GENERAL INDEX. 
 
 Phagocytosis, time of occurrence of, 
 
 136 
 Phagocytes, varieties of, 135 
 
 degeneration of, 135 
 
 substances engulfed by, 136 
 Pigment, in tertian plasmodia, 20 
 
 diagnostic value of, 321 
 
 in aestivo-autumnal plasmodia, 36, 
 
 3 8 
 in quartan plasmodia, 27 
 
 Plasmodia, discovery of, 6 
 
 biology of, 19, 26, 35, 37, 40 
 
 cultivation of, 92 
 
 demonstration of, in blood, 3 1 1 
 
 in sections, 320 
 
 destruction of, 343 
 
 extracorporeal existence of, 40, 
 
 5 8 
 objects mistaken for, 318, 319 
 
 resistance of, 343 
 
 species of, 1 5 
 
 staining of, 22, 29, 39, 312 
 Plasmodium vivax (tertian), 19 
 
 action of quinine on, 364 
 
 cultivation of, 92 
 
 development of, 20, 56 
 
 differential diagnosis of, 319 
 
 gametes of, 43, 370 
 
 history of, 19 
 
 hyaline forms of, 20, 22 
 
 in latent infections, 161, 228 
 
 intracorpuscular conjugation in, 
 246 
 
 macrogametes of, 43 
 
 microgametes of, 44 
 
 microgametocytes of, 43 
 
 movement of, 20 
 
 pigmented forms of, 20, 22 
 
 pigment of, 20, 22 
 
 protoplasm of, 21, 22 
 
 size of, 20 
 
 sporogenic forms of, 42 
 
 sporulating forms of, 21, 22 
 
 staining reactions of, 22 
 
 structure of, 22 
 Plasmodium malariaz (quartan), 27 
 
 band forms of, 30 
 
 cultivation of, 92 
 
 development of, 27, 48, 56 
 
 differential diagnosis of, 319 
 
 gametes of, 48, 370 
 
 history of, 26 
 
 hyaline forms of, 27, 29 
 
 macrogametes of, 48 
 
 microgametes of, 48 
 
 microgametocytes of, 48 
 
 movement of, 27 
 
 pigmented forms of, 27, 29 
 
 pigment of, 27, 29 
 
 protoplasm of, 27, 29 
 
 quinine and, 368 
 
 size of, 27 
 
 sporogenic forms of, 47 
 
 sporulating forms of, 28 
 
 staining reactions of, 29 
 
 structure of, 29 
 
 Plasmodium falciparum (tertian aestivo- 
 autumnal), 37 
 
 cultivation of, 92 
 
 development of, 37, 56 
 
 differential diagnosis of, 320 
 
 gametes of, 48, 370 
 
 history of, 34 
 
 hyaline forms of, 37, 39 
 
 in latent infections, 161, 228 
 
 »nicrogametes of, 50, 52 
 
 ■microgametes of, 51, 53 
 
 microgametocytes of, 51, 52 
 
 movement of, 38 
 
 pigmented forms of, 38, 39 
 
 pigment of, 38, 39 
 
 protoplasm of, 38, 39 
 
 quinine and, 369 
 
 size of, 38 
 
 sporogenic forms, 48 
 
 sporulating forms of, 39 
 
 staining reactions of, 39 
 
 structure of, 39 
 Plasmodium falciparum quotidianum 
 (quotidian aestivo-autumnal), 
 
 35 
 
 cultivation of, 92 
 
 development of, 35, 56 
 
 differential diagnosis of, 320 
 
 gametes of, 48, 370 
 
 history of, 34 
 
 hyaline forms of, 3 5 
 
 in latent infections, 161, 228 
 
 macrogametes of, 50, 52 
 
 microgametes of, 51, 53 
 
 microgametocytes of, 51, 52 
 
 movements of, 36 
 
 pigmented forms of, 36, 39 
 
 pigment of, 36, 39 
 
 protoplasm of, 36, 39 
 
 quinine and, 369 
 
 size of, 3 5 
 
 sporogenic forms of, 48 
 
 sporulating forms of, 37 
 
 staining reactions of, 39 
 
 structure of, 39 
 Pleurisy, occurrence of, 226, 277 
 Pneumonic septicaemia, 277 
 Pneumonia, brocho-, 276 
 
 fibroid, 277 
 
 lobar, 276 
 
 malarial, 223 
 Polyuria, occurrence of, 271 
 Prognosis, factors influencing, 298 
 
 age and, 299 
 
 general consideration of, 298 
 
 in aestivo-autumnal malaria, 299, 
 
 3°° . 
 
 in complications, 302 
 in malarial cachexia, 302 
 in pernicious malaria, 300 
 in quartan malaria, 299 
 in sequelae, 302 
 in subcontinued forms, 301 
 in tertian malaria, 299 
 locality and, 298 
 occupation and, 299 
 
GENERAL INDEX. 
 
 475 
 
 Prognosis, physical conditions and, 
 299 
 
 race and, 298 
 
 social conditions and, 299 
 Predisposition, age in, 114 
 
 altitude in, 105 
 
 atmospheric conditions in, 112 
 
 climate in, 104 
 
 locality in, 104 
 
 moisture in, 106 
 
 occupation in, 114 
 
 race in, 113 
 
 rain in, 108 
 
 season in, 109 
 
 sex in, 113 
 
 social conditions in, 114 
 
 soil in, 106 
 
 time of day in, 106 
 
 winds in, 108 
 Prophylaxis, general consideration of, 
 342 
 
 biological methods of, 348 
 
 chemical methods of, 351 
 
 destruction of plasmodia, 343 
 of mosquitoes, 347 
 
 drainage in, 351 
 
 education regarding, 3 56 
 
 isolation of patient, 3 53 
 
 physical methods of, 351 
 
 screening in, 3 54 
 
 summary of methods of, 357 
 
 use of quinine in, 343 
 Protozoa, conjugation in, 247 
 Puerperal fever, malaria mistaken for, 
 281 
 
 occurrence of, 280 
 Pulse, in tertian cases, 171 
 
 in aestivo-autumnal cases, 180 
 
 in quartan cases, 175 
 Pyaemia, differential diagnosis of, 335 
 Pyelitis, occurrence of, 335 
 
 Quartan malaria, 26, 175 
 
 diagnosis of, 330 
 
 frequency of, 175 
 
 Plasmodium of, 26, 47 
 
 prognosis of, 299 
 
 sub-continued form of, 252 
 
 symptoms of, 175, 252 
 
 treatment of, 360 
 
 typhoid and, 287 
 Quinine, history of, 360 
 
 action of, on plasmodia, 361 
 
 as a test for malaria, 307 
 
 contraindications to, 378 
 
 dosage of, 376 
 
 effect on temperature curves of , 1 84 
 
 eruptions due to, 379 
 
 methods of giving, 373 
 
 preparations of, 371 
 
 salts of, 371 
 
 substitutes for, 378 
 
 time of administration of, 371 
 Quotidian aestivo-autumnal malaria, 
 35. 182 
 
 diagnosis of, 330 
 
 Quotidian aestivo-autumnal malaria, 
 frequency of, 176 
 illustrative cases of, [95 
 Plasmodium of, 3 5, 48 
 prognosis of, 299 
 symptoms of, 182, 252 
 treatment of, 360 
 
 Race and predisposition, 1 13 
 
 and prognosis, 298 
 Recovery, spontaneous, 259 
 
 conjugation and, 261 
 
 etiology of, 260 
 Recurrences, occurrence of, 239 
 
 conjugation and, 245 
 
 etiology of, 244 
 
 time of, 239 
 Relapsing fever, parasites of, 413 
 
 differential diagnosis of, 335 
 Respiratory system, 276 
 
 complications in, 276 
 Retina, malarial diseases of, 150, 273 
 Rheumatism, acute, 280 
 
 Sacharoff 's classification, 1 5 
 
 Salochinin, 380 
 
 Schaudinn's classification, 16 
 
 Schistosoma hcsmatobium, 281 
 
 Schizogony, occurrence of, 18 
 
 Schizont, structure of, 22, 29, 39 
 
 of quartan plasmodium, 27, 29 
 of quotidian aestivo-autumnal Plas- 
 modium, 3 5, 39 
 of tertian aestivo-autumnal Plas- 
 modium, 38 
 of tertian plasmodium, 20, 22 
 
 Schuffner's dots, 26, 31, 40 
 
 Season, relation to, 85, 109 
 
 Septicaemia, occurrence of, 277 
 
 Sequela?, 267 
 
 of the circulatory system, 269 
 
 of the gastro-intestinal system, 269 
 
 of the genito-urinary system, 270 
 
 of the glandular system, 271 
 
 of the nervous system, 267 
 
 of the organs of special sense, 273 
 
 other sequelae, 274 
 
 Serum therapy, 385 
 
 Skin, symptoms connected with, 188, 
 274 
 diseases of, 281 
 
 Species, of plasmodia, 14 
 diagnosis of, 330 
 interchangeability of, 14 
 
 Spinal cord, pathology of, 1 50 
 
 Spirochaetes, description of, 445 
 biological position of, 446 
 cultivation of, 451 
 demonstration of, 457 
 distribution of, in man, 456 
 geographical distribution of, 446 
 immunity to, 453 
 morphology of, 447 
 pathogenicity of, 451 
 
476 
 
 GENERAL INDEX. 
 
 Spirochetes, 
 
 Spirochata plicatilis, 447 
 
 recurrcntis, 447 
 carter i, 450 
 duttoni, 448 
 novyi, 450 
 
 transmission of, 454 
 Spleen, floating, 272 
 
 abscess of, 272 
 
 crescents in, 1 54 
 
 enlargement of, 154, igo 
 
 free plasmodfa in, 1 54 
 
 focal necrosis in, 1 55 
 
 haemorrhage in, 1 54 
 
 macrophages in, 1 54 
 
 pathology of, 1 54 
 
 phagocytes in, 154, 155 
 
 pigment in, 1 54 
 
 puncture of, 322 
 
 rupture of, 272 
 Sporoblasts, description of, 60 
 Sporogony, description of, 56 
 Sporonts, 58 
 Sporozoites, description of, 60 
 
 staining of, 62 
 Sporulation, description of, 21, 28, 37, 
 
 39 
 
 in aestivo-autumnal plasmodia, 3 7 , 
 
 39 
 in quartan plasmodium, 28 
 in tertian plasmodium, 2 1 
 relation of, to paroxysms, 144 
 Staining of plasmodia, 22, 29, 39, 312 
 of aestivo-autumnal plasmodia, 39, 
 
 3*3 
 
 of quartan plasmodium, 29, 312 
 
 of sporogenic forms, 51, 318 
 
 of tertian plasmodium, 22, 312 
 
 Giemsa's method of, 317 
 
 Leishman's method of, 315 
 
 Marino's method of, 316 
 
 methods of, 313 
 
 Nocht's method of, 315 
 
 Plehn's method of, 316 
 
 Romanowsky's method, 314 
 
 Wright's method of, 313 
 Stomach, pathology of, 152 
 Sub-continued fever, 252 
 
 prognosis of, 301 
 
 symptoms of, 2 53 
 Sweats in malaria, 173 
 
 in quartan fever, 176 
 
 in quotidian aestivo-autumnal, 
 182 
 
 in tertian aestivo-autumnal, 180 
 
 in tertian fever, 173 
 Symptomatology, 1 7 1 
 
 analysis of, 184 
 
 of malarial cachexia, 2 58 
 
 of quartan fever, 175 
 
 of quotidian aestivo-autumnal 
 fever, 182 
 
 of pernicious infections, 215 
 
 of tertian aestivo-autumnal fever, 
 180 
 
 of tertian fever, 171 
 
 Temperature, discussion of, 144, 219 
 
 analysis of, 184 
 
 atypical temperature curves, 184 
 
 cause of atypical curves, 184 
 
 in quartan fever, 1 7 5 
 
 in tertian aestivo-autumnal fever, 
 180 
 
 in quotidian aestivo-autumnal 
 fever, 182 
 
 in tertian fever, 1 7 1 
 Tertian malaria, 19, 161 
 
 diagnosis of, 330 
 
 frequency of, 171 
 
 Plasmodium of, 19, 42 
 
 prognosis of, 299 
 
 recurrences in, 243 
 
 symptoms of, 171, 252 
 
 treatment of, 360 
 Tertian aestivo-autumnal malaria, 37, 
 163, 180, 194 
 
 clinical illustrations of, 203 
 
 diagnosis of, 330 
 
 frequency of, 176 
 
 plasmodium of, 37, 48 
 
 prognosis of, 300 
 
 symptoms of, 180, 253 
 
 treatment of, 360 
 Tinnitus aurium, 378 
 Tongue, characters of, 188 
 Tonsillitis, occurrence of, 281 
 Toxin, malarial, 143, 145 
 
 relation to fever, 144 
 Transmission of malaria, 79 
 
 by air, 79 
 
 by inoculation of malarial blood, 83 
 
 by mosquitoes, 84 
 
 by water, 81 
 Treatment of malaria, 360 
 
 aristochin in, 380 
 
 Esanophele in, 383 
 
 euchinin in, 380 
 
 methylene blue in, 380 
 
 phenocoll in, 380 
 
 quinine in, 361 
 
 Roentgen's rays in, 384 
 
 salochinin in, 380 
 
 serum therapy, 385 
 
 substitutes for quinine, 378 
 
 Warburg's tincture in, 384 
 
 of cachexia, 382 
 
 of convalescence, 381 
 
 of pernicious fevers, 382 
 
 of special symptoms, 381 
 Trophozoites, 20 
 Trypanosoma gambiense, 428 
 
 blood in infections with, 439 
 
 biology of, 436 
 
 biological position of, 430 
 
 cultivation of, 434 
 
 demonstration of, 439 
 
 distribution in man of, 438 
 
 examination of cerebro-spinal 
 fluid, 439 
 
 geographical distribution of, 430 
 
 gland puncture in infections with, 
 441 
 
GENERAL INDEX. 
 
 477 
 
 Trypanosoma gambiense, 
 
 history of, 428 
 
 intermediate host of, 435 
 
 morphology of, 430, 433 
 
 multiplication of, 434 
 
 pathogenicity of, 437 
 
 staining of, 442 
 
 transmission of, 438 
 Trypanosoma lewisi, 442 
 
 brucei, 442 
 
 dimorphon, 442 
 ■ equinum, 442 
 
 equiperdum, 442 
 
 evansi, 442 
 
 theileri, 442 
 Trypanosomiasis, differential diagno- 
 sis of, 335 
 Tuberculosis, as complication, 277 
 
 differential diagnosis of, 335 
 Typhoid and malaria, 280, 284 
 
 differential diagnosis of, 332 
 
 Ulcers, gastric, 269 
 
 Uninhabited regions and malaria, 115 
 
 Urinary system, symptoms connected 
 
 with, 190 
 Urine, changes in, 140 
 
 acidity of, 140 
 
 albumin in, 142 
 
 chlorides in, 142 
 
 color of, 141 
 
 Diazo reaction in, 142 
 
 Urine, indican in, 142 
 
 iron in, 142 
 
 nucleo-albumin in, 142 
 
 pepton in, 142 
 
 phosphates in, 141 
 
 quantity of, 140 
 
 reaction of, 141 
 
 sodium and potassium in, 142 
 
 specific gravity of, 141 
 
 total solids of, 141 
 
 toxicity of, 142 
 
 urea in, 141 
 
 uric acid in, 141 
 Urticaria, occurrence of, 188 
 
 Vacuoles, differentiation of, 310 
 Vegetable organisms and malaria, 5 
 Vertigo, occurrence of, 191, 274 
 Viscera, pathology of, 149 
 Vomiting, occurrence of, 184, 382 
 treatment of, 382 
 
 Warburg's tincture, 384 
 Water, transmission by, 81 
 
 experiments with, 82 
 Winds, relation of, 81, 108 
 
 Yellow fever, differential diagnosis of, 
 333 
 
 Zygote, malarial, demonstration of, 327 
 
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