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a study of some fatal 
 "cases of malaria. 
 
 LtBRARY 
 OF THE 
 
 THE PRESaVTERlAN hq. 
 
 LEWELLYS F. BARKE R , M . B.,Tor..^ 
 
 Associate in Anatomy, Johns Hopkins University, and Assistant Resident Pathologist, 
 The Johns Hopkins Hospital. 
 
 Eeprinted from The Johns Hopkins Hospital Beporls, Vol. V, 1895. 
 
 BALTIMORE 
 The Johns Hopkins Press 
 
 1895 
 
JOHN MURPHY & CO., PRINTERS, 
 BALTIMORE. 
 
 
A STUDY OF SOME FATAL CASES OF MALARIA. 
 
 By LEWELLYS F. BARKER, M. B., TOR., 
 
 Associate in Anatomy and Assistant Resident Pathologist. 
 
 PAGE. 
 
 I. Introduction, - - - - 5 
 
 II. Case A. — Aestivo-atjtumnal Malaria; Anomalous Symptoms 
 
 DURING Life, 6 
 
 III. Case B. — Aestivo-autumnal Malaria ; Grave Abdominal Symp- 
 
 toms, --- 13 
 
 IV. Case C. — Acute Aestivo-autumnal Malaria ; Death from Acci- 
 
 dent ; Acute Necrotic Lesions in Liver and Spleen. 
 The Relation of Malaria to Cirrhotic Procisses, 19 
 
 V. Case D. — Double Tertian Malarial Infection, Associated 
 WITH General Streptococcus Infection ; Symptoms 
 OF AN Acute Nephritis with General Anasarca 
 
 MANIFESTED DURING LiFE. NOTE ON THE CONCUR- 
 RENCE OF Bacterial or Protozoan Infections with 
 Malaria, - 29 
 
 VI. On the Unequal Distribution of the Parasites in the body in 
 
 Malarial Infection, ---------47 
 
 VII. On Phagocytosis in Malaria, ------- 54 
 
I. 
 
 INTRODUCTION. 
 
 The material for the following study was derived from the bodies 
 of patients coming to autopsy in the Pathological Laboratory of the 
 Johns Hopkins University and Hospital between 1889 and 1894. 
 
 For the permission to study the tissues and to extract protocols 
 from the post-mortem records I have to thank Professor W. H. Welch ; 
 the clinical histories of the cases have been put into my hands through 
 the courtesy of Professor William Osier. 
 
 Since the discovery of Laveran's parasite which rendered possible 
 under ordinary circumstances the early recognition of a malarial 
 infection by means of the microscopical examination of the fresh blood, 
 it has become a comparatively rare occurrence for a patient, to die 
 of this disease. The study of the pathology of malaria is consequently 
 limited to the few instances in which the patients die from traumatism 
 or from some inter-current disease, and to those rare cases of pernicious 
 malarial infection which terminate fatally. 
 
 The tissues from the cases referred to in this paper were hardened some 
 in alcohol, some in Miiller's fluid, and others in Flemming's solution. 
 For general study the tissues fixed in strong alcohol served best, while 
 for the investigation of certain points those fixed in Flemming's so- 
 lution gave excellent results, those preserved in Miiller's fluid being 
 the least satisfactory. The tissues were imbedded in celloidin and in 
 paraffin. For staining haematoxylin and eosin, alum-cochineal, sa- 
 franin, gentian violet, aqueous magenta, Weigert's fibrin-stain and 
 the triple stain (Ehrlich-Biondi) were employed, while for the study 
 of the pigments and of the iron-containing compounds derived from 
 the red blood corpuscles certain sections were treated with ammonium 
 sulphide and others with hydrochloric acid and ferrocyanide of potas- 
 sium ^ (method of Perls). 
 
 ^ Concerning the reactions for iron and the unsatisfactory nomenclature of iron- 
 containing compounds, cf. article by J. J. Abel, Virch. arch., Bd. 120, p. 204; also 
 articles by A. B. Macallum, Proc. Eoy. Soc, &c. 
 
 5 
 
6 Leioellys F. Barker. 
 
 In order to determine accurately the relation of the parasites and 
 pigments to the tissues many sections both stained and unstained were 
 examined in media of different refractive power. For this purpose 
 water, glycerine, balsam, a saturated solution of acetate of potassium, 
 Farrant's medium, and solutions of chloral-hydrate were employed. 
 
 The enormous strides made in late years in the clinical studies of 
 malaria has rendered a re-working of the pathology highly desirable. 
 The majority of the investigators have contented themselves with the 
 study of the blood taken from the peripheral circulation, or from that 
 obtained from tappings of the spleen made during life. Some how- 
 ever, among them Bignami, Marchiafava, Guarnieri and Golgi in 
 Italy, Metschnikoff, Laveran, Kelsch and Kiener in France, and Osier, 
 Councilman, Abbott and Dock in America have made contributions 
 to our knowledge of the pathology of the affection as it concerns the 
 internal organs of the body. 
 
 In this report will be found the clinical histories of four cases of 
 malaria, in three of which the parasites were of the aestivo-autumnal 
 and in one of which they were of the tertian type, together with 
 a description of the pathological findings in each. As an appendix 
 are added certain observations dealing with the unequal distribution 
 of the parasites in the body, and with phagocytosis in malaria. 
 
 II. 
 
 Case A. — Aestivo-autumnal malaria ; anomalous symptoms during 
 life. 
 
 L. K., aet. 81, was admitted to Prof. Osier's wards July 18, 1889, 
 complaining of pains in the head and of coldness and numbness of the 
 feet and hands. Had in earlier life been always healthy^ and on 
 admission was a healthy-looking vigorous man for his age. On July 
 9th, while engaged in berry picking in a field in Anne Arundel Co., 
 Md., he suffered from heat stroke, remaining unconscious for two hours 
 and having to be carried to his home. The next day he was up and 
 about again, and felt able to work, but had not been altogether well 
 since, having suffered from headaches and occasional chilly sensations. 
 
 On admission the following note was made : " Healthy looking, 
 much sunburnt, pulse full, walls of blood vessels soft, no oedema of 
 feet. The lungs are clear in front and behind ; the expiration is a 
 
A Study of Some Fatal Cases of Malaria. 7 
 
 little prolonged. The apex beat of the heart is neither visible nor 
 palpable, the sounds are weak, the second being scarcely audible at 
 the base. The area of liver dullness is reduced. The spleen is not 
 enlarged ; the urine is light yellow in color, specific gravity, 1010 ; 
 no albumen, no casts." 
 
 Concerning the further progress of the case, we have the following 
 account from Prof. Osier. 
 
 " I saw the patient only during the first four days of his stay at the 
 Hospital, and thought that he was suffering from the effects of a sun- 
 stroke. He was given a tonic mixture. The patient's temperature 
 was normal, but on the 20th and 21st the morning records were 97.6° 
 and 97.8° respectively. 
 
 On the 25th, at 11.30, he had a chill; the temperature rose to 
 105° and remained high all the afternoon. At 7.30 p. m. it was 
 again 105°, and he was given a graduated bath. 
 
 Throughout the 26th the temperature fell, but did not go below 
 101° ; the pulse was rapid and feeble. 
 
 On the 27th the temperature at 8 a. m. was 100.5° ; in the after- 
 noon it rose to 103°, and in the evening was 100.3° ; pulse, 104, 
 extremely irregular and intermittent. There were feeble r^les, with 
 a high pitched percussion note in the right infra-scapular region. 
 Towards evening the patient sweated profusely and the breathing was 
 of the Cheyne-Stokes type. 
 
 On the 28th the temperature fell rapidly, sinking from 103° at 4 
 p. m. of the 27th to 97.3° at 8 a. m. of the 28th, and to 95.5° at 10 
 a. m. The pulse was extremely feeble and irregular. He vomited 
 twice. There has been no expectoration. The breath sounds at the 
 right base have been very feeble. Throughout the afternoon of the 
 28th the temperature rose and at 8 p. m. was 100°. 
 
 On the 29th the Cheyne-Stokes breathing persisted, and the patient 
 had slight diarrhoea. His speech was disturbed but he appeared to 
 be conscious. Throughout the 30th, 31st and August 1st he sank 
 gradually and died on the morning of the 2d. 
 
 I did not see the patient from the date of his chill until the morning 
 of the 2d, just before his death. The case was regarded as one of low 
 anomalous pneumonia. The day after the chill it is stated in the note 
 that the blood was examined with negative results ; but there is no 
 initial to indicate by whom the examination was made." 
 
8 Lewellys F. Barker, 
 
 Autojjsy. — (Professor Welsh.) (Abstract from the records of the 
 Pathological Laboratory). 
 
 Anatomical Diagnosis. — Malarial fever, with malarial parasites in 
 the blood and spleen; soft, swollen, pigmented spleen; pigmented 
 and myristicated liver ; pulmonary emphysema ; general muco-puru- 
 lent bronchitis ; pulmonary oedema ; catarrhal colitis. 
 
 Exterior. — Body, 168 cm. long ; much emaciated. Hernial tumor 
 in each groin. Rigor mortis well marked. Livor mortis in dependent 
 parts. On belly and chest are a number (20-30) dark red liver spots, 
 slightly elevated, which do not disappear on pressure. 
 
 Abdominal Cavity. — Loops of small intestine lie loosely in the her- 
 nial sacs which open by wide mouths at internal inguinal rings into 
 the peritoneal cavity. Spots of fibrous thickening on peritoneum 
 covering mesentery of small intestine. Old pigmented patches on 
 pelvic peritoneum. Firm old adhesions binding tightly together the 
 under surface of the liver and gall-bladder with the adjacent parts of 
 the duodenum and ascending and transverse colon. The capsule of 
 the liver along its anterior border and on the adjacent convexity is 
 opaque, white, thickened and wrinkled, owing to old fibrous thick- 
 ening. The diaphragm on the right side reaches the lower margin 
 of fifth rib, on left, lower margin of sixth rib. The peritoneal cavity 
 contains about 50 cc. of clear yellowish serum. 
 
 Thoracic Cavity. — The anterior surface of the pericardium, save a 
 triangular area much smaller than normal, is covered with the em- 
 physematous lungs. There are old fibrous adhesions between the 
 pleural surfaces of the posterior parts and apices of both lungs. On 
 anterior surface of middle lobe of right lung are some old white 
 fibrous nodules, the size of a pin's head and larger. There is a small 
 amount of clear serum in each pleural cavity and also in the peri- 
 cardial cavity. 
 
 Heart. — Weight, 290 grams ; small ; myocardium of a deep brown 
 color ; some thickening of aortic and mitral valves along lines of 
 closure, but apparently not enough to interfere with the functions of 
 the valves. Some atheromatous deposits in pockets of aortic valves. 
 Endocardium of left ventricle thickened and opaque. No fibrous 
 patches in myocardium except at tips of musculi papillares. Chordae 
 tendineae of mitral valve somewhat thickened and retracted. The 
 coronary arteries present near their origin moderate atheromatous 
 
A Study of Some Fatal Cases of Malaria. 9 
 
 thickening, and are rather tortuous. Loose dark red clots and some 
 decolorized post-mortem clots in both ventricles. 
 
 Lungs. — Markedly emphysematous, swollen, not collapsing readily, 
 of a soft cushiony feel, air cells in anterior part of lungs near inner 
 margin reach size nearly of pins' heads. Considerable pigmentation 
 with coal. On section the dependent parts of lung are much con- 
 gested and there is moderate general oedema. Both large and smaller 
 bronchi contain much muco-pus, which can be squeezed out in opaque 
 thick whitish drops. The bronchitis is general. The pulmonary 
 parenchyma everywhere contains air. There is no pneumonia. On 
 pleura at apices of both lungs are some old fibrous scars and immedi- 
 ately beneath the pleura are a few old black calcified nodules the size 
 of split peas. 
 
 Spleen. — Weight, 192 grams ; length, 13 cm. ; width, 8 cm. ; thick- 
 ness, 3.5 cm. The capsule is extensively thickened and opaque, and 
 the organ is surrounded by old fibrous adhesions. The consistence is 
 soft, the organ being almost diffluent on section. Color, dark browQ 
 or blackish-brown. Malpighian bodies not readily distinguishable 
 in the soft dark -colored pulp. 
 
 Kidneys. — Surface smooth, save some indication of foetal lobulation. 
 Capsules not adherent. Cortex measures 6 mm. in thickness ; striae 
 distinct and regular. Weight of each kidney 196 grams. Dimensions, 
 10 X 5 cm. There is a small white fibroma the size of a split pea in 
 cortex of left kidney. Adrenals apparently normal. 
 
 Bladder. — Contains about 5 cc. of whitish fluid. Mucosa normal. 
 Prostate moderately enlarged and contains many corpora amylacea. 
 
 lAver. — Weight, 1650 grams. Dimensions, 24 x 15 x 6.5 cm. Cap- 
 sule opaque and thickened along anterior margin. Prevailing color 
 on section brown or bronzed. Centers of acini of a reddish brown, 
 peripheries of a lighter brownish color. The gall bladder contains a 
 moderate amount of brownish yellow bile ; bile duct patent. 
 
 Pancreas. — Firm, pale, normal. 
 
 Large Intestine. — Rectum contains very hard, yellowish scybala 
 coated with mucus. Balls of firm yellow faeces in colon and caecum. 
 Mucous membrane of large intestine, particularly of sigmoid flexure 
 and colon, coated with firmly adherent, stringy, very tenacious, white 
 mucus, often peculiarly arranged in irregular anastomosing lines. 
 The mucus is about of the consistence observed in the discharges of 
 mucous or membranous diarrhoea. 
 
10 Lewdlys F. Barker. 
 
 Small Intestine. — Contains fluid or semi-fluid yellow material and 
 presents areas of hyperaemia and of coating with mucus. 
 
 Stomach. — Contains a little partially digested food. Mucous mem- 
 brane of pyloric region coated with a thin layer of mucus. On 
 anterior wall, 4 cm, from pylorus, is a mucous polypus 6 mm. long, and 
 4 mm. thick, with a smooth, round extremity ; not constricted at base. 
 Near base of polypus is a round depression with smooth edges and 
 floor communicating with an oblong depression by a narrow similar 
 but elongated depression. The round depression is 3 mm. in diameter, 
 the oblong measures 4 x 2 mm. These depressions extend in depth 
 to about that of the mucous membrane. The floor of the depressions 
 looks as if covered with smooth mucous membrane. There is no 
 stellate cicatricial tissue in or near these depressions, nor is there any 
 evidence of change on the outer surface of the stomach. 
 
 Brain. — Arteries of base very atheromatous ; considerable increase 
 of cerebro-spinal fluid; white substance of hemispheres presents 
 numerous puncta vasculosa. Brain otherwise appears normal. 
 
 Microscopical examination of blood from finger shows a few pale 
 bodies of shape and size of red corpuscles or larger, containing pig- 
 mented Plasmodia ; also free round pigmented corpuscles, the pigment 
 in molecular movement (varying in size from blood plate to twice this 
 size) ; also pigmented crescents, the pigment in a ring in the middle ; 
 in one specimen of splenic pulp two actively moving free flagella. 
 In the capillaries of the brain are a few pigmented corpuscles. 
 
 Examination of the hardened tissues. — A microscopical study of the 
 organisms and tissues confirms the findings at autopSy and the di- 
 agnosis of an aestivo-autumnal malarial infection. The unequal dis- 
 tribution of the parasites and especially the accumulation of immense 
 numbers of them in the capillaries of the mucous membrane of the 
 stomach render this case of more than ordinary interest. 
 
 The Liver. — On examination with very low powers (8 to 16 di- 
 ameters) there are very few pigment masses large enough to attract 
 notice; in marked contrast to what could be observed with these 
 powers in the liver of Case C (tertian infection). 
 
 With higher powers intravascular phagocytes, especially macro- 
 phages, are seen to be comparatively few in number. The malarial 
 parasites are not especially numerous in the liver. They vary in size, 
 and have a yellow tint in tissues hardened in Miiller's fluid ; some 
 
A Study of Some Fatal Cases of Malaria. 11 
 
 contain almost no pigment ; others contain very fine granules of 
 brownish black pigment ; still others contain distinct dark central 
 blocks of pigment. A few of the organisms appear to be free in the 
 blood or included within red corpuscles. The majority are inside mono- 
 nuclear leucocytes ; a few have been taken up by polynuclear leucocytes. 
 The latter cells also contain free pigment in granules and blocks. 
 There is marked participation of the endothelial cells of the capillaries 
 of the liver in the phagocytic process. These cells, the cells of Kupifer 
 and the iutracapillary macrophages contain a few parasites, pigment 
 in granules and in blocks, infected and non-infected red corpuscles, 
 fragments of corpuscles, and particles of irregular size and shape that 
 yield the blue iron-reaction. Some of the phagocytic cells, especially 
 the endothelial cells, contain brassy corpuscles (globuli rossi ottonati 
 of the Italians). From many of the pigmented capsules in the larger 
 cells fine lines of yellowish brown pigment can be seen radiating out 
 into the protoplasm. The pigment is chiefly situated in cells at the 
 periphery of the lobules. In certain areas bright yellowish pigment 
 in considerable quantities can be seen running along the rows of liver 
 cells. The liver cells themselves are large, swollen, finely granular 
 and often vacuolated. The nuclei of the liver cells vary in size and 
 in vesicularity. The central veins of the lobules and the neighboring 
 capillaries are dilated and the liver cells near them contain brownish 
 pigment. The spaces between the liver cells and the capillary walls 
 are exaggerated. Some of the liver cells themselves contain malarial 
 pigment. No areas of necrosis can be made out, but as no tissues 
 from this case were preserved in absolute alcohol small necroses could 
 easily be overlooked. There is a slight excess of lymphoid cells in 
 the portal spaces, and a few larger pigmented cells are present in the 
 connective tissue of these spaces. 
 
 The Spleen. — The blood vessels are distended, especially those of the 
 pulp. In places there are actual haemorrhages into the pulp tissue, 
 and numerous red corpuscles can be made out among the cells of the 
 pulp-cords. The capsule of the spleen is slightly thickened and the 
 stroma is denser than normal. There is an astonishingly large number 
 of organisms present. These vary in size, and are of the aestivo- 
 autumnal variety, the majority appearing to be nearly full grown. 
 They are not numerous in the larger vessels of the spleen, but are 
 very abundant in the blood of the smaller vessels of the splenic pulp. 
 
12 Lewellys F. Barker . 
 
 A large number of well formed organisms, infected corpuscles, remains 
 of organisms and corpuscles, and fine and coarse pigment are con- 
 tained within phagocytes. The macrophages are of about the same 
 size or a little larger than those described in the liver. Many of 
 them contain brassy corpuscles. The endothelial cells and the cells 
 of the splenic pulp itself, as well as the mononuclear leucocytes, con- 
 tain foreign products. Here and there a large vesicular parasite with 
 very little pigment is visible, and a few crescents can be made out, 
 although they are probably much more numerous than the study of 
 hardened tissues alone might have led us to infer. They were present 
 in considerable numbers in the fresh blood taken from the spleen at 
 autopsy, but on account of the deformity resulting from hardening 
 and the pallor of the bodies of these forms, we have experienced the 
 same difficulty in recognizing them in sections which has attended the 
 studies of other observers. The pigment is mainly contained in the 
 splenic pulp ; the Malpighian bodies are comparatively free from it, 
 and when pigment is to be made out in the latter, it is usually included 
 within large cells around the arterioles. 
 
 The Kidney. — There is a moderate degree of chronic diffuse ne- 
 phritis, some of Bowman's capsules showing slight fibrous thickening. 
 The glomeruli for the most part fill the capsular spaces. A moderate 
 amount of pigment is to be seen within the glomeruli, chiefly con- 
 tained in the endothelium of the glomerular capillaries ; some of it 
 being within mononuclear cells inside the capillaries. The endothelial 
 cells of the intertubular capillaries and of the small veins contain 
 occasionally at the poles of their nuclei granules and masses of 
 malarial pigment. Occasionally inside the vessels a mononuclear cell 
 containing one or more tolerably well preserved organisms can be made 
 out. No parasites were seen in the kidney outside of phagocytes. 
 The epithelium lining the convoluted tubules is swollen and filled 
 with fine granules. Some of the cells are actually necrotic, the nuclei 
 refusins: to stain. A number of the tubules in the cortex contain 
 within the protoplasm of their lining epithelium masses of bright 
 yellow pigment. Occasionally hyaline casts are met with in the 
 collecting tubules. 
 
 The Stomach. — The findings in the sections of the stomach are of 
 interest. The capillaries and veins of the mucous membrane are 
 widely dilated, many of the larger and smaller veins being engorged 
 with red blood corpuscles, whose outlines are perfectly well preserved. 
 
A Study of Some Fatal Cases of Malaria. 13 
 
 and in certain areas inside nearly every red corpuscle is a parasite 
 with a central block of brownish black pigment. Along with these 
 masses of infected corpuscles there are often found numerous mononu- 
 clear macrophages crowded with blocks of malarial pigment like that 
 to be seen in the infected corpuscles. There are places where the 
 lumina of the veins appear to be narrowed near the base of the mucous 
 membrane and as though blocked with macrophages damming back 
 infected corpuscles. The arteries and veins of the submucosa are 
 singularly free from infected corpuscles. The distribution of the 
 parasites in the capillaries is very irregular ; while in one area all of 
 the capillaries may be closely crowded and distended with infected 
 corpuscles, in other places quite near by the vessels may be almost 
 entirely free from them. Besides the macrophages already described 
 there are large red-corpuscle-carrying cells within the veins and ca- 
 pillaries, filled with blood corpuscles which stain intensely with eosin. 
 These cells contain large single nuclei which often send out processes 
 among the red corpuscles in the protoplasm. Some of the smaller 
 vessels appear to have their lumina entirely filled with huge cells of the 
 kind describedj forming veritable casts. These cells must exercise 
 considerable influence in obstructing the on-flow of blood. The surface 
 of the mucous membrane in maoy places refuses to stain, and frag- 
 mented nuclei are visible evidences of superficial necrosis. 
 
 The Heart. — There is an excess of brown pigment at the poles of the 
 nuclei of the muscle cells ; otherwise there are no striking alterations. 
 
 Cerebrum. — Only an occasional infected corpuscle can be made out 
 within the capillaries ; a few of the endothelial cells lining the capil- 
 laries are phagocytic. Portions were saved from only one or two 
 parts of the cortex. 
 
 Thyroid Gland. — In the vessels of this organ as elsewhere in the 
 peripheral circulation it is rarely that infected red blood corpuscles 
 are to be seen. 
 
 III. 
 
 Case B. — Aestivo-autumnal malaria ; grave abdominal symptoms. 
 
 John B., age 34, admitted to the Johns Hopkins Hospital, Sep- 
 tember 10th, died September 16th, 1890. The following is Prof. 
 Osier's clinical note of the case : 
 
14 Lewellys F. Barker. 
 
 "I saw him in the dispensary at 1.30 p. m. He was very weak 
 and tremulous, with eyes congested, cheeks flushed, and with a dazed, 
 stupid appearance. The tongue was swollen, heavily furred and in- 
 dented. He looked like a man who had been drinking, and I told 
 his brother that it would be impossible for us to admit him to the 
 wards in his present state. He assured me, however, that he had not 
 been drinking to excess, and on ascertaining that there was not the 
 slightest trace of salcoholic odor in the breath, I signed the order for 
 his admission. 
 
 The following history was obtained. Family and personal history 
 good. The patient is a sailor by occupation, and has enjoyed excellent 
 health ; he left Boston for Savannah five weeks ago ; spent a week in 
 the latter place, and as the weather was oppressive he, with several 
 of his shipmates, was in the habit of sleeping on the grass all night. 
 He remained well on the voyage to Baltimore, where he landed August 
 31st. He was about the house all the week, though not feeling quite 
 himself, but the present illness dates from Sunday the 7th, when, 
 without any chill or fever, he began to have vomiting. He felt ex- 
 tremely weak and prostrated, so that he could not get up on Monday 
 morning. Throughout Monday and Tuesday the vomiting continued 
 at intervals and he was completely prostrated. He had no chills, but 
 on Monday and Tuesday he took some quinine pills. In the dis- 
 pensary, after failing to detect any alcoholic odor in his breath, and 
 on learning that he had recently come from the South, the blood was 
 at once examined ; large numbers of Laveran's organisms were found, 
 which rendered the diagnosis clear. His temperature on admission 
 into the ward was 101°, pulse 104, small, tension not increased, ra- 
 dials not stiff. The abdomen was soft ; nowhere tender. The edge 
 of the spleen was just palpable on deep inspiration ; upper border of 
 dullness at the ninth rib. 
 
 Apex beat of heart in 5th interspace within nipple line ; sounds 
 clear ; examination of the lungs negative. 
 
 Blood. — Small intra-corpuscular forms in extraordinary abundance, 
 often 6 or 8 to be seen in the field of the tV im. The majority of them 
 are not pigmented and undergo very rapid changes in outline. The 
 pigmented forms have the granules more concentrated than is usual 
 in this stage of the evolution of the parasites. An unusual number 
 of the leucocytes present pigment granules. » 
 
A Study of Some Fatal Cases of Malaria. 15 
 
 11th. Very bad night ; much vomiting ; temperature sank to 
 98.6° at 10 p. m., and to 98.2° by 8 a. m. At the morning visit the 
 patient looked depressed; tongue heavily furred ; pulse 80, small and 
 thready ; respirations 20. Had no headache and complained chiefly 
 of profound weakness. At noon the temperature began to rise and 
 at 4 p. m. reached 102.2°, and for 6 or 8 hours remained about 
 102°, gradually falling through the early morning hours and at 8 
 a. m. reaching 98.5°. The blood condition remains practically about 
 the same. 
 
 12th. 10 a. m. Patient passed a better night. The vomiting has 
 stopped but the tongue is still furred ; no increase in the splenic dull- 
 ness. The bowels have been freely opened. He still looks depressed 
 and dull, and complains of a feeling of great prostration. 
 
 13th. Temperature has been about 98° for the past 24 hours, 
 pulse 72, small. The vomiting has not been so distressing, and he 
 has taken the milk and brandy better than on any day since admission. 
 The blood examination shows a marked diminution in the number of 
 corpuscles containing the plasmodia, the diminution being doubtless 
 due to the influence of the quinine. 
 
 14th. Temperature has been subnormal, not rising above 97.5° all 
 day. The vomiting has returned, and for the first time the vomitus 
 contained blood, not in large amount, but sufficient to color the fluid. 
 His mind is perfectly clear, and his sole complaint is of the extreme 
 depression. 
 
 15th. 10 a. m. Patient's condition is worse since 8 p. m. last 
 evening. The temperature has been below 97°, and at 12 midnight 
 sank to 96° ; pulse, 64 ; respirations, 20. Tongue still swollen, heavily 
 furred and indented. Note on the blood to-day is : " plasmodia very 
 much diminished in number. Leucocytes still show much pigmen- 
 tation." The urine is amber colored, specific gravity, 1010 ; acid, 
 contains a slight amount of albumen. At 9 p. m. I made the fol- 
 lowing note: "Patient is in a very peculiar condition; is drowsy, 
 dull, roused with difficulty, and does not answer clearly. He has 
 behaved oddly all day, and has been very restless. There has been 
 very little vomiting ; temperature has been subnormal, and is now 
 96.5°. For the first time the tongue is distinctly dry," 
 
 16th. Through the night the patient was very restless and had 
 much hiccough ; was not delirious, but acted queerly. The tempera- 
 
16 Lewellys F. Barker. 
 
 ture sank through the night, and at 2 a. m. was 96° ; at 4 a. m. the 
 thermometer could not be made to register more than 95°, and the 
 temperature remained at this point until 10 a. m. The vomited matter 
 last night contained flakes of blood enough to tinge the whole fluid. 
 He had retention of urine and this morning 1500 cc. were withdrawn, 
 which showed a narrow ring of albumen and contained hyaline and 
 granular tube-casts. The nurse says that he does not understand 
 questions, but he seemed to recognize me, and gave fairly rational 
 answers, but complained of great oppression in the abdomen. The 
 pulse is 72, and considering his condition the volume and tension were 
 remarkably good. At 6 p. m. I made the following note : " Tempera- 
 ture has risen through the day and is now 97.2°. The tongue is dry, 
 pulse 96, regular and of very fair volume. He is extremely restless, 
 and his face has a dusky hue ; the respirations are at times gasping, 
 24 to the minute. He answers questions, but talks and rambles in 
 an incoherent way. To-day very few red blood corpuscles have been 
 found containing plasmodia ; the leucocytes are still much pigmented." 
 Patient became much more restless, threw himself about on the bed, 
 then became unconscious, and died at 8 o'clock. The treatment con- 
 sisted of half-drachm doses of quinine every six hours, which was 
 given hypodermically when the vomiting became excessive. 
 
 Autopsy 15 hom^s after death. — Body 161 cm. long, well nourished, 
 post-mortem discoloration of dependent parts and of face and neck. 
 Peritoneum smooth, a little darkened and slaty in appearance, no ex- 
 cess of fluid in abdominal cavity. No pleural adhesions ; pericardial 
 and pleural cavities dry. Right side of heart distended with fluid 
 blood ; left ventricle empty and contracted. Heart valves all normal 
 except for slight atheroma at attached borders of aortic cusps. Myo- 
 cardium pale, otherwise normal ; left lung crepitant, anteriorly and 
 in lower part of upper lobe congested and ©edematous. Right lung 
 still more ©edematous, deeply engorged at base. A small piece cut 
 from extreme posterior part of lower lobe on this side sinks in water. 
 The bronchi contain frothy mucus. 
 
 The Spleen and Liver. — The spleen measures 8 x 13 cm., is ex- 
 tremely soft, almost diffluent. The pulp is of a dirty brownish-red 
 hue ; the capsule is thin and shows a few superficial hemorrhages. 
 The liver is large, slate-gray in color ; its capsule is slightly thick- 
 
A Study of Some Fatal Cases of Malaria. 17 
 
 ened and opaque. Just above the gall bladder on section the 
 substance is moderately firm and has a uniform bronze or slaty tinge. 
 The outlines of the lobules are not well defined. There is deep 
 pigmentation about the portal canals and the smaller bile ducts are 
 distended. 
 
 The Kidneys are large and swollen ; the surfaces are mottled. 
 The capsules are adherent in places. On section the consistence is 
 firm. The Malpighian tufts are prominent and congested ; the 
 medullary rays are pale and between them the lines of vessels are 
 deeply reddened. No areas of opacity are visible. The cortex is 
 distinctly though slightly pallid. The adrenals show no marked 
 alteration. 
 
 The Stomach. — Contents are liquid and of a yellowish color. The 
 mucous membrane has a slatish-grey tint, and on the anterior surface 
 near the lesser curvature are the scars of two small ulcers and on the 
 posterior wall three other flat cicatrices are visible. The bile duct is 
 patent and the portal vein is free. The contents of the small intestine 
 are reddish-brown in color, the mucous membrane is congested in 
 places. Peyer's patches are not swollen, although the lower ones 
 have a shaven beard appearance. The colon is deeply congested in 
 places and covered with tenacious yellow faeces. There is no in- 
 testinal ulceration. 
 
 The Brain. — The dura presents on its surface well back on the 
 right side a small hemorrhage. The pia over the cortex is smooth, 
 in it, over the middle of the first right frontal convolution close to 
 the longitudinal sinus, is an area of brownish-black pigmentation 
 about 1 cm. in diameter. The membranes and vessels at the base 
 appear normal. On section the substance of the brain looks natural 
 except for turgidity of the vessels. 
 
 Microscopical Examination. — The Liver. — The malarial pigment is 
 situated chiefly in the outer half of the lobules and is principally en- 
 closed in cells. The liver capillaries are engorged with blood. In 
 some of these many of the red corpuscles contain malarial parasites 
 which vary in size from extremely minute forms to larger bleb-like 
 organisms almost as large as the corpuscles. Some of these parasites 
 contain only a little fine pigment ; others none at all. Some of the 
 liver capillaries are quite free from parasites, while others are crowded 
 with organisms each containing a central block of brownish-black 
 
18 Lewellys F. Barker. 
 
 pigment. A few of the intra-corpuscular organisms not enclosed in 
 phagocytes show fine lines of yellowish pigment granules radiating 
 from them, which appear sometimes to extend beyond the limits of 
 the corpuscle in which they are contained. Most of the organisms 
 are contained within cells. In this case the endothelium of the hepatic 
 capillaries and the cells of Kupffer have played the greatest role in 
 the phagocytosis. There are some large mononuclear intra-vascular 
 phagocytes, but most of the organisms and the remnants of organisms 
 are contained within the protoplasm of the endothelial cells, being 
 often, though not always, situated at the poles of the nuclei. In the 
 intra-capillary macrophages, which are of smaller size than those 
 occurring in the liver of Case D, the nucleus is frequently surrounded 
 by black pigment blocks. The swelling of the endothelial cells of the 
 capillaries is marked, being sufficient, one would think, to oifer serious 
 impediment to the progress of the blood. The liver cells themselves 
 are swollen and granular, and many of them are filled with yellow 
 pigment masses. In places they are atrophied and the capillaries in 
 the atrophied areas are correspondingly dilated. 
 
 The Kidneys. — AH the blood vessels of these organs are dilated, 
 the veins of the pyramids being especially wide. There is irregular 
 dilatation of the glomerular capillaries. Comparatively few parasites 
 are present in the kidneys, although some distinct forms are visible 
 within the veins and capillaries. A small number of phagocytic cells 
 can be seen (intra-vascular phagocytes and endothelial cells). The 
 capsules of some of the glomeruli have undergone fibrous thickening ; 
 in places the capsular endothelium is proliferated. The epithelium 
 of the convoluted tubules is swollen and granular, and there are 
 numerous hyaline casts to be seen in the small collecting tubules. 
 In the pyramids haemoglobin casts can be made out. 
 
 The Brain. — A few infected corpuscles can be seen within the blood 
 vessels. Here and there a phagocytic endothelial cell occurs. In 
 one spot there is a very small infarct showing necrosis of the cerebral 
 tissue, hyperaemia at its margin, and an accumulation of mono- and 
 polynuclear cells. There are no other marked changes. 
 
 No other tissues were saved from this case. This is unfortunate, 
 since from the grave gastric symptoms observed during life an ex- 
 amination of the contents of the capillaries of the mucous membrane 
 of the stomach would have been interesting (vide Case A). 
 
A Study of Some Fatal Cases of Malaria. 19 
 
 IV. 
 
 Case C. — Acute aestivo-autumnal malaria ; death from accident ; 
 acute necrotic lesions in the liver and spleen. Remarks on the 
 relation of malaria to cirrhotic processes. 
 
 R. G., aet. 22. Pole, single, laborer, admitted to Prof. Osier's 
 wards October 5th, 1892. He complained of chills and fever, and 
 on entrance was suffering from a paroxysm, during which his tempera- 
 ture reached 106.8° F. He had been working at Locust Point (a 
 part of the city near the harbor in which malarial infections frequently 
 occur) when he was taken ill, two weeks before his application to the 
 Dispensary for treatment. On admission his blood was examined and 
 found to contain only a few hyaline intra-cellular parasites. 
 
 The physical examination of the heart and lungs yielded no ab- 
 normal signs. The respirations were hurried, the pulse was frequent 
 and slightly dicrotic. The lower edge of the spleen could be easily 
 palpated, reaching a point two fingers-breadth below the costal margin. 
 The liver dulness was not increased. The patient vomited everything 
 taken into the stomach, including the quinine administered, so that 
 other methods of exhibiting it had to be resorted to. On the next 
 day the blood was carefully examined twice, but no malarial parasites 
 could be found. The leucocytes were not increased in number. The 
 patient complained of severe abdominal pain on the following day ; 
 two slides of blood were examined in the early morning but no ma- 
 larial parasites could be found. The patient met with an accident, 
 associated with profuse hemorrhage, and died in the afternoon. 
 
 At the autopsy, which was made by Dr. Flexner while the body 
 was still warm, the typical lesions of an acute malarial infection were 
 found. There were numerous ecchymoses scattered over various 
 parts of the skin and over the serous membranes. The muscles were 
 brownish-red in color. The lungs were moderately pigmented ; the 
 heart valves were normal. Heart's flesh pale. Anterior mediastinal 
 glands softened and reddened. 
 
 Liver. — Weight, 2200 grams ; surface smooth ; substance of a dark 
 brown color ; consistency soft ; lobules invisible. 
 
 Spleen. — Weighed 800 grams ; measured 23 x 11 x 5 cm. ; diffluent ; 
 deep dark red in color ; Malpighian bodies visible ; pulp abundant. 
 2 
 
20 Lewellys F. Barker. 
 
 Pancreas and kidneys normal ; stomach, intestines and bladder 
 normal. Lymph glands in hilum of spleen and about the pancreas 
 swollen, softened and deeply congested. Culture tubes of agar-agar 
 inoculated from various organs at the autopsy remained sterile. 
 
 The Spleen: Microscopic Examination. — The lesions in this organ 
 resemble much those seen in certain acute bacterial infections. The 
 organ, especially the pulp, is markedly hyperaemic. In places there 
 are evidences of extravasation. On examining the pulp with higher 
 powers the contents of the capillaries and veins are seen to be complex. 
 Besides large numbers of ordinary red blood corpuscles there are a 
 number containing malarial parasites of the aestivo-autumnal type. 
 The majority of the latter, however, are enclosed within mononuclear 
 cells. Well preserved organisms are by no means numerous and the 
 contents of the phagocytes consist largely of remains of malarial 
 organisms and shrunken corpuscles containing more or less brownish- 
 black pigment. The number of red blood-corpuscle-carrying cells is 
 much increased ; huge cyst-like cells, usually mononuclear, the nucleus 
 sometimes having radiating processes which run out toward the peri- 
 phery of the cells, are seen sometimes containing thirty, forty, fifty 
 or more apparently well preserved red blood corpuscles which stain 
 deeply in eosin. The pulp cells themselves are large and swollen, 
 and frequently contain within their substance other cells, chiefly with 
 nuclei of the lymphoid type ;' sometimes also polynuclear leucocytes, 
 and very often a number, five, ten or even more completely colorless 
 red blood corpuscles. These cells contain in addition infected red 
 blood corpuscles, free malarial parasites, the more or less broken down 
 remains of parasites and free malarial pigment often arranged in 
 dotted lines. Besides these large mononuclear cells in the vessels 
 there are very many small and large lymphocytes seen crowding the 
 lumina of the vessels. There are also a few polynuclear leucocytes, 
 some ordinary large mononuclear leucocytes, and an occasional giant 
 cell with budding nuclei, resembling those normally present in the 
 bone marrow. The protoplasm of many of the cells in the pulp-cords 
 stains deeply in eosin. Sometimes the protoplasm of these cells is 
 highly refractive and the nucleus does not stain at all, or it may be 
 broken up into a number of fragments irregular in size and shape. 
 In these cells one or more polynuclear leucocytes are often to be seen, 
 the hyaline protoplasm being sometimes closely crowded with them. 
 
A Study of Some Fatal Cases of Malaria. 21 
 
 In some places in the pulp there are actual focal necroses, very- 
 much like those which are to be seen in typhoid fever. In these, 
 particularly in the more recent ones, large necrotic cells with hya- 
 line protoplasm and fragmented nuclei can be made out along with 
 lymphoid cells, polynuclear leucocytes and endothelioid cells. In 
 the larger necroses the necrotic cells may be almost entirely obscured 
 by the collection of lymphoid cells and the leucocytes with poly- 
 morphous nuclei. In these areas there is evidence of division by 
 amitosis with distortion of the nuclei (abschniirungsvorgange), and 
 scattered among the cells a number of minute nuclear fragments are 
 visible. There are also in these areas large phagocytes containing 
 within their protoplasm malarial parasites and pigment, polynuclear 
 leucocytes, intact and broken down red blood corpuscles and nuclear 
 fragments. 
 
 The endothelial cells lining the vascular spaces are evidently pha- 
 gocytic. They contain within their protoplasm, usually at the poles 
 of the nuclei, the remains of malarial organisms, broken down blood 
 cells, free malarial pigment, and irregular masses of blood pigment 
 which yields the blue iron reaction. The Malpighian corpuscles 
 themselves are swollen ; there has been proliferation in the lymphoid 
 cells. Among the lymphoid cells can be seen a few large cells re- 
 sembling somewhat the cells of the pulp, often containing within 
 them mononuclear and polynuclear cells, red blood corpuscles, and 
 sometimes malarial organisms and malarial pigment. These are best 
 studied in specimens stained with methylene blue and eosin. Numerous 
 capillary thrombi can be made out scattered through the spleen ; these 
 thrombi resemble closely those seen in the liver of this case. One 
 is tempted to think of a relation existing between these capillary 
 thrombi and the focal areas of necrosis. 
 
 The Liver.— The capillaries generally are dilated, in some areas 
 more markedly than in others. Within the capillaries are many red 
 blood corpuscles, a few red blood-corpuscle-carrying cells, lymphoid 
 cells, small and large, a few polynuclear leucocytes, and in some parts 
 of the liver large phagocytes. The latter may contain within their 
 protoplasm, besides well formed malarial parasites of the aestivo-au- 
 tumnal type, shrunken remains of parasites, fine malarial pigment, 
 red corpuscles, particles of haemosiderin, lymphoid cells, and occa- 
 sionally polynuclear leucocytes. The endothelial cells lining the 
 
22 Lewellys F. Barker. 
 
 capillaries are in places much swollen, their nuclei are large and 
 vesicular, and within their protoplasm are sometimes visible the same 
 substances as those mentioned as occurring within the intra-vascular 
 phagocytes. The endothelial cells are so much swollen in places that 
 thej materially narrow the lumina of the capillaries. The spaces 
 between the capillary walls and the liver cells are wider than normal 
 and there is a considerable degree of atrophy of the rows of liver 
 cells. The liver cells contain an excess of brownish-yellowish pig- 
 ment. Some of the liver cells have giant nuclei. The cells of Kupf- 
 fer, between the capillary walls and the rows of liver cells, are swollen 
 and some of them are evidently phagocytic. Occasionally lymphoid 
 cells are visible in the spaces between the capillary walls and the liver 
 cells. The findings within the lumina of the hepatic capillaries are 
 of interest. The number of cells with nuclei of the lymphoid type is 
 astonishing. Many of these are of the size of ordinary lymphocytes, 
 others being somewhat larger. Occasionally cells containing baso- 
 philic granules within their protoplasm are visible within the capil- 
 laries, and in one or two instances they are seen included within the 
 protoplasm of makrophages. In one section two or three cells within 
 the capillaries possessed budding nuclei quite like those of the giant 
 cells in normal bone marrow. One of these of large size appeared to 
 be acting as a phagocyte as it contained within its protoplasm malarial 
 pigment and a single mononuclear cell. Some of the phagocytes 
 which are partially or completely necrotic are surrounded or invaded 
 by leucocytes with polymorphous nuclei. A number of the endo- 
 thelial cells are also degenerated or necrosed. Single and multiple 
 liver-cell-necroses occur scattered throughout the section, forming 
 necrotic areas of varying sizes, sometimes as large as those seen in 
 typhoid fever. When one or two liver cells only are necrotic the 
 lesions are tolerably distinct. The nuclei of the necrotic cells are 
 fragmented or absent and those of the neighboring liver cells may be 
 shrunken and deeply stained. The protoplasm of the cell is hyaline, 
 stains deeply in eosin, and may be invaded by polynuclear leucocytes. 
 In larger areas the pictures are more complex and somewhat diffi- 
 cult to explain. The necrotic liver cells have either been removed 
 or are obscured by the accumulation of other cells. In these foci 
 usually, however, the remains of liver cells and of their nuclei are 
 visible, especially in the periphery. Accumulated here are a number 
 
A Study of Some Fatal Cases of Malaria. 23 
 
 of cells with small sharply stained nuclei, lymphoid cells, polynuclear 
 leucocytes, and spindle-shaped cells with vesicular nuclei. In addition 
 there may be large phagocytic cells containing lymphoid cells, poly- 
 nuclear leucocytes, red blood corpuscles, nuclear fragments, and some- 
 times malarial pigment. It is no easy matter to decide as to the 
 origin of all these different cells, although with thin sections and 
 careful study the source of most of them can be made out. It is not 
 always possible, however, to say what are endothelial cells and their 
 derivatives, and what are to be regarded as blood cells and their 
 derivatives. Some of the small deeply stained nuclei are probably to 
 be looked upon as the offspring of leucocytes which have divided in 
 situ by amitosis, as the nuclei of these cells show various distortion 
 processes (abschniirungsvorgange). Sometimes a cell with hyaline 
 protoplasm and a degenerating nucleus can be seen surrounded by a 
 number of cells whose protoplasm overlaps and seems actually to be 
 mingling with the protoplasm of the degenerating cell, although on 
 close focusing the boundaries of the various cells can usually be made 
 out. The cells inside necrotic cells frequently show fragmented 
 nuclei and hyaline protoplasm. The number of cells inside a single 
 dead liver cell varies. In one the nuclei of ten foreign cells, most of 
 them polynuclear leucocytes, were included, and the nucleus of one of 
 these latter was fragmented. 
 
 There are numerous thrombosed capillaries to be made out in thin 
 sections (vide Plate V, Fig. 1). Sometimes a single capillary appears 
 to be occluded, and a few leucocytes with distorted nuclei are seen lying 
 in the thrombus. In other places two or more neighboring capillaries 
 are plugged, and in addition to the white cells in the thrombus, leu- 
 cocytes, mono- and polynuclear, can be seen aggregated in considerable 
 numbers in the neighboring capillaries. There may be a diminution 
 in size, evidences of degeneration, or a total disappearance of neigh- 
 boring liver cells. Plate V, Fig. 2 shows the condition better than any 
 description. The occurrence of so many of these thrombosed capil- 
 laries in the same sections with the areas of focal necrosis is suggestive, 
 and one is very much tempted to look upon the larger areas of necrosis 
 as advanced stages of a process which began with capillary thrombosis. 
 
 The triangular portal spaces present a very peculiar appearance. 
 The connective tissue is crowded with cells containing nuclei of the 
 lymphoid type so that the tissue reminds one of the structure of ordi- 
 
24 Lefwellys F. Barker. 
 
 nary lymphoid tissue. In the adventitia of the portal vein contained 
 apparently in loose spaces are very many lymphoid cells. The portal 
 veins show in section many mononuclear and a few polynuclear leu- 
 cocytes, besides many makrophages such as have been described in 
 the splenic veins and in the liver capillaries. There were no lesions 
 of tuberculosis anywhere in the body, and no bacteria were demon- 
 strable by cultural methods or in sections of the organs. 
 
 The Kidney. — ^The lumina of the convoluted tubules in the laby- 
 rinth are wide, and the projecting epithelium lining them is somewhat 
 swollen. The glomeruli do not completely fill the capsular spaces ; 
 in some of the latter coagulated albumen may be seen. Some of the 
 tubules in the medullary rays contain in their lining epithelium 
 yellowish pigment. The kidney is almost free from malarial organ- 
 isms and from malarial pigment, although occasionally a brownish- 
 black particle is visible in a glomerulus. 
 
 The Mesenteric Lymph Glands. — The lymph sinuses, especially in 
 the medulla, are wide and are filled with cells. These cells for the 
 most part irregular in shape contain vesicular nuclei and an abundant 
 protoplasm which stains in eosin and they resemble in general the 
 endothelial cells which normally lie upon and are wrapped around the 
 reticular framework. There are also many large and small lympho- 
 cytes and a few red blood-corpuscle-carrying cells. Some cells like 
 those filling up the lymph sinuses can be seen among the lymphoid 
 cells in the lymph follicles and cords. They occasionally contain 
 within their protoplasm malarial organisms and their remains. 
 
 This case, it would seem, may be of help in explaining the relation 
 of malaria to cirrhosis of the liver and allied diseases. 
 
 Even in the early descriptions of malaria the important influence 
 of the disease as a causative factor in the production of chronic inter- 
 stitial inflammations of some of the internal organs, and especially of 
 the liver and kidneys is mentioned. Frerichs and Lanceraux both 
 believed in a chronic hepatitis of paludal origin. Kelsch and Kiener 
 working at the disease without any appreciation of the importance of 
 the malarial parasites laid stress upon the changes in the liver secondary 
 to malaria and describe both parenchymatous and interstitial forms 
 of hepatitis. They refer to three varieties of the latter and discuss at 
 length the character and distribution of the lesions in the liver. These 
 same authors describe two main types of chronic disease of the kidneys 
 
A Study of Some Fatal Cases of Malaria. 25 
 
 dependent upon malaria, the first, a diiFuse malarial nephritis or glo- 
 merulo-nephritis, and the second, a nephritis characterized by a small 
 granular kidney. Bartels, Rosenstein, Bouillaud, and others had 
 early referred to the relation existing between malaria and chronic 
 disease of the kidney. Laveran emphasised a chronic interstitial 
 pneumonia of malarial origin, and Durozier in 1870, and also Kelsch 
 and Kiener referred to the frequent occurrence of vegetative or ulcera- 
 tive endocarditis in chronic malaria and believed that the lesions 
 of the heart valves might be directly referable to the action of the 
 malarial poison. Finally, chronic degenerative and fibroid processes 
 in the spinal cord and brain have been attributed by some authors 
 to malaria. 
 
 On the other hand, by not a few authors the possibility of cirrhotic 
 processes being due to malaria has been stoutly denied. It has been 
 justly claimed that in many of the cases reported as instances of 
 chronic inflammation due to malaria insufficient attention has been 
 paid to the possible responsibility of other etiological factors, such 
 as alcoholism, syphilis, and tuberculosis. 
 
 Dr. Osier has particularly pointed out the difficulty of saying in a 
 given case of cirrhosis of the liver or kidneys that malaria has been 
 the cause, and in his experience the association of malaria with cir- 
 rhosis has been very uncommon. Dr. Welch has seen only one case 
 of malarial cirrhosis of the liver in New York, and that was in an 
 Algerian. 
 
 The foregoing study has, however, convinced me that there are 
 conditions present in malaria which are generally recognized as being 
 capable of giving rise to chronic fibroid processes, and it would be 
 strange did the latter not occur more or less frequently. Bignami 
 in a very careful study of chronic malarial cases in Italy has come to 
 a similar conclusion and traces with much acumen the chain of events 
 from the onset of an acute malarial infection to the development of a 
 cirrhotic process. 
 
 A careful consideration of the various phenomena associated with 
 acute malaria will show that there are many ways in which a chronic 
 interstitial inflammation could arise. Thus looking upon the chronic 
 interstitial inflammations as being due most often to a primary de- 
 generation of certain of the tissue elements, the new growth of fibrous 
 tissues being secondary, we can think of many possible causes of the 
 
26 , Leioellys F. Barker. 
 
 former. Thus, the profound changes in the character of the blood 
 serum consequent upon the alteration and destruction of large numbers 
 of red blood corpuscles and leucocytes, the intermittent hyperemia in 
 the viscera, the setting free of the malarial pigment, and the accumu- 
 lation of the latter in the cells and tissues, the multiple capillary 
 thromboses which sometimes occur, the disturbances of digestion in 
 many of the cases, the areas of necrotic cells which can be demon- 
 strated in liver Spleen and kidneys, these are sufficient to convince 
 one of the existence of many possible injurious influences. 
 
 The evidences in favor of the idea that the parasites produce definite 
 toxines and that large quantities of these are set free during segmen- 
 tation after each paroxysm is already considerable. The clinical 
 phenomena in general and especially the increased toxicity of the 
 urine after the paroxysm would seem to point to this. It must be 
 remembered, however, that as yet no toxine has been proven to be 
 formed by the parasite. It matters little, however, whether the toxic 
 substances are produced by the parasites directly, or are in part the 
 indirect result of their action upon the red blood corpuscles, the white 
 cells or tissue juices. There is sufficient evidence that some toxic agent 
 is at work. The cloudy swelling seen in the organs, the fever, the 
 acute splenic tumor, but more especially the actual necroses early 
 demonstrable under the microscope, make it impossible to doubt 
 this fact. 
 
 In our description of Case C we have referred to the extensive 
 focal necroses in the liver and in the spleen. Single cells, small groups 
 of cells and quite large areas of cells were found in a state of hyaline 
 necrosis where the nuclei refused to stain and the protoplasm showed 
 an increased affinity for acid dyes. In such necrotic areas numerous 
 cells were present, some of them leucocytes with polymorphous nuclei, 
 others small mononuclear cells. In some of the older ones spindle- 
 shaped cells could be seen. Fragmentation of nuclei and phagocytosis 
 were visible, and there were multiple capillary thrombi to be made 
 out. We have referred to the extensive necroses of the spleen pulp 
 cells, of the red blood corpuscles and of the leucocytes. In many 
 bacterial infections similar areas of necrosis have been proven to be 
 due to the toxines which the bacteria produce. Reed for typhoid 
 fever and Welch and Flexner for diphtheria have shown that the 
 soluble products of the bacilli alone circulating in the blood are 
 
A Study of S&me Fatal Cases of Malaria. 27 
 
 capable of giving rise not only to diffuse parenchymatous changes, 
 but also to definite focal lesions, areas of cell-death of varying size. 
 Later Flexuer, experimenting with blood serum, has shown that 
 the serum of one animal will produce focal necroses in the liver 
 kidney and spleen of an animal of a different species when injected 
 intravenously into the latter. He further proved that these focal 
 necroses could later result in the production of chronic interstitial 
 processes in the liver and kidney. 
 
 In the liver, following the necroses, there was such an accurate repro- 
 duction of the cirrhosis seen in human beings that, as he put it, "a 
 separate description seems superfluous." Areas of newly formed and 
 forming connective tissue proceeded from the portal spaces, and also 
 from the capsule ; these were irregularly distributed throughout the 
 organ. Newly formed bile ducts were numerous ; but what was of 
 particular moment was the association with these of another process, 
 namely, acute degenerative changes in the liver substance which were 
 distinctly to be recognized as the starting places of the cirrhotic 
 processes. " The necroses and disintegration of the liver cells with 
 emigration of the leucocytes went directly over into the new growth 
 of fibrous tissue. New fibrous tissue could be formed within lobules, 
 apparently independently of the iuter-lobular connective tissue and 
 of the capsule, just as there are independent foci of necroses in this 
 situation." 
 
 It is easy to understand how the normal serum of the individual 
 could be altered by the disease so as to become definitely toxic. Aside 
 from the increased toxicity of the serum due to the presence of malarial 
 toxines, the destruction of large numbers of red blood corpuscles and 
 the setting free of young parasites, of pigment, and of masses of haemo- 
 globin, cannot fail to be of considerable import. And although there is 
 no experimental evidence bearing on this point, it is not impossible that 
 the isotonie of the blood serum could be so affected as to lead to serious 
 alterations not only in the constituents of the blood but also in the 
 cells of the organs. That haemoglobinaemia and haemoglobinuria 
 occur sometimes in malaria is well known. Haemoglobinaemia alone 
 can give rise to an acute splenic tumor, or to an acute nephritis, as is 
 well known in cases of poisoning by the chlorate of potassium and in 
 the intoxication of one animal by the blood serum of an animal of a 
 different species. The alterations in the functions of the spleen, liver, 
 
28 Lewellys F. Barker. 
 
 and alimentary canal could easily lead also to important changes in 
 the blood serum. 
 
 The relations of the melanaemia to cirrhotic processes is worth 
 considering. The malarial pigment tends to accumulate in the peri- 
 phery of the hepatic lobules and in the trabeculae of the spleen. It 
 remains, too, for some time after the infection has disappeared, and 
 it is not impossible that the irritation caused by the presence of this 
 pigment could give rise to a chronic interstitial inflammation, perhaps 
 analogous to the pneumonoconioses. It seems less probable, however, 
 that the pigment is responsible for a new growth of fibrous tissue than 
 that the latter is secondary to degeneration due to toxic effects. 
 
 It has been generally believed that any pathological condition which 
 leads to an intermittent hyperemia of an organ may give rise to a 
 chronic interstitial inflammation. In malaria there can be but little 
 doubt that there is variable hyperemia of the liver and spleen with 
 the paroxysms, just as the size of the spleen and liver varies in re- 
 current attacks of malaria. 
 
 The capillaries in the liver spleen and kidney are frequently found 
 dilated especially in certain areas. Whether this is at all dependent 
 on the distribution of the makrophages it is difficult to say. 
 
 Finally the influence of the disturbances of the digestive processes in 
 malaria must not be omitted in considering the etiology of cirrhotic 
 inflammations. There is general obstruction in the tributaries of the 
 portal vein, and this alone would suffice to materially alter the as- 
 similation. But in addition, as we have seen, the vessels of the mucous 
 membrane of the stomach and intestines may be occluded in certain 
 cases by thrombi of parasites or of infected red corpuscles. In some 
 instances the nutrition may be so interfered with that the mucous 
 membrane becomes necrotic. Undoubtedly in such instances substances 
 absorbed from the lumen of the alimentary canal are far from normal. 
 
 There can be no doubt, considering the comparative rarity of cir- 
 rhosis following malaria, that the individual pre-disposition must be 
 an important factor in those cases in which it occurs. Associated alco- 
 holism or arterio-sclerosis for example might render the tissue cells 
 less resistant to the poisonous substances, whatever they may be, or 
 prevent the normal processes of repair. 
 
 That there may be different kinds of cirrhosis of the liver following 
 malaria is not impossible. Thus there was no obvious relation in 
 
A Study of Some Fatal Cases of Malaria. 29 
 
 Case C between the enormous increase in round cells in the portal 
 spaces and the focal necroses or the capillary thrombosis. Nor was 
 there any evidence that the round cells were being converted into 
 fibrous tissue. Still these collections were quite like those which one 
 sees in fresh nodules of cirrhosis of the liver. Dock has observed a 
 similar extensive perivascular portal infiltration in a very acute case 
 of malaria in a young man. 
 
 V. 
 
 Case D. — Double tertian malarial infection, associated with general 
 streptococcus infection ; symptoms of an acute nephritis with general 
 anasarca manifested during life. Remarks on the bacterial in- 
 fections and protozoan invasions tohich may be concurrent with 
 malaria. 
 
 Abstract of clinical record. (Prof. Osier.) 
 
 L. W., aet. 23, oysterman, married, admitted January 9th, 1892, 
 complaining of shortness of breath with general dropsy. Family 
 history unimportant. Patient has been previously healthy; denies 
 syphilis ; gonorrhoea nine years ago. Has never used alcohol in 
 excess. Some three months before entrance, his work required him 
 to stand in cold water daily for about two weeks. At the end of this 
 time he noticed that his feet and body began to swell, that his urine 
 was scanty and high-colored, sometimes even bloody, and that fre- 
 quently he had to rise two or three times during the night to urinate. 
 Somewhat later he observed that he was becoming short of breath, 
 especially on exertion. Three weeks before admission he had a severe 
 shaking chill, the first during his illness, and for the next two weeks 
 he had chills nearly every day. During the past week, he states 
 that he has had no chills. The dropsy has gradually increased, and 
 the dyspnoea has become progressively more intense. Of late the 
 urine has not been bloody, and the amount, he thinks, is larger than 
 formerly. 
 
 Temperature on admission, 97.8°. Pulse under 100. Anasarca 
 general. Patient rather dull and stupid. Pilocarpine ^ gr. hypo- 
 dermically repeated once caused profuse sweating. 
 
 Note dictated October 1, 1892. — "Medium sized man of good muscu- 
 lature ; lips and mucous membranes a little pale ; tongue coated ; face 
 
80 Lewellys F. Barker. 
 
 much swollen ; feet and legs oedematous. Abdomen a good deal 
 distended. Respirations, 24; pulse, 84. 
 
 Thorax. — Percussion, resonance good in front ; deficient behind at 
 i^ight base where vocal fremitus is absent and the respiration is distant. 
 On auscultation the sounds are clear in front; behind and in the 
 axillse numerous fine rales are audible. Heart sounds clear at apex 
 and base. 
 
 Liver dulness merges almost directly into colon tympany at the 
 7th rib. Splenic dulness begins at the 8th rib. Though uniformly 
 distended the abdomen is tympanitic and no movable dulness can 
 be obtained. 
 
 Urine. — Dark in color, 1000 cc. in amount. Sp. gr., 1017 ; albumen 
 abundant ; many hyaline, darkly granular and epithelial casts present." 
 
 This case was looked upon clinically as one of acute nephritis. The 
 existence and character of the fever were noted as unusual. 
 
 Dr. Osier, in commenting on the case in clinic, alluded to the ex- 
 istence of the fever, the mode of onset, and to the occurrence of chills, 
 and stated that the existence of malaria was negatived by the absence 
 of Plasmodia from the blood. Unfortunately, through a misunder- 
 standing among the assistants, each believing that the other had looked 
 for the parasites, no examination of the blood had been made. 
 
 By January 23rd, the patient had become more oedematous. The 
 pulse was 140 ; fluid was now demonstrable in the right pleural sac 
 and in the peritoneal cavity. The urine still contained large quantities 
 of albumen and casts. The fever persisted and was rather remittent 
 in type ranging between 99° and 104° F. Hot baths, diluents and 
 diuretics were given. 
 
 On the 24th and 25th the patient was much worse, took nourishment 
 badly ; the respirations were rapid and the pulse was feeble. The 
 general anasarca became extreme and there was marked conjunctival 
 oedema. The heart sounds remained clear throughout the whole 
 course of the disease. Death occurred on the 26th of January, seven- 
 teen days after admission. 
 
 Autopsy. (Dr. Councilman.) 
 
 Anatomical Diagnosis. — Acute malarial fever ; general streptococcus 
 infection ; subacute Bright's disease; malarial pigmentation of organs ; 
 chronic passive congestion ; general anasarca ; infarctions of kidneys ; 
 erysipelas. 
 
A Study of Some Fatal Cases of Malaria. 31 
 
 Body of strongly built light mulatto ; face and neck markedly 
 oedematous ; livor mortis in dependent parts ; general subcutaneous 
 oedema ; scrotum markedly swollen. On the left shoulder, and on 
 the inner aspect of both thighs there are blebs containing clear straw- 
 colored liquid surrounded by areas of reddish discoloration. 
 
 The peritoneal cavity contains about one litre of straw-colored fluid, 
 which contains large soft clots. The pleural cavities also contain a 
 considerable amount of serous fluid. 
 
 Heart of medium size, chambers contain fluid blood and soft clots ; 
 weight, 300 grams ; myocardium dark reddish-brown in color ; all 
 valves normal. Aorta abnormally small and thin, measuring in cir- 
 cumference, just above valves, 4.5 cm. ; at middle of thoracic aorta, 
 4 cm. ; at diaphragm, 4 cm. ; at bifurcation, 2.75 cm. The common 
 iliac vessels measure 2 cm. in circumference; the left subclavian, 1.9 
 cm. ; the innominate, 2.5 cm. Pulmonary artery normal. 
 
 The Lungs. — The surfaces of both are smooth, and both are crepi- 
 tant throughout. The consistence is increased, color dark red, moderate 
 coal-pigm entation . 
 
 The iiver.— Weight, 1600 grams; dimensions, 25 x 16 x 8 cm.; 
 Surface smooth ; exquisite outlining of lymphatic network on surface. 
 Consistence about normal. Color on section dark chocolate-brown 
 color. Lobules visible. 
 
 The Spleen is small, weighs only 100 grams; size, 12 x 7 x 3 
 cm.; capsule smooth, not much thickened; consistence very firm. 
 On section the substance is almost black, of a much darker tint than 
 the liver. The Malpighian bodies are not visible. The trabeculae 
 are visible and apparently increased in thickness. 
 
 The Kidneys together weigh 400 grams. They are both alike in 
 size and general appearance. On the surface of each a few small fresh 
 infarctions with hemorrhagic margins are visible. The capsules strip 
 off easily. The general color of the external surfaces of the kidneys 
 beneath the capsules is yellowish-brown, marked by scattered opaque 
 darker areas, and here and there by minute hemorrhages. The whole 
 kidney has a rather soft oedematous feel. On section the cortex has 
 a yellowish appearance and is rather translucent ; pyramids reddened, 
 contrasting sharply with the lighter colored cortex. On some parts 
 of the cortex the striae are well marked, in others they are less apparent 
 or invisible. Average width of cortex 1 cm, A small amount of 
 
32 Lewellys F, Barker. 
 
 fluid exudes from the cortical substance on pressure. The glomeruli 
 are indistinct. The pancreas is oedematous. The adrenal glands 
 are normal in size but it is noticeable that they are darker in color 
 than normal. 
 
 The stomach is moderately dilated ; both it and the intestines con- 
 tain an excess of mucus. The intestines are generally distended and 
 their walls are oedematous. 
 
 The bone-marrow is intensely pigmented, reddish-brown in color. 
 The brain is small, especially in the frontal regions ; weight, 940 
 grams. The pia is firmly adherent. No marked pigmentation. No 
 hemorrhages or focal disease. 
 
 The Blood. — Examined fresh from the peripheral veins and various 
 internal organs showed enormous numbers of malarial parasites, most 
 of them nearly full grown, others only half grown (tertian type), many 
 of them enclosed within the protoplasm of large mononuclear leuco- 
 cytes. No flagella seen. 
 
 Frozen Seetions of the kidney show a very little fat in fine droplets 
 in the glomeruli. The epithelial cells of the tubules in the labyrinth 
 are much swollen and are filled with fine albuminous granules and 
 hyaline droplets. 
 
 Many of the tubules are dilated and are lined by low epithelium. 
 Casts are numerous in sections and in urine collected from the bladder. 
 Coagulated albumen is visible in the capsular spaces, in frozen sections 
 made from bits of kidney previously fixed in boiling water. The 
 capsular epithelium is swollen and evidently proliferated. 
 
 Bacteriological Examination. (Dr. Flexner.) 
 
 Cover slips from the heart's blood prepared and stained in the 
 ordinary way showed numerous chains of streptococci. 
 
 Cultures. — At the autopsy, the surface of the organs was burned with 
 a hot knife, punctured through the burned area, and tubes of agar- 
 agar were inoculated from the internal tissues. Esmarch roll-tubes 
 were employed ; after being kept in the thermostat for twenty-four 
 hours at 37° C they were examined with the following results : The 
 tube from the lung was found to be closely crowded with extremely 
 minute colonies of streptococci, no other micro-organisms being present. 
 The heart's blood, kidney, liver, bone-marrow and spleen all yielded 
 many colonies of streptococci, here also in pure cultures. The tube 
 from the spleen contained many more colonies than that from the liver. 
 
A Study of Some Fatal Cases of Malaria. 33 
 
 The tube inoculated from the bile contained a few — about one dozen — 
 colonies of streptococci. Tubes were also inoculated from the fluid 
 in the erysipelatous blebs and from the ©edematous subcutaneous 
 tissue at their margins. In those from the latter a pure culture of 
 streptococci was obtained. 
 
 Microscopical Examination.— The Liver.— In sections examined 
 with very low powers (8 to 16 diameters), it is easy to make out 
 dilatations of the central and sublobular veins and of the capillaries 
 about the central veins, and also that the large amounts of dark 
 malarial pigment which are present are rather peculiarly distributed. 
 Instead of being most abundant, as is ordinarily the case, according 
 to those who have examined large numbers of malarial livers, at the 
 periphery of the lobules, in this instance the pigment is situated in 
 more or less well-marked zones which correspond nearly to the outer 
 limits of the areas of dilated capillaries. Small amounts of pigment 
 press into the areas of capillary dilatation, and some pigment can be 
 seen in the parts of the lobules in which the capillaries are not dilated, 
 but the great bulk of the pigment is certainly present in the zones 
 described. The portions of the lobules nearest the central veins, and 
 those nearest the peripheries are comparatively free from malarial 
 pigment. 
 
 On examination with higher powers, the black and brownish-black 
 malarial pigment is seen to be chiefly included by large makrophagic 
 cells within the liver capillaries, and it is to the accumulation of these 
 cells in the zone previously described, that the peculiar distribution 
 of the pigment as seen with very low powers must be attributed. 
 These large cells in which by far the greater portion of the malarial 
 pigment is contained, vary considerably in size shape and general 
 appearance. The smallest ones correspond in size to the ordinary 
 mononuclear leucocytes, the largest reach the size of giant cells, and 
 are equal in bulk to three four or more times that of the smaller ones. 
 Between these two limits there are many intermediate sizes. Many 
 of the cells have round smooth margins, others are polyhedral, many 
 are oval or ovate in shape. These cells usually contain a single round, 
 or more often an oval vesicular nucleus; sometimes two vesicular 
 nuclei are present. The protoplasm of these cells, when not too much 
 obscured by included substances, can be seen to take a feeble stain in 
 haematoxylin and often to contain larger and smaller vacuole-like 
 
34 Lewdlys F. Barker. 
 
 spaces, some of which may represent fat droplets. But as a rule the 
 protoplasm is scarcely visible, owing to the presence of the large 
 accumulations of extraneous substances and structures which have 
 been included within it. It was somewhat puzzling at first to decide 
 as to the exact nature of the different contents of these cells. In thick 
 sections the protoplasm appears to be filled simply with coarse irregular 
 masses of black and blackish-brown malarial pigment, but in thin 
 sections and by, various modifications in the staining technique it is 
 possible to distinguish easily a number of different morphological 
 elements. In the largest cells, the protoplasm of which is crowded 
 with black pigment, it can be made out that most of the pigment does 
 not exist in irregular blocks (although some apparently does), but in 
 definite, more or less regularly spherical masses. Often there is an 
 appearance as though a malarial organism, which has been included, 
 had suffered rupture of its capsule, allowing the partial escape of the 
 pigment. From the shrunken malarial capsules (in which the pig- 
 ment exists usually as a more or less fused and homogeneous mass, 
 rather than as distinct granules as seen in the well preserved organisms) 
 delicate dotted lines of minute pigment particles can be seen running 
 in different directions out into the protoplasm of the phagocytes. 
 Occasionally in these very large cells, much more often in the smaller 
 ones, well developed spherical tertian malarial organisms, with pig- 
 ment granules arranged in lines in their peripheries and central non- 
 pigmented areas can be seen. The number of included organisms and 
 shrunken capsules (cadavers, corpses, or debris of malarial organisms), 
 is often large. As many as twenty and even thirty were counted in 
 some cells, and doubtless a number of the very large cells, where the 
 bodies lie closely crowded in different planes so that they can be 
 counted only with great difficulty, contain even greater numbers of 
 them. Dark brownish-black pigment in little clumps, resembling that 
 seen near the centers of segmenting tertian organisms, is also observed 
 within these cells, and part of the irregular masses of malarial pigment 
 may represent aggregations of this segmental pigment. 
 
 Included in many of these large cells are visible red blood corpuscles, 
 sometimes only one or two, sometimes large numbers of them — true 
 red blood-corpuscle-carrying cells. There are also numerous irregular 
 yellow particles and masses which look like fragments of red cor- 
 puscles. On (or in) some of the corpuscles granules of malarial 
 
A Study of Some Fatal Cases of Malaria. 35 
 
 pigment are seen infected red blood corpuscles (?). In specimens 
 hardened in alcohol, stained with alum-cochineal, and treated with a 
 fresh solution of ferrocyanide of potassium to which a little pure hy- 
 drochloric acid had been added, very instructive views of the contents 
 of these makrophages are obtainable. Many of the yellow particles 
 and masses give very definitely the blue haemosiderin reaction, and 
 in this way a much better idea of the number of partially destroyed 
 red blood corpuscles present can be gained. The fully formed in- 
 traphagocytic red corpuscles do not as a rule give the haemosiderin 
 reaction, but retain their yellowish tint ; some of them indeed are 
 distinctly brassy in appearance, although these brassy corpuscles are 
 by no means so numerous in the liver of this case as in that from a 
 case of an aestivo-autumnal infection. Occasionally, a red disc of full 
 size and normal shape will give the distinct Berlin blue reaction, and 
 at times particles of malarial pigment can be seen lying on such a blue 
 disc. A great many of the fragments of corpuscles do not yield the blue 
 color with the ferrocyanide mixture, so that in the large cells yellow 
 corpuscles, yellow fragments, blue corpuscles and blue fragments lie 
 mixed in varying proportions, along with altered and unaltered 
 malarial parasites and malarial pigment. 
 
 As might be expected in cells whose protoplasm is burdened with 
 such large amounts of deutoplasm, the position and shape of the nu- 
 cleus often deviate widely from the normal. Nearly always placed 
 excentrically, the nucleus is sometimes pushed to the extreme margin 
 or end of the cell, and instead of exhibiting its ordinary oval contour 
 it may assume a stellate or more often a crescentic outline. Sometimes 
 indeed the nucleus is seen to be fragmented, or to be absent altogether, 
 and in such cells the protoplasm has a swollen glassy appearance and 
 is much more refractive than normal. 
 
 Besides the malarial organisms and their remains, blood corpuscles 
 and their derivatives, many of these edacious cells contain within their 
 protoplasm still other objects. Thus it is not uncommon to see inside 
 them one or more white blood cells. These included white corpuscles 
 usually have nuclei of the lymphoid type, sometimes they have poly- 
 morphous nuclei ; or again the two kinds may be present together 
 lying alongside one another in the protoplasm of the same including 
 cell. Sometimes these incorporated white cells contain within their 
 protoplasm well preserved malarial organisms or free pigment. Their 
 3 
 
36 Lewellys F. Barker. 
 
 nuclei as a rule stain sharply, and their protoplasm does not appear 
 to be abnormal. At other times the protoplasm of the included cells 
 is more highly refractive than normal, and has a clear glassy look; 
 the nuclei may be fragmented and stain intensely, or they may be 
 entirely necrotic and refuse to take up any of the ordinary nuclear 
 dyes. When the large cell is necrosed (hyaline protoplasm, fragmented 
 or non-staining nucleus) and contains within it white blood corpuscles, 
 these are likely? to be leucocytes with polymorphous nuclei. 
 
 Finally in the protoplasm of the makrophages (the case being one 
 of general streptococcus infection) cocci occur singly, in chains, or in 
 groups of chains ; sometimes the streptococci lie within the protoplasm 
 of included white blood corpuscles. 
 
 The makrophages above described lie usually close to the walls of 
 the capillaries but do not appear to have any organic connection with 
 the walls. Sometimes a single one is large enough to practically close 
 the lumen of a capillary. They appear, too, to be lodged quite fre- 
 quently at the junction of capillaries and to cause obstruction to the 
 flow of blood. 
 
 There is an astonishingly large number of well preserved tertian 
 malarial organisms, nearly fully developed, present in the liver. A 
 comparatively small proportion of these apparently uninjured organ- 
 isms are free in the blood or enclosed simply in red blood corpuscles. 
 The majority of those in the blood-vessels are enclosed within the 
 protoplasm of the large mononuclear leucocytes, from one to six in a 
 cell, and a few within the protoplasm of leucocytes with polymorphous 
 nuclei ; although in these latter one rarely sees more than one or two 
 in a cell. As has already been mentioned, a few well preserved ma- 
 larial parasites are found among the contents of the free makrophages, 
 and as will be pointed out later, occasionally uninjured parasites at 
 the same stage of development as those in the blood are discernible 
 inside the endothelial cells lining the hepatic capillaries. All these 
 organisms appear to be of the same size and present very much the 
 same appearances. They are nearly full grown and ready for seg- 
 mentation ; indeed two definite segmenting bodies (central pigment 
 surrounded by minute oval hyaline bodies) were seen in the blood in 
 one section of the liver. The malarial organisms in alcohol sections 
 in this case studied carefully with the best apparatus are seen to be 
 tolerably regular spheres, consisting of a thin peripheral layer in which 
 
A Study of 8ome Fatal Cases of Malaria. 37 
 
 all the pigment is included, and a central more or less spherical mass 
 which does not contain pigment. The brownish-black pigment is 
 not always irregularly distributed in the outer layer, but in favorable 
 specimens it can be seen to have a definite arrangement in lines, with 
 clear spaces between, running like meridians at certain intervals in 
 the directions of the poles. Even in the organisms with ruptured 
 capsules this arrangement can sometimes be made out. The central 
 or usually slightly excentric spherical non-pigmented area stains in 
 certain basic dyes, often quite intensely in methylene blue, only feebly 
 and often not at all in haematoxylin and in aqueous magenta (vide 
 Spleen Plate). The outer layer of the organism in which the lines 
 of pigment run takes no tint with these dyes. The pigment in some 
 organisms tends to accumulate toward one pole, and to retract from 
 the other. This morphology of the organism can best be made out 
 in the larger veins, where the plasmodia are very numerous. The 
 free organisms and infected red blood corpuscles, like the leucocytes, 
 have a tendency to collect along the walls of the veins, where in this 
 case (there being a leucocytosis of considerable degree), together with 
 the leucocytes large phagocytic cells and chains of streptococci, they 
 form masses of considerable size clinging to the venous walls. In 
 some of the veins, however, leucocytes and organisms are fairly evenly 
 distributed among the red corpuscles throughout the lumina of the 
 vessels. Some of the capillaries and smaller veins are crowded with 
 cells malarial parasites and streptococci. The leucocytes (mono- 
 and polynuclear) scarcely ever contain the shrunken remains of the 
 parasites, but besides the well preserved forms there is seen in them 
 an occasional ruptured organism, segmental pigment, and sometimes 
 streptococci. Here and there the nucleus of a white corpuscle is frag- 
 mented, and a mononuclear leucocyte may be seen enclosing within its 
 protoplasm a lymphocyte or a leucocyte with a polymorphous nucleus. 
 The spindle-shaped endothelial cells lining the small veins, and 
 especially those of the hepatic capillaries, present interesting appear- 
 ances. Many of them contain small fragments of straw-colored blood 
 pigment, and in the protoplasm of some of them malarial pigment, 
 malarial organisms, and the remains of parasites are included. Some- 
 times streptococci are to be seen within the endothelial cells. The 
 extraneous matter in the endothelial cells does not as a rule greatly 
 increase their bulk, being arranged more or less regularly at the poles 
 
38 Lewdlys F. Barker. 
 
 of the nuclei, but now and then endothelial cells are met with which 
 are much swollen, contain large masses of pigment and parasitic re- 
 mains, and almost obliterate the lumen of the capillary. Occasionally 
 lymphoid cells or polynuclear leucocytes are seen within them. Some 
 of the endothelial cells have hyaline protoplasm similar to that de- 
 scribed as occurring in the necrotic makrophages. 
 
 In the sections stained with alum cochineal which were afterwards 
 treated with the'acid ferrocyanide solution and examined with a low 
 power, the walls of the capillaries (more marked in some regions than 
 in others) are seen to be outlined by delicate blue pigment. Exami- 
 nation with higher powers shows this to be haemosiderin within the 
 protoplasm of the capillary endothelium. Not all of the particles of 
 straw-colored pigment, however, in these cells yield the haemosiderin 
 reaction ; while in some of the cells they are all turned blue, in others 
 they all remain yellow, and again cells are seen with blue and yellow 
 particles mixed in varying proportions. 
 
 The spaces between the capillary walls and the liver cells are 
 generally exaggerated, more especially towards the centers of the 
 lobules. The cells in these spaces (Kupffer's cells) have acted as pha- 
 gocytes ; they are swollen and exhibit contents analogous to those 
 which characterized the intra-capillary makrophages. The swelling 
 of these cells in some places has been so great as to press the ad- 
 jacent capillary wall markedly out into the capillary lumen. The 
 rows of liver cells, more especially those about the central vein, are 
 atrophied and are narrow. The cells contain an excess of yellow- 
 brown pigment; the nuclei are more numerous than normal, are 
 shrunken and stain intensely in nuclear dyes. There are very few actual 
 necrotic liver cells to be seen, but now and then one is visible containing 
 a fragmented nucleus, or a nucleus which does not stain at all. The 
 protoplasm of these cells is hyaline and may be invaded by leucocytes 
 with polymorphous nuclei. The liver cells do not contain malarial 
 organisms or pigment. Much of the yellowish-brown pigment within 
 the rows of liver cells yields a blue reaction with Perl's test. In some 
 areas the actual ectasis and liver cell atrophy is extreme. In those 
 where the changes in the liver cells are the same the capillaries appear 
 to be collapsed and the number of nuclei present is striking. The 
 liver cells of the peripheries of the lobule are large and some of them 
 contain giant nuclei. In the connective tissue of the portal spaces 
 
A Study of Some Fatal Cases of Malaria. 39 
 
 there are some large cells filled with clumps of dark malarial pig- 
 ment. There is a slight increase in the number of lymphoid cells 
 in these spaces. 
 
 Spleen. — The comparatively small size of the spleen is due to the 
 existence of chronic interstitial changes. On microscopic examination 
 the capsule and trabeculae generally are found to be much thickened, 
 and there is thickening and fibrous transformation of the reticulum of 
 the pulp. The spleen, however, also shows evidences of less chronic 
 lesions. The spleen-pulp is hyperaemic and there is a marked in- 
 crease in the number of colorless cells in the pulp-cords and within 
 the splenic veins and capillaries. A goodly number of red blood- 
 corpuscle-carrying cells can be made out. While some of these cells 
 contain only red blood corpuscles as inclusions, in others are also 
 seen malarial parasites and pigment together with some nucleated 
 white cells. 
 
 There are large numbers of malarial parasites in the large and small 
 splenic blood-vessels, exactly similar to those described in the liver. 
 Some are free in the blood, or lie on or in infected red corpuscles ; 
 the majority of well preserved organisms are contained within the 
 protoplasm of cells ; there are from one to six in each of the cells, 
 which are of the size and general appearance of large mononuclear 
 leucocytes. As a rule the nuclei of these cells stain well, but oc- 
 casionally they do not take the dyes at all. A few well preserved 
 organisms and some free brownish-black (segmental?) pigment are 
 to be seen within the leucocytes with polymorphous nuclei. The 
 nuclei of a few of the mononuclear and polynuclear leucocytes in the 
 splenic capillaries are fragmented, the chromatin being broken up 
 into deeply staining masses of varying sizes. 
 
 In addition to these cells there are in the splenic capillaries, veins 
 and pulp, many makrophages, large usually mononuclear cells, whose 
 swollen protoplasm is crowded with masses of malarial pigment, the 
 shrunken remains of malarial organisms, organisms with ruptured 
 capsules, and occasionally with one or several well preserved organ- 
 isms in the same stage of development as those free in the blood. 
 These cells contain in addition many red blood corpuscles and frag- 
 ments of red corpuscles, part of which yield the haemosiderin reaction. 
 On some of the included red corpuscles particles of fine malarial 
 pigment are visible, suggesting that these corpuscles when received 
 
40 Lewellys F. Barker. 
 
 into the phagocyte were infected with malarial parasites. These 
 makrophages may contain, like those in the liver, white cells, and 
 some of these included cells may contain other cells, so that one sees 
 cell within cell within cell, and as the protoplasm of all three may 
 contain extraneous substances, one may speak of phagocyte within 
 phagocyte within phagocyte. The nuclei and protoplasm of including 
 and included cells vary in appearance — sometimes the former, some- 
 times the latter ^how evidences of degeneration or necrosis. Strepto- 
 cocci are very abundant throughout the spleen ; they appear in single 
 chains and in masses of chains. They are especially well defined in 
 the sections stained with methylene blue and eosin, and in those pre- 
 pared according to Weigert's method for the differentiation of fibrin, 
 bacteria and hyaline. They can often be seen enclosed within the 
 protoplasm of cells, mononuclear and polynuclear leucocytes, intra- 
 vascular makrophages, and endothelial cells. Some of the small 
 veins and splenic capillaries are actually thrombosed with masses of 
 streptococci, white corpuscles, malarial organisms and phagocytes, 
 matted together with filaments of fibrin. 
 
 The endothelial cells in the spleen, like those of the liver, are 
 swollen and contain within their protoplasm blood pigment, part 
 of which has been transformed into haemosiderin. A few of them 
 also contain malarial organisms, cadavers of parasites, and free fine 
 and coarse malarial pigment ; streptococci may be seen within some 
 of them. 
 
 A certain number of the large makrophages within the splenic 
 pulp are arranged in groups, and present a peculiar appearance. The 
 cells are much swollen, and besides the ordinary contents of collapsed 
 organisms etc., large areas of the swollen protoplasm show yellowish- 
 brown pigment arranged in dotted lines ramifying through the proto- 
 plasm, which is often hyaline, so that we have something which looks 
 like tangled masses of pigment lines, often over-lying and hiding the 
 nucleus from view, and enclosing minute areas of hyaline protoplasm 
 within the felt-work (vide Plate VI). These lines of pigment often 
 appear to run out from the pigment masses enclosed within the cells. 
 The pigment in these lines when in focus is seen to be dark brownish- 
 yellow in color, while that out of focus may be of a pale straw color. 
 The malpighian corpuscles of the spleen are somewhat swollen and 
 are almost entirely free from coarse malarial pigment. On close 
 
A Study of Some Fatal Cases of Malaria. 41 
 
 examination, however, fine malarial pigment, yellowish-brown in 
 color, arranged often in lines, and not enclosed within cells, can be 
 made out in many of the malpighian bodies lying in the interspaces 
 between the lymphoid cells. 
 
 The Kidney. — An examination of many glomeruli shows consider- 
 able variation in the size of the capsular spaces. While in some 
 instances the glomerulus almost completely fills out Bowman's capsule, 
 the space being a mere chink, in others the latter is equal in size to 
 one-third of the whole capsule. The space is not always empty but 
 may contain coagulated albumin, red blood corpuscles and shadows, 
 or a few mononuclear cells (desquamated epithelium). The fibrous 
 capsules are not thickened except occasionally where an atrophied 
 glomerulus is visible. Frequently just outside the capsule of Bowman 
 a narrow clear space can be made out, and this may contain a few 
 cells, chiefly polyuuclear leucocytes, or even be crowded with them. 
 In many of the capsules the capsular epithelium is evidently pro- 
 liferated, the whole inside of the space being lined by nuclei with 
 intensely staining chromatin. The glomerular capillaries vary in 
 their size and contents; some of them are empty, others are dis- 
 tended. Occasionally one is seen to be plugged with streptococci. 
 The number of white corpuscles within the glomerular capillaries 
 also varies ; they are very irregularly distributed ; in some glomeruli 
 scarcely any are present; in others one two or more of the glomerular 
 capillaries may be packed full of polynuclear leucocytes. In a section 
 stained in methylene blue, a capillary is visible plugged at one point 
 with streptococci and crowded throughout the rest of its extent with 
 leucocytes with polymorphous nuclei, — reminding one forcibly of the 
 appearance of the capillary glass tubes in an experiment in positive 
 chemotaxis. On the other hand masses of cocci may be seen with no 
 neighboring leucocytic accumulation. The nuclei of the polynuclear 
 leucocytes vary in appearance ; some stain sharply and take on the 
 ordinary forms ; others stain less sharply, have a blurred look and 
 assume bizarre shapes. The protoplasm of the polynuclear leucocytes 
 frequently contains granules or minute clumps of granules of malarial 
 pigment, occasionally a well-formed parasite or short chains of cocci. 
 There is some malarial pigment in the glomeruli contained within 
 the protoplasm of mononuclear cells. The majority of the malarial 
 parasites in the glomerular capillaries are outside nucleated cells. 
 
42 Lewellys F. Barker. 
 
 Here and there in specimens stained with aqueous magenta a giant 
 spindle-shaped nucleus is visible. 
 
 The lumina of the convoluted tubules are for the most part wide 
 and are lined with rather low cubical epithelium. There are a few 
 areas of dilated tubules, in which the lining epithelium is flattened so 
 as to resemble endothelium. The nuclei of the epithelial cells as a 
 rule stain normally, although in some swollen cells they stain feebly, 
 and in some tubules the nuclei are shrunken and the chromatin stains 
 more intensely than normally. 
 
 Many of the convoluted tubules and collecting tubules contain 
 hyaline casts ; and hyaline droplets are visible within the swollen 
 lining epithelial cells. These droplets, both the finer and the coarser, 
 and the upper portions of the hyaline casts stain intensely in Weigert's 
 fibrin stain. Occasionally desquamated epithelial cells and a few red 
 blood corpuscles and round yellowish striped urinary concrements are 
 to be seen within the lumiua of the tubes. 
 
 The intertubular capillaries contain enormous numbers of strepto- 
 cocci (methylene-blue, Weigert's fibrin stain). Many of them are 
 dilated and completely plugged with cocci, and sometimes chains of 
 cocci are visible in narrow pericapillary spaces. As in the glomerular 
 vessels, some of the intertubular capillaries are crowded with leuco- 
 cytes. Some of the small veins in the cortex are actually thrombosed 
 with masses of streptococci, large numbers of malarial parasites, white 
 corpuscles (some of which are necrotic), and pigment clumps. No 
 bacteria other than streptococci are present anywhere in the kidney. 
 
 In the interstitial tissue of the kidney there is a slight but evident 
 increase in the number of cells of the lymphoid type. There are 
 small nodal masses of smaller and larger round cells, usually with but 
 little perinuclear protoplasm, many of them with fragmented nuclei. 
 These minute nodes may contain, besides lymphoid cells, single poly- 
 nuclear leucocytes or epithelioid cells. 
 
 Sections of the kidney treated with ferrocyanide of potassium * and 
 hydrochloric acid show an almost entire absence of cells containing 
 haemosiderin. Here and there, however, a little is visible within the 
 protoplasm of the endothelium of the vessels. 
 
 The infarcted areas of the kidney present the lesions ordinarily 
 seen under these circumstances — anaemic necrosis and neighboring 
 reaction. The whole of the necrotic area — glomeruli, tubules, blood- 
 
A Study of Some Fatal Cases of Malaria. 43 
 
 vessels, interstitial tissue — refuses to stain in the ordinary nuclear 
 dyes, and has an increased affinity for eosin. The only nuclei which 
 stain are those of polynuclear leucocytes which have invaded the in- 
 terstitial tissue everywhere, and are accumulated in large numbers 
 at the margins of the infarcted areas, and in the neighboring dilated 
 blood-vessels. There is extensive nuclear fragmentation in these poly- 
 nuclear leucocytes, and the most varied distortion-processes (abschniir- 
 uno-svorgange) of their nuclei are visible. Many of the blood-vessels 
 at the apices and in the peripheries of these infarctions are thrombosed 
 with streptococci, enormous numbers of malarial organisms, over 100 
 of which were counted inside the lumen of one vessel, and white cells. 
 Small bits of the kidney hardened in Flemming's stronger solution and 
 stained with aqueous magenta yield very instructive sections. Fine fat 
 droplets are visible in the glomeruli and in the epithelium lining the 
 capsular spaces. The convoluted tubules are not extensively fatty ; 
 some are entirely free from fat droplets, others show numerous smaller 
 and larger droplets, especially at the proximal ends of the lining epithe- 
 lial cells. Fine fat droplets are also visible in the protoplasm of some 
 of the leucocytes in the vessels, and also in the smooth muscle fibres of 
 the arteries. The desquamated epithelial cells within the lumina of 
 the tubules contain numerous rather coarse fat droplets. The cells of 
 the convoluted tubules in sections prepared in this way are seen to 
 be finely granular and the hyaline degeneration of the protoplasm is 
 well shown. Many of them contain large vacuole-like spaces which 
 sometimes displace the nuclei. In some of the tubes free red blood 
 corpuscles, polynuclear leucocytes, and malarial organisms are visible. 
 The last named are sometimes free or lie on red blood corpuscles, 
 sometimes they are enclosed within cells. They are to be seen in 
 both polynuclear and mononuclear cells within the lumina of the 
 convoluted tubules. In one tubule, besides numerous red blood cor- 
 puscles and shadows, four free well-fotmed malarial organisms and a 
 mononuclear cell containing within its protoplasm five malarial or- 
 ganisms of the same stage of development can be made out. Pictures 
 such as these were seen too often to be accounted for by technical 
 accidents. Occasionally red corpuscles malarial parasites and white 
 cells are visible within the glomerular capsular spaces. 
 
 The Bone Marrow. — The malarial parasites in the marrow are for 
 the most part enclosed within mononuclear cells ; numerous makro- 
 
44 LeweUys F. Barker. 
 
 phages are here present with contents very similar to those described 
 for these cells in the spleen. Streptococci are numerous, some free in 
 blood-vessels others enclosed within white cells. The endothelial cells 
 contain blood pigment at the poles of the nuclei — part of which yields 
 the blue reaction. There is an increase in the number of the white 
 cells in the marrow, and a considerable number of nuclei are fragmented. 
 Nucleated red blood corpuscles are abundant, as are also degenerated 
 red corpuscles, Qccurring singly and in clumps. Some of the strepto- 
 cocci in sections treated with ferrocyanide of potassium and hydro- 
 chloric acid yield a sharp blue reaction, so that the chains of cocci 
 look as though stained in methylene blue. The same result was 
 obtained with some of the cocci in the spleen. 
 
 The Adrenal Glands. — In the literature, the lesions of the supra- 
 renal capsules in malaria have not received the attention which the 
 findings in this case would show that they deserve. The arteries and 
 veins of the capsule are wide and contain many malarial organisms as 
 well as single chains and masses of streptococci ; the lumina of some of 
 the veins are completely filled with accumulated leucocytes (mononu- 
 clear and poly nuclear), malarial parasites in and outside of red cor- 
 puscles and streptococci. A few makrophages are also present in the 
 veins of the capsule. There are irregular areas of vascular dilatation 
 throughout the sections. The vessels of the zona glomerulosa are 
 generally distended, as are those of the medulla ; in the zona fasci- 
 culata and in the zona reticularis the capillary and venous dilatation 
 occurs in areas. It will be remembered that in the liver the rows of 
 liver cells had undergone an extent of atrophy corresponding to that 
 of the capillary dilatation ; similarly here in the area of capillary 
 ectasis the adrenal cells are small. 
 
 Malarial parasites are numerous in all the distended vessels ; many 
 of them are obviously within red corpuscles, a large number are en- 
 closed mthin the protoplasm of mononuclear leucocytes — from one to 
 four in a cell. Polynuclear leucocytes are numerous; they often contain 
 segmental pigment and occasionally a malarial organism. The ma- 
 krophages, with contents like those in the liver and spleen, are present 
 in considerable numbers in the adrenal capillaries, being somewhat 
 irregularly distributed through the cortex and medulla ; they are per- 
 haps most abundant in the outer portion of the zona fasciculata, and 
 fewest in the zona glomerulosa which is tolerably free from pigment 
 
A Study of Some Fatal Cases of Malaria. 45 
 
 masses when looked at with very low powers (8 and 16 diameters). The 
 endothelial cells are phagocytic here as in the liver, their nuclei are 
 large and vesicular, their protoplasmic contents quite similar to those 
 of the intra-capillary makrophages, except that they consist rather 
 more of blood pigment and less of malarial pigment, the foreign 
 substances being arranged mainly at the poles of the nuclei. Outside 
 the capillary walls, between them and the adrenal cells of the zona 
 fasciculata, here and there mononuclear makrophages are visible, not 
 unlike the phagocytic cells of Kupffer in the liver. It is possible to 
 make out, too, that a few of the true adrenal cells in places contain 
 within them malarial pigment and infected corpuscles — a fact which 
 should not surprise us when we consider the close relation of certain 
 parts of the adrenal parenchyma to the veins which has been recently 
 demonstrated by Manasse. 
 
 In places there are capillary thrombi of pure streptococci, and cocci 
 in single chains or in clumps are irregularly distributed in the capil- 
 lary districts. Here and there in sections stained in methylene blue 
 they are visible inside of cells (leucocytes, makrophages, endothelium 
 of capillaries). 
 
 Many of the adrenal cells, often in foci, are swollen, vacuolated, 
 and fatty, and show fragmented nuclei. The chromatolytic changes 
 are best seen in sections stained in aqueous magenta. 
 
 The Lungs. — The pulmonary and pleural veins are widely dis- 
 tended, and in them enormous numbers of malarial organisms are 
 visible. The parasites are chiefly in red blood corpuscles, but many 
 of them have been included, often along with strejDtococci, by white 
 cells (chiefly mononuclear, but also polynuclear). The white cor- 
 puscles tend to accumulate in groups, and they, together with infected 
 red corpuscles, makrophages, free malarial parasites, and masses 
 of streptococci, are frequently massed near the walls of the vessels. 
 The parasites are present, too, in considerable numbers in the 
 pulmonary capillaries and in branches of the pulmonary artery. 
 Lesions associated with coal pigmentation, and moderate emphy- 
 sema are present, otherwise the lungs show no marked alterations. 
 No other tissues from this case were preserved for microscopic 
 examination. 
 
 The fact that the malarial infection was not recognized during life, 
 the enormous number of parasites, the extensive phagocytic processes, 
 
46 Lewellys F. Barlcer. 
 
 and particularly the mixed infection and the lesions in the kidneys 
 make this case one of more than ordinary interest. 
 
 It may not be out of place here to make a few general remarks 
 concerning the bacterial infections and protozoan invasions which may 
 be concurrent with malaria. 
 
 In the clinical section of this fasciculus (Report by Thayer and 
 Hewetson) the accurrence of multiple malarial infections is considered, 
 and the fact that an individual may be infected at the same time with 
 different groups or generations of the same organism or of organisms 
 of different types, is found to account for many of the manifold mani- 
 festations of the disease which may be met with. But in addition to 
 a knowledge of such multiple malarial infections, a consideration of 
 the possibility of the co-existence with malaria of other protozoan 
 infections, and of certain bacterial diseases, both local and general, 
 throws some light upon certain problems connected with malaria which 
 have been heretofore obscure. 
 
 Concerning protozoan infections concurrent with malaria little is 
 known. In the Johns Hopkins Hospital one case of malaria has been 
 met with in which there was an associated dysentery due to the 
 amoeba coli. 
 
 The bacterial infections which may be associated with malaria are 
 numerous. In the first place the occurrence of a complicating pneu- 
 monia in malaria, which led years ago to so much polemical literature, 
 is now satisfactorily explained. The pneumonias which were be- 
 lieved to be due to a malarial poison are now known to be due not 
 to this cause, but to an associated bacterial infection. Manson and 
 others have described forms of pneumonia peculiar to the disease 
 when occurring in conjunction with malaria, and it was believed that 
 this pneumonia was particularly prone to terminate fatally. The 
 review of the whole subject by W. T. Howard in 1859 had an im- 
 portant influence, and still merits careful reading. Osier opposed the 
 view that the pneumonia in malaria was special to the latter disease. 
 Finally Bignami, Marchiafava and Guarnieri have described cases 
 which came to autopsy, at which careful bacteriological examinations 
 were made, by which it was proved that the croupous pneumonias of 
 malaria, like other cases of croupous pneumonia, are due to infection 
 with the micrococcus lanceolatus. 
 
A Study of Some Fatal Cases of 3Ialana. 47 
 
 In addition to croupous pneumonia, bronchitis and broncho-pneu- 
 monia are frequent complications of malaria, and probably may be 
 due to any one of the pyogenic organisms. The much disputed typho- 
 malarial fever, by the light of our present knowledge, presents no 
 difficulties. It is now well established that the majority of cases of 
 so-called typho-malarial fever and typho-intermittent fever are really 
 genuine cases of typhoid fever. That a typhoid infection may co-exist 
 with an invasion by the malarial parasites is indeed certain ; upon 
 this point the cases reported by Osier and by Gilman Thompson have 
 left no room for doubt. 
 
 The rare cases in which an acute ulcerative endocarditis is seen in 
 conjunction with malaria, now that the etiology of the endocarditides 
 is better understood, will probably turn out to be examples of mixed 
 bacterial and malarial infection. 
 
 Erysipelas sometimes co-exists with malaria ; at least one such case 
 has been met with in the wards of this hospital. 
 
 Of the predisposition to dysentery depending upon alterations in 
 the nutrition of the mucous membrane lining the alimentary canal we 
 have already spoken. The chances of bacterial ingress and the possi- 
 bilities of a general septic infection in such cases is obvious. Cases of 
 general streptococcus infection, such as the one described under the 
 head of Case D, are undoubtedly rare. 
 
 VI. 
 
 ON THE UNEQUAL DISTRIBUTION OF THE PARA- 
 SITES IN THE BODY IN MALARIAL 
 INFECTION. 
 
 The recognition of the existence of pigment in the blood and 
 in the various internal organs of patients suffering from malarial 
 infection antedated by many years the discovery of the organisms of 
 malaria by Laveran in 1880. But the studies of these earlier observers 
 went beyond the recognition of its mere existence, since it was noted 
 by quite a number of them that the pigment was not equally dis- 
 tributed throughout the body. Thus, in the well known case of 
 Meckel in an insane patient, in whom the spleen was enlarged and 
 deeply pigmented, particles of pigment were found in various parts 
 
48 Lewellys F. Barker. 
 
 of the body, and it was suggested that these had been swept out of 
 the spleen by the blood and carried by the current to the other organs. 
 
 Virchow in 1848, in describing the melanaemia of a malarial 
 patient, speaks of the large accumulation of pigment in the spleen 
 and liver, and at the same time notes the finding of this substance 
 enclosed in the cells in the blood of the heart. 
 
 Planer suggested that the comatose and apoplectic forms of severe 
 malaria might be explained by the lodgment of emboli of pigment in 
 the brain capillaries. Frerichs attributed the atrophy of the paren- 
 chyma of the liver, observed in some of the cases, to obstruction in 
 the liver capillaries. 
 
 Since the discovery of the malarial parasite, those who have had 
 opportunities of studying specimens of the fresh blood from a large 
 number of cases of malarial infection, have not only been able to 
 recognize certain distinct types of parasites as belonging to the various 
 clinical forms of the disease, but have also been able to add some 
 curious facts relative to the distribution of the organisms in the blood 
 and organs. Councilman, Celli and Marchiafava and others observed 
 in cases of the comatose form of pernicious malaria, the frequent oc- 
 currence in the brain of capillaries plugged with parasites. Council- 
 man, too, early pointed out that the number of crescentic forms of 
 the organism in the circulating blood was seldom large, but that 
 their tendency was to accumulate in considerable numbers in the spleen. 
 
 The question of the unequal distribution of the parasites in the 
 body assumes especial importance when considered in connection with 
 the three main types of the malarial organisms. Without entering 
 into a detailed description of the individual observations which have 
 led up to our knowledge of the subject as it may at present be 
 formulated, the broad statement may be made that in infections with 
 quartan parasites one sees the most equal distribution of the parasites 
 throughout the blood and various organs, and that in infections with 
 parasites of the aestivo-autumnal variety the most unequal distribution 
 is encountered. In infection with parasites of the tertian type, the 
 character of the distribution may be said to stand between that of 
 the quartan and that of the aestivo-autumnal infections, approaching 
 perhaps a little more closely to the former. 
 
 In the quartan fevers the parasites are nearly always to be seen in 
 numbers in the blood in any of the peripheral parts, and during the 
 
A Study of Some Fatal Cases of Malaria. 49 
 
 paroxysm many segmenting bodies, although they show a decided 
 tendency to accumulate in the organs, are observable in the blood 
 taken from the finger-tip or from the lobule of the ear. Indeed, so 
 regular is the distribution of the organisms throughout the body in this 
 type of malarial fever, that a tolerably definite estimate of the severity 
 of the infection can be made simply from the number of organisms 
 to be seen in the fresh blood slide. 
 
 The parasites in tertian fever, although usually quite abundant in 
 the circulating blood, show decidedly a more marked tendency to 
 accumulate in the internal organs, such as the spleen, the liver, and the 
 marrow of the bones. This is notably true at the time of the par- 
 oxysms when the segmenting organisms, although usually still present 
 in severe infections in considerable numbers in the peripheral blood, 
 are for the most part retained in the internal organs and especially 
 
 in the spleen. 
 
 But it is in the infections with the aestivo-autumnal parasites, in- 
 fections which include the majority of comatose and other pernicious 
 cases, that the most curious and marked variations in the distribution 
 of the parasites are to be met with, and the findings in these cases 
 have gone far to make clear the diverse and startling clinical mani- 
 festations to which these infections may give rise. It is in these 
 cases more particularly that pathologists, through observations at post- 
 mortem examinations, have been able to make important contributions 
 to the understanding of a disease, the main progress in which is un- 
 doubtedly due to the work of the clinical investigators. 
 
 In the aestivo-autumnal infections, the number of organisms in 
 the blood circulating in the peripheral parts afford as a rule very 
 insufficient data upon which to base an idea of the severity of the 
 infection. As clinical experience has taught, numerous slides pre- 
 pared from the peripheral blood may show very few organisms, and 
 these often of the type most difficult to recognize, while in a drop of 
 blood taken from the spleen quite a large number of the parasites 
 may often be made out with ease. 
 
 The occurrence of segmenting organisms in the peripheral blood is 
 a phenomenon of extreme rarity in aestivo-autumnal infections. 
 
 Golgi, Bignami and others have pointed out the fact, which can 
 easily be substantiated by careful observation, that in aestivo-autumnal 
 malaria the distribution of the parasites may vary in different parts 
 
50 Lewellys F. Barker. 
 
 of the same organ. Thus in the fluid obtained from tapping the 
 spleen in different regions, the number of organisms is prone to vary 
 considerably, and in sections of the spleen, liver, and other organs, 
 it is not difficult to convince one's self of the disparity in the number 
 of organisms in different vascular territories. 
 
 Among the most interesting and most important of the local accu- 
 mulations of the parasites is the formation of parasitic thrombi. In 
 the comatose forms of malarial fever it is not uncommon to find 
 capillaries and small veins in the brain distended with masses of 
 malarial parasites of the aestivo-autumnal variety, which probably 
 are identical with the so-called pigment thrombi of the early observers. 
 These may be pigmented organisms and segmenting forms, or accord- 
 ing to Bignami, the thrombi may sometimes be made up of the small 
 pale non-pigmented bodies first described by Marchiafava and Celli. 
 
 The profound disturbances of nutrition necessarily consequent upon 
 such a condition, which is not unfrequently accompanied by necrosis, 
 would alone, without a consideration of the effects of the toxines which 
 the parasites produce, suffice to explain many of the clinical phenomena 
 referable to intra-cranial involvement. 
 
 It is not to be supposed that in any given case, all the capillaries 
 are alike affected. As a matter of fact, while two or three may be 
 completely filled with parasites, their neighbors for some distance 
 around may be almost or entirely free from them. When we consider 
 the many variations possible in the implication of the capillaries in any 
 organ, the diversity of the disturbances of the cerebral functions 
 observable clinically becomes easily understandable. It is not difficult 
 to conceive that herein may lie the key to the transitory aphasias, the 
 variation in degree extent or duration of the paralyses, or of the 
 mental irregularities occasionally noticeable in the severer forms of 
 aestivo-autumnal fever; and when, along with other things, we 
 remember that comparatively limited disturbances of the circulation 
 in certain of the vital centres, such as the medulla,^ suffice at times 
 to cause sudden death, it is not surprising that the type of malarial 
 infection which is associated with the possible occurrence of the 
 capillary thrombi of parasites should have won for itself the title 
 of malaria pernidosa. 
 
 ^ Marchiafava has recorded a case in which he noticed a special localization of the 
 parasites in the neighborhood of the bulbar nuclei. 
 
A Study of Some Fated Cases of Malaria. 51 
 
 In describing the findings in Case B, attention was directed to 
 the accumulations of parasites within the capillaries and small veins 
 of the mucous membrane of the stomach, and to the necroses on the 
 surface of the mucosa, which could fairly be attributed to the dis- 
 turbances in the nutrition of the part. There are numerous instances 
 in the literature in which, after death, a similar condition has been 
 found in the vessels of the mucous membrane of the intestines, the 
 patient during life having shown the symptoms of profound intestinal 
 disturbance and even of an acute dysentery. The cases are so charac- 
 teristic as to be worthy of a definite place in nosology and the names 
 malaria perniaiosa cholerica, and malaria pernioiosa algida have been 
 suggested to describe these forms. 
 
 It would probably be fair, arguing by analogy, to assume — and 
 many observations would seem to confirm the view — that the occur- 
 rence of similar parasitic thrombi in other organs of the body may 
 lead to alterations in nutrition and function which materially influence 
 the course and progress of the disease. 
 
 Any attempt to explain the reasons for this unequal distribution is 
 beset with many difficulties. While the slow circulation and the 
 calibre of the vessels in certain organs certainly play a part, yet the 
 distribution of parasites in all forms of malaria is, as we have seen, 
 very different from that of inert substances when introduced into the 
 circulating blood. Undoubtedly, many factors have to be considered, 
 and how far any one or more are concerned in a given case is difficult 
 to determine. 
 
 In another section, in which phagocytosis is dealt with, the locali- 
 zation of the parasites in certain organs inside of cells will be more 
 fully commented upon. As Bignami suggests, the activity or in- 
 activity of the phagocytes of a certain organ may have an important 
 influence upon the distribution. He lays stress, too, upon the fact 
 that the parasites are usually endoglobular, and that infected red 
 corpuscles, from loss of elasticity or other physical alteration, may be 
 impeded in their progress and tend to accumulate in the viscera in 
 which the circulation is slowed. It is certainly true that in the 
 abdominal area where the slowness of the circulation is accentuated 
 in malaria, owing to obstruction in the liver by endothelial swelling 
 or accumulation of makrophages within the capillaries, the massing 
 of the parasites is ordinarily marked, while in organs in which the 
 4 
 
52 Lewellys F. Barker, 
 
 circulation is most active, very few parasites as a rule are present. 
 That the parasites and infected red cells collect along with the white 
 corpuscles on the inner walls of the larger veins is a fact which could 
 be confirmed in many of the specimens from the autopsies of this re- 
 port, but as to the explanation of this phenomenon nothing is as yet 
 certainly known. 
 
 As regards the tendency in the pernicious cases to the formation 
 of thrombi composed of parasites in certain vascular territories our 
 knowledge is most at fault. The idea that certain capillaries become 
 plugged with makrophages, and that in the dilated vessel behind the 
 point of obstruction the corpuscles in the stagnant blood all become 
 infected, will not suffice for the explanation of all the instances. 
 That vaso-motor influences in certain vascular areas play, as Bignami 
 suggests, an important r6le seems plausible, especially in cases of the 
 pernicious algid form. 
 
 It is perhaps not impossible to learn something from the analogies 
 observable in tumor metastases, in bacterial infections or even in simple 
 intoxications. It has long been a puzzle to pathologists why in cases 
 of general sarcomatosis or carcinosis, where the distribution is through 
 the general circulating blood, that in some cases one organ or set of 
 organs, in other cases other portions of the viscera have remained 
 free or nearly free from metastatic growths. 
 
 Again as regards the general bacterial infections those who have as 
 a matter of routine made bacteriological investigations of all the 
 organs at a number of autopsies, will be familiar with the fact that 
 in such cases the bacteria even at perfectly fresh autopsies are by no 
 means equally apportioned through the blood and viscera. Indeed, 
 it is a common occurrence to find that one or two of the organs contain 
 relatively many fewer bacteria than the others. But that there is 
 little regularity in the inequality of distribution is shown by the study 
 of numerous cases of general infection with the same micro-organism, 
 e. g. the streptococcus. Whereas the plate cultures made from the 
 spleen in one case of septicaemia may be closely crowded with colonies 
 and those from the liver contain only a few, in another instance the 
 conditions may be exactly the reverse. Every one is acquainted with 
 the relative immunity of some organs in acute general miliary tuber- 
 culosis, an immunity which can be made out often from the naked 
 eye appearances alone, although it is often difficult to decide whether 
 
A Study of Some Fatal Cases of Malaria. ^ 53 
 
 the irregularity is an expression of a primary inequality of distribution, 
 or to differences in the resistance offered to the local multiplication of 
 the distributed organisms or again to the different effect which they 
 produce on the tissues in which they develop. 
 
 And after all when we consider the fact that in malaria we have to 
 deal with a crude mixture of malarial parasites, blood corpuscles and 
 blood plasma, the anomalous distribution of the parasites, as ascer- 
 tained by post-mortem examinations, should be much less difficult to 
 account for than the unequal diffusion through the organs of sub- 
 stances which are dissolved in the blood, a phenomenon which of late 
 has attracted considerable attention. It is scarcely necessary to call to 
 mind that normally certain chemical bodies are removed from the 
 circulating fluid by various glands to serve in the manufacture of 
 secretions. Again, the discovery of the accumulation of poisons in 
 certain organs, e. g., morphine in the liver, spleen and bone marrow, 
 and certain other vegetable poisons in the liver, for purposes of elimi- 
 nation or neutralization must be reckoned among the observations 
 which help to make general toxicology interesting. In the domain 
 of bacterial toxicology, Welch and Flexner have demonstrated the 
 occurrence of definite focal lesions in the tissues of the body produced 
 by a soluble poison circulating in the blood, a finding which is scarcely 
 compatible with any assumption other than that the dissolved poisons 
 are not evenly distributed even in the individual organs. 
 
 Now that the vital characteristics and varying sensibilities of uni- 
 cellular organisms are becoming better known and appreciated, we 
 have learned to have more respect for a cell as an individual, and the 
 conclusion that this unequal distribution is dependent upon a com- 
 plexity of factors will not excite surprise. If it be borne in mind 
 that the parasites are constantly exercising their metabolic functions ; 
 if the question of food relations and that of the influence of excre- 
 tory substances from the parasites together with the alterations in the 
 metabolism of the cells of the various tissues (e. g., those dependent 
 upon the destruction of red corpuscles) be taken into account, it will be 
 seen that the whole problem of anomalous distribution, as influenced 
 by factors incident to the parasite and factors incident to the cells, 
 may become extremely complicated, and that we can scarcely hope in 
 the very near future that all the intricacies, whether they be due 
 simply to mechanical factors or to those which we must regard as the 
 outcome of vital influences, will be explained. 
 
54 , Lewellys F. Barker. 
 
 VII. 
 ON PHAGOCYTOSIS IN MALARIA. 
 
 Among those who have insisted upon the importance of the part 
 played in raalaHa by the so-called phagocytes are Metschnikoff, 
 Guarnieri, Bignami, Laveran, Dock, and especially Golgi and Basti- 
 anelli. As has been said above, a study of the literature shows that 
 malarial pigment had been observed in the cells of the different organs 
 and in the white cells floating in the blood long before the parasitic 
 nature of the disease had been established, and a great deal of this 
 pigment is now known to be within the bodies of the parasites. 
 
 The inclusion of the malarial pigment and of the malarial parasites 
 within white cells, fixed or floating, occurs in all cases of malaria, 
 although the extent of the process varies somewhat in different in- 
 dividuals, and with the different varieties of malarial infection. The 
 microscopic examination of the cases which came to autopsy here, 
 showed that the reports of other observers on this subject had not 
 been exaggerated. 
 
 The cells actively concerned in phagocytosis are not all of one kind. 
 Besides different varieties of leucocytes, certain of the fixed cells of 
 the organs, the endothelial cells generally, but especially those in the 
 liver and spleen, the cells of Kuppfer in the former, and the cells of 
 the pulp-cords in the latter, take no unimportant part in the process. 
 
 The contents of these different phagocytic cells vary also. Speaking 
 generally, it may be stated that the cells concerned may enclose within 
 their bodies any of the following : (1) red blood corpuscles, many of 
 them altered, others apparently little changed ; (2) fragments of red 
 corpuscles ; (3) masses of haemosiderin (probably formed within the 
 cells) ; (4) malarial parasites, in different phases of the developmental 
 cycle, many of them endoglobular, many of them degenerated or going 
 to pieces ; (5) malarial pigment, especially the central pigment clumps 
 from segmenting parasites ; and (6) white cells both mononuclear and 
 polynuclear. A phagocytic cell is sometimes seen to contain all of 
 these structures at one time, but this is not a common observation. 
 Special names have been assigned to the phagocytic cells in accordance 
 
A Study of Some Fatal Cases of Malaria. 55 
 
 with the character of their contents — thus the leucocytes containing 
 malarial pigment are spoken of as " pigment! ferous " or " melani- 
 ferous ; " the cells containing red corpuscles as " globuliferous ; " 
 while those containing parasites are known as " amoebiferous " cells. 
 Following this nomenclature the cells containing other phagocytes 
 might be called " phagocytiferous," just as those containing white 
 corpuscles have been spoken of as " leucocytiferous/' but it is doubtful 
 if much is to be gained by any extension of this awkward terminology. 
 The different forms of phagocytes seen in our cases have been fully 
 described in the protocols of the microscopic examinations, and need 
 not be further considered here. One point to which attention may 
 perhaps be directed is the manifest division of labor which exists 
 among the various forms of phagocytic cells. While any one of the 
 varieties seemed capable of taking up at times almost any of the 
 substances above mentioned, yet when the tissues are studied care- 
 fully it is easy to make out that they do not all contain these various 
 substances in the same proportions, but that as a matter of fact the 
 white corpuscles and endothelial cells appear to possess more or 
 less definite elective affinities. For example, in Case T> while the 
 mononuclear leucocytes contained the majority of well preserved 
 parasites, the polynuclear leucocytes showed a preponderance of the 
 segmental pigment ; while the makrophages in the spleen and liver 
 contained large numbers of infected and otherwise altered red cor- 
 puscles and remains of malarial parasites, the endothelial cells of the 
 spleen and liver often contained blood pigment to the exclusion of all 
 other visible kinds of foreign material. Laveran, Councilman, and 
 Golgi early noted that leucocytes carrying pigment were most abundant 
 in the blood just after the onset of a paroxysm, and suggested that 
 the increased number of pigmented corpuscles might depend upon 
 the setting free of large quantities of pigment during segmentation. 
 Supposing that there might exist a periodicity to the phagocytosis 
 corresponding more or less nearly to the developmental cycle of the 
 parasite, Golgi made certain studies, the result of which convinced 
 him that the idea had a basis in fact. From these investigations he 
 concluded that the white cells in the organs, particularly in the spleen, 
 played even a more active part in phagocytosis than those in the 
 blood, a conclusion which had also been reached by Metschnikoff 
 from the study of sections of the spleen and liver in malaria. Basti- 
 
56 Lewellys F. Barker. 
 
 anelli found further in his extensive study of the leucocytes in malaria 
 a marked increase in the number of pigmented leucocytes in certain 
 cases at the beginning of the febrile paroxysm, but as might have 
 been expected saw less evidence of periodicity in the aestivo-autumnal 
 cases. He seems inclined to attribute the major share of the phago- 
 cytic work to the large mononuclear elements. The same writer 
 confirmed the observations of Bignami concerning the degeneration 
 of phagocytic leucocytes and suggests that the diminution in the 
 number of leucocytes in malaria may be attributed to this cause. 
 John S. Billings, Jr., who made accurate counts of the total number 
 of leucocytes, and also differential counts of the various forms of white 
 corpuscles by Ehrlich's methods of color analysis, before, during and 
 after the paroxysms, found that in certain cases there was always a 
 diminution in the number of leucocytes during the febrile paroxysm. 
 In a chart accompanying his ' article in which a composite curve of 
 the temperature is compared with a similar one representing the 
 number of white corpuscles, it is evident that, while just before the 
 chill the number of white cells to the cubic millimetre is approxi- 
 mately normal, there is a steady though not very marked increase in 
 the number for from two to three hours until a maximum is reached, 
 after which there is a relatively sharp and steady decline correspond- 
 ing with the fall in temperature until a minimum is reached which is 
 considerably below the normal. As to the color analysis of the leuco- 
 cytes, Bastianelli found a decrease in the leucocytes with polymorphous 
 nuclei with an increase in the large and small mononuclear elements. 
 According to Billings a decrease in the polynuclear and an increase 
 in the large mononuclear cells is constant, while there is no regularity 
 as to the percentage of small mononuclears and eosinophiles. 
 
 The clinical observations just referred to are of considerable interest 
 in connection with the appearances in the organs at autopsy, and it is 
 interesting too to compare the examples of phagocytosis observable 
 in the blood drawn from the circulation during life (vide a report by 
 Thayer and Hewetson) with those seen in the sections from the cases 
 now reported. According to these observers it is extremely rare to 
 notice any active phagocytic tendencies on the part of the mononuclear 
 elements to parasites in blood taken from the finger or ear, although 
 it is by no means uncommon to see a leucocyte with a polymorphous 
 nucleus gradually enclose a flagellating parasite or a fragmented ex- 
 
A Study of Some Fatal Cases of Malaria. 57 
 
 tra-cellular body in the fresh blood slide. It will have been seen 
 above, however, that in the blood in the sections from Case D 
 the majority of parasites are enclosed within large mononuclear 
 leucocytes. It has been stated, too, that neither the parasites nor 
 the including cells necessarily show evidences of degeneration. The 
 question naturally arises, "Could the enclosing of the parasites 
 by the large mononuclear leucocytes in this case have been a post- 
 mortem phenomenon ? " Dock has shown that the malarial parasites 
 are arrested in their development soon after the death of the patient, 
 and it is of course quite conceivable, though in my opinion it is 
 improbable, that certain changes occurring in the parasites inside 
 the body after death rendered them suitable to be taken up by 
 the large white cells. It is unfortunate that in this case no blood 
 examination was made during life. So many of the large mononu- 
 clear leucocytes as seen in the sections contain parasites within 
 their protoplasm, that had the ingestion occurred ante-mortem it could 
 scarcely have been overlooked upon examination of the fresh blood. 
 
 The original statement of Metschnikoflf that the endothelial cells of 
 the capillaries, especially in the liver, take up the parasites has been 
 questioned by some observers. The tissues from the autopsies here 
 reported unquestionably confirm Metschnikoff's statement, though as 
 we have said, the endothelial cells are much more prone to take up 
 the remains of altered blood corpuscles than to include malarial 
 pigment or the parasites. 
 
 The red blood-corpuscle-carrying cells and the huge phagocytic 
 cells of the spleen attract special attention. When one studies sections 
 of the spleen and sees the enormous number of these makrophages, 
 the accumulations of fragmented red corpuscles, the necroses, and the 
 dilatation of the blood-vessels in this organ, he has not to go far to 
 seek an explanation for its enlargement in malarial infection. The 
 number of makrophages which are carried from the spleen through 
 the splenic vein into the liver cannot fail to be of considerable signi- 
 ficance. As was pointed out in the description of the tissues they 
 frequently appear to occlude the liver capillaries, and to offer a serious 
 impediment to the onflow of blood. Guarnieri thought that this 
 obstruction in the liver capillaries might account, in part at least, for 
 the enlargement of the spleen (venous stasis), and suggested that 
 possibly the pernicious forms of malaria might depend upon an in- 
 
58 Lewellys F. Barker. 
 
 toxication due to the disturbance of the functions of the liver — a 
 view which he has doubtless given up long before now. 
 
 The question may fairly be asked, "What becomes of these migrated 
 spleen cells loaded down with ingested material?" If we can judge 
 by an examination of the tissues elsewhere, there are comparatively few 
 carried through the liver into the general circulation, unless indeed 
 the greater number of them have been diminished in size, and have 
 gotten rid of sodae of their contents so that they were able to pass 
 through. This they could do in part through cellular digestion. It 
 seems to me, however, that, carrying as they do, besides malarial 
 parasites and malarial pigment, considerable quantities of haemoglobin 
 and of blood coloring matter already altered within the cell so as to 
 give the blue iron reaction, these cells may exercise an important 
 function in carrying to the liver the materials for the manufacture of 
 bile. It is not inconceivable that these makrophages lying in direct 
 contact with the endothelium of the hepatic capillaries could yield up 
 a portion or all of their contents to the latter. It would indeed be 
 interesting if it should turn out that the blood pigment in the makro- 
 phages, in the vascular endothelium, and in Kupffer's cells stood in 
 some such direct relation to the bile manufactured by the liver cells. 
 Certainly the liver cells must draw their iron substances from the 
 blood, and from what we know now-a-days of the varied capacities 
 of white blood corpuscles and of endothelial cells, the occurrence of 
 some such interchange of raw materials as has been hinted at would 
 not be surprising. It may be that the study of pathological accentu- 
 ation of the bile-making activities of the liver may throw light in the 
 future on the still obscure physiological processes which go on in 
 this organ .^ The metabolic processes of the body tend towards eco- 
 nomy ; the re-making of materials by diflPerent organs is common, 
 the refuse from one organ often being essential for the nutrition and 
 well being of certain of the others (law of Treviranus) ; and this being 
 so, the relations of phagocytosis to the nutritional activities of the 
 body form an interesting topic for investigation. 
 
 The makrophages in the vessels of the mucous membrane of the 
 alimentary tract have been mentioned in connection with Case A. 
 Dock describes finding one similar cell in one of his cases. It is 
 
 ^ Compare the researches of Dr. William Hunter, On the Physiology and Pathology 
 of Blood Destruction, Brit. Med. Jour., 1892, ii, p. 1159 and 1223. 
 
A Study of Some Fatal Cases of Malaria. 59 
 
 generally stated that eosinophilic cells never act as phagocytes in 
 malaria. The late Dr. Oppenheimer, however, recently showed me 
 in a slide of fresh blood a makrophage which contained large, round, 
 yellowish, refractive granules which closely resembled the ordinary 
 eosinophilic granulation ; the cell enclosed several infected corpuscles. 
 
 It is not improbable that the active process of phagocytosis, aside 
 from the mechanical obstruction which the cells may cause, helps to 
 determine the irregular distribution of the parasites in the body. At 
 any rate it is certain that the parasite? tend to accumulate in ordinary 
 cases in the spleen and liver, the sites where the phagocytosis is most 
 active. We have already pointed out, however, that the phagocytosis 
 can be only one of many factors which influence the distribution. 
 
 There is a considerable amount of literature bearing upon the re- 
 lation of phagocytosis to " natural resistance " and to " spontaneous 
 cure " in malaria. It is a perfectly well ascertained fact that many 
 patients suffering from malaria do, when placed under more favorable 
 hygienic conditions, get entirely well without the administration of 
 quinine or of any other drug. It is by no means uncommon to see 
 patients begin to improve almost immediately after being put to bed 
 in a hospital ward, the paroxysms becoming successively less severe, 
 and the organisms gradually disappearing from the blood until all have 
 vanished. What the natural mechanisms of defense are which lead to 
 spontaneous cure, and which inhibit the growth and multiplication of 
 many parasites even in the severer infections, it is as yet impossible 
 to say definitely. All authorities are agreed that many of the progeny 
 of segmenting organisms are disposed of at the end of each paroxysm, 
 since did all the young ones gain entrance to red corpuscles and go on 
 to full development, the blood would after a very few paroxysms show 
 very few uninfected red globules, and those who hold that the blood 
 serum kills off many of the small hyaline forms before they gain 
 entrance to the interior of red corpuscles are not without grounds for 
 their belief. Others maintain that the white corpuscles, the endothe- 
 lial cells, and the spleen-pulp cells enclose many of the segments 
 immediately, even before they have been deleteriously affected by the 
 blood serum. The relative efficiency of the blood serum and of the 
 phagocytes with relation to natural resistance, is being fought out on 
 this as well as on other grounds. There can be little doubt {vide pro- 
 tocols) that many of the parasites taken up by the phagocytic cells are 
 
60 Lewellys F. Barker. 
 
 enclosed within red corpuscles, and it may very well be that the 
 alteration in the bodies of the red corpuscles may help to determine, 
 especially in the spleen, their inclusion by white cells. That the re- 
 reception of the parasites can do harm to the cells in many cases would 
 seem to be evidenced by the fact that many of the makrophages are 
 necrotic, their nuclei staining feebly or not at all in basic dyes, and their 
 protoplasm showing an increased affinity for acid dyes like eosin. The 
 diminution in the number of leucocytes after a paroxysm, however, is 
 much more probably due to the effects of toxines set free at segmen- 
 tation, and if so would be quite analogous to the similar diminution 
 (leukolysis) which immediately follows the experimental injection of 
 bacterial toxines into animals. 
 
 The changes which the parasites undergo within the bodies of the 
 white cells are interesting to watch. It would appear that sometimes 
 the parasite ruptures and that the pigment is gradually set free to be 
 distributed in more or less regular lines throughout the protoplasm 
 of the including cell. How long the parasites may live after inclusion 
 appears doubtful. That they are taken up while alive seems certain 
 from the many observations of skilled investigators. It is usually 
 taken for granted that the phagocyte is the active agent and takes up 
 the parasites, a much more likely view than that the parasites enter 
 the white cells to feed on their deuteroplasm (fragmented or degener- 
 ated red corpuscles). It is not certain, however, that the parasites 
 may not continue an intra-phagocytic existence at least for some time, 
 especially if the protoplasm of the phagocyte is degenerated. Golgi 
 has even gone so far as to suggest that the parasites may grow and 
 multiply within certain of the body cells. Bignami cannot conceive 
 of any explanation for the so-called " cases of latent infection " in 
 malaria, that is, those instances in which an apparently cured malarial 
 infection subsequently becomes active, without the patient having in 
 the meantime been exposed to re-infection in a malarial district, except 
 by assuming the continuance of some resistant forms inside of cells. 
 Bignami argues that inasmuch as certain cells, leucocytes and endo- 
 thelial cells for example, are known to take into themselves a certain 
 number of sporulating forms, and further, since in patients with a 
 recently cured malarial infection who have died from some intercurrent 
 disease certain cells in the spleen, liver and bone marrow, retain the 
 traces of infection, it is much more likely that the germs of latent 
 
A Study of Some Fatal Cases of Malaria. 61 
 
 infection remain stored up in these cells than that they should exist 
 for such a length of time free in the circulation. For if the parasite 
 is capable of assuming some persistent form (crescentic or otherwise)/ 
 it is scarcely likely that such a form could long be retained inactive 
 in the intercellular fluids, since it would almost certainly be taken up 
 by phagocytes. Bastianelli and Bignami, however, combat Golgi's 
 idea of the intra-cellular development of the parasites. There are 
 many examples of latent bacterial infections, and the resistance of 
 certain bacterial forms to the intra-cellular digestion is generally 
 appreciated (cf. the researches of Wyssokowitch, MetschnikoflP, et ai). 
 For the present, however, it must be granted that we do not fully 
 understand all the conditions which underlie latent infection. 
 
 Among the more interesting of the observations on phagocytosis in 
 malaria are those dealing with the inclusion of certain phagocytes by 
 other phagocytes — sometimes of phagocyte by phagocyte even to the 
 third degree. As has been stated, the including cell sometimes 
 looks necrotic, while in other instances it is the included cell which 
 shows degenerative changes ; occasionally both cells yield normal 
 staining reactions. That such inclusions are not infrequent the sections 
 from the fatal cases described in this report indisputably prove. Any 
 attempt at explanation must be speculative. We can conceive of 
 active small cells being attracted to the degenerating protoplasm of a 
 large cell. This might explain the instances where the including cell 
 looked degenerated. Or we can imagine the makrophage taking into 
 its substance an enfeebled small phagocyte, in which case the included 
 cell will be degenerated. Finally we can conceive of a small active 
 phagocyte being attracted to a large, more sluggish phagocyte by the 
 masses of food stuff (broken down red corpuscles, etc.) contained 
 within the latter. A consideration at the present time of such canni- 
 balistic and thieving tendencies on the part of the white cells would 
 lead us too far afield, but such studies are among the many attractive 
 problems connected with the sociology of cells, which, it is to be hoped, 
 the physiologists will work out in the near future. 
 
 ^ As Bignami points out, it is evident that some explanation other than the re- 
 sistance of crescents is necessary to account for the obstinacy of certain tertian and 
 quartan infections. 
 
DESCRIPTION OF PLATES. 
 
 PLATE in. 
 
 Case C. — Liver — showing an accumulation of small round mononuclear cells in 
 a portal space. 
 
 PLATE IV. 
 
 Case C. — Liver — stained with haematoxylin and eosin — showing an area of 
 necrosis with accumulation of leucocytes, many of which have distorted nuclei. 
 Fine particles of malarial pigment may be seen within the endothelial cells of the 
 capillaries and within some of the leucocytes. 
 
 Near the lower angle of the drawing a small thrombus containing numerous 
 leucocytes is visible. 
 
 PLATE V. 
 
 Case C. — Liver ; haematoxylin and eosin ; high power. 
 
 Fig. 1. — Hyaline thrombosis of an hepatic capillary; accumulation of leucocytes; 
 nuclear distortion ; a little malarial pigment present. 
 
 Fig. 2. — Thrombosis of adjacent capillaries; disappearance of intervening liver 
 cells ; leucocytic accumulation ; distortion and fragmentation of nuclei. 
 
 PLATE VI. 
 
 Case D. — Spleen in mixed malarial and streptococus infection. Tissue hardened 
 in alcohol ; section stained in methylene blue ; accumulation of parasites and cocci 
 within the vessels. Many of the malarial parasites have been absorbed by phago- 
 cytes. In the lower angle of the large vessel to the right a large mononuclear 
 leucocyte is visible which contains four parasites. Occasionally cocci and malarial 
 parasites are to be seen, inside the same phagocyte. 
 
 The makrophages in the splenic pulp, some containing coarse clumps, others finer 
 particles of malarial pigment, are numerous. 
 
 Inside the vessels the makrophages are quite like those described within the 
 hepatic capillaries of this case. 
 
 Some of the endothelial cells contain malarial pigment within their protoplasm. 
 
 A blue-stained non-pigmented sphere within the malarial parasite is well shown 
 in several parts of the drawing. 
 
 63 
 
The Johns Hopkins Hospital Reports. 
 
 Vol.V. Plate in. 
 
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