CORNELL UNIVERSITY LIBRARY David Albert Hauck Endowment Cornell University Library RM 741.P48 ^ PfOff in therapy and nonspecific resistan 3 1924 012 178 079 Cornell University Library The original of tiiis book is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924012178079 PEOTEIN THERAPY AND NONSPECIFIC RESISTANCE THE MACMILLAN COMPANY MBW YORK ■ BOSTON • CHICAGO ■ DALLAS ATLANTA ■ SAN FKANCISCO MACMILLAN & CO., Limited LONDON • BOMBAY • CALCUTTA MELBOURKB THE MACMILLAN CO. OP CANADA, Lro. TORONTO PROTEIN THERAPY AND NONSPECIFIC RESISTANCE BY WILLIAM P. PETERSEN, M.D. ASSOCIATE IN PATHOLOGY, TJNIVEESITY OP ILLINOIS, COLLEGE OF MEDICINE, CHICAGO, ILL. WITH AN INTRODUCTION BY JOSEPH L. MILLER, M.D. PROFESSOR OF MEDICINE, RUSH MEDICAL COLLBQB, TJNIVBBSITT OF CHICAGO, CHICAGO, UAi. r Jl3eto gotb THE MACMILLAN COMPANY rl922l All rights reserved nminD IN iH£ umi£D states of amsbica COPTEIGHT, 1922 Bt the maomillan company. Set up and printed. Published Januaiy, 1922. Press of J. J. Little & Ives Oompany New York, U. S. A. M. b. L. "Thus there exists a fashion in medicine, as in the other affairs of life, regulated by the caprice and supported by the authority of a few leading practitioners, which has been frequently the oc- casion of dismissing from practice valuable medicines, and sub- stituting others less certain in their effects and more questionable in their nature. As years and fashions revolve, so have these neglected remedies, each in its turn, rise again into favour and notice, whilst old receipts, like old almanacks, are abandoned until the period may arrive, that will once more adapt them to the spirit and fashion of the times. Thus it happens that most of our "New Discoveries" in the Materia Medica have turned out to be no more than the revival and adaptation of ancient practices.'' — From the Introduction of Paris' Pharmacologia, Kew York, 1830. PREFACE The conception that the organism in its resistance to disease and de- fense against bacterial invasion depends on biologic reactions essen- tially specific has dominated medical thought, medical experimentation, and medical practice for a period of over thirty years. They have been years of tremendous progress in the theory and the practice of medicine. Indeed, the advance, as contrasted with that of the ages gone before, has been so vast and far-reaching that we have by as- sociation come to regard this progress and the underlying trend of medical thought and theory, i.e., specificity, as practically identical. The idea of therapy on a nonspecific basis seems therefore at first glance a step backward, investigation of such a subject illogical, if nothing worse. And as we might expect on such premises, the present interest in nonspecific therapy did not originate on the basis of a con- vincing theory or promising laboratory experimentation. It was the clinic that forced upon our attention certain therapeutic results which could not be ignored, results so startling in many ways that our con- ception of the mechanism of recovery from disease has had to be re- cast. The theoretic basis to account for the results has been lacking, at least our current conception of immunity and of resistance to dis- ease has been found wholly inadequate to explain the clinical results. This seeming empiricism, this lack of exact knowledge concerning the mechanism of the nonspecific reaction has been the chief point of at- tack for whatever criticism has been presented. A brief examina- tion of the subject will, however, reveal that nonspecificity need not be as illogical, theoretically, as a cursory view might lead us to be- lieve. If we keep the focus of our attention on the reaction of the body to injury — on inflammation — ^we find that this reaction, no mat- ter how produced, — be it bacterial invasion, intoxication, or trauma, — is fundamentally similar under all circumstances. The type of cellular reaction may vary to some degree, the amount and composition of the exudate may differ, but the basic alterations are always alike. We deal with a consistent effort to dilute the noxious agent, to re- move it by intracellular or extracellular digestion, to neutralize it; these failing, then to wall it off, to put it outside of the current of normal tissue activity. If now we seek to alter this process therapeutically we have two distinct avenues of approach. The one is interested solely in the cause of the inflammatory reaction — if a bacterium, to produce an anti- X PREFACE Bacterial agent — ^if a toxin, to produce an antitoxin — if a chemical, to introduce a neutralizing substance. We see at once that in so far as the causes of inflammation may be unlimited, so oiu- specific agents would have to be unlimited. The alternative lies in the endeavor to alter the inflammatory re- action of the body itself. We may seek to augment its nat\u-al course, hastening autolysis and resorption, or attempt the reverse, retarding autolysis and stimulating the reparative phases, as we may wish. This is a true "ergotropie," as v. Groer has termed it, a therapeusis whereby we alter the reaction of the organism to the etiologic agent, rather than endeavoring to influence the causative factor of the inflammatory process directly. Such a therapy must of necessity be nonspecific in the immimological sense. Perhaps it will be well to make clear at the very beginning that the nonspecific reaction brings into play no new and heretofore un- known factors of resistance. It deals largely with reactions previously studied and which have always been employed by the organism in overcoming disease, with or without our conscious interference. It does deal, however, with the stimulation of these forces and when skill- fully invoked brings to bear a sunamation of the varied measures of defense of which the organism is possessed. It is quite probable that these potential forces may have been latent or held in abeyance until the nonspecific reaction brings them into activity. It has been observed that the antibodies (agglutinins, precipitins, opsonins, etc.) are "shed" or cast off from the cells after a nonspecific injection; so, too, fibrinogen and thrombokinase are increased and a variety of enzymes are poured out from the cells into the circulation. If nonspecific therapy is after all merely a method that deals with heretofore known reactions we must be prepared to accept the probability that it obeys all the commonly observed laws of biologic reactions. If we regard it as a method of stimulation — ^plasma activa- tion — it follows that it can only be effective when the protoplasm is still in fit condition to respond to stimulation. Once the stage of ex- haustion has been reached the mere irritation of the nonspecific agent is no longer able to bring about any alteration in the disease process other than an aggravation. The observations that have been made the basis of this monograph have been gathered partly at first hand, both clinically and ex- perimentally, more largely from a survey ~of such literature as the exigencies of the war have made available to me. The summarizing of our present knowledge in this particular field has seemed of some pos- sible value, not with the idea of popularizing a new therapeutic meas- ure but rather in stimulating interest in a direction that seems to offer decided possibilities of advance. I have therefore merely indi- cated some of the methods at present employed in nonspecific therapy without effort to define precise modes of application or indications for PREFACE xi therapeutic use. On the other hand I have endeavored to present the possible theoretical basis and some of the collateral fields of ap- plication as fully as our present knowledge will permit. A great num- ber of problems and questions of decided practical importance could unfortunately be merely mentioned without further discussion. In the presentation of the clinical results so far reported I have endeavored to maintain an attitude of caution. If at times I have erred from pure objectivity I must accept the blame in perhaps pre- senting the clinical reports of a number of observers whose enthusiasm has perchance outweighed their judgment. We must remember that it was the clinic that directed the attention to this form of therapy. During the short space of seven years nonspecific therapy has gained a firm foothold in clinical thought and practice; to-day it is recognized even by immunologists as one of the factors in resistance to disease. Whether, as Much surmises, nonspecific resistance and nonspecific immunity are of greater importance to the organism than are the specific forces should not for the time being concern us; our interest should be centered on applicability, methods and causes. Only when the vast field has been partially explored will it be permissible to judge the ultimate importance. While I have retained the name Protein Therapy, it should be recognized that Protein Therapy deals merely with one of a large group of agents which can be used to elicit the nonspecific reaction. Other terms have been applied— "Colloid Therapy"; "Shock Therapy"; "Foreign Protein Therapy"; "Heterovaccine Therapy," but inasmuch as it is the reaction of the patient that is of importance, not the sub- stance that causes the reaction, a name much broader in its signifi- cance should be used. "Ergotropie," the term coined by v. Groer, is possibly correct and most expressive in that it emphasizes the re- action of the patient and properly ignores the substance that causes the reaction. How far-reaching the field of nonspecific stimulation is in its vari- ous modifications becomes apparent from a consideration of the num- ber and the character of the agents which have been employed to bring about therapeutic results. Even the purely physical and me- chanical means — including irradiation, electricity, baths, massage, etc. — must be included in the survey because in some measure they bring about changes in the organism similar in character to those that we shall discuss in the following pages. To Dr. Otto L. Schmidt, who very kindly read the manuscript and made a number of suggestions, and to Dr. Joseph L. Miller, whose in- terested cooperation I have at all times enjoyed, I am under grateful obligation. To Miss Josephine Bates of New York I am indebted for her careful revision of the bibliography. W. F. P. INTRODUCTION Seven years have elapsed since the attention of the profession was first seriously attracted to the nonspecific character of vaccine therapy. The literature previous to this, however, contained considerable evi- dence suggesting this viewpoint. Immunologists and members of the medical profession were so engrossed with the idea that favorable re- sults could only be secured by specific means that this evidence was largely ignored. As a consequence of the stimulation given by the earlier investi- gators there has developed an extensive literature upon this subject. A considerable number of agents, many of them proprietary in char- acter, have been recommended as possessing special virtues. The marked febrile reaction with its accompanying shock inherent in the more toxic substances first used in this form of therapy prevented its widespread adoption. This may be considered as most fortunate. It is well that this procedure was restricted until more unanimity of opinion was established in regard to indications, dosage and therapeutic value. Indiscriminate use of any new and more or less untried method of treatment, especially when associated with possible danger, is to be discouraged. Its application in conditions where it is not indicated would tend to place it in bad repute and might delay the development of a method of real but possibly limited value. It is opportune, therefore, that this subject be fully presented to the profession by some one familiar with the problems of immunity, well informed upon the literature of Protein Therapy, and who at the same time has enjoyed clinical experience in its application. Dr. Pe- tersen, in conjunction with Dr. Jobling, were the American pioneers in this work. Through their carefully controlled clinical observations and logical deductions they have stimulated other investigators. To all those interested in the treatment of infections — and this includes both physicians and immunologists — this book will be most welcome, presenting as it does in a comprehensive manner a com- plete analytical review of the subject, which will be of assistance in furnishing a basis for further carefully controlled studies. Joseph L. Miller. CONTENTS Introduction > > . xiii THE METHOD CHAPTER I Historical 1 Therapy of typhoid fever by Fraenkel and Rumpf — Specificity of Tuberculin —Fixation abscess of Fochier — Nucleic acid — Colloidal metals — Auto- serotherapy — Tumor treatment — Leukocytic extracts — Paraspecific therapy of Paton — Deutschmann serum — Schafer vaccine — Intravenous gonococcus vaccine — Intravenous typhoid vaccine in typhoid fever — Heterobacterio-therapy of Renaud and Kraus — ^Protein split products — Milk — Recognition of the nonspecific factor in therapy. CHAPTER n The Nonspecific Agents 12 Counterirritation: Cautery, Seton, Fontanelle, Blisters, Rubifacients — Serums: Normal, human, horse, sheep, beef, goat, chicken serum, etc. Immune Serums: Human convalescent serum — Antimeningitis, anti- dysentery and antistreptococcus serum — ^Diphtheria and tetanus anti- toxin — Antiyeast serum (Deutschmann serum) — Antituberculosis serum (Marmorek, Maragliano, etc.) — Related Agents: Plasma-serum of Richet — Blister serum — Pleural fluid — Cerebrospinal fluid — Joint fluid — Proteins: Egg and seralbumin — Milk — Fat-free milk — Casein — Gelatin — Plant proteins — Nucleo-proteins — Nucleo-hexyl — Protein Split Products: Proteoses (Albumoses) — ^Deuteroalbumose— Globin — Histamine Witte— Peptone — Enzymes: Trypsin — Amylopsin — Leukoprotease — (Leukocytic Extract) — Tissue Extracts: Tumor extracts and autolysates — Cartilage and other tissue extracts (Heilner) — Organotherapy — Vaccines: Typhoid — ^Dysentery — Colon — Cholera — Meningococcus — Cionococcus — Staphylo- coccus — Streptococcus — Pyocyaneus — Pneumococcus — Influenza and diphtheroid vaccines — ^Mixed vaccines — ^Vaccinurin, Danysz vaccine and Much's antigen — Bacterial Extracts and Related Substances: Tubercu- lin^ — Typhin — Coley's fluid — ^Phylacogens — Bacterial autolysates — Col- loidal Metals: Gold — Silver — ^Platinum — Mercury — Sulphur — lodin — Zinc — Iron — Antimony — Manganese — Copper, etc. — Miscellaneous: Dis- tilled water — Hyper- and hypotonic salt solution — Sugar solutions — Formalin— Solusin — Hetol — lodidea — Turpentine — Yeast — Irradiation — Sunlight — Roentgen rays — Radium rays, etc. — Biological alterations — Depression immunity. CHAPTER III The NoNSPBciFia Reaction -. . 46 Chill — ^Temperature — Pulse rate — Blood pressure — Sweating — Nausea and vomiting — Splenic enlargement — Effect on menstruation — Nervous ir- ritability — Herpes and urticaria headache — Delirium glandular activity — Nitrogen balance — Effect on weight curve — Renal effects— Permea^ XV xvi TABLE OF CONTENTS PAGB bility of blood sugar— L3miphagogue effecfc— Leukocytes — Erythrocytes — ^Platelets — Blood sugar — Fibrinogen — Thrombokinase — Serum and l3rmph enzymes — ^Protease — Peptidase — Lipase — Antiferment — Anti- bodies — Effect on the Wassermann reaction. ■ CHAPTER IV The Focal Reaction 70 The question of specificity of Focal Reactions — Classification of Focal Re- actions — ^Activating agents— Diphasic character of Focal Reactions — Mechanism of Focal Reactions: Li Vascularized Foci — ^In Avascular Foci (Tuberculosis)- Therapeutic application of the Focal Reaction. THEORIES CHAPTER V Theoeies Concerning the Mechanism op the Reaction 83 Weichardt's theory of Plasma activation — Selective stimulation — Hyper- thermia — Nolf's theory — Enzjones — Antibodies — ^Wright's theory — ^The leukocjrtes — Cell permeability (Starkenstein). CHAPTER VI The Phobable Mechanism op the Reaction 99 Protein Intoxication and Detoricaiion — ^The Mechanism of Recovery in Pneumonia — The Ferment-antijerment balance in Pneumonia and in Tuberculosis — The Reaction in Carcinoma — ^The Effect on Local In- flammation — ^The Effects of the Reaction in Localized Lymphatic Dis- ease (Typhoid) — ^The Effects of the Reaction in Localized Lymphatic and Interstitial Disease (Lobar Pneumonia) — The Effects in Generalized Infection (Septicemia). CHAPTER Vn The Relation op the Skin to Nonspecific Resistance 128 Skin Reactivity — ^Depression — Activation — Relation to Internal Medicine — Esophylaxis — ^Heliotherapy — Mechanism of Recovery in the Acute Exanthemata — Resistance to Syplulis. THE CLINICAL RESULTS CHAPTER Vm Abthbitis ;•:•;:• 142 Clinical reports — ^Discussion — Safety — Effect on Endocarditis. CHAPTER IX Typhoid Feveb 153 Typhoid vaccine — Intravenous injections — Heterovaccines — Albumoses — Comparative results — Milk injections and other procedures — Discussion — Mechanism of normal recovery — ^Therapeutic precautions — Para- typhoid fever. TABLE OF CONTENTS xvii CHAPTER X PAGE GONOKEHEA AND ItS COMPLICATIONS 170 Culver's report — Gonorrheal arthritis — Other complications — Local injec- tions of milk, salt solution, iodides, etc. — ^The Provocative Reaction — Adnexal Inflammation. CHAPTER XI Infectious Diseases 185 Anthrax — Diphtheria and diphtheria carriers — Dysentery (Bacillary) — Erysipelas — Influenza and influenzal pneumonia — Lethargic encephalitis — Parotitis and orchitis — Pneumonia (Lobar) — Puerperal infections — Scarlet Fever— Septicemia — Smallpox — Tetanus — Trench Fever — Tuber- culosis — Typhus Fever— Vincent's Angina. CHAPTER XII Spirochetal and Protozoal Infections 206 Relapsing Fever — Syphilis — Weil's Disease — Malaria. CHAPTER XIII Miscellaneous Diseases 210 Asthma — Angioneurotic Edema — Anemia: Secondary, Pernicious — Hemor- rhagic Diathesis — Nephritis — Pyelitis — Neuritis — Diseases of the Ear — Neoplasms — Diseases of Children. CHAPTER XIV The Treatment of Paresis, Tabes and Epilepsy 224 CHAPTER XV Diseases of the Skin ■. . 230 CHAPTER XVI Diseases of the Etb ■ 236 CHAPTER XVII Inflammation >: 242 CHAPTER XVin Indications and Contraindications -• . .""'•' ~. . 247 APPENDIX The Proteins and tubir Split Products 252 (I) The Native Proteins — Albumins — Globulins, etc. — (II) Conjugated Pro- teins — Chromoproteins — Glucoproteins — Phosphoproteins (Casein) — Nucleoproteins, Etc. — (III) Derived Proteins — (a) Primary: Proteins — ^Metaproteins — Coagulated Proteins — (b) Protein Split Products — Secondary Derivatives — Proteoses (Albumoses) — Peptones — Peptids — (c) The Amino Acids. PEOTEIN THERAPY AND NONSPECIFIC RESISTANCE PROTEIN THERAPY CHAPTER I THE HISTORY OP PROTEIN THERAPY The remarkable fact that some individuals are resistant to infec- tious disease while others are not; that of two seemingly equally strong individuals, the one may die, the other recover from the same in- fection, has always interested biologists and physicians. Naturally enough the efforts to explain resistance to disease have varied with the mode of biological thought current at any given period. It was not until the development of our instruments of precision made possible the work of Pasteur and of Koch that the study of the causal relation of micro-organisms to certain disease processes diverted the interest of the medical mind from the philosophic tendency that had characterized the early half of the last century, to the concrete, the direct, the specific ideation upon which modern science is founded. Naturalistic generalization gave place to accurate biological observa- tion. And with pathological and bacteriological definition of disease processes, the mental attitude of the physician likewise changed in regard to resistance to disease as a general phenomenon to inquiry regarding resistance to specific disease processes. The brilliant era of specificity in therapeusis that was ushered in by the work of v. Behring, the fascinating serological researches of Ehrlich and of Bordet, the discovery of the specific spirochsetecide by Ehrlich in the field of chemotherapy, stamped with the seal of success these years of medical advance — advance made wholly on a back- ground of the strictest specificity. Naturally enough in such a period of successful achievement, minor currents passed unnoticed. Clinical observations that did not fit in with the prevailing mode of thought were but half heartedly put forward and soon passed into oblivion. Wright but recently pointed out a few such instances that came to his attention during the past twenty years: ... "I confess to having shared the conviction that immunization ia always strictly specific. Twenty years ago, when it was alleged before the Indian Plague Commission, that antiplague inoculation had cured eczema, gonorrhea, and other miscellaneous infections, I thought the matter unde- 1 2 PROTEIN THERAPY serving of examination. I took the same view when it was reported in connection with antityphoid inoculation that it rendered the patients much less susceptible to malaria. Again, seven years ago, when applying anti- pneumoeoccus inoculation as a preventive against pneumonia in the Trans- vaal mines, I nourished exactly the same prejudices. But here the statis- tical results which were obtained in the Premier Mine demonstrated that the pneumococcus inoculation had, in addition to bringing down the mor- tality from pneumonia by 85 per cent., reduced also the mortality from other diseases by 50 per cent. From that on we had to take up into our categories the fact that inoculation produces in addition to 'direct' also 'collateral' immunization." . . . Several other observations must be recalled. In 1893 Eugene Frankel reported on the treatment of some 57 cases of "typhoid fever treated with subcutaneous injections of typhoid bacilli. The results were promising. In an address delivered at the same time Rumpf pre- sented a similar series of typhoid patients, but treated with subcutane- ous injections of a pyocyaneus vaccine. Rumpf based his work on the experiments of Buchner and his pupils who had emphasized that in tuberculosis, the infection then under most intensive study in Ger- many, not only tuberculin but other bacterial products could activate previously latent powers of resistance. Romer, working along the same line, had found that tuberculous animals could be killed by ex- tracts obtained from pneumobacilli and bacillus pyocyaneus just as well as with tuberculin, i.e., that such animals were susceptible not only to a specific intoxication because of some abnormal sensitiza- tion, but that they were susceptible to other toxic products as well be- cause of their infection. Rumpf concluded that while soluble toxins might be specific and call forth a specific response on the part of the patient, all bacteria probably contained a common component — non- specific — against which immimization might conceivably be carried out. He first made up and used a streptococcus vaccine, but it pos- sessed no therapeutic properties so far as typhoid fever was concerned. It was then that he made up his pyocyaneus vaccine and with it achieved results that in many ways equalled those that Frankel had obtained with typhoid vaccines. In his series of 30 cases there were two deaths, one from pneumonia, the other from perforation. Rumpf observed that following his subcutaneous injections chills and sweating were not uncommon. Usually the temperature and the pulse began to come down within two days after commencing the vaccines; the earlier the treatment was commenced the more notice- able the effect on the clinical course. He called attention in par- ticular to the euphoria that was observed after the injection. This paper, published at a time that witnessed the introduction of diphtheria and tetanus antitoxin, was practically ignored; the more readily when several competent observers, working with small series of cases it is true, could not confirm Riunpf s results. THE HISTORY OF PROTEIN THERAPY 3 Then Horbaczewski introduced nucleins and found that lupus vul- garis reacted with a typical focal reaction to the nuclein, that is, the nuclein injection caused a focal reaction about the lesion just as well as the specific substance. Kiihne next analyzed the tuberculins and noted the large amount of protein split products therein contained. Koch was cognizant of the fact that the fever-producing element in the tuberculins was not part of the specific effect which he was seek- ing to accentuate; others (such as Hueppe and Scholl) insisted that it was just this nonspecific bacterial protein that accounted for the entire tuberculin reaction. As a result particularly of Kiihne's work, Matthes and Krehl began their well-known experiments with protein split products in tuberculous animals. In using various proteins to bring about the tuberculin reaction in tuberculous guinea pigs they found among others that milk injections would also activate the focus. In this work Matthes made several observations that have a di- rect bearing on the problem under consideration. He noted for in- stance that tuberculous guinea pigs reacted not only to tuberculin with the well-known temperature rise, but to injections of deutero- albumose as well. With small doses such animals responded with a typical rise in temperature ; large doses caused a fall in body tempera- ture and the death of the animal. Nontuberculous animals would at times react with temperature to the deuteroalbumose injection, but never to the same extent as infected animals. The dosage as compared to tuberculin was large, nevertheless the results caused considerable doubt in his own mind as to how far specificity entered into the tuber- culin reaction and interested him in the role of protein split products in the causation of fever. To the same period of time belongs the reintroduction of the arti- ficial abscess (the fixation abscess of Fochier), a therapeutic pro- cedure related to the seton and the f ontanelle. Fochier used the sterile abscess (produced by injecting turpentine) in puerperal infections with some success. The method was in vogue for a number of years. From Sahli's clinic Bauer published observations on a series of cases of pneumonia treated with such sterile abscess formation (1 to 2 c.c. of turpentine being injected to produce the abscess). The number of cases so treated was too small to be of any particular value but it was noted that a stimulation of leukocytes was always brought about as a result of the injection. The introduction of nucleic acid by Horbaczewski has been men- tioned. In the course of the next twenty years nucleic acid and its salts and related chemical compounds that cause a leukocytic reaction found their way into the treatment of infectious diseases. Their use was advocated because it was assumed that their action consisted in a general tissue stimulation. Colloidal metals, especially the silver preparations, had come into use after their introduction by Crede. First it was assumed that the 4 PROTEIN THERAPY silver preparations possessed particular streptococcicidal properties and they were consequently injected in septic conditions due to strep- tococcus infections. It was then noticed that one could obtain equally good results in a number of infections due to other organisms. Finally the colloidal metals have come to be recognized as piurely nonspecific reactive agents. In the same category must be placed a rather commonly used procedm-e, the method of autoserotherapy of Gilbert. Introduced in 1894 for the treatment of pleurisy with effusion it found consider- able clinical application. The technic consisted in withdrawing a small amount of fluid from the pleiu-al cavity and reinjecting it under the skin. At times a slight temperature reaction was observed follow- ing it. Eisner studied the reaction in experimental animals and ob- served that a leukocytosis usually followed the injection; to this, and to the general constitutional reaction he attributed the therapeutic benefit. Zimmermann had also noted the leukocytosis which he had ascribed to the stimulation of the tissues by autolytic products that had acciunulated in the pleural exudate. He even proceeded to show that the injection of peptone would produce such a leukocytosis, but did not continue to the logical conclusion of his experiments. Later the method of autoserotherapy was extended, particularly in the field of dermatology. In tumor treatment we have had two related measures. These have been the Beard Trypsin treatment of carcinoma and the use of Coley's Fluid, the latter used especially in sarcoma. Quite apart from the theoretic basis that was put forward to support their use in malignant disease, it is to be noted that both agents were followed by a severe constitutional reaction — chiH, fever, increased local pain and evidence of an inflammatory reaction, followed by occasional clinical improve- ment, both in the general health of the patient and the arrest of the tumor growth for a period of time. Whether actual cures were ever effected is for the present study unimportant; both reactions were typical nonspecific phenomena and the effect on the local process just what would be anticipated vmder the circumstances. A method closely related to these is that of the injection of tumor autolysates. These are injected either intramuscularly or intrave- nously in small doses and are almost invariably followed by evidences of a general reaction on the part of the patient (Funkenbein, Blumen- thal) as well as by changes in the nitrogen balance (Bauer, Latzel and Wessely). Another nonspecific method and one that has at times been fol- lowed by very favorable clinical results has been that of the injection of leukocytic extracts in patients ill from a variety of infectious dis- eases. Petterson had observed that in animals such injections seemed to have a very decided protective effect against infection, and Opie, too, had made similar observations. In 1908 Hiss and Zinsser began THE HISTORY OF PROTEIN THERAPY 5 to use such an extract in patients. They were not able at the time to account definitely for the therapeutic effect obtained but Zinsser has since expressed the opinion that the results were probably to be accounted for on the basis of a nonspecific reaction. Occasional clinical reports were made during the period between 1890 and 1910 which detailed success in infectious diseases through a number of therapeutic measures purely nonspecific in character, among them those of Paton, who used normal serum and diphtheria antitoxin in the treatment of tuberculosis, arthritis, and cerebrospinal meningitis. Paton's work was based on preceding observations made by De Minicis, who had treated a small series of diphtheria cases with diph- theria antitoxin per os, and on those of Lilienthal and of McCallum, who had reported that diphtheria antitoxin possessed curative prop- erties when given in a variety of infections such as sepsis, tuberculosis, adnexal inflammatory conditions, lupus, etc. Paton published a small volume detailing his clinical experience with the use of diphtheria antitoxin given by mouth ; he found that not only normal horse serum but sheep serum and ox serum possessed the stimulating qualities to which he attributed the therapeutic effects. This paraspecific sero- therapy has been used extensively in France. Darier has collected some of the clinical literature concerned with the reaction and more recently Cumston has discussed it. That the injection of diphtheria antitoxin might at times produce a transient increase in the temperature of the patient had been observed very early by Ewing, who also noted the leukocytic response after injections, that is, a primary leukopenia lasting for about one-half hour, fol- lowed by a leukocytosis. The use of normal horse serum in the treat- ment of certain alterations of the coagulation balance of the blood has also become quite common in recent years (Weil) and inoculation of the patients serum, plasma or whole blood, either subcutaneously or intravenously — autoserotherapy as it is termed — has been practiced especially by the dermatologists. Within the past five years some success has been reported in this limited field but the method was never recognized as being part and parcel of a general reaction. In 1917 Deutschmann, seeking to find a method of treatment for certain eye diseases against which remedial measures were unsat- isfactory, began the immunization of horses with yeast cells and used the serum for the treatment of a variety of infectious diseases. Yeast has for many years been supposed to augment the resisting powers of the body when given by mouth; yeast extract has also been given subcutaneously for the same purposes and has also been applied in the treatment of malignant diseases (especially by Italian clinicians on the basis of the work of Sanfelice). When so injected the effect is probably due to the nuclein content of the extract. In Deutschmann's work about 2 c.c. of the serum was injected 6 PROTEIN THERAPY and this was followed by the usual nonspecific reaction — a slight rise in temperature, pronounced euphoria, occasional crisis in acute infectious disease, etc. In America we had, however, one treatment that received con- siderable imfavorable notoriety, a nonspecific method in its effects, although introduced on a different basis. In 1911 Schafer reported the therapeutic use of a bacterial product with which he had obtained remarkable recoveries in certain infectious diseases. This work was done at a time when the subject of mixed infec- tions was prominently under discussion as an etiological factor in dis- ease development. Schafer formulated a theory of immunization to fit the successful use of his mixed vaccine. This was that in treat- ing a disease, one had not only to consider the specific exciting organ- ism in the vaccine, but that the secondary invaders — ^the heterogeneous group of semisaprophytic and saprophytic bacteria that were in sym- biotic relation with the origiual invader — had to be considered in the vaccine as well. Schafer demonstrated his vaccine mixture in several hospitals, treating chiefly arthritic cases. The injection, usually made intrave- nously because subcutaneous injections were very painful, was always followed by a severe general reaction, no matter whether the thera- peutic result was good or bad. In some cases the success following the single injection was remarkable; in others, merely the memory of the very unpleasant chill and fever — "the Ordeal by Chill and Fire" as one facetious patient expressed it — remained, with no thera- peutic benefit. The selfsame vaccine in one case cured arthritis, in another a catarrhal jaimdice, in another a neiuralgia. At this time a pharmaceutical house purchased Schafer's formula and began a coimtry-wide exploitation of the same, using a trade name for the product. The entire campaign, naturally enough, met with decided disapproval on the part of the medical profession, not only because of the proprietary nature of the product and the blatant commercial method of its introduction, but because of the lack of scientific or laboratory study that was evident from the very beginning. Herescu and Strominger attacked the problem from a different position. Noting the morphological similarity that exists between the gonococcus and the meningococcus, they began using antimeningococ- cus serum in the treatment of gonorrheal arthritis, gonorrheal ophthalmia, septicemia, and other gonorrheal complications, with con- siderable success. The use of mixed gonococcus vaccines had become quite common both in France and in Germany and in their clinical application a number of observers began to use them intravenously in relatively large doses. In the gonorrheal complications (and in iritis of non- gonorrheal origin — ^Kreibich) it was found that this form of injection was frequently satisfactory. Brasch, who studied the general re- THE HISTORY OF PROTEIN THERAPY 7 action that followed the injections, noted in particular the typical effect on the leukocytic picture. We have then a whole list of agents and methods that have been employed, some empirically, others with a definite immunological theory underlying their use, but all, whether bacteriological product, or enzyme, or chemical, producing a more or less marked constitutional reaction on the part of the patient. It is curious that this common feature was not emphasized or even recognized as a possible part of the therapeutic mechanism. Throughout the period under discussion, when these various meth- ods and substances were being introduced, vaccinotherapy as ad- vocated by Wright was being tried out in practically every form of infection; not always with success but with sufiBcient result to keep the method in use in medical practice. When failure resulted there were, as a rule, extenuating circum- stances upon which to throw the blame. At first it had been the practice to use as a vaccine an organism of the type known to cause the particular infection with which we were dealing. Then when results were not forthcoming, effort was made to isolate the particular organ- ism causing the infection in order to produce an autogenous vac- cine. This failing, we had the consolation that we probably had not succeeded in isolating the particular strain that had caused the in- fection. On the basis of his opsonic work Wright had differentiated a negative and a positive phase of resistance following the vaccine in- jection. The dread of the negative phase was sufficiently impressed on every inununologist to prevent the use of large doses of vaccine or such that would lead to a general reaction on the part of the pa- tient. Indeed, ever since the time of Koch's work with tuberculin, when overzealous workers using large doses of tuberculin had often done irreparable damage by breaking down the normal connective tissue defense of the patient, immunologists had used great care in avoiding general systemic reactions. When vaccines were carefully used there was no doubt that the patient gave evidence of increased antibody production, measured both by the opsonic index, the agglutinin titer and the method of complement deviation, but here again the therapeutic result did not measure up to the expectation. Immune bodies might be stimulated to a sufficient degree but the patient was not cured. The modem conception of protein therapy and nonspecific re- sistance was a direct development, however, of this work with vac- cines. In typhoid fever the therapeutic use of vaccines, either made up of killed but otherwise unaltered organisms, or of bacteria altered in a number of ways, had been given rather extended use and with fair clinical results. In the decade following the year 1906, the bacteri- otherapy of typhoid began to be a recognized procedure. The dura- 8 PROTEIN THERAPY tion of the disease was undoubtedly shortened thereby and the mortality lowered, but the difference between the treated and the xm- treated cases was seldom striking enough to popularize the method among the general profession. Then it was that in Argentine a group of physicians began the intravenous use of typhoid vaccine. Penna, Tores, Dessy, Grafinola, Fossati, and others thereby obtained quite remarkable results, the disease in some cases being aborted almost at its inception, in others terminated by crisis, in others by lysis shortly after the injection. Kraus, who was working in Argentine, heard of these results and after observing the effects investigated whether other organisms would not produce the same results when so injected. He foimd this to be true with colon vaccine. Quite independently Ichikawa had reported on the advantage of the intravenous injection of typhoid vaccine at a meeting of the Medical Society of Osaka in April, 1912, and in 1914 reported his results with 87 cases of typhoid treated with a sensitized vaccine. The normal mortality in his untreated cases was over 30%; when treated with the vaccine intravenously the mortality sank to 11% and in more than half the cases the disease was terminated after the first or second injection. Ichikawa made the further interesting observation that when he treated paratyphoid fever with the same typhoid vaccine, he obtained equally good results, i.e., the result was not due to a strictly specific reaction. Ichikawa found that following the typhoid injections in the paratyphoid patients, the spe- cific paratyphoid antibodies were mobilized. Some hemorrhages were noted after the injections, although the author considered them less frequent in the vaccinated group than in the unvaccinated. Heart disease and pregnancy he naturally con- sidered contraindications to the therapeutic injections because of the pronounced reaction that followed the administration of intravenous therapy. We had then two reports of heterobacteriotherapy that had yielded startling clinical results — typhoid treated with colon bacilli and para- typhoid treated with typhoid vaccine — clinical results that could not well be denied, although the immunologist might still allege that we were dealing with a group reaction, rather than a true heterobacterial vaccine effect. Kraus, however, definitely settled this point when he reported favorable results in puerperal infection treated with colon vaccine and with this as a basis began the treatment of scarlet fever, plague and septicemia. A predecessor of Kraus and perhaps the first observer who clearly pointed out the value of heterobacteriotherapy was Renaud (1911). He had been working with typhoid vaccine killed by quartz light radi- ation and noted that the injection of such vaccine had a definite THE HISTORY OF PROTEIN THERAPY 9 therapeutic effect on a number of inflammatory conditions of non- typhoidal origin. Clinical results such as those reported by Renaud, by Kraus and by Ichikawa were not to be explained away as due to accident. The conception of strict specificity in therapeusis that had been built up in the laboratory had to give way before a clinical demonstration that could no longer be ignored. Our recognition of nonspecific therapy really had its inception with these three papers. Nor was it long before a series of corroborative observations appeared in the European literature from a number of clinics and in a number of diseases. Many clinical phenomena heretofore obscure and never satisfactorily ac- counted for on our older conception of immunity began to appear relatively simple and understandable when studied from the new point of view. From heterobacteriotherapy it was but a logical step to attempt the intravenous injection of bacterial components and bacterial split products, then to protein split products of nonbacterial origin and finally to the realization that any substance which was capable of inducing the shock reaction on the part of the patient would result in general in the same therapeutic change. We were dealing with an ergotropie as von Groer termed the reaction — "eine Umstimmung" — of the whole organism (analogous to our term desensitization) which made it resistant to intoxication. Soon a number of agents were so used. Schmidt and Saxl introduced milk injections, Liidke the in- jection of proteoses or albumoses, Mittlander the use of hypertonic salt solution. Distilled water and foreign sera were next added and recently the ancient method of producing sterile abscesses — by injecting minute doses of turpentine and hypertonic salt solution — has been revived. It was recognized, too, that some of the older substances, such as nucleic acid, colloidal metals, enzymes, lipoids and a long list of substances, the therapeutic effect of which had been variously ex- plained, all belonged in the same category. When reviewed from this point of view it became evident that they all brought about a general reaction which manifested itself as a rule in the chill, the fever and the leukocytosis, and those which were most successful clinically were the ones following the use of which the reaction was greatest. It had also been the common experience with the entire group that in order to be effective they had to be given early in the disease; when used late the effect was much less certain. In view of the undeniably striking therapeutic results at times achieved with nonspecific therapy certain enthusiastic workers im- mediately went to the extreme view that specificity was valueless in therapeusis and were ready to throw overboard the accumulated results of the past thirty years. And the best known and most widely used of our specific agents, diphtheria antitoxin, was the one that was 10 PROTEIN THERAPY first brought into question. Bingel treated about 1,000 cases of diph- theria, one-half of the group with the specific antitoxin, the other half with "empty," i.e., normal horse serum. According to his report the clinical results were equally satisfactory in both series. Subse- quently a number of German clinicians went over his results but could not confirm them to the extent that Bingel had claimed. One point of value was, however, brought to our attention by this discussion of the antitoxin question. Along with the specific antitoxin value the serum contained a nonspecific stimulating element in the horse serum protein. Our modern highly concentrated sera naturally have lost this nonspecific factor to a considerable degree in the process of concentration, thus justifying the criticism that has repeatedly found expression in recent years, that the modern concentrated serum did not seem so effective, all things considered, as the old serum which was not so high in antitoxin units. Concentrated antitoxin contains less of the nonspecific factor; whatever may have been the clinical value of this element has been lost in the modern preparations. (Meyer.) This recognition of dualism in the therapeutic effect, the specific antitoxic factor and the nonspecific stimulating factor of the diph- theria antitoxin merely illustrates the importance of the unbiased study of all factors in therapy. We are fairly well grounded in oiu: knowledge of the specific factors of immunity. Our knowledge of the nonspecific elements is still de- cidedly fragmentary. Enthusiasm in one direction should not for an instant obscure our vision of all other possible factors in resistance. Here in America interest in this particular phase of resistance was stimulated by the work of Vaughan and Wheeler, of Opie and his associates and later by that of Jobling and his co-workers. During the course of these latter studies we had imder observa- tion a series of animals intoxicated with a variety of bacterial and other protein substances and noted in these animals a marked mobili- zation of senmi enzymes. When we became familiar with the work of Kraus and Ichikawa we studied the problem from the point of view of its practical application and concluded that at least part of the therapeutic effect must be due to enzyme action. Inasmuch as we had previously found that other agents besides bacterial vaccines would produce precisely the same enzyme mobilization we concluded to try a series of protein split products in patients ill with typhoid fever. While this work was under way an identical investigation carried out by Liidke with albumoses came to our knowledge, delayed of course by the exigencies of the war. Miller and Lusk had in the meantime also become interested in this form of therapy and were the first in this country to report a larger series of cases so treated. They used both typhoid vaccine and secondary proteoses in their work. Smith in a paper published at the same time reported on the therapeutic bene- THE HISTORY OF PROTEIN THERAPY 11 fit of the anaphylactic shock reaction in patients suffering from gon- orrheal complications. The publication of these papers directed the attention of the American profession to this form of therapy and there have since appeared a number of reports dealing with nonspecific therapy in a variety of diseases. These will be discussed in detail. CHAPTER II THE NONSPECIFIC AGENTS In the practice of nonspecific therapy a large number of therapeutic agents have been used, varying from the ancient forms of counter- irritation to our present methods of heterobacteriotherapy, of protein therapy and of the intravenous injection of colloidal metals or other colloidal substances. In discussing these various agents that we have at our disposal to induce the "plasmaactivation" or the "ergotropie" as one may choose to term the reaction, it will be of some interest to include a number because of their historic association or because of their theoretic rather than their practical therapeutic value. Their inclusion is therefore not to be regarded as an endorsement of their usefulness in therapeusis nor as an advocacy for their employment in practice. They are gathered together imder a single group be- cause it seems most probable that their occasional utility — and of this there can be no question in some instances — seems based on a similar reaction that they bring about in the body, i.e., true tissue stimulation and activation, exercising their therapeutic power by alter- ing the reactivity of the whole organism, rather than influencing di- rectly the cause of the pathological process. The following list, ex- tensive though it is, is by no means complete. The various drugs that possibly are useful because of a similar stimulation — among them some of the mercury preparations; cinnamic and succinic acids and their salts, formic acid, quinin, the antipyretics, iodin, etc., — have not been included because it would lead the discussion too far afield. A large number of other and older methods that at some time in history have been used in medicine and which probably had as the basis of their usefulness the same general reaction, have also been omitted be- cause a discussion of them, other than emphasizing the historical con- tinuity of their employment as nonspecific agents in therapeusis, would have no value. THE NONSPECIFIC AGENTS COUNTEEIEEITANTS Cautery Seton Fontanelle Moxa Blister Bubefacient Blood and Serums Normal — Himnan, Horse, Steep, Beef, Goat, Chicken, etc. Immune — ^Human Convalescent Serum; Autimeningococcus Serum, Anti- dysentery Serum, Antistreptococeus Serum. 12 THE NONSPECIFIC AGENTS 13 Diphtheria and Tetanus Antitoxin. Antiyeast Serum (Deutschmann Serum). Tuberculosis Serum (Marmorek, Maragliano, etc.). Belated Agents — ^Plasma Serum (Eichet), Blister Serimi, Pleural Fluid, Cerebrospinal Fluid. Proteins Egg Albumin and Seralbumin Milk Fat-free Milk Casein Gelatin Plant Proteins — Nucleoproteins — Nucleohexyl Protein Split Products Proteoses Deutero-albumose Histamin Globin Witte Peptone Enzymes Trypsin Amylopsin Leukoprotease (Leukocytic Extracts) Tissue Extracts Tumor Autolysates and Extracts Cartilage and Vascular Extracts (Heilner) Organotherapy Vaccines Tjrphoid, Dysentery, Colon and Cholera Vaccines. Meningococcus and Gonococcus Vaccines. Staphylococcus, Streptococcus, Pyocyaneus and Pneumococcus Vaccines. Influenza, and Diphtheroid Vac- cines, etc. Mixed Vaccines — Vaccinurin, Danysz' Method. Muchjs Antigen. Bacterial Extracts and Belated Products Tuberculins Typhin Coley's Fluid Phylacogens Bacterial Autolysates Colloidal Metals Gold Silyer Manganese Platinum Sulphur Mercury Zinc Iron Miscellaneous Hypertonic and Hypotonic Salt Solutions Sugar Solutions Distilled)Water Formalin Solusin Hetol lodids Turpentine Antipyretics Teasts Irradiation — Sunlight Eoentgen Bays Eadium Biological Alterations Depression Immunity 14 PROTEIN THERAPY COUNTERIRRITATION (Thermocautery, Seton, Fontanelle, Moxa, Blisters, Rubefacients) These, perhaps the most ancient of our methods of intervention in disease processes, purely empirical in origin, represent undoubtedly a form of nonspecific therapy. Crude and barbarous in their applica- tion though some were, there can be little doubt as to their occasional efficacy. Their very antiquity, their widespread use among all peoples and their long continuance in practice more than warrant this as- sumption. And their supposed effects on inflammation — the accelera- tion of repair — relief from pain — ^hastening of absorption of exudates, might be expected to follow as a result of nonspecific protein therapy as we now imderstand it. Every one of these procedures has as its basis the production of a focus either of necrosis — such as produced by the cautery; of sup- puration — as with the use of the seton or the fontanelle; or in the milder forms the production of an area of exudation, inflammatory in character, usually serous or seropiunilent. The absorption of these pathological exudates by the body must lead to a tissue stimulation — perhaps milder in degree and longer in duration — similar to that which follows in the wake of our more modern nonspeciflc therapeutic in- jection. Bloch was one of the flrst to call attention to the fact that our nonspecific therapy is but part and parcel of this older practice of counterirritation. While counterirritation was, as a rule, limited in its applica- tion to localized inflammation and seldom if ever used in acute infectious diseases, we do find that it was recommended in inflamma- tory rheumatism, curiously enough the one disease in which modern nonspecific therapy has perhaps been most consistently successful. The Actual Cautery was considered the most effectual agent. We now know that following a burn the resorption of necrotic material from the burned area may result in a typical protein shock reaction, either acute or protracted, depending of course on the degree and the area of injury. Pfeiffer has recently studied in detail the flooding of the organism with proteolytic enzymes following both bums and evitable infection of such issues. The Seton, the Fontanelle, and Moxa were all methods designed to produce a superficial suppuration over a longer period of time. Not only were necrotic tissue products being absorbed from such foci, but a heterovaccination carried out at the same time because of the in- evitable infection of such tissues. The milder methods produced merely local irritation of the skin either with vesication or hyperemia; absorption of a slight inflam- matory exudate might take place from both. In all of these pro- THE NONSPECIFIC AGENTS 16 cedures, differing but in degree, we have the elements of the modern nonspecific therapy, the absorption of a foreign protein (disintegrat- ing autogenous material — either burned tissue, disintegrating leuko- cytes, fibrin or serum from an exudate) — ^the reaction of the body to this material with increased activity; stimulation of the bone marrow; mobilization of leukocytes, of enzymes; the lessening of the nervous irritability, etc. Counter irritation was, however, limited in its application to lo- calized inflammatory conditions, differing in so far from the applica- tion of the nonspecific methods at present in vogue. CaUeja has but recently devised a method of therapy which he considers an immunization against necrosis based essentially on these older methods. CaUeja assumes that the derivatives of empiric medicine, the blisters, the fixation abscess, etc., owe their efBcacy to the fact that they induce an active and a passive immunization against the efPects of the necrosis of the tissues in the disease process. Subcutaneous injection of 3 or 4 drops of chloroform at different points, to a total of from 3 to 5 c.c, is a con- venient method of this "causticotherapy," and he supplements it with horse serum prepared like diphtheria antitoxin, only using instead of diphtheria bacilli, human tissue scraps rendered necrotic with chloroform. The term "counterirritation" and the theories advanced to ex- plain the therapeutic measure in the treatment of disease have gone out of fashion, together with the agents that were used for many years. At times and under certain undetermined conditions results were achieved by means of counterirritant measures that were quite satisfactory. But counterirritation was a therapeutic measure abso- lutely empirical in character and the fact that no possible theory of modern medicine could account for its potential benefit was perhaps one of the reasons that modern medicine discarded the practice. As Gillies has expressed it, "The remedy, or let us say mode of treat- ment, fell into disrepute not because it failed as a remedy or as a mode of treatment, but for the very peculiar reason that we do not under- stand and cannot explain how it succeeds, for it is allowed that not infrequently it does succeed." Curiously enough we continued to elaborate procedures that were obviously similar to counterirritation both in character and in their therapeutic object, but under a variety of new names and based on modern scientific theories of immunity. So, for instance, the autoserotherapy used in pleural exudates whereby a small amount of the pleural exudate is withdrawn and reinjected under the skin of the patient, in mechanism analogous to the older form of vesication. It was not, however, until within the last few years that the pos- sibility was suggested by observers interested in nonspecific therapy that the same mechanism that was concerned in the one was possibly involved in the other; Luithlen has even ascribed the possible thera,- 16 PROTEIN THERAPY peutic effects of repeated bloodletting to biological alterations related to protein therapy. BLOOD, SERUMS AND RELATED AGENTS Blood Transfusion. — One of the very early methods of nonspecific therapy involved the transfusion of whole blood from human or animal sources; with the method a reaction on the part of the patient was a common observation. It was this reaction that made the method dangerous, because it could not be controlled and yet it seems to have been recognized that in its occurrence lay the usefulness of the method as a therapeutic measure. Hasse used sheep's blood in the treatment of a large number of diseases (1874) and Eckert (1876) definitely rec- ognized that the injected or transfused blood did not act as a substitute but as a chemical irritant for the organism which had received the injection. Bier made similar observations and while at times certain clinical improvement followed these earlier attempts the methods never came into prominence because of obvious limitations. In the modern use of transfusion we are dealing only with the effort at sub- stituting or making good a serious loss of serum or corpuscles and every effort is made to avoid a reaction on the part of the recipient. Normal Human Serum. — Autoserotherapy. — The use of normal hu- man serum, drawn from another individual or from the patient (auto- serotherapy) for either subcutaneous or intravenous reinjection, is not a new procedure. The use of normal serum in hemorrhagic diathesis in particular has been in vogue a number of years. (Weil, 1908.) It is probable that in the mechanism of clotting a colloidal rearrange- ment of sufficient magnitude is brought about so that the serima be- comes toxic for the homologous organism, and that it is this change which accounts for the fact that the serum brings about a general reaction. Serum when first defibrinated is decidedly toxie to the homologous animal, a fact that should be kept in mind in judging the reaction elicited. Freund in studying this question noted that when defibrinated blood was injected in experimental animals within 15 minutes after drawing the same, death followed very promptly; if a little more time elapsed the ani- mal went into collapse; if injected within 30 minutes the animal reacted with fever. From this time on the serum, up to 20 hours after preparation, produced merely a very slight febrile disturbance. In recent years a number of interesting papers have been published deal- ing with the injection of homologous serum, especially in the hemorrhagic diseases. In the American literature, too, the method is very favorably reported. (Freeman, Huber, MacFarlane, Kaiser, Sophian, Hartmann, Belhboni, Eosenberger, LeClainche and Vallee, Jousset, Mosti, Eosler, etc.) In using autoserotherapy blood is drawn from a vein of the pa- tiesnt Mid this is permitted to clot~-or may be defibrinated. The THE NONSPECIFIC AGENTS 17 serum drawn from the clot (or after centrifuging the defibrinated blood) is reinjected intravenously, usually once or twice during the course of the week. Little or no reaction follows the procedure and the therapeutic success is not very brilliant, considering the amount of time consumed, with th3 manipulation. Perry substituted horse serum with seemingly good results. Normal Animal Serum. — Horse serum, beef serum, goat senmi, sheep serum, chicken serum, to mention but a few that have been used, were first injected subcutaneously, in more recent years intra- venously; the dosage that can be used with safety varies with the serum, its age, method of preparation, whether preservatives have been added and the sensitization of the patient. As much as 250 c.c. of beef serum have been given intravenously (in anthrax) without injury; indeed the larger doses have in most cases been more satisfactory than the smaller ones. The reaction to these serums is as a rule very mild, only occasionally is a fever and chill observed. Before in- jecting serums of this type a skin test should be made to determine whether the patient is possibly sensitive to the serum the use of which is contemplated. With repeated doses the reaction, contrary to the result with many of the other nonspecific agents, may become more severe, even when the injections are made within the time period usually alloted before active sensitization will occur. Intravenous in- jections must always be made very slowly even when there is no evidence of sensitization. If the patient has become .sensitive great caution must be observed, although Smith has made use of the fact that patients become sensitized to serum injections, for therapeutic results. He found that when patients became sensitive to serum in- jection and reacted with some temperature increase and a general sys- temic reaction, a definite curative effect was to be observed on local inflammatory conditions (gonorrheal complications). Normal serum was recommended for injection in cases of diphtheria by Bertin as early as 1895. Immune Serum. — The use of the serum of convalescent patients for injection either subcutaneously or intravenously is a procedure that also dates back for a considerable time. It was used in typhoid fever with some success but the most extensive application has possi- bly been in the treatment of scarlet fever, and more recently in the treatment of influenza. To be used successfully large doses must be employed and the treatment given early, two facts that suggest very strongly that the effect is due less to any antitoxic or antibacterial property of the serum, than to the nonspecific stimulating effect of the serum proteins. Weisbecker had used subcutaneous injections of convalescent serum in scarlet fever in 1897, but the method was not extensively used until Reiss and Jungmann emphasized the value of the treatment with larger doses. From 80 to 100 c.c. of serum are now commonly em- 18 PROTEIN THERAPY ployed, being injected intravenously whenever practical. Rehder bases his dosage on the body weight, injecting 2 c.c. of serum per kilo. Very little attention has therefore been paid to the determination of the isoagglutinins that may be present in the serum injected intrave- nously and at times rather severe reactions have been reported (Gries- bach) , probably because of the neglect of this precaution. Of course the serum used should be tested by means of the Wassermann reaction before injection. Antibacterial Serums and Antitoxins. — Antitoxins of various kinds and Antibacterial Serums have been widely used, these including diph- theria and tetanus antitoxin, antistreptococcus, antipneumococcus, anti- dysentery serum, etc. This paraspecific serum therapy, as it is com- monly termed, has found extended use both in France and England, and to some extent in this country. Such serums are not only used for injection — (intravenous, intramuscular and subcutaneous) — but have been given orally. Paton in his "New Senun Therapy" discusses this method and the results obtained therewith. "In 1895 Bokenliain had observed that the administration of diphtheria antitoxin seemed effective against streptococcus infection; De Minicis the following year administered diphtheria antitoxin orally in five patients with good results; in 189Y Lilienthal observed the efficacy of Streptococcus Serum in a variety of surgical conditions, while McCallum tried injec- tions of diphtheria antitoxin in tuberculosis, lupus and adnexal inflam- mations with good results. "On this basis Paton began his work, using antitoxins as well as sheep, horse, and beef serum interchangeably in a large series of cases and vari- ous diseases, with at times very interesting results. "Darier took up this study in France and quotes a considerable litera- ture dealing with therapy of this kind. "In pneumonia Talamon in 1901 treated about 115 cases with consid- erable success with diphtheria antitoxin; Mongour used it in broncho- pneumonia and pulmonary abscesses and Laim.ois also treated several cases. Deronet and Jeulin applied the treatment in 31 cases of pleurisy; their favorable report was confirmed by Faure in a small series of cases. Burkard used serum in the treatment of exophthalmic goiter and Bloch obtained good results using tetanus antitoxin. Weil reported on the use of such sera in hemophilia as well as in peritonitis, sepsis, puerperal in- fection, etc. Freund in 1911 tried normal horse serum in the toxemia of pregnancy. In typhoid Mongour and Cazamin, Marotte and Oui used diphtheria antitoxin; Albert Levy used it in dysentery. In arthritis L. Eamond and Chiray, Passavy and Chauvet and Guithard reported excel- lent results. Iritis was treated by the same means and in erysipelas Lau- nois, ApostoUeaum, Polak and Mayweg reported good results." Cumston has but recently called attention to the fact that in France paraspecific therapy has been commonly employed both in the army and in civilian practice, particularly in ocular infections. Diph- theria antitoxin is usually used for oral administration in military THE NONSPECIFIC AGENTS 19 practice but where the conditions are favorable the subcutaneous and intravenous use is preferred. It is said to relieve pain and induce a pronounced euphoria. The dosage, as may be expected, is not a fixed one. The serums are in this case given not for their antitoxic property but for their nonspe- cific stimulating effect. A very small dose in a sensitive patient may be sufiicient to induce a severe reaction ; usually however the dose may be fairly large after a careful determination has been made as to the de- gree of sensitization of the patient. The agents of this type have the advantage that they can be obtained in sterile containers ready for administration. They do not as a rule give any striking therapeutic results such as one may observe from the more toxic agents but offer a relatively safe means of experimentation until the physician be- comes more or less familiar with therapy of this type. Deutschmann Serum. — The general increase in resistance to in- fection that is observed after the use of yeast led Deutschmann in 1907 to try out a novel method of this principle. He immunized horses with yeasts for a considerable period of time and then used the serum in a number of diseases. He was interested chiefly in eye diseases, but the serum was tried out in a variety of acute infections as well. He had observed that his yeast-immunized animals all became more resistant to general infection, and believed that this change in re- sistance was due to a serum alteration. The serum was injected into patients both subcutaneously and in- travenously, but in relatively small dosage, — from 2 to 4 c.c. In his series of cases there were 24 pneumonias treated with the serum, of whom three died. In four of the cases a crisis was observed inamedi- ately after the injection. In all of the cases the euphoria following the injection was well marked. The serum has been used in general sepsis, erysipelas, various inflammatory conditions, — furunculosis, otitis media, impetigo, eczema, — and with seemingly good results in eye conditions — traumatic inflammation — hypopyon keratitis, iridocy- clitis, iritis, etc. (Bockhoff.) In lupus vulgaris a marked local inflammatory reaction was observed as with all other similar nonspecific agents. Tuberculosis Serum. — The commonly used preparations of Mara- gliano and of Marmorek cause reactions in tuberculous patients that have been ascribed to various immunological alterations but are very probably due to their action as nonspecific proteins. The temperature is increased after injection, focal reactions take place, there is an increase in the amount of sputum, etc. Just as with other nonspe- cific agents used in the treatment of tuberculosis, incipient cases are frequently benefited, advanced cases on the other hand are unfavorably infiuenced. Related Agents. — Plasma Serum has been used particularly by French observers. Grigant and Montier have used the method in the 20 PROTEIN THERAPY treatment of influenza. Rabbit plasma is mixed with human serum and injections of this mixture are given intravenously. Blister Serum, an infrequently used method, consists in producing a local vesicle in some area of the skin, withdrawing the fluid transudate and reinjecting the same. It possesses no properties of unusual ac- tivity. Pleural Transudates and Exudates (also termed autoserotherapy). Gilbert at the Medical Congress at Rome in 1894 reported that he had successfully treated pleuritic effusions by withdrawing a limited amount of fluid from the chest and reinjecting the same under the skin of the patient. The resorption of the pleural exudate was said to be greatly hastened. A long list of clinicians soon published re- ports with the method, most of them with favorable results — Fedde, Gerouzi, Tchigaoff, Nassetti, Marcon, Dxu-and, Schniitgen, Duncan, Modinos, Indelli, Fieri, Landmann, Linser, Spiethoff, St. Mello — a summary of the work having been collected in a review by Fish- berg. The technique is very simple; 5 to 10 c.c. of fluid are withdrawn from the chest on alternate days or at longer intervals and reinjected subcutaneously without withdrawing the needle to the surface of the skin. In some instances a very slight temperature rise has been noted to follow the injections; in most cases, however, no reaction follows. Zimmermann studied the mechanism involved and observed that a leukocytosis followed the injection. He was of the opinion that the reaction was due to autolytic products of tissue degeneration that were contained in the pleural fluid and made the observation that when he injected such products of tissue destruction — ^peptones — in animals, a leukocytosis resulted. Eisner also observed this leukocytosis. Lyter has recently gone over the subject and has come to the conclusion that the injections of pleural fluid have little or no influence in hastening the absorption of the exudate. In 23 cases carefuUy followed, treated by withdrawing 5 c.c. of fluid daily and reinjecting the same, 8 were com- pletely reabsorbed in two weeks' time — 34%, while in the balance the effusion did not lessen as a result of the treatment. Ljrter observed prac- tically no leukocytosis and in only two of the 8 rapidly resorbing cases did he observe any temjyerature reaction at all. It seems probable that the method is at best a very mild stimulant of resorption because the nonspecific response is practically negligible as far as the effect on temperature and leukocytosis is concerned. Perkins has recently modified the procedure somewhat in that he draws a larger amount of fluid from several patients, pools the samples and adds the same to citrated saline solution. To this a 5% solution of carbolic acid is added (to 10% of the total volume) . Of this mix- ture he begins injections of from 1 to 2 c.c. subcutaneously, gradually increasing the dose until he gives from 10 to 25 c.c. THE NONSPECIFIC AGENTS 21 Cerebrospinal Fluid. — v. Zielinski has published results obtained in the treatment of typhus fever with subcutaneous and intravenous injections of cerebrospinal fluid drawn from the patient. The dose was usually 15 c.c. and he claims to have obtained good results from such injections. Joint Fluid, — Dufour and Debray announce that the fluid from a gonococcus process in a joint answers all the requirements for an efficient and harmless autogenous vaccine when injected subcutane- ously. There is no need to heat or sterilize the fluid; they injected it under the skin of the thigh, and state that the general symptoms, and the general and localized pain rapidly subsided, and the tem- perature gradually declined in their three cases. The effect on the urethral and vaginal processes could not be determined as local meas- lu-es had been tried there as usual. The Local Effects of Serum, of Normal Salt Solution and of lodid Injections. — ^The treatment of wounds and of local tissue inflamma- tion by means of local injections of serum, homologous as well as foreign, is a more recent development. Miiller has discussed the effect and the possibilities and Wright in his studies on local tissue resistance to infection has also made use of this method. When so employed in cellular inflammation the injection is followed by marked ameliora- tion of the local symptoms, pain, tension and swelling being markedly diminished. The local injection of physiological salt solution is said to be followed by a similar analgesia. The method has been most extensively employed in the treatment of gonorrheal complications, especially epididymitis. As a rule 10 c.c. of serum or salt solution are injected into the scrotum near the site of the inflammation. These methods are related to Bier's method of treatment by passive hyperemia. As a matter of fact Bier has called attention to the effect of foreign protein injections in infectious diseases in a very early paper and has always been an advocate of related measures. NATIVE PROTEINS Von den Velden seems to have been one of the first to have used native protein injections in therapy with the distinct thought under- lying this procedure that he was thereby stimulating certain nonspe- cific fermentative reactions in the body which would be useful in in- creasing the general resistance to disease. He found for instance that the vasomotor activity around the local pathological area was in- creased, that there was evidently an increase in the lymph flow, of the leukocytic reaction, etc. Ovalbumin and Seralbumin. — ^Von der Velden at first used solu- tions of ovalbumin and seralbumin in 5% and 10% solution. This he 22 PROTEIN THERAPY injected subeutaneously in doses of from 5 to 10 e.c. ; later he used intramuscular and intravenous injections. Holler has also used ovalbumin. The general reaction is negligible and the therapeutic effect not striking. Milk. — The intramuscular injection of milk was introduced by Schmidt and by Saxl in 1916 to induce a protein reaction, i. e., the typical rise in temperature observed following other agents. Milk offered the advantage that it would be easily available to the profession. The method is very simple. Ordinary pasteurized (or fresh) milk is boiled for from 5 to 10 minutes and when cooled, from 5 to 10 e.c. are injected intragluteally, or into other muscles — arm, back, etc. The injection is followed in some instances by a chill (not as se- vere as that following typhoid vaccine), and by a temperature rise that reaches its maximum in from 6 to 8 hours and then subsides within 24 hours. A well marked leukocytosis, ranging from 15,000 to 40,000, also results. Milk has a decided styptic effect when so injected and as Doellken has shown is of particular value in diseases associated with hemorrhages. This effect is probably due to its effect on the liver parenchyma, which, together with the bone marrow, seems to be especially stimulated by the milk injections. Thrombokinase and fibrinogen appear in increased amoimts in the senun after injec- tion. Locally there may be considerable pain at the site of the in- jection. Milk being composed of many and varying elements, efforts h&Ye been made to identify those components that might be most effica- cious. The bacterial content in particular has been held responsi- ble for the reaction produced by the milk injection. Indeed Bessau, Decastello and E. F. Mueller believe that the reaction is due wholly to the bacteria that are contained in the milk, and Uddgren found that the reaction following sterile milk injections was relatively mild in character. She has determined that commercial milk, even after boiling for from three to five minutes, may still contain a few viable organisms. Boiled for ten minutes the milk was always found to be sterile. Uddgren believes the reaction of the milk is due to bacterial derivatives or protein split products contained in the milk. Ryhmer, who obtained rather unsatisfactory results with milk injections — he tried it in diphtheria carriers, in hemorrhage, in anemia, osteomyelitis, sepsis and Barlow's disease — also believes that the reaction is due wholly to the bacteria contained in the milk because with fresh sterile milk he obtained practically no re- action. When repeated injections of milk are given the reaction of the pa- tient may increase to some extent, differing in this manner from the effect of reinjection when bacteria and proteoses are used. There seems to be relatively little danger of sensitization or of anaphylactic shock following repeated milk injections; many thousand injections have THE KONSPECIFIC AGENTS 23 been reported and but few cases of shock following the repeated in- jections (Sachs, Oppenheim, Lubliner, van Randenborgh) . The last observer is of the opinion that some of the milk preparations (caseosan, etc.) are more apt to be followed by shock symptoms than are milk injections. Where shock symptoms have occurred it is by no means ex- cluded that part of the injection may not have accidentally reached a vein. Great care should always be exercised that the injections are intramuscular. The fact that there is relatively very little sensitization of the patient following milk injections has been variously accounted for. The human organism is not, as a matter of fact, very susceptible to anaphylactic shock under any circumstances, and Salus has sug- gested that in the case of the milk injections the fact that the milk has been boiled would tend to dedifferentiate it and diminish the ten- dency to sensitization. Slawik recommends the use of human milk in place of cow's milk, especially in the treatment of infants. He found that both wet-nurses and atreptic infants were refractory to such injections, there being absolutely no temperature response. According to Epstein adults re- act to human milk with an increase in temperature, etc., just as they do to cow's milk. Local injections of milk have been used by Weiss and others in the treatment of buboes and local inflammatory processes. While a general reaction results, there is a decided local effect similar to that noted when serum and physiological salt solution are injected locally. (Vide.) For intravenous injection fat-free milk has been prepared by thoroughly extracting the milk with fat solvents and later carefully evaporating the solvent that may, after gross separation, still be present in the milk. Ceisein (Aolan, Caseosan). — Lindig and Miiller both proceeded to refine this so-called "milk therapy" by using purified casein in its place. This has the advantage of being a chemically constant product, free from bacteria, for which one might presumably determine a standard dosage. Lindig has used a 5% solution. This is prepared by adding 5 grams of purified casein to a N-10 solution of sodium bicarbonate (20 c.c), shaking and agitating the same until the casein is all dis- solved and then adding 80 c.c. of distilled water. Of this solution from % to 1 c.c. is given intravenously. Injections are followed as a rule by a chill in about 1 hour, some headache and a moderate increase in temperature — about 3° F. Miiller has used a similar casein preparation which has recently been placed on the European market under the trade name of Aolan. While Lindig considers that the casein represents the active substance 24 PROTEIN THERAPY that is responsible for the reaction that follows milk injections, Miiller is of the opinion that the casein, just as the milk itself, rep- resents merely a foreign body and that the other constituents of the milk will also give a similar reaction. A similar preparation — Caseosan — has also been recently placed on the market. Both are merely solutions of casein in sterile containers. Casein occupies a rather unusual position among the native pro- teins because of the rapidity with which it is split and particularly because it is hydrolyzed by erepsin; the latter fact would make the splitting of the injected casein probable in almost any of the tissue fluids. Riedel calls attention to the fact that the mono- and diamins derived from the casein would act as powerful activators for tissue activity and, as a result, for enzyme activity. Gelatin. — The use of gelatin for intravenous injections was recom- mended a number of years ago because it was assumed that the gelatin would be much more efficacious in retaining water in the vascular bed in cases of shock and after severe hemorrhage, as the gelatin forms a hydrosol. The injections were at times followed by evidences of a nonspecific reaction of mild degree — chill, sweating, and febrile rise. Clark has recently studied the reaction of rabbits to such injection. The possibility that tetanus may follow injections of gelatin, especially when given subcutaneously, must be kept in mind. (Weber.) Plant Proteins. — Miinch has reported on the use of plant "press- saft" for parenteral injections. In this country a number of such agents, of unknown origin or composition, supposedly derived from plants, are on the market and are exploited under proprietary names. A rather amusing inconsistency is to be noted in that these non- specific proprietary agents are prepared for specific purposes, that is for each disease there is reconomended a specific "nonspecific" agent. Nucleic Acid and the Nucleins. — ^Nucleic acid was first brought to the attention of the scientific world at a meeting of the Basel Natiirforscher Gesellschaft in 1874 when Miescher discussed its chem- istry. It was not, however, until almost twenty years later that Hor- baczewski introduced it into medical practice and observed its leuko- cytic stimulative properties. Maurek shortly after reported on the effect of subcutaneous injections on the leukocytic picture and on the temperature curve, and Netter introduced it in France. It was soon extensively used in a number of infectious diseases and in a variety of degenerative diseases of the central nervous system, such as general paralysis, tabes, etc. Chantemesse and Parlavecchio both studied the effect of nuclein injections on antibody formation, finding that both alexins and agglutinins were increased, while Fox and Lynch have in very recent years studied the effect of nuclein injections on the leukocytosis of dogs. Brown and Ross have studied the leukocytic THE NONSPECIFIC AGENTS 25 reaction in connection with injections in a series of mental dis- eases. The dosage depends on the preparation. Usually as much as 0.5 gm. of the sodium nucleinate is given subcutaneously, this being fol- lowed by a leukocytosis in from 4 to 10 hours after the injection and a febrile reaction which may persist for 24 hours; this is usually mild in character and does not as a rule exceed 2° F. A modification of this method is the Nudeohexyl recently prepared. It is a compound of nucleic acid and hexamethylintetramin that is used in 10% solution for intravenous injections. The dosage is about 10 c.c. Levy claims to have found it useful in the treatment of typhus fever. PROTEIN SPLIT PRODUCTS That protein split products will, on injection, increase the tolerance both to further injections and resistance against infection is an ob- servation that has been made quite a number of years ago, among others by Vaughan and his associates in this country. It is only in recent years, however, that the various split products of proteins have come to be recognized as therapeutic agents. Nolf has used proteoses in diseases associated with hemorrhage, as in hemorrhagic diathesis, paroxysmal hemoglobinuria, etc., with the idea of increas- ing the coagulability of the blood. To Liidke belongs the credit of first using proteoses in the treatment of acute infections. Nolf be- gan their use for this purpose somewhat later and since then a large number of clinicians have published their resultsi with this dis|- tinctly "protein therapy" as it came to be termed. In our experience a variety of proteoses (albumoses) prepared from different proteins, will give a very prompt and satisfactory reaction. It has been shown at various times that the primary proteoses are somewhat more toxic than the secondary proteoses for animals, but in therapeutic injections the difference in effect may not be appreciable. Liidke used deuteroalbumoses, these being now prepared commercially for therapeutic use in Germany. The derivation of the protein split product that is used is of con- siderable importance in regard to its toxicity. Schittenhelm and Weichardt in their studies noted the difference in toxicity of protein split products derived from different native proteins. Kaznelson study- ing this question with particular reference to the therapeutic use of deutero-albumoses tried out deutero-albumose prepared from fibrin, from gelatin, from wheat, horn, silk, etc. Injected subcutaneously they were all followed by considerable local pain at the site of the injection. Intragluteally the local reaction of these albumoses dif- fered little from that following milk injection. The intravenous effect differed considerably. Thus the hetero-albumoses prepared from 26 PROTEIN THERAPY fibrin were much more toxic than the others. Those from gelatin followed next in the severity of the reaction while those derived from wheat, horn, silk, etc., gave little or no reaction. From the studies of Baehr and Pick it seems most probable that the toxicity of protein preparations such as these depends to a large degree on the presence or absence of the cyclic or ring compounds in the protein molecule. Perhaps, too, the size of the colloidal aggre- gate is of importance in determining the reaction after intravenous in- jection. The dosage of the Deutero-albumoses and of the other primary and secondary proteoses so far used, has varied. In our own work we have used from % to 2 c.c. of a 2% solution of secondary proteose. Liidke first used about 2 c.c. of a 2% solution; recently he has in- jected from 1 to 2 c.c. of a 10% solution; Holler used 1 c.c. of a 10% solution. Jobling as well as the writer have been under the impression that small doses repeated at frequent intervals offer the best mode of administration. Jobling in his Harvey Lecture recommends begin- ning with a dose of 0.25 c.c. of a 1 % solution and determining if the patient reacts with much temperature. If there is no general reaction from this dose a somewhat larger dose can be selected for injection the following day. This is particularly advisable in the more toxic forms of infectious diseases; in arthritis, on the other hand, it may be better to give a relatively large dose (after its reactivity is known) at the beginning and induce a sharp reaction. The reaction follow- ing the injection depends not only on the dose but on the type of dis- ease from which the patient is suffering, just as with milk injections. (Schmidt.) The patient does not become sensitized to proteose injections; rather a degree of tolerance is established, so that following or re- peated injections do not give an equal response on the part of the patient. In animal experimentation there is some evidence that sensitiza- tion, at least to the higher proteoses, can be established. In the hu- man there has been no evidence of this effect, at least as far as can be determined from the clinical reaction that follows after repeated injections. It is very doubtful to my mind if a therapeutic effect can be achieved unless a general reaction is brought about in the patient. Nolf emphasizes that shock should be avoided — "when one employs proteosotherapy to cure a patient of an infectious disease one should avoid shock — at least the violent shock which I have described. But it seems to be an advantage to produce a mild reaction which I have called the 'peptone effect' in contrast to 'peptone shock.' " Efforts of many workers have been directed in producing some agent that would not produce a severe reaction— that is, the nausea, THE NONSPECIFIC AGENTS 27 chill, sweating and fever — and would at the same time give an equally satisfactory therapeutic result. There is little doubt that from the clinical standpoints such an agent would be a very desirable one, and it is an idea that should be kept in mind. But we are confronted with the probability that, as will be pointed out in the chapter on The Focal Reaction, the posi- tive phase or mechanism of recovery after nonspecitic injections is a function, or at least very closely related to the degree of the negative phase or the intensification of the disease process that is clinically manifest in the reaction of the patient. Just as in local foci of disease a marked augmentation of the inflammation, both after specific vaccine injections (as after the injection of "Arthigon" Schultz found that gonorrheal lesions healed best after severe reactions) or nonspecific injections is followed as a rule by clinical improvement, so in the general infections a relatively severe re- action is more frequently followed by an abortive recovery than when the reaction is very mild or absent. I cannot too strongly emphasize, however, that the utmost care and judgment must be ex- ercised and a considerable degree of experience must be gained in the treatment of such diseases as arthritis or of local inflammations before the attempt is made to treat general infections, unless the physician wishes to court disaster. The entire question of dosage and of the proper reaction is still an open one. I believe that the method of Holler is a safe one and one that can be recommended. Holler injected his cases of in- fectious diseases with a daily dose of deutero-albumose that was just suflBcient to elicit a mild reaction. In some diseases he administered two doses daily. This method is certainly much safer than the ad- ministration of a single huge dose which may be more than the patient can bear. V. Biedl has made use of Histamin, using 0.5 mg. for intravenous injections. The results were not particularly satisfactory, nor were they much better when Witte Peptone was employed. On the other hand both Nolf and Gow have used Witte Peptone with evident success. Gow employs a 10% solution. This is made up by dissolving 10 gm. of the dry peptone in about 5 c.c. of hot freshly distilled water and bringing the volume up to 100 c.c. Of this from 8 to 10 c.c. are slowly injected intravenously. The effect of the intravenous injection of various split products of proteins both from the physiological as well as the pharmacological standpoint has been intensively studied both in this country and in Europe and the literature is so well known and readily available that it will not be necessary to enter into it here. The effect of the intra- venous injection of Histamin has been more recently studied by Dale and Laidlow. 28 PROTEIN THERAPY They found that in eats the injection of from 1 to 2 mg. per kilo, was followed by a marked fall in blood pressure, there was a clumping of the blood platelets (for the significance of the clumping of blood platelets and its bearing on anaphylaxis the article of v. Behring is of interest), a leuko- penia — the leukocytes stick to the lining of the vessels — and in a relative polycythemia with increased viscosity. These latter changes are due to the increased permeability of the capillaries, as a result of which they esti- mated that about 40 per cent, of the plasma was lost from the vascular bed. ENZYMES Tr3^sm. — A method that was considerably exploited some years ago was the so-called Enzyme Treatment of cancer, advocated by Beard, which consisted in the subcutaneous injection of a trypsin solution. It is very problematical whether any malignant disease was ever actually cured by the injections; focal reactions were of course noted, with a diminution of the size of the larger tumors be- cause of the increase in the autolytic processes in the neoplasm. The injection was practically always followed by a general reaction on the part of the patient, evidenced by the chill, sweating and tempera- ture rise. After this acute reaction the patient would have several days of relative comfort. Amylopsin was usually combined with the trypsin for injection. Leukocytic Extracts. — ^Leukocytes contain antibacterial substances (Moxter, Petterson, Schneider) and an effort was made to utilize this property therapeutically. Petterson used leukocytic extracts in dogs that were at the same time injected with anthrax bacilli; there was evidence of an increased resistance. Later he used a similar method in testing the increased resistance of guinea pigs treated with leukocytic extracts and infected with typhoid bacilli. Opie made similar experiments with dogs and later Hiss, and Hiss and Zinsser carried the method to actual trial in human infectious diseases. Leukocytes were as a rule obtained from rabbits, washed and sus- pended in distilled water. Usually the entire suspension was in- jected. Leukocytic extracts have been used in the treatment of pneumonia, staphyococcus infections, erysipelas, etc., with apparently favorable results. Considering the enzyme content of the polymorphonuclear leu- kocyte it seems probable that the injection really represents a mix- ture of enzyme and heterologous protein, as far as the patient is concerned; the injection is followed by a leukocytosis (Alexander), but otherwise with little general constitutional reaction. Leukocytic extracts have been placed on the market for therapeutic use, and Archibald and Moore, Leonard and Harmer have published results obtained after the injection of leukocytic extracts. Tunnicliff, who has recently studied the effect of leukocyte injections, finds that the leukocytosis that is observed after the injection persists for from THE NONSPECIFIC AGENTS 29 1 to 4 days and that the leukocytes are particularly active (young forms). TISSUE EXTRACTS Tumor Autolysates. — Efforts to influence disease processes by means of autolysates from tissues and tissue extracts have centered largely about malignant neoplasms and a considerable number of substances have been used by clinical observers. The work of Beard has already been mentioned; the fact that tumor cells seem very rich in heterolytic proteoclastic enzyme (Wolff and Blumenthal) stimulated repeated efforts to prepare some substance from tumor juice that would have a therapeutic action. All substances so far used cause a typical protein reaction and are without specific action on tumor cells. The most recent report of such a preparation is that of Joannovics and his associate Scherber. Bier and Sticker be- gan similar studies some twenty years ago, using foreign proteins (foreign serum, lymph, organ juices) combined with atoxyl. Cartilage Extracts. — Heilner in recent years prepared an extract from cartilage called "sanarthrit" which, injected in chronic arthritis, causes in some cases marked alleviation of the symptoms. Heil- ner introduced the substance for the treatment of gout, on the as- sumption that in gouty diathesis the cartilage, because of its chemical structure, offered a site of particular affinity for the deposition of uric acid and related compounds. Therefore the injection of such material in a soluble form might aid in the elimination of the exciting metabolic products. It was soon found, however, that other arthritic processes, infectious in origin, were also influenced by the injections so that the theory was no longer tenable. It is now the expressed opinion of a number of observers that the reaction is merely a non- specific one and similar in character and in its therapeutic possibilities and limitations to the other agents of this group. Vascular Extracts. — The most recent preparation of this nature is an extract of vascular tissue (blood vessel walls, etc.) which is said to have some effect in arteriosclerosis. Organotherapy.— Borchardt, in recent communications, has made the statement that all the tissue extracts, unless they offer very definite glandular substitution, as thyroid extracts do, or contain enzymes (and are therefore enzymatic agents) represent merely nonspecific agents which stimulate the organism in a nonspecific way. It is at least very probable that in a measure their effect is due to such activity. Borchardt is also of the opinion that the injection of relatively small amounts of blood subcutaneously (Weinland) and the injec- tion of marrow extracts (Danilewski, Fowler, etc.) as well as splenic extracts have their therapeutic basis on the same nonspecific stimula- tion of the hematopoietic system. 30 PROTEIN THERAPY Esch considers the results obtained with organotherapy in men- strual disturbances from the same point of view. As proof of the plasmaactivation Borchardt brings a niunber of interesting experi- ments. Using immunized rabbits he has found that the injection of asthmolysin (0.0008 adrenalin and 0.04 infimdibular extract), of spermin and also of thyroid extract greatly increased the titer of the immune bodies in the serum. The thyroid extract was active even when given by mouth. As a result of his experiments he considers any of these agents useful in the infectious diseases. THE VACCINES Before taking up the question of the use of vaccines in produc- ing a nonspecific response it may be well to quote briefly from a re- cent paper of Wright. Inasmuch as Wright has done more than any other immunologist to emphasize the factor of strict specificity in vaccine therapy, introduced the method of estimating such specific re- sponse on the part of the patient by means of the opsonic index, recommended the use of autogenous vaccines, etc., it is but fitting to record his present attitude. "Let me start quite at the beginning. Long after the principle of pro- phylactic inoculation had established itself in medicine, it was accepted that to inoculate microbes into the already infected system would be as illogical as to instill further poison into an already poisoned system. Pasteur was the first to teach us here a distinction. He pointed out, in connection with immunization against rabies, that a vaccine might legiti- mately come into application in the incubation period. That was the be- ginning of therapeutic immunization; and from that time forth it was recognized that you may legitimately inoculate in the incubation stage, and try to get in advance of the infection. But it was in everybody's mind that immunization took 10 days to establish itself. When I showed in connection with antityphoid inoculation that bactericidal substances were very rapidly elaborated, it became plain that this involved shifting the old landmarks and taking in further territory for therapeutic immuni- zation, and one had to ask oneself all sorts of penetrating questions. One had to ask oneself in connection with 'generaHzed infections' at what par- ticular stage of the infection one was to regard the body as overmastered by the bacterial poison, and incapable of further immunizing response. Again, in connection with localized infections' one had to inquire whether they should not be envisaged as general infections indefinitely arrested in their incubation stage, and whether they might not, in consonance with that, be brought within the sphere of inoculation. "Further consideration suggested that the problem of therapeutic in- oculation can be approached also from a point of view different from that taken up by Pasteur. With respect to immunizing response, the body had been visualized as a single and undivided unit. That is clearly erroneous. One region of the body may be making immunizing response while the other is inactive. For instance, in the stage of incubation it is presumably THE NONSPECIFIC AGENTS 31 only the region wHcIl is actually harbQ^ijng tte microbe, and in tie stage of generalized infection it is presumably the entire body wbicb is incited to respond. And again, in localized infection we may — ^making here some reserves — assume that we have only localized response. "Placing ourselves at this iwint of outlook, therapeutic immunization will, it is clear, be theoretically admissible so long as there remains in the body any part which is not already making its maximum i m munizing response. And the program of therapeutic inoculation would accord- ingly consist in exploiting in the interest of the infected regions of the body the immunizing responses of the regions which are uninfected. "Results of Vaccine Therapy "Keeping that now in view, let me try, very briefly, to tell you what are, in my view, the results which have been achieved by applying this thera- peutic method. I can do that in a very few words. "In every form of infection a certain quota of unequivocal successes may be credited to the method, and especially successful results have been obtained in furunculosis and acute inflammatory sycosis; in 'poisoned wounds' — ^meaning by that localized cellulitis set up by a streptococcus in- fection; in streptococcal infections taking the form of lymphangitis, in erysipelas; in tubercular adenitis, tubercular joint infections, tubercular dactylitis, tubercular orchitis, and tuberculous infections of the eye, es- pecially in phlyctenules of the conjunctiva; again in bronchitis, in chole- cystitis, and gonorrheal rheumatism. The most dramatic and convincing — convincing because here no other therapeutic measures are employed as adjuncts— are the successes obtained in streptococcal lymphangitis, in streptococcal cellulitis — ^I am thinking of those cases which have already been incised without striking benefit — and in conjunctival phlyctenules. "When we analyze the successes and failures* of vaccine therapy the following points come out quite clearly: — "(1) Vaccine therapy is generally unsuccessful where the infection — as in phthisis — is producing constitutional disturbance and recurring pyrexia. "(2) Vaccine therapy is also generally unsuccessful where we have to deal with unopened abscesses, or sloughing wounds with corrupt discharges. "(3) In long-standing infections vaccine therapy is much less success- ful than in recent infections. "To see what auxiliary measures should be applied in these cases, I must take you back for a moment to the region of general principles. . . . * I here, as clear thinking exacts, exclude from the failures of vaccine therapy the failures of that preventive inoculation against individual infections to which vaccine therapy is the usual precursor. The efficacy of such prophy- lactic procedure is a question apart. But I may usefully point out to you that the superior credit which attaches to antityphoid inoculation, and preventive inoculation against infective diseases generally, as compared with preventive inoculation against what I may call individual infections, is probably attributable to the fact that, in the case where we are dealing with an infective disease, the external circumstances are as favorable to success as they are in the case of inoculation against "individual infections" unfavorable. 32 PROTEIN THERAPY "Nonspecific Immunisation "In the foreground stands the question of nonspecific immunization. That immunization is always strictly specific counts as an article of faith; and it passes as axiomatic that microbic infections can be warded ofi only by working with homologous vaccines; and that we must in every case before employing a vaccine therapeutically, make sure that the patient is harboring the corresponding microbes. I confess to having shared the con- viction that immunization is always strictly specific. Twenty years ago, when it was alleged, before the Indian Plague Commission, that anti- plague inoculation had cured eczema, gonorrhea, and other miscellaneous infections, I thought the matter undeserving of examination. I took the same view when it was reported in connection with antityphoid inocu- lation that it rendered the patients much less susceptible to malaria. Again, seven years ago, when applying pneumococcus inoculations as a preventive against pneumonia in the Transvaal mines, I nourished exactly the same prejudices. But here the statistical results which were obtained in the Premier Mine demonstrated that the pneumococcus inoculations had, in addition to bringing down the mortality from pneumonia by 85 per cent, reduced also the mortality from 'other diseases' by 50 per cent. From that on we had to take up into our categories the fact that inoculation produces in addition to 'direct' also 'collateral' immunization. This once recognized, presumptive evidence of collateral immunization began gradually to filter into our minds. Among, I suppose, many thousands of patients treated by vaccine therapy in private and in hospital, it happened every now and then that a patient was treated with a vaccine which did not correspond with his infection, and that that patient indubitably benefited. Again, it was not an uncommon experience for the subjects of a very chronic in- fection (such as pyorrhea) who were treated first by a stock vaccine, and afterwards with an auto-vaccine, to assert that they derived more benefit from, and to ask to be put back upon treatment by the stock vaccine. "Prom such cases hints are conveyed to us that there may exist a use- ful sphere of application for collateral immunization; and that such sphere may, perhaps, be found in those cases where the infection is of very long standing, and where the patient has become very sensitive to, and has probably come very near the end of his tether in the matter of immunizing response to, the particular species or strain of microbe with which he is infected. It will, with regard to such patients, be remembered that they constitute the third of those three classes of cases to which I referred to at the onset of this lecture as very intractable to vaccine therapy. "We are, however, here considering primarily the question of principle; and in connection with this what is of fundamental importance is: that we should discard the confident dogmatic belief that immunization must be strictly specific, and that we should in every case of failure endeavor to make our immunization more and more strictly specific. We should instead proceed upon the principle that the best vaccine to employ wiU always be the vaccine which gives on trial the best immunizing response against the microbe we propose to combat. "I would point out that this would almost certainly not involve any revolutionary change in the accepted practice in either serum therapy or THE NONSPECIFIC AGENTS 33 in propliylactic or ordinary therapeutic inoculation. But it would mean taking into account in cases which proved intractable to treatment with the homologous vaccine the possibility of seeking for collateral immuniza- tion by inoculating a microbe or mixture of microbes other than that with which the patient is infected. The trial of this procedure might perhaps recommend itself where from the outset there is very little immunizing response to the homologous vaccine, and also where, as in long-standing cases of tubercule or streptococcus infection, the power of direct immuniz- ing response to the corresponding vaccines is becoming exhausted." This use of bacterial vaccines for "collateral immunization" as Wright uses the term, or for nonspecific stimulation, is a modem con- ception that dates practically from the work of Renaud and of Kraus. The former used typhoid vaccine in the treatment of a number of non- typhoidal diseases ; the latter treated typhoid patients with colon vac- cine, and then proceeded to treat puerperal infection and other acute infections with typhoid and colon vaccines with remarkable results. Until this time the fear of overdosage had kept back investigation in this particular field. The disastrous effects that had at times followed the injection of tuberculin in tuberculosis had made a profound impres- sion on medical men, and the emphasis placed on the negative phase of the opsonic curve after vaccine injection had a similar effect. With the introduction of the sensitized vaccines of the French school larger doses came to be used, but here again a generalized reaction was avoided. Occasionally one finds records of more heroic dosage and cures following on general reactions; thus Szily cured a severe ophthalmoblennorrhea with several large doses of gonococcus vaccine. Following the publication of Kraus's results a large number of observers have used heterovaccinotherapy in the treatment of dis- eases of various kinds. The reaction of these various bacterial vac- cines varies of course; in general, however, the following bacteria have given results. Typhoid Vaccine. — The toxicity varies greatly with the age and the strain. For convenience the vaccine is usually made up with 100 million organisms to the cubic centimeter, of this approximately 25 to 50 million may be given at the first dose if the particular vaccine is not too toxic; great care must be observed. Typhoid vaccine is followed by a prompt chill and temperature reaction, usually by a leukocytosis. Headache is a common accompaniment. Colon Vaccine. — Colon vaccine is usually followed by a severe reaction, which may, however, be delayed for several hours after the injection. Headache is usually severe after several hours. It has been used more frequently by English observers. The dosage should not exceed 25 million for the first intravenous injection; for later re- actions this may be increased. Dysentery. — Dysentery strains of all types when injected, both 34 PROTEIN THERAPY subeutaneously or intravenously, are relatively toxic and resemble typhoid and colon vaccines in their general effects. Cholera, prodigiosus, proteus, and a number of other organisms have been injected intravenously by various observers. Meningococci. — The dose used is usually about 100 million. The injection is followed by a prompt chill that has its onset in from 15 minutes to one hour and lasts usually a half hour. Headache is com- mon, nausea and vomiting quite exceptional. The temperature rise is marked and reaches its maximum in from 6 to 8 hours. Herpes has been commonly observed after the injections. Gonococci. — Dosage and reaction similar to the meningococcus. Leukocytosis is well marked with both types of organisms and reaches a maximum in from 5 to 7 hours. With the gonococcus vaccine herpes is less frequent. Streptococci. — The streptococcus is evidently not as toxic as the typhoid and colon bacilli, and the reaction is frequently delayed from 8 to 10 hours. A dosage of 100 million is usually followed by only a mild temperature reaction. A chill is not so common and the leu- kocytosis is lacking. The vaccine does not seem to be a good agent for nonspecific stimulation. Staphylococci. — Similar in dosage and in reactivity to the strep- tococcus vaccine. Followed by a leukocytosis of considerable extent and has been found more useful than the streptococcus vaccine. Pyocyaneus. — Pyocyaneus Vaccine was one of the first used for heterovaccinotherapy (by Rumpf in the treatment of typhoid in 1893). Its use has not been extensive enough to justify any con- clusions as to its value. Dollken has used it in the treatment of gummata. Pneumococcus. — In dosage and reaction similar to the strepto- coccus, with a certain degree c^ latitude with different strains. The leukocytic response is not marked; indeed may at times be absent. Influenza Bacilli. — Influenz^: bacilli injected intravenously have been given in doses of from 50 to 100 million organisms with relatively little reaction on the part of the patient. There is as a rule no chill, but the temperature response may be from 2° to 3° F. several hours after the injection. Diphtheroids. — Both diphtheroids and diphtheria bacilli seem to produce little reaction when injected intravenously. A dosage of from 25 to 200 has been injected intravenously, followed after a long latent period (10 hours) by some general reaction, slight chill, tem- perature rise of from 1° to 2° F. and headache. Usually there is no leukocytosis. While all these organisms may produce some reaction, either mild or severe, they are by no means quite comparable in their effect on the leukocytic response. Schittenhelm, Weichardt and Greissham- mer have called attention to some of the differences that exist follow- THE NONSPECIFIC AGENTS 35 ing the intravenous injection of different kinds of bacteria, certain organisms being followed by a prolonged leukopenia instead of a leukocytosis, others producing myelitic stimulation, others a lym- phatic stimulation, etc. Dollken in his recent discussion and study of heterobacteriotherapy brings out the fact that the stimulation by different bacteria may not be omnicellular, but rather selective; that the clinical result, too, is by no means independent of the kind of organism injected. Thus he found that while pyocyaneus vaccine was effective in gummata, a pseudodiphtheria vaccine was quite without effect. In neuralgia a prodigiosus vaccine gave an excellent clinical result, while cholera and dysentary vaccine was not followed by equal clinical improvement. In a like measure in the treatment of acne neither prodigiosus nor pyooyaneus vaccine proved useful, while the autogenous vaccine was promptly followed by improve- ment. The injection of vaccines is not , like milk , followed by any styptic effect ; on the other hand, they are not as alaile hemolytic",^ as nucleohistone and albumoses may be. The resistance to rein- jection also differs with the different organisms. Thus there is a rapid tolerance, or increased resistance established to typhoid, pyocyaneus, pseudodiphtheria and several other vaccines, while milk , representing a native protein , may at times become more marked in its effect with subaenuent injections . Mixtures of vaccines have also been employed. Thus the "Arthi- gon" of Bruck contained a number of strains of gonococci and 10% of protargol and was used extensively in Germany in the treatment of gonorrheal complications. "Vaccinurin" is a recent mixture rec- ommended by Dollken for use in neuralgia and neuritis and consists of prodigiosus organisms and staphylococci which have been permitted to autolyze. Banysz' method of treating disease has been discussed in full in a recent number of the Bulletin medicdle. He describes anew the tecknic and his experience in 352 cases since 1913. In seeking for an efficient antiana- phylactic, he started from the theory that the focus of production of the substances generating the anaphylaxis in the majority, if not in all, of the chronic, noncontagious diseases, is in the bowel: The albuminoid matters or microbian contents of the intestinal canal passing into the blood through the congested intestinal mucosa act as antigens and induce the anaphylactic state of the organism. Consequently, he reasoned, the microbes isolated from the intestinal contents ought to act as antigens when inoculated or ingested. The microbes are isolated from a scrap of stool by sowing on ordinary culture bouillon and then making pure cultures on gelose, and then mixing the cultures in the same proportions as found originally. This is diluted with physiologic serum, sterilized with heat and the dose determined by weight. For ingestion, the dose is 1/10 to 5/10 mg. of the microbian bodies; for injection 1/1,000 or 1/1,200 mg. At first he made an autogenous antigen for each patient, but finding that the species and 36 PROTEIN THERAPY proportions of bacteria were so uniform, he used a polyvalent heterogeneous preparation in some cases. Much's Antigen. — Much has recently described a vaccine which he terms "Immunvollvaccine' for intramuscular injection, which he has used in the treatment of influenza. It is prepared from a niun- ber of nonspecific antigens: (a) Reactive proteins, the metabolic products of several nonpathogenic bacteria, (b) a lipoid mixture from bile, and (c) a fat mixture of animal derivation. The theory imder- lying such a mixture is that of partial antigens which he has developed in tuberculosis. BACTERIAL EXTRACTS AND RELATED SUBSTANCES The use of bacterial extracts and of bacterial growth products to produce a nonspecific temperatiu's increase is not a recent inno- vation. Tuberculins have been used for this purpose for some time, es- pecially in the treatment of paresis, as introduced by v. Jauregg. For this purpose a relatively large dose is used, beginning with 0.01 mg. and increasing rapidly until as much as 0.5 mg. is injected. The temperature reaction is a prolonged one; usually a leukocytosis is produced. It offers no particular advantages over milk injections which produce practically the same results. Kaiser has used Tebelon, the isobutyl ester of oleic acid (intro- duced by Stoeltzner) , in a number of surgical conditions. Like other nonspecific substances it acts as a pyrogenic agent even in nontuber- culous diseases. Typhin. — ^Biedl in 1915 noted that the nonspecific reaction could be elicited with histamin, the toxicity of which had been previously studied, v. Groer made use of this knowledge in preparing a mix- ture of nucleoprotein and histamin from typhoid bacilli which he called "typhin" to be used in place of whole bacilli for intravenous injections. The chief advantage of the preparation lay in the fact that with such a substance the dosage might be standardized and the reaction gauged. With this "typhin" v. Groer treated 23 cases of typhoid, of whom 18 made a prompt recovery and 5 died. In the case of a typhoid patient that recovered by crisis after the in- jection and died a few days later from an intercurrent condition, v. Groer observed at the autopsy that the ulceration of the bowel had practically healed and that the spleen was small (v. Wiesner has recorded similar observations). It is interesting to note that v. Groer found no increase of anti- bodies in the serum of patients after the injection despite the fact that such patients made an excellent and prompt recovery after the injections. THE NONSPECIFIC AGENTS 37 Intramuscular injections are recommended for common use. He also gave small doses of digitalis a few days preceding the injection in severely toxic cases. Coley's Fluid.— This consists of fluid culture products of the strep- tococcus and pyocyaneus. It is used particularly in sarcomata in which it was usually followed by a severe systemic reaction and some evidence of digestion and autolysis of the tumor, but never to the ex- tent of complete eradication of the neoplasm. Pneumococcus Autolysate. — Among bacterial autolysates which were prepared on a specific basis but which in all probability were effective, when therapeutically active, as nonspecific agents were the pneumococcus autolysates of Rosenow, recommended for use in lobar pneumonia. Phylacogens {Schafer's Vaccine.) — These represented bacterial growth products of a number of bacteria first prepared by Schafer and used with some success in arthritis. They were later prepared on a commercial scale and marketed under the trade name of Phylacogens. Inasmuch as the method of preparation and exact com- position is not known, the reaction merely a nonspecific one, other and less expensive agents will be found more satisfactory and more easily controlled. COLLOIDAL METALS Colloidal metals were perhaps first used as therapeutic agents by Crede in 1895. Crede used silver preparations on the assumption that they were actively streptococcocidal, and they were introduced by him in the treatment of streptococcus infections. The range of application was, however, soon extended to septic conditions in gen- eral (it was no longer considered a specific streptococcicide but to pos- sess heterobactericidal properties) and latterly it has been surmised that its usefulness depended not on its particular chemical structure but on properties of colloidal metals in general which produced the nonspecific reaction and were therefore typical ergotropic agents. Earlier workers had followed Crede in the interpretation of the method of action (Marquis dos Santos and Alphonse Pinto) ; Albrecht sur- mised that the catalytic property of the finely dispersed metals might have a definite relation to the therapeutic effect; while later the reactive leukocytosis that followed the injections was studied and held responsible for the therapeutic result. (Dunger, Sahli, Bruntz and Spillmann.) Bonnaire and Kausch both noted and emphasized the important fact that following the intravenous injection a chill, fever and leu- kocytosis were commonly observed. This febrile reaction, just as in other nonspecific reactions, varies considerably with the disease process. In sepsis Kausch noted that the high temperature dropped promptly by lysis, whereas afebrile cases, such as carcinoma, responded 38 PROTEIN THERAPY with a sharp febrile rise. Eberstadt in treating erysipelas did not observe any initial rise in temperature following the injection; a lysis occurred in his four cases. The fact that colloidal metals are active catalytic agents has led to the theory that in the organism they act therapeutically by virtue of this property as inorganic ferments. Vergely in a recent review calls attention to this effect in connection with the enormous surface developed by colloidal preparations of this type. A liter of a 0.5 per thousand solution of colloidal gold, for example, presents a surface of 150,000 square centimeters, while the same weight of gold in a compact form presents a surface of only 50 square milli- meters. In therapeutics, they whip up the organism but if it is unable to respond, they can do no good. If the patient is imable to produce more leukocytes, there is no chance of success. In selecting the colloid to use, he advises the metal that has been found most active against the bacteria, etc., involved. He adds that injection of a col- loid may favor the production of a fixation abscess when this is attempted at the same time. There is a place for colloidal thera- peutics, he concludes, besides vaccine therapy and serotherapy, but its principal indication is in chronic disease or infection. While the reaction that follows the injection of colloidal metals may be quite severe, relatively few untoward effects have so far been reported in the medical press. Eyth and Moser have reported deaths; Saito, Eberstadt, Kausch and Werler have reported severe shock re- actions. Injections must be made very slowly; therapeutic results can be expected only when the metals are given early in the dis- ease process. A variety of colloidal metals have been prepared for therapeutic use, some of which are on the market as commercial preparations. The colloidal silver-albumen preparations have been used longest. Arsenic, iodin, manganese-copper and platinum, zinc, manganese, gold, iron, sulphur, mercury, tin oxid, etc., have been used with vary- ing success. The dosage depends of course on the amount of metal dispersed in the solution and on the degree of reaction produced, both variable factors, that require a certain amount of trial for each preparation. The treatise of Searle covers the field of recent English work with colloidal metals. Of the silver preparation the dosage has varied in practice from the minute doses given by Gellhaus, who used fractions of a cubic centimeter, to those of Kausch, who commonly injected from 10 to 25 c.c. and even gave as much as 100 c.c. of a 2% solution intra- venously. The colloidal metals are given not only intravenously and sub- cutaneously, but have been used locally, given per os and even as clysma. Alexander, for instance, gives first one injection intrave- nously (10 c.c. of a 2% solution), then follows the next day with a THE NONSPECIFIC AGENTS 39 clysma of 50 c.c. of a 5% solution. K. and R. Klotz have used it in the form of a clysma, giving 1 mg. daily during the course of pneu- monia. The question arises in connection with the injection of these metallic preparations how much of the reaction, and consequently of the thera- peutic benefit, is due to the dispersed metal and how much to the protective colloid that the manufacturer adds to his solution to make it stable. Thus for the commercial iodo-coUargol preparation the composition is stated by the manufacturer to be 31% in silver, 37% iodin and 31% protective coUoid. Other preparations vary in the amount of protective colloid added and the substances used for this purpose. Auld has published some illuminating experiences in this connection. He had been working with colloidal platinum solutions for several years and found one particular preparation very effective therapeutically. This was an old solution that had been in his laboratory for some time. Intra- venous injections of from 3 to 7 c.c. resulted invariably in a sharp reac- tion on the part of the patient — a chill commencing in about half an hour, the temperature rising to 104° F. and 105° F. and the patient complaining of nausea and headache. This reaction occurred both in normal individuals and in patients suffering from a variety of ailments. His othei platinum preparations did not give this sharp reaction and the therapeutic effect likewise was lacking. On further investigation of the matter Auld ascer- tained from the manufacturers that this particular preparation had been stabilized by a solution of veal peptone (0.4%) together with 1% glucose. This peptone on trial gave an identical reaction on the part of the patient as the original platinum solution and could be used therapeutically with equal success. The use of the colloidal metals has been very extensive in a variety of clinical fields, both for septic conditions as well as in certain special conditions such as skin diseases, venereal diseases, etc. Thus Reichmann has obtained good results in sepsis, endocarditis and rheumatism; Bichon in rheumatic iritis; Salomon, and Labbe and Moussaud (colloidal gold) in typhoid; Richter in trench fever; Klewitz in endocarditis. A number of general articles covering the subject have been published which will be found of interest: Guaita, Meyer, Kausch, Bockemueller, Cowadias, Loeper and Wahram, Laumonier, etc. It has been found that after the injection the colloidal metal is deposited chiefly in the liver, the spleen and the bone marrow (Voight) . A separate field for therapeutic application of the colloidal metals lies in their use as adjuvant agents in radiotherapy. In this connec- tion considerable progress has been made in recent years. The colloidal metals, like many of the other nonspecific agents, are as a rule less active on reinjection. Bottner, however, believes that he has been able to demonstrate that the organism may be sen- sitized to collargol and that on reinjection in proper time intervals, the patient will react more strongly than with the first injection. 40 PROTEIN THERAPY This has a definite value in such conditions as arthritis where a sharp reaction on the part of the patient is usually very desirable. MISCELLANEOUS Hypertonic and Hypotonic Salt Solutions.— The injection of large intravenous doses of salt solution in the treatment of typhoid fever dates from the report of Englander. Englander while treating a case of typhoid that had had a severe hemorrhage injected some 300 c.c. of normal saline intravenously. This was followed shortly after the injection by a severe chill, and the usual nonspecific re- action. The following day the temperature declined to 35.2° C. (95.4° F.), and the patient made a prompt recovery by lysis that commenced the day following the injection. Other cases were then treated by Englander with the same method. Sodium chlorid cannot, however, in the light of our present knowledge be considered as an indifferent substance to the organism. The observation of Hutinel that salt causes fever even when injected in infants in small doses has been the subject of considerable dis- cussion, Samelson contending that such temperature disturbance was due to the fact that impurities were injected with the salt or in the water used in making up the salt solution. Bendix and Bergmann came to the same conclusion. More recent observations concerning the role of the sodium ion in its relation to the permeability of cell membranes, and the role of the water content of the tissues in the mechanism of fever leave the status somewhat uncertain. Instead of using large doses and producing a marked reaction in the patient as Englander did, Danielopolu has used repeated small doses of hypotonic salt solution (.065) in the treatment of typhus fever. By this method he claims to have obtained remarkable re- sults. Two other methods have been devised in which salt solutions are used, both for local injection. Eisel has injected from 10 to 15 c.c. of physiological salt solution locally between the scrotum and tunica vaginalis in cases of epididymitis. It is said to be followed by a diminution of pain and hastening of resorption. The production of salt abscesses is another method recently de- vised, but one that cannot be recommended. This is produced by injecting a (5 to 8 c.c.) concentrated soltition of salt intramuscularly (30 parts sodium chlorid, 1 part calcium chlorid, 100 parts water) and was recommended by v. Szily and Stransky. Needless to state, in this case an abscess usually forms and from it autolytic products are absorbed; as Luithlin has pointed out, it is merely a form of the older "fixation abscess" of Fochier with the disadvantage that the method is very painful and leads frequently to complications. Raege and Zieler, who have both used the method, condemn it. THE NONSPECIFIC AGENTS 41 Sugar Solutions. — The use of sugar solutions (usually glucose) for intravenous injections in sepsis, in pneumonia and other infectious diseases has been repeatedly reported, with some evidence of clini- cal usefulness. There is usually a slight temperature reaction fol- lowing the injection and a leukocytosis of from 5,000 to 20,000. Audain and Masmonteil inject from 500 to 2,000 c.c. daily and re- port satisfactory results in sepsis, erysipelas and rheumatism. The isotonic solutions are made up as follows: For glucose 47.6 p.m., for saccharose 103.5 p.m., for lactose 108.9 p.m. The use of sugar injections in the treatment of tuberculosis led Hasenbein to suggest sugar injections to produce focal reactions in general. He used a 50% solution of cane sugar in doses of from 3 to 5 c.c. to which was added 1 c.c. of a 2% solution of novocain (in- tramuscular injection). In females suffering from gonorrhea there was a typical focal reaction with first an increased secretion, fol- lowed later by a diminution. Distilled Water. — Reactions have been reported from distilled water when injected in relatively large amounts intravenously. Formalin. — Torry, working with acute and chronic rheumatism, has injected formaldehyd intravenously to produce the shock re- action. The toxic agent which brings about the reaction according to Torry is probably a formaldehyd-protein compound. The dosage is as follows: Formalin is used (37% solution of formaldehyd) and of this from 1.5 to 3 c.c. are injected after diluting in from 200 to 300 c.c. of physiological salt solution. Diuing the administration there is some bronchial irritation and lacrimation. After the injection a typical protein shock reaction occurs in about half an hour's time, i.e., chill, fever, sweating, etc. Solusin.— From Szily's laboratory another chemical mixture has been published, interesting rather than useful. This consists of 1.4 parts of bichlorid of mercury, 0.5 part sodium arsenate, 24 parts of sodium iodid and distilled water 100 parts. Of this mixture from 1 to 2 c.c. are injected and the patient is said to react with a typical chill, fever, sweating, etc. Ammoniacal copper sulphate in a 4% solution has been used by Noire for intravenous injection in puerperal infections. Hetol, the sodium salt of cinnamic acid. Sodium Succinate, Suc- cinimid, Levurine and Tylmarin, Formic Acid (Krull) , to mention but a few of the drugs that have been used as nonspecific stimulants, are all characterized by a leukocytosis following their injection. The use of the active toxic agent of Bee stings and Snake Venom has been reported for a number of diseases, the former with par- ticular success by Terc and Langer in the treatment of arthritis. lodids.— A discussion of the probable mechanism of the therapeutic effect of the iodids migbt be of value in this connection, but inasmuch as 42 PROTEIN THERAPY the subject should be treated together with a number of related chemical problems in an extended manner, the present treatise will not offer a suitable opportunity. Jobling and Petersen have discussed some of the features in a paper published in the Archives of Internal Medicine, where the litera- ture will be found. It seems very probable that the iodids play a con- siderable role in the stimulation of tissue, particularly in the enzyme phenomena. Sherrick's and Solhnann's interesting observations on the alteration of the reactivity of the skin to cutaneous injections, the reaction of tuberculous patients (Petersen) and of carcinoma patients (Moresowa) are but a few instances of this effect. The property of the iodids in in- creasing the rate of diffusion of a number of substances in colloidal systems evidently is closely related to their therapeutic effect. Turpentine. — The use of turpentine for subcutaneous injections is an old procedure that in a modified form has been very recently re- introduced in the treatment of skin diseases and inflammatory con- ditions. Fochier in the early nineties had introduced the "Fixation Abscess" as it was termed, produced by injecting about 1 c.c. of tur- pentine subcutaneously and intramuscularly. The abscess was used in certain acute infections, including pneumonia, puerperal fevers, adnexal inflammation, etc. In many ways this was merely the re- introduction of the very ancient method of producing an "issue" by the use of seton or fontanelle. More recently the French and German clinicians have modified this method and are now injecting minute quantities of turpentine (20% of turpentine in olive oil) intramuscularly in frequently re- peated doses. The mechanism involved is merely the production of a multitude of small sterile areas of inflammation and necrosis, with tissue stimulation from these foci. It is said to be used with suc- cess in a number of skin diseases and the French observers have used it extensively in the treatment of influenzal pneumonia, etc. According to Karo the turpentine mixture in olive oil — 4 parts in 16 parts of olive oil — is borne much better if one adds a sedative such as eukupine. This lessens the pain at the site of injection. Naturally care must be taken to avoid the subcutaneous tissues and inject wholly intramuscularly. Karo has more recently recommended the use of "Terpichin." This is absolutely free from rosins and oxids and is combined with quinin which seems to increase its activity. The injections which are similar to those of turpentine — intragluteal and usually biweekly — are followed by a well marked general stimulation of the patient as well as a leukocytosis. Antipyretics. — The nonspecific effect — plasmaactivation — that re- sults from the use of certain drugs has recently been studied by Koniger. He has come to the conclusion that the antipyretics have such an effect quite apart from the usual pharmacological effect here- tofore studied, an effect which can be demonstrated if the dosage THE NONSPECIFIC AGENTS 43 IS given in proper intervals. The effect is diphasic, as with all other nonspecific agents. Yeast. — The use of yeast is an ancient one in therapy. Hippocrates is supposed to have applied it in the treatment of leukorrhea ; during the Middle Ages it is said to have been prescribed in plague; it was not until the middle of the last century, however, that it was used on a larger scale (Mosse) and since then its popularity has gone through several cycles of advance and of decline. In furunculosis, in anthrax, in diabetes, in suppurative processes, in diseases of the gastro-intestinal tract, in arthritis, and in sepsis it found many ad- herents during the earlier revival but by the end of the century it had again practically vanished as a therapeutic measure. Brocq revived its use in 1899. In the period from 1900 to 1907 a great number of clinical reports were published, together with some ex- perimental data (Lardier, Krause, Hedrich) ; more recently Hawk and his associates have published a series of cases, chiefly acne, (vul- garis and rosacea) and furunculosis, in which excellent results were obtained by yeast therapy. Besides the skin diseases. Hawk and his coworkers reported favorable results in acute bronchitis, urethritis, conjunctivitis, arthritis deformans, etc. In all of these conditions it is reported that, apart from any influence on the local pathological con- dition, the general nutrition of the patient was improved. Even when given via the intestinal tract there is evidence of a stimulating ef- fect of the yeast in the leukocytosis which is demonstrable after its use. Recently Wolf and Lewis have endeavored to establish some basis for the therapeutic use of yeast by investigating whether the inges- tion of yeast would in any way influence the antibody titer of the serum of experimental animals. Their results were negative. Light Rays — ^Roentgen Rays — ^Radium — Photodynamic Agents. — These agents may in some measure bring about a systematic re- action on the part of the patient, depending on the dosage, the organ or the pathological tissue irradiated and the amount of necrosis already present or produced by the agents under consideration. All these agents first stimulate tissue .cells, later with prolonged exposure, cause the death of the cell. In both cases substances enter the blood stream that cause a general reaction on the part of the patient; this may be mild in character, may cause a severe febrile reaction, or even complete shock with lowered blood pressure, prostration, and even death. After the moderate reactions of this type, if the patient is in fairly good condition and able to respond, a definite euphoria, an im- provement of the appetite, nutrition and general well-being may set in, just as after other nonspecific agents. In this category must be placed the effect of heliotherapy in the treatment of tuberculosis and other chronic infections, the effect of 44 PROTEIN THERAPY remote Roentgen irradiation on asthma (Schilling-Drey and Lesser, etc.), on the hastening of ossification (Stettner), on furunculosis (Schrews), on local inflammatory processes (Kaznelson and St. Lo- rent) , the effect of radium on arthritis, gout, adnexal inflammation, etc. (Gudzent) . The shock following actual bums or that following the effect of photodynamic agents such as those introduced and studied by von Tappeiner, has its place in this same category. (Pfeiffer.) Biological Alterations. — ^As will be pointed out more fully in the chapter on The Focal Reaction, it is very probable that a variety of alterations in the organism may bring about effects on pathological processes similar to those that we induce artifically with nonspecific injections. The menstrual cycle and pregnancy, chilling, prolonged exercise, intoxication arising from faulty gastrointestinal absorption, starvation, even endocrine disturbance and the effect of nervous excita- tion must be considered from this point of view. In a like manner the products of an inflammatory reaction in one tissue may bring about a nonspecific reaction of the entire organism and so alter pathological processes elsewhere. A number of dermatol- ogists have called attention to this possibility in connection with the clinical observation that in extensive luetic or tuberculous lesions of the skin the internal organs are apt to be relatively free from dis- ease. The discussion of these problems will be taken up in a later chapter. Depression Inmniiiity. — Even acute diseases are profoundly altered by shock effects due to intercurrent conditions. Thus the malarial paroxysm will in the typhoid patient frequently bring about either a temporary or permanent detoxication (Zupnik, v. Miiller and Leiner), and v. Jauregg has even inoculated patients with malarial plasmodia (in cases of paresis) as a therapeutic measure. The acceleration of wound healing after ery- sipelas (Goebel), or the effect of erysipelas on tumor growth, the effect of pregnancy on tumor growth (Slye) are all related phenomena. Morgen- roth, Biberstein and Schnitzer have recently studied immunity conditions bearing on this problem v^hieh can only briefly be outlined at this time. They have been experimenting with superinfection or superimposed infec- tion, as this field of investigation has thus far resisted any attempts to harmonize its findings with the prevailing theories in regard to immunity, and as experimental studies in this field seemed to promise good results. They started with the commonly accepted theory that the infected organism acquires an immunity against superinfection, and against a like, super- imposed infection, but they became interested in the investigations of Land- steiner and Finger, who maintain that the organism infected with syphilis is by no means immune to a new syphilitic infection, as has been commonly supposed. Their experiments demonstrated that mice with an experi- mental, chronic streptococcus infection, streptococci being found in the blood and in the organs, possess immunity toward a superinfection with THE NONSPECIFIC AGENTS 45 streptococci, as is shown by the fact that when given a streptococcus dose, such as will kill normal animals within twenty-four hours, they show no change in their behavior. They are immune not only toward the strain of streptococcus with which they were primarily infected but also against foreign strains of streptococcus. However, this immunity is not absolute but relative, for it is broken down by a strain of especially high virulence, in which case the infection runs an acutely fatal course, as in the controls. This partial immunity does not lie in the fact that the superinfection does not "take"; on the contrary, the streptococci used for the superinfection appear in the blood and organs, and by the aid of especially "marked" strains could be shown to remain present for some time. The partial im- munity consists, therefore, merely in a depression of the virulence of the infection. This immunity was developed in from six to twenty-four hours after the experimental infection. It does not seem to have anything to do with anaphylaxis, but presents a new kind of immunity. They theorize that the passing of an acute infection into a chronic phase is conditioned by the development of this "depression immunity." The latter is not the result of the chronic infection, but every infection that is not rapidly fatal has its course determined by the depression immunity. Each phase of the infection is the result of the antagonism between the causal germ and the degree of depression immunity at the moment. This assumption throws light on natural immunity and all other forms of immunity which do not fit into the picture of immunity from antibody production. Otto Wiegand has recently contributed to the same subject and Berliner and Citron working with chicken cholera in guinea-pigs have confirmed the findings of Morgenroth and his associates. CHAPTER III THE NONSPECIFIC REACTION The ifitravenous injection of bacterial suspensions such as typhoid bacilli, colon bacilli or staphylococci, their intramuscular injection in larger dosage, the intravenous injection of bacterial or other protein split products such as proteoses ; of colloidal metals ; of distilled water or hypertonic salt solution; of various serums and antitoxins; the intra- muscular injection of milk or casein, the subcutaneous injection of nucleic acid or sodium nucleate, the production of sterile abscesses with minute injections of turpentine, are all followed by a reaction that varies from a mere stimulation of leukocytes, to mild febrile reactions, and to extreme shock pictures associated with profound vasomotor paralyses. The reaction varies with the substance used, its method of application and absorption, and its dosage; with the type of infection with which we are dealing; with the number of previous injections; with the physical condition of the patient; with the duration of the disease from which the patient is suffering; with the temperature of the patient at the time of the injection and other individual factors. We do not yet know how much of the reaction that we elicit is necessary to bring about the therapeutic effect that we seek to achieve. We know that some substances provoke fewer symptoms that are uncomfortable to the patient and yet seem quite as efficacious in their result. On the other hand some substances are followed with only a mild reaction and seem much less effective than the methods that are seemingly more drastic in their action and much more unpleasant for the patient. Certain of the agents always give a reaction in both normal m- dividuals and persons ill from disease and give a reaction in a rela- tively short period of time after the injection. Typhoid vaccine belongs in this category. The colon bacillus more often gives a de- layed reaction, while some of the protein split products such as the albumoses may produce a reaction in diseased individuals but not in a normal person when the same dosage is employed. Holler, while working with deutero-albumose in patients, tried its effect on himself over a period of over two weeks. In patients the intravenous in- jection of 1 c.c. of a 10% solution was invariably followed by a slight drop, then a rise in temperature of from 2 — 3° C, a chill, occasionally sweating, rarely 46 THE NONSPECIFIC REACTION 47 an urticaria, etc. When he injected it in himself these symptoms were entirely lacking. He gained in weight during the course of the injections. This in general has been our experience in normal individuals when we have injected small doses of secondary proteoses intravenously. The reaction on the part of the patient depends to a considerable degree on the amount of bacterial destruction that follows the injection or the amount of necrotic tissue involvement of the patient. Just how much of the nonspecific reaction is essential, whether the discomfort of the intravenous bacteriotherapy can be modified by using the protein split products without sacrificing any of the remark- able therapeutic effects that are at times achieved, is not to be de- termined at present but must be the subject of further clinical investi- gation. For purposes of orientation we have in the following pages described the reaction that follows the intravenous injection of typhoid bacilli in moderate dosage — 25 to 50 million organisms; not because it may be the ideal form of therapy of this type but because it is the reaction which is most familiar clinically and, because of the availability of the vaccine, the most easily obtained agent for ex- perimentation. It is practically impossible to ascertain beforehand, because of the varying individual factors, the degree of the reaction that will be produced. When, however, experience has been gained with a definite preparation and with a certain class of clinical material it is usually possible to gauge the results that are to be expected with some measure of exactitude. Needless to state it is an elemental precaution to begin with a small dose when undertaking a study of the effect on patients. The Chill. — Usually the first symptom that comes to the attention of the patient following the injection is a chill or rigor. This may set in as early as fifteen minutes after the intravenous injection of typhoid bacilli or a proteose solution, usually within 30 minutes, but may be delayed for several hours. When colon bacilli and some other organisms are used the chill may not be observed for several hours, in one of our cases not until 8 hours after the injection. With intramus- cular milk injections the rigor commences in from two to three hours. The degree of the reaction varies — ^there may be merely twitch- ing of the leg or arm muscles, or the chill or rigor may be quite general and severe and last from 20 minutes to an hour. Commonly this phase of the reaction begins to wear off in from one-half to three-quarters of an hour after its inception. During this time the patient may complain of actual sensation of chilling and demand extra covering and hot water-bottles; in other cases there is merely the muscular twitching and trembling with- out sensory disturbance. In the acute arthritides this phase of the reaction may be of considerable discomfort to the patient be- cause of the added motion and its resulting pain in the involved joints. 48 PROTEIN THERAPY The analgesic effect that follows shortly in the wake of the chill as a rule compensates for this short period of increased pain. The Temperature Curve.— The temperature reaction of the patient varies greatly with the vaccine or protein used, and even when one ad- heres to a single agent such as typhoid vaccine, differences in the age of the vaccine, the dosage, the strain of bacilli and the method of killing the bacteria when the vaccine is prepared, all have a definite effect on the reaction; and this apart from the individual variation that we meet on the part of the patient — variations that depend, as already men- tioned, on the disease, its duration, the previous temperature, previous injections, etc. With the subsidence of the chill or during its later stages the temperature of the patient has as a rule commenced to rise. In typical arthritic cases running a febrile course of from 100° F. to 101° F. the injection of typhoid vaccine will raise the temperature to about 103° F. or 104° F., the maximum increase being recorded in from three to four hours after the injection. With intramuscular milk injections the temperature maximum may not be reached until six or eight hours after the injection. As a rule the defervescence is more rapid with the intravenous injections, but even in the case of the milk injections the former level is reached within 24 hours. Subcutaneous nuclein injections are followed by a febrile reaction that begins later and recedes more slowly than observed with the other methods. Schmidt has classified the reactions following milk injections into 5 groups, according to the degree of febrile reaction of the patient following a uniform amount of milk intramuscularly injected. In the first group are the cases that react with 37° C. or under; in the second that react with 37° C. to 38° C. (98.6°-100° F.) ; in the third that react with 38° C. to 39° C. (100°-102° F.) ; in the fourth that react with 39° C. to 40° C. (102°-104° F.) ; in the fifth that react with 40° C. to 41° C. (104°-106° F.). Schmidt and Kaznelson worked chiefly with milk injections, using 10 e.c. injected intragluteally. The temperature rise occurred usually in from 6 to 8 hours and was at times accompanied by a chill (rather rare), more often by sweating, and some headache. The blood pressure was not altered. Herpes were seldom noted. The temperature increase at times persisted for from 24 to 48 hours. Among the five groups into which Schmidt and Kaznelson have classified their patients it will be of interest to observe some of the cases in the first three groups. They are as follows : Temperature under 37° C, Group I Carcinoma, 4 (98.6° F.) (Normal) Secondary Anemia, 1 Myotonia (Thomsen's Disease), 1 Diabetes, 2 Influenza, 1 THE NONSPECIFIC REACTION 49 37" C, to 38° C, Group II Hysteria, 1 (98.6°-100° F.) Achylia, 1 Icterus, 1 Acromegaly, 1 Chlorosis, 1 Posthemorrliagic Anemia, 2 Gonitis, 1 Polyarthritis, 3 Chronic Arthritis, 2 Carcinoma, 8 Diabetes, 3 Cholecystitis, 1 38° 0. to 39° C, Group DI Tuberculosis, 4 (100° to 102° F.) Gumma, Liver, 1 Hemophilia, 1 It is of peculiar interest to observe the relative resistance of the carci- noma cases of this series to temperature response following the injections (most of these were stomach and esophageal cases). The reactivity of the neoplasms varies greatly — some observers report rather violent reactions; others, such as Schmidt, believe that they are examples of decided resist- ance. It seems most probable that the reaction depends largely on the amount of necrosis present in the tumor, its vascularity and its ana- tomical position. Schmidt correlated this relative resistance to the milk injections with his previous observations concerning the relatively low "Infection Index" of carcinoma patients and their resistance to vaccines. Wetzel believes that the absence of a febrile reaction to parenteral injection of milk is not constant enough to aid in diagnosis, although it is occasionally conspicuous in diabetes and cancer. Schmidt noticed that the reaction was independent of the dosage to a considerable degree, although after one or more doses had been given, the reaction became less marked. It depended to a large degree on the individual, and the type of the disease. Thus in a normal person one can inject as much as 1 c.c. of a 10% solution of al- bumose without appreciable temperature reaction or constitutional effect of any nature. In an arthritic patient the same injection may raise the temperature two or three degrees; in a typhoid or tuberculous patient by as much as five degrees (F.). On the other hand, when the same dose is injected in a pneumonic patient who already has a high temperature (let us say 103° F.) the tempera- ture may not be increased, or may actually show a decline without any preliminary increase after the injection. Habetin, using 0.5 gm. of sodium nucleate subcutaneously in a series of some 60-odd patients ill with a variety of diseases, classified his reactions according to the system of Schmidt. It will be observed that the most marked pyrogenic effect is manifest in diseases involving hematopoietic organs and those in which definite 50 PROTEIN THERAPY foci of pathological tissue exist such as sarcoma, tuberculosis, etc. The degree of febrile reaction is independent to a considerable de- gree of the agent or the dosage; it depends on the infection and the state of the patient, i.e., on an individual factor. Malaria Tuberculosis Acute Arthritis Gonitis Multiple Sclerosis Diabetes Coxitis Banti's Disease Morbus Maculosis Werlhofii Typhoid Pernicious Anemia , Chlorosis Sarcoma Pyemia Endocarditis I II iii iV 2 5 4 4 2 4 1 2 3 6 1 1 3 3 1 1 1 1 1 1 3 1 2 1 1 1 1 1 Gow, who early employed heterovaccines, came finally to the use of the colon vaccine as being most dependable, other vaccines such as streptococcus, etc., being followed by little temperature effect. He noted the fact that the reaction varies greatly in different individuals, just as had Schmidt. A dose of 50 million might in one instance cause a severe reaction but little in another. For therapeutic result Gow concluded that a moderate reaction was essential. That the injection of bacteria would cause fever and that the reaction depended to some degree on the digestion of the bacteria was noted many years ago. (Gamaleia.) Eoux and Lepine had observed the pyrogenic ef- fect of the other protein substances before this, while Charrin and Euffer determined that the pyrogenic effect of the bacteria was thermostable, that is, they heated the bacterial emulsions to 110° C. and were still able to get the original pyrogenic effect on injection. The later studies of Buchner, Schittenhelm and Weichardt, of Fried- berger, Vaughan, etc., are of course well known. The Pulse. — Coincident with the temperature reaction the pulse is almost invariably increased to some extent, usually about 15 to 30 beats per minute. With the onset of the sweating the peripheral dilata- tion brings this down to almost the preinjection level. As a rule the quality of the pulse is not altered, and arrhythmia, if present before- hand, is not increased. Cyanosis is uncommon ; I have observed it only once following an injection of proteoses in a case of typhoid fever. In this case the cyanosis was a transient phenomenon and the patient THE NONSPECIFIC REACTION 61 went on to a complete recovery from his typhoid in two days. Cyanosis is but infrequently noted in the literature. Gow has re- cently studied the pulse rate in patients receiving peptone injec- tions intravenously. He finds that the higher the leukocytosis, the greater the rise in pulse frequency after injections. The increase in pulse rate in his cases varied from 5 to 20 beats per quarter minute. The pulse frequency returned to normal in from 3 to 5 minutes after the injections. With vaccines these effects are of course greatly delayed. The character of the pulse and its rate is of decided importance in de- termining which cases are suitable for injection. In typhoid a rapid pulse rate (over 100) is a contraindication to nonspecific therapy. Experimen- tally it has been shown that small doses of proteoses stimulate the heart muscle, the amplitude and the force of the beat being increased (Weichardt). In several cases of long-standing heart lesions associated with arthritis we have watched the size of the heart after nonspecific injections — both during the acute reaction and the defervescence. In these cases the left border went out about 1 cm. and returned to the preinjection size in from 24 to 48 hours. The patients showed no evidences whatever of any cardiac decompensation. Naturally only cardiac patients that were in good con- dition were selected for the injections. The Blood Pressure. — Scully was one of the first to undertake sys- tematic studies on the blood pressure of patients after typhoid vaccine injections. It is of course quite difiicult to obtain an accurate reading during the time that the patient has a chill, but enough observations have been recorded to indicate that there is a slight increase in blood pressure during this time. When the chill has subsided and the period of perspiration sets in, the blood pressure shows a progressive decline of from 10 to 25 mm., reaching a maximum in from 6 to 8 hours, and returning to the normal pressure within 24 hours. Considerable variation is noted, however, in individual cases, depending on the dosage, the agent used and the infection of the patient. When injections are given to a typhoid patient in the later stages of the illness, where evidence of an unstable vasomotor system fol- lowing the long continued toxemia is apparent, we have observed a vasomotor paralysis extending over a period of 48 hours and very refractory to stimulation. In one such case the systolic pressure sank to 55 mm. and remained very low for 24 hours. This patient had been running a very high typhoid temperature for 4 weeks with- out any evidence of improvement. Following the recovery from the injection his temperature remained normal and the patient made a complete recovery. A number of factors enter into the effect on the blood pressure. It has been noted for instance that the subcutaneous injection of relatively large doses of typhoid vaccine — Besredka or Vincent — during typhoid fever, while it has a much less apparent effect on the patient in fhe form of chill, fever and sweating, seems to be 52 PROTEIN THERAPY followed by far greater depressing effects on the cardiovascular system than the intravenous injection of small amounts of typhoid vaccine. After milk injections Miiller has observed a slight primary decrease, then an increase in the blood pressiure. While the effect on the blood pressure depends on individual fac- tors — ^the duration of the disease, the agent used, etc., the fall in the blood pressure which accompanies shock effects depends largely on a dilatation of the vascular bed in the splanchnic area. The peripheral dilatation which one can observe with the sweating of the patient does not produce the extreme drop in the blood pressure that the splanchnic engorgement does. Difierent animals respond to the injection of protein split products, peptone, histamin, etc., with difierent effects on the blood pressure, de- pending on which part of the vascular bed is subject to constriction, on stimulation of the vasomotor nerves, etc. The liver of camivora responds with a spasm of the capillaries with a resulting diminution of the blood sup- ply to the right heart and a lowering of the blood pressure. The primary ef- fect is followed by a dilatation. The liver of the herbivora is quite in- different, indicating a difference in innervation. The spasm of the arteri- oles of the portal area results in a passive filling of these vessels while in the lungs we have also a contraction of the arterial system with a re- sulting dilatation of the right heart, accompanied by a fall in pressure in the left heart and the general circulation. In discussing this mechanism Mantner and Pick call attention to the fact that the difference in the effect of the shock poisons in herbivora and camivora is easily explained by the differences in the behavior of the various capillary systems. Simonds has recently noted this same difference in the behavior of the musculature of the hepatic vein and has drawn conclusions similar to those of Mantner and Pick. Dale's conception of the mechanism does not quite follow that here presented. It becomes apparent from a consideration of the possible mechanism in the dog and the human after such shock effects why stimulants such as adrenalin are relatively ineffective while vasodilating agents such as caffein are said to be followed by more effect in the acute stage of shock depend- ing on such vasoconstriction of the hepatic vein and its branches. The possibility that other factors enter into the change in the blood pressure is by no means excluded, v. Behring laid great stress on the finding of thrombi in the capillaries of the lungs in acute anaphylactic shock and Hanzlik and Karsner have recently called attention to the fact that the intravenous injection of a number of colloids and typical non- specific agents may be followed by such changes in the finer capillaries. Sweating. — Shortly after the subsidence of the chill the patient may sweat profusely; in arthritic patients one finds this most fre- quently; typhoid and pneumonic patients are less apt to sweat after the injections, but may do so if the injection is followed by an in- crease in temperature and a critical fall. THE NONSPECIFIC REACTION 63 A number of observers have claimed that the mere production of a profuse perspiration will relieve arthritic symptoms and a variety of therapeutic procedures have been elaborated which have as their object the production of a sweat, either by applying ejcternal heat or the administration of a variety of drugs. There seems little doubt that many patients are relieved to some extent by such measures but there is almost invariably a recurrence of the symptoms after the sweating has stopped for 24 hours. The possible mechanism that is involved in any therapeutic stimulation of the skin such as occurs when the patient is sweated is discussed in the chapter on the relation of the skin to internal diseases. Nausea and Vomiting.— This is occasionally observed after rela- tively large doses of vaccines or after particularly toxic strains of bacteria. It is usually an indication that the dosage has been too large or that the patient is particularly sensitive. The entire gastro- intestinal tract will frequently show increased peristalsis. Palpable Spleen. — Gow has observed that the spleen may become palpable immediately after the reaction. Effect on Menstruation. — Lux has observed that the menstrual flow is augmented after nonspecific injections. Nervous Irritability. — Kling showed some years ago that during the period sensitization following on the injection of some protein parenterally the nervous irritability of the animal was considerably increased. Following nonspecific injections it has been found that a similar alteration takes place but the effect on the threshold of the nerve reaction is a diphasic one. There is for a short period following the injection a lowering of the threshold for nerve stimuli, clinically demonstrable by the increase in the pain, and the general hyperex- citability. This is followed by a period of lessened susceptibility to pain, somnolence, and the clinical manifestations of the marked euphoria which has been commented on by almost every one who has had experience with nonspecific therapy. Dollken, working with neuritides has observed a similar reaction in the local effect on nerve tissues. He found that after heterovaccine injections there would be a re- sponse on the part of the lesion either in a negative sense — increased pain, etc., or as a positive phase — analgesia and complete restitution to normal in some instances. Herpes and Urticaria. — Herpes has been observed to follow a num- ber of intravenous injections. We have noted a labial herpes after use of typhoid and colon vaccines (certain strains seem to be more prone to produce herpes than others). Auld has reported an occasional herpes after intravenous injection of colloidal metals. Gow has observed such eruptions after heterovaccination and they have also been reported after milk injections. Urticarial eruptions are not so common. We have observed one 54 PROTEIN THERAPY quite generalized rash in an arthritic patient that came on within three hours after the injection and had disappeared after 24 hours; other observers also report that skin manifestations are unconunon in their experience. Headache. — Headache of the frontal region is a common symptom following typhoid and colon vaccine injections, but is observed less frequently after milk and other substances. The headache is not as a rule of long duration, lasting usually not more than two or three hours after the chill. Delirium. — In diseases associated with marked intoxication, such as typhoid, typhus and erysipelas, the intravenous injection of non- specific agents may at times be followed by intensification of the disease manifestations and among them delirium may at times be ob- served. It is usually a very transient phenomenon that disappears as soon as the febrile reaction diminishes; only rarely does one observe any disorientation that persists past the reactive period following the injections. Care must of course be observed in excluding alcohol- ics from nonspecific injections, for such patients may develop a de- lirium tremens during the reaction which, once elicited, may lead to a fatal termination. Several such cases have come to our atten- tion. Glandular Activity. — ^Weichardt has carried out a number of ex- periments in which he has shown that the injection of moderate amounts of protein split products increase glandular activity. He demonstrated this in lactating goats as well as for the salivary glands of a number of animals. Dollken has reported an increased secretion of bile following milk injections. The question of the galactagogue effect of parenteral injections of milk, of interest to the pediatrician, has been the subject of con- siderable investigation, but has not been conclusively settled. Slawik, during the course of his work with nonspecific injections in infants, had occasion to inject several wet-nurses. Dunkan is said to have observed a galactagogue effect after the injection of milk parenterally in lactating women, but Slawik in his cases was not able to confirm this result. Lonne has published observations that indi- cate an increased secretion of milk after parenteral injections, but his conclusions have been criticized by Kirstein, although the latter does not deny the possibility of glandular activation. Nitrogen Metabolism. — ^The nitrogen balance shows considerable variation both experimentally and clinically following the parenteral introduction of the proteins and their split products. It is of course beyond the scope of this discussion to examine so-called specific dynamic effect of proteins in their general effect on the normal metab- olism after ingestion, although certain facts that have been derived from a study of this field indicate that there are fundamental differ- ences involved in the cellular reactivity incident to the digestion of THE NONSPECIFIC REACTION 65 proteins as contrasted to the absorption and metabolism of the car- bohydrates and fats. A number of years ago Italian observers noted that in normal animals the injections of small doses of toxins and of tuberculin were followed by an augmentation of the nitrogen metabolism (ex- cretion) followed by a period in which an excess of nitrogen was stored. Animals treated with small doses of tuberculin would gain in weight as contrasted to normal animals without injections. Much work has been done during the course of studies on anaphy- laxis, and inasmuch as this simulates the picture that we obtain in nonspecific therapy to a considerable degree, the results are not without interest in this connection. Schittenhelm and Weichardt noted the immediate increase in the nitrogen excretion in anaphylactic dogs after a shock. Thus one dog from a normal excretion of 1.88 gm. per day excreted 2.8, 3.3, 2.65, 2.41 the days following shock, amounts far in excess of the amount of protein injected to produce the shock. Segale noted the same effect and Manoiloff observed an increased excretion of nitrogen in rabbits despite the fact that the temperature had diminished. Hirsch and Leschke have studied the same subject in a very thorough manner. They found that with fairly large doses of an- aphylatoxin a negative nitrogen balance obtained, whereas smaller doses or mild shocks often led to a positive balance. They noticed that the excretion of nitrogen did not necessarily bear any direct relation to the temperature of the animal resulting from the vari- ous pyrogenic agents. Breed's studies are also of interest in this connection. In the patient the injection of the nonspecific agents with the re- sulting reaction is associated with an increase in the nitrogen ex- cretion just as such shocks are associated with an increased metabolism in animals. In a number of cases that we have followed the total nitrogen excretion of the urine increased from 20% to 30% above that excreted before the injection. After about two days the nitrogen excretion again reaches the normal and for a variable period after this time there exists in many patients a diminution in excretion. The Weight of the Patient. — Uddgren has followed the weight of a series of patients given intramuscular milk injections. This included 4 groups. In the first were included patients who received "market" milk, with rather severe temperature reactions. In the second were those who received alternating doses of either "sterile" or market milk. In the third group were those who received a series of injections of either the one or the other. In the fourth group were patients who received the "sterile" milk entirely. The results were as follows: I. Usually some increase of weight during course of injections. More often a slight decrease followed later by an increase. 56 PROTEIN THERAPY II. Well marked increase in weight. III. Usually slight decrease during first series of injections, later an increase. rV. Little if any alteration. In a few cases a well marked in- crease in weight. In this connection we must keep in mind the possibility that such changes in weight as here observed may be due to alterations in the water balance of the tissues, rather than an actual increase in tissue substance. Albuminuria. — ^According to all clinical observers the injections are not followed by any alterations in the urine that would indicate an ir- ritation of the kidney parenchyma. The only exception to this general statement is the effect that at times follows the intravenous injection of colloidal metals. With these it has been observed that after the subsidence of fever (in influenza) the injection may at times be fol- lowed by the reappearance of casts and some albumin in the urine if they had been present at the time of the acute illness. In this case the agent seems able to activate a low-grade inflammation which may still be present. Uddgren observed no kidney irritation in about 100 cases in- jected with milk. In only two cases was a trace of albumin noted after the injections and this was a purely transient phenomenon, v. Aaron, who examined the disposal of casein injected intravenously in animals, found that 58% of it was excreted through the urine, a fact that must be considered if traces of albumin are reported in the urine after milk injections. On the other hand, several observers (Dollken, Schmidt, etc.) have reported that when nonspecific injections are made during the course of an acute illness accompanied by albiuninuria and casts in the urine, the urinary findings clear up very promptly after the injections. Dollken noted this particularly in his patients ill with Weil's disease where a high-grade albiuninuria cleared up inmiediately after the injections. Diuresis. — Injections are frequently followed by a diuresis of some extent. Riedel has called attention to this fact. Permeability of the Blood Vessels. — ^Luithlen in 1912 studied the effect of the intravenous injection of various substances, such as serum, gelatin, starch, and crystalloids, on the course of the common skin re- actions and as a result of his preliminary work investigated the per- meability of the capillaries after such injections. His method consisted in injecting Ringer's solution into the abdominal cavity of rabbits, then following with the intravenous injection of the agents that he wished to study, then determining the permeability of the abdominal capillaries by injecting sodium iodid and also sodium ferrocyanid in- travenously and testing the rate at which these substances had entered THE NONSPECIFIC REACTION 57 into the fluid in the peritoneal cavity. The colloids depressed the rate; crystalloids increased the permeability when studied under these condi- tions. Similar studies were made by von den Velden. Siegert as well as Schmidt studied particularly the effect of pro- tein injections on the smaller vessels. They found that small doses increased the permeability, while large doses decreased the rate. The most recent studies are those of Starkenstein. These were carried out by producing corneal ulcers in rabbits and then observing the rate at which dyes (sodiiun fluorescin, etc.) would diffuse out at the site of the lesion after a variety of nonspecific injections. Apart from milk, albumoses and collargol he tried out a large number of drugs including quinin, atophan, salicylates, adrenalin, methylene blue, iodin, etc. According to his observation practically all these sub- stances were followed by a diminution of the permeability of the capillaries and he accounts for their antiphlogistic effect on this basis. From the effect noted on the lymph system and the experiments on the capillaries above described it seems very probable that the effect of the nonspecific injections is to increase the permeability of the capillaries for a short period and later to cause a definite lessen- ing of the permeability. The reaction and the direction of its maxi- mum effect will depend largely on the dosage employed and to some degree on the agent used. The Lymphagogue Effect. — It is well known that certain sub- stances, which Heidenhain classified as lymphagogues of the first class, among them peptone, egg albumin, tissue extracts, etc., cause a marked increase in the lymph flow, supposed to be derived largely from the liver (Starling) . This increased flow may continue a considerable time following such injection. Teague and McWilliams have recently ad- vanced the explanation that this lymphagogue effect is responsible for the therapeutic effect of protein injections in that the antibodies of the blood stream are forced into the lymph spaces and there destroy the in- vading organism. Davis and Petersen investigated this effect on the lymph flow, using large dogs in whom a lymph flstula was estab- lished at the thoracic duct and then injecting killed colon vaccine in- travenously to produce the shock effect. When necessary small doses of morphin were given. If the animals were injected too soon after the operation and before complete recovery had been made from the anesthetic, considerable resistance to the shock was manifest and the temperature reaction was delayed for several hours. Lymph Volume. — The increase in the rate of the flow of the lymph followed immediately upon the injection and in severe intoxications two periods of maximum flow occurred, the first immediately after the injection and persisting for from 20 to 30 minutes, the second after approximately 1 hour, the latter increase being continued over a longer period of time. When the intoxication was not so great the 58 PROTEIN THERAPY two-phase curve did not occur, the increase being less in extent but persisting for a longer period of time. (Fig. 1.) Concentration of the Lymph and Serum. — The concentration of the lymph proteins following the injection is considerably increased, as determined by the Kjeldahl method for total protein nitrogen, while the concentration of the nonprotein nitrogen may decrease. LYMPH FLOW 5M1NUTE TIME INTERVALS Fig. 1. — Volume of lymph flow following Bacillus coli vaccine injection. The Leukocytes. — Few of the changes following nonspecific ther- apy have received the study or attention that the leukocytic reaction has. The earliest workers with nonspecific methods of treatment fol- lowed the leukocytic picture with great care, particularly because some of the earlier methods — the fixation abscess, yeasts, nuclein injections, colloidal metals, etc. — were developed at a time when clinicians began to pay considerable attention to the leukocytic count. The role of the leukocyte in immune processes is by no means an exhausted field of research; indeed it is one that in many ways seems to offer an exceptionally attractive approach to innumerable problems still obscure. Nageli in his "Blutkrankheiten" surmised that a leukocytosis that resulted as an expression of an immune reaction on the pait of the bone marrow might be of decided therapeutic use. Fiessinger and Marie have for many years emphasized the impor- tance of the enzymes of the leukocytes in infectious disease while the work of Metchnikoff and his pupils has so thoroughly covered the general field of phagocytosis that it will be unnecessary to enter THE NONSPECIFIC REACTION 59 into a subject that is so well known and the literature of which is so accessible. The discussions in Zinsser's "Infection and Resistance" give a comprehensive idea of the subject. The experimental production of a leukocytosis, and the study of the leukocytosis that is produced after the injection of a variety of substances of bacterial, protein or chemical derivation have been car- ried on for a considerable period and inasmuch as the results are quite comparable with those obtained in the human it may be well for a moment to consider the present status of our knowledge of the subject. The effect of the injection of bacteria and bacterial extracts on the leukocytes was studied experimentally by a large number of investigators. Lange, injecting typhoid bacilli in rabbits, noted that after large doses there was an immediate leukopenia that was later followed by a recovery and a leukocytosis, in one of his cases going to 43,900. Polymorphonuclears were found to predominate, with transitional and large mononuclear cells appearing later. He observed the presence of normoblasts as well as a polychromatophilia ; myelocytes were also noted. Goldscheider and Jacob using staphylococci observed a similar reaction, although the re- active leukocytosis did not reach the extreme degree that Lange found. Schlesinger using streptococci could only determine a leukopenia. When typhoid bacilli were used for a repeated series of injections Hirschfeld found that the bone marrow became atrophic. Studer studied the effect of typhoid and coli toxin on the leukocytes and Priedlander using staphylo- cocci observed that with these organisms he obtained a maximum leu- kocytosis with relatively no leukopenia preceding it. Samson-Himmel- stjerna, one of the earlier observers, noted a leukopenia after peptone in- jections. Andrews found that the colon bacillus produced the greatest leu- kopenia in rabbits, staphylococci and diphtheroid bacilli less than colon bacilli. He was of the opinion that in immunized animals there was a more pronounced reactive leukocytosis than in normal animals. Gay and Claypole in their work on the mechanism of recovery in typhoid fever reported studies which seemed to support the contention that in immunized animals the leukocytic response on reinjection was greater than in normal animals and that this was a specific reaction. Mc Williams was not able to confirm these findings. It is very probable that as a re- sult of sensitization the whole organism becomes more responsive and will react more readily and more intensely to a reinjection, but recent work such as that of Bieling would rather indicate that to a considerable degree it is immaterial what the agent is which is injected, as long as it has an irritant or stimulating effect. Schittenhelm, Weichardt and Greisshammer went over this phase of the reaction of animals to bacterial and other proteins and came to the following conclusions : The intravenous injection of native protein, peptone and bacterial pro- tein causes in the dog an immediate leukopenia depending not only on the size of the dose but on the character of the agent. Native protein pro- 60 PROTEIN THERAPY duces sueli a leukopenia only after sensitization, peptone witli tte first injection. Among the bacterial agents the typhoid bacillus when injected produces the most persistent leukopenia ; some varieties of tuberculin, colon bacilli and staphylococci also have the same effect. On reinjection the leukopenia becomes less marked in degree and duration. The authors sug- gest that this effect is due to a functional paralysis or depression of the bone marrow. It is probable that in a great part the peripheral leukopenia so observed is due to the accumulation of the leukocytes in the internal organs — spleen, liver, etc. If the injected dose is too large the animal of course dies in this shock or depression stage. The stage of leukopenia is followed by one of leukocytosis which per- sists for from three to six days ; the degree of the reaction is diminished on further injections. Of the bacterial injections typhoid and staphylococci produce the most marked leukocytosis. This reactive leukocytosis that follows is of myeloid type — ^that is, of neutrophile polymorphonuclears, large mononuclears and transitional types. Eosinophils are at times also increased. The lymphatic apparatus is rela- tively passive. The protein split products and the bacterial proteins also stimidate the hematopoietic system, as indicated by the appearance of normoblasts, meg- aloblasts and polychromatic reds in the days following the injection. Two or more factors enter into these changes that have been observed in the relation of the leukocytes after nonspecific injections. The leuko- penia that foUows immediately is due to an accumulation of the leukocytes in the internal organs — lungs, spleen, liver, gastrointestinal tract and the bone marrow. Dale is inclined to the belief that because of changes in the intima of the capillaries and smaller vessels the leukocytes tend to adhere to the walls and therefore do not appear in the circulating blood. The leukocytosis that foUows the leukopenia is a reactive phenomenon due to a stimulation of the bone marrow. Andrews followed the Arneth count and found that the neutrophils with undivided nuclei outnumbered the divided ones. The presence of bone marrow cells of various types after the reaction was further evidence of the stimuJation of the marrow. During the height of the reaction the leukocytes are more actively phagocytic than normally, the ingestion of erythrocytes by the polymorpho- nuclear leukocytes being observed after typhoid injection. That a leukocytosis followed the subcutaneous injection of nu- cleins was noted when they were introduced about thirty years ago; Bauer studied the leukocytosis that followed the fixation abscess and a similar reaction on the part of the leukocytes was observed to some degree after serum injections, after the intravenous injection of colloidal metals, following autoserotherapy, etc. With the development of nonspecific therapy and the endeavor to find a satisfactory theoretical basis for the therapeutic results obtained, a number of investigators naturally turned to the study of the leukocytic reaction and its possible bearing on the problem. Some believe that the chief factor in the therapeutic result lies in the leukocytic stimulation, others see merely an accessory factor in THE NONSPECIFIC REACTION 61 the leukocytic response, still others deny the leukocyte any role in the mechanism of recovery by nonspecific methods. The problem is one of considerable importance and it may be well to consider the facts that have been reported. Scully studied the leukocytosis in some detail. In his arthritic cases treated with typhoid vaccine injected intravenously, the injec- tion was first followed by a leukopenia (the leukocytes dropping from an average of 14,000 to about 5,000) , following this the process would be reversed and a leukocytosis make its appearance. This would frequently reach 30,000 or 40,000; in one case the count was 62,000. When subsequent injections were made the reaction was usually less marked. In the primary leukopenia Scully found that the absolute number of polymorphonuclear leukocytes decreased, rising later from the nor- mal of about 60% to over 90% of the total. Scully found that the large mononuclears were decreased during the first three hours, but after that again maintained their normal proportion. The lym- phocytes were relatively and absolutely decreased, as were the eosino- philes, although these latter at times showed a slight increase later. Rohonyi found that the leukocytes increased following typhoid vac- cine injections but that the leukocytosis bore no relation to the thera- peutic effect obtained. He also noted that there was some increase in eosinophiles. Gow also studied the blood cytology in the cases that he treated with heterovaccines and peptone injections. He ob- served the primary leukopenia which involved all elements and noted that after one hour the polymorphonuclear leukocytes still outnum- bered the lymphocytes but that from that time on the young forms of neutrophils became more abundant (the neutrophils with un- divided nuclei outnumbered those with divided nuclei). After 72 hours he was of the impression that preinjection conditions were re- stored. During the height of the leukocytic reaction his counts averaged from 20,000 to 30,000 and myelocytes and normoblasts were to be observed. Holler and Weiss studied the leukocytosis that was to be ob- served after milk injections, as did also Schmidt and Kaznelson. The latter observers found a very slight increase in the eosinophiles after the first stages of the reaction had subsided. Their observations on the lymphocytes would lead one to believe that the effect on these blood elements was more protracted than Gow's observations would indicate. They state that they were increased over the normal for a period of several days after the polymorphonuclear leukocytes had reached preinjection figures. Schmidt and Kaznelson have grouped the leukocytic reaction that follows parenteral milk injection into three classes. They observed first a group in which a primary leukopenia was followed by a leu- kocytosis consisting largely of polymorphonuclear neutrophils. In 62 PROTEIN THERAPY a second group, in which a leukocytosis was already present (as in leukemias) the injection was followed by a decrease in the number of neutrophiles. In the third group the reaction consisted chiefly in an increase in the number of mononuclear elements. Miiller has emphasized particularly the myelocytic stimulation that is brought about by milk injections. While the lymphatic apparatus was practically unaffected, myelocytes were thrown into the circula- tion in abundance, indicating a marked stimulation of the bone mar- row. Recently Nagao has studied the cellular changes that follow the intravenous injection of killed nonhemolytic streptococci into guinea- pigs. Most of the cocci were taken up in leukocytes within five or ten minutes, and cocci could be found in circulating leukocytes for as long as three hours. The cocci and polymorphonuclear leu- kocytes accumulate in the lungs during the first ten minutes, and it is here that most of the cocci reach the interior of the phagocytes. At the same time there is a general leukopenia, and the polymorphonuclear leukocytes of the spleen are reduced to about one-fourth the nor- mal number. There is a similar reduction of such leukocytes in the bone marrow. After thirty minutes the lungs are nearly normal, the number of leukocytes in the blood may be normal or increased, and there is a beginning accumulation of the leukocytes in the liver and spleen. There is also a marked proliferation of the endothelial cells of the liver and spleen, and of the leukocytes of the bone mar- row. In from two to three hours there is a marked accumulation of leukocytes with ingested cocci in the liver and spleen, the number of leukocytes in the blood is increased, and immature leukocytes ap- pear in the blood and bone marrow, indicating an exhaustion of the leukocyte-forming power of the marrow. It is suggested by Nagao that the reaction of a patient to vaccine treatment may be deter- mined in some degree by frequent examination of the blood, the ap- pearance in it of immature leukocytes indicating danger of exhaustion of leukocytogenic centers in the marrow and elsewhere. Cowie and Calhoun in this country made a detailed study of the leukocytic reaction following intravenous typhoid injections. They observed the primary leukopenia and found that the maximum re- action took place between the 4th and the 9th hour after the in- jection, their leukocyte counts then ranging about 30,000. The poly- morphonuclear cells which appeared were new cells with large nuclei. Large lymphocytes frequently disappeared at some time following the injection. The small lymphocytes never wholly disappeared although they were greatly decreased, in one case to 200 cells per c.mm. The transitional cells were usually below normal in number while the eosinophils were not increased. They observed the appearance of great numbers of myelocytes which were to be found sometimes within THE NONSPECIFIC REACTION 63 one-half hour after the injection and in one case reached the total of 800 cells per c.mm. Among these basophiles were frequently ob- served. Nucleated red cells, both megaloblasts and normoblasts, were also observed. Tiirck irritation forms were also noted (acidophile granular lymphocyte forms) and irregular small lymphocytes. Cowie and Calhoun consider that the leukopenia is due to an emigration of the leukocytes to the internal organs. According to their observa- tion they obtained the most satisfactory clinical results in those patients that responded best with a high leukocytosis. Holler, on the other hand, does not consider a leukocytosis an essential factor in the therapeutic result. Liidke as well as Holler noted a slight eosinophilia after the albumose injections. Other nonspecific agents produce a leukocytosis of varying degree and studies have been made on the blood cytology following in- jections of serum, nucleins, colloidal metals, salt solution, turpentine, iodids and a number of related substances. (Pfenninger; Hammett, Kessler and Browning; Paaschen; Fiessinger and Marie, etc.) Miiller considers that digestion leukocytosis represents merely the leukocytic reaction to the protein split products absorbed dur- ing the course of digestion. The Erythrocytes. — Schittenhelm, Weichardt and Griessheimer ob- served the erythropoietic irritation that followed a variety of bacterial injections, just as other observers before them had noted the presence of many nucleated red cells after such intravenous injections. Clinic- ally it has been observed that the red count is increased after non- specific injections in anemia; in pernicious anemia the increase is as a rule transient and uncertain. Platelets. — Duke has observed that small doses of typhoid vaccine increase the number of blood platelets while larger doses cause a diminution in the number. Cowie and Calhoun report that the platelets after typhoid injection increase in number and size. Dollken, on the other hand, found no constant alteration in the platelets after milk in- jections although he found a decided styptic effect from such injections in cases of hemorrhagic diathesis. He concluded from his observa- tions that the platelets were probably not concerned in the altera- tion in the coagulation rate. Blood Sugar. — Lowy observed a very prompt increase in the amount of blood sugar following nonspecific injections. (Milk.) Fibrinogen. — The amount of fibrinogen in the blood is increased in about 6 hours after milk injection and remains at a high level for a period of about 8 days. (Lowy, von der Velden.) Moll ob- served the increase in fibrinogen after the injection of gelatin and serum. Thrombokinase. — Thrombokinase is increased very shortly after milk injections. Deutero-albumoses, bacteria and colloidal metals have little effect on the coagulation mechanism. 64 PROTEIN THERAPY Serum and Lymph Enzymes. — During the course of a series of studies on the alterations in serum enzymes in animals after anaphy- lactic shock, after the intravenous injection of protein split products, of bacteria, of kaolin, of trypsin, etc., Jobling and his associates estab- lished the fact that as a result of these various injections the animal responded with a mobilization of proteolytic enzymes as well as of lipases. Diastase was not altered to the extent that the other enzymes were changed. The increase in the titer of the protease was very strik- ing after severe intoxications such as those produced by typhoid or colon bacilli. In view of the fact that the flow of the lymph is markedly augmented and dilutes the blood and that the blood volume is greatly diminished after shock because of the increased permeability of the vessels (Dale has re- cently observed a diminution of the volume by as much as 40% after his- tamin injection), Davis and Petersen studied the enzymes of the blood and lymph separately after intravenous injection of colon vaccine. The results of these experiments were as follows : Protease. — The effect of the bacterial shock on the protease content of the lymph and serum was marked in extent. Three types of reaction could be distinguished: (a) the fluctuations in titer may occur simultaneously, (b) those of serum may precede those of the lymph, and flnally (c) there may be no relation of the one to the other. Peptidase. — The fluctuations of the peptidase, or ereptase titer, do not parallel those of the protease; indeed the curves may be quite dissimilar. As a rule the increase makes its appearance later than that of the protease and is less extensive. When alterations in titer do occur they appear almost simultaneously in both the lymph and serum, although in a few experiments the ferment was first to be observed in the serum. It is at any rate apparent that the entrance into the blood stream can be direct and does not need to take place via the lymph channels, although under normal conditions, i.e., feeding, this seems to be the one portal of entry. Lipase. — While the increase in this ferment occurs in both lymph and blood following shock, it seems to make its appearance first in the serum. In the patient the effects of nonspecific injections on the enzymes are not as marked as they are in experimental animals. In a study of serum alterations in patients after nonspecific therapy, Petersen followed the changes to be observed in (a) the stalagmometric read- ings, in (b) the total nitrogen of the serum (concentration of the serum), (c) the noncoagulable nitrogen, and the titer of the enzymes, (d) protease, (e) ereptase, (f) diastase and (g) esterase, The results were as follows: (a) There was a concentration of the serum. (b) The nonprotein nitrogen was practically unaltered. (c) The serum protease almost invariably decreased after the shock but later increased progressively for a period of from three to four days. THE NONSPECIFIC REACTION 65 (d) Tte serum peptidase usually increased in the cases tliat responded with clinical improvement. (e) The diastatic activity of the serum usually diminished. (f) The lipolytic activity of the serum showed no constant alteration. 1 O-^ ^ + - - 60 .. _ ., \ ^' "" * bo . . / / 1 1 zo _L ._ B 6b \ bo .1 /\ 4o __ " ' / ^^ \\ ^ 20- _ _|_ \ C 1 8o . <>0 .. ^ ^ < 4o .1 V"'" ' "^-L^^ " Zo 1 11 H 11 n iM 'yir\ 1 EiG. 2.— Changes in antiferment titer following protein shock. X indicates injection. 66 PROTEIN THERAPY The Antiferment. — In the course of studies undertaken seyeral years ago Jobling and Petersen presented evidence that seemed to indicate very strongly that the anti-enzyme (antitrypsin) of the serum consisted of the finely dispersed lipoids which contained imsaturated carbon bonds in their chemical structure. More recent research has in general confirmed the view that the antienzyme is lipotropic and not related to the proteins although it may physically be closely bound to some of these serum constituents. In animal experimentation Jobling and Petersen determined that there was an increase in the antiferment after practically every form of shock to which the animal was subjected — anaphylactic, bac- terial, protein, etc. Clinically it had been observed that the anti- ferment was increased in cachexia, during acute febrile diseases, in pregnancy, after vaccine injection, serum sickness, etc. In the patient injected with vaccines intravenously the fluctua- tion in the antiferment titer were followed by Petersen and the types of reaction are illustrated in the accompanying chart (Fig. 2) . "The changes in the antiferment of the blood serum are usually well marked and quite uniform in the eases that react favorably to the stock therapy. Chart A illustrates the changes taking place for a three-day period of observation in a case with complete recovery from an acute arthritis following intravenous injection of 60 mg. of a primary proteose The persistence of the increased antiferment titer may be much less in duration, as shown in the Chart B. This case, K. H., was one of multiple subacute arthritis which did not improve to any marked extent after in- jection of typhoid vaccines, although there was temporary relief. "rinally, the cases that show no permanent improvement seldom show any increase in the antiferment, indeed almost always present a decrease in the titer follovring the shock, as illustrated in the third and fourth charts, C and D." Antibodies. — ^With the introduction of modern methods of nonspe- cific therapy immunologists turned naturally to an investigation whether or not the therapeutic effect of the injections might not be due to some alteration in the antibody titer of the serum of the patient. As a matter of fact the effort to increase antibody production by stimu- lating the organism in a variety of ways is by no means a recent subject of experimentation. Thus Solomonsen and Madsen found that if horses were immunized with diphtheria toxin and then in- jected with pilocarpin the titer was much higher than before the pilocarpin injections. Obermeier and Pick, using 5% and 10% pep- tone solution for injection, found that animals sensitized three months previously responded with a marked increase in precipitins after the injections. Dieudonne immunized rabbits with typhoid bacilli and then injected hetol and observed a decided increase in the antibody titer. Similar observations have been recorded for nucleins, for colloidal metals and for paraspecific serum injections. THE NONSPECIFIC REACTION 67 Hektoen, working with rabbits sensitized long before to horse serum, found that when at a subsequent period the same animals were injected with some other variety of serum, the animals again yielded the specific horse agglutinin first formed. This flushing out of a specific antibody under the stimulus of some other and quite differ- ent protein has been suggested as a basis of the therapeutic effect of nonspecific therapy. Thus Miiller and Weiss thought that this was the explanation of their results in the treatment of gonorrheal complications with gon- ococcus and other vaccine, but serological tests failed to confirm this view. Ichikawa assumed the same basis for his experiments in typhoid. Experimentally the results of Conradi and Bieling, and Bieling deserve much interest in this connection, indeed the facts brought out in Bieling's recent paper would seem to have a direct bearing on a number of important questions in infectious diseases. Conradi and Bieling treated rabbits with typhoid bacilli and determined the titer of agglutinin. They then injected colon, dysentery and diph- theria bacilli and observed the same increase in agglutinins that has been described in Hektoen's paper. Bieling has continued these experiments and has found that animals sensitized to dysentery are able to form antibodies against typhoid bacilli when only minute doses of typhoid antigen are injected into them. The sensitized ani- mals can elaborate specific antibodies when only a minute fraction of the amount of the new antigen that would be required in a normal animal is injected. In other words, the first immunization leaves the animal in a state of nonspecific hypersensitiveness during which it is much more reactive to stimuli of all kinds. The results of these experiments which have been confirmed and extended by Pinner and IvanCevic have their direct bearing on the problem under consideration and aid in explaining some of the di- vergent observations that have been recorded by clinicians after non- specific injections. We may expect that if injections are made in patients who have been previously immunized that they will respond with an increase in the antibody titer of the serum; if they are in- jected during the course of a disease, antibodies which have been formed in the cells but not yet cast off may be "shed" as Larson has suggested, and we may then determine an increase in the serum. On the other hand, if they have been thrown into the circulation during the course of a disease as rapidly as formed, we cannot expect any increase in the titer. We may also assume that with the stimulation of the cellular activity ("plasmaactivation") the cells will respond by producing an increased amount of antibodies if they are still capable of such response. Baluit found that in typhoid patients injected intravenously with typhoid vaccine, there was no definite alteration in the antibodies 68 PROTEIN THERAPY unless perhaps an increase in the opsonins. The agglutinins and bactericidal substances were not increased. Lijdke found the complement somewhat decreased but found that there was no consistent increase in antibodies, v. Groer as well as Svestka and Marek observed no increase in agglutinins after the injection of "typhin" in typhoid patients. Dollken, using milk, noted that the injections did not alter the titer of dysentery agglutinins in patients ill from dysentery. When he used a specific vaccine he did observe an increase of these antibodies, but clinically there was no difference in the effect on the disease whether milk or specific vaccine was used. Reibmayr also found no changes in the agglutinins follow- ing the injection of typhoid vaccines. Flechseder, on the other hand, observed an increase in agglutinins after albumose injections in typhoid patients, while Parlavecchio found an increase in agglutinins and in complement after the injection of nucleins. Borchardt determined that organ extracts (adrenalin, spermin, thyroid, etc.) increased the agglutinin titer of experimental animals, in one case from a titer of 1:20 to 1:5120 and in another case from 1:1280 to 1:12,240. Culver's investigations are perhaps the most extensive in this field. The opsonins and bactericidal substances were studied in the serum of sixteen patients suffering from gonorrheal arthritis. An injection of killed gonococci or proteose solution was given intra- venously every seventy-two to ninety-six hours until three to five in- jections had been given. The serum was taken for study just before each injection. Ten of these patients received successive injections of proteose and six received killed gonococci. No marked difference was seen in the results of the two groups. His conclusions are as follows: "Primary and secondary proteose preparations stimulate antibody production or mobilization for spe- cific organisms in gonococcal arthritis, in a manner not to be dis- tinguished from that produced by the injection of the specific organisms themselves. "In gonococcal arthritis, there is either no change or a decrease in the antibody content of serum within the first twenty-four hours following an intravenous injection, in all excepting the first injection when the lytic substances seem to be slightly increased during this time. "In favorable cases the first injection usually causes the greatest clinical benefit. However, refractory patients may give a similar lysin increase during the first twenty-four hours following an injec- tion; hence the subjective and objective improvement in favorable cases cannot be unquestionably attributed to an increase in anti- bodies alone. However, little as these substances may have to do with the early relief of symptoms in gonococcal arthritis, it may be THE NONSPECIFIC REACTION 69 that they have considerable to do with the final recovery from the infection by their influence upon the primary focus." Culver observed that both the opsonic and bacteriolytic titers of the serum of patients suffering from gonococcal arthritis were normal or below normal before any injections were made. This has been previously observed by Irons and others for the opsonin content of serum from these patients. Irons also demonstrated that spontaneous fluctuations in antibody content occur in gonococcal arthritis and that by massage of the affected joints or the infected prostate there resulted an opsonin increase not altogether unlike that produced by an injection of killed gonococci. Culver believes that any antibody change which results from an injection of a sub- stance which produces a chill might well be explained by the motion of the affected parts during the chill. But since the curves regularly show an increase in lysin and a decrease in opsonin after the first injection and reaction, while each succeeding injection is usually fol- lowed directly by an antibody decrease regardless of the intensity of the reaction, it does not seem that the joint motion has much to do with it here. The above antibody changes occur in serum of patients with acute, subacute, or chronic joints with no appreciable difference between these classifications. Some serums were studied after a small amount of protein was injected, large enough to increase the leukocytes and temperature but not sufiicient to produce a rigor. These injections were followed by antibody changes not unlike those produced by the more severe reactions. The Effect on the Wassermann Reaction. — Uddgren found that following milk injections, Wassermann negative luetic patients fre- quently became Wassermann positive. Zeisl finds that gonorrheal patients after an injection of "Gonargin" or "Arthigon" may give a positive reaction. This observation is related to that of Strickler, Munson and Sidlick who found that after salvarsan injections non- syphilitic patients may become serologically positive. Conradi and Sklarek have also observed changes in the Wassermann reaction after intravenous injections of typhoid vaccine. CHAPTER IV THE FOCAL REACTION In the preceding chapter the changes that take place in the organism after nonspecific injections have been discussed in detail. We will now have to consider a related subject of utmost importance from the therapeutic as well as the theoretical standpoint, namely, the focal reaction that becomes evident about inflammatory foci after nonspecific injections. Just as the general symptomatology of the patient may be accentuated after the injections, so it has been ob- served that preexisting inflammatory lesions, endogenous or exogenous in origin, will very frequently become more acute, with an apparent increase in pain, tenderness and hyperemia. This increased reaction is usually followed by a diminution of the objective evidenc^ of inflammation until in many instances a complete restitution to the normal is brought about. In order to understand the possible sig- nificance and therapeutic importance of this phenomenon it will be necessary to briefly review our present conception of such focal re- actions. Ever since the tuberculins were introduced early in the nineties the concept of the focal reaction, the "Herd Reaktion," at the site of the inflammatory lesion has been so closely associated with the diagnostic and the therapeutic principles of the tuberculin as hypothe- cated by Koch that the field has been limited largely to a con- sideration of this particular disease. This view of the focal reaction, exemplified, let us say, in a local disease such as lupus or an apical involvement, needs no further elucidation. By some the term "local reaction" is, however, used synonymously; it should of course be reversed for those reactions that occur at the site of the injection of the tuberculins. By common consent we may assume that positive local and gen- eral reactions are regarded as corroborative evidence that at some time the organism has been infected with tubercle bacilli; to the focal reaction we generally attach greater significance in so far that the observation of the focal reaction following tuberculin injection is regarded as proof not only of infection but of activity as well. It is regarded as strictly specific in the sense that only tuberculous processes respond to tuberculin injections. On this assumption the 70 THE FOCAL REACTION 71 immunologists have elaborated theories to picture the processes go- ing on at the site of the reaction. According to Wassermann and Bruck the reaction takes place when the injected tuberculin joins with an "antituberculin" at the focus and the complement is bound by these two reacting bodies. The fixed complement is then able to "digest" the focal material and so cause the well-known lytic phenomena that we associate with focal activation. Wolff-Eisner and others have expressed the idea that all the tuberculin manifesta- tions are due to preformed specific "lysins." These break up the nontoxic tuberculin; only the tuberculin so altered can initiate the various reactions. The entire mechanism, according to the humoral views, depends on the presence of lysins— i.e., "much lysin — much reaction." As a matter of fact little or no evidence has been put forward to support this humoral theory, but, on the contrary, much convincing evidence discrediting it. No antibodies of the kind hypotheticated have been demonstrated. Nor does a parallelism exist between the local, focal and general reactions, such as would be predicated if the reaction were a humoral one. On the contrary, while a general reaction follows in the wake of a focal reaction, the local reaction is under these circumstances suppressed. But practically every clinical phenomenon has, nevertheless, been interpreted according to these theories with resulting confusion. One illustration will suffice. Menzer noted that tuberculous foci would respond with a typical "Herd Reaktion" after the injection of a streptococcus vaccine and that tuberculous patients would very frequently have a general reaction. From this he drew the conclusion that such reactions merely indicated that a secondary infection with streptococci had been imposed on the focus and that the evidences of reaction which he observed merely confirmed the specific concept. As a matter of fact it was through the demonstration of the focal or "Herd Reaktion" that the theory of specificity for the tuberculins gained wide credence. We fitted a theory to the observation and then proceeded to interpret every clinical observation in this or the related fields to conform to our theory. Reasoning in a vicious circle retarded the study of actual clinical conditions and particularly held back the proper recognition of certain factors in cellular resistance which are of great importance not only in tuberculosis but in in- flammation in general. Inasmuch as experience with tuberculosis is common to every physician, the consideration of the focal reaction in the tuberculous is perhaps of greatest interest and importance, but the problem is so closely bound up with inflammatory reactions in general that it may be permissible to include certain references to conditions of non- tuberculous origin in this discussion. 72 PROTEIN THERAPY Concerning the Specificity of Focal Reactions. — ^Perhaps the fact that the focal reaction is not a specific reaction must first be emphasized. Practically every inflammatory focus, irrespective of its etiology, will react (focal activation) to tuberculin as well as to a great variety of other agents, chemical or biological in character. Investigators in tuberculosis have long recognized the fact that the tuberculous lesion responds with a focal reaction to a variety of substances. Baldwin mentions nucleoprotein, nuclein, al- bumoses, cinnamic acid, cantharidin, pilocarpin. Fishberg adds potas- sium iodid and creosote. But the recognition that nontuberculous inflammatory foci will likewise respond to such agents has only been discussed in recent years. Perhaps the paper of Schmidt is of greatest value in this connection. Schmidt began his observations on the Poncet type of arthritis. This tuberculo-toxic form of disease exhibits a well-marked focal re- action following the injection of tuberculin — that is, the joint be- comes more painful, and swollen, there is an increased limitation of motion and the tissues become hyperemic. This stage is later fol- lowed by improvement in the clinical picture (the negative phase is followed by a positive one), the end results usually being an improvement over that obtaining before the tuberculin injec- tion. But Schmidt found that if instead of injecting tuberculin, milk was used, he obtained exactly the same reaction at the site of the lesion, during the same period of time, and with the same positive phase following in the wake of the reaction (i. e., a therapeutic effect) . Fur- ther, when he turned to nontuberculous joint lesions and injected minute doses (.001 gm.) of Old Tuberculin (relatively rich in nonspe- cific proteins) he obtained a similar focal reaction. Classification of Focal Reactions. — The German clinicians have gathered considerable data concerning the reactions that follow milk injections (used merely as a convenient nonspecific protein) and Schmidt has arranged the following groups in which there is a re- sponse with a typical focal reaction following milk (and other) injec- tions: I. Inflammatory foci of infectious origin. II. Localized inflammatory processes endogenous or traumatic in origin. m. Diatheses. I. Inflammatory Foci op iNFECTiotrs Origin. — Classified under the first group we include pulmonary foci of tuberculous origin. Schmidt and Kraus, Petersen, Holler, Dollken and others have called attention in recent papers to this phenomenon. Proteoses, iodids, milk, nucleins and other agents will bring about a focal re- THE FOCAL REACTION 73 action and a sharp general systemic reaction. Tuberculous foci in lymph glands, in the kidney and the genito-urinary tract and else- where respond in a similar manner. Closely related we find the effect on leprous lesions. Josephson describes the activation of a case of macular leprosy following the accidental injection of a relatively large intravenous dose of vaccine. Among the nontuberculous inflammatory foci can be included the tonsils which at times flare up after a nonspecific injection. Schmidt describes such a case in which a milk injection activated a latent angina with the coincident appearance of mild joint pains. Inflam- matory activation can be observed following milk injections in cases of furunculosis and in some instances more than the usual amount of constitutional reaction. Thus the normal diabetic does not react with a temperature rise to milk injections, but if suffering from furuncles will frequently do so. We also note arthropathies, the nega- tive phase of which, with its increased pain, swelling and limitation of motion, is not an uncommon clinical observation and has been fully discussed by a number of observers. Inflammatory foci in the ap- pendix and the gall-bladder, erysipelas, inflammatory lesions of the eye, inflammatory lesions of the respiratory tract, of the female adnexa and the male genito-urinary tract, etc., are also found. Schittenhelm observed that following the injection of typhoid vaccine old fistulas would show an increased amount of secretion; bronchiectatic patients would secrete more mucus ; chronic appendiceal lesions would become more painful and tender, etc. The activation of quiescent malarial foci has assumed diagnostic importance and will be more fully discussed. Papules of syphilitic origin react with an increased hyperemia just as do other inflamma- tory foci. In a general way one can make the statement that any circum- scribed inflammatory process irrespective of its bacterial etiology or its location will frequently light up with a typical focal reaction after a nonspecific injection and usually within 24 hours after the injection. Of these various processes tuberculous lesions are perhaps more sen- sitive because of a more profound sensitization of the tissue cells of the host against protein in general — as suggested by a recent dis- cussion by Wolff-Eisner. II. Localized Inflammatory Processes Endogenous or Trau- matic IN Origin. — In this category must be placed certain of the toxic forms of arthritis, such as the Poncet type, as well as gout. In- flammatory lesions of the kidney, and inflammatory lesions of the eye, including iritis, albuminuric retinitis, etc., are also among the local- ized processes. Healing fractures, such as Dollken has described, respond with a typical focal reaction. Neuritis is to be included in this group. 74 PROTEIN THERAPY III. Localized Lesions on a Basis of a Diathesis. — Using this term in the broader significance as defined by Pfaundler, the follow- ing conditions might be included: The lancinating pains of tabes which at times follow on nonspe- cific injections, as well as an occasional gastric crisis. In paresis the psychic state may be decidedly disturbed and the disease manifestations become more apparent following nonspecific injections. This is not an uncommon experience in the treatment of paresis as outlined by v. Jauregg. In epilepsy an attack may be inaugurated if a large dose of a nonspecific agent is administered (Adrenalin-Benedek) , just as in chronic alcoholics an attack of de- lirium tremens may follow such an injection. In this sense we may consider that a latent symptomatology may abruptly unfold its various manifestations following injections of protein. Activating Agents. — ^We must for a moment stop to consider the agents that are involved in eliciting this nonspecific reaction. Because of the early work in this field we commonly regard the nonspecific re- action as one that follows the intravenous injection of a vaccine — let us say typhoid vaccine, or such protein derivatives as proteoses, or more recently the use of milk (given intramuscularly). Not only do such injections bring about the reaction and the focal activation, but certain general biological alterations such as coincident but remote disease processes, metabolic alterations of endocrine origin, fatigue, in- testinal intoxication, blood-letting. Roentgen exposures, trauma, altera- tions in the skin, chilling, — counterirritation — as well as certain drugs bring about exactly the same focal alteration. The activation of a tuberculosis by an angina, a remote trauma, the menstrual cycle, by influenza or measles; the provocation of a malarial paroxysm (the result of a splenic focal activation) by an intercurrent disease, by prophylactic vaccination, by severe fatigue, long railroad journeys, overheating, exposure to intense light, chilling or drenching, dietery fault, alcoholic excess and the various other factors that the experi- ence of the war has brought to light; the focal reaction about latent arthritic lesions which Pemberton has described after irradiation, ra- dium, thyroid extract, excitement, etc.; the classical activation of gonorrheal processes by a variety of seemingly remote causes; the precipitation of lancinating pains or a tabetic crisis following a "cold"; the origin of a delirium tremens following a trauma; the onset of pellagrous symptoms after exposure to sunlight; these are but a few examples of a universal phenomenon heretofore com- monly observed but not recognized as having a common back- ground. It is very probable that many puzzling clinical manifestations ^njd unusual features of certain diseases may readily be explained THE FOCAL REACTION 75 and will appear in a very simple light if we keep in mind the basic idea that the particular symptom complex under study may be due solely to the activation of an inflammatory focus of exogenous or endogenous origin in the manner of the "Herd Reaktion." Many of the curious metabolic disturbances at times associated with dia- betes and nephritis can readily be accounted for on such a basis. Even pharmacological study reveals evidence of this same nonspe- cific effect on inflammatory lesions. Thus the commonly observed Jarisch-Herxheimer reaction (the flaring up of syphilitic skin lesions under specific treatment) is an example,* while the activation of a tuberculous lesion after iodid medication is an even older observa- tion. So, too, we may get an ulcerative catarrhal condition when a uremic colitis is carelessly treated with calomel, while Koniger, in a recent paper, has even been able to demonstrate that the anti- pyretics, when given in proper interval doses, all bring about a nonspecific "plasmaactivation" and must therefore be included among those agents potentially capable of bringing about focal re- actions. This widening of the concept of the focal reaction makes it of decided importance in the special pathology of internal diseases. Acute conditions may often be nothing more than the exacerbation of heretofore latent processes of definite bacterial etiology or perhaps of a diathesis. On this basis can be explained the fact that children often respond with a severe angina to a fault in the diet ; that an ap- pendicitis will become acute following an angina, a remote trauma or an injection of a prophylactic dose of vaccine; that a gastric crisis or lancinating pains will commence after some remote exciting cause or an asthmatic attack occur under the influence of some meteor- ological or climatic alteration. In many ways this basis for the immediate etiology of an ap- pendiceal inflammation or the flare-up of a gall bladder seems more rational than the suggestion that we deal with a specific localization of bacteria, so altered in their metabolic demands and peculiarities that they will grow only in certain tissues. This latter hypothesis which Rosenow has developed ignores the fact that in the history of acute inflammatory processes one may note a preceding history of remote trauma or systemic shock of some kind or a metabolic dis- turbance of nonbacterial origin just as often if not more frequently than a history of a preceding infection. The Diphasic Character of the Focal Reaction. — ^While in the preceding pages the attention has been centered on the fact that a variety of agents may be used to elicit the tuberculin reac- * The so-called sensitization of the skin to metallic colloids is similar in character. Hift found, for instance, that if he injected electrargol intravenously after having injected small amounts into the skin previously, the involuted skin papules would again flare up. 76 PROTEIN THERAPY tion (focal) one can also determine that nontuberculous processes respond with a focal reaction to tuberculin. Schmidt illustrates this with two convalescent cases of polyarthritis which had been free from fever and local symptoms, pain, etc., for over two weeks. Both cases on receiving 0.001 gm. O.T. subcutaneously, responded with severe pain in the joints previously involved, slight periarticular swell- ing and some limitation of motion; the duration of the reaction was of course transient. I have had occasion to repeat these observations of Schmidt's and in a considerable percentage of the cases studied I have found that the observation holds true. In processes that can be observed at the exterior surfaces of the body, particularly in the violent activation of chronic inflammatory lesions, one can observe the dualistic nature of the reaction — and this is of paramount im- portance in the therapeutic application of the reaction — a negative phase in the sense that the tissue is altered more from the normal than heretofore, i.e., the evidences of inflammation are increased — pain and swelling augmented, function impaired, etc.; then a positive phase during which there is a progressive diminution of the inflammation until the preinjection status is again reached or passed, the balance swinging in this direction until practically normal conditions are re- stored. Augmentation of the inflammation is followed by a diminu- tion until healing is accomplished — the pendulum swings from one side to the other in the wave-like curve that we find expressed so conomonly in many biological processes — in the opsonin curve, the antiferment ciu've, in the leukocj^tic response, in the coagulation mechanism, in cell permeability, all indicative of the exquisite lability of the balance that exists in living protoplasm. The focal reaction has its counterpart in the general reaction of the patient that usually accompanies the reaction, occasionally in the tuberculous, more often in acute infections and corresponds obviously with Weichardt's period of "plasmaactivation." This dual- ity observed in both the focal reaction and the general reaction is of utmost therapeutic interest. It is reasonable that we would seek to make the negative phase, representing an augmentation of the inflammatory process as short as possible and the positive phase relatively intense and protracted. But the possibility arises, based on clinical observation, that the de- gree and extent of the positive phase (curative) is closely dependent upon and correlated with the negative phase, i.e., that their relative intensity is proportional. We may conceive the negative phase, which in point of time always precedes the positive one, as an exogenously produced irritative process, the positive one, on the other hand, as an endogenously prepared, more or less physiological process of vital repair. Clinically, as far as focal reactions are concerned (as for instance in tuberculosis), it is chiefly the negative phase that comes to our attention in the form of the activation phenomena with which THE FOCAL REACTION 77 we are familiar. But, from analogous studies in focal reactions else- where it must be assumed that, with proper dosage, the positive phase and the increased tendency to healing follows about the lung focus just as it does about a joint lesion that can be objectively studied. In this duality of the reaction lies the usefulness of the focal reaction as a therapeutic measure. Mechanism of Focal Reaction. — ^Vascularized Inflammatory Foci. — During the course of the past five years we have become fa- miliar with the biological alterations that take place in the organism after tuberculin injections as well as after the so-called nonspecific agents. These changes, described in the preceding chapter, are nu- merous and complex but the more important can be placed in two groups: (1) those that deal with cellular stimulation, and those (2) that result primarily from alterations in the permeability of the cells. The former have been broadly included by Weichardt under the term "Plasmaactivation." Under the stimulus of moderate doses of nonspecific agents cellular activity is markedly increased. This finds its expression in increased secretory activity of gland cells, increased activity of muscle cells (myocardium), increased activity of leu- kocytes (phagocytosis), etc. The changes that take place in the permeability of the cell membrane have been studied by Luithlen, by Starkenstein and others and represent a decidedly diphasic phenomenon. The permeability of (the capillaries is first increased as evidenced in the great increase in the lymph flow and in the concentration of the blood; the permeability of the tissue cells is increased — ^with a re- sulting outpouring of enzymes, of fibrinogen and prothrombin, of immune bodies, etc.; the increased permeability of the nerve cells is associated with a lowering of the threshhold for nervous impulses and becomes manifest clinically in increased susceptibility to pain, general irritability, headache, etc. When this first phase has passed compensation takes place in a lessened permeability of the cells, with effects that are to be anticipated — lessened susceptibility to intoxi- cation, lessened nervous irritability — lessened exudation — a lowering of enzyme concentration, etc. Numerous other observations have been made that are, in my opinion, subordinate in interest to these two fundamental alterations in the permeability of the cell membranes and the general stimulation of the protoplasm. With these considerations in mind we can approach the study of the mechanism possibly involved in the focal reaction about inflam- matory tissues from a relatively simple point of view. In an inflammatory focus supplied with highly vascularized gran- ulation tissue the systemic effects of a tuberculin injection or the in- jection of a nonspecific agent will bring about (1) an increase in the exudation of fluids — ^with increased redness and swelling because 78 PROTEIN THERAPY of the transient increase in the permeability. With this there is as- sociated (2) an increase in pain and tenderness both because of the increased pressure and the lowering of the threshold or nerve stimuli. There will be (3) increased digestion at the focus of inflammation; if there is no necrotic material present in the focus there may be no evidence of increased systemic intoxication; if the amount of necrotic material is large there will first result an increase in systemic in- toxication when the material split down is absorbed; with more complete digestion at the focus, complete detoxication may re- sult. All these changes we associate with the focal activation that follows nonspecific injections. To these must be added another factor and one more complex. It concerns the observation that any cell previously involved in an inflammatory reaction responds to stimuli of all kinds more readily than a normal cell. Objectively we can observe this in involuting skin lesions. The augmentation in the inflammatory reaction which we have induced brings with it, as we have seen, an increased lymph flow. Coincident with it there has been a relative increase in enzymes — protease, ereptase (peptidase) lipase, etc., — an increase in the anti- bodies (if the patient has been previously immunized or if the infection has existed for some time), an increase in the leukocytes (after the initial leukopenia), together with an increase in their phagocytic activity, and an increased coagulability of the blood. The antibody, the leukocytic and the enzyme alterations must exert a considerable effect on an infecting agent as well as on the removal of necrotic material; the tendency toward restitution to the normal would be enhanced. It is this phase that we see in the so-called second or positive phase. Its coincident constitutional effect that we witness in the euphoria, in the lowering of the temperature, improvement of the circulation, etc., is due to at least three factors — (a) the destruction of toxic material at the focus after the primary increase in digestive activity, (b) lessened susceptibility of the cells of the body to intox- ication (due to the lessened permeability) , and (c) actual protoplasmic stimulation (partly from the nonspecific or specific agent injected, partly from the toxic material liberated from the inflammatory focus). This later factor varies greatly and the clinical estima- tion of the possible degree of this variation requires experience and care. Tuberculous Foci. — Turning from the vascularized inflammatory focus to the tubercle we find other conditions. In Schmidt's paper the view emphasized is that in the general tuberculin reaction we are most likely dealing with both specific and nonspecific factors, an opinion similar to that which we have expressed in a previous paper. Schmidt) has stated this concept as follows "But it is probable that in the question of specificity or nonspecificity, the placing of the one versus THE FOCAL REACTION 79 the other is a mistake — that it should rather be the examination of specificity and nonspecificity, i.e., that both factors enter into the reaction and it should be determined how far each factor is involved." Our concept has been that while the systemic reaction was largely nonspecific in that the means used to elicit it need not be specific, the focal reaction itself, once initiated, brings in its wake a truly specific stimulation because the inflammatory reaction may lead to the libera- tion of disintegrating bacterial material and possibly even living bacteria. These substances would secondarily lead to a specific response on the part of the body.* At least three factors must be considered in the mechanism of the focal reaction in tuberculosis, apart from the anatomical pecu- liarities of the tubercle as contrasted with other inflammatory proc- esses. Specific. — These concern primarily a tissue sensitization against tubereuloprotein, strictly specific in character, cellular in its localiza- tion and not necessarily associated with the older conception that was built up about the humoral antibodies. Indeed I am of the opinion that the latter may very well be relegated to a subordinate position in the field of tuberculosis. Inasmuch as this subject of tissue sensi- tization has been extensively discussed by a number of workers, par- ticularly by Krause in this country, it will be unnecessary to enter into this phase here. General Hypersensitiveness of the Tuberculoids. — Granted that the tuberculous focus responds to smaller doses of tuberculin than does a focus of nontuberculous origin, how are we to account for the fact in view of the- practical avascularity of the tubercle? That the speci- ficity concept of the immunologist will no longer explain the accumu- lated evidence is to-day acknowledged, and Wolff-Eisner accepts the change in our viewpoint in a recent paper. I can but very briefly enter into the more lengthy theoretical discussion that he presents. He first emphasizes the relation that exists between the diet and exudative diathesis,, defining this latter condition as due to the ab- * It is this factor that Klemperer in his recent criticism of Schmidt's claims has ignored. Klemperer foimd that following milk injections in tuberculous patients they did not become resistant to following injections of tuberculin and vice versa. Injections of milk bring about a febrile reaction in a large per- centage of individuals; they bring about a focal reaction in only a limited number of tuberculous patients, just as tuberculin injections are followed by focal reactions in an irregular number. If the injection of milk brings about (in the tuberculous individual) a systemic reaction without focal activation, a following injection of tuberculin may still give rise to a typical general reaction. If, on the other hand, a focal reaction results, either by specific or nonspecific means, local tuberculin reactions are suppressed for some time following the general reaction. Klemperer is, however, quite justified both in his criticism of the local reactions reported by Schmidt following milk injections in tuberculous patients and in his views concerning the possible harm from activation of tuber- culous foci following milk injections. 80 PROTEIN THERAPY sorption of proteins and protein fragments insufficiently degraded in the intestinal tract, i.e., a protein sensitization. He then develops the more or less definite association of the exudative diathesis and spas- mophilia with scrofula; while he does not regard the scrofula as the cause of the diathesis, he inclines to the definition of Feer that "scrofula is tuberculosis on the basis of an exudative diathesis." Wolff-Eisner is inclined to the view that in tuberculosis there is evi- dence of an exudative diathesis with sensitization against tuberculfai and also against proteins in general. This latter which is nonspecific and general in character accounts, in his estimation, for many of the evidences of similarity in the clinical course of tuberculosis and those observed in an exudative diathesis. Not only is scrofula "tuberculosis on the basis of a diathesis" but the tuberculous lesion itself, involving as it does the prolonged absorption of partially split proteins from the necrotic foci, may ultimately bring in its train symptoms that are commonly regarded as due to a diathesis. As such he regards the changes observed in the cornea, skin lesions such as the tuberculids, the decided alterations in the reactivity of the sympathetic and central nervous systems to which Moro, Pottenger and Ferranini have called attention. While we have been familiar with the increased nervous lability of the tuberculous individual for a long time, we have failed to grasp the dependence of the increased irritability on the general hypersensitiveness to proteins. Not only does this nervous irritability indicate the close parallelism to the diathesis of the child, the tendency to effusion is also evident in the tuberculous patient — one has but to call to mind the common appearance of pleural, peritoneal and joint effusions. The alteration in the vasomotor stability also finds its expression in the frequent appearance of urticarial eruptions after tuberculin injections. It will be recalled from the previous discussion of the effects of nonspecific injections on the permeability of vascular endothelium that, depending on the dosage or the degree of irritation (or stimulation if we wish to use that term) there may result either an increase or a decrease in the permeability. We may expect that the effect of the tuberculin (or the living virus) will also find some expression in changes in the permeability in one direction or another. According to Wolff-Eisner we find the clinical demonstration of this experimental observation in the effect of the tuberculous invasion of lung tissue, where in one instance we find an exudative change, in another an indurative process. Plasma£Lctivation. — The third factor involves the consideration of the effects which any nonspecific provocative agent would have on an inflammatory lesion such as the tubercle; the tubercle would react as any seminecrotic focus of other etiology would react were it not for the fact that the tubercle is practically avascular. Tubercles react to nonspecific injections (or to nonspecific stimuli of other origin) only THE FOCAL REACTION 81 when they are of the exudative type or when the connective tissue delimitation of the tubercle is either incomplete or exceedingly labile. It is to be recalled that as one of the results of plasmaactivation proteolytic enzymes appear in the serum and in inflammatory foci and that the polymorphonuclear leukocytes are increased in number and in activity. The augmented digestive activity results in a loosening of the connective tissue defense of the tubercle. If sufficiently intense a typical focal reaction — activation-absorption of necrotic material and systemic reaction — can result in this way, just as after stimula- tion due to specific tuberculins. The Therapeutic Application of the Focal Reaction. — Schmidt is of the opinion that the local reaction, elicited by means of specific or nonspecific agents (such as milk), is of definite value in tuber- culosis, and together with Kraus cites some twenty-odd cases to sup- port his view. While it is of course not to be denied that in a very limited number of cases this may be true, we are of the opinion that the tubercle offers a decided exception to the general rule that the active stimulation of a chronic inflammatory focus is of therapeutic value. We have pointed out that for vascularized inflammatory lesions such stimulation affords a rational method of therapy. In the tubercle we deal with the constant danger that the limitation of the lesions by means of the connective tissue encapsulation may be sufficiently dis- organized that an extension of the process and irreparable injury may result. Irrespective, therefore, of the theoretical probabilities that therapeutic focal activation may be beneficial, in the tuberculous lesion it is a hazardous procedure (Lewin). Before leaving the subject it must be pointed out that nonspecific stimulation of the tuberculous patient (not involving focal reactions) has been found very useful both with certain drugs (and these include the commonly accepted ones such as creosote, succinates, arsenicals, etc.), as well as with serum injections such as Czerny and Eliasberger have recently reported. That the milder nonspecific injections seem to have a decidedly stimu- lating effect on the metabolism of infants has been previously reported. (Plantenga, etc.) The peculiar therapeutic importance that attaches to the diphasic character of the focal reaction has been previously discussed. Through the existence of inflammatory foci in various organs the omnicellular stimulation by means of the various nonspecific agents (the ergotropie of v. Groer) becomes to a certain extent an organotropic. It is in this sense that we must consider the effect of the treatment of paresis by means of tuberculin injections and similar therapeutic measures. A combined therapy of nonspecific and etiotropic agents may be of value, and experiments in this direction have been reported by Kyrle and Scherber, who have used milk injections in conjunction with mer- cury in the treatment of syphilis, or the use of milk injections and salicylates in the treatment of arthritis, the use of milk injections and 82 PROTEIN THERAPY luminal in the treatment of epilepsy, or the treatment of lupus with tuberculin and salvarsan (the latter in this case serving as the non- specific agent) . Our older method of treating syphilis with alternating courses of mercury and iodids made use of this form of a combined specific and nonspecific method for many years; the nonspecific effect of theoiodids is, however, not marked; the effect is to be sought rather in the effect of the iodids in facilitating the diffusion of the mercury. If a more active agent than iodids is used the mercurialization of the patient can be very rapidly brought about. While therefore the local reaction has therapeutic possibilities which should be studied and developed, we must always keep in mind that there are possibilities for harm in the reaction. Just as during a malarial attack a syphilis may flare up (Noel) , so a tuberculous lesion may become activated after a salvarsan injection or a prophylactic vaccination. Veilchenblau has described an apoplectic attack (old syphilitic) in a patient who was given an arthigon injection for a complicating gonorrhea. CHAPTER V THEORIES CONCERNING THE MECHANISM OF THE REACTION When the clinical results of nonspecific therapy were first made known we were quite at a loss to account for the results obtained. It represented empiricism pure and simple, and being diametrically at variance with current conceptions of immunity and resistance it was to be expected that scientifically trained physicians would be decidedly skeptical — ^the more so since the heroic measures at first utilized to bring about the reaction were not without inherent danger. But when, with increasing evidence of clinical success, the importance of the reaction could no longer be ignored we had to seek for some explana- tion to account for the therapeutic benefit even though we had to recast our entire conception of the mechanism of recovery from disease. The evidence of the reaction of the patient — the chill, fever, sweat and leukocytosis — might all be assumed to have some bearing on the therapeutic result. We knew from experience that after a severe chill the septic case might have a defervescence and recover from the infec- tion. We knew that an intercurrent febrile course might favorably influence a preexisting disease process. We knew that a thorough sweat would frequently relieve the symptomatology of many diseases. And the importance of the reactive leukocytosis in resistance and its significance in prognosis had been sufiiciently impressed upon us in a number of diseases, especially in pneumonia. But none of these observable reactions on the part of the patient seemed in itself sufficient to account for the striking effect that occasionally followed the nonspecific injections. In examining the published experience of a number of clinics it was found to be a common observation that nonspecific therapy gave best results if used early in a disease process. It was also noted that the beneficial effect from the reaction depended to a considerable extent on its severity; later injections, to which the patient responded with diminished severity, were less efficacious. These two clinical observations proved a valuable clew to a partial solution of the mechanism that underlies nonspecific therapy. The fact that the most marked therapeutic effect could be attained early in disease rather than late led to the realization that in injecting the 83 84 PROTEIN THERAPY various substances we were stimulating the organism — late in dis- ease, in an exhausted patient, stimulation would naturally be un- availing. The fact that the degree of stimulation and reaction de- termined the therapeutic effect was evidence of one of the frequently- observable biological balances in which the end reaction (recovery in this case) seems proportionately greater than the stimulus (intoxi- cation) . Weichardt's Theory. — Weichardt, whose work with protein in- toxication and fatigue intoxication is well known, based his explana- tion of the nonspecific reaction on these two basic observations and the term "Plasmaactivation" or "Omnicellular Plasmaactivation" with which Weichardt has sought to designate the mechanism involved in nonspecific therapy is perhaps a satisfactory one in that we may include imder it the many possible and probable alterations that are inaugurated by the reaction without limiting our conception to any one feature. Bessau has but recently pointed out that the favorable therapeutic action corresponds to Pfeiffer's older conception of means to increase the resisting power of the organism, for Pfeiffer showed that a variety of interventions in acute infections induced an im- mediate increase in the resisting power. Inasmucli as few investigators in this field of researcli Have had the experience that Weichardt has had, it may be well to go back for a mo- ment to the fundamental observations that underlie his conception of 'Tlasmaactivation." Gamaleia, in 1888, had observed the pyrogenic effect of bacteria and noted that the degree of temperature rise produced by the injection of bacteria had an intimate relation to the state of digestion of the bacterial cells. Later Charrin and Euffer noted that when bacteria were heated to a temperature of 110° C. they still retained this property of causing a rise in the temperature, while other nonbacterial proteins also caused an increase in the temperature (bouillon and organ extracts). As a matter of fact, the observation that such substances were pyrogenic was made previously by Eoux and Lepine. Later Buchner worked along the same line, incidentally observing the fact that on reinjection the animal may respond differently than after the first injection (one of the early observations of sensitization and anaphylaxis). Ott and Collmar had tried out a variety of protein split products — albumoses, peptone, and neurin — in the smaller laboratory animals, but had obtained very irregular pyro- genic effects. Then Krehl and Matthes published a series of observations concerning the effect of bacterial and other split products on animals (normal, and sensitized by some infection such as tuberculosis), the results of which have already been discussed. Krehl noticed particularly that the experimental animals varied in their sensitiveness to the protein split prod- ucts. The guinea pig was most susceptible to deuteroalbumose, the rabbit less so and the dog least, quite the same relation that we find in anaphy- lactic shock. Schittenhehn and Weichardt and their associates — ^Hartmann, Greiss- hammer, Strobel, etc. — ^made intensive studies of the temperature curve, the leukocytosis, the nitrogen excretion and general clinical picture fol- THEORIES OF MECHANISM OF REACTION 85 lowing protein injections of various kinds in a variety of animals. The leukocytic picture and the temperature curves have been discussed under their respective sections. They noted among other things that the ex- cretion of nitrogen was markedly augmented when the animal was sensi- tized and then injected, or when a very toxic protein such as that derived from the colon or typhoid bacillus was injected. The derivatives of nuclear destruction in particular were found to be increased. While the effect on the temperature might be relatively negligible, such injections, particularly in dogs, might produce a change in the leukocytic picture lasting at least a day and an increased nitrogen metabolism that would cover a period of 4 days. In dealing with protein intoxication Weichardt and Schittenhelm em- phasize that the bacterial bodies contain too large a variety of proteins and protein split products to obtain a clear picture ; the isolated components had to be studied before conclusions could be drawn. They observed that proteins that were made up largely of monoamino-acids, such as peptones derived from silk, casein, hair or edestin, were practically not toxic to the organism; on the other hand, the diamine rich complexes, such as histones and protamins, were exceedingly toxic. According to Euppel these are pres- ent in particularly large amounts in a number of bacteria. When attached to form some other grouping, as for instance a nucleohistone, the histone becomes nontoxic. Detoxication can therefore take place in the direction of synthesis as well as in the further lysis of the protein complexes. Of course, even on lysis toxic amino-acids may be formed, as when beta-imid- azolylethylamin is formed from histidin. (Studied by Barger and Dahl, Biedl and Kraus, Schittenhelm and Weichardt.) From their further studies in this direction, Schittenhelm and Wei- chardt concluded that the conjugated proteins such as nucleoprotein, hemo- globin, glutokyrin sulphate, etc., were relatively nontoxic, whereas the pro- tein components of these complexes were manifestly toxic (globin, histone, protamin) as indicated by their effect on the blood pressure, temperature, respiration, coagulability of the blood and lethal effect. It is not necessary to add that this toxicity is just as pronounced when the derived protein is homologous in origin. While in general the richness in the diamino- acids of these compounds is paralleled by their toxicity, this is not the only factor involved. Of exceeding interest is their work with hemoglobin, which, apart from a slight temperature effect, was practically nontoxic. They were, however, able to sensitize animals against it. On the other hand, globin was much more toxic. When conjugated with hemochromogen this toxicity again disappeared. This fact is of particular interest in several pathological con- ditions, such as malaria, where the appearance of the chill and the high temperature reaction has been ascribed to the liberation of hemoglobin and its derivatives. Cowie and Calhoun on the other hand are inclined to the belief that it is due to protein derived from the Plasmodia. Weichardt and Schittenhelm made the further observation that the continued injection of the proteins that caused a toxic reaction was fol- lowed by a definite cachexia and ultimately by death. This protein cachexia seems a fairly constant phenomenon and has been observed by Dold as well. 86 PROTEIN THERAPY Weichardt then proceeded to study the pharmacological effects of small and large doses of the various higher molecular groupings of the split products of proteins on individual organs. Small doses were found to stimulate the heart muscles as well as the hematopoietic system, larger doses to reduce the activity. Similar experiments were made on the activation of the manunary glands of goats. A series of goats secreting equal amounts of milk were injected with various amounts of protein split products and the activation of the metabolism, as indicated by the amoimt of milk secreted, could be studied di- rectly. As a result of his researches and clinical experience Weichardt has come to the conclusion that when we make use of nonspecific therapy we stimulate all the cells of the organism to greater activity in the production of either specific substances antibacterial in char- acter or merely increase the general resistance to intoxication by speed- ing up the mechanism of detoxication — either synthetic (the forma- tion of conjugate proteins from the toxic forms) or lytic (the degrada- tion of the toxic fragments to the amino-acids) or in some other way hastening the elimination of the intoxicating material. In several recent papers he has emphasized a number of points of interest. Thus his general conception that nonspecific therapy is a plasmaactivation — a stimulation of the cell metabolism and func- tion, of physiological effort rather than a pharmacologic alteration in the biological processes leads to a correlation with the problem of fatigue, to which he has devoted a considerable study. Weichardt, contrary to the theory of Dollken,* considers this stim- ulation or activation as omnicellular. The leukocytosis, the increase of oxidation, of catalysis, the mobilization of enzymes and antibodies all indicate a general rather than a localized stimulation of some particular kind of tissue. This stimulation does not involve any alteration in function. The organism by nonspecific reaction acquires no new method of defense, probably does not overcome infection or intoxication through agencies other than those always at its disposal. But the stimulation repre- sents a summation, a cumulative effort of the defensive agencies of all the organs. And as a necessary corollary it is but logical that we can achieve no therapeutic effect when once the organs have by com- plete exhaustion been rendered incapable of reaction, as in terminal stages of disease processes or in profound intoxication, etc. While the stimulation does not involve any new method of de- * Dollken considers certain proteins and other agents as selective in charac- ter. Thus milk which was found to be more styptic in its effects than vaccines or albumoses, he considers active in this way because of greater stimulation of the liver — mobilization of fibrinogen and thrombokinase — deutero-albumose being more effective in mobilizing antibodies, etc. It seems probable that while selective differences may exist, a general protoplasmic stimulation is the phenomenon which must primarily be considered. THEORIES OF MECHANISM OF REACTION 87 fense, differences in reaction exist between normal individuals and individuals ill, or sensitized. The cell that has been sensitized re- sponds more promptly with a mobilization of protective agents, both specific antibodies as well as enzymes and other nonspecific factors in resistance. Inasmuch as the subject of cell stimulation is so closely bound up with cell fatigue, Weichardt has schematically drawn up the accom- panying classification of the substances and agencies that are opera- tive in cell stimulation and therefore in resistance. (Page 88.) These agents fall into active and passive groups; the passive ones being such that take something — Weichardt lays particular weight on the paralyzing effect of fatigue toxins — protein split products — from the cell. They are identified by the fact that their activity becomes manifest only when symptoms of fatigue have become evi- dent in the organ, and then the effect can never bring about an aug- mentation of function over the normal — a mere restitution is the limit of their range. Given good resorption their effect becomes apparent at once, while in high-grade fatigue they fail to change the function to any degree. With the active agents we deal with a true activation whereby the cells are excited to a high grade of activity, demonstrable not only in fatigued but in nonfatigued cells. The dosage is of impor- tance as Weichardt showed in the experiments on isolated organs and organ systems. The dosage must be proportional to the organ to be stimulated and its condition. Usually a definite latent period can be determined before the maximum stimulation becomes manifest. Now if we keep in mind this relation of stimulation and fatigue, that small amoimts of split products (fatigue toxins) may stimulate to greater activity while large amounts will cause only depression, a common observation of nonspecific therapy — namely the fact that on repeated stimulation by intravenous injections the organism fails to react — becomes intelligible. The stimulation wears off, in severe fatigue the reaction may fail entirely. Schittenhelm in his recent view of nonspecific therapy calls at- tention to the fact that the derivation of the protein split product used for nonspecific injections cannot be indifferent to us. Undoubted differences must exist in their physiological properties of stimulation or depression. There is no doubt that chemically defined proteins would be best and some work has already been done in this direction. But it must be kept in mind that while we may use a definite protein complex to begin with, split products will also be produced during the course of the reaction from the metabolites of the body and will enter into the reaction. The euphoria that follows the nonspecific protein therapy can be observed after a variety of similar procedures, both chemical and physical. It is observed after the injection of colloidal metals and Nonspecific P 1 asmacti- vation I n c r e a sed Act ivity of Oxidases, C a t a 1 y sts, Endocrine organs. Leu- kocytes, etc. a o ■-3 > ■-I3 en 'o a) a o tf Increase of C a r b h y- drate Metab- olism By means of organotropic agents that permit bet- ter perfusion of the organ. i.2 I o S- > tas ^ <1> ID *i iS r3 ^ O ■«'«£■§'"& a" O -U Z +3 Activating effect of split products de- rived from first effort. 5P 1>! 1^ Fig. 3. — Classification of substances and agencies operative in cell stimulation and resistance. 88 THEORIES OF MECHANISM OF REACTION 89 Weichardt calls attention to the fact that a similar state is to be observed after the use of faradic current (Bergonie). Most likely the stimulation of the lymphatic flow whereby fatigue products are rapidly removed is related to this effect. Schittenhelm and Stroebel a number of years ago emphasized the fact that under normal circumstances protein split products do not get into the circulation, that they are foreign to the blood and their presence would be manifest at once in an intoxication. Protein metabolism, reconstruction and molecular rearrangement and deg- radation take place within the cell. In this cellular metabolism the protein split products have a dual effect. In small amounts they irritate (stimulate) the cellular activity. In larger amounts they are depressants. Weichardt's "omnicellular plasmaactivation" means simply that we make use of the same agents in proper dosage to stimulate and since we use an intravenous route, all the cells of the organism are stimulated at the same time. Selective Stimulatioii. — Dollken considers that differences in thera- peutic effect exist between the various nonspecific agents, that some of them stimulate particular organs or organ groups and presents a number of obser- vations to support his contention. In several papers he has pointed out dif- ferences in effects when various bacterial injections are made — heterobac- teriotherapy — thus pyocyaneus vaccines were found effective in gummas, pseudodiphtheria vaccines were not ; cholera and dysentery vaccine were not effective in neuralgia, while vaccines made up with prodigiosus organisms were very satisfactory. On the other hand neither prodigiosus nor pyo- cyaneus vaccines gave any clinical result in acne, while an autogenous vaccine did. The effects could therefore not be considered identical. When comparing the styptic effect it was noted that the bacterial vaccines were practically without effect whereas milk was very active. ... It was interesting to note, too, that while the local reaction at a focus might be equal for two different substances, the end results might be wholly differ- ent. Thus both prodigiosus vaccine and milk gave equal reactions about arthritic foci, but the clinical results with the prodigiosus vaccine were not good. On the other hand, when treating neuritis the prodigiosus vaccine gave better results than did milk injections. Dollken is of the impression that the nonspecific stimulation is not omnicellular as Weichardt has suggested but that certain organs are stimu- lated by different agents to a greater degree than others, these being the liver, spleen, kidney and bone marrow; a decided effect is also obtained on joints, the tissues of the eye and some of the glands and paraglandular structures. Dollken has made the interesting observation that the effect on joints is not merely a bactericidal one, as might be inferred when an infectious arthritis is improved, but even joint inflammations such as those of gout are also relieved, certainly not a bacterial affair. Dollken noted that the repeated injections of heterovaccines, milk and similar substances resulted in different reactions. Thus the resistance of the body increases rapidly to further injections of pseudodiphtheria bacilli, to typhoid bacilli and to the baciUus pyocyaneus; the resistance to tuber- 90 PROTEIN THERAPY culin and to prodigiosus vaccine goes up much more slowly. Repeated injections of milk and of deuteroalbumose give rise to steadily augmented temperature reactions, indicating a certain degree of sensitization. Then, too, the fact that following the injection of heterovaccines the euphoria so commonly present after the other agents is seldom noted, also indicated some difference. It may be well to leave the question whether the plasmaactiva- tion is onmicellular or organotropic and take up some of the other the- ories that have been advanced to explain the nonspecific reaction. Effect on Thermoregulatory Mechanism. — ^Paltauf suggests that the effect might be due to thermogenic substances in the vaccine injected. After the stimulation of the heat-regulating center an ex- haustion might be expected, as an expression of which he regarded the defervescence after nonspecific injections in acute febrile diseases. This explanation, which Lowy supports, does not take into considera- tion the frequent permanency of the defervescence. Saxl considered the hyperthermia as the vital factor which stimu- lated both antibodies and leukocytes and was also directly effective on the disease process. RoUy and Meltzer have studied this question. In animals that were infected with a single overwhelming dose of some infectious agent, the effect of raising the temperature was not apparent in the course of the disease process ; on the other hand, if the animals were infected with small repeated doses and over a longer period of time it became apparent that by increasing the temperature the infectious process was favorably in- fluenced. The opsonic power of the serum of the fever animals was in- creased over that of the controls; the bacteriolytic property was not en- hanced. There seemed no difference in resistance to pure toxins but Eolly and Meltzer observed that the agglutinin production by the heated animals was increased. Animals that were kept at a high temperature for a period of over 20 days showed no parenchymatous degeneration, but did show a loss of weight and were anemic. Liidke has determined that high temperatures per se are not damaging factors in infections, for if in infectious diseases the temperature is arti- ficially raised, the disease is seemingly favorably influenced. Liidke has noticed, however, that on artificially increasing the temperature we may activate latent organisms. He has observed that typhoid bacilli that have (in convalescence) been dormant in the spleen or bone marrow, may again enter the blood stream on superheating the organism, i.e., a hyperpyrexia may at times be a cause of relapse in typhoid fever. Antibodies that had gradually disappeared after an infectious disease or following immunization artificially produced, were again found in the serum after any procedure that increased the body temperature, whether by increasing the external temperature, influencing the thermal center of the brain or by injecting pyrogenic drugs. Liidke is therefore inclined to the opinion that the therapeutic effect of hot baths and sweats during the course of any infectious process could be accoimted for on this basis THEORIES OF MECHANISM OF REACTION 91 and considered the use of antipyretic substances as illogical, apart from the direct toxicity that they might possess. Uddgren, as a result of extensive study with milk injections, has come to the conclusion that the hyperthermia is not responsible for the clinical improvement. Working with eye diseases she found that with "sterile" milk the reaction of the patient was very mild but the clinical results were just as good if not better than wheai market milk was used which gave a severe reaction. Weiss has applied this theory in the treatment of gonorrheal infections with very hot baths. The gonococcus is very susceptible to heat so that it oSers a suitable field for trial. He has used baths heated to 42° C. In some instances favorable results have been reported ; most patients are not able, however, to stand the treatment (Scholz). (Kapperer.) Nolf 's Theory, — Nolf assumes that the mode of action is the fol- lowing: "Peptone is an easily assimilable antigen. The pathogenic microbes, on the other hand, antigens, are difficult of assimilation. A single mechanism brings about the assimilation of both when they are given by a parenteral route. It is probable that the administra- tion of peptone has the power of stimulating this mechanism and of thus augmenting the destruction of the microbes. As the pro- teosotherapy is essentially a nonspecific method, it can with advan- tage be given in association with more or less specific chemical sub- stances when the latter alone are insufficient for bringing about the cure. For this reason I have used proteosotherapy in conjunction with hexamethylenamin in the treatment of typhoid fever, and with sodium salicylate in daily doses of 6 gm. in the treatment of septi- cemia caused by streptococci and staphylococci and in acute arthritis." V. Groer believes that we are dealing with an alteration of the entire organism — ^"eine Umstimmung" or a desensitization, largely due to the loss of the cell receptors, whereby the cell becomes less liable to intoxication. This view will be discussed more fully in the follow- ing chapter. Enzymes. — Holler, Lindig, Friedlander, von den Velden as well as Jobling and Petersen have emphasized the importance of the proteo- lytic enzymes mobilized after the injections. Lindig introduced casein injections on this basis and Jobling and Petersen used proteoses with the same purpose in mind. Lindig's hypothesis has been as follows: The serum of the pregnant woman and the new-born child contains proteolytic enzymes which digest casein; these enzymes are of importance in preventing infection. Other agents may stimulate enzyme action, such as colloidal metals, salt solution, etc., and they have been successfully used in therapy. Lindig considers that the enzymes are heterolytic and that they may be derived either from the leukocytes or from glands. If too large doses of proteins are injected an excess of enzymes floods the serum, tissue-lysis occurs and 92 PROTEIN THERAPY the protein cachexia to which Weichardt has called attention may result. Antibodies. — The effect of the nonspecific injections on the mobili- zation of specific antibodies has been studied by a number of ob- servers. Liidke had observed that proteose injection would mobilize antibodies in immune animals and introduced proteose injections in patients on this basis. He was not able to determine a constant in- crease, however, no matter what the clinical result of the injection. In a more recent paper he states that in general the agglutinin titer is markedly increased in the typhoid cases that he had injected, and that there is an increase in the bactericidal property of the serimi. As has been stated in a previous chapter the results in this regard are conflicting. Recently, Larson has published some experimental work bearing on this point. He proceeded on the theory that many bacteria such as streptococci, pneumococci, etc., are imperfect antigens, correspond- ing to the heated tetanus toxin, the toxoid; that during a streptococcus infection such as an acute arthritis, antibodies are formed against the streptococci, but as this organism does not possess the second stimu- lus — the exfoliative stimulus — ^that is necessary to cause the antibodies to be cast off into the blood stream, not sufficient immunity is estab- lished to overcome the infection. This stimulus, Larson assumes, is supplied by the nonspecific agent — the vaccine, foreign serum, pro- teose, etc. In other words, the stimulus necessary to cause the cells to produce the antibodies is specific, but the stimulus causing the cells to throw off the antibodies is not necessarily specific. Using rabbits immunized to sheep's corpuscles Larson found that the in- jection of foreign proteins greatly augmented the antibody content of rabbits that had only a very low antibody content before the in- jection. On the other hand, if a rabbit had originally responded with a high concentration of antibodies the secondary injection of a foreign protein did not further increase the antibodies present in the senun. From these premises Larson draws the conclusion that the in- jection of foreign protein enables the organism to throw off the so- called sessile antibodies and get them into the circulation. In view of these facts, it is possible that the various agents may act as stimulants of the hematopoietic tissue, thus suddenly flooding the body with immime substances, thereby overcoming the infection. According to Wright, vaccine injections were supposed to be followed by a negative phase, at least so far as the opsonic power was con- cerned. Contrary to this generally accepted view. Bull has recently shown that this does not hold true following the intravenous injection of a typhoid vaccine in immunized rabbits. Bull noticed that the antibodies were not diminished; on the contrary, they were rapidly increased following the injection. If this is the mechanism involved, THEORIES OF MECHANISM OF REACTION 93 it is important to bear in mind that the stimulus itself is not a specific factor, but that the hematopoietic system has been attuned to respond to a nonspecific stimulus with the production of a spe- cific substance. Larson raises a question in this connection that has occurred to many in the treatment of pneumonia (especially of type I) where some observers claim to have obtained results with normal horse serum equal to those attained with the specific serum. That is, are we dealing with the actual amelioration of symptoms be- cause of the antibodies contained in and injected with the horse serum, or with a nonspecific reaction in which the antibodies that bring about the cure of the patient are derived from the patient under the stimulus of the injection? The fact that Type I serum does not particularly influence Type II pneumonia would speak against the supposition raised by Larson. As a matter of fact this alteration of the antibody content after the injection of foreign proteins is by no means a constant affair in clinical studies and cannot be considered the sole basis of the thera- peutic result. Thus v. Groer found no increase in antibodies after the injections, while Rohonyi found not only that the antibodies, in- cluding the agglutinin titer, the bactericidal titer and the opsonic index, were not altered but were at times actually decreased after the therapeutic injection and this despite the fact that the patient was clinically cured. Rohonyi made the further interesting observa- tion that in some of these afebrile typhoids a positive blood culture was at times obtained several days after the injection and after the subsidence of the clinical symptoms. This finding has not been confirmed. (Decastello.) Wriglit's Theory — "Wright believes that the old conception that vaccines are contraindicated in acute infections because it would be like adding poison to a poisoned system does not apply in infections because immune responses are primarily developed in the infected area and as long as some portions of the body remain which are not involved, these uninvolved por- tions may be activated by vaccine inoculations for antibody formation to aid the involved portions as a reserve force in overcoming the infection, and that, contrary to previous conceptions, it is found that antibodies are rapidly formed when vaccines are injected into healthy tissues. In this connection he calls attention to the great benefit that was obtained from vaccine inoculations especially in "Poisoned wounds" with streptococcus cellulitis, lymphangitis, erysipelas, etc., and states that the most striking results are obtained when vaccines are employed early in acute cases. As a means of more clearly expressing immunizing processes, he pro- poses a series of new terms. Terminology, as now applied in immunology, has a pronounced tendency to confuse the average reader. It is difficult for him to keep the importance of such words like antigen, amboceptor, agglutinins, precipitins, lysins, opsonins, etc., in their proper relations to immunizing processes without a consequent confusion of ideas. He has attempted to clear up this matter by pointing out that in infectious proc- 94 PROTEIN THERAPY esses and immunity there are essentially two factors at work ; ferment pro- duction by the infecting organism for the purpose of preparing the food on which it lives, with the incidental destructive influence on the involved tissues; and tissue produced ferments which have a destructive influence on the invading organisms and their poisonous products. The application of the word ferment is well understood and by pointing out that infection is sustained and immunization established by ferment action, the difficulty of conveying thought through the use of new words is avoided. The sub- stances known as agglutinins, precipitins, lysins, opsonins, etc., may all be regarded on this basis as cell produced ferments exerting varying de- structive influences on the invading organisms. This power of cells to produce germ destroying ferments would conform to what Wright calls phylactic power. Kataphylaxis would designate a condition in which cell secreted protective ferments are freely conveyed to the infected area; anti-kataphylaxis would indicate the reverse condition and epiphylaxis applies to an augmented immunizing activity by calling into operation some reserve immunizing force. Whether these newly coined words will more clearly convey a fixed comprehension of the immunizing process than the terms heretofore employed remains to be seen. In the application of vaccines much emphasis is laid on the importance of creating conditions by which the iromunizing substances are conveyed to the infected area; contending that therapeutic immunization will less frequently fail through faulty conveyance to the infected area than through inefficient antibody formation. This is accomplished by efficient drainage, removing necrotic tissue, instilling hypertonic salt solution, irritating ap- plications, hot fomentations, etc. Wright's experimental work showing that the bacillus of gas gangrene and tetanus bacilli wiU not grow in freshly supplied blood serum but will grow freely where the serum is contaminated with streptococci or staphy- lococci, while streptococci will grow in unaltered serum, is most interesting and shows the importance of removing necrotic tissues and inducing a free flow of blood plasma in these infections. Since streptococci and staphylo- cocci grow freely in blood serum, he calls these organisms serophites. That these organisms are destroyed by leukocytes is most cleverly demonstrated by his glass lath experiment. Here he shows that when the leukocytes are washed with serum, bacterial destruction takes place by phagocytosis, whereas when the leukocytes are washed with normal salt solution, the organisms are destroyed by the mere presence of the leukocyte. Where destruction takes place by phagocytic action it is clearly accomplished by a digestive process and where bacteria are destroyed or inhibited in their growth by the near proximity of the washed leukocytes, this action is necessarily due to some ferment action by the leukocyte. That bacteria destroying properties develop when killed staphylococci or streptococci are added in proper numbers to normal blood, either in vitro or in vivo, is clearly demonstrated and it is found that this germ destroying power is both specific and nonspecific. This, he contends, conforms to clinical ex- perience and furnishes a scientific basis for obtaining therapeutic results from vaccines aside from their specific immunizing action. This non- specific action of vaccines also explains the fact that often better results are obtained from the use of stock vaccines than from autogenous prepa- THEORIES OF MECHANISM OF REACTION 95 rations; that in such cases the patient has probably come very near to the end of his tether in immunizing responses to the existing infection when collateral immunization will accomplish the desired results. This he con- siders very important, because it embraces such a large percentage of cases and says : "We are, however, here considering primarily the question of principles, and in connection with this what is of fundamental importance is, that we should discard the confident dogmatic belief that immunization must be strictly specific, and that we should in every case of failure endeavor to make our immunization more and more strictly specific. We should instead proceed on the principle that the best vaccine to employ will always be the vaccine which gives on trial the best immunizing response against the microbe we propose to combat. "I would point out that this would almost certainly not involve any revolutionary changes in the accepted practice in either serum therapy or in prophylactic or ordinary therapeutic inoculation. But it would mean taking into account in cases which proved intractable to treatment with the homologous vaccine the possibility of seeking for collateral immuniza- tion by inoculating a microbe or mixture of microbes other than that which the patient is infected." Wright's work emphasizing the importance of the tissue enzymes in local resistance to bacterial infection is of interest, although we are of the impression that the terms that have been coined by him are superfluous and will merely add to the confusion produced by an already overburdened nomenclature. It would seem much more rational to determine the exact role of enzymes already known and for which we possess adequate terms, in the reactions that are involved in tissue resistance ; only when we have exhausted this field would it seem justified to bring in new terms to cover hypothetical factors. The antibody reactions should not be confused with enzyme reactions, no matter how much we may be tempted to do so. Ottenberg and Wallach, who have repeated some of Wright's ex- periments on the production of nonspecific bactericidal substances by methods described by him, failed to confirm his findings. Leukocj^osis. — The reactive leukocytosis that follows nonspecific injections has been repeatedly studied and the suggestion was ad- vanced quite early that the therapeutic effect was to be sought in the artificial leukocytosis established. As noted elsewhere this leu- kocytosis which follows a primary leukopenia, is largely polymorpho- nuclear in character; occasionally an eosinophilia has been described (Holler, Rohonyi), suggesting some relation to the anaphylactic pic- ture. It has, however, been the general experience that the therapeutic effect need not parallel the leukocytosis that follows the injections: certain cases respond very favorably as far as clinical results are concerned but show relatively little increase in the white count; in other cases the hyperleukocytosis will be very marked but the thera- peutic effect absent. Gay in this country brought out the role of 96 PROTEIN THERAPY the hyperleukocytosis as a possible factor in recovery from acute infections and considered the reaction specific. This view was not upheld, however, by later workers — Zinsser, McWilliams, etc. Mueller has studied the leukocytic response in considerable detail and calls particular attention to the fact that myelocytes and nucleated red cells make their appearance very frequently after the nonspecific injections, indicating a very profound stimulation of the bone marrow. On this basis he has recommended and used milk in- jections in the treatment of secondary anemias. Mueller's results rather support the contention of Dollken that nonspecific injections do not necessarily stimulate the entire organism but may be se- lective, i. e., acting chiefly on the liver, bone marrow, etc. Starkenstein's Theory. — Perhaps one of the most suggestive and illuminating researches in the field of the mechanism of nonspecific therapy has been that of Starkenstein. Starkenstein would, in the first place, widen the concept of the reaction from that of a protein therapy, or a heterotherapy to one embracing the entire collection of agents — a true nonspecific therapy — including not only the bacterial or pro- tein substances in common use, but the metallic colloids, the various drugs that have been developed such as succinimid, qiiinin, arsenic, etc., and even purely physical methods, von Groer has covered this in using the term "Ergotropie" to designate this form of therapy. Starkenstein has been able to show that the various agents under consideration bring about such a change. The method used is a relatively simple and direct one and consists in injecting sodium fluorescin into dogs and watching the permeability of the vessels of the eye to the dye under normal conditions and following the injec- tion of the various nonspecific agents. In a similar fashion the agents were studied in their effect on a keratitis produced by mustard oil. The definite retarding or accelerating action of the drugs on inflamma- tion could be studied in this way. Finally Starkenstein deter- mined the alteration of the toxicity of strychnin and of phenol in dogs that were injected with the agents. Starkenstein found very definite alterations. Using the dye it was found that distilled water, calcium chlorid, milk and salt injections all altered the permeability of the vessels. A long list of substances was found to be "entzundimgshemmend" (anti-inflammatory). This included the following: quinin, ethereal oils, calciimi salts, morphin, nicotin, atophan, salicylates, antipyrin, magnesium sulphate, adrena- lin, serum, plasma, gelatin, silicic acid, starch, methylene blue, salt, water, fuchsin, iodin. In the experiments dealing with intoxication Starkenstein calls attention to a fact that a number of Italian observers had pre- viously noted, namely the antagonism existing between toxic sub- stances (Lusini, Lo Menaco, Kleine, Brunner). THEORIES OP MECHANISM OF REACTION 97 A sublethal dose of the one poison will protect to a degree against a toxic dose of the next poison. When Starkenstein tried out the toxicity of strychnin in normal animals and animals previously in- jected with atophan, milk, or calcium chlorid, the prepared animals were found to be resistant to the poison. With phenol poisoning analogous results were obtained with one exception. While animals injected previously with albumose, atophan and calcium chlorid were more resistant to phenol intoxication, the animals injected with milk were less so. Starkenstein is inclined to the interpretation that this paradoxical result is due to the fact that the phenol is more soluble in the lipoids of the milk and that this lipotropic property brings about a more prompt distribution and the greater activity of the poison. Clinically Starkenstein noted excellent results by the nonspe- cific treatment of herpes zoster, venereal complications, eye and ear diseases and erysipelas; in these cases there was at first an invariable increase in the inflammatory process and the local reaction at the site of the lesion, together with a leukocytosis. Scar formation was ob- viously hastened. Blood sugar was also found to be augmented after the injections. As a result of these studies Starkenstein concluded that the nonspe- cific agents have a definite effect on the permeability of the vessels, and therefore on inflammatory processes; that the irritability of the ner- vous system, both sympathetic and central, seems diminished and that the organism as a result of these demonstrable changes becomes more resistant to such poisons as strychnin and phenol. It is of course known that the irritabilty of the central nervous system is increased during protein sensitization and diminished after protein shock, ob- viously conditions analogous to those studied by Starkenstein. This alteration in the permeability of the capillaries and con- sequent effect on inflammatory foci has also been studied by Luithlen, by Siegert and by Schmidt who consider it of importance in the non- specific therapeutic effect. Rohonyi has suggested that the effect of the nonspecific injec- tions is to produce a neutralizing substance against the invading bacteria and antitoxin. No experimental evidence points in this direction. Pemberton has suggested another factor that may be involved, particularly in the mechanism of recovery from arthritis after intra- venous injection of typhoid vaccine. He calls attention to the im- provement that occurs in arthritis after lowering of the food intake of the body, when the body draws on its glycogen store. According to his studies there seems some relation of the glycogen metabolism and the pathological alterations of arthritis. During the reaction that follows intravenous injections there is every reason that we have an 98 PROTEIN THERAPY increase in the rate at which glycogen is metabolized, and Pemberton believes that the increased catabolism of the glycogen as well as the incidental low food intake that occurs for the day following the in- jection may have some relation to the cure of the disease, although it cannot be the sole factor in bringing about the result. CHAPTER VI TSE PROBABLE MECHANISM OP THE REACTION In discussing the theories proposed to explain the mechanism of the therapeutic processes which we are calling into play when non- specific therapy is used, it will be well for the moment to dismiss the rigid conception of antibody immunity that has been built up on the researches of Ehrlich and the contemporary French and English workers, not because it is unimportant, rather because of the com- plication that it introduces. Antibody immunity is a vital factor in protection against infectious disease and in overcoming actual bacterial infection. In the nonspecific reaction the therapeutic benefit, however, seems largely independent of the specific antigen-antibody balance. The fact that we do not discuss the antibody theory in this connection should not give the impression that it is to be ignored as a factor of defense and of resistance. Intoxication by Protein Split Products. — Antibody resistance has been studied most completely in connection with the neutralization of the specific soluble toxins that are secreted by certain bacteria, notably the diphtheria bacillus, tetanus bacillus, etc. But we are beginning to take greater cognizance of the fact that in dealing with bacterial in- toxication we have to do with other and less clearly defined toxic sub- stances, broadly termed endotoxins to designate the fact that they form an integral part of the bacterial body. Some of these are possibly native proteins to which the infected organism can become sensitized, while others may be primarily toxic to the infected organism without previous sensitization. We must also consider: (a) Preformed protein split products which are toxic. This toxicity may be due to particular molecular grouping as the native protein molecule is broken up in the normal metabolism of the bacterial cell or to the chemical con- figuration of the fragments; those containing the benzol ring with its various addition radicals being most toxic (Baehr and Pick), (b) Protein split products formed as the bacterial protein is frag- mented in the host — after the bacterial cell has died, i.e., not neces- sarily preformed in the bacterium, (c) Toxic growth products derived from the bacterial metabolism and excreted, (d) Toxic metabolic products derived from the pathologic cellular metabolism of the in- vaded organism (Jobling and Petersen, Zimmermann, etc.). In all these enumerated sources of toxic material derived either from the 99 100 PROTEIN THERAPY bacterial cell and its metabolites or possibly from the pathologically altered activity of cells of the invaded body, proteins and their split products are the chief components with which we have to deal.* Schittenhelm has emphasized the general conception that the splitting of proteins (apart from the gastro-intestinal processes) is purely an intracellular phenomenon and that whenever we have to do with extracellular proteolysis we deal with a pathological condition with tremendous inherent possibilities of intoxication. It is therefore oiu: chief concern to investigate and review our present knowledge of protein intoxication, of enzymatic detoxication of the poisonous pro- teins, of resistance to protein intoxication and of the bearing of this knowledge to the problem of nonspecificity. Detoxication. — It is apparent that the fundamental factor in over- coming bacterial intoxication (not due to the soluble exotoxins) lies in the ability of the cells or fluids of the invaded organism to digest the toxic protein fragments (and the native protein to which the organism may have become sensitized) to the lowest degradation product — ^that is, to the nontoxic stage, and in this way overcome the deleterious effect. This detoxication may also be brought about by the formation of addition products, by polymerization and by proteosynthesis in gen- eral. Enzyme activity, then, no matter under what immunological term we wish to classify the particular phase, must be considered among the basic phenomena which have to do with overcoming bac- terial invasion itself. The study of the proteolytic enzymes and their relation to pathological conditions, of the factors that accelerate and the factors that retard enzyme activity should lead us to some final field wherein by controlling enzyme activity we may be able to achieve therapeutic results. The role of the enzymes in pathological conditions has until very recent years been a relatively neglected field of study. Enzymes, whatever may be their nature or their composition, must have formed the basis of the structure upon which the animal organism built up it system of immunity. The unicellular organism must certainly endeavor to overcome harmful extracellular forces by means of its ability to excrete enzymes, and the intracellular enzymes, too, must be called into play when some parasite invades the cell. The path- finding work of Metchnikoff was based on this idea. Specific im- munity must have been a much later development of this primitive and nonspecific factor of resistance. A number of investigators have at various times sought to identify the specific activity of anti- bodies, more especially the activity of complement, with various ♦While this view of the subject is plausible and quite generally accepted we must by no means ignore the fact that even here contradictory evidence has accumulated, a discussion of which will be found in the recent papers of Zinsser and of Tiele. These observers seek to find the source of the intoxication due to the "endotoxin" producing bacteria, as well as the intoxication in anaphylaxis, in certain physical alterations of the serum, as yet not clearly defined. THE PROBABLE MECHANISM OF THE REACTION 101 known enzymes, but without apparent success. The most recent work that has aroused the interest of the medical profession in this con- nection has been that concerned with the so-called Abderhalden re- action. Abderhalden sought to show that whenever a specific protein was introduced parenterally into the blood stream, specific enzymes were mobilized which digested the protein so injected. This reaction of the enzyme and the substrate was demonstrated by means of the dialysis reaction. Unfortunately for this work the center of interest was early shifted from a study of the fundamental phenomena to par- ticularistic and technical disputation of details involved in the clini- cal popularization of the test. Abderhalden was undoubtedly preju- diced in favor of the idea of the specificity of proteolytic enzymes because of his study and his familiarity with the beautiful specificity displayed by the enzymes that hydrolyze the carbohydates. How- ever, when one considers that the variety of carbohydrates with which the organism has to deal is relatively limited as contrasted with the endless combinations possible in the protein molecule, this prejudice is not necessarily logical. Possibly Abderhalden was influenced, too, by the immunological conception of specificity; indeed he seems to have had the hope that just this problem would find its solution in the specific proteases. The proof, however, that the Abderhalden reaction itself did not have the merit of strict specificity that its originator claimed for it (Plaut, Peiper, Jobling and Petersen, etc.), carried with it the tendency of checking further investigation in this field. In this country a number of workers became interested in enzyme activity in relation to pathological conditions. Among these may be mentioned Opie and his associates and Jobling and his coworkers. Their papers have appeared chiefly in the Journal 0/ Experimental Medicine during the years 1910 to 1917. Buchner, Matthes and Krehl, Schmidt-Muhlheim, Schittenhelm, Fano, De Waele, Beidl and Kraus, Weichardt, Vaughan, Friedberger, Pfeiffer and numerous other investigators have established the causal relation between intoxication and fever and the protein split products. We therefore assume that with bacterial invasion the intoxication of the organism is due very largely to proteins and their split products derived from the bacteria. We must also deal with toxic protein material that is derived from the pathological tissues of the patient and perhaps from alterations in the colloidal state of the blood plasma that take place under certain conditions. For the moment the source of the proteins need not concern us. If we are justified in ascribing major importance to the protein derivatives, we are assuredly justified in studying the mechanism of detoxication which must primarily involve the role of the proteolytic ferments that will break down the toxic complexes to nontoxic forms. 102 PROTEIN THERAPY The Serum Enzymes. — In the blood stream several proteolytic enzymes are known to occur. These include the leukoproteases : (a) one that acts in a slightly alkaline or neutral reaction and is capable of splitting native proteins largely to the proteose stage; (b) one that acts in a reaction slightly acid, with a digestive range similar to the first; (c) an erepsin-like enzyme active in a neutral medium and freely hy- drolyzing proteins from the intermediate stages (albumoses and pep- tones) to the amino acid forms. These enzymes seem to be derived from disintegrating but not from living polymorphonuclear leukocytes and fluctuations in the peripheral leukocyte count are not indicative of the relative titer of the enzyme concentration. (Hedin, Jobling and Petersen, etc.) Apart from the leukocytes as sources of proteolytic enzymes we must consider those derived from the gastro-intestinal tract, the large abdominal organs and from areas pathologically altered, either by infection or by trauma, burns, toxins, etc. These enzymes include a tryptase or protease — a polyvalent trypsin-like ferment active in a neutral or slightly alkaline reaction. In the human this enzyme is normally present in only a very slight amount, but under certain conditions (pneumonia, leukemia) may be markedly increased. In cer- tain animals one can also increase the amoimt by moderate stimulation of the liver (by Roentgen irradiation, etc.). In many of the smaller laboratory animals these enzymes are present in a considerable amount in the serum, especially in those that have no leukoprotease present in the leukocytes (guinea pigs, rabbits, etc.). Serum ereptase or peptidase is an enzyme able to digest partly hydrolyzed proteins to the animo acid stage. It is normally present in himian serum in small amount. But after feeding it is increased, probably entering the blood stream from the gastro-intestinal tract via the lymph cm-rent. It can also be augmented by stimulating the gastro-intestinal tract by means of short Roentgen ray exposure. In smaller animals this enzyme is present in relatively large amounts. We have to deal in general with two types of proteolytic enzymes, (a) the true proteases capable of digesting the native proteins, and (b) the erepsin-like enzymes (peptidases) that are able to digest only partly hydrolyzed proteins ; both active in neutral or at the most in a reaction varying from the neutral to only a slight extent. The enzymes of the first variety are, however, not active under normal conditions in the blood serum because their activity is inhibited or checked by the antiferment of the serum. In small localized areas the amoimt of true protease liberated by disintegrating leukocytes or by other causes may be sufiicient to saturate the antiferment and in this case digestion may go the entire stage from native protein to amino-acids. As a general rule the protease derived from the leu- kocytes, active in the slightly acid reaction, is more active than the alkaline acting protease and autolysis therefore goes on much more THE PROBABLE MECHANISM OF THE REACTION 103 rapidly when the hydroxyl-hydrogen ion balance veers to the acid side. The increasing acidity acts, too, in hastening autolysis in an- other way in that the antiferment property of the serum is diminished as the acidity is increased. Both factors enter into the speeding up of enzymatic process when the reaction becomes slightly acid. These proteolytic enzymes of the serum must not be confused with serum complement or alexin, as is frequently the case in im- munological literature. In the antibody lysis of bacteria Jobling and Petersen showed that there was no associated proteolysis. What- ever type of enzyme activity may be involved in bacteriolysis, pri- marily it is not associated with proteolytic digestion. The evidence, uncertain though it is, rather indicates that the lipolytic enzymes are more closely concerned in this type of reaction. Inasmuch as the true proteases of the serum are present only in relatively small amounts under normal conditions and are active only under special conditions (the decrease of the inhibitory factors) and then only locally, it is evident that the ereptases may assume greater interest. The ereptase is potentially a detoxicating agent. Bearing in mind the fact that the toxic proteins are proteins that are already par- tially hydrolyzed or conjugated proteins dissociated from their non- protein radical, an enzyme that will attack these partially hydro- lyzed proteins (albumoses [proteoses], peptones, etc.) and hydrolyze them to the amino-acid stage must necessarily be an agent of de- toxication. A mobilization of this enzyme could then be considered only as of beneficial significance, never as a factor in the production of an intoxication, although the enzyme may appear accompanying intoxications. A spontaneous increase in the amount of this en- zyme during the course of disease should therefore be coincident with clinical improvement, and conversely, the diminution of the enzyme should permit the accumulation of toxic split products and an in- crease in intoxication. It may be permissible to digress for a moment in order to study this condition in greater detail and examine the relations as they are presented to us in lobar pneumonia. Pneumonia. — For a number of years investigators have emphasized the possibility that a definite relation exists between the inception of the crisis and the activation of the proteolytic ferments in the area in- volved. Edsall and Pemberton in particular advanced this idea and endeavored to make the logical clinical application of hastening auto- lysis as a therapeutic measure in cases of delayed resolution. Later Jobling and his associates studied the serum ferment and antiferment during the course of lobar pneumonia, noting that just preceding the crisis protease was demonstrable in the serum while the antiferment began to diminish from the high titer prevalent throughout the early part of the disease. The work of Weiss on the crisis is similar in char- acter and sets forth analogous conclusions. Lord and Nye have 104 PROTEIN THERAPY approached the same problem and lay stress on the changes that occur in the hydrogen ion concentration of the exudate of the pneu- monic lung, which, on being increased, makes possible a suitable reaction for the augmented activity of the proteolytic enzymes. Ab- derhalden in investigating the enzyme activity of pneumonic sputmn before and after the crisis was not able to determine the presence of any peptidase before the crisis, but with the inception of the crisis found such enzymes present in large amounts. The fundamental idea underlying the studies in this direction has been that apart from the intoxication arising directly from and incident to the growth of the pneumococcus, toxic split products were absorbed from the exudate, which indeed could be considered a mass of foreign pro- tein undergoing slow digestion before the crisis. Active autolysis once under way, only the lower and nontoxic split products would be absorbed and the environments for the further proliferation of the pneumococcus would become unfavorable, for, as Almaggia has shown, pneumococci are very susceptible to products of autolysis. In this phenomenon the reaction is primarily a local and a cellular one, in- volving the liberation of sufficient leukoprotease from the disintegrat- ing leukocytes and the gradual alteration in the reaction of the medium so that the inhibitory factors — i.e., the alkalinity and the excessive amount of antiferment — are overcome. Of the varieties of the proteolytic enzymes entering into this reaction, Jobling and his associates studied in particular the protease, as before mentioned, while Petersen and Short studied the ereptase titer. We can assume that this latter form of enzyme activity would be of favorable import in the process inasmuch as it could lead only to detoxication through the complete destruction of toxic pro- tein fragments. The first two charts illustrate common clinical pictures in lobar pneumonia, the one recovering by lysis, the other terminating fatally on the ninth day of the disease. Case No. 1. White man, 43 years of age, entered hospital March 14, 1917, after an illness of 36 hours. Diagnosis : Lobar pneumonia of lower right lobe; course uneventful, recovery by lysis by the tenth day. (See Fig. 4.) It will be observed that the ereptase titer (peptidase) remained uniformly low during the first three days when examined, then in- creased to approximately 3 times the former titer on the 8th day of the illness and then again diminished. The increase coincides with the period of clinical recovery. The antiferment titer shows the usual increase early in the disease and a diminution during the period of lysis that is frequently observed. Case 'No. 2. Colored man, 27 years of age, entered the hospital April 18, 1917, having been ill for two days. Diagnosis : Lobar pneumonia of the lower left lobe ; aortic regurgitation. On the third day there were evidences THE PROBABLE MECHANISM OF THE REACTION 105 of the involvement of the right lobe as well, and the patient became pro- gressively worse, death taking place on the ninth day of illness. It will be noted in Figure 5 that the titer of the ereptase is in this case the reverse of the previous one, a decrease being appar- .rEaCERATUKB CUB7E (V iSenun samples tal:enj PEPIIDASB TITER 0? 3EHUM ItaltB 1 3 e 1 - ''^ X^ ^ ^ V KUlteKH^T or SSHUU Fig. 4. — The ereptase (peptidase) and antiferment titer during the period of lysis in pneumonia. 106 PROTEIN THERAPY ent after the 3rd day that persisted until death. The antiferment during this time progressively increased. This reaction curve of the enzymes is characteristic for fatal pneimionias. The case illustrated by Figure 6 is perhaps the most interesting in illustrating the relation of the ereptase titer to the clinical condition of the patient. TialPERArDEB 0UK9E n... 4-i4nt m' ^o £i ?' ^3 ^i >w-fi>i 3 ' r i. . ■ ■ r ■ ]i - Y ;< , < _JlS ^< lor 1 1 lOfp ^ P ; ±~"± 105- qrt + -- ^°*l 1 1 lilh\!l^l[ilJI ill IM mNiIi io3f fc--: — ±: ^^ f-? ,„r"^ = --E- = -:::ZE-5EE±^=bi±EEE;^E;EE lor i_:i::S-i^::---^s-^ -------- ^t-^,-- + -_ .„.= = = ;-Zi = z = = = -; = :=!?=i::; = = = = ^ = = i = = = = = ; = 100 =F^ ^-'Z ^^5 4 _|_ \ 99' =C^ -L_^ ^ ■M^"--T"=^"*-"p^=^"'^TlT"r"*" y tSeruiB 'collected SEHUH PEPIIBASB * ■■ ■ ' ^^^^ ^""'^^_„-- PER care tstiTsaiBST ot sehuii jBhltltlon X : / / : / Fig. 5. — The ereptase titer and antiferment in pneumonia terminating in death. THE PROBABLE MECHANISM OF THE REACTION 107 Case No. 3. White man, age 34 years, entered the hospital on March 5, 1917, with a diagnosis of lobar pneumonia of the lower right lobe of three days' standing. The course of the disease was quite protracted. By the 4th day after admission the temperature had declined and the patient TEMJERATnB£ CTOVZ (Stiaddd zT>n»s Indicate serlodff of elljileal ia^tivtsBiA. ) Fig. 6. — ^The relation of the clinical condition during pneumonia to the serum ereptase and antiferment. was clinically improved when an extension to the middle lobe occurred. The temperature increased for several days, then declined to the 8th day. At about this time the lower left lobe became involved, which entailed an- other rise in temperature, followed by a period of partial recovery with a long period of violent temperature fluctuations superseding. A month after admission the patient was still running an irregular febrile course 108 PROTEIN THERAPY althougli greatly improved clinically. At this time a final blood examina- tion was made. We have in Figure 6 shaded the portions when the patient was making clinical improvement after each lobe was involved. The evidences of clinical improvement — pulse, respiration, subjective symptoms and physical findings — coincided with typical changes in the enzyme concentration of the serum as can be observed from the chart. An increase in the ereptase titer took place during each period of improvement studied (the time blood samples were drawn is indi- cated on the chart by X) but declined when the clinical condition was unfavorable. The antiferment on the other hand invariably tended to diminish during the favorable periods and to increase with the increase in the lung involvement. These alterations are so typical and so clear cut that their clinical significance cannot well be ques- tioned, even though the interpretation of the changes may be open to discussion. In the pneumonia that terminates by crisis or by lysis an in- crease in the ereptase titer was invariably observed by us either preceding or accompanying the clinical change. In cases that termi- nated unfavorably such an increase was not found, the titer in these cases usually remaining below that observed in normal individuals. The antiferment titer of course does not directly influence the activity of the ereptase, nevertheless as the patient improves the antiferment diminishes. The entire condition is one therefore that favors a rapid digestion of proteins. Ferment-Antiferment Balance. — ^When we now come back to our consideration of the true proteases we deal with a reaction which is much more complex in its character and its possibilities for two rea- sons: (a) The enzyme action may involve the splitting of native pro- teins to the higher split products. If this concerns a nontoxic native protein to which the body is not sensitized it implies that a new toxic substance is produced in the organism itself. If on the other hand it involves a toxic protein or one to which the organism has become sen- sitized, then the enzyme can act, too, as a detoxicating agent when it splits the protein, (b) The ferment action is balanced by an anti- ferment and we have therefore to deal with two variable factors. For purposes of illustration the pneumonic condition will again serve. Let us assume that the pneumonic focus with its mass of cellular detritus represents, for the normal tissue, simply so much foreign material from which it must free itself by digestion. As long as digestion proceeds slowly, higher and more toxic split products will be absorbed as such; digestion proceeds slowly because the leu- kocytes are still living (therefore not shedding their ferment), be- cause of the alkalinity of the reaction of the exudate, and the large THE PROBABLE MECHANISM OF THE REACTION 109 amount of antiferment present in the exudate which, of course, inhibits digestion. If now the antiferment is lowered, either because of the change in the reaction or because it is saturated by protease mobilized from some other organ, while at the same time protease and ereptase are liberated locally, the patient will be detoxicated promptly as digestion changes from a state of inhibition to one of acceleration. In this case the liberation of the true protease would be associated with detoxication. Let us assume on the other hand that we are dealing with a quiescent tubercle, one that is sufficiently protected by a connective tissue encapsulation to prevent the absorption of toxic material from the focus that has been walled off. If for any reason the identical serum reaction or local reaction that has been hypotheticated above should occur in such a patient quite the opposite clinical effect would ensue. The liberation of protease would, along with the reduction of the antiferment (protective) titer, promptly begin to digest away the connective tissue of the capsule and allow some of the toxic material from the focus and the native proteins of the focus as well, to escape into the general circulation with a resulting intoxication of the patient and activation of the focus. Fluctuation of the protease titer can therefore be assumed to influence pathological processes in a fundamental way and at times with diametrically opposite clinical results. But this fluctuation of the protease is under the control to a certain extent of the antiferment or inhibitory substance, which thereby becomes an integral part of the balance which we have under consideration. Here we leave the enzymes and have to deal very probably with lipoid substances. The antiferment is not an antibody in the immunological sense, although it was early so con- sidered; it consists of the highly dispersed unsaturated lipoids of the serum and of the lymph and the tissues.* Its titer varies there- fore with at least three conditions: (1) the amount of the lipoids present, (2) the dispersion of the lipoids, (3) and the chemical struc- ture, that is, the degree of unsaturation. All these conditions are subject to considerable variation and any of them may cause a change in the titer. Thus changing of the dispersion by acidifying, by salting and by heating to a sufficient degree inactivate the antiferment, physical adsorption by certain chemically inert adsorbing surfaces such as fuller's earth, barium sulphate, agar, etc., lowers the titer; solution of the lipoids by chloroform, ether, acteone, and certain of the alco- hols removes the antiferment from the serum. The soaps of the unsaturated fatty acids are perhaps the most comparable substances which are available and with them one can simulate many of the * The evidence concerning the nature of the antiferment is conflicting. Bach and Teale were not able to confirm the results of Jobling and Petersen. The papers of Tachigara, Fujimoto, etc., should be consulted. 110 PROTEIN THERAPY reactions that can be obtained with the serum antifennent. There is much evidence that the antifennent lipoids are in more or less close physical combination with the serum albimiin. With this fraction they are thrown out of solution with the usual methods of separating the serum proteins. Clinically it is known that the antiferment is augmented during a number of conditions, notably in the acute infections, in pregnancy, in carcinoma and cachectic states in general; following anaphylactic and other shock reactions, including therapeutic vaccination, and in certain pathologic processes of the central nervous system char- acterized by degenerative changes. In other words, the increase in antiferment is part and parcel of a general reaction phenomenon of the body. This increase seems purposeful in that an increase in the antiferment titer would tend to counteract the negative nitrogen balance incident to the heightened destruction of proteins of the body commonly observed in toxic conditions. This relation of the antiferment to the rate of protein metabolism has been worked out in rabbits and dogs during inanition by Jobling and Petersen. They found that the execretion of nitrogen in the starving animal was in inverse proportion to the amount of antifer- ment in the senmi, as will be apparent from the following table: Animal % Inliibitioii Nitrogen Excreted No. (Average for 5 Days) (Total for 5 Days) 1 41% 4.24 gms. 2 66% 2.95 gms. 3 71% 1.97 gms. 4 73% 1.99 gms. This holds true evidently for the himaan, although it has not yet been fully worked out in normal individuals. Wilson, for instance, noted the increased storage of nitrogen during pregnancy, a condi- tion associated with a well-marked increase in the antiferment titer. After vaccine shock or protein shock we often find the same increase in weight during the time when the antiferment titer is increased. Thus Holler injected himself over a period of two weeks with daily intravenous doses of 1 c.c. of deuteroalbumose solution (10%) ; there was no clinical reaction corresponding to that observed in patients ill from any disease. The chill, sweating and temperature were all absent but he gained in weight during the course of the injections. This has been the general experience of the clinic as well as the labora- tory. rf we keep these simple enzyme balances in mind, many of the changes which are encountered following nonspecific therapeutic in- jections will appear quite simple and logical. One balance consists of (a) the true proteases capable of splitting native proteins all the THE PROBABLE MECHANISM OF THE REACTION 111 way to their lowest split products. These can act, therefore, either as (1) intoxicating agents when splitting nontoxic native pro- teins to the toxic stage, (2) or as detoxicating agents when free to split the partial products of digestion to the nontoxic forms or when splitting a native protein to which the body has become sensitized. These enzymes are counterbalanced by (b) the antiferment of the serum, a variable factor. The ereptase (c) or peptolytic enzyme, capable of splitting only the partly hydrolyzed proteins (toxic) to the amino acid stage (nontoxic) and therefore to be regarded as a detoxicating agent, not counterbalanced by an antienzyme and there- fore free to act whenever present in the serum and the tissues. This conception of a balance of variable factors which at one time may act in a detoxicating manner, and in other cases may intensify a disease process, has been discussed fully in several papers and we need go no further into the details at this time. (Jobling and Pe- tersen, Jobling, Eggstein and Petersen, and Petersen.) Nonspeciiic Injections in Carcinoma. — ^Von den Velden, who was one of the very first to use nonspecific methods in the treatment of disease (1906), early expressed the hypothesis of enzyme action as the basis of the therapeutic results and has maintained this ever since. He began his work using small subcutaneous doses of serum albumin and ovalbumin in 5 and 10% solution. Prom these he passed to the use of convalescent serum, tetanus antitoxin, normal horse serum, and finally to the use of milk injected intramuscularly. In treating several cases of inoperable carcinomata he observed that following the injection the pa- tient reacted with a period of malaise and of fever for a period of several days and then for a time the general condition of the patient improved. There were a gain in weight, a better appetite, lessened pain, etc. Under the treatment the tumor would, at times, show de- cided regressive changes. With tuberculin injections Dabney ob- served a similar effect. This experience of von den Velden is cited in this connection merely because it is typical of the result achieved by all the non- specific agents in the treatment of carcinomata and other malignant diseases. Beard got the same result when he injected trypsin; Coley's fluid and tumor autolysates give a similar reaction; colloidal metals give it. The mechanism is the same in all cases, the clinical picture is identical, the results are similar, i.e., there are evidences of a decided focal reaction, even of tumor regression in size, but the actual proliferation of the neoplasm is not checked because the vascularized portions of the tumor are in nowise interfered with, the regression being due to an increase in the necrosis of the cen- tral and less vascularized portion of the neoplasm. Let us assume that an injection of milk has been made intra- muscularly in such a carcinoma case. The temperature heretofore has been practically normal. Several hours after the injection there 112 PROTEIN THERAPY may be a chill, the temperature rises sharply and instead of dropping after a few hours, as it would in an ordinary infectious case, stays high for from 24 to 48 hours. Usually this reaction is accompanied by general malaise and every indication of increased inflammatory reaction about the tumor. After this period the temperature drops, the patient feels better than before the injection, gains in weight, pain is lessened and retrogressive changes are noted in the tumor. It has been shown that following such an injection of a nonspecific agent a definite shifting of the ferment-antiferment balance takes place so that the antiferment is lessened and the activity of the protease increased. At the tumor site this means that this protease begins to digest some of the native proteins of the necrotic debris. Toxic split products are liberated, they diffuse out from the focus into the surrounding healthy tissue, cause irri- tation, the attraction of leukocytes, vascular engorgement, increased tension and with it increased pain. It is during this period of absorption of the soluble split products that the febrile period and systemic effect of a general malaise are observed. The leukocytes attracted by the digestive inflammatory reaction partly succumb, partly migrate from the field. A certain amount of leukoprotease is certainly liberated from them. During this period, too, we have an increase in the amount of nitrogen excreted — i.e., a negative balance. Then follows the period of recovery of the balance and the change to the reparative side. The antiferment is increased over the amount present before the injection; the protease action is checked, in- creased amounts of ereptase make their appearance and detoxicate whatever remnants of split products still remain near the focus. During this period the patient manifests every sign of clinical im- provement — euphoria, increase of weight, appetite, etc. The in- crease of weight that follows the increase in the antiferment curve has been worked out in a series of clinical conditions by Breed. The tumor in the meantime may have actually decreased in size by the effects of the reaction because a certain amount of necrotic material has been digested away. It is of course evident that the living tumor cells need in no way be susceptible to the effect of the enzymes and that the reaction, as far as a matter of cure is con- cerned, is not to be regarded as a therapeutic agent for such malig- nant conditions. It may have a place in the therapy of malignant conditions if by producing an inflammatory reaction repeatedly we can, either by cellular or vascular changes, aid in the resistance of the body to the neoplastic invasion (Theilhaber). Until we have certain knowledge of these factors in tumor growth we must un- fortunately deal more or less empirically with the conditions. Nor must it be forgotten that the inflammatory reaction that is brought about may at times not be helpful but may actually stimulate the tumor cells to greater activity and malignancy, and therefore be of THE PROBABLE MECHANISM OF THE REACTION 113 decided harm to the patient. If, however, it is clearly kept in mind that only clinical improvement and amelioration is sought and the measures used in this sense, then it may have a place in our legiti- mate methods of treatment in inoperable cases. This reaction and its effects on the local condition as detailed here is quite similar to that which has been studied in regard to the tuberculous focus and is more fully entered into elsewhere. The Reaction in Local Inflammation. — It is of paramount impor- tance for the purpose of studying the role of the enzymes in this non- specific reaction to keep in mind the fact already emphasized in the introduction that the reaction of the body to injury, whether chemical or physical or bacterial, is, within certain limits, always the same. In- flammation, no matter how produced, is fundamentally alike in char- acter and in its results. If we view recovery from this point of view it is instantly ap- parent that nonspecific therapy offers something more substantial than an evanescent therapeutic fad or a bizarre fancy of the day in medi- cine. It is rather a procedure that has as the foundation of its mechanism biologic processes at once the most primitive and the most universal of all those over which the organism disposes in its measures of defense and resistance to trauma and disease. If it can actually be demonstrated that inflammation is altered by nonspecific reactions we can conceive that the hastening of the process will be evidenced in two ways: in one, that a beginning in- flammatory process will subside without suppuration, in the other, that an advanced or rapidly advancing inflammatory process will undergo softening and resolution. As a matter of fact these are precisely the reactions that do take place when we treat local inflammatory processes by nonspecific means, the venereal bubo being a condition of this type that has been extensively studied. (Odstreil, Miiller, Schneller, Antoni, etc.) When a bubo is treated by the intragluteal injection of milk one can observe a definite focal reaction which reaches its maximum in from six to eight hours with an increase of pain, local tenderness and hyperemia. Following this a period of analgesia sets in. If such a bubo is taken under treatment early, suppuration never takes place, the process subsiding without it. If the local infiammation, on the other hand, is further advanced when treatment is commenced, softening occurs soon after the in- jection, but if further injections are then made no incision or drain- age is necessary, according to Miiller, because the necrotic and softened material is rapidly absorbed. In only one out of 25 cases did Miiller find it necessary to drain the bubo. This effect on local inflammatory processes, which has been dis- cussed at greater length in the chapter on The Focal Reaction, can be demonstrated after nonspecific injections wherever the lesion is so 114 PROTEIN THERAPY located that it can be observed directly, as in the skin or mucous mem- branes. In the deeper tissue it is made clinically evident by the invariable symptomatology that follows the injections — first an in- crease in the evidence of pain and temperature, later a complete subsidence, either transient or permanent as the case may be. We believe that the explanation for these phenomena is relatively a simple one, although it involves at some time practically all of the tissues and structures about the focus of inflammation, changes in both the blood and lymph vessels and nerves, as well as in the local tissues directly involved. With the injection there is first apparent an increased excitability of the central nervous system and the sympathetic system; later this subsides and ends in a period of lowered excitability. There is at first apparently a direct effect on the capillaries so that they become more permeable — the lymph flow is increased, the tension of the local inflammatory focus is greater — the pain augmented. Later the reverse sets in and the capillaries become less permeable. But in the meantime certain alterations have occurred in and about the focus. We may assume for the purposes of illustration that we are dealing with this early bubo — a certain amount of toxic ma- terial (protein split products from the necrotic tissue of the venereal focus, bacterial endotoxins, perhaps soluble toxic materials from bac- teria, perhaps a few bacteria themselves have filtered in along the lymph channels) has been brought to the gland and has incited an inflammatory reaction. This finds its expression in the hyperplasia of the endothelial cells of the lymph channels, in an attraction of polymorphonuclear leukocytes and the exudation of fluids into the tissues. As yet there has been no necrosis. The tissue fluids bathing these cells contain little protease or ereptase but much antiprotease (antitrypsin) so that digestive proc- esses are held in abeyance. Under ordinary conditions the intensity of the intoxication is therefore not diminished and tissue necrosis finally results, both the fixed cells and some of the polymorphonuclear leukocytes being affected. From the latter we now have the libera- tion of a considerable amount of protease, sufficient to saturate and thereby negate the effect of the antiferment in a circumscribed area — digestion begins to take place — solution of tissue and fluctuation. If on the other hand at an early stage the patient is given a nonspecific injection the focus is very promptly flooded — the lymph flow as measured in the thoracic duct is increased fourfold — and in the fluids now exuded (the permeability of the capillaries being in- creased by the nonspecific injection) there is carried considerably more protease as well as ereptase, while the antiferment is diminished. The toxins present are not only diluted but their digestion is com- menced by the enzymes. Necrosis is prevented by this effect on the toxins. The capillaries now become less permeable, the fiuids THE PROBABLE MECHANISM OF THE REACTION 115 are diminished, tension and pain lessened and restitution to the nor- mal takes place. On the other hand we may suppose that the process had already- proceeded to the stage of actual destruction of some cellular ele- ments. We bring about the nonspecific reaction at this period. Here the flooding of the area with exudate, the lowering of the antifer- ment, the increase in the proteolytic enzymes will of course accelerate the autolytic processes already commenced. But this digestion will coincidently tend to diminish the acute toxic effect of the split products and other toxic protein material that originally caused the inflamma- tion; solution of the necrotic focus with subsidence of the acutely inflammatory phase of the reaction will result and the further treat- ment by nonspecific injections will merely aid in the absorption of this soluble material from the focus. It becomes clearly evident therefore that the identical reaction may alter an inflammatory focus in seemingly diametrically opposite ways — restitution without sup- puration, as well as the acceleration of suppuration with absorption following. The Reaction in Inflammation of Nonbacterial Origin. — Nor must it be presumed that this process as here depicted holds true merely for a bacterial process. A similar reaction takes place when we deal with gout and when we deal with a chemical injury such as that following a typical "war gas" effect, as for instance mustard gas. Von den Velden's observations will be of interest in this respect. "I had considerable opportunity in the field to study the effect of nonspecific therapy in mustard gas poisoning, being led to try the method not only by the clinical observation but by the autopsy findings as they presented themselves to us. I need but briefly men- tion in this connection that the effects of the gas, as shown in the effects on the mucous membrane of the respiratory tract, varies from the mildest catarrhal inflammation to widespread and extensive croupous and finally ulcerative changes. In view of the oftentimes decidedly malignant and complicated course of the clinical picture, I endeavored to treat as early as possible the cases in which the toxic manifestations were most severe, or those in which the clinical picture was one becoming progressively worse from day to day, in order to avert the secondary pneumonias and the abscess formation and especially the ominous bronchial stenosis so common a sequel. From my previous experience with nonspecific therapy an early inter- ference by means of an acceleration of the inflammatory processes might be expected to yield very gratifying clinical results. Of course, these might be of purely symptomatic nature. "While my experience extended over a larger number, I have recorded observations on approximately 100 cases of gas poisoning treated either with horse serum (5-10 c.c. intravenously), milk (10- 20 c.c, intramuscularly) and tetanus antitoxin (5-15 c.c, intrave- 116 PROTEIN THERAPY nously) with from one to three injections. The cases included mod- erately severe incipient cases with severe hoarseness and beginning bronchial stenosis without secretion; severe cases with croupous in- flammation extending from the pharynx deep into the bronchial tree, some of them already complicated by pneumonia; as well as older cases with severe bronchorrhea (with as much as 3 liters of se- cretion per day) with evident peribronchitis, pneumonia, abscesses and in some instances lung gangrene. It is natural that in these latter cases the injection had little or no effect and that the most satisfactory results were achieved in those of the first category. Inasmuch as a spontaneous recovery is, however, very common in this class of patients this result was to be expected. It was in the second class of patients, however, that the most convincing evidence as to the value of the injections — and this not only in my own estimation but in that of my attending colleagues as well — was forthcoming. In from 6 to 10 hours after the injection the first favorable results of the injection were to be noted, first in a diminu- tion of the stenotic symptoms — lessening of the cyanosis, improve- ment of respiration, diminution of the cough and a freer secretion. Very instructive was the solution of a membrane that had been present in the pharynx of a patient and which could be observed readily. And to this local effect, which was of far-reaching thera- peutic benefit in the further progress of the lung pathology, as well as indirectly on the circulation, there was added, sometimes only after two or more injections, a more or less pronounced critical drop in the temperature curve, an effect the origin of which one may ex- plain in a variety of ways. I unfortunately have not been able to tabulate the results as compared to cases not treated with injections because of fortuitous circumstances. "The success, which surely cannot be specific in any way, corre- sponds to experience gained with nonspecific injections in other dis- eases and the effect on the pathological process is similar: — a marked local effect on the more or less severely inflamed mucous membrane of the respiratory tract with an acceleration of the dissolution of membranes, a cleaning of ulcerative processes and perhaps an in- hibition of inflammatory processes just beginning. The success was so frequent and apparent that chance was to be excluded. "On the skin lesions the injections seemed to have no effect. With collargol intravenously injected, I gained the impression that ef- fects similar, but not so striking, were to be obtained, and it may be of interest to note that Aschoff obtained comparable re- sults in the treatment of gas poisoning by injecting diphtheria anti- toxin." General Inflammations of Bacterial Origin. — So much for the therapeutic effect to be observed on local pathological processes. When we deal with general infections we meet conditions less THE PROBABLE MECHANISM OF THE REACTION 117 simple and in which speculation and conjecture must enter to a larger extent. Perhaps it will be most satisfactory to discuss the status of our information in a definite variety of diseases, each dif- fering in fundamental pathology, and each yielding different results when nonspecific therapy is used. (A) In typhoid fever we deal with an infection originating with a gastro-intestinal infection followed by an infection chiefly of the lymphopoietic system and a concurrent bacteriemia. Here the in- toxication is principally due: (1) to native proteins derived from the typhoid bacillus and to which the organism has become sensi- tized diiring the incubation period of the disease, (2) to very toxic protein split products contained in the body of the bacterium (endo- toxins), and (3) to split products from the bacterial cell when it undergoes proteolysis. The disease is one to which an active im- munity can be established. (B) In pneumonia, on the other hand, we are dealing with an in- fection differing from this materially. Leaving undetermined its method of invasion — whether primarily a blood invasion that localizes in the respiratory tract or an extension directly along the respiratory tract (which seems most probable), we deal with a localized inflammatory process, probably without sensitization of the body to the native protein of the pneumococcus, a process in which the toxic manifesta- tions are due to an absorption of the higher split products derived from an inflammatory exudate (fibrin, cell detritus, etc.) located actually on the surface of the body (considering the pulmonary alveoli in their actual relation to the surface an invagination, not from their mere anatomical position as part of the internal organs) . Be- cause of the vascular supply the alveolar surface is naturally an ideal absorbing structure, so that, while largely isolated during the course of a lobar pneumonia from the general circulation, absorption is still sufiiciently great to cause a profound intoxication. The pneumococcus protein itself is not particularly toxic and as already stated the organism not necessarily sensitized to it; the bulk of the toxic manifestations must come from the splitting of the exudate in the pulmonary alveoli. It will be recalled that Kaznelson found the split products obtained from fibrin particularly toxic. Here we deal with recovery frequently by crisis rather than by lysis and with an immunity of low grade and of relatively short duration. (C) Finally we might take as an example a pure septicemia of the streptococcus type, without localization, where intoxication is as- sociated with marked virulence on the part of the organism rather than by the production of a soluble toxin from the bacterium or a toxic autolytic product from tissues of the invaded host. Typhoid Fever. — Our observations in typhoid fever are perhaps most complete and from them we may be able to construct a picture of the processes that follow the nonspecific reaction. Let us assume that 118 PROTEIN THERAPY we have given a proteose injection to a typhoid patient during the first week of the illness. He has responded with the typical chill, a sweat, rise in temperature curve, and a leukocytosis. Following the reaction his temperature comes to normal and remains so, the patient feels well and as far as can be determined is clinically cured. In some 20-30% of typhoid patients injected we can observe precisely this result. What has cured the patient? 1. It has been stated that despite this clinical recovery typhoid bacilli may in some instances still be cultivated from the blood of the patient several days after the injection (Rohonyi). Decastello's work throws much doubt on this particular point. 2. The patient may still present rose spots, an enlarged spleen, a positive diazo reaction and a leukopenia (Liidke) ; Holler in his series only noticed the occasional splenic timior after the recovery. 3. Healing of typhoid ulcers takes place within a few days after the injection, as determined by autopsy in patients dying of inter- current disease, after recovery by means of nonspecific therapy (v. Wiesner). 4. Fluctuations in the antibody concentration of the serum do not account for the recovery. In some cases they are increased, in others actually diminished, despite comparable clinical results. Nor is the hypothesis valid that when diminished it affords evidence that the antibodies have been used up during the process of recovery. Recovery from typhoid takes place normally in leukemic patients who never produce antibodies (Moresci, Howell). 5. The cells of the organism are all stimulated (omnicellular plasmaactivation of Weichardt) when injected intravenously. The stimulation can be measured in the increased activity of the glandular parenchyma, in increased motility of smooth musculature, in the in- creased work capacity of the heart muscle. 6. The permeability of the cells is altered. Due to this effect and the coincident stimulation above mentioned, enzymes, fibrinogen, thrombokinase and glycogen are thrown into the circulation, and anti- bodies, if the organism has been previously sensitized, are also dis- charged from the cells and flood the blood stream. 7. The altered permeability of the cells finds further expres- sion in the augmentation of the lymph flow, directly to be observed about an inflammatory focus or to be measured at the thoracic duct. It is also manifest when the permeability (to certain dyes) of the capillaries about an inflammatory focus is studied. The endothelium becomes at first more permeable, later less so. 8. This change in the permeability of the cell membrane whereby the exchange outward and inward is augmented must of course de- pend on actual changes in the physical structure of the lipoid- phase which probably forms the membrane of the cell. 9. This change in the membrane of the cell probably accounts THE PROBABLE MECHANISM OF THE REACTION 119 for the increased resistance to intoxication after the injection and forms part of the mechanism of antianaphylaxis. Whether an actual loss of lipoidal constituents of the cell membrane takes place which, when thrown into the circulation, then form part of the antiferment, is not determined. 10. An increase in the antiferment of the serum occurs after the injection and persists as a rule for some days. 11. The alteration in the cell membrane is evidenced further- more by the change in the irritability of the central nervous system and in the sympathetic nervous system. 12. There is finally a mobilization of leukocytes due to a more or less specific stimulation of the bone marrow. While all these changes are brought about there seemingly are two that are of vital importance — the stimulation of the cells — plasma stimulation of Weichardt — and the alteration of the permeability of the cellular membrane. All the others are of interest and very likely to take some part in the result, but all are more or less due to these two fundamental changes. There is an increased tolerance to intoxication. The patient, de- spite the fact that he may still have a positive blood culture, no longer is sensitive to intoxication. The experimental basis for this clinical observation has been laid by Starkenstein who demonstrated that after a variety of nonspecific injections the organism becomes more resistant to intoxication, even to poisons such as phenol and strychnin. This is probably due to the decrease in the permeability of the cell membrane that follows on the initial increase in permeabil- ity. The toxic material is more rapidly destroyed. Due to the cellular stimulation and the mobilization of the proteolytic enzymes, pro- teolysis is hastened. This affects (1) the native protein of the typhoid bacillus to which the body during the course of the incu- bation period has been sensitized and (2) the toxic split products derived from the bacillary disintegration (endotoxins) which are now split to their lowest stages and eliminated. The lymphagogue effect (increased permeability of the capillaries) floods the lymph spaces. If we conceive of typhoid fever as a local disease and not a septicemia, the curative process must take place at the site of the lesion. It has been demonstrated that both in nor- mal and immune animals the antibody concentration is greater in the plasma than in the lymph. The serum in typhoid fever is in- variably rich in bacteriolytic substances, the transient and low- grade bacteriemia notwithstanding. With the active passage of anti- body rich plasma into the lymph spaces the destruction of the typhoid bacilli will take place and healing will be explained. (This theory was put forward by Teague and McWilliams.) The increase in the anti-enzyme in the lymph spaces makes the 120 PROTEIN THERAPY further proliferation of the bacteria difficult. Bacteria must obtain their nitrogen from the lowest degradation products of proteins; they cannot use peptones and proteoses and the higher split products. When the antitrypsin is increased their extracellular protease is in- activated and their metabolism interfered with (Wright). On this basis we have observations that account not only for the detoxication of the patient, which is commonly observed after non- specific protein injections (the euphoria being a constantly reiterated clinical observation) but for the actual destruction of the bacteria and the checking of their further proliferation. Into this mechanism other factors may and possibly do enter. Thus the question of the effect of the leukocytosis has repeatedly been raised. The intravenous injection almost invariably results in a marked augmentation of the peripheral leukocyte count, following the initial leukopenia. This has been considered as the possible mechanism involved in the recovery. But it has been observed that recovery may take place without the appearance of this leukocytosis. Inasmuch as the blood serum itself is able to destroy the bacilli without the intervention of leukocytes, their usefulness in this con- nection is not of paramount interest. As a matter of fact Rous has shown that the typhoid bacilli may be protected from the effects of serum lysis after they are ingested by the endothelial leukocytes. It is much more probable that the role of the leukocyte lies in its detoxication of the bacillary proteins of typhoid bacilli already dead when ingested, or so altered by serum contact that the leukocyte can finally destroy them after ingestion. Of course the concentration of the leukocytes in the internal organs — spleen, liver, lymph glands, intestinal tract, lungs, etc. — immediately after the injection (during the time of the peripheral leukopenia) at the very site of the chief local foci of the typhoid proliferation may lend particular importance to the leukocytic reaction in typhoid fever. Lobar Pneumonia. — ^Let us turn to examine the effects of non- specific therapy in lobar pneumonia. Blake and Russell have in recent papers thrown considerable light on the questions involved in the mode of infection in lobar pneumonia and their observations confirm the clinical impression prevalent for a considerable period that true lobar pneumonia takes place by extension of infection along the trachea. Ac- cording to their study the pneumococcus invades the lung tissue at some point or points near the root of the lung, spreading subse- quently throughout the lobe by way of the interstitial framework and the lymphatic system. It is therefore to be regarded primarily as an interstitial infection of the lung. Rosenow, among others, as a result of blood culture work had endeavored to place pneumonia among those diseases that are primarily a septicemia and later be- come localized in some tissue of predilection. But Blake and Rus- sell foimd that the blood became infected from the bacteria having THE PROBABLE MECHANISM OF THE REACTION 121 gained access to the blood stream from the lymphatics and that this bacteriemia took place quite early, even before the onset of clinically localizing symptoms. Pneumonia must be regarded, therefore, as a directly localized disease and not primarily as a septicemia. It is the critical termination of the disease that has always in- terested physicians and a number of ingenious theories have been elaborated to account for the process. But as long as we sought the solution of the problem along strictly immunological lines none of the hypotheses put forward seemed sufficient to account for all the phenomena observed. At times antibody concentration was altered before or during the crisis, at other times no alteration could be demonstrated. In more recent studies a different line of thought has been fol- lowed, and it has been made probable that we must seek part of the explanation in purely physicochemical alterations that seem oper- ative in the mechanism of the crisis. Miiller some years ago em- phasized the importance of the proteolytic enzymes of the involved lung area in bringing about resolution. Later Jobling, Petersen and Eggstein advanced the hypothesis that the intoxication in pneumonia was of dual origin, from the invading organisms and also from the autolytic products of the involved tissue and exudate. Weiss, Lord and Nye have developed this same thought. According to this conception recovery in pneumonia is associated with the inaugura- tion of active proteolysis of the pneumonic exudate, brought about, according to Lord, by an increase in the local acidity to such a de- gree that the autolytic enzymes find a suitable medium for activity; according to our conception, by an increase in the amount of auto- lytic enzyme either from destroyed leukocytes (leukoprotease) or from mobilized protease from distant organs, and associated with a decrease in the antienzyme (antitrypsin), by saturation with the ex- cess of protease, by increase in acidity, or by the general lowering of the antitrypsin titer of the body. The whole phenomenon in its sharp demarcation bet;ween profound intoxication and complete re- covery resembles more closely a chemical reaction in vitro than a biological reaction in vivo. In so far as we may consider the in- volved tissue as being isolated from the general circulation, as Kline and Wintemitz have pointed out, the process must of necessity be largely local in its origin and effect. Recovery must be coincident not only with the destruction of the bacteria but also with the re- moval of the great mass of fibrinous and cellular detritus. In all of its essentials it is therefore an autolytic process and our hopes of thera- peutic influence must be based not only on the idea of overcoming the infecting organism but also of favorably influencing the autolytic changes. The very isolation of the lung tissue from the general cir- culation after the disease process has once made headway favors 122 PROTEIN THERAPY autolysis, for if the tissues were freely supplied with blood serum, with its greatly increased antiferment, autolysis could not take place. We can on this basis understand that the pneumonic process, apart from complications, will tend to be a short and self-limited one, for even if the invading organisms are very virulent and kill off the leukocytes in the alveoli, their very destruction will liberate protease and when digestion is commenced, terminate the disease. But the crisis, although as a rule associated with the disappear- ance of the organism, need not on this basis at all times imply that the invasion has been overcome. The one is a physicochemical process, in the other we deal with an immunity phenomenon. Blake and Rus- sell describe two experimental observations that are illustrative of precisely this condition — one instance of recovery by crisis in which the blood culture remained positive for 48 hours after the crisis and clinical recovery; the others were cases with crises on the 7th and 9th days, respectively, then normal temperature for several days, followed by a rise in temperature and death of the animals. At autopsy a resolving pneumonia was found; death in these cases being due to a persistent pneiunococcus septicemia. Clinically such cases are occasionally encountered. They conclude that their re- sults are "not out of harmony with the theory of Lord that other important factors besides the development of humoral antibodies are necessary to bring about recovery. It is not unreasonable to con- sider pneiunonia as comprising two distinct though intimately re- lated processes, one always present being the local lesion, the other, present in a variable number of cases, being a general infection of the body as manifested by the occurrence of a pneumococcus septi- cemia. Though ultimate recovery must primarily depend upon the ability of the patient to prevent or terminate the general infection once established, presumably through the existence or the develop- ment of humoral immunity, it does not follow that recovery from the local process with resolution of the pneumonic consolidation need be either coincident with recovery from the general infection or de- pendent on the same mechanism. In fact it would seem well estab- lished by munerous clinical observations that recovery from the gen- eral pneumococcus infection when it exists usually precedes, by sev- eral days at least, recovery from the disease at the time of crisis. On the other hand certain of the observations cited above would seem to indicate that recovery from the local process as shown by a rapidly resolving pneumonia may occasionally occur prior to re- covery from the general infection, or even when death from the gen- eral infection subsequently takes place. In view of the above con- siderations it would seem not improbable that at least a dual mechanism may be concerned in bringing about final recovery from lobar pneumonia." The cultural experiments of Thomas and Parker lend support to this view. THE PROBABLE MECHANISM OF THE REACTION 123 Now let us observe the effects of the nonspecific reaction in this disease. In the case illustrated in Figure 7 the patient was admitted to the hospital on the 5th day of April, 1917, with a history of ill- ness for 5 days previous to admission. The diagnosis on examina- tion was a frank lobar pneumonia of the upper left lobe. Two days after admission he was given a small dose of typhoid vaccine intra- venously (25 million) following which he experienced a slight chill, some rise in temperature and then a fall in the temperature until the next day when it remained normal for several hours in the morn- ing. After this remission it rose again by the evening and then came down by lysis at about the normal time. This, it may be as stated, is a typical result, and portrays the experience that we have had when small doses of vaccine are so administered. There are usually a moderate chill (not as severe as in typhoid, for example), a slight rise in temperature, then a critical drop in the temperature and a normal temperature curve for several hours. Usually the former or a temperature slightly lower than that observed preinjectionally is then maintained and the disease continues its unaltered course. Euphoria, a decided clearing of the sensorium, improvement of the pulse and of the vascular tone of the patient are commonly observed after the injection if it has not been too great in dosage. The physical findings of the chest are as a rule not altered. Miller summarizes his experience with 15 patients so treated as follows: "Fifteen consecutive patients -with lobar pneumonia entering Cook County Hospital were treated by a single intravenous injection of typhoid vaccine. The dosage used was 30 millions, the minimum amount required to give a chill. All reacted by a rise in temperature and a leukocytosis. In nine patients the vaccine did not modify the course of the disease. In six, the patient was detoxicated following the injections. The pulse, tem- perature and respiration returned to normal, the cough and pleural pain subsided, and the patient stated that he felt much better. In three of the six cases the improvement was temporary, as after the lapse of from twelve to twenty-four hours the symptoms returned with unmodified severity. In three cases the detoxication was permanent; however, the patients had a moderate temperature for from three to four days, to the time at which the crisis would normally appear. They were, however, entirely free from evidence of intoxication. There was no relation between the severity of the chin, the temperature reaction and degree of increased leukocytosis, and the beneficial results of the vaccine." One might characterize the changes as a temporary detoxication that leaves the general course of the disease process unaltered, a result that might be anticipated from the pathology. The biological alterations previously described, i.e., the enzyme mobilization, the 124 PROTEIN THERAPY TEHPERATiniE COHTB 0-. 4-5--I7 , ; 8 ■) ;ra ■ fi/ J «- . ; :.:._ss::_.a: :::3;xxa;"r:; __. 1 105* i--5 ^--^±--^^^rir^±-^ 104- ^ - - T - - lb i S i J — S n= - - i S ^ ^^ ^ ^ ^ 101- 1 rFEi::^Tr_T^:ni+_j_x *° = = = i::i:: "-=F:;:^ ^^ 5 ^±±=n-T-q= = : = ;:: = :i-:— ^-- ^^S±--5 ±^+ — :^ -•EEEEEEEEE = = -EEEEEh|EE|||g|EE|EE g°lt« SERUM PEPTIEASE m^.^^^ AHTIFETUtEirr OP SEHUU Fig. 7. — Serum ereptase and antiferment titer in pneumonia subject to vac- cine shock. alteration in the permeability of the capillaries and of the cells of the nervous system and the general plasma stimulation might lead to a detoxication of whatever noxious material might be present in the circulation, and the increase in the threshold of cellular resistance to intoxication lead to a state of relative detoxication so that the THE PROBABLE MECHANISM OF THE REACTION 125 patient would for the time being seem improved — have a lowered temperature, euphoria, increased vascular tone, etc., but it is hardly to be expected that the changes would be sufficiently great to effect the immense and relatively inert local disease process, isolated, as it in a measure is, from the general circulation. Here the production of toxic materials would proceed largely unmodified; these would ac- cumulate, would finally get out into the general circulation to a suffi- cient degree and again produce symptoms of general intoxication. If pneumonia were a disease characterized by a long incubation period, during which there would develop not only sensitization to the protein of the invading organism but in which the beginning of immunization could take place, then nonspecific therapy — plasma- activation — might aid in the process of shedding the preformed anti- bodies — would possibly mobilize them and so bring about recovery. But beginning as it does without an incubation period of any extent this factor is not involved in the mechanism. From the single large dose we can therefore expect little result other than a transient one. But of course there are exceptions. One such may be of interest in this connection. It concerned a boy of 12 years brought to the hospital after one day's illness with a frank lobar pneumonia of the upper left lobe. The interne, using typhoid vaccine as a routine, by accident injected a large dose (500 million organisms) intravenously. The child reacted with a severe chill, the temperature increased to 107° F. and he became delirious. The next morning the temperature of the patient was normal, and remained so without further fluctuation. All physical signs of consolidation had disappeared within 24 hours after the injection. Naturally the production of such a severe reaction is wholly unwarranted as a clinical method and the results are merely mentioned to illustrate that while it may in rare instances be possible to alter even the large pulmonary processes, such a result is quite uncommon. Of course, when we are dealing with a bronchopneumonia the conditions differ to some extent. So, too, the possibility that repeated small injections used as stimulants (plasmaactivation) may be pro- ductive of favorable results need not be discussed in this connection. Sepsis. — When now we come to the diseases characterized by a true multiplication of bacteria in the blood stream and observe the abrupt termination of such septicemias that have been recorded following the intravenous injection of the nonspecific agents (Werner, etc.), the problem becomes one of decided complexity. Our effect on local in- flammation falls away, we must deal wholly with the destruction of bacteria multiplying in the blood stream. Here, too, the mere detox- ication of the patient that has been discussed in connection with pneu- monia, is not the total effect of the injection. This detoxication, the result of the vascular and cellular alterations in permeability, of enzyme stimulation, etc., is of course apparent in septicemia as well as 126 PROTEIN THERAPY in pneumonia, but the occasional abrupt termination of the disease, the destruction of the invading parasite, is an additional factor that must be accounted for. That foreign protein injections have an influence on the course of a sepsis even in experimental animals has recently been demonstrated by Weichardt. In a series of mice injected with streptococci he found that if injections were made before the streptococci were injected, or as late as 24 hours after the injection, there was no appreciable differ- ence between the protein and the control animals ; if the foreign protein was injected from 4 to 8 hours after the infecting dose of streptococci a definite effect on the duration of life of the mouse was apparent. It seems probable that in this condition the effect on the leukocytes and on the antibody concentration is of greater importance than in the disease processes heretofore discussed. Where the body has been in- fected for some time the cells have as a rule become sensitized, have within them an increased amount of receptors, fixed antibodies. If these, as a result of some "shock," are thrown into the circulation the body cells will become less sensitive, not being able to fix the same amount of antigen; on the other hand the antibodies now free in the blood stream are able to affect the bacteria. The augmentation of the agglutinin and opsonin titers in particular will be of value in clumping the bacteria so that they will tend to accumulate in the great filtering centers of the blood stream — such as the spleen, bone marrow, liver, etc. (Bull.) In addition to this fact we find that the coincident effect on the leukocytes in the reaction following the nonspecific reagents is a primary leukopenia that lasts for a variable period of time, but usually for several hours. This does not represent a destruction of leukocytes, but merely the accumulation of the cells in the internal organs — lungs, liver, spleen, bone marrow, etc. We deal here with two factors that by simple mathematical reason- ing (the increase of proximity) favor phagocytic destruction of bac- teria — the accumulation of bacteria, clumped and opsonized, in the blood filters — the accumulation of polymorphonuclear leukocytes in the same locations. While these processes are operative, the direct stimulation of the hematopoietic organs may be of value. The proliferation of leukocytes as indicated by the number of young forms (Arneth count) that are to be observed in the circulation after nonspecific reactions would mean that where the bacteria have accumulated and clumped — the bone marrow, spleen and liver — these yoimger leukocjrtes, pre- sumably active and of enhanced phagocytic power, would encounter the invading organisms and engulf them. If we survey the mechanism in the various pathological processes that we encounter, in strictly local inflammations (bubo) , in localized lymphatic infections (typhoid), in localized organ involvement THE PROBABLE MECHANISM OF THE REACTION 127 (lymphatic, interstitial and external) as in lobar pneumonia, or finally in true septicemic conditions, we find that no one factor can be identi- fied in the mechanism as of paramount importance. In the local reaction the alteration of the permeability of the cells and the complex changes in the inflammatory reaction that this entails seem of greatest importance, together with the detoxication of toxic proteins by the acceleration of enzyme activity. In the typical lymphatic involvement represented by typhoid fever the increased permeability of the vessels and the flushing of antibody rich fluids into the lymph spaces, the desensitization of the patient as a result of later cell membrane changes and the general increase in cellular activity, in vascular tone, in the tone of the central nervous system, etc., are perhaps the more important factors. In pneumonia, on the other hand, we may be able to overcome the effect of the intoxication for a temporary period by increasing the enzymatic rate of destruction of the toxic proteins, as well as by increasing the resistance of the cells to the toxic effect, but we are not able sufiiciently to alter the physicochemical balance that exists in a more or less isolated lobar lesion, and on which the inception of the crisis depends. Here, then, we have to deal largely with a transient detoxication. In the true septicemias it seems more probable that, apart from these factors that tend to diminish intoxication — that is, the enzyme mobilization and the decreased permeability of the cells — the actual destruction of the invading bacteria must be due to leukocytic diges- tion and perhaps the direct effect of the serum antibodies mobilized. The clumping of the bacteria and their accumulation in the internal organs and bone marrow bring them in closer proximity to the leuko- cytes, which, as a result of the injection, have also been concentrated in the internal organs and bone marrow. It is at any rate apparent as a result of these considerations that different disease processes are diversely affected by the nonspecific agents, depending on peculiarities of localization, on the source of the material that is responsible for the intoxication, on the degree of sen- sitization and immunization of the patient. While nonspecific agents may produce a reaction that is fundamentally alike, the effect on different disease processes may differ considerably. CHAPTER VII THE RELATION OF THE SKIN TO NONSPEOIFIO RESISTANCE Skin Reactivity. — The fact that the skin and its reactivity can be influenced by a variety of systemic pathological changes and through therapeutic procedures has been observed by physicians for many cen- turies, indeed ever since counterirritation by means of blisters and chemical irritants was introduced (about 1600 A. D.). "We often find in cases of intense irritation of internal organs that blisters will not vesicate the skin, but that as soon as the disease is modified they will produce their usual effect," wrote Stokes (as quoted by Gillies). Trans- lated into our more modern procedure we find this same phenomenon observed when we apply the tuberculin reaction to the skin of a patient during any acute disease, or in pregnancy or in cachexia, and note that the reaction, normally obtained in practically every adult, has disap- peared. It is not needful in this connection to review more than briefly recent ideas that have been advanced by a number of observers con- cerning the direct reactions of the skin to various stimuli, or the change of the skin activity following certain general alterations of the organ- ism. It is known that the tuberculin reaction cannot be elicited during acute infections, pregnancy, cachexia, senmi disease, etc. Similar observations have been recorded for vaccines. Thus Matthes and Rautenberg have recently shown that the digestion prod- ucts of typhoid bacteria which were used as a vaccine have a far greater local effect in the normal individual than in those ill of typhoid fever. Hoke, working with the intracutaneous test, found that the trau- matic reaction, as well as the intracutaneous tuberculin reaction, were increased in leukemia as well as after thyroid feeding, while in cases of cachexia, in fever, in local infection and in deeply pigmented skin the reaction was diminished. Depression. — Certain general conditions of the body, quite diverse in their origin, are able to suppress the reactivity of the skin to tuber- culin. These general conditions are obviously not specific; that is, they need bear no relation to tuberculosis, nor do they alter the anti- bodies and in this way effect the tuberculin reaction in a specific manner because it has never been shown that there is any parallelism 128 RELATION OF SKIN TO NONSPECIFIC RESISTANCE 129 between antibody content and skin reactivity. Then it was observed that the reactivity of the skin could be inhibited by injections of various kinds — the heterologous and homologous serums, colloidal metals, starch, in fact after nonspecific injections of various kinds. Luithlen took up the experimental study of the alteration of skin reactivity from the vascular side. Using croton oil as an irritant he has observed that after the injection of normal serum of any kind — homologous and heterologous — after plasma injections or blood transfusion, after gelatin or Witte peptone, after colloidal silicate and after starch injections the reactivity of the skin was markedly de- pressed. Crystalloids did not alter the reactivity, in some instances actually seemed to increase the reaction. Luithlen soon recognized that this alteration had nothing to do with any commonly recognized biological or antibody action on the part of the serum, but was due to an alteration produced by practically every colloid injected. This change he considered dependent on an alteration in the per- meability of the capillaries. In determining this change in permeabil- ity he proceeded as follows: Rabbits were injected with Ringer's solu- tion intraperitoneally (100 c.c.) and then 2 c.c. of a 10% solution of sodium ferrocyanid was injected intravenously. The rate at which the ferrocyanid permeated the Ringer's solution in the abdominal cavity was then determined by adding hydrochloric acid and ferric chlorid to samples drawn from the peritoneal fluid at various time intervals and noting the time when the first blue coloration was ob- tained. The normal time was about 2 minutes. Similarly the per- meability to sodium iodid was determined and found to be about 1 minute. Variations were noted with the age of the animal and its state of nutrition. When such animals were now injected with the various colloids which had been found to depress the reactivity of the skin, it was found that they all decreased the permeability of the capillaries as measured in the manner that has been described. Salts did not alter the rate of permeability very much, but repeated bleeding had a definite effect on diminishing the permeability. Activation. — If the reactivity of the skin can be altered in the sense of a depression we must accept the corollary that nonspecific factors may possibly be able to accelerate the cutaneous reaction. And of this we have abundant evidence in the effect of thyroid feeding and of iodid therapy to which Sherrick called attention some years ago and which has been confirmed and amplified by a number of other workers — Kolmer, Sollmann, Stokes, etc. We are therefore led to the inevitable conclusion that elements wholly nonspecific in our ordinary sense of immunological specificity may be of decided importance in the mechanism of the skin reactions. Clinically, too, we have been forced to the same conclusion as a result of observations on a variety of skin reactions which have been 130 PROTEIN THERAPY elaborated during the course of the past ten years. Not only was the luetin reaction found to be unreliable when iodids were administered but even with these excluded the specificity of the reaction is by no means to be depended upon. Thus Blechmann has but recently pub- lished a series of 80 cases in which he injected luetin. In this group of children his luetin was positive in about 35% of the congenital luetics, while in about 40% of nonluetic children he also obtained a positive luetin test. So, too, the typhoidin reaction has been found an absolutely unreliable index of the immunity of the patient. Other skin reactions, such as the gonococcus reaction, the placental reaction for pregnancy and the pnemnococcus reaction, have failed for the same reason. Only where we deal with a disease depending very probably on a definite hypersensitization of the patient, such as in asthma, are the skin reactions useful. When skin reactions are under consideration one inevitably thinks of the tuberculin (either the v. Pirquet or the intracutaneous test) reaction as the most typical and best known of the whole group. The general reaction — subcutaneous injection — should by no means be considered in the same category. It is very probable that the tuber- culin reaction, which for ordinary clinical purposes we may consider specific, has a very large element of nonspecificity in its mechanism — much larger than is ordinarily considered probable, as has been fully discussed in the chapter on The Focal Reaction. Such a phenomenon would by no means be an anomaly in medicine; indeed our Wasser- mann reaction is an example of just this same condition. Elaborated on a theory of strict specificity it has resolved itself into a specific clinical test that is based on a physical mechanism in which the anti- gen-antibody reaction plays no part. We must recognize, too, that the evanescent reactions or wheals that we observe in determining sensi- tization to proteins (asthma, etc.) are fundamentally different in many respects from the tuberculin reaction. Clinically it has been determined that from the time of the birth of the individual the organism begins to alter in its reactivity of the skin. At first negative to tuberculin, the reactivity increases pro- gressively with the age of the individual until in adult life a maximum is reached and maintained quite consistently except for certain periods of depression, some of which have been previously mentioned. But during this period the skin does not only become sensitive to tuber- culin, but increasingly sensitive to a series of other bacterial and plant proteins and extractives; so to colon and dysentery and cholera pro- teins, to bacterial toxins, peptones, etc. We deal obviously with a more or less general "sensitization" or "Umstimmung" or "allergy," as we may choose to term the condition. Now, this allergy may be a more or less specialized property of the skin, indeed may be localized in certain areas of the skin. As a result of it the tissues acquire the ability to react more energetically and RELATION OF SKIN TO NONSPECIFIC RESISTANCE 131 more promptly to outside stimuli — whether specific, as with tuberculin, or nonspecifically as when other proteins are injected in and about an area previously injected with tuberculin, or finally when substances nonprotein in character such as sugar or starch are used. (Stokes.) Even those investigators who have heretofore been the most ardent advocates of the specific character of the tuberculin reaction, such as Wolff-Eisner, have been compelled to accept the inevitable conclusion that in the tuberculous individual the skin (and the body as a whole) is hypersensitive not only to tuberculin but to proteins in general. In a paper published with Sexsmith we have pointed out a possible basis on which some of the clinical experiences as well as the conflicting experimental data might be more readily understandable. Enzymes in Skin Reactions. — Considering both the phylogenetic and ontogenetic development of the skin and its function it is apparent that its power to secrete enzymes is one that is more or less inherent in the epithelial cell — ultimately highly specialized and differentiated in some of its developed organs, rudimentary and potential perhaps in the structures that serve later primarily for protection rather than in the active metabolic processes. As a protective structure its efficacy will depend to a large extent on its ability to react both very rapidly and very strongly against either invasion or intoxication. When one examines the enzymes of the skin one observes apparently a decided difference in the enzymes of the infant or young skin as contrasted with the adult. The young skin contains more ereptase (erepsin or peptidase) and little lytic protease; the adult skin on the other hand little ereptase and more protease. Neither type of skin contains much antienzyme. Let us suppose that we inject peptone into the young skin. The ereptase could immediately detoxicate the material injected and there would be no necessity for an inflammatory reaction. If we inject a native protein which only becomes toxic when it is split, the infant skin (containing less protease than the adult) is not able to split the protein, no toxic products are formed and there is no reaction. Indeed the action of whatever protease is present in the young skin seems decidedly synthetic rather than lytic. If now we examine the picture in the adult we find the exact reverse. If a peptone is injected there is little ereptase present to detoxicate it and the material is present in the tissues long enough to set up an inflammatory reaction. If on the other hand we use the native protein the presence of sufficient protease in the skin will permit the same to be broken up with the formation of protein split products toxic to the cells and an inflammation will be the result. The relative paucity of ereptase will here delay the detoxication. Inasmuch as our ordinary agents that we use in eliciting skin reactions are usually mixtures rather than pure protein or protein 132 PROTEIN THERAPY split products the enzyme reaction will seldom be as clear cut as here portrayed. But why the tissues react more readily the second time is a question that is of such vast biological significance that we can merely surmise some of the more superficial and obvious alterations that are involved. Even were we to consider nothing but antibody reactions in the im- munological sense recent work would indicate that this alteration — allergy — is not necessarily specific. Bieling has demonstrated that any primary sensitization leaves the body in a state of high grade hyper- sensitiveness. Animals immunized to cholera, for instance, required but a minute fraction of the ordinary dose of typhoid antigen to bring about a high degree of immunity to typhoid. The fact that a second- ary injection of a heterologous protein or other nonspecific agent will mobilize the antibodies formed against a previously injected antigen is of course well known and has been extensively studied by Bieling, Hektoen, Johnson and others. The cell has been so altered that its reactivity is increased, as though a dull instrument had been suddenly shaped to razor-like keenness. To what degree this involves more or less permanent alterations in the physical make-up of the cell ecto- plasm, in how far the protoplasm of the cell is involved, is of course purely speculative. We must go back for a few moments and consider the possible mechanism of the suppression of the skin reactivity to which we have called attention in relation to certain conditions, such as pregnancy, acute infectious diseases, cachexia, etc. If in the nonspecific enzyme action that goes on in the skin the proteolytic activity can be sup- pressed, then intoxication and inflammation that is due to the splitting of native proteins to the toxic forms should also be inhibited. Such inhibition can take place when the chemical reaction of the medium is not suitable or when we have an excess of antiferment present. All of the states during which the skin reactions are suppressed are con- ditions associated with an increase in the titer of the serum anti- ferment. Stern made a careful study of the suppression of the tuber- culin reaction during pregnancy, when the antiferment titer of the serum is of course greatly augmented. Blote confirmed this work and showed that this was by no means a specific phenomenon because when he used an extract of jequirity in place of the tuberculin he obtained a similar result. This increase in the antiferment titer which oceurs after nonspecific injections of various kinds, after seriun sick- ness, during antianaphylaxis, is coincident with the alteration in the permeability of the capillary endothelium to which Luithlen, von den Velden and others ascribe the alteration in the skin reactivity and which must also have a large share in the mechanism. Meyer has studied particularly the inhibition in the cutaneous reactions to tuberculin which takes place after prophylactic typhoid vaccination. Here, too, we deal with a nonspecific reaction, with an RELATION OF SKIN TO NONSPECIFIC RESISTANCE 133 increase in the antiferment titer, alterations in the permeability of the vessels, and temporary depression of the irritability of the vasomotor system and central nervous system which lasts for a period of a week or so after the injection. The converse of this clinical observation has to deal with the reactivation of skin foci by nonspecific injections after they have undergone involution. Thus it has been observed that old tuberculin papules will become active when a subcutaneous injection of tuberculin is given in some remote area of the body, when milk is injected or colloidal metals injected intravenously. To what degree elements of specificity enter into this reactivation is by no means determined. Munzer observed that when partial antigens (Dyche-Much) were injected they would often reactivate old intracutaneous tuberculin papules while milk injections did not have this effect. Closely related is the effect of the iodids and other chemical agents which on administration activate involuting papules. If intra- cutaneous skin tests are made with luetin or tuberculin during active iodization of the patient, the skin reaction, instead of being limited to mere papule formation, usually goes on to the complete pustule stage of inflammation. Now the iodids act, as do the related chemical agents, either by lowering the antiferment titer ( Jobling and Petersen) or by nonspecifically stimulating the tissues (and so increasing the amount of protease and other enzymes in the tissue fluids) or finally because of their effect in hastening the rapidity of diffusion of other salts (and colloids) in colloidal systems. The end result is of course the same — digestive processes are hastened. The two other conditions — leukemia and thyroid feeding — in which the skin reactivity is in- creased are associated with a diminution of the antiferment titer and an increased enzyme activity.* When, therefore, involuting papules flare up under nonspecific injections we must consider the possibility that the following changes may form the basis of the inflammatory reaction. With the height of the nonspecific reaction (negative phase — digestion) a considerable amount of protease is mobilized locally and generally and the anti- ferment is diminished. If in an involuting area a certain amount of undigested protein material is still present, digestion will commence, protein split products will be liberated at the focus and the lesion will again flare up — that is, we will witness a focal reaction. The local cells, it is to be remembered, are particularly reactive in such a con- dition. When the patient is iodized and an intracutaneous test made we seem to deal simply with a condition where digestion has been able *The fact that iodids may have no direct effect on tissue autolysis in vitro as Albrecht has recently demonstrated has no direct bearing on the point at issue which in vivo concerns rather the mobilization of protease from normal tissues and their effect on tissues that have undergone degenerative change. 134 PROTEIN THERAPY to proceed much farther and more rapidly than in the uniodized patient. When the injection is made a certain amount of tissue injury- is done. Some of the cells will be injured both from the trauma and from the toxic material injected. In the uniodized patient the in- hibition of digestion due to the antiferment checks autolysis to a degree, the process is delayed sufiSciently so that no great amount of split products are present at any one time. The rate of formation will not exceed the rate of diffusion. In the iodized patient, on the other hand, the rate of digestion being greatly accelerated, protein split products will accumulate in the cutaneous tissues in an amount greater than the rate of diffusion, more tissue injury will be done; with autolysis leukocytes will be attracted and a pustule will re- sult where under ordinary circumstances merely a papule would have been formed, or a papule will result in an individual in which the reaction normally would have been absent. While from these observations it is apparent that nonspecific fac- tors can undoubtedly influence the tuberculin reaction or the other skin reactions both in the sense of depressing them or accelerating the reactivity of the skin, we must by no means lose sight of the fact that a specific element enters into the cutaneous reactivity. In my opinion it is probable that the explanation for the fact that the tuber- culin reaction is clinically specific and fairly reliable while similar skin reactions (typhoidin reaction, etc.) are not, is to be found in the fact that the tuberculous individual, because of his continuous ab- sorption of proteins, is in a state of generally increased sensitiveness to proteins. This hypersensitiveness is of a degree sufficient in tu- berculosis to overbalance the nonspecific factors which in other dis- eases interfere so greatly that the interpretation of the skin reactions becomes both difficult and unreliable. The Relation of the Skin to Internal Medicine. — ^While in a general way these studies have been undertaken from the point of view of the dermatologist, a wider viewpoint that includes the relation of the skin and its reactivity to problems in internal medi- cine has found expression in a number of papers. Particularly the study of the various diatheses has interested a group of investi- gators. Thus Schulz, using dilutions of carbolic acid to bring about skin reactions, determined that children with exudative diathesis usually revealed an increased irritability of the skin. It seems prob- able that the severity of the vaccina reaction and the reaction to the parenteral injection of proteins that such children often show is to be associated with this change. But the hypersensitiveness, according to Schulz, is not limited to children; many adults suffering from eczema have been found by him to be decidedly hypersensitive. Brocq's investigations in this connection are of importance. It has been Brocq's contention that in such hypersensitive individuals — and RELATION or SKIN TO NONSPECIFIC RESISTANCE 135 families — there exists a so-called "arthritic milieu" as a result of which they are particularly susceptible to a variety of pathological altera- tions. They react to outside trauma or stimuli of such mild degree that would, in the normal individual, provoke either no response at all or at the most a very negligible reaction. Eczema, lichen, urticaria, food and drug idiosyncrasies, herpes, furunculosis, pruritus and psori- asis are regarded by him as belonging in this category. To it he also adds hay fever, asthma, gout, adiposity, migraine and neuralgia. Even Bloch accepts the first five of the skin diseases as belonging to this "arthritic" group of diseases. The French clinicians have carried this conception to its logical conclusion and do not speak of eczema as a disease entity but of "eczematization" (Besnier, Darier, Rapin and V. Hirschberg, etc.). It is by no means excluded that this sensitization takes its origin from some primary bacterial infection — tonsil, gastro-intestinal (gall bladder and appendix) or respiratory. Esophylaxis. — ^The association of skin reactivity and internal con- ditions has recently been illustrated in experiments of a different nature. During the course of investigations on the mechanism of intoxication and death from burns, Pfeiffer observed that a marked mobilization of proteolytic enzymes occurred after even superficial biu'ns of the skin. As a result of this observation and others closely related he felt justified in including the intoxication of burns among those due to protein split products. In view of the relatively rich enzyme content of the skin such a mobilization after stimulation might be anticipated. But in so far as this mobilization, when it is within physiological limits, or under therapeutic control, may play a role in influencing internal diseases, the study of the skin reactivity becomes of interest to us not only in the sense that it protects against disease entrance — an "exophylaxis," as Hoffmann has termed it, but because of its importance on the internal organs as well — an "esophylactic" effect. Bloch and Hoffmann have both discussed this subject in recent papers which seem of considerable interest in connection with the mechanism to which attention has been called. Bloch has expressed the conviction that the skin possesses a biological function, heretofore unappreciated, by means of which the vital organs are protected from bacteria, or at the most have but to deal with a minute amount of attenuated bacteria. Taking into consideration the more recent work concerning the phenomena of allergy as observed in tricophyton infec- tion, in tuberculosis and syphilis he emphasizes the fact that "the skin above all other organs plays a leading role in allergic immunity and sensitization, as contrasted with serum immunity, such as that of diphtheria, tetanus, etc., where the serum is the carrier of the anti- disease mechanism." The allergic alterations — vaccination against variola — the funda- 136 PROTEIN THERAPY mental observations of Koch on the production of tubercles in the skin, which, in the infected animal, assume a much stormier and rapid course — the researches of v. Pirquet on the vaccination allergy in tuberculosis, syphilis, and fungus infections — all point to the skin as fundamentally involved in the mechanism of resistance. Perhaps it plays some role even in recovery in the acute exanthemata, such as measles and scarlet fever; in variola its importance is obvious. Heim has recently expressed the opinion, which was current many years ago and still is more or less popular in folk medicine, that the skin eruption of the acute exanthemata is involved as part of the mechanism of recovery. His conception is that the organism endeavors to rid itself of the toxic substances through the skin, that a leukocytosis occurs there and that the latter is of utmost importance in digesting the toxic material. While in bald outline the theory may seem crude, it is possible that there may be some connection, as Heim has suggested, between the skin eruption and the mechanism of recovery, as I shall endeavor to point out later. Hoffmann calls particular attention to the clinical observation that the internal organs are frequently spared from serious involvement both in syphilis and in tuberculosis when the skin lesions are extensive. In order to emphasize the importance of the skin in its relation to internal medicine he calls attention to a number of other facts that are more or less pertinent. The fact that an intoxication ensues when large areas of the skin are put out of function by varnishing or burning; that the large bulk of epithelial tissue, with its elaborate network of intercellular canals and its proximity to the vascular corium would facilitate absorption of secretions; that the folklore of many genera- tions expresses the idea that in the exanthematic diseases the internal organs are spared to the degree that the eruption is manifest in the skin, with the therapeutic conclusion that anything that will increase the eruption influences the patient favorably (Heim also calls attention to this tradition) , all indicate, even if only in a general way, that the skin may be of importance in overcoming infection. Hojfmarm's Theory. — Hoffmann makes the epigramatic statement that "the skin is the grave of the parasites." The fact that so many acute infections involve the skin — ^measles, scarlet fever, variola, ty- phus, syphilis, etc. — has led him to the conclusion that the skin plays some active role in immimity. In how far some internal secretion of the epithelimn, to what degree the vascularized papillary body with its ready inflammatory response enters into this mechanism, he does not suggest. This ability to respond readily with inflammation might be anticipated both from the phylogenetic as well as from the ontogenetic development. Thus the skin of the adult reacts more rapidly and to a wider range of substances than that of the infant, the skin of the human more readily than that of lower animals. Light Rays. — ^Perhaps the effect of light on the skin and the recent RELATION OF SKIN TO NONSPECIFIC RESISTANCE 137 use made of this effect in the therapy of internal disease is of particu- lar interest in disclosing the degree to which the skin reactivity can make its influence manifest on the metabolism of the internal organs and pathological processes there present. When a patient is exposed to light rays in the manner developed by Bernhardt, by Rollier and others, certain systemic changes occur which in many ways resemble very closely the reaction that we have described for the protein shock reaction or the nonspecific reaction. Rollier observed an increase in eosinophils as well as in hemoglobin and red cells. D'Oelsnitz ob- served changes in the temperature, in the respiration and in the blood cytology. The temperature and the respiration are both increased at the beginning, the pulse rate may be accelerated to some extent — all of the reactions depend greatly on individual factors and particularly on the disease from which the patient is suffering; in tuberculosis, par- ticularly on the type of the tuberculous lesion, whether active or latent, etc. The leukocytes that are produced are usually young forms, although in the reaction mononuclears predominate; eosinophils were also observed by D'Oelsnitz. Dual Effect of Heliotherapy. — Just as in other nonspecific re- actions the effect of the sunlight on the skin and the effect on patho- logical conditions is a dual one. Thus it may activate an inflammatory focus. In active progressive tuberculosis with hemorrhage and a septic type of temperature, exposure may do decided harm. In its genera] effect the reaction set up is similar in character and duration to that elicited by tuberculin and the contra-indications are the same. Thus a latent tuberculosis on exposure to prolonged sunlight may react with a typical temperature, increase in pulse-rate and the general malaise that we associate with the tuberculin reaction. And just as it is a dual reaction the negative phase is followed by a positive one. That is, the difference between irritation and stimulation and overstimulation is a matter of very small margin and depends on the individual, as Pottenger has pointed out. Sunlight has no specific effect on tuber- culosis; it is not a cure in the ordinary sense of the word. It is merely a stimulant similar in character to many of the other nonspecific agents which are able to cause a focal reaction and thereby influence the process. Its difference from some of the other forms of therapy lies in the fact that the leukocytic response that follows heliotherapy seems to be rather a lymphocytic than a polymorphonuclear reaction. In nontuberculous affections it has been recommended in general con- valescence, where it is followed by an improvement in the anemia (effect on hematopoietic system) and in the weight of the patient. Aimes has found it very useful in acute articular rheumatism, in tracheobronchial adenopathies and in neurasthenic patients. (Kellogg) . Lovett has reported excellent results in chronic infections. Heliotherapy as Protein Therapy. — It seems most probable that instead of seeking to find the cause of the therapeutic effect of the 138 PROTEIN THERAPY sunlight in some hypothetical internal secretion of the skin which is stimulating the entire organism, it will be found much simpler to con- sider that the effect of the sim raying of the skin tissues brings about a mild (or severe, depending on the degree) form of nonspecific shock. We know from Pfeiffer's work that actual burns will do this. Between the erythema of a burn due to actual heat and that due to sunlight there is not much difference as far as the patient or the effect on the organism is concerned. The epithelial tissues become hyperemic and absorption from them is accelerated. Skin enzymes — ^protease and lipase, perhaps some ereptase in younger individuals, — are swept into the circulation, together with some protein split products due to diges- tive stimulation in the skin. The agents that ordinarily provoke the nonspecific reaction are therefore available— the enzymes present in the serum can now attack seminecrotic or necrotic foci and there accelerate the preexisting inflammatory reaction — i.e., set up a focal reaction — a tuberculin reaction — ^with its resulting train of increased temperature, malaise, etc. As a result of the protein split products derived from the skin the organism is of course stimulated in the typical nonspecific manner and the effect on the hematopoietic system, on the irritability of the nerves (Singer, Pottenger), on the general metabolism, is similar to that which we have seen with the other non- specific reactions. Differences exist in the type of leukocytic response, which seems to be more lymphatic in the case of heliotherapy. An- other possibility of particular value in tuberculosis may be found in the relative richness of the epidermal tissues in lipases which, when mobilized after heliotherapy, might, theoretically, prove of decided value in resistance to tuberculosis. The effect of heliotherapy in causing a focal reaction can best be illustrated when one follows the effect on a tuberculous focus such as an area of lupus. Even when all direct effects of the rays are excluded by means of black paper, a lupus lesion will react with a typical focal reaction after a general sun bath just as it does after tuberculin injec- tion, after milk injection or any of the other nonspecific agents. Tuber- culous foci have been observed to become much more "sensitive" or reactive to other stimuli such as x-rays or concentrated red rays, etc., after general heliotherapy. Local Applications. — Hoffmann calls attention to the fact that other therapeutic measures, soap inunctions, mustard baths, sweating, coun- terirritation, etc., may involve precisely the same mechanism. When we examine the acute exanthemata from this point of view, it will become apparent that the skin manifestations and their severity may well have some influence on the general course of the disease. Granted that the nonspecific reaction produced by injecting various substances may terminate an infectious disease abruptly — and the clinical evi- dence is sufficiently varied by this time to permit such a general state- , fflgjit-^we have seen that it is immaterial how this reaction is elicited. RELATION OF SKIN TO NONSPECIFIC RESISTANCE 139 For therapeutic effects certain agents have been found more effective than others, but within certain limits they are all more or less effective. Acute Exanthemata. — If in an acute exanthema we regard the huge skin involvement in the nature of an inflammatory reaction, it follows that from it not only enzymes but toxic split products are being absorbed very rapidly when the hyperemia that is part of the inflam- matory reaction becomes pronounced. When the skin reaction reaches its height we know that it is accompanied clinically by an increase in the temperature and that defervescence usually follows in the wake of this increase. The normal mechanism of recovery in these acute dis- eases may therefore involve precisely the same nonspecific reaction that we now seek to make use of therapeutically in other conditions. In variola the appearance of the skin eruption is of course coinci- dent with the improvement in the general condition that is so char- acteristic of the disease — ^the lowering of the temperature, the pulse rate, the pronounced euphoria, etc. — and the secondary fever is purely an absorption fever when suppuration sets in, similar in its character and course to that of any other suppurative condition. Focal Activation from Intracutaneous Injections. — Perhaps one of the most striking illustrations of the importance of skin stimu- lation and its effect on remote disease processes is afforded by the recent work of Miiller. The interesting fact has been brought out by him that the intracutaneous dosage required to bring about a focal activation may be l/30th less than the dose required if given intramuscularly or intravenously, and it is of course immaterial what agent is used in the skin injection. Thus he found that "arthigon," typhoid and cholera vaccine, tetanus or diphtheria antiserums and even salt solutions were able to elicit focal provocative reactions as tested in gonorrheal urethritis. His results emphasize the fact that relatively minute and seemingly insignificant skin reactions may exert a tre- mendous effect on remote pathological lesions and that we must seek the mechanism of this phenomenon in metobolic alterations produced in the skin, not in peculiarities of the agent that we happen to use to bring about the reaction. Needless to state, the tuberculin therapy of Ponndorf (which consists of intracutaneous injections of tuberculin) is related to the alterations that Miiller has studied. And, as we might expect, a variety of clinical conditions have been reported to improve after the Ponndorf technic. Thus Kroschinski found that neuralgia, neuritis, tabetic pains, acne and furunculosis responded to the tubercu- lin injections made in this manner. Syphilis. — When now we turn to examine the clinical statement that is often made, namely that in syphilis accompanied with extensive skin lesions, or in tuberculosis that has its chief site in the skin, the internal organs are as a rule free from pathological changes, we find considerable evidence of a clinical character to support the assertion. 140 PROTEIN THERAPY General paralysis, tabes and tertiary lesions are said to be very un- common in countries in which the skin lesions are most manifest; racial differences seem to play some role, too, in the variation of distribution. In our American negro it is stated that the parasyphilitic manifesta- tions are less frequent than in the white race, although vascular lesions are certainly common enough. According to some syphilogra- phers even malignant syphilis, when in its early stages it is most manifest in the skin, is prone to spare the internal organs. According to a number of investigators the possibility must be considered that this effect is due to selective afifinity of certain strains of the spirochete (Nichols, Matzenauer, etc.) ; Hoffmann would rather implicate the immunizing effect that is due to the early skin involvement. Clinically it has been shown that tabetics and general paralytics seldom give a history of severe luetic skin involvement; usually the history given is that the skin manifestation was merely transient and that there were no other secondary manifestations. Bloch assumes that it is the failure of the skin allergy that is the chief cause, particularly of nerve syphilis, either because of the constitutional inability of the skin to react or because the opportunity was not given the skin to react. The wide distribution of the spirochete soon after it gains admission to the body would, in my opinion, rather exclude this latter explana- tion. But it must be remembered in this connection that the spirochete, or rather the reaction that the spirochete sets up in the tissues, is rela- tively easily influenced by nonspecific means. One has but to recall the effect of tuberculin on the involution of the syphilitic papule, the effect of the injection of colloidal metals (particularly silver) on the rate of proliferation of Spirochceta pallida in experimental animals, the effect of intercurrent diseases on the manifestations of syphilis, the pronounced effect of the iodids on the absorption of gummata and in the alteration of the skin reaction to luetin, etc. If the secondary lesion and the gumma are so easily affected by these means it is very probable that the inflammatory reaction in the skin, no matter how produced (even if by the specific inciting organism) — with its resulting absorption of enzymes and of protein split products — ^may act as a nonspecific agent and have some therapeutic effect on lesions located internally. It has even been suggested that the efficacy of the mer- curial inunction over other methods of mercurial therapy is due to the fact that the skin is stimulated mechanically. The fact that the tissues of the central nervous system afford a very favorable milieu for the spirochete when once it has penetrated must not be lost sight of. The meninges, being relatively easily pene- trated by the spirochete, are infected early and often in syphilis. It is the ectodermal brain substance which has to bear the brunt of the spirochetal changes, for the pia, although early involved, seems to rid itself much more readily. Both the brain substance and the cornea, containing neither lymphocytes nor adventitial cells, react but poorly RELATION OF SKIN TO NONSPECIFIC RESISTANCE 141 to the spirochete, and the effect of syphilis is strikingly similar in both cases, as Gartner has recently pointed out. Specific therapeutic meas- ures have been found equally unsatisfactory in syphilitic lesions in both tissues. If we are able to bring about a nonspecific stimulation we at times seem to be able to secure a much more prompt effect on the luetic lesion ; the therapeutic application of the principle has been discussed under the respective subjects. It seems probable that the clinical impression of increased resist- ance to syphilis on the part of the internal organs when skin involve- ment has been extensive may have some definite basis, in that a severe inflammatory reaction in the skin during the time of the invasion by the spirochete might, by nonspecifically stimulating the body, increase the resistance of certain of its tissues that normally are more sus- ceptible to the spirochete. If this reaction occurs sufficiently early the virus might be prevented from gaining a firm foothold in the susceptible tissue and in this manner later parasyphilitic lesions might become less frequent in such individuals. CHAPTER VIII ABTHBITIS The treatment of arthritis has been one of the most satisfactory fields in which nonspecific therapy has been applied. The contra- indications are few, the evidence of improvement is strikingly apparent to the patient as well as the physician, and the relief from the pain so welcome that the discomfort that may be involved in the method is usually willingly borne. Miller and Lusk were the first to report on cases of arthritis treated with proteoses and with typhoid vaccine in their service at the Cook County Hospital in Chicago. This series of 24 cases gave promise of excellent results, and in a second paper published shortly thereafter they reported on the results in 85 additional cases. Somewhat smaller doses of the typhoid vaccine (from 40,000,000 to 75,000,000) were given to their patients in this second series. They used proteose or pollen extract in a few instances, and the resulte obtained would indicate that with the proper dosage, improvement similar to that observed after the use of the typhoid vaccine would take place. In the second series there were 45 cases of acute arthritis, of which 4 were gonorrheal in origin; the period which had elapsed from the onset ranged from two to forty-five days. Previous to com- ing under the authors' care 33 had been under more or less active drug treatment, usually with salicylates. Of those who had been imder previous drug treatment, 29 reported that they had not improved under this treatment, and 4 had been moderately benefited. With typhoid vaccine, 29 of the 45 patients recovered promptly; that is, the pain, redness and swelling disappeared in from one to five days, and usually within from twenty-four to forty-eight hours. From one to four injec- tions were necessary to bring about these results. Of the remaining patients, 8 showed great improvement with only some stiffness or slight pain remaining. Six showed only moderate improvement; in 2 no benefit was derived from the treatment, although one of these received eleven and the other thirteen injections. Nine of the patients had recurrence, 5 of those discharged as cured and 4 of those discharged as improved. Seven of these were reinjected and either recovered or showed marked improvement. In the 4 acute gonorrheal cases in this series, less benefit was derived from the treatment than in those of other drigin. 142 ARTHRITIS 143 Twelve patients with subacute arthritis were treated; in 10 the condition cleared up in from three to five days after from one to four injections, although in 2 of them there was still slight stiffness or sore- ness in one or more joints at the time the treatment was discontinued, clearing up, however, a few days later. Two showed marked improve- ment after two or three injections, but subsequent injections failed to bring about further improvement. Among those discharged as cured recurrences were recorded in 2, 1 of these recovering after further in- jection; the other patient did not return to the hospital for further treatment. Nine cases of chronic arthritis with marked acute exacerbation were treated and in 8 the acute symptoms cleared up promptly with from one to three injections. Nineteen patients with arthritis of from a few months to several years' duration were grouped as chronic arthritis. Only those cases were selected in which there was definite evidence of activity, and ankylosis was not marked. Ten of these patients after from one to five injections showed a definite improvement, the acute tenderness and discomfort on motion was much relieved. The patients became less helpless. As a rule not all of the affected joints were bene- fited. The results, however, were such that it would seem the treat- ment had been actually beneficial. Not all of these cases have been followed, but there are several in which, after the lapse of several months, the improvement had been maintained. Five showed mod- erate improvement, and 4 were not benefited. The maximum num- ber of injections given any of these patients was thirteen, being given daily in the beginning and later every two or three days. In 5 patients included in this group the arthritis was apparently of gon- orrheal origin, and 3 of these showed such marked improvement that they might be pronounced as cured. This is in contrast to the resistance to the treatment of the acute gonorrheal cases. One of these gonorrheal cases was of several months' duration and for three months previous to entering the hospital the patient had been compelled to use crutches. After three injections he was able to get out of bed without assistance, and up to the present time (four months) has not had a relapse. It is the very striking results ob- tained in a few cases of this character which have led the authors to believe that in certain instances the results obtained cannot be equaled by any other of the present methods of treatment. The results in the cases of chronic arthritis are on the whole, however not especially striking. The tendency to recurrence is great, per- haps owing to the persistence of a focal infection. It is essential, therefore, that where this method of treatment is employed, it be preceded by the usual efforts first to locate and remove the local infection. The reaction provoked by the intravenous injection of the typhoid 144 PROTEIN THERAPY vaccine was severe. There was always a very marked rise in temper- ature, and with few exceptions a marked chill. The headache as a rule was severe, and nausea of a few hours' duration was not m- frequent. In 3 cases, all alcoholics, delirium developed at the height of the fever, in 1 case continuing for thirty hours. Marked dyspnea was observed in a few cases. In only 5 of their patients did Miller and Lusk deem it advisable, on account of the violence of the re- action, to discontinue the treatment after a single injection. No fatalities occurred as a result of the treatment, but it should be borne in mind that evidence of cardiac weakness or hypertension was considered a contra-indication to the treatment and such pa- tients were not injected. Scully later reported on another 24 cases of whom 40% cleared up promptly after a single injection and Thomas, working at St. Luke's Hospital, treated an additional 20 cases. Of these 30% were permanently relieved from pain. Other American workers have reported on extended series of cases. Thus Cecil used the method in 40 cases, of which 26 were of the ordinary rheumatic type, 7 acute toxic arthritis and 7 of gonor- rheal origin. Cecil gave typhoid vaccine intravenously, using a dosage of 30 to 100 million. By accident a few patients received a larger dose (400-500 million) but the reaction was not much more severe. Of the rheumatic and toxic arthritides 40% recovered com- pletely in from two to ten days without the use of salicylates. The remaining 20 patients all received salicylates at some time of their stay in the hospital, either before or after their vaccine treatment. Of these 17 were cured or greatly benefited under the combined treat- ment. Cecil noted that while the pain in the joints was frequently completely relieved, a degree of muscular pain persisted in the mus- cles, particularly in the muscles of the back. The seven patients suffering from gonorrheal arthritis made very slow improvement by the vaccine treatment. Cecil concludes that the method is undoubtedly efiBcient in many cases of acute arthritis, but that it is unpleasant for the patient and may be dangerous when administered to improperly selected patients. It is interesting to note that several of his patients developed herpes labialis following typhoid vaccines (we had the same experience with certain strains of vaccine; others never were followed by herpes). One patient developed delirium tremens. Snyder has reported a series of 110 cases, in which a relatively small dosage — 5 to 10 million organisms — ^was employed, with ex- cellent results. Snyder considers the method more satisfactory than any other at present available. No kidney injury was observed fol- lowing the injections. Pemberton treated 19 cases of arthritis with intravenous injec- tions of typhoid vaccine— using 25 million organisms of the U. S. Army ARTHRITIS 145 yaccine. Of this group 7 definitely improved (36%) and in two the results were uncertain; in the rest there was no change, although one of the patients was apparently made worse. In more than half of the patients the temperature rose to a more or less uniform height — 103° to 104° F. Pemberton, working with military cases, calls attention to the fact that many of these soldiers had received repeated injections of typhoid vaccine subcutaneously without effect whatsoever on the arthritic disability, while the intravenous injection, which seems to stimulate the catabolic processes of the body as a whole, may after a single injection, produce evident clinical improvement. Harding also treated a number of cases (17) while in military service, but reports that his results were not satisfactory. Cross treated 14 cases with typhoid vaccine, using an intravenous dose of from 25 to 250 million organisms. The results were quite satisfactory, most of the cases clearing up very promptly; there were no ill effects and no endocarditis was observed following in the course of the disease. While he observed a leukocytosis following the in- jections he does not consider this the sole factor in the cure of the arthritis. According to his experience "with larger doses and greater severity of the chill the patient has experienced greater and quicker relief than with small doses" this coinciding with the experience that other observers have had in arthritis. Cadbury treated 27 cases of arthritis of varied etiology with intra- venous injections of typhoid vaccine. The results were as follows: 4 acute arthritis (uncomplicated) cured. 1 rheumatism with cardiac complications and sepsis — improved. (2 cured 7 markedly improved 7 slightly improved 5 gonorrheal arthritis-i . . •, 1 luetic improved Gow has also published his experience with nonspecific therapy, using either proteoses or heterovaccines, and concludes that in cer- tain forms of arthritis great benefit has been derived from intra- venous protein therapy. Vaccine is given entirely for a shock effect. The type of joint disease which responds best, in Gow's experience, is the multiple infective arthritis for which no active source of pri- mary infection or septic absorption is demonstrable. While Gow regards intravenous protein therapy as of great value in certain care- fully selected cases — more particularly of arthritis, the septicemias and coliform infections — he states most emphatically that it is not a panacea for all ills; and even in those diseases in which it is of use it is to be regarded solely as an accessory weapon to be employed 146 PROTEIN THERAPY in conjunction with, not to the displacement of, other remedies. Cowie and Calhoun have made a very detailed and careful study of a small series of arthritic cases that had proved intractable to other forms of therapy, including 2 cases of chronic multiple peri- arthritis deformans; one each of hypertrophic arthritis deformans, chronic multiple periarthritis deformans, atrophic arthritis and hyper- trophic spinal arthritis; two of acute rheumatism; two other cases were treated, one a gonorrheal vulvovaginitis and the other a sup- pm-ative mastoiditis, complicated by chronic pulmonary tuberculosis. Typhoid vaccine in relatively large dosage — 1 billion organisms — was used to give the reaction, which was in some instances quite severe. Under the vaccine treatment most of the arthritic cases made noticeable improvement, although it was not to be expected that pathological alterations which had become chronic would be percept- ibly changed or modified. The case of ^oilvovaginitis was not com- pletely cured despite several injections. The chronic suppuration of the ear was completely cured after the second injection. In a re- cent paper Cowie has briefly reviewed his experience with protein therapy. He finds it most useful in acute and subacute arthritis. Boyd has also employed typhoid vaccine, using it in a relatively moderate dosage (50 million) with success in a variety of diseases originating in focal infection, including arthritis. In the European literature one finds nmnerous observations con- cerning the use of nonspecific therapy in arthritis. Typhoid vaccine has been employed less frequently, but milk injections, following the original recommendation of Miiller and Weiss, have been commonly used. (Edelmaim, Panczyscyn, etc.) Colloidal metals have also found favor, while Edelmann found that a combined form of therapy — ^using salicylates and milk injections — gave results that practically assured success in every case. Voigt, Moewes, Voigt and Corinth (iodid-silver colloid), Mukerjee (colloidal sulphiu- and mercury), Reichmann (colloidal silver), re- port on arthritis treated with the intravenous injection of colloidal metals. Zimmer used casein injections both intravenously and intramus- cularly, the dose varying from 1 to 5 c.c. of a 5% solution. He reports on 150 ambulatory cases treated in the Polyclinic and some 30 cases treated in private practice. The cases included arthritis de- formans, old rheumatic and traumatic arthritides as well as a num- ber of other origin. His general experience led him to the belief that the most desirable results were obtained when the injections elicited a strong focal reaction with a relatively mild general reaction. His cases of subacute arthritis and gonorrheal arthritis were either cured or markedly improved. The immobility incident to the older gonorrheal involvements was not altered. ARTHRITIS 147 In arthritis deformans there resulted a definite improvement in mobility as well as a lessening of the pain. Gout. — In these cases a focal reaction of considerable extent was precipitated with prompt resorption. In several cases of neuritis there was prompt improvement. The use of the cartilage extract of Heilner — "sanarthrit," in chronic arthropathies has been reported upon by Umber and Meyer and also by Reinhart, by Sonntag and by Lampe. Umber reported satisfactory re- sults in patients and Meyer has made some experimental studies on arthritis in animals. Reinhart treated 23 cases of chronic arthritis in whom the pathological alterations had in some instances been of very long standing, with decided bony changes visible on Roentgen exam- ination. In 22% of these cases there was almost complete cure, some of the patients who had been bedridden for long periods of time being able to be up and about after two or three injections, and the improvement was permanent. In 48% there was some improvement, part of this being permanent also. The other cases, despite repeated injections showed no improvement whatsoever. There was no doubt in Reinhart's mind that the effect of the "sanarthrit" was due solely to the nonspecific reaction that followed the injections. Roos in his recent discussion of the treatment of arthritis dis- cusses the use of sanarthrit and reports one case so treated. Stern has treated some 25 cases of arthritis with Heilner's san- arthrit of whom 10 showed no improvement. In 4 cases the con- dition was made worse, in only 8 was there some evidence of im- provement, and this was usually a subjective finding. Denecke has compared the effects of sanarthrit and casein injections in 30 cases. The milk, casein and "gonargin" injections resulted in less focal re- action and he does not consider the effects quite like those obtained with sanarthrit. Discussion. — The treatment of acute arthritis has offered one of the most attractive fields of therapy for nonspecific procedures and the re- sults have in general been very satisfactory. In perhaps 40% of the cases one or two injections completely terminate the disease, in an- other 30% the improvement is marked and recovery made complete on further injections, while in the balance there may be either a transient improvement with a relapse later, or no marked clinical improvement. It is true that the methods as so far employed are not pleasant for the patient — ^typhoid vaccines, or vaccines of any kind in sufficient dosage to cause a severe reaction ; proteoses, or milk, are all followed by a chill, headache, a sharp febrile temperature reaction, occasionally nausea and a general feeling of malaise. And yet the general clinical experience has been that a sharp general re- 148 PROTEIN THERAPY action is followed by the best clinical results. Of course, efforts have been made to inject substances that would give the same therapeutic effect without the severe reaction. Brooks and Stanton have, for instance, used the lower fractions of digestion products obtained from ox fibrin for injections in arthritis. With this product they claim to have obtained satisfactory clinical results with practically no unpleasant systemic reaction on the part of the patient. The dosage of these lower split products was about 12 milligrams for intramuscular injection, while one-fourth or one-third of this dose was given for intravenous injection. They observed improvement in all of the 8 cases of arthritis treated with this preparation. Their experience differs from that of the majority of the clinical observers in their ability to obtain therapeutic results without marked general reaction. It has been our experience in treating arthritis that unless a sharp reaction was elicited at the first injection, subse- quent injections would as a rule be followed by little or no clinical improvement. We have felt that arthritis was one of the diseases where such a sharp reaction was justified and where typhoid vaccine, toxic though it is, seems to give the most brilliant results. Usually the arthritic patient is an excellent risk, is not very toxic, and has few contra-indications, so that a more or less heroic method of therapy is entailed with less danger than in other forms of disease. Apart from the immediate cure of the disease another factor of im- portance enters into consideration when we deal with arthritis, namely the carditis that so often complicates the picture. Nonspecific therapy seems to have little or no influence on an endocarditic process once it is established unless small doses are given over a long period of time; even then its absolute value is not certain. Single large doses may at times influence the temperature of such cases for a day or two, but not, as a rule, over a longer period of time (Kinsella). It is probable, however, that the early termination of the arthritic process by nonspecific therapy does prevent the establishment of endocarditis in a definite number of cases and in the prevention, rather than the cm'e of endocarditis, this form of therapy perhaps offers a valuable aid. From the point of view of the hospital management of arthritic cases another factor of importance must be emphasized, namely, the relative cost of maintenance of the arthritic case. If by any form of therapy the period of hospitalization can be shortened from the average of 5 or 6 weeks to a period of a week or two, its usefulness from an economic standpoint will be apparent. Possibly an unbiased review of the subject, such as that recently published by Torrey, will be of greater value than my personal im- pression, which perhaps may be prejudiced in favor of this form of treatment. ARTHRITIS 149 Torrey first recalls the rather interesting work of Terc, who treated a large number of rheumatic cases with bee stings, following which the patient often reacted with a typical general reaction — fever, general malaise, etc. When the sting was repeated over a period of time the patient became more or less refractory and during this re- fractory period the symptoms of the arthritis disappeared. Langer later repeated this work, using an extract of the bee poison, but his clinical observations were not so extensive nor so conclusive as those of Terc. More recently Dold has investigated the poison of the bee and has tried to sensitize animals to the bee toxin, but without re- sult. Torrey then continues: "The lack of result with sera and vaccines, unless the administration is followed by a definite febrile reaction, and the good result following such reaction, no matter what agent is used, indicates that a nonspecific agent alters bodily condi- tions materially. It is not clear whether actual infection is influ- enced by allergic or anaphylactic reaction. More reason exists for the view that the change affects the toxic expression of the infection, and that, while the organisms are still retained in viable form, their presence, or products, do not excite response by marked tissue change. There is probably a prompt detoxicating action exerted in the blood or tissues by the allergic response to the introduction into the blood stream of a foreign protein. While a similar response may be elicited to a less degree by subcutaneous or intramuscular injection of toxic proteins the sudden and full effect is attained only by intravenous injection where the protein is put into the blood unmodified by pas- sage through other tissues and unaltered by cell or membrane selec- tion. The usual typhoid prophylactic initial dose of 500 million killed typhoid bacilli given subcutaneously seldom gives a severe reaction; if given intramuscularly there is more apt to be a more marked febrile response, while one-tenth of that dose given intravenously will as a rule promptly produce a chill and a sudden rise in tempera- ture to 103°-105°F. (39.4°-40.6°C.). The ultimate gain in specific immunity against typhosus infection will be much greater in the for- mer case but a detoxicating action and termination of acute inflamma- tory processes will follow promptly after a severe reaction to the small dose given intravenously but not after the gradual absorption of the larger subcutaneous dose. Two questions suggest themselves: (a) While experience offers abundant evidence that arthritis can be promptly terminated by such intravenous therapy, is it a safe procedure and does it for this pur- pose show any decided advantages over salicylate therapy? (b) Granting that arthritis may be controlled by this means, is there any indication that carditis is prevented or favorably influenced? (a) Regarding the safety of the procedure. Bacterial extracts or emulsions vary so greatly in their toxic effects that great care must be used in the selection of the strain and the estimation of the dose. 150 PROTEIN THERAPY As Miller states, it is necessary always to start with a minimum dose of vaccine until its toxic index has been gauged. The writer has heard of a fatality resulting from the intravenous use of typhoid bacilli. The reaction is so severe that it would, offhand, appear that the margin of safety was a narrow one. On the other hand long series of cases so treated have been reported by Miller and Lusk, by Cecil and other American observers. As for the use of unknown quantities of mixed organisms with no means of duplicating surely the strains used, it would seem ex- tremely hazardous to use such products intravenously; and where such severe reactions are concerned, very difficult in any event to judge dosage. It would appear safer to use a definite compound as suggested by Jobling (proteoses) where the dose can be accurately determined by weight and where stability can be assured. The writer has used formaldehyd intravenously to accomplish the same reaction. The toxic agent introduced here is probably a combination of formaldehyd and serum protein. The systemic re- sults are similar to those accomplished by the bacterial injection. Two years ago the writer with his resident physicians at the Phila- delphia General Hospital treated 29 cases of acute and chronic ar- thritis by this method. In these cases careful search was made for signs of renal changes, blood breakdown or other signs of renal damage but we could find no evident bad effects. It might be said that while bad results have not been shown to follow careful intravenous therapeutic measures we are dealing with a most potent agent and the safety of this procedure has not been as- sured. It is probably not justifiable to employ this method of treatment routinely unless more is to be accomplished than simple relief of the arthritis. In most cases salicylates and good nursing will accom- plish this result in a few days' time. (b) As regards the second query. Is the development of carditis prevented or favorably influenced by this form of treatment? a much larger collection of cases will be necessary before this question can be answered. It is said that established active endocarditis is not eradicated; further, that when endocarditis is present arthritis tends to recurr after intravenous treatment, showing that the infection re- mains. The writer has not used intravenous therapy in cases with severe endocarditis or in those showing evidence of severe myocardial de- generation. The patients were selected as a rule among younger adults either refractory to salicylates or showing a very severe degree of arthritis, or those who, having observed results in other patients, requested this form of treatment. These patients were usually la- borers from railroad construction gangs or workers in munition plants and it has been impossible to follow up these cases properly, but ARTHRITIS 15i it must be said that at the time of leaving the hospital none of them showed any serious cardiac damage. We endeavored to keep all rheumatic patients in bed for three weeks after the temperature reached normal and succeeded in most cases in doing so. Any measure that will protect against carditis will be of tremendous importance and while in this case we may be merely clutching at a straw the subject should be studied carefully. It is recognized that infection is prone to implant itself upon the heart in which there has been tissue damage and it is more than possible that endocardial damage results first as a toxic expression, as it may in the Joints, and that the liability of a permanent infection may be reduced by the detoxicating action of the allergic response. The writer's feeling is that serious cardiac trouble is less apt to develop when this form of therapy is used. Realizing the risk attendant on its use he is still i alined to try it on young and vigorous individuals where the myocardium is not greatly damaged." This conservative resume of Torrey's is quoted in full because of its dispassionate and critical perspective and because it emphasizes several points that should be kept in mind — whether it is a dangerous method of therapy; if not, is it a better method than our present one, and finally, does it prevent cardiac complications? While we by no means believe that the goal in therapy has been reached when we inject typhoid vaccine intravenously — other agents may be much better and may be much less uncomfortable for the pa- tient — ^yet we have never seen any ill effects from moderate doses of typhoid vaccine injected intravenously when reasonable care was exercised to exclude alcoholics and severe heart cases. It is considered safe enough to enable one hospital to make the injection a routine procedure for all rheumatic cases entering the service. Our present expectant therapy or salicylate therapy fails in a definite percentage of cases. In a good number it is temporarily ef- fective and is followed by a relapse. In others cardiac complications are superimposed even during the course of the salicylate treatment. It is furthermore a protracted therapy and therefore an expensive one. Nonspecific therapy does frequently effect improvement and cure of the disease where salicylates have been used without avail. Usually one or two injections will disclose whether or not we can ex- pect much relief by the nonspecific agent and when it is effective, it is rapidly so. My own impression is that it materially lessens the number of cardiac complications, although I cannot present definite statistics to that end. And in terminating the disease abruptly we lessen the number of chronic arthritic cases, which, once established, are so intractable to treatment. To the clinician who is satisfied with his present method of treat- 152 PROTEIN THERAPY ment of acute articidar rheumatism, or of chronic arthritis, nonspe- cific therapy naturally has nothing to offer. To those of us who are not so satisfied I believe it adds a definitely useful agent and at times a very powerful one. Indeed to those who are interested in nonspecific therapy or the mechanism involved, the arthritic cases offer a particularly valuable field for research. There is practically no risk to the patient — as there might be in more or less experi- mental work on the more acutely ill — the signs of improvement or retrogression are objectively imder the control of the physician and the interesting focal reaction elicited by the nonspecific agents at the inflammatory site can be carefully observed, especially in the more chronic type of arthritis. The mechanism that is involved in the recovery of the patient is still quite obscure. It is to be taken for granted that we must first of all seek to remove any apparent focus of infection. Whether the joint pathology always represents actual bacterial invasion or at times merely a focal reaction of hypersensitive tissues is by no means a settled question. We do know that the nonspecific injection brings about a focal reaction and that the mechanism of recovery hinges on this reaction. Whether, as a result of the reaction the local tissues become immune to the toxic effect of bacteria still alive in the focus, whether it means merely an increased tolerance to toxic split products set free at a distance and to which the local tissues had heretofore been sensitive, or whether we deal with the actual de- struction of bacteria which had become localized in the joint is not determined. We can simply point to the analogy that exists between the skin and the joint tissues in their property of distinct local sensi- tization, and to the fact that the reaction, being a focal one (a Herd reaktion), can be brought about by a great variety of agents and metabolic alterations (the recent paper of Gaisbeck on acute arthritis and hemiplegia is of interest in this connection) ; and as such is typical in its manifestations both in the negative phase (increased inflamma- tion) and the positive phase (decreased inflammation). For the therapist it is the latter that is of greatest interest. CHAPTER IX THE TREATMENT OF TYPHOID AND PARATYPHOID FEVER Investigations in the treatment of typhoid fever formed the basis upon which our modern conception of the nonspecific factors in therapy are based, not only in the very recent contributions to the literature, but in the older work such as that of Rumpf. Typhoid Vaccine. — In the decade preceding the war the thera- peutic use of typhoid vaccines in typhoid fever had been developed particularly by French scientists (Chantemesse and Widal, Vincent, etc.) and a number of vaccines were elaborated by them, each with some supposed point of superiority. The sensitized vaccine of Besredka had been used with a measure of success. Stem many years ago had suggested the use of an antitoxic agent, while the use of convalescent serum was introduced by Hammerschlag and used also by Konigsfeld, von Jaksch and Pollak. A comprehensive review of this period and of vaccine therapy in typhoid fever in general will be found in Gay's monograph, as well as in the report of Krumbhaar and Richardson. The latter reached the conclusion that the larger the dose of vaccine, the better the therapeutic result. But large doses of vaccine were not in vogue; one hesitated in giving large reactive doses in chronic diseases where there was little risk; naturally enough this caution was more than observed in such an acute condition as typhoid fever where logically it would seem to be decidedly unwarranted to add more toxin to an already overburdened organism. Intravenous Injections. — From two quite independent sources, however, this established view was rather abruptly overthrown. In Argentine a group of clinicians found that if they injected typhoid vaccine intravenously during the course of typhoid fever certain remarkable critical terminations of the disease were to be observed; in other cases the disease terminated by lysis shortly after the injec- tion; even those that were not affected in so far as the temperature course was concerned seemed much less toxic than before the injection. This work, carried out by Penna, Torres, Dessy, Grafiolo, Fossati and others, formed the basis on which Kraus later began his work with heterovaccination in typhoid fever. At about the same time Ichikawa published a series of cases of typhoid fever treated with intravenous injections of typhoid vaccine with similarly striking results. He used a sensitized vaccine for the 153 154 PROTEIN THERAPY purpose, made up as follows: 10 loops of fresh typhoid culture were suspended in 10 c.c. of human typhoid convalescent serum and in- cubated for 5 or 6 hours. The organisms were then centrifuged from the serum, washed three times in physiological salt solution, suspended in 100 c.c. of physiological salt solution with 0.3% phenol and finally shaken for 1 hour. The vaccine was not heated. Of this emulsion 0.5 c.c. was diluted in a syringeful of saline before injection and the whole slowly injected intravenously. In most of Ichikawa's cases a single injection sufficed to terminate the febrile course of the disease; in some the result was not quite so marked. After the critical drop in the temperature the temperature would again rise in these cases, usually remaining intermittent in type and much lower than before. The general condition of these latter pa- tients was always much better after than before the injection. In the refractory cases the injection was usually repeated once and even twice until the desired result was obtained. Ichikawa assumed that the effect on the temperature curve was due to a mobilization of antibodies that had been formed in the cells during the course of the infection but had not been thrown into the general circulation until the vaccine was injected intravenously. The mortality in this first series was 11%, rather high in itself, but not in comparison to the death rate in untreated cases in the Osaka Hospital, which was around 30%. Ichikawa did not observe any ill effects from the vaccine injec- tion; indeed he considers it unjustifiable to neglect the advantages of intravenous therapy merely because certain inherent dangers are, theoretically, to be considered. He watched particularly for cardio- vascular changes but did not have any collapse cases, and hemorrhages were less frequent in his vaccinated cases than in the untreated. In a few cases he did observe hemorrhages from 1 to 3 days after the injections; usually they were slight and not alarming in character. In two cases he observed hemoptysis, twice nose-bleeding, and in two cases hemorrhages into the skin, but they were all mild in character and did not recur. The reaction that occurred — chill, fever to 40° C, relatively high pulse, occasional nausea, dyspnea, etc. — was transient; even the increased temperature never persisted over 24 hours. Heterovaccines. — ^Kraus and Mazza reported their work in 1914 in which not only the results obtained with intravenous injection of typhoid vaccine in typhoid fever was described, but the use of hetero- vaccines was taken up. Ichikawa had previously noticed that with typhoid vaccine he could treat paratyphoid fever just as well as typhoid. Kraus and Mazza found that colon vaccine did just as well, and besides reported on the effect of the intravenous injection of such vaccines in puerperal infection, where relatively long stand- ing infections were promptly terminated and the disease process TYPHOID AND PARATYPHOID FEVER 155 cured. Kraus suggested the extension of the method of treatment to a number of diseases such as scarlet fever, plague, septicemia, etc. Other reports were soon published dealing with nonspecific therapy in typhoid fever; most of the observers first used typhoid vaccine. Thus Rhein tried it in 33 cases. He prepared his vaccine as follows: To 5 c.c. of Halle typhoid vaccine and 0.5 gm. pure phenol, physio- logical salt solution was added to a volume of 100 c.c. Of this prepa- ration he employed 0.6 to 1.4 c.c. diluted with 8 c.c. physiological salt solution for intravenous injection. Within one to two and a half hours a rise in temperature and a chill of varying severity and duration (five to thirty minutes) occurred in 94 per cent, of the cases. Injections were made only in patients in whom the diagnosis was clear clinically or bacteriologically. Three of the patients treated showed paratyphoid bacilli A in the blood. Patients exhibiting the steplike curve of defervescence were excluded, as were also those suffering with complications such as pneumonia, pleurisy, nephritis, or myocarditis. Status typhosus, with delirium and bronchitis, but with good pulse, was not looked upon as contra-indication for injec- tion of vaccine. Thirty -three patients received the injections and 6 of these had a second injection. In 9 cases there was a critical fall of temperature within one day after the first injection and in 1 case after the second. In 13 cases a favorable effect on the tem- perature curve was noted after the first injection and in 3 cases after the second injection. In 8 patients there was no effort whatever on the temperature curve, and in 2 of these a second injection was also without visible effect. On the other hand, 3 patients who were un- affected by the first injection reacted favorably after the second. In the 3 cases of paratyphoid fever a critical fall of temperature was not observed, but there was a gradual lowering in the fever. Of the patients injected, 3 died; in none could the death be attributed to the injection. Of all the patients treated, only 1 suffered from intestinal hemorrhage, which occurred six days after the injection. Other complications were not observed in the injected patients. No evidence of collapse even in patients with weak pulse was seen. The reaction of the patient to the injection was studied with relation to the following clinical signs or symptoms: Bronchitis, palpable spleen, roseola, diazo-reaction, leukocyte count, eosinophil count, and bac- teriemia. A favorable response to the injection could not be corre- lated with any of these. However, after crisis, comparatively many eosinophils (100 to 200 per c.mm.) appeared in the blood in twenty- four hours in spite of the leukopenia, and the diazo test remained positive as long as three days after the temperature was normal. It was noticeable that with larger dosage (4 c.c.) the crisis was of shorter duration. Since no ill effects followed the injection, and, on the contrary, in 48 per cent, of the cases the fever was shortened and in 30 per cent, cure followed within two days, Rhein believed 156 PROTEIN THERAPY that in every case of uncomplicated typhoid fever, bacteriotherapy should be tried. Biedl and Eggreth also gave their experiences with the vaccine treatment of typhoid fever. Biedl treated a series of 22 cases of severe typhoid fever in the beginning of the second week; the blood culture was positive in all of these. Of this number 2 are excluded. Both were men with high fever, status typhosus, and recurring epistaxis, the last nose-bleed occuiring one day before in each case. Two hours after injection of the vaccine there occurred in each patient an uncontrollable hemorrhage from the nose which led to death. Of the remaining 20 cases, 11 received Vincent's vac- cine (typhoid bacilli killed with ether), first 100 million, later 250 million to 300 million in 2 c.c. of salt solution, and 9 were treated with Besredka's vaccine intravenously (sensitized living typhoid bacilli) in doses of 250 million to 300 million in 2 c.c. of salt solu- tion. The end result was as follows: Of the cases treated with Vin- cent's vaccine 3 died; 2 received subcutaneous injections and died fourteen and eighteen days respectively after the injection; 1 treated intravenously, after an initial favorable response, died in the third week from severe bronchopneumonia and heart weakness. Evi- dently none of these deaths were due to the vaccine. The remaiaing 8 patients recovered. All of the patients treated with Besredka's vaccine recovered. Biedl's impressions were decidedly favorable. After intravenous injection the temperature rose in one to two or three hours from 39° to 40° C. (102.2° to 104° F.), in one case even to 42° C. (107.6° F.), followed in twelve to eighteen hours by a critical fall of temperature to normal. No signs of collapse were observed; indeed, in two cases the injection was made when the patients were in a state of collapse with a pulse which could not be counted. Within three hours the temperature rose, the pulse became much fuller with a rate of 100 per minute. Following crisis the patients felt much better. The patients treated with Besredka's vaccine remained afebrile. Some of the other patients had slight evening elevations of temperature; in none above 38° C. (100.4° F.). Eggreth treated a series of 43 cases of typhoid with a single intravenous injection of 0.5 to 1.0 c.c. of Bes- redka's vaccine. Subcutaneous injections had produced no result. In 34 cases of Eggreth's series a critical fall of temperature followed within three to twelve hours after the injection, frequently with pro- fuse sweating and marked relief of headache and delirium. Of these patients 31 remained afebrile; the remaining 3 developed fever after twelve, fourteen, and fifteen days, due respectively to endocarditis, to bilateral purulent parotitis, and to suppurative osteoperiostitis. The majority of the patients received the injection between the sev- enth and sixteenth day of the disease. In a group of 8 cases in the fourth and fifth week of the disease, suffering with broncho- or pleuro- pneumonia, the injection was ineffective. The forty-third case died TYPHOID AND PARATYPHOID FEVER 157 three hours after the injection. An autopsy was performed which revealed typical typhoid lesions in the small intestine, pneumonia, and myocarditis. The patient had been brought to the hospital imcon- scious and desperately ill, and a poor risk. Paltauf, at whose re- quest Biedl and Eggreth had reported their experiences from the military hospitals, uttered a word of warning, as he had heard of a few instances of collapse following the intravenous use of Bes- redka's vaccine. In the earlier experience collapse and even death after the intra- venous injection of relatively large doses of typhoid and other toxic vaccines was not uncommon (Kraus and Mazza, Boral, v. Reuss) and the caution expressed by Paltauf is more than justified. The early doses were tremendous and would put even a healthy individual to considerable strain; that patients severely ill would occasionally suc- cumb to the treatment was therefore not unexpected. At a meeting of the Gesellschaft fiir Aerzte in Wien (June 18, 1915) a number of clinical reports were presented which are of in- terest. Nobel treated 14 cases of typhoid with intravenous typhoid vaccine injections. Of these 11 were cured after one injection, 3 died. Zupnik, who used typhoid, meningococcus and albumose in- jections, brought out the fact that small doses were much prefer- able to the larger ones heretofore used, because the therapeutic re- sult was just as good and the danger to the patient much less. Fleck- seder treated 41 cases of typhoid with intravenous injections of Bes- redka vaccine. Of these 21 cases proved refractory. In 20 cases the temperature came down after several injections. He used fairly large doses and saw several cases of vasomotor collapse. In two cases a hemorrhagic nephritis developed. He therefore considered the treatment of doubtful value, particularly in severe cases. Stoerk used albumoses and obtained results that were similar to those ob- tained with typhoid vaccine. Meyer reported a series of cases treated with typhoid vaccine with typical results but in a later discussion is rather inclined to think that the intravenous injection of typhoid vaccine is too strenuous. He has come to the conclusion that some of the milder agents will be found much more satisfactory for general use. Lucksch has reached the same conclusion. Other earlier reports are those of v. Czylharz, V. Czylharz and Neustadtl, Neustadtl, Reibmayr and Decastello, Sladek and Kotlowsky. Reibmayr and also Decastello reported on a series of cases treated with cholera and colon vaccines. In Decastello's cases he injected 30 million organisms (colon) which gave a sharp reaction. In 10 cases of typhoid fever 4 responded by defervescence by crisis, 1 by lysis after the first injection. Three more cases became normal by lysis after the third injection; in two cases there was no effect 158 PROTEIN THERAPY to be observed on the course of the disease following the injection. Thus heterovaccine therapy was, clinically at least, definitely es- tablished and has come to be accepted even when the vaccine is used subcutaneously. Stein in presenting the results on about 1,500 cases of typhoid treated by him both subcutaneously and intrave- nously found that by either method of administration colon vaccine would give comparable results. The theory could still be advanced that the vaccines injected were more or less related biologically and that group reactions might im- munologically account for the result, an idea that Ichikawa had ad- vanced to account for the success of the typhoid vaccine in para- typhoid fever. Milk and Albumoses. — Even this last resource of our older concep- tion was swept away with the demonstration of the fact that typhoid fever could be treated with equally good clinical results with intra- muscular injections of milk or intravenous injections of protein products. Liidke in 1915 reported on 23 cases of typhoid fever treated with intravenous injections of deutero-albumose and later reported on a series of 78 cases of typhoid fever and paratyphoid B fever with the following results: In 26 cases there was a complete, critical defervescence. In 10 cases there was a complete defervescence in from 3 to 5 days. In 31 cases the temperature came to normal in from 7 to 12 days, while in 11 cases there was no appreciable effect on the temperature curve. The deutero-albumose used by Liidke contained about 15% of salt as well as some protalbumose and was used in the majority of cases in 10% solution. In the normal individual the injection of 1 to 1% c.c. of this solution caused no reaction. (In one normal individual a second injection given after an interval of two weeks produced a slight chill and a rise in temperature that persisted for about 4 hours.) Liidke has never seen an unfavorable effect on the pulse follow- ing proteose injections in any acute infection. There were no deaths in these 78 cases of typhoid or paratyphoid fever. The average dura- tion of the disease in these cases was from one to two weeks and he has noted, as others have constantly reported, that the earlier the treat- ment is inaugurated, the better the results. Perhaps the largest series treated with deutero-albumoses is that of Holler (350 cases). His method of injection differed materially from those heretofore employed in that he gave daily injections, usually commencing with 1 c.c. of a 10% solution and increasing the dose about 0.5 c.c. with each injection, depending of course on the reaction. His cases were all kept on a fluid diet, were given charcoal as well as urotropin, but otherwise had no medication apart TYPHOID AND PARATYPHOID FEVER 159 from the proteose injections. His mortality was only % per cent.; he experienced no prostration or hemorrhage of moment in the en- tire series. The average duration of the disease was 10 days. Nat- urally the earlier the cases came to treatment, the more apparent and satisfactory were the results. During the course of his experi- ence he used ovalbumin, adrenalin, typhoid convalescent serum, horse serum and pleural exudate intravenously, but for general use he ob- tained the most satisfactory results with the proteose. Jobling and the writer treated a series of typhoid cases with a secondary proteose preparation, some of which were reported in a pa- per published in 1916, and Miller and Lusk, and Miller reported on the treatment of typhoid fever both with typhoid vaccine, with prote- oses and with pollen extract. Nolf has also used peptone in typhoid fever with satisfactory results. In 1916 Schmidt, Luithlen, Saxl, Bruck and Kiralihyda, Miiller and Weiss, introduced intramuscular milk injections. Two factors tended to popularize this agent — the relative ease of administration (intravenous injections being at times more or less formidable) and the availability of milk — so that for the past three years one finds perhaps most of the reports on the effects of nonspecific therapy based on experience gained with milk injections. Saxl, Bruck and Kirali- hyda at first reported on the use of milk on gonorrheal complica- tions, but Saxl shortly reported on 26 cases of typhoid fever treated with injections of this kind. In almost all cases, after an initial temperature increase that persisted for about two days, the tempera- ture came to a normal level by lysis. Corinaldesi gave intravenous injections of 1 c.c. of a 2 or 4 per cent, solution of deutero-albumose in a case of typhoid and one of paratyphoid, according to Liidke'g technic. No benefit was apparent. Then he tried intramuscular in- jections of 5 or 10 c.c. of sterilized milk in five patients with lobar or bronchopneumonia or typhoid and was astonished at the prompt and permanent improvement that followed one, two or three injec- tions, without disturbances or much local reaction. There was only rarely a slight chill and it was mild. His findings thus confirm the way in which parenteral introduction of some protein substance is able to stimulate the defensive forces and aid in the throwing off of the disease, irrespective of the nature of the protein injected. Galambos made an effort to determine which of these agents so far described might be of greatest value. In a series of 136 cases he used deutero-albumose, vaccines (colon, gonococcus and staphylo- coccus) and salt solution. In 25 cases treated with injections of 1 c.c. of a 4% solution of deutero-albumose he obtained a critical drop in the temperature in 50% of the cases. Vaccines seemed much less effective; more and repeated injections had to be given in order to obtain the same result. The dosage varied, about 25 million of colon 160 PROTEIN THERAPY and gonococcus organisms were injected, 250 million of the staphylo- coccus, in order to obtain a satisfactory reaction. When 100 c.c. of physiological salt solution was injected a defer- vescence was obtained in 70% of the cases. In the total series the mortality was 6% and the results can be summarized as follows: Critical defervescence 22% Prompt lysis 22% Marked improvement 18% Moderate improvement 9% No effect 28% As a result of his investigation Galambos inclined to the treat- ment with protein split products. The treatment by salt solution injections was first reported by Englander. Englander while treating a bleeding typhoid case injected about 300 c.c. of salt solution intravenously and found that this was followed by a typical chill and a defervescence the following day. Mitlander later reported on the same method. Comparative Results. — Galambos — ^who studied the intravenous therapy of typhoid and paratyphoid fevers with Besredka's vaccine and with albumose, heterovaccines and salt solution, as just mentioned — reported later on the treatment of 120 cases with methylene blue. He considers intravenous treatment limited in its application for sev- eral reasons : it requires a certain degree of skill and experience on the part of the physician, who must rule out contra-indicated cases — myo- carditis, pneumonic complications, etc.; there are associated with the in- jections certain dangers of hemorrhage and of collapse (from 1% to 2%) ; the substances used are not chemically defined and experience must be gained with the dosage before one can be fairly safe in using the method. This came to Galambos' attention when he reviewed his earlier and his later results with nonspecific therapy. In his last 50 cases where he used only a small dose of Besredka vaccine intravenously (^4 c.c.) he had no hemorrhage or collapse at all, and he likewise had no ill effects in his series of 60 cases treated with albumoses. The intravenous injection of larger amounts of salt solution was found too cumbersome for routine use. To overcome some of these practical objections he b^an the use of methylene blue, which, being a chemically defined substance, could be standardized, and while, being a protoplasmic stimulant as the others, could be given by mouth without a marked reaction. He gave 1.2 gm. per day in doses of 20 cgm. every 4 hours. The effect on the temperature was usually apparent in a few days, usually declining by lysis. The euphoria so commonly observed in nonspecific therapy was apparent in most in- stances. The medication was continued some days after the temperature reached normal. If discontinued too early an occasional recrudescence ■was noted. TYPHOID AND PARATYPHOID FEVER 161 In 120 cases so treated the severity of the disease was roughly as fol- lows (50 cases of mild disease were not treated at all) : 63 moderately severe ; typhoid 2 ; Para "A" 35 ; Para "B" 4 ; undetermined 22 23 severe; " 5; " 11; " 1; " 6 9 very severe; " 2; " 4; " 1; " 2 Of the typhoid cases many had had a prophylactic injection shortly before their admission to the ward. (There was probably no vaccination against paratyphoid, although it is not specifically stated in Galambos' paper.) The results of the methylene blue therapy was as follows : In 13% lysis set in immediately after the treatment. 26% lysis somewhat more delayed. 13% favorably influenced, but not much effect on temperature. 44.6% not influenced. 3.4% died. Compared to the results with the vaccine therapy before used the mor- tality was somewhat less but the general effect on either critical or lytic termination of the disease not so apparent. When one comes to study the comparative value of the intravenous method of therapy as contrasted with the subcutaneous injection of vaccine in the treatment of typhoid fever, the statistics of Barrenscheen are of value. Barrenscheen treated over 200 cases of typhoid, using Besredka's vaccine intravenously as well as subcutaneously; a small series was also treated with the Vincent vaccine subcutaneously. TJnfavor- Cured ably Infl. Not Infl. Died Besredka Intravenously 136 cases 8Y = 63% 5 = 3.6% 34 = 25% 10 = Y.35% Besredka Subcutaneously 52 cases 26 = 50% 3 = 5.1% 17 = 32% 6 = 11%- Vincent Subcutaneously 19 cases 4 = 21% 3 = 15% 12 = 63% = The intravenous dose was 100 million (sensitized vaccine) and if the patient was not afebrile after the first injection a second dose was given after two or three days; no more than three doses were given, because Barrenscheen found that if the patient was refractory it was useless to continue. In 30% of the cases a critical termination of the disease was obtained after a single injection. For subcutaneous injection he used 500 million organisms, followed two days later by 1,000 million if there had been no effect on the temper- ature. This dose was increased somewhat for the third injection but he never gave more than a total of 9,000 million organisms during the entire course of the treatment. As a result of his experience Barrenscheen considers, as other observers 162 PROTEIN THERAPY also do, that the first week or ten days of the ilhiess offers the best time for treatment; after the third week he considers it not only valueless but dangerous (because of the danger of hemorrhage or perforation). He does not give it in any cases where the pulse is over 100, where there is any evidence of lung complication or where a tendency to hemor- rhage is present — ^nose-bleeding, blood in stool, etc. If these conditions are observed the mortality would be even lower than that obtained in his series, for many of his results that were unsatisfactory were the result of his earlier efforts when he was not sufS.ciently experienced. In only one case did he find that death was due to a complication resulting directly from the injection. This was a perforation that came to notice immediately after the injection. In four cases a rather widespread roseola was observed shortly after the injection. It had no further significance but might disturb an inex- perienced clinician. The intravenous injection seemed much superior to the subcutaneous, not only apparent in the statistical result but because of the prompt bet- tering of the general condition of the patient. Headache and insomnia disappeared, the appetite improved and the mental conditions always cleared up. On the other hand this effect was never so apparent after the subcu- taneous injections and there seemed no doubt in his mind that the effect of the subcutaneous dosage was bad on the pulse. Both after the Besredka, more frequently after the Vincent vaccine the ill effect on the pulse was observed and in some instances stimulants had to be generously used before the equilibrium was restored. Following the intravenous injections the usual reaction was observed, vrith temperature reactions from 40° to 41° 0. (104° to 105.8° F.), in one instance to 41.9° C. (106.3° F.). The pulse never went over 120 and always remained of good quality and the patient without evidence of cardiac impairment — there was no dyspnea, cyanosis, etc. After the second injec- tion the temperature response was not as high as with the first, nor was the leukocyte count altered as much. During convalescence the patient should be kept rigidly in bed, at least for a week after the temperature has been normal, and careful attention given the diet and the bowels. In several cases where the patient became constipated a temperature reaction was observed which lasted several days. Occasionally a pronounced bradycardia was found during convalescence. Pulse counts as low as 36 to 50 were not uncommon in these cases, while an arrhythmia was at times present. Barrenscheen is under the impression that no myocarditis was present in his cases, but the fact that he lost two cases who got up and walked around two days after their recovery by crisis might lead one to think otherwise. Grote treated 24 cases of typhoid with milk injections with good results but came to the conclusion that the injections must be given early if they are to be effective. Mark White has reported on the treatment with normal horse senmi; E. F. Miiller on the use of casein injections, both with favor- able results. Ullmann treated typhoid with "Dispargin," a silver colloid; Salomon has reported favorable results in 141 cases treated TYPHOID AND PARATYPHOID FEVER 163 with a colloidal gold preparation and Labbe and Moussaud have also made use of the latter agent. Svestka and Marek used "Typhin," the nucleohiston prepared from typhoid bacilli. In 60 cases so treated they grouped the clini- cal results as follows: In one case the temperature increased for the day following the injection, then fell and remained normal. In 14 cases remissions began, the temperature coming down with tha usual remissions normally observed in the late stages of typhoid. In the balance of the cases the remissions became greater but the disease continued the usual length of time. In 21 cases 2 injections were made; in 11, 3 injections. They observed no increase in the agglutinin titer of the serum after the injections. Neustadt and Marcovici treated 25 cases of typhoid with "Typhin" and as a routine measure gave digitalin 2 days before the injection to counteract any tendency of collapse on the part of the vascular sys- tem. In 21 cases the injection was made intravenously. In 11 of these cases there was apparent a decided influence on the disease process — in 5 of these 11 the fever terminated by crisis; 4 cases gave evidence of some alteration and apparent shortening of the course of the disease; 3 cases were much less toxic after the injections; 3 patients died, one in collapse. Of four cases injected intramuscularly, 2 were influenced favorably, but the effect was not as marked as with the intravenous injections. Svestka and Marek consider that the method can be used with- out harm to the patient and is of decided value when given early in the disease, but they did not hesitate to give it even late in the disease if the cardiovascular tone was good. They consider the state of the circulatory apparatus the chief factor in judging whether or not the patient is a suitable risk, although they excluded markedly cachectic patients as well. After the injection improvement in the general condition of the patient was apparent in practically every case. Slaymaker reported on a few cases treated with typhoid vaccine given intravenously, the dosage varying from 25 million to 100 mil- lion. While only 9 cases were treated there were no marked re- sults, apart from some evidence of reaction and improvement in two of the cases. One patient died. From his experience Slaymaker was not inclined to continue the use of the method. Silvestri, using milk injections, found that this treatment seemed to increase the tendency to shock and hemorrhage in the twelve cases that he observed. In judging the relative safety or danger in the method of therapy it may be well to present briefly the statistics recently gathered by Vaughan in the American Army and others from military sources. These represent the results in vaccinated troops and may be considered quite satisfactory under military conditions. 164 PROTEIN THERAPY Observer Cases Inocula- tions Mortality Per Cent. Bernard and Paraf 26 28 50 38 15 270 1242 5 4 2 3 1-2 • • •' '3-4 • • •' 0.0 Hunermann 2.6 Hunermann 6.6 Crossonini 7.1 Crossonini 8.0 Campani and Gallotti 8.6 Hawn, Hopkins and Meader 13.1 Bonnel 13.3 Vauglian 11.0 Total A. E. F., 11 months 13.0 H. Bourges 0.0 Freund 8.3 If we compare such a series as that of Holler (350 cases) with its mortality rate of about % of 1%, to the statistics collected by Vaughan it would seem reasonable to conclude that the nonspecific method of therapy is, with reasonable precautions, rather more satis- factory than the mere expectant treatment. Kibler and McBride noted that the immediate effects of the intra- venous injection of the typhoid vaccine, such as chill, rise and fall of temperature, leukocytosis, and changes in the concentration of agglutinin and opsonin, usually in the direction of an increase, were the same in the normal man as in the typhoid patient. Except so far as they showed that leukocytosis is rather constant after the in- jection of vaccine, they did not support any particular view advanced to explain the action of intravenous injection of foreign protein in infectious diseases. The number of cases observed (six) , possibly too small to allow any conclusions as to the therapeutic effect of typhoid vaccine in typhoid, seemed to correspond fairly well with the re- sults obtained in larger series. Bacillus carriers have been treated with milk injections and with intravenous typhoid (para) vaccine with satisfactory results. Kar- rell and Luksch have employed milk, while Herz, using vaccine injec- tions, was able to clear up 4 out of 5 patients. Discussion. — A considerable number of observers have endeavored to determine whether or not there is an increase in the amount of anti- bodies in the serum which would 'account for the recovery of the patient after nonspecific therapy. The general summary of the observations on this particular ques- tion is that while such an increase may at times be demonstrated, it is by no means a constant result of the injection and cannot there- fore be identified as being the sole cause of the abortive recovery of TYPHOID AND PARATYPHOID FEVER 165 the patient. The agglutinin titer, which has been most often studied, is normally found to be rather high after the early stage of typhoid fever is passed and after nonspecific injections it is at times increased, at other times diminished. Nor does the increase or decrease bear any relation to the therapeutic result. Thus Rohonyi found that in some of his patients who had recovered after a single injection by a critical drop in temperature, there was no increase in the agglutinins, in opsonins or in bacteriolysin; indeed in some cases he was able to get a positive blood culture two days after the patient was clinically free from every evidence of active disease — an observation which Decastello has not been able to confirm. Liidke was not able to de- termine any constant increase in the amount of agglutinins or of opsinins after his deutero-albumose injections. Baluit observed no change in the agglutinins or the bacteriocidal antibodies, but obtained some evidence that the opsonins were increased. Svestka and Marek found no increase in agglutinins. Flechseder on the other hand claims to have observed an increase in agglutinins after albumose injections in typhoid fever. While it is apparent that the inconstant results exclude the anti- bodies as sole factors in the recovery, the possibility that their sud- den flooding of the lymph spaces after the permeability of the capillaries is increased following the protein shock may be a vital factor in overcoming the infection. Whether or not cell receptors (sessile antibodies that may have increased in amount following immunization or infection without their being cast off into the general circulation) are under shock conditions mobilized and in this way increase the titer after nonspecific therapy is here a point at issue. That rabbits immunized to some specific bacterial or other protein may, on nonspecific stimulation, respond by the "shedding" of the specific antibody is an old observation. Dieu- donne observed that rabbits immunized with typhoid bacilli and then injected with "Hetol" responded by an increase in the antibody production. Solomonsen and Madsen found the same true of diph- theria horses after pilocarpin injection, and Obermeier and Pick found that an injection of 5% or 10% peptone increased the agglutinin titer of rabbits immunized more than 3 months previously. Kutcher has observed that patients immunized to typhoid and cholera will show an increase in the agglutinins for dysentery (paraspecific ag- glutinins) and the mass immunization of large bodies of men with typhoid vaccine gave opportunity during the course of the war to observe that many varieties of shock (acute infectious diseases of various kinds, etc.) were followed by a flooding of the serum of such individuals with large amounts of agglutinins. Conradi and Bieling and also Johnson made experimental observations along the same 166 PROTEIN THERAPY line, while Parlovecchio found, as had Chantemesse, that the injec- tion of nucleins increased the agglutinin and alexin titer. Ardin- Delteil, Negre and Raynaud have also reported increase of agglutinins and bactericidal substances in serum after nonspecific injections. Other procedures include the stimulation of the sympathetics (Stuber) , the injection of alcohol (Friedberger) , arsenic (Agazzi), salvarsan (Friedberger and Masuda), blood-letting (Friedberger and Dorner), all of which are followed by an increase in antibody titer. It seems very probable that when the cells have become im- munized during the course of the disease, a certain number of re- ceptors are available but have not been shed. These are possibly mobilized when nonspecific injections are made. In a previous chapter the possible mechanism that underlies the re- covery in typhoid fever by means of nonspecific therapy has been fully discussed, so that it will not be necessary to again enter into the subject here. A number of interesting questions present themselves, however, as a result of clinical observation in more recent years concerning the normal recovery from typhoid fever. In persons who have been previously sensitized or immunized the course of the disease is fre- quently more stormy and somewhat shortened while the difference in the mortality may not be great as contrasted with the unvaccinated. On the other hand we know that recovery can take place without the appearance of antibodies in the blood stream, as Moreschi has demonstrated in leukemia. Certainly the presence or absence of the antibodies can no longer be made responsible for the clinical course of the disease. On the other hand the period of defervescence with its great varia- tions in the daily temperature curve is very suggestive of the reaction of the organism to nonspecific injections. One can conceive that the daily acciunulation of toxic proteins produces a summation of toxic effects with a resulting effect on the temperature curve. After the "shock" effect has passed the remission with its alteration in perme- ability and cellular stimulation, sets in and as the process is kept up the organism gradually becomes resistant to the intoxication un- til finally defervescence is complete. The study of Aller would rather confirm this conception; he presents a number of interesting examples which cannot be discussed in detail at this place. Holler's work would lead one to suspect such a basis for the normal mechanism of recovery for when he injected his proteoses in daily small doses similar temperature effects were achieved and the patient was soon completely afebrile. Ludke has recently expressed this same view. So, too, one can observe a variety of modifications of the tempera- ture curve even after a single nonspecific injection. The crisis may be prompt and complete. In other cases where a continuous high TYPHOID AND PARATYPHOID FEVER 167 temperature has been observed, daily remissions in the temperature curve will set in after a single injection; in others the average height of the temperature curve may be altered so that from a continuous temperature of about 102° F. the temperature after the injection will have a level around 100° F., as though the heat regulation had been attuned to a new level. The question of the mechanism of recovery brings with it the query, When is the patient cured? Does freedom from symptoms con- stitute cure? It has been pointed out that after the therapeutic crisis a positive blood culture may still be obtained, the spleen may still be palpable for a few days, the roseola remains a short time, the diazo reaction may persist, etc., the while the patient will be free from fever and in excellent condition. As a result of the treatment the body does not react to the typhoid bacteria. It is desensitized, not necessarily free from the infection. Very likely, though, a similar condition obtains frequently during normal recovery from typhoid fever as is evidenced by the persistence of bacteria in the bile tracts, the gastro-intestinal and urinary systems or in the isolated foci that may become manifest weeks after the clinical recovery from the febrile course. As a matter of fact Holler found no cases of carriers in his 350 cases of typhoid fever treated with proteoses, and Herz states that typhoid carriers can be freed following protein therapy. Re- lapses occur occasionally, but Liidke observed that these were much milder in character and of shorter duration than in untreated cases. Bresler in his review of modern typhoid treatment brings out the fact that the small number of relapses in cases treated with non- specific injections is quite apparent and he also believes that a dis- tinct improvement of the circulation takes place even when there has been no direct effect on the temperature. The observation of Wiesner to the effect that the typhoid ulcers ■commence healing immediately after the therapeutic injection is of mterest in this connection. From the therapeutic standpoint it is ^aaturally important that the patient, even after defervescence, should oe kept quiet in bed for at least ten days and longer if there is any evidence of myocardial impairment. Therapeutic Precautions. — There are three chief dangers that must loe kept in mind in the treatment of typhoid fever by nonspecific therapy. The first concerns intoxication. When we are dealing with a profoundly toxic patient we must be reasonably certain that he is able to bear the increase in intoxication which seemingly occurs after the nonspecific injection and which is probably due to a rapid destruction of typhoid bacteria. We have observed one such case in a profoundly intoxicated, obese typhoid patient who, despite the gravity of the risk involved, was injected with a small dose of proteoses and died within 168 PROTEIN THERAPY an hour following the chill. At autopsy no lesions other than those of typhoid fever and a marked cloudy swelling of all parenchymatous tissues and a toxic myocarditis were observed. The other two dangers are related to the gastro-intestinal tract. When nonspecific therapy is used the intestinal tract is affected to a considerable degree, depending on the severity of the reaction, the agent used, etc. There is first of all an increased motility. Coinci- dent with it there is an engorgement of the vessels of the bowel. Both of these factors may result in an increased possibility of perfora- tion and of hemorrhage. Clinicians who have had largest experience with the treatment of typhoid fever state very definitely that these dangers are theoretical rather than actual. When fatalities occur following the treatment the dosage employed in producing the reaction may have been too large or the agent selected not the best one for use. The injection of both typhoid bacilli and also of proteoses is not followed by the styptic effect that we see after milk injections, and the vaccine, too, has the added disadvantage of being decidedly toxic in itself, both factors that would incline one to favor any of the other agents rather than the typhoid vaccine. The question of dosage is one that has not been definitely settled. Of course, the massive doses of typhoid bacilli that have at times been employed (1 billion and more) by American observers and which were naturally followed by disasters of various kinds should not be countenanced in typhoid fever, however well they may be tolerated in other conditions. When typhoid vaccine is used only enough organisms should be injected to provoke a mild reaction — from 10 to 25 million — and sim- ilarly moderate doses with other bacterial vaccines. When relatively nontoxic agents are employed such as proteoses, colloidal metals, nucleins, etc., one can follow two courses. Either to give sufficient to provoke a general reaction and perhaps repeat the dose after sev- eral days if the fever has not been altered, or give small daily doses, none of which are themselves sufficient to provoke a severe reaction. Holler has used this latter method with success ; it is the method that Jobling and the writer have preferred to follow when dealing with typhoid fever. The immediate results may not be quite as brilliant as when larger doses are used, but there is certainly much less danger of precipitating some decidedly grave complication. For general use we cannot too urgently emphasize these considerations. In order to overcome some of these potential dangers, Neustadl and Marcovici usually prepared their patients, especially those that had been ill for some time and in whom there were evidences of vaso- motor instability, with digitalis. Jobling and the writer tried to overcome the motor activity of the gastro-intestinal tract and the TYPHOID AND PARATYPHOID FEVER 169 consequent danger of hemorrhage and perforation by using opiates be- forehand. There seemed to be little control, however, of the in- crease in peristalsis. Zupink, Miiller and Leiner, Matko and Holler stimulated their cases with caffein given before the injections. If the pulse is over 100 and there are evidences of vasomotor instability, if the patient is profoundly toxic or cachectic, if there has been any bleeding — epistaxis, gastro-intestinal, etc., if cyanosis is present, if the disease has continued for several weeks before treat- ment is commenced, or if there is any evidence of pneumonic compli- cations, it is not advisable to try nonspecific therapy. If given under such conditions the clinician must consider the dangers involved and seriously weigh the chances for collapse or hemorrhage or per- foration and determine whether or not they are overbalanced by possible advantages. PARATYPHOID FEVER It will be recalled that Ichikawa treated a number of paratyphoid cases with typhoid vaccine with good results. Holler in his series of infectious diseases treated 140 cases of paratyphoid fever with small daily injections of deutero-albumoses. There were 7 deaths in this series. The indications and contra-indications are those that have been discussed imder the subject of typhoid fever. CHAPTER X GONORRHEA AND ITS COMPLICATIONS The intravenous injection of vaccines in the treatment of gonor- rheal complications is a procedure that antedates by a few years the more general application that we now consider under the subject of protein therapy. Bruck and Sommer had in 1912 and 1913 made use of a polyvalent gonococcus vaccine for intravenous injections in a variety of complications, such as arthritis, epididymitis and acute prostatitis, with remarkable results. Within certain limits their re- sults paralleled the severity of the systemic response that followed on the vaccine injection. The reaction that was observed consisted of the usual rise in temperature, a leukocytosis, occasional chill and sweating, etc. It will be recalled that previously the morphological similarity of the gonococcus and the meningococcus had led Herescu and Strominger to use antimeningococcus serum therapeutically against gonococcus infections. That fever or at any rate intercmrent infections have at times a decided effect in altering the course of a venereal infection and its complications had been noted for a number of years and had been dis- cussed by Finger, Gohn and Schlagenhaufer in 1895. In 1916 Miiller and Weiss reported excellent results in gonorrheal complications with their intergluteal injections of milk and a nucleinate, similar to those of Bruck and Sommer. A nxmiber of workers at once made prelimi- nary trials of the method in this clinical field, including Schmidt, v. Tanner, Friedlander, Elschnig, Luithlen, etc. Smith in this country had independently come to a similar point of view in the treatment of patients suffering from gonorrheal compli- cations in using specific sera or normal horse senmi. Some of these became more or less sensitized to the serum and on further in- jection, responded with a decided general reaction. These patients in particular were the ones that gave the most promising clinical results, so that Smith emphasized the importance of this state of sensi- tization and the coincident temperature rise in the therapeutic result obtained. The experimental research reported by Arloing, Dufourt and Langeron confirms the clinical observation that it may be possible to cure certain infections by inducing an anaphylactic shock. The research was done on guinea-pigs inoculated with pyocyaneus cultures. Even a slight shock was enough to arrest the infectious process. The clinical cure was accompanied by the destruction of the germs in the blood and by the acquirement of immunity. 170 GONORRHEA AND ITS COMPLICATIONS 171 Culver's Investigation of Gonorrheal Arthritis. — ^These reports led Culver to investigate the specificity of the therapeutic procedure. He selected a series of cases suffering from gonorrhea and some com- plications (arthritis, etc.) ; these were divided into four groups, the first of which was treated by the intravenous injection of a gonococ- cus vaccine, the second a similar dose of meningococci, the third of colon bacilli, the fourth of a deutero-albumose solution. No local or general treatment other than the injections was given. Gonococcus Vaccine. — In the first series Culver gave 100 million killed gonococci and repeated the dose every fourth or fifth day. The greatest number of injections given one person was 6, most of them received 5, one received but one injection. The injections were fol- lowed by a chill of variable severity coming on in 20 minutes to 1 hour and lasting 15-30 minutes. The chill was at times accompanied by headache, usually of short duration. Exceptionally, there was nausea and vomiting during the first few hours, but never severe and always transient. This occurred often in patients who had disobeyed instructions by eating heartily within a few hours of the injection. At the onset and during the chill the patient often complained of severe pain in the affected parts (focal reaction). Invariably the disagreeable effects of the reactions, if any appeared, disappeared in about 24 hours, and for the next 24-72 hours a variable degree of comfort was experienced. The pain and the tenderness, together with the swelling of the joints, were much improved. This prompt improvement was most likely to be of only 2-4 days' duration, and then there was a stiffness of the affected joints with some pain on motion, but usually in a much less severe form. These relapses gradually decreased in severity following succes- sive injections until eventually none appeared. In some instances there was no relapse, even following the first injection. Injections were repeated on the 3rd-5th day, or usually just as the joints began to show a return to their old condition. This seems to be a more efiScient method of injecting than daily injections. With daily injections, the patient is at all times having a reaction or just recovering from one. His general condition is not so good nor does the local disease respond so well. It is usual for the severity of the reaction to decrease following repeated injections, and this decrease seemed directly proportional to the number of injectiops previously given. In patients, both of whom had numerous subcutaneous injections of gonococcal vaccine, there appeared immediately following each in- travenous injection a very transient reaction characterized by flush- ing of the face, cyanosis, dyspnea, and a tingling sensation over the surface of the whole body. These reactions lasted 1-2 minutes, after which the patients felt perfectly at ease until the usual reaction ap- 172 PROTEIN THERAPY peared in 20 minutes- 1 hour. This anaphy lactic-like reaction may have been due to a partial sensitization from the previous subcutaneous injections. Three other patients in this series developed a mild type of a very similar condition, on the 3rd intravenous injection. The typical temperature curve following these injections revealed a slight fall during the first part of the chill, followed by a gradual rise, which reached its maximtim in 4-6 hours, and gradually fell to normal in 24 hours. The leukocyte counts during a reaction and following were some- what variable. Usually a mild leukocytosis just before and during the first part of the chill was observed, soon followed by a marked leukopenia, which appeared toward the end of the chill; a count as low as 2,000 being observed repeatedly during this stage of the re- action. This condition was soon followed by a gradually developing leukocytosis, reaching its maximum in 5-7 hours, and remaining mod- erately high for 24-30 hours. A return to normal occurred in about 48 hours. Meningococcus Vaccine. — The second series of 15 patients was treated with killed meningococci in the same dose and at similar intervals as in the gonococcus series. The reactions as far as could be determined were similar in every detail to those produced by the gonococcus vaccine. One instance of % double reaction occurred following the 1st injection, and 1 patient developed this condition after 2 injections. None of this series had had previous subcutaneous or intravenous injections. The leukocyte cm-ve, in general, likewise followed that of the first series very closely. One very startling difference was observed be- tween the 2 groups. Over one-half the meningococcus series de- veloped a more or less severe herpes of the lips and mucous membrane of the mouth, first appearing in 48 hours and remaining for 4-7 days. This condition did not follow any but the 1st injection, and did not be- come aggravated or recur when further injections were made in a susceptible person. Colon Bacillus Vaccine. — This series contained but 9 patients. The reactions were in every way like those produced by meningococcus and gonococcus with the exception that the size of the dose required to produce the same results was very much less. At first a dose of 100 million organisms was given, but the reactions were so severe that 25 million were finally used as the initial dose, this to be increased if necessary to produce the desired results. Deutero^albumose. — A secondary proteose made from casein was used (80 mg.) in 4% solution on a series of 4 patients, the initial dose being 2 c.c. The reaction showed some variations from those produced by bacterial suspensions, in that the chill never took place before 1 hour after the injection, and that there was no headache or GONORRHEA AND ITS COMPLICATIONS 173 nausea following any of the injections; also the fever and leukocytosis did not reach the height produced by bacterial suspensions. Sufficient experience with this solution, however, was gained to convince one that the reaction and therapeutic effects are very similar and equally as effective as those produced by bacterial suspensions, as well as giving rise to less disagreeable reactions. As far as therapeutic results are concerned there was no notice- able difference between the 3 bacterial suspensions or the albumose solution. To produce results therapeutically a reaction is necessary. That is, a chill must occur which is invariably followed by the temperature and leukocyte changes noted. A dose insufficient to pro- duce a definite chill was not followed by as marked a temperature as the leukocytic reaction, and clinically there was not only no thera- peutic benefit, but sometimes patients became more uncom- fortable than before. The reactions following injections in non- gonorrheal patients were not to be distinguished from those produced in infected patients. These observations were made by injecting a series of patients with chronic skin lesions with no history or indication of gonococcal infections. The size of the dose required to produce a reaction, the chill, temperature, and leukocytosis was alike in every way in the infected and the noninfected patients. Thirty-one patients suffering from arthritis associated with gonor- rheal urethritis were treated. Most of these cases were acute or sub- acute, but some were of 5 months' duration, and many were over 10 weeks' duration when the treatment was begun. As might be expected, the most striking results were obtained in the acute and subacute cases ; however, the most refractory instances were also in the acute class. Those suffering for long periods appeared to respond more slowly to the treatment, but fortunately seemed to suffer from no recurrence or new joint involvements during the course of the treatment. All but 3 of the arthritic patients were apparently completely cured or manifested a decided improvement. The length of treatment varied from 2 days to 1 month. Unusual effects were seen in 3 patients with acute arthritis, so severe that sedatives were necessary to give them rest for the first 2 days in the hospital. After a single reacting dose in each instance they felt so well that they insisted on getting out of bed, and in 3 days they walked from the hospital. Two of the patients had effu- sions in the knee joints, which completely disappeared before their discharge from the hospital. Equally striking was the instance of a man who had been confined to his bed for 4 weeks with arthritis of almost every joint of both lower extremities. These lesions had come on during the third week of gonorrhea. After the third inj ection, he was 174 PROTEIN THERAPY up and walking about, and after the 6th injection he was apparently completely cured. The 3 refractory cases mentioned were all acute, and seemed not to respond at all or very slowly to this form of treatment. One would show considerable improvement for a day or two, but invariably would lapse back to the original condition; a second recovered completely ex- cepting one knee joint, which contained a marked effusion and seemed not to be affected by repeated injections, while the third did not re- spond from the first to repeated injections of albumose solution. Bnick noticed similar refractory cases which he explained by the absence of the homologous gonococcus strain from his polyvant vac- cine. It is evident that this explanation will not suffice, but whether it is due to a special resisting power of the particular infecting gono- coccus or to some peculiarity of the infected host, it is impossible to say. Such patients react with fever and leukocytosis as do all others. Epididymitis. — Twelve patients with acute epididymitis were treated, and invariably the pain would subside after the first injection. Usually not more than two injections were necessary, and indeed in most instances one proved sufficient to effect a cure. The swelling began to subside within 24 hours after the first inj ection. In no instance did the patient remain in the hospital over a week, excepting in one case in which an overdose was given. That these injections are not prophylactic against the development of new complications is evidenced by the fact that occasionally one sees a patient under treatment develop an acute epididymitis or an involvement of a new joint. Again, a patient may leave apparently cured of arthritis to return in a few weeks suffering from epididymitis. On account of the fact that the reaction following these injections is followed by a chill and general reaction of more or less severity, a very complete physical examination is necessary beforehand. Such a reaction necessarily calls for increased cardiac activity, so one should proceed with caution when a patient with coexisting organic heart disease presents himself. The smallest reacting dose of meningococci was given to one man who was suffering from mitral regurgitation of long standing but perfectly compensated, together with acute epi- didymitis. He passed through the chill with no distress, but in three hours after the injection he became cyanotic, his pulse became irregu- lar and feeble, and he had marked precordial pain. This condition lasted 10-15 minutes, and he had no further inconvenience. No other cardiac irregularities were noted in the entire series. Arnold and Holzel cite Lewinski's case of acute cardiac insufficiency develop- ing after the intravenous injection of gonococci. Heart disease was not known to be present. On the other hand, Luithlen reports a case of gonorrheal endocarditis successfully treated in this manner. There are many instances reported, however, of cardiac symptoms develop- ing in the presence of organic heart disease following these injections, GONORRHEA AND ITS COMPLICATIONS 175 so one should exercise care and judgment in the selection of cases. Renal Involvement. — From the proper dosage in this series, there were noted no other symptoms attributable to the injections. Special at- tention was given the kidney function, particularly in three patients who had received large doses of colon bacilli. In no instance did al- bumin appear in the urine, nor did any indication of kidney involve- ment arise. One patient having a chronic diffuse nephritis with con- siderable albumin in the urine had two injections with no appreciable change in the kidney function. This seems to be significant, as Breed and others had found that there is quite a marked increase in nitrogen output after such a re- action, this increase being maximum on the sixth day. She advises a low protein diet for a few days before such injections to prevent a possible kidney change. Foekler reported epileptiform seizures after similar intravenous in- jections, and Fischer in one instance noted cerebral symptoms, which passed off in 24 hours. Delirium was noted in three patients of this series, all of which had received large doses of colon bacilli. Culver was particularly impressed with the possibility that the febrile reaction itself, the mere increase in the body temperature might be involved in the therapeutic effectiveness of the nonspecific therapy. A number of observers who at former times considered this factor in resistance to infection and recovery from disease, among them Wal- ther, Hildebrand, Englehardt, Roily and Meltzer, have reached the conclusion that high temperature artificially produced has a favorable influence on any established infection; on the other hand, cold seems to retard the formation of immune bodies. The optimum temperature for the growth of the gonococcus in vitro is 97°-98° F. Any appreci- able increase in temperature has a very deleterious effect on the life and growth of the organism. A sudden rise to 102° F., or over, means certain death of the culture. When acute epididymitis develops, does the fever produced thereby have anything to do with the spontaneous cure of gonorrhea? Many patients with infections terminating thus have had considerable fever during the onset of the complication. On the other hand, patients are seen with infections terminating in a similar manner having had a normal temperature throughout; this, however, does not seem to be a common occurrence. Experimental urethritis in man has been produced, but Finger, Gohn, and Schlagenhaufer regularly failed when the experimental patient had a temperature of 102.2°-104° F. due to some preexisting disease. Culver calls attention to a patient who entered the hospital with acute urethritis of 3 days' duration. A positive gonococcus culture was obtained on entrance. The second day in the hospital he had a 176 PROTEIN THERAPY chill, followed by a temperature of 105° F. Malarial parasites were found in the blood, but the chills and fever were allowed to con- tinue for 4 days, at the end of which time all evidence of local in- fection had disappeared. He remained in the hospital for 2 weeks, without recurrence of the infection, having had no local treatment whatever. The influence of fever on these infections in the medical wards is of course well known; one rarely, if ever, sees a gonorrheal infection coexisting with some fever-producing disease like pneu- monia, typhoid, or malaria while gonorrheal infections are relatively common among the chronic nonfebrile conditions. The therapeutic results in the group which forms the basis of this report very noticeably correspond to the temperature increase and to hyperleukocytosis. Considering the fact that the gonococcus is heat sensitive both in vitro and in vivo; that fever patients cannot be experimentally infected with the gonococcus; that a fever-produc- ing disease spontaneously cures previously existing gonorrheal in- fections, there can be but little question that fever artificially pro- duced plays some part in the recovery from these infections. How much influence, if any, the leukocyte increase in the peripheral circulation has, cannot easily be determined, for when artificially produced in the manner employed here, the fever and hyperleukocytosis are invariably present together. It is apparent that the usual treatment of gonorrheal arthritis is not satisfactory in all instances, when almost daily one can see an ankylosed joint and atrophied muscles following this condition. Should this treatment by intravenous protein injections prove to give perma- nent results in this condition, as present data seem to indicate, are we justified in usiag such a measure? In view of the chronicity of the disease and the destructive complications that commonly arise it would appear to be a rational procedure when properly used and controlled. However, until some substance is obtained whose dosage can be more definitely standardized, it would seem that this form of treatment should not be generally used by those not thoroughly fa- miliar with the reaction and the manner of regulating the size and interval of dosage of such, as used in the work here reported. In a recent review of his work Culver states that in his experi- ence at one of the military camps during the war where intravenous injections of gonococcus protein was made in every case of epi- didymitis, the results were most satisfactory, the average stay in the hospital being from 5 to 6 days. Even the primary localization of the organism in the urethra or extensions of the infection into the prostate and seminal vesicle responded more readily to local treatment after nonspecific injections of this kind than cases not injected. Since the publication of these papers by Culver a considerable literature on the subject has been accumulating, all of which reveals :pr§gtJcally the same general clinical experience — namely, that non- GONORRHEA AND ITS COMPLICATIONS 177 specific therapy is of decided usefulness in the treatment of gonor- rheal complications, either local or remote, but that in the treat- ment of the primary infection of the mucous membrane itself our older methods are of greater value and dependability, although certain observers are of the opinion that as an adjunct method of treatment it has its decided value even here. Keyes makes the following statement: "It is not generally ap- preciated that the reason for the extreme susceptibility to recurrence of joint lesions with each gonorrhea, in a patient who has once had arthritis, is a susceptibility in the joint, not in the urethra. At its onset the use of vaccines or serum may be worth while. Two or three doses of antigonococcus serum at the moment when a joint is beginning to become inflamed may abort the infection, as may also a heavy dose of gonococcus vaccine; this usually by the systemic re- action produced. "But once the joint infection is established, vaccines are not to be relied on. I have tried all the specific and nonspecific forms that have been commended to me, including horse serum and typhoid vac- cines administered intravenously. If these are employed in sufiB- cient dose to give a systemic reaction, a temporary benefit may be obtained, and occasionally a permanent benefit. But the rule is that these treatments do not appreciably influence the course of the dis- ease." Luithlen has had considerable experience in the treatment of gonor- rheal complications, using an intravenous injection of gonococci (100 million to the c.c.) as a rule to elicit the reaction; he specifically recommends, though, that local treatment should in no instance be neglected. In the treatment of old torpid venereal ulcers, soft chancres and ulcers persisting after buboes he injects about 50 million organisms intravenously two or three times at intervals of several days, or if intramuscular injection is preferred injects from 300 to 500 million, in some cases as much as 800 million organisms. Bloch, who recognized that the vaccine therapy as used in in- travenous injections was really related to our older method of counter- irritation or "Ableitungs-Therapie," has also used gonococcus vaccine and typhoid vaccine in gonorrheal complications, the latter especially in gonorrheal rheumatism. He obtained the best clinical result with the severest clinical reaction, in some instances the temperature reach- ing 106° F. Gow has also tried out a diphtheroid organism intravenously (using first a dosage of 40 million, later 200 million) in a case of gonorrheal arthritis. There was relatively little reaction from this organism, a chilly sensation was noted about 14 hours after the injec- tion, a rise of 2° F. in the temperature 2 hours later, and some head- ache. A leukopenia followed the injection. The result was not very satisfactory. 178 PROTEIN THERAPY Konteschweller in his review of "pyretotherapy" states that he has obtained very satisfactory results in the treatment of gonorrheal rheumatism. He used milk, kephyr and peptone to elicit the reactions. Pakauscher uses "Fulmargin," an electrically prepared colloidal metal; this gives little general reaction but seems to be useful nevertheless in the treatment of gonorrheal complications. Ullmann mentions the successful use of milk in gonorrheal arthritis ; Eraser and Duncan have recently reported on the treatment of a small series of such arthritic cases treated with intravenous vaccine injections. The vaccines they used had been stored for several months after their preparation, and they were, therefore, probably more or less detoxicated. Whether a de- toxicated vaccine has any specific properties or not requires proof. They suspect that a vaccine minus its endotoxin consists simply of non- specific proteoses in a colloidal form. The injection of these, possibly nonspecific constituents, would seem to have caused the production of specific antibodies. Clinically they seemed to get the same result from injections of T.A.B. vaccine as from a gonococcus or mixed vaccine. The chief reason for using a gonococcus vaccine was that a supply was available, and its use afforded a great facility for graduating dosage. Freshly prepared typhoid vaccine often causes so severe a reaction that they would not risk giving it intravenously. Injections of endotoxins always produce toxic symptoms with but lit- tle or no increase of antibodies. Marked improvement followed in all of the fifteen cases treated. No benefit seemed to result from an injection that was not followed by pyrexia. At the time treatment was commenced, the patients were extremely debilitated with a rather fast and weak pulse, which was easily accelerated. The in- jections were all intravenous. The size of the doses used compares favorably with the doses recommended by Thomson for his detoxi- cated vaccine. The largest dose of gonococci was 2,000 millions. The myositis of gonorrheal origin has been favorably influenced by intravenous injections of "arthigon" by Sachs while Reichmann has described a favorable influence of collargol injections in the treat- ment of gonococcus endocarditis. Local Injections. — The use of milk, recommended by Miiller and Weiss, has been quite extensive not only for intragluteal injection and systemic reactions (Gellis and Winter) but for local injection in or about the complication. Weiss has treated a number of cases of epididymitis in this manner, injecting from 5 to 10 c.c. of milk sub- cutaneously in the scrotal skin, and obtained excellent results. This treatment by local injections about the site of the lesion was commenced by R. Miiller who observed that if serum was so injected it improved localized disease processes. Sandek then treated some 100 cases of gonorrheal complications with this method and obtained excellent results. The analgesia following the injections was aston- ishing. GONORRHEA AND ITS COMPLICATIONS 179 Sandek found that if he injected salt solution or potassium iodid in from 1 to 5% solution he obtained results that were similar in many respects. There was of course no general systemic reaction when the treatment was carried out in this manner. Eisel has continued observations on this method of local injections of physiological salt solution and has reported on 30 cases in which from 10 to 15 c.c. of physiological salt solution were injected between the scrotum and the tunica vaginalis. He states that the pain was lessened very promply and resorption of the inflammatory exudate facilitated in all of the cases of epididymitis so treated. Other observers have treated gonorrhea and gonorrheal complica- tions with tuberculin (E. F. Miiller) and with turpentine injections. Piirckhauer, who has tried the latter in acute urethritis, considers such injections of value as adjuvants but not useful in bringing about com- plete recovery from the acute infection, his experience coinciding therefore with that reported with the use of the other related agents. Karo has also used turpentine injections in gonorrheal complications, adding a small amount of eucupin to the dose to lessen the local pain that follows when only turpentine is injected. The largest series treated in this manner is that of Krebs who has treated several hun- dred cases of acute and chronic gonorrhea, with particularly good re- sults in the severer infections. According to his report the course of the acute disease was shortened and complications lessened. In- jections were given every three to five days; after the second injec- tion local treatment was commenced with choleval or with potassium permanganate. While he considers that every case should have local treatment, the general treatment with the turpentine injections had a marked effect in lessening the pain and the secretion after a very short time. Reenstiema has made use of a combined specific and nonspecific method of treating the closed gonorrheal complications. He injects not only a specific antigonococcus serum but with it a typhoid vaccine to give the general reaction. With this combined method he claims to have obtained very satisfactory results. Franzmeyer has claimed good results in the treatment of acute gonorrhea by using intravenous injections of collargol combined with local treatment. Sommerfeld, who treated 42 men and 10 women ill with acute gonorrhea with collargol intravenously, did not find the results as satisfactory as local therapy. Cohn has reported the treat- ment of 86 men of whom only 13 proved refractory to the nonspecific therapy. Weber, too, has reported that as an adjuvant, the intravenous injection of colloidal metals is of benefit in the treatment of acute gonorrhea. Nuclein has also been used (Boas) while Brown has re- ported on results with normal horse serum as well as diphtheria anti- toxin. He observed that the dose of normal serum which had to be used to secure results was much larger than the diphtheria antitoxin. 180 PROTEIN THERAPY On the other hand, Riecke has reported that he has never observed a single recovery of an acute gonorrhea following the fever therapy unless local treatment was instituted. From our present knowledge of infections of the mucous membranes it is probable that in acute infec- tions nonspecific therapy has a limited field as an adjuvant to local therapy, while in the gonorrheal complications it finds a much wider and more useful application. Buboes. — Stark and Odstrcil began the use of milk injections in the treatment of buboes, which, like the other gonorrheal complications, seem to respond very well to this form of therapy. Miiller and Weiss had already noted that certain gonorrheal complications yielded quite readily to the milk injections and Miiller himself has published some 25 cases of buboes treated by means of milk injections. With one exception all of these (17 early cases, 7 older ones) were cured with- out surgical incision. Miiller gave injections of milk every 3-4 days using from 5-6 c.c. of milk for the purpose. Usually the local reaction reached its maximum in about 8-9 hours when the greatest pain was noted, after which the part affected became analgesic. In the treat- ment of the old cases an average of 5 injections of milk were made; in the earlier cases 3 or 4 injections suflSced for a complete cure. Tross- arello has also reported on the successful use of milk injections in the treatment of buboes. In 15 cases the injections practically aborted the lesions. Schneller treated but two cases with milk injections, but both made complete recoveries without surgical intervention. Guszmann has reported that milk injections are followed by ex- cellent results in the treatment of soft chancres, while Antoni using aolan (casein) obtained equally good results in soft chancres and buboes. Reichenstein used milk in both buboes and epididymitis. The buboes usually softened rapidly and were then incised; the epidi- dymitis also showed retrogression shortly after the treatment was commenced. No more than three injections were ever necessary. Almkvist treated 8 cases of buboes with turpentine with tuberculin and with nuclein injections. The cases all made a rapid and complete recovery. Kraus, on the other hand, treated 20 cases of gonorrhea (acute) with milk injections (5 to 8 c.c.) without much apparent benefit. In 7 cases there was no general reaction to the injections; the focal reaction likewise was not marked in any of the cases. Grabisch, using turpentine injections, obtained favorable results in gonorrheal complications such as buboes, cystitis and even pyelitis. Karo, who has recently employed "terpichia," a turpentine prepara- tion combined with quinin, has reported on the use of this agent in a very large series of cases. In acute gonorrhea he has used it in combination with the usual local treatment but considers that the GONORRHEA AND ITS COMPLICATIONS 181 injections shorten the course of the disease as well as prevent com- plications. The ordinary complications are relieved in a very short time and even the arthritis is very favorably influenced. Provocative Reaction. — In a recent paper Miiller has discussed a subject that is of considerable and increasing importance in the genito-urinary field, namely the provocative reaction in male urethral gonorrhea. While I have referred to it more fully in the chapter on focal reactions, a note of it should be made at this place. We are familiar with the effect of alcoholic excess on the course of an acute gonorrhea. Many of our modern therapeutic methods are frequently followed by a similar provocation of a latent gonor- rhea (such as the use of bougies, Kollmann dilatation, silver salts in higher concentration, hydrogen peroxid, etc.), and their use is fol- lowed by an increase in the discharge and the finding of organisms in the smear. On examination it is observed that the copious leu- kocytic discharge consists of fresh leukocytes, not old forms which may have been present in the focus for a longer period of time. They are the result of a myelotic stimulation that is induced by the re- action when the gonococci are stirred up at the focus, and are there- fore to be regarded in the nature of a defensive reaction. Every pro- cedure that first lowers the resistance — either locally as with the vari- out traumas mentioned, or generally, as after alcohol, after an inter-' current disease, after a nonspecific vaccination — is followed by this myelotic stimulation and an increase in the discharge. If provoked by a local method new paths may be opened for the spread of the in- fection, and it therefore entails an element of danger. Miiller noticed that the intracutaneous (first used by Hecht) injection of aolan (casein) was followed by a marked effect on the infections of the mucous membranes and in applying this to gonorrhea found that in from 6 to 8 hours after the injection there was noted a distinct itch- ing of the urethra, followed by an increased flow of pus and usually the possibility of demonstrating the presence of the organism within 24 hours after the injection. Nevermann has applied this reaction with success in women. Adnexal Inflanimation. — It will be recalled that Kraus in his early work with heterovaccines found that he could definitely terminate the fever of puerperal sepsis in a number of cases when colon vaccine was injected intravenously. Since that time a number of observers have been interested in treating not only such cases, but adnexal inflammation in women due to other causes — venereal infection, tuber- culosis, etc. For this purpose several methods have been used — ^milk injections, salt injections, colloidal metals, turpentine injec- tions, etc. In general it may be stated that in this form of inflamma- tion the single shock dose — whether milk or vaccine or colloidal metal — is less satisfactory than any form which is carried out over a longer period of time and is milder in character. Considering the 182 PROTEIN THERAPY extent of the inflammatory changes and their peculiar character this result might be anticipated. In general it may be stated that the findings that hold true for venereal infection in the male hold true in the female, that is, that the acute infection, either cervical, urethral or uterine, is not influenced very much by this form of therapy, that the complications, on the other hand, are remarkably amenable to treatment and at times give exceptionally good results. Menzi treated 117 cases with collargol injections, using from 2 to 10 c.c. of a 2% solution every two days. He states that of 34 cases of urethral gonorrhea, acute and subacute, 23 became nega- tive bacteriologically. Of 7 cases of chronic urethritis, all became negative. Of 24 cervical infection 23 became negative. Two cases of uterine infection were imchanged. Lux, who obtained good re- sults in gonorrheal complications with injections of collargol, obtained negative results in acute infections, and Sonunerfeld, too, did not see that in acute cases the treatment was as eflScacious as local treatment. Kleemacn treated 51 patients of this type with injections of 2% collargol; of these 11 were cured, 20 improved, while 20 were not altered clinically. Kleemann is of the impression that the injections shorten the com'se of the disease and when combined with local treatment are of manifest assistance. Infections of the uterus were also foimd by him to be refractory. Konteschweller recommends "pyretotherapy," produced by any of the common nonspecific agents, as of value in tubal inflanunation. Gerstein, working at the clinic at Halle, had used milk injections, but the general effects were at times rather unpleasant so that Kauert first used aolan (casein preparation). With this he treated 16 cases of pyosalpinx. Only one case reacted with a temperature rise and there was practically no leukocytic reaction; In these cases Kauert saw very little clinical change. Not obtaining any results with the aolan Kauert turned to milk injections, but here, too, his results were not successful. This corresponds to the results reported by Chiaudano. Trossarello gave parenteral injections of milk in the treat- ment of forty-five cases of gonococcus infection and in fifteen cases of venereal bubo. In the apyretic there is an interval of two or three hours before the chill follows the injection, and this allows ambula- tory treatment as the patients are able to reach home before it. No benefit was apparent in the cases of urethritis, prostatitis, epididymitis and arthritis, but in ovarian and tubal disease marked benefit was realized. All were improved, some after a single injection. His re- sults in these twenty cases of adnexitis surpassed, he says, those ob- tained with specific vaccines or antiserums ; the pain subsided promptly even before any objective improvement was apparent. He injected into the buttocks 5 or 10 c.c. of ordinary milk, at intervals of three or four days, to a total of five injections. The febrile reaction seems GONORRHEA AND ITS COMPLICATIONS 183 to be the main factor; the best results were noted in the patients that presented the strongest reactions. Arweiler, working with Lindig on casein injections (intravenous), reports satisfactory results in adnexal inflammations, the tumor masses showing definite regression and the patients a general improvement in condition. Schonfeld tried the method recommended by v. Szily and Stransky (salt abscess) in 36 cases of acute and subacute gonorrheal infections in women. They obtained very poor results; only those made a re- covery in whom abscess formation occurred. The method is painful and certainly not to be recommended. More recently a number of clinicians have tried the method of turpentine injection with evidently more success. Fuchs, as well as Schubert, while in military service, had tried intramuscular turpentine injections in suppurating wounds without any effect (where we al- ready have a large suppurating surface from which necrotic products are being absorbed, this result is to be anticipated), but found that when used in adnexal inflammation he obtained quite remarkable re- sults. Zoeppritz and Kleeman had previously reported a fairly large series of cases and Fuchs reports 30 gynecological cases treated by the injection of 0.5 c.c. (of 4 parts of turpentine, 0.2 part of eucupin and 16 parts of olive oil) every 4 days intramuscularly. The site of the injection was the axillary line just below the crests of the ilium, in- jection being made very deep. Kleemann's cases numbered over 60 and included all varieties of adnexal inflammation. In this series 36 were completely cured, 21 improved and 3 were not improved. He observed that the fever as a rule diminishes after a short time and the size of the adnexal tumor decreased until in many instances it was no longer possible to palpate the mass. He used turpentine with a small amount of novocain to prevent local pain after the injection. The cases selected were bilateral adnexal inflammations, with the tumor masses varying in size from 2 to 10 cm. in diameter, with oc- casional temperature, menstrual disturbance — pain, bleeding, etc. In five of the cases a chronic gonorrhea was manifest. The results of the treatment were very satisfactory, convalescence being established much sooner than with the ordinary local or expectant treatment. Not only was the local tumor mass reduced in size — Fuchs states that the large masses reduced in two weeks' time to the size of a walnut — but the pa- tients felt better in general and the appetite was stimulated. Occa- sionally a temperature reaction of from 1° to 2° C. was observed fol- lowing the injection; these cases gave the most striking clinical im- provement. In no case did he have any untoward effect or find any injury from the treatment; in over 200 injections there was no abscess formation. According to Fuchs the treatment is of very definite gynecological 184 PROTEIN THERAPY value, even in the treatment of early adnexal inflammation accom- panied by acute symptoms and much pain and profuse hemorrhage. The pain diminishes after the second injection, menstruation becomes normal after the next period and the adnexal swelling is reduced. The fact that these results can be achieved with an ambulatory treatment is of further advantage. Sonnenfeld has also reported on 115 cases of gonorrheal as well as nongonorrheal adnexal inflammatory lesions treated with turpentine injections. He considers the method of tremendous advantage in the conservative treatment of inflammatory conditions of this type. Hellendall states that when on the basis of thirty cases Zoppritz demonstrated this method recently before the Verein der Aerzte at Diisseldorf , no adherents championed it during the discussion that fol- lowed, while Pankow presented two series of cases, one treated with and one without turpentine, and emphasized that the results indi- cated that there was no difference between the old conservative treat- ment and the turpentine treatment so far as the final effect was con- cerned. In Hellendall's own case, that of a yoimg woman of 19, the ineffectiveness of turpentine injections was shown by a later operation, although it was a case in which good effects should have been appar- ent, if ever. Kronnenberg is also of the opinion that the turpentine injections are without influence on the course of adnexal inflammation. Hinze reports 205 cases, 35 of which came to operation; 65 were treated by the usual conservative methods and 105 with turpentine. He injected 0.5 c.c. of a mixture of 0.1 gm. of turpentine oil and 0.4 gm. of olive oil, in the posterior axillary line from two to three finger- breadths below the crest of the ilium. The long cannula prevents the fluid being ejected into muscle or subcutaneous tissue, which in- creases the pain unnecessarily. In addition, in most cases, moist heat and hot air or hot-water treatment were employed. The discomfort following the injections was not severe and usually subsided in from four to five hours, but in several cases the pain lasted from three to four days, sometimes radiating into the leg on the same side. In 8 of the cases of pyosalpinx either a cure or marked improvement was effected. The results were very favorable in the 52 mild cases. As a rule these cases could be dismissed as cured in from two to three weeks. In the chronic cases, the pains usually disappeared after a few injections, and when the patients were dismissed in three or four weeks the tumors had decreased considerably in size. Hinz's judg- ment, therefore, is that turpentine injections constitute progress in conservative treatment of affections of the adnexa. However, that recurrences are not uncommon goes without saying. Other observers have used autoserotherapy (Ishikawa) and Hasen- bein has used injections of sugar solutions. CHAPTER XI INFECTIOUS DISEASES ANTHRAX The treatment of anthrax by means of injections of normal beef serum is a procedure inaugurated by Kraus and his associates, and has been discussed by them in a series of articles. They use beef serum twice heated to 56° C. for 30 minutes and inject from 30 to 50 c.c. or more intravenously or intramuscularly. According to Kraus' recent address, over 380 cases have been treated by him with this method with a mortality of less than 6.2%, as contrasted with the mortality of about 10% with expectant treatment. The injections are made repeatedly, usually in 12 hour intervals, although as a rule not more than three injections are necessary. Serum sickness has seldom been observed. Solari reports the results in 6 cases, all of which recovered. Langon treated 13 with similarly satisfactory results. Lignieres, however, was not able to confirm these findings. Recently several experimental studies have been reported dealing with the problem, including those of Turro, of v. Hutyra and Maninger, Gerlach, Kraus and Beltrami and of Kolmer, Wanner and Koehler. The latter observers were able to determine some degree of bacteri- cidal property in the normal beef serum, but hardly sufficient to ac- count for the marked clinical effect induced by the serum injections. Heretofore it had been assumed by a number of clinicians that the effect of the beef serum might be due to the content of natural anti- anthrax amboceptors in the serum of the animals used for injection, because of the possibility of a degree of immunity present in the serum of cattle where anthrax is prevalent. V. Hutyra and Maninger's tabulated results show that no pro- tection was afforded rabbits inoculated with anthrax by treatment with normal beef, horse or sheep serum. DIPHTHERIA AND DIPHTHERIA CARRIERS One of the most remarkable reports concerning the application of nonspecific methods in therapy has been that of Bingel, which has created considerable discussion because it throws doubt on the spe- cific value of our most widely used and most representative of specific sera, namely diphtheria antitoxin. Bingel treated 471 cases of diphtheria with diphtheria antitoxin 185 186 PROTEIN THERAPY and 466 alternating cases with empty horse serum— that is, normal horse serum which contained no antitoxin. The results as far as could be judged in the two series showed no difference in the mortality, in the duration of the illness, or in the number of complications. As a matter of fact Bertin is said to have used injections of normal serum as early as 1895 in diphtheria, and Roily as well as v. Striimpell also employed "empty" serum. In 1912 Lorey again called attention to the subject. Attention is called to Bingel's paper not because it describes a desirable mode of procedure that is to be commended, but because of its theoretic and practical importance. There can be no doubt that specific antitoxin will exhibit incomparable superiority over nor- mal horse serum both in practical therapeutic application and in ani- mal experimentation. But in practice the observation of Bingel has been confirmed, even if not in a large series, by Dorn and by Meyer. Klotz has recently reviewed the entire subject. There has been an often expressed observation among a number of clinicians during more recent years that the modern highly con- centrated diphtheria antitoxin does not always give the same satis- factory results that our older, less concentrated preparations did. Of the older preparations larger doses of serum had to be injected. The work of Bingel makes clear the basis for this conviction. That is, we are dealing in diphtheria antitoxin with two factors that are of therapeutic value, the specific antitoxin content and the nonspecific stimulating property of the serum proteins. The more highly con- centrated the preparation, the less of the nonspecific element will be retained. This is probably the reason that the more modern serums have at times seemed followed by less therapeutic effect than the for- mer preparations. As a matter of fact when some of the older litera- ture is reviewed one finds observations concerning the temporary rise in temperature following diphtheria antitoxin injections, as well as the temporary leukopenia and the later leukocytosis that we now recognize as part of the phenomena that follow after the various nonspecific injections (Ewing). A number of investigators have repeated Bingel's method, using the method of toxin neutralization in guinea pigs. Calhoim, for in- stance, as well as Kraus and Sordelli, foimd a slight protection with normal horse serum; other observers have found little or no protec- tion. The lack of confirmation in animal work does not, however, rule out a therapeutic effect in human diphtheria. Liidke has for instance treated 15 cases of diphtheria in adults with albumoses. (2-3 injections of from 3-5 c.c. of a 10% solution.) The therapeutic effects were quite comparable to those obtained with specific serum therapy. In 7 cases the first injection was followed by a complete disappearance of the diphtheritic membrane and the retiUTi of the temperature curve to normal within 24 hours. In three cases in which a stenosis already INFECTIOUS DISEASES 187 existed the injections were followed by an increase in the swelling and the stenotic symptoms, the usual effect of nonspecific injections on local inflammatory processes. In 5 cases there was no apparent effect on the disease. Paschen has used milk injections to free diphtheria carriers of their throat infection. Of 54 cases 37 were free in from 4 to 6 days, 7 in 14 days, while in 10 cases there was no effect of the injection on the throat culture. In emphasizing the fact that the high fever is one of the factors that aids in overcoming the condition, Paschen points out the fact that of these 10 refractory cases 5 did not react with any fever to the milk injections. Miiller has also reported that nonspecific injections — milk and casein — are effective in ridding the mucous membranes of the throat and nasal passages of diphtheria infection in the case of chronic car- riers, BACILLARY DYSENTERY The war with its attendant epidemics of dysentery both in the military forces and in the civilian populations afforded European clinicians considerable opportunity to study not only the prophy- laxis but the therapeusis of the disease as well, and we now have reports available from a number of sources. Among them Nolf has published several papers which are available in the American litera- ture dealing with both specific and nonspecific intravenous therapy; Adler was perhaps the first to report on the use of milk injections; Holler, in his large series of infectious diseases treated with deutero- albumose injections, has included 50 dysentery cases and Dollken has reported a number treated with milk injections. Inasmuch as Nolf's experience was quite extensive, at first with specific serum therapy, then with vaccines subcutaneously admin- istered and later with intravenous bacteriotherapy, it may be of in- terest to quote extensively from his recent paper. "The treatment of ulcerative dysentery gave ns only temporary results so long as we had recourse to the methods of the books. Specific sero- therapy proved futile. Therefore, because of the inefficacy of these methods, we had, toward the end of the epidemic of 191Y, employed vaccinotherapy in the chronic cases that remained. When possible to isolate a dysenteric germ from the intestine, we made and employed an autogenous vaccine; otherwise we used a vaccine of a Flexner bacillus type made from a gelose culture killed by heat. At this time the vaccine was administered subcu- taneously, in progressively increasing doses, the initial dose being usually 10,000. To obtain the desired result it was necessary to raise the dose frequently to from 5 to 10 billion. These large amounts of sterilized cul- ture are regularly well tolerated, though often during from twelve to twenty-four hours after the injections, one observes a little fever, headache and lassitude, with more frequent and less consistent stools, sometimes 188 PROTEIN THERAPY slight colic, and at the site of injection a little infiltration witli moderate pain. AU these sequelae soon pass away and, as a rule, disturb the patient but little. "Vaccinotheeapt in Old Chbonic Cases "In the winter of 191Y-1918, we still were receiving eases of chronic dysentery of which the onset dated back several months or several years. We applied the same treatment, but with this difference, namely, that the initial dose was regularly a million germs, and that the dose was raised progressively up to from 5 to 10 billion. The results obtained continued to be favorable. In every case the general condition was improved, and the intestinal symptoms steadily decreased. In the majority, the cure was com- plete and definite. At times there seemed to be complete cure at the end of the treatment, but at a later period the symptoms returned. In some cases the stools, although regular and only one or two a day and without blood and mucus, yet remained soft, and there persisted a little intestinal instability and discomfort. "We should probably have continued the subcutaneous method of ad- ministration of the vaccine, had we not, in other affections, particularly bacteriuria due to the colon bacillus or the staphylococcus, observed that the intravenous method of administration was more efficacious and more rapid in its effects. We therefore began the administration of the vaccine by the intravenous route in baciUary dysentery. "The Intravenous Method in Acute Dysentery "We applied the treatment not only to those with confirmed ulcerative dysentery, but also to all those in whom the course of the disease made one fear the development of the ulcerative form, that is to say, in every case in which, after one week, a dietetic and drug treatment had not brought about a cure, or at least promise of a speedy cure. "The doses were given at four-day intervals, the initial dose being regu- larly 10,000 germs, then 30,000, then 50,000, then 1,000,000, etc. In general, the betterment of the patient did not long delay. The fever dropped by lysis, with some recrudescences more or less marked on the days of the vaccine therapy and the next day; and the intestinal symptoms improved coincidently. In many cases of moderate intensity a complete cure was effected when the dose of 500,000 was reached. In the more refractory cases, it was necessary to push the vaccine up to about 10 million. "In fifty-two cases treated in this way, we had only two deaths. All the other patients left the hospital cured, except two whom military necessity forced us to send away too soon. We have no doubt that in these two cases also the continuation of the treatment would have resulted in a cure in a relatively short time. By vaccinotherapy we were thus able to avoid the dangerous tendency toward chronicity which in 191Y was pro- duced in a considerable number of our patients. This last result we considered particularly gratifying. "The complete record of the epidemic of bacillary dysentery of 1918 shows a complete cure, at the latest in a few weeks' time, in 500 eases except only two patients who died, and two who had left before the cure was complete. INFECTIOUS DISEASES 189 "Conclusions "I believe I am justified in concluding from these observations that vac- cinotherapy and more especially vaccination intravenously is the most ef- fective therapeutic method in bacillary dysentery in its chronic forms and in the acute forms that show little tendency toward cure. It appears also that the method is more efficacious when it is applied early. The intra- venous route has the advantage that it permits results from doses one- thousandth the size of the subcutaneous doses. Not having had occasion to try this method in cases of Shiga bacillus desentery, it is impossible for me to speak of its utility in this form of dysentery. "In acute dysentery, intravenous vaccinotherapy cures quickly in cases exhibiting protracted fever and lasting diarrhea with hemorrhagic and slimy stools, these being the cases that are refractory to other therapeutic meth- ods, including serotherapy." Of course, the bacteriotherapy is not a specific procedure ; the same effect can be obtained when the reaction is produced by any of the other agents. Milk injections, first used by Adler in dysentery and cholera, were also used by Dollken, who employed them because of the marked styptic effect following intramuscular injections; he did not, how- ever, observe any actual change in the coagulation time of the blood of dysentery patients before and after the treatment. It is to be assumed that in the early stages of dysentery when hyperemia and engorgement of the mucosa are not yet pronounced and where we are dealing merely with small petechial hemorrhages and a hyper- secretion, the injections will be followed with the best clinical result and this is actually found to be the case in clinical practice. Dollken injected 5 c.c. of milk intramuscularly (occasionally less). Sometimes after 5 or 6 hours a definite focal reaction was to be observed in the form of increased evacuations containing more blood. The recovery was very prompt after this period. Usually the first day after the injection the blood was considerably less, even absent in some stools. This was observed to continue after the second in- jection. Usually after 5 days blood was no longer present. The spasm of the small bowel was almost always relieved after the first injection; the tenesmus in 4 or 5 hours after the first injection. An interesting fact was noted in regard to those cases that had had al- buminuria. This was invariably gone after the injection. Contrary to the experience of Nolf, Dollken did not observe much effect on the temperature curve after the milk injections, although in some cases a defervescence was noticed after the second injection. In cases treated with specific sera and vaccines this same lack of ef- fect on the temperature of course holds true. In more advanced cases the ulceration does not yield to treatment 80 readily. After about 5 days, however, improvement is noted in 190 PROTEIN THERAPY the tenesmus and obstipation, but the hemorrhages are apt to per- sist longer. In cases that have diphtheritic membranes Dollken ob- tained good results after repeated injections. Of theoretic interest was the fact that in cured cases Dollken was at times still able to cultivate the causative organism (Flexner) from the stool; the agglutination titer of the patient's serum, no matter what the clinical outcome, was not altered by the milk injections, but after specific vaccination was increased. Deutero-albumose, tried in several cases by Dollken, was not as satisfactory. Holler, on the other hand, has treated 50 cases of bac- illary dysentery (Kraus and Shiga) with daily injections of deutero- albumose and in this series had only two deaths. Liidke treated 14 cases of severe dysentery (12 Shiga and 2 Flexner Type) with deutero-albumose injections (3 to 6 injections of from 1-2 c.c. of a 10% solution). Apart from absolute rest in bed, heating pads, and proper diet, there was no other therapy used in these cases. In from 3 to 6 days 12 patients were markedly improved — the stools were normal and free from blood or mucus, tenesmus had disappeared and the general condition and appetite returned to normal very rapidly. In two cases, in which an earlier effort with serum therapy had been unavailing, the injections of deutero- albumoses was also without effect. Furno treated 5 cases of hemorrhagic dysenteriform colitis, due pos- sibly to mixed infection, with intravenous injections of proteoses (10 to 12 c.c. of 10% solution). He found that by prompt therapy of this kind the disease is arrested before it reaches the ulcerative stage. Reiter found on the other hand that in a small series of cases only one case actually improved. Schelenz, using polyvalent serum and also injections of dysentery vaccine, found that while the course of the fever was not altered very much, the blood disappeared from the stool, the diarrhea decreased and the general condition of the patient improved. While specific serum has been used by many clinicians, general opinion seems to confirm the conclusion of Nolf that it is not of great value unless given in huge doses either intramuscularly or intrave- nously and frequently repeated. Pfeiffer used 100 c.c. of polyvalent serum irrespective of the bacteriological finding and gave five to six injections; usually a slight systemic reaction would be observed after the injections. The size of the dose necessary and the fact that it must be given very early if it is to be useful at all leads to the con- clusion that the effect can only be found in the nonspecific stimula- tion by the serum, rather than in any specific antibody content. Schit- tenhelm's results would lead to the same conclusion, v. Scilly and Vertes made use of this feature by injecting their patients with "solusin," a rather toxic agent described elsewhere, from the use of INFECTIOUS DISEASES 191 which they claim to have obtained results equally as satisfactory as from the specific serum injections. ERYSIPELAS The treatment of erysipelas by means of antistreptococcal serum, usually by subcutaneous injections, is by no means a recent procedure, nor one concerning the value of which an agreement has been reached by clinicians. Chantemesse used Marmorek serum in some 500 cases and gained the impression that the process of recovery was accelerated. After 24 hours the swelling, induration and pain began to diminish while within a few hours after the injection the general condition of the patient improved. Jochmann, who had a considerable experi- ence, concluded that where the local inflammation was to be influ- enced, subcutaneous therapy was valueless, but that in the severely toxic cases with delirium, rapid pulse, etc., the effect of the serum was manifest in improving the general condition. Since the introduction of the intravenous methods of administra- tion of antistreptococcus serum, or with nonspecific methods, one can determine a more marked effect on the disease, both locally and in the general effect on the patient. Together with Jobling and Manier we commenced the treatment of erysipelas in 1915 with proteoses in- jected intravenously. The results in several cases have been presented by Jobling. Since that time the writer has had opportunity of ob- serving a series of about 15 additional cases treated either with prote- oses, milk, or typhoid vaccine and the results have in all cases been very satisfactory, indeed in some cases seemingly quite remarkable. The rapid subsidence of the intoxication, the general improvement of the sensorium and cardiovascular apparatus gave striking evidence of the decrease in the intoxication. The local process is also influenced, usually not, however, until there is evidence of the systemic effect in the euphoria and lessening of the toxicity of the patient. French clinicians have used subcutaneous injections and oral ad- ministration of normal serum as well as diphtheria antitoxin in the treatment of erysipelas for a number of years (Launois, Darier, Apostolleaun, Pollak and Mayweg) with some success, but in recent years the intravenous injection of such sera has evidently been fol- lowed by more apparent effects on the course of the disease. Koller, Uhlig, Basset, Campani, Frank and Bugolli report on cases so treated and Boyksen, who used normal horse serum, treated a rather large series. In severely toxic or extensive infection he administered 20 c.c. intravenously together with 10 c.c. subcutaneously ; in the milder cases only 10 c.c. was given intravenously. The colloidal metals have also been employed, at times with suc- cess. (Eberstadt, Cholewa, Capitan, etc.) Holler calls attention to a fact which we have observed at vari- 192 PROTEIN THERAPY ous times, namely, that intravenous injections of this kind may be followed by a very marked reaction on the part of the patient, so that even relatively small doses may incite a severe general reaction. Holler treated 32 cases of erysipelas with small daily injections of deutero-albumose, all of whom made a prompt and uncomplicated re- covery. The reaction was, however, at times quite severe, in some cases the patients becoming delirious for a short period following the chill. Nolf has described the use of peptones, Kraus, Tumheim and Reichenstein obtained satisfactory results with milk injections while Blumenau treated 77 cases with nuclein injections. In this series the favorable effect was more apparent in the general condi- tion of the patient than on the local process. Audain and Masmon- teil used sugar solutions; Englander reports that following the intra- venous injection of salt solution — 100 to 150 c.c. — the temperature usually returned to normal very promptly; v. Szily and Schiller used typhoid vaccine successfully. A munber of observers have obtained satisfactory results with either direct or artificial sunlight. (Bruce and Hodgson, Capelle, Klapp, etc.) Schmidt has recently reported on a series of 52 cases treated with milk injections. Of these 44 involved the face, 4 the upper extremi- ties, 3 the lower and in one case the abdominal skin was involved. The results were as follows: Upper Lower Defervescence Face Cases Extremity Abdomen 1st Day after injection . 27 2 1 1 2nd " " " 8 2 2 3rd " " " . 4 ■ ■ ■ ■ , , Of the 4 cases that did not respond until the 3rd day, one had an angina, and two had a lymphadenitis colli (tuberculous). The five remaining cases which persisted longer than 3 days were all complicated by other infections. INFLUENZA The recent pandemic of influenza gave opportunity to study the effect of a great variety of nonspecific agents on the clinical course, particularly of the complicatmg bronchopneumonia, and a considerable literature has developed which can only be briefly reviewed at this time. Colloidal Metals. — Teller reported satisfactory results with col- largol. Capitan, who treated 321 cases of uncomplicated influenza and 208 cases of bronchopneumonia of influenzal origin, used a col- loidal arsenic preparation, which he had previously found useful in tuberculosis and syphilis. The preparation contained 3 mg. of arsenic and 2 mg. of silver per cubic centimeter, and of this from 6 to 9 c.c. were injected either intramuscularly or intravenously. He de- INFECTIOUS DISEASES 193 termined a favorable effect on the pulse rate and the general con- dition of the patient; the temperature usually declined in about 3 days after commencing the treatment. Van Andel and Heymans both used collargol in a small series of cases with favorable results. Hodel found both collargol and the fixation abscess useful in influ- enza. Holden used colloidal silver and Richard, Remond and Netter have also reported on the use of similar metallic preparations. Tail- lens treated some 300 cases of influenza and complications with a number of different agents. Salvarsan was not effective, euesol and galyl were also found useless; colloidal metals were only useful in very large doses. Wachter used collargol in influenza and obtained good results if it was administered sufficiently early. In the pleurisy following pneumonias it was also useful. He recommends care if there is any nephritis present because he observed that several cases had a recur- rence of casts and albumin in the urine after the collargol injections. Witte also recommends such intravenous injections if they can be given early enough. The fixation abscess and turpentine injections (collobiase) seem to have been used with considerable success. Taillens reports that injections of turpentine gave him better results than the other agents that he employed (see above). He used it in 38 cases. Netter, who treated 230 simple influenza cases and 309 cases with complications, found that his mortality was about 22%. Cases treated with in- jections of colloidal tin oxid were not influenced very much. He also employed normal serum and collargol without much effect. A fixation abscess was employed in some cases with perhaps better results. Pehu and Pillon claim to have found turpentine injections useful in the treatment of bronchopneumonia, especially in children. Netter, Vergely, Roumaillac and also Klingmiiller used turpentine in- jections. Swiss clinicians have employed the fixation abscess with apparent success. Thus Hodel treated 156 cases of influenzal pneu- monia. Of these 102 were treated with intravenous injections of elec- targol, the dosage being from 5 to 20 c.c. The mortality was 20%. In 15 cases treated with the fixation abscess the results were much better. Probst describes his experience in the epidemic of 1920 as well as in those of 1918 and 1919. His experience then and with recent cases has confirmed his previous announcements in regard to the benefit from a fixation abscess induced by subcutaneous injection of 1 c.c. of turpentine. He ascribes its efficacy to the hyperleuko- cytosis which it induces, as influenza is accompanied by pronounced leukopenia. He thinks this explains also why influenza is mild post- partum, because the hyperleukocytosis of parturition renders the in- fection mild, and there is nothing so effectual, he declares, to induce hyperleukocytosis as the fixation abscess. He warns not to incise the 194 PROTEIN THERAPY abscess until the disease is subsiding (apyrexia), and then to make an ample incision and clear out the abscess thoroughly. Niemeyer has used intravenous injections of gelatin, but only in a few cases. Milk has been used by a number of clinicians. Von den Velden treated about 90 cases with serum, as well as milk, with results which he claims were very satisfactory. Of the milk 10 to 20 c.c. were injected intramuscularly two or three times during the course of the disease. Miinzer and Ptitz also found that milk injections favor- ably influenced the disease. Patschkowski treated 40 cases of in- fluenzal pneumonia with milk injections (10 c.c). Repeated injec- tions were given if the effect was not suflacient after the first dose. In this series 8 patients died. He observed that the typical reaction of increased fever and a chill were often lacking when the injections were made in such pneumonic patients. Zalewski and Miiller re- port very favorable results after the injection of aolan, a milk prepara- tion that is not followed by a severe reaction. Serums. — Diphtheria Antitoxin was repeatedly given a trial. Kautsky used injections of about 3,000 units and claims good results. Vaubel used injections of 1 c.c. in 20 cases with favorable results. Bettinger treated 18 cases with satisfactory results and Lustig treated 100 cases, all of which had pulmonary complications, with injections of 10 c.c. of antitoxin. The results were very satisfactory as contrasted with untreated cases in the same clinic. Crohn also reports 17 cases so treated. There were all uncomplicated influenza. Antistreptococcus Serum was employed by Hughes and also by Grote. The latter treated some 40 cases with antistreptococcus serum, horse serum and convalescent serum and Maale has reported similar results. Friedemann has used a polyvalent serum in 20 cases and considered the effect favorable. Normal Serum and Convalescent Serum have found extended em- ployment, and seemingly with satisfactory clinical results Reiss used normal serum, convalescent serum, normal horse serum and diph- theria antitoxin, injecting from 20 to 200 c.c. intravenously with excellent results. The temperature usually fell within 36 to 48 hours. Grigant and Montier made use of the plasma serum of Richet — a mixed rabbit plasma and human serum — which when injected early in the course of the disease was followed by satisfactory results. Other clinical observations have been reported by Pfeiffer and Prausnitz; Brodin, Lesne and Saint-Girons, Aguirre, Ehrenberg and Bachmann, Huff-Hewitt; Francis, Hall and Gaines; Hoist; Ross and Hund, Luithlen and Winterberg, Bogardus, Pauly, Redden, Foldes and Hajos, O'Malley and Hartman, Stoll, Liebmann and others. Vaccines. — ^While a considerable number of observers have used specific vaccines as therapeutic agents, the reaction from the injec- tion of influenza bacilli is not very marked and the nonspecific effect INFECTIOUS DISEASES 195 therefore not pronounced. Gow, for instance, has injected 75 million or more organisms intravenously without producing a chill, but did observe a temperature rise of 2° F. after three hours. There is little leukocytosis to be observed from such injections. J. Black Milne has reported on the use of mixed vaccines and Snyder has treated 20 cases with intravenous injections of typhoid vaccine. There were no deaths in the series and Snyder considered the method of decided value. Cowie and Beaven have also used typhoid vaccine in the treatment of pneumonia but consider it of value only in the early stages of the disease. An extensive series of 2(30 cases has been re- ported by Roberts and Gary who employed a vaccine made up of 100 million organisms per cubic cm. of each of the following: influenza bacilli, pneumococci, staphylococci and streptococci. Of this vaccine they injected from 0.5 to 1 c.c. intravenously. In their series so treated there was no evidence of injury to the patients in any way. The mortality of the treated cases was 9.5%; in a series of 86 pa- tients not treated with vaccine the mortality was 31.2%. In the treated series 36% recovered by crisis, in the untreated series 20% so recovered. Much's Vaccine. — Much, Schmidt and Peemoller have reported on the use of a nonspecific vaccine made up as follows: Reactive proteins derived from a number of nonpathogenic bacteria; a lipoid mixture from bile and a fat mixture of animal origin. This so-called "immunvollvaccine" was elaborated on the basis of the "partial anti- gen" theory of Much's. They report satisfactory results with the vaccine in the treatment of influenza. Hypertonic Salt Solution. — Borchardt and Ladwig have reported that they obtained good results following the intravenous injection of small amounts of salt solution (5-10%), as well as with con- valescent serum. Their cases numbered 98; they remark particularly on the detoxication evident in the more severe cases. Albumoses. — Ten severe cases of influenza were treated by Liidke with albumose injections. In 5 of them an immediate effect of a single injection was apparent — the patients recovering by crisis. In 2 cases pneumonia developed together with empyema. Both made protracted recoveries. In 3 cases the temperature came down only after a number of injections. LETHARGIC ENCEPHALITIS Laubie and Marinesco report the rapid recovery of patients ill with lethargic encephalitis following intraspinal injections of tetanus antitoxin. Brill has also used spinal injections of serum. Grunwald has injected from 80 to 100 c.c. of convalescent serum intragluteally in cases of lethargic encephalitis. The effect on the temperature and pulse rate was prompt, lysis occurring in 3 days after the injection. 196 PROTEIN THERAPY Neuralgias persisted for some time after the temperature had returned to normal. Voorthius claims to have found the fixation abscess useful in encephalitis. MEASLES Both Holler and Miiller have treated cases with albumose and with milk injections. Pehu and Pillon report that injections of tur- pentine were very satisfactory. PAROTITIS AND ORCHITIS Salvaneschi has reported that the injection of diphtheria anti- toxin is of considerable value in the treatment of parotitis and in the orchitis frequently complicating parotitis. More re- cently Bonnamour and Bardin have reported 65 cases of mumps which had such treatment (20 c.c. of serum subcutaneously) . Of these 57 entered the service without a complicating orchitis and none of them developed this complication; in 8 there was testicular pain on admis- sion with a beginning orchitis which resolved promptly after the first or second injection. They consider the serum injections not only of value in the treatment of the orchitis, but as a prophylactic against the development of orchitis. PNEUMONIA (LOBAR) In the chapter on the Mechanism of the Protein Re- action the efi'ect of injections on the course of lobar pneumonia has been discussed. As we might expect, severe reactions may be followed by a temporary defervescence, but they do not as a rule effect the pulmonary lesion when once it is established. One finds occasional references in the literature in which foreign protein therapy has been used with a measure of success (Monguzzi — milk and gono- coccus vaccine, Talamon — diphtheria antitoxin, etc.), but the method cannot be considered of established value. On the other hand it is by no means excluded that when specific serum therapy is used (chicken serum, hiunan serum, horse serum), or specific vaccine therapy (as for instance the Rosenow pneumococcus autolysate) part of the thera- peutic effect may not be due to the protein injected. Injections such as those described by Huntoon (soluble antibodies) always bring about a marked reaction on the part of the patient and are effective only when given early in the course of the disease, observations sug- gestive of nonspecific effects. PUERPERAL INFECTIONS Lindig tried injections of casein in several cases of puerperal in- fection. One case had had a continuous fever for two months. Three INFECTIOUS DISEASES 197 injections of 1 c.c. each were given intravenously. These were fol- lowed by chills which usually began one hour after the injection; some headache was also noted. After the first injection there was no temperature rise, nor was it marked after the second injection given the following day, but after the third injection was made 4 days later, there was a reaction of 2° C. The patient was completely cured after the third injection. Lindig treated several other cases with similar results. The effect here noted in the temperature curve was reflected in the effect on the leukocytes. After the first injection there was usually only a slight leukocytosis, but with the second or third injection this was much more marked. A well-marked euphoria was observed in every case. Kraus in his early work on heterovaccination found that he could bring the febrile course of puerperal infection to a prompt termi- nation by injecting typhoid and colon vaccine intravenously. Arweiler in a Dissertation has taken up the use of casein injec- tions in considerable detail and Lindig has reported on the use of such injections as a method of prophylaxis in the puerperium. His re- port covers the results in 61 cases. The colloidal metals have been used with some success (Siegel) ; Whitehouse reports success following the intravenous injection of Flavine; Werner has confirmed the earlier reports of Kraus in using typhoid vaccine. Gow uses Witte Peptone. The first dose which may be given intravenously to a septicemic adult is from 8 to 10 c.c. The quantity is increased by 2 c.c. every other day or so until 16, 18 or 20 c.c. are given at a time. The injection must be made slowly and for that reason Gow employs Nolf's technic using a record syringe and a very fine bore needle — ^with a No. 28 it is impossible to introduce the solution too quickly. In cases of puerperal septicemia the injection of peptone tends to cause an immediate and rapid fall in blood pressure, a rise in the pulse frequency, and if the patient has a leukocytosis, it rapidly induces a high degree of peripheral leukopenia — all these phenomena being of very short duration. Of these changes, the easiest to record as a guide is the pulse frequency, and while the injection is in progress the nurse keeps count of the radial pulse, calling out the number each quarter of a minute. Though he is convinced the peptone is a very valuable adjunct to sensitized vaccine, Gow makes no extravagant claim that it always brings a septicemia to an end, and he cautions any who may look for a dramatic and sustained fall of temperature after its use that most times they will be disappointed. Bianchi gave parenteral injections of milk in thirty-six obstetric and twenty-one gynecologic cases. He reports that it seemed to pro- mote and accelerate the cure in certain cases and ward off serious disturbances, but when severe puerperal septicemia was under way, 198 PROTEIN THERAPY no benefit could be detected. Under any conditions the effect did not much surpass that from the ordinary measures, drugs, vaccines, fixation abscess, mercuric chlorid by the vein, etc. But the harmless- ness of this milk form of protein therapy, its availability, and its ex- cellent influence in reducing objective and subjective pain and in en- hancing the defensive powers of the organism, impose its use on a large scale, he declares, especially during the early stage, when it is most potent. SCARLET FEVER The treatment of scarlet fever by means of serum injections dates from the year 1897 when both v. Leyden and Weisbecker used the serum of convalescent patients in a series of patients ill from scarlet fever. Jochmann and Rumpel in 1903 tried subcutaneous injections, using a dose of about 20 c.c, without obtaining results that were par- ticularly striking. Indeed the results from subcutaneous injection have in general been rather unsatisfactory, unless huge doses are used. It was not, therefore, imtil Reiss and Jungmann published their pa- per some years later that more attention was given the subject. Since that time Russian and Austrian clinicians have reported ex- tensively on the use of antistreptococcus serum, with at times excel- lent results. Apart from convalescent serum, the antistreptococcus serum of Moser, prepared by immunizing horses with strains of streptococci freshly isolated from fatal cases of scarlet fever, has met with considerable success (Axenow). In the earlier period the serum was given subcutaneously and the results were never striking. Reiss and Jungmann, however, used their serum intravenously and with this method of injection the re- sults have been much more satisfactory. Convalescent serum being rather difiBcult to obtain in large quantity the injections have been limited as a rule to about 20-90 c.c, while with other serums the dosage has been much larger, several hundred c.c. being used. Jochmann, who followed this form of therapy for a number of years, considers that intravenous serum injections, if given early in toxic cases, lessen the toxicity, usually hasten defervescence and seem to lessen the nmnber and severity of postscarlatinal complications. Synnott has also reported on the use of convalescent serum and Weaver has discussed the question fully. Glaser has recently reported a series of grave scarlet fever cases treated with pooled convalescent serum. In 15 cases it was given intra- muscularly in doses of from 50-80 c.c. In 40% of these cases the temperature came down by prompt lysis. Complications did not seem to be influenced by the treatment. In 28 cases in which the serum was administered intravenously the effect on the temperature curve was apparent in every case. Occasionally the intravenous injection was followed by a chill, some headache and temporary weakness, but INFECTIOUS DISEASES 199 he saw no unfavorable result from the injections. All recent ob- servers insist that if effects from the serum are to be expected the same must be given within the first three days of the illness. (Rowe, Bennecke, Zingher, Koch, Moog, Reiss and Hertz, etc.) Moog as well as several other clinicians used normal serum in doses of 80-100 c.c. In 25 cases 7 responded with a critical drop in the temperature; 13 dropped by lysis; 2 cases died, while in 3 there was no effect. Rehde, who treated 89 cases, used normal serum in 14. In both series the results were equally satisfactory. Usually a mild, general reaction was observed following the intravenous injection, that is, the temperature was increased for a short time, a chill noted, as well as some headache; Griesbach in a series of 21 cases observed this reaction repeatedly in his series (8 out of 21 reacted with a chill) and 4 patients went into collapse. Krause, who treated 28 cases of scarlet fever with convalescent serum, also has observed collapse symptoms in a large percentage of the cases (25%). In his series there were, however, only 4 deaths and in 24 the temperature came down promptly after the injections. This collapse observed by Griesbach and Krause is, however, quite unusual and Reiss, who has so far treated 221 cases, states that he has never had one case in which collapse and death followed the in- jection. Schultz and Ehrmann have also treated a large number of cases with intravenous serum injections. Ehrmann's cases numbered over 200 and his results were very favorable. He emphasized the im- portance of injecting early in the course of the disease if results are to be, expected. Schultz' cases numbered 184, of whom 102 were treated with normal serum, 67 with convalescent and 15 with both kinds of serum. He reports very apparent improvement in about 60% of the cases following the .injections. Prinzing has studied the effect of serum treatment on the com- plications with the following results: Lymphadenitis collci occurred in 15.5% of the injected cases, in 34% of the noninjected; otitis media in 9.3% of the injected, in 10.8% of the noninjected; nephritis in 8.2% of the treated and in 18.9% of the nontreated cases. Holler has published a series of 32 cases of scarlet fever treated with injections of deutero-albumose (twice daily, 1 c.c. of a 10% solution). There were no deaths in the series and no complications. The course of the disease was in each instance shortened. Liidke treated 14 cases of severe scarlet fever with albumose in- jections. The fever very frequently ceased promptly after a single injection, the skin eruption likewise fading and the exfoliation began very promptly. There were no complications and no nephritis was observed. There was no doubt in Liidke 's opinion that the injec- tions resulted in a material shortening of the course of the disease. 200 PROTEIN THERAPY In general it may be stated that following the intravenous in- jection of convalescent human serum, normal human, as well as horse or other serum in cases of grave scarlet fever, the patient re- acts with a slight increase in temperature and occasionally with a chill; in the majority of cases this is followed by a prompt lysis or crisis. The toxic manifestations of the infection are usually dimin- ished, the patient feels better, complications are diminished in num- ber, but preexisting complications are not influenced appreciably. There seems very little that is specific in the reaction, for it is im- material whether immune streptococcus serum, convalescent serum, normal human or animal serum is used, or whether proteoses (al- bmnoses) are employed. Even salvarsan, according to Jochmann, is followed by a typical reaction on the part of the patient, in effect similar to senun injection, so that he considers the employment of the one or the other merely a matter of individual preference. SEPTICEMIA The treatment of septicemia by means of nonspecific injections has at times undoubtedly yielded brilliant clinical results; more often, unfortunately, there has been no apparent effect on the course of the disease. Perhaps the failures are due to the fact that nonspe- cific therapy has almost invariably been left as a final resort when the patient was quite exhausted and incapable of stimulation. It is to be remembered that the very fact that in the true septicemia we are dealing with bacterial proliferation in the blood stream and that thereby all parts of the organism are already being stimulated — or overstimulated as the case may be — ^makes any therapeutic ap- plication of this nature practically hopeless at the very start. Never- theless one does at times witness quite remarkable and dramatic re- coveries by crisis or by lysis after nonspecific injections. The older literature, in which the injection of colloidal metals was dealt with, is quite extensive and need not be reviewed at this time. The re- sults were on the whole inconclusive. While recoveries were observed that seemed definitely contingent on the therapeutic injection; in other cases there was no apparent result. Reichmann (6 cases, 5 deaths) . In the more recent literature other procedures have been mentioned, some of which seem to have been followed by very favorable and con- sistent results. Brown has discussed the use of the metallic colloidal preparations. Hypertonic sugar has found advocates (Baradulin, Audain and Masmonteil), and immunized blood has also been used (Steel). Wright has suggested a method of using such immunized blood for transfusion. The mode of preparation is to treat the blood of a healthy individual with vaccine, then transfuse the infected in- dividual with such immunized blood. INFECTIOUS DISEASES 201 Kalberlah claims to have obtained very good results by injecting typhoid vaccine. Gow has recently used peptone injections for intravenous injections in septicemias and has combined them with subcutaneous injections of streptococcus vaccine (sensitized). By this method he claims to have obtained excellent results; Nolf, too, has had success with peptone injections. In two cases of streptococcus sepsis recovery occurred in 4 and 8 days respectively after intravenous injection of deutero-albumose. (Liidke.) There was a very severe chill after the injections. In one case of tetragenous sepsis there was prompt recovery after a single injection. Among the more recently introduced colloidal metal preparations "argochrom," a methylene-blue-silver combination, seems to have found considerable favor. Wendt treated 14 cases with this agent and considers it of value. Weichardt in a recent paper which takes up the effect of protein therapy in the pneumonococcus sepsis of mice, states that both Jaschke and Freund have obtained favorable results in septic cases with protein therapy. SMALLPOX Holler reports on the treatment of variola with daily intravenous injections of deutero-albumose. The results are described as satisfac- tory. TETANUS A rather remarkable experience is that reported by Liidke in the treatment of 7 cases of tetanus. These were all cases in which severe spasm had developed after incubation periods of from 7 to 11 days. The treatment consisted of injections of deutero-albumose of from 3 to 5 c.c. of a 10% solution, given in 24- or 48-hour intervals. No spe- cific serum and no magnesium sulphate was used. All cases recovered in from 7 to 22 days. Liidke observed the characteristic effect of non- specific therapy on nerve irritability in that the spasms were first aug- mented after the injections, then diminished in intensity. Kaznelson also treated two cases with albumose injections. One case recovered, the other ended fatally. TRENCH FEVER Paul Jungmann treated a large series of cases of trench fever (Wolhynian Fever) with colloidal metals without result, despite the fact that a typical nonspecific reaction was elicited, with a severe chill, fever, etc. Often the patient was seemingly cured, with the temperature curve normal and the other symptoms in abeyance, but finally the clinical course of the disease again became manifest. 202 PROTEIN THERAPY With typhoid vaccine and old tuberculin a similar reaction and ef- fect was obtained, just as one finds that as a result of intercurrent infections, pneumonia, etc., the symptomatology of the trench fever may almost completely disappear. The nonspecific injections, accord- ing to Jungmann, had no direct effect on the course of the disease other than described. Kirchberg, on the other hand, who used collargol intravenously, states that during the time that the patients were under observation there was no return of the fever after the injections, and the anemia was also markedly improved. Richter, too, found that collargol in- jections were followed by satisfactory results. TUBERCULOSIS In the discussion of the focal reaction and the relation of the skin reactions to nonspecific factors, evidence has been presented that tuberculins are active as non-specific agents and it should be kept in mind that their therapeutic effect can be accounted for largely on such a basis. In a general way the experience with tuberculins has been the following: Large doses in active cases cause a rapid progression of the disease, with cavity formation, increased tendency to hemorrhage, etc. Even small doses in active cases are not without some danger. In the inactive cases large doses may acti- vate the focus ; moderate doses may be followed by an improvement, or no apparent effect on the focus. In incipient cases large doses may occasionally be followed by complete and rapid recovery; more often though the effect is a harmful one. Keeping in mind the fact that resistance to tuberculosis is largely cellular and that the effect of nonspecific stimulation is always at first associated with increased digestive phenomena, we might antici- pate these effects. An active process will be made more active, an inactive one may be activated; on the other hand, a small incipient lesion may, by activation, digestion, etc., occasionally be rapidly healed. In a general way this agrees with the experience that has been gained with protein therapy in the treatment of pulmonary tuberculosis. Holler found that while early cases may react well and there may be an increase in the general resistance, advanced cases may give noticeable evidence of autolysis and extended cavity formation. Mueller found that if he treated cases with slight apical lesions and only moderate evidence of activity, the entire process might be cleared up after a few injections of milk. Naturally in such cases we bring about a decided focal reaction and the organism must be in physical condition to withstand and detoxicate all the necrotic ma- terial that is liberated by the digestion at the point of infection and to destroy bacilli that are freed in the process. If it cannot do this we will merely spread the infection. INFECTIOUS DISEASES 203 Schmidt and Kraus report very remarkable results following milk injections in early tuberculosis; Klemperer has gone over a somewhat larger series of cases but could not confirm their findings. Czerny and Eliasberger have attacked the problem from another point of view. They have taken a series of very emaciated tuber- culous children (26) and have given them frequent injections (daily injections of from % to 1 c.c.) of horse serum. While the injections have no direct effect on the tuberculous process, 12 of the children showed a striking improvement in general condition. This effect on the nutrition and on the general condition of children has been re- ported by other observers as well. Tuberculous Meningitis. — Hollis and Pardee call attention to the use of intraspinal injections of foreign protein (they used antimen- ingitis serum) in the treatment of tuberculous meningitis, reporting the recovery of 5 patients out of a series of 8. They regard the therapy as nonspecific, and call attention to the fact that the use of serum in the treatment of syphilis of the spinal cord — although combined with a specific drug — must also be regarded as a form of therapy based on the irritation of the meninges, with the therapeutic effect following as a result of the reaction. Experimentally Baldwin and L'Esperance have noticed some in- crease in fibrosis in tuberculous guinea pigs after treatment with typhoid vaccine. Bohme, using a variety of nonspecific substances, vaccinurin, pus, influenza bacilli, streptococci and milk injections, could determine no alteration in the course of tuberculosis in the guinea pig. TYPHUS FEVER During the course of the war a number of investigators have had the opportunity of trying nonspecific therapeutic agents in typhus fever. These have included deutero-albumose, salt solution, colloidal metals, convalescent serum and vaccines of various kinds. Holler found that his method of therapy — daily injections of deutero-albumose intravenously — was most efiicacious in typhus when he was able to begin the treatment within the first two days after the onset; in that case he was frequently able to terminate the disease by crisis. When given later, while it shortened the course of the disease and had a pronounced effect in modifying toxicity, the re- sults were not so striking. In fifteen untreated cases the mortality was about 50%. In 50 treated cases only three patients died. Equally favorable results have been described by Tagle, who began such therapy on the basis of Nolf's work, and by Opazo. Tagle applied the injections in 59 cases of typhus. Aside from one patient that died in less than forty-eight hours, the mortality was about 5 per cent. He declares that the absence of all ill effects 204 PROTEIN THERAPY confirms the harmlessness of the method for all ages. The general health improves, the duration of the disease is shortened, and con- valescence sets in earlier. The benefit was more pronounced the earlier the injections had been begun. His report represents exten- sive research by the different physicians on the hospital staff, much experimental and laboratory work being carried on preliminary to and during the clinical experiences. Nolf's technic was closely followed, except that the acidity of the solution of peptone in physiologic salt solution was reduced to 4.3 per thousand, and the remedy was put up in 5 c.c. capsules. About 10 c.c. was given as the first dose, to robust adults; otherwise from 4 or 5 c.c. For older children, up to 6 or 8 c.c. giving afterward only about half of the initial dose, and allowing an interval of forty-eight hours to elapse. In almost all the cases a second injection was given and, exceptionally, a third, with only 1 or 2 c.c. A subcutaneous injection of 2 or 3 c.c. of 20 or 25 per cent, camphorated oil was given every six hours day and night, with 0.25 c.c. of 1 per thousand epinephrin in each syringe. The patient must be kept in repose. The blood pressure falls during and immediately after the intravenous injection of peptone, but if it is made slowly (1 c.c. per minute) and if epinephrin has been given, the drop is slight. The coagulation time of the blood is much re- tarded. Analysis of the blood showed that the urea content could be disregarded with this protein therapy as the latter only slightly aug- mented it, and it soon dropped to below its previous figure from the rapid reaction to the injection, while the dietetic restrictions in typhus aid in its being speedily cast off. Analysis of the urine like- wise showed that the injections of peptone had no detrimental in- fluence on the kidneys and hence there were no contra-indications on the part of the kidneys, except, of course, with grave nephritis. There are no characteristic findings in the vu:ine in typhus. The fever charts given show the attenuating and abbreviating influence of the protein therapy better than anything else. An interesting fea- ture of the cases was that when the temperature had gone down im- der the injections, a further injection did not induce any appreciable reaction. The production of antitoxins can then be regarded as suflB- cient and the case as cured. In every case improvement in the general condition was unmistakable. Opazo reports the application of Nolf's method in 27 cases of typhus, with 14 recoveries, 4 in convalescence and 7 still under treat- ment; 2 of the patients died, but the disease in their cases had reached a stage when reaction was no longer possible. He reiterates that the protein therapy induced a favorable reaction which modified the disease and all the symptoms. In his experience the reaction was prompter and more effectual in children than in adults. He is now applying this protein therapy as the routine in all cases of typhus. Kalberlah reports good results from the intravenous injection of INFECTIOUS DISEASES 205 typhoid vaccine. Bouygues has employed colloidal metals and Coglievina, who used dispargin — a colloidal silver preparation, — re- ports that the course of the disease was much less toxic and the mor- tality lower than in untreated cases. He gave on an average about 4 injections. Tietze used a 3% solution of collargol (5 c.c.) and noted a lessening of the toxicity. The use of silver and antimony colloids has been suggested by Uhlenhuth and Frommes, but the number of cases treated by them has been too small to justify final conclusions. Gyozi treated a number of cases with autoserotherapy and found that it seemed of decided benefit particularly in the older cases. Gudzent treated two cases with convalescent serum without apparent success. Raubitschek treated 25 cases with subcutaneous injections of normal horse serum. The mortality was about 6%. v. Zielinski used intravenous injections of the patient's own cerebrospinal fluid. In 20 severe cases 5 died. Munk has published a comparative study of the treatment of typhus with normal horse serum, peptone and with nucleohexyl. More recently Schultz, Charlton and Hatziewas- silow have discussed a heterovaccine method which they claim has given good results. They used 2 loops of 48 hours' growth of typhoid organisms (killed at 60° C.) which were mixed with 5 c.c. of the pa- tients' serum. This sensitized vaccine was then injected. A rather sharp reaction followed the injection but the clinical results seemed very satisfactory. In the series of 5 cases all recovered. Perhaps a method that is equally successful is that described by Danielopolu in his recent treatise on Typhus Fever. The author uses daily injections of hypotonic salt solution (0.065) which are given intravenously. In his untreated series the mortality was very great, in the treated fully 90% recovered, VINCENT'S ANGINA Capitan treated 200 cases of Vincent's angina with intramuscular injections of colloidal arsenic (6 c.c). The cure was complete in from 24 to 48 hours. No local treatment was necessary. Stuhl re- ports a similar nonspecific method of therapy in using tuberculin in the treatment of Vincent's angina. While he treated but a small number of cases the results were quite striking. CHAPTER XII SPIEOOHETAL AND PROTOZOAL INFECTIONS RELAPSING FEVER Bouygues reports that he has found the injection of colloidal metals useful in relapsing fever. SYPHILIS The fact that intercurrent diseases, particularly the acute infectious diseases, have a distinct effect on the manifestations of syphilis has been frequently observed by clinicians (Zehner). The effect may be apparent in delaying the onset of secondary eruptions or in hasten- ing the involution of skin lesions already present. Neumann has dis- cussed the subject quite thoroughly in Nothnagel's Special Pathology. In view of the effect of temperature it was natural that with the study of protein therapy efforts would be made to determine what effects would be apparent on syphilitic skin lesions after nonspecific injections, and Biach as well as Kyrle, Weiss and Luithlen have de- scribed the involution of the skin lesions after protein therapy. Nat- urally the question is of greater theoretic than practical interest be- cause we are fortunate in possessing much more efficient specific agents. In the last two years considerable attention has been devoted to the study of silver preparations and their application in syphilis. The injection of colloidal silver has been found experimentally to prevent the proliferation of spirochetes in the tissues of rabbits (Kolle and Ritz) and silver preparations (collargol) have been used (see v. Notthafft) clinically with apparent success. Silver-salvarsan is not included in this category because its effect is of coiu-se es- sentially specific. The effect of iodids should undoubtedly be included in the group of nonspecific agents because the mode of action in stimulating tissue autolysis (although by an indirect method, as demonstrated by Jobling and Petersen) is quite analogous. It is very probable that the non- specific agents will have a place in the treatment of syphilis as ad- juvants that permit us to make specific treatment more intense by facilitating the rapid distribution of the specific agent. Applications have been made of this theory by Schacherl, by Hauber and by Szedlack. 206 SPIROCHETAL AND PROTOZOAL INFECTIONS 207 Schacherl has reported on the combined specific and nonspecific treatment of 10 syphilitic neuro-arthropathies. In these cases only one was temporarily cured, 5 showed some retrograde change, while 4 were unchanged. In 16 cases of cerebral lues, the results were as follows: In 5 cases of hemoplegia, 1 was cured, 3 were improved. Five were of the disseminate type; of these 2 were cured, 3 improved. Three cases presented only eye symptoms. One of these was cured, one improved and one not changed. Schacherl noticed that the Wassermann reaction was much more rapidly changed under the combined treatment than with mercurial treatment alone; it seemed very probable that the mercury was much more rapidly absorbed, because stomatitis was more frequently noted under the combined method than when mercury salicylate was given alone. Stiickgold, who has treated a number of cases of congenital lues with the milk "fever" therapy, rightly observes that one cannot expect to permanently cure syphilis by means of such therapy; all that one can expect is a remission of the disease manifestation. But he is convinced that the combination of the nonspecific reaction with spe- cific agents is of particular value. He observed that with the combined therapy one required much smaller doses of the specific drugs to obtain therapeutic results and to infiuence the Wassermann reaction. Schreiner used milk and peptone injections along with specific treatment in syphilis and found that the Wassermann reaction be- came negative much sooner in such cases than in those that were put solely on specific treatment. The effect on the Wassermann re- action has been studied by several observers after Uddgren called attention to the fact that in luetics a single injection of milk might render the serum positive (previously negative). Scherber found that in luetics an intercurrent febrile disease might have the same effect. In the therapy of syphilis by means of salvarsan the induction of an antianaphylactic state on the part of the patient has been found of value in preventing the occurrence of the salvarsan shock reaction. Bushman describes the method of Stokes, which consists of giving a preliminary dose of salvarsan (1/10 the total dose) ; this is undoubt- edly sufficient to cause an alteration in the permeability of the cells and so lessen the possibility of later intoxication. Mention has already been made of the fact that Jungmann used salvarsan interchangeably with serum in the treatment of scarlet fever. WEIL'S DISEASE A number of observers have reported that Weil's disease is fa- vorably influenced by the injection of convalescent and normal serum (Heidenheim, Herbach, Mann; Kleinberger obtained no conclu- 208 PROTEIN THERAPY sive results). Inasmuch as milk injections seem to be very active in influencing the liver (increase in thrombokinase, fibrinogen, shed- ding of glycogen, etc.) Dollken determined to use milk therapy in place of the serum — either normal or convalescent. The styptic ef- fect of the milk injections might be expected to become manifest in the course of the disease. In one very severe and quite hopeless case he injected 3 c.c. of milk; the bleeding from the intestine ceased after five hours but the patient nevertheless died. In other less toxic cases Dollken observed a decided effect on the pigmentation of the skin. In several cases injected with albumoses and with milk there was practically a clearing of the jaundice in from 48 to 72 hours. A mild grade of jaundice persisted, however, in these cases despite further injections. The effect on the albuminuria was also quite marked, a single injection being suflBcient to completely clear up the urinary findings. Dollken was not able to follow his cases for any length of time so that it is not possible to draw any positive conclusions from the work. There seems little doubt that nonspecific injections, par- ticularly of milk, are able to effect the liver metabolism considerably and may so alter disease processes which have their principal effect in the liver parenchyma. Inada and his associates have also studied the effect of the injection of serum on the course of Weil's disease. MALAEIA Activation. — ^The provocative effect of "nonspecific injections has been made use of not only in activating latent gonococci, but also in cases of suspected malaria. Thaller noticed that after milk injections in cases that were sus- pected of malarial infection the plasmodia could be demonstrated after the reaction in a certain number of cases. In thirty cases so in- jected 13 responded with the usual milk fever, in 12 a malarial type of fever was activated, in 5 there was no effect. Habetin used sub- cutaneous injections of nucleic acid to mobilize the plasmodia and Heese found that after nonspecific injections plasmodia could be dem- onstrated and paroxysms commenced one week after the injection. Schlesinger observed that malaria plasmodia were mobilized after typhoid inoculation; Freund also observed the activation of an old malaria after an intravenous typhoid injection, while Zupnik, V. Miiller and Leiner report an interesting case of a double infection with typhoid and malaria in which the malarial paroxysms resulted in a typical nonspecific defervescence of the typhoid fever. Therapy. — Silvestri would support the specific treatment of malaria with injections of foreign protein, serum, adrenalia, strychnin, etc., claiming that the combined treatment is better than when quinin is used alone. It is very possible that such measures may be useful SPIROCHETAL AND PROTOZOAL INFECTIONS 209 in facilitating the diffusion of the specific drug and getting more effect on latent foci of the plasmodia. Schimert reports the treatment of some 70 cases of tropical ma- laria which had become refractory to quinin. These were chronic cases and in poor physical condition. He tried autoserotherapy and obtained a clinical recovery in 85% of the cases, that is, the patients were improved physically, gained in weight and were able to be at work, although the parasites were not altered by the treatment in- stituted. CHAPTER XIII MISCELLANEOUS DISEASES ASTHMA The recognition that asthma and hay fever were to be grouped among diseases due to sensitization of the patient in the nature of an anaphylaxis, has opened a series of exceedingly valuable and interest- ing investigative and clinical problems. Naturally the asthmas due to cardiac impairment or anatomical alterations result- ing from tuberculosis cannot be included in such a category, but there is evidence acciunulating that in this latter group of cases we must admit certain elements of sensitization. In Wolff Eisner's recent discussion one finds the admission that the tuberculous individual presents a definite hypersusceptibility to a number of pro- teins of nontuberculous origin so that asthmatic phenomena in tuber- culous individuals are to be expected. So, too, in the true asthmatic we must expect that attacks will be precipitated not only by specific antigens but by a variety of metabolic alterations or shocks which may bring about focal activation such as has been discussed in the chapter of focal reactions. During pregnancy asthma may become manifest (Hepworth, Salaberry), although as a rule the reverse is more common — -that is, asthmatics are usually free from attacks. Onset of attacks after remote trauma (Loeper and Codet) or psychic disturbances are common examples of the phenomenon. As long as the conviction was entertained that desensitization was as specific as sensitization, efforts at therapy naturally centered about the determination of the particular protein that might be the cause of the disease and the endeavor to bring about an increased resistance or tolerance by subcutaneous injection of the antigen. Walker's publications in this field are of particular importance. Walker's method, which consists of desensitization by vaccination, is usually followed by quite satisfactory and often permanent results. In recording observations on the treatment of asthmatics which were sensitive to various proteins and also those in whom no specific sensitization could be determined, Walker describes the therapeutic result in this latter group of 150 patients who were not sensitive to any protein with which they were tested. It may be well to quote Walker's observations in full: "The following comparisons as regards treatment may be made between sensitive and nonsensitive asthmatic patients. In the previous article, which concerned patients sensitive to proteins, and in the 210 MISCELLANEOUS DISEASES 211 first part of this article which concerns patients sensitive to bacterial proteins, it was shown that in general a favorable prognosis could be anticipated irrespective of the age of onset of asthma or the age of the patient when treated. With the nonsensitive patients, however, the later the age of onset and the later the age of the patient when treatment is begun, the more unfavorable the prognosis. The duration of asthma alone played little part in the prognosis in either type of case. Seventy-five per cent, of the sensitive patients were relieved of asthma by treatment with the proteins to which they were sensi- tive, whereas only 40 per cent, of the nonsensitive patients were re- lieved of asthma by treatment with vaccines. The permanency of relief of asthma in the sensitive patients was of much longer duration than in the nonsensitive patients. Both the sensitive and the nonsen- sitive patients illustrate specificity in the treatment of bronchial asthma; that is, the specificity of proteins in the treatment of sensi- tive cases and the specificity of bacteria in the treatment of nonsensi- tive cases. We have, however, only inferred that nonsensitive asth- matic patients are not benefited by treatment with proteins. Because of the more or less general belief that infections may be alleviated by nonspecific protein therapy — and in the case of chronic arthritis this is frequently found to be true — it seems worth while to mention our results in the treatment of the infectious or nonsensitive type of bronchial asthma with proteins. "Many of the nonsensitive or infectious type of asthmatics have been treated with various proteins. Three patients who were in the hospital wards because they were having severe asthma every day were given, intravenously, typhoid vaccine without improvement in the asthmatic symptoms. A week later a larger dose was given without any benefit. After this the patients were given, subcutane- ously, two hundred million autogenous streptococcus vaccine made from their sputum in dextrose bouillon. A few days later one patient was somewhat improved, another seemed a little better and the third was not improved. A week later still the autogenous vaccine was in- creased to 250 million and a few days after this one patient was very much better, another was considerably improved and the third was somewhat better. The autogenous vaccine was given each week with gradual improvement in each instance until two patients left the hospital three weeks later and the third patient was able to leave in five weeks. Therefore, the intravenous typhoid vaccine was fol- lowed by no benefit, whereas the autogenous streptococcus vaccine was followed by a gradual though distinct improvement. Several of the nonsensitive summer asthmatics and some of the other nonsensitive cases were given courses of treatment with various pollen without benefit. A few nonsensitive patients were given wheat proteins and a few were given large doses of peptone subcutaneously without bene- fit. This latter niQthQd of treatjnent is dangerous unless the patient 212 PROTEIN THERAPY is tested with peptone to rule out the possibility of his being sensitive to it. We feel that this fad of injecting patients with proteins to which they are not already sensitive is, in general, apt to be a mis- take; the possibility of sensitizing patients to proteins, exclusive of typhoid vaccine, seems to outweigh the chance of improvement by such treatment." On the basis of the fact that in antianaphylasis (or desensitiza- tion) a nonspecific element is at times observed, other methods have been devised which are at times applied more easily than the spe- cific methods that Walker has used. Only larger clinical experience will enable us to draw conclusions. It must be borne in mind, too, that our conception of protein therapy must not be limited to the intra- venous injection of typhoid vaccine or peptone. Many of the milder reactions continued over a longer period of time may be foimd much more effective. Auld has reported on the use of peptone injections (dissolved in physiological salt solution to which a small amount of sodium car- bonate is added) given either intravenously or subcutaneously. This treatment has been instructive in respect of the grouping of asthmatic cases. Two main groups occur which show no tendency to pass into each other. One group comprises such as quickly respond to the treatment, and the effect is more or less lasting, the recurrences being infrequent and milder in character. The other group is resistant, and is subdivisible into such as are totally resistant and those in which, by careful immunization, the disease may be largely overcome. Pagniez and Widal, Abrami and Brissaud use peptone by mouth and Cordier uses peptone enemas. The peptone seems to be polyvalent for most of the substances causing the anaphylaxis. Some require the continuous use of the peptone; others do better when it is given for three to eight days followed by an interval of the same length. By this means they have succeeded in curing the tendency in time in many cases, the time required for complete desensitization depending, however, on the personal equation. Other observers have used col- loidal metals and Boyd reported that he had successfully treated several cases of asthma with typhoid vaccine (50 million organisms intravenously) . Danysz considers that the intestinal flora furnish the substrate for the antigen which sensitizes the patient in asthma, in certain skin and gastro-intestinal diseases. In an antiphylactic treatment he uses the bacteria isolated from the stool for subcutaneous injection with apparently good results. Together with Miller we have used Intravenous injections with 'typhoid vaccine in asthma in a number of cases. In some the results were quite satisfactory, in others there was no apparent effect on the attacks ; the latter group including particularly the cases in which food sensitization was demonstrable. It is possible that a method such MISCELLANEOUS DISEASES 213 as that of turpentine injections might be more satisfactory because the effect is prolonged over a considerable period of time. Sterling has reported the use of nonspecific vegetable proteins in asthma ; a number of observers have reported satisfactory results with endocrine glands of various types — ovarian substance (Fishberg), pituitrin (Bensaude and Hallion, Zueblin), as well as with normal horse serum (Zener) and the various antitoxins — diphtheria and tetanus. Danysz has discussed the general theory of antianaphylaxis or desensitization in a recent paper in connection with related dis- eases due to manifestations of hypersensitization in the skin and gastro-intestinal tract. The indiscriminate use of sera of various kinds in asthmatics is a practice that should be discouraged because a number of deaths have been reported as a result of such injections. (Boughton.) It must be borne in mind that in this condition we are dealing with a patient highly sensitive to protein shock and great care should be exercised. ANGIONEUROTIC EDEMA Schulmann relates that discovery of a transient phase of hemolysis, the crise hemoclasique, in a number of cases of Quincke's disease has confirmed its analogy with other affec- tions in which anaphylaxis is a factor, and treatment on this assump- tion is proving successful. He applies it in the form of autohemo- therapy, drawing 2 c.c. of blood into a syringe from a vein at the bend of the elbow, and he reinjects the blood into the neighboring sub- cutaneous tissue, merely drawing the needle out of the vein and point- ing the tip in another direction in the tissues of the arm. He has made hundreds of these injections and never had a mishap, but the desensi- tization may take up to two months, although there is relief almost from the first. Three typical cases are described; one woman of 31 had been subject to attacks of angioneurotic edema since before puberty, returning at different points and lately becoming more fre- quent and lasting for three or four days. She was given three in- jections a week and by the end of the third month the tendency seemed to have been arrested. She returns every three or four months to have a few injections of the kind made. In another case the attacks had been recurring every two or three days during the six months following a childbirth, and they were accompanied with headache and urticaria. There has been no recurrence during the year since the course of thirty-five injections. SECONDAEY ANEMIA A number of observers claim to have obtained satisfactory stimu- lation of the hematopoietic system following nonspecific injection. 214 PROTEIN THERAPY particularly milk, and have used it in the treatment of anemia. Thus Miiller describes its use in the treatment of secondary anemia. In pernicious anemia Grote obtained fair results with the injection of milk, one case increasing in blood count over 900,000 in a period of 8 days. As a rule he obtained little febrile reaction after the in- jections, contrary to the experiences of Schmidt in this class of cases. Miiller claims to have had favorable results in bringing about re- missions after milk injections (aolan) which increased the blood count and brought about an increased feeling of well being on the part of the patient. Hollaender as well as Fischer reports some success with coUargol injections. The effect is never a permanent one. HEMORRHAGIC DIATHESIS Dollken has devoted considerable attention to the effect of non- specific therapy on blood diseases. That serum injections of various kinds have been found useful, indeed have in many instances been our only resource in the hemorrhagic diseases is, of course, well known and the literature is readily accessible so that it will not be nec- essary to enter into a discussion of it at this time. (P. Emile Weil, Chalier, Kurtz, Lewisohn, Berghausen, Know, Peterson.) * Dollken assumes that the bleeding in purpura is largely due to two factors — an increased fragility of the blood vessels and the altera- tion in the blood coagulability whereby it does not clot while in con- tact with the tissues. Perhaps when once shed the blood may show some delay in coagulation, but Klinger and others have denied this. Dollken considers the alteration in the platelet count as a symptom rather than a causative factor because in cases that have been long cured he has observed that the diminution in the platelet count may persist. The leukocytosis of spontaneous fever, following vaccine injec- tion, and following the intravenous injection of deutero-albumose has practically no effect on the outcome or course of a purpura, the stimu- lation of the spleen and bone marrow that is involved seems insuffi- cient to alter the disease process. (See also the paper of Radovici and lagnov.) On the other hand, milk injections seem to have a particular effect on the blood vessels of smaller caliber and on the coagulation ♦The effects of the serum injection are possibly due to the alterations in the amount of fibrinogen and thrombokinase that follow nonspecific injections of various kinds. Moll observed this increase and von den Velden, and Lowy have confirmed it for gelatin, serum, peptones and parenterally injected proteins in general. Moderakowski and Orator also studied the effect on fibrinogen and confirmed the previous workers. Wohlgemut has in a very recent paper demon- strated that the increase in fibrinogen probably results from liver stimulation, but that the thrombokinase arises elsewhere. MISCELLANEOUS DISEASES 215 mechanism, the styptic effect being very apparent. Thrombokinase as well as fibrinogen are increased and the permeability of the capil- laries altered, small doses seeming to increase the permeability, larger ones to diminish it. Dollken therefore decided to use milk in cases of purpura and was surprised to observe the rapidity of the effect on the disease. He made injections of about 5 c.c. every three days, intramuscularly. There was little inconvenience; on the contrary, a marked euphoria was observed after the injections. In only one instance did a hema- toma appear at the site of the injection and this disappeared after 24 hours. Bleeding into the tissues stopped 5 hours after the injection, a most interesting feature being the observation that this clinical re- sult was manifest without effect on the number of the blood platelets in the circulation. The permeability of the vessels does not seem to be altered as rapidly as the effect on the coagulation mechanism, because small petechia were noted to appear until about 24 hours after the injection. The resorption of blood from the tissues commenced promptly after the alterations in coagulation had taken place. After from 7 to 8 hours small hemorrhages in the mucous membranes of the mouth could be observed to be decreasing in size; in another 8 to 10 hours the smaller ones had disappeared and the larger areas showed con- siderable retrogressive change. Large areas of bleeding showed a broad yellow band of discoloration from 1 to 2 c.c. wide around the margin in from 18 to 24 hours where regression had occurred, and the tension of the hematomas was lessened. Dollken details his experience in one severe case of purpura. The patient bled two hours from a small skin abrasion, and the bleeding recommenced on the slightest renewed trauma to the scab. The paraf- fined blood coagulated in 9 minutes. Deutero-albumose (.05 gm. in- travenously) merely increased the bleeding that had occurred from a small skin puncture from the ear for several days. The following day a puncture still bled for 14 hours; the paraffined blood coagulated in 14 minutes. During this time numerous fresh areas of hemorrhage had been observed over the body. The patient was then given 5 c.c. milk intramuscularly. In 5 hours all bleeding ceased. After 8 hours the petechise in the mucous membrane of the mouth were de- creasing in size. Bleeding from a new skin puncture in the ear lobe now ceased in 20 minutes and the paraffined blood coagulated in 8% minutes. Platelets were absent during the entire clinical change. Leukocytosis was moderate. All cases that had albuminuria before- hand showed clear, albumin-free urine after the injections. Bosanyi has found that intravenous injections of salt solution have given him results that are more satisfactory in purpura simplex, morbus Werlhofii and hemophilia than any other method that he had 216 PROTEIN THERAPY employed. He describes the result obtained in 7 cases, the first two of which received injections of 5 c.c. of 3% salt solution. Later he used larger doses (about 10 c.c. of a 5% solution) and with these the results were striking. The bleeding usually ceased after a few hours. Injections, given daily, were without reaction on the part of the patient. He is under the impression that the result on coagula- tion is due to the reversal of the exchange between the capillaries and tissues so that there is an actual imbibition of "tissue fluid" and coagulating accelerating substances from the tissues by the blood stream, based on the work of von den Velden. Vines would effect hemorrhagic conditions by means of anaphy- lactic shock effects or sensitization. Vines bases his method on the following considerations: The intradermal reaction is a modified form of anaphylactic shock of general as well as of local significance, in which the stimula- tion of the thrombogenetic functions of the somatic cells is a salient feature. The changes in coagulability of the blood in anaphylactic shock occur in two stages: a period of acceleration which occurs early, followed by a period of retardation; further, that the predomi- nance of the former or the latter depends on the lesser or greater severity of the shock. The intoxicating injection in a sensitized individual may act as a catalytic agent in inducing the intracellular reactions which constitute the anaphylactic phenomena. In cases of hemophilia. Vines says, the diu-ation of the effect of the intradermal reaction is dependent on the duration of the anaphylactic period. But the shorter or longer duration of this effect is also directly dependent on the greater or lesser severity of the hemophilic condition. He describes 3 cases so treated, all being sensitized to sheep serum and small doses of sheep serum injected interdermally after sensitiza- tion. In the first two cases the second injection caused an increase in the blood clotting rate of the individual, which was evidently quite permanent, in the third case the effect was less apparent. Confirm- ing Vines' observations, Rouchetti reports two severe cases of hemor- rhagic purpura which abruptly subsided when serum sickness, with urticaria, followed an injection by the vein of normal horse serum or of serum from the emulgent vein of goats. A similar method to stop bleeding after operation has been used by Neirotti and Viola. Neirotti and Viola report two cases of persisting hemorrhages after a minor operation, finally arrested by the anaphylactic shock from the subcutaneous injection of normal horse sermn, eighteen hours after a preliminary injection of 10 c.c. Voight treated several cases of scurvy with milk injections and noted a prompt styptic effect, as well as general improvement of the patients. MISCELLANEOUS DISEASES 217 NEPHRITIS The albuminuria that accompanies many acute febrile diseases is very promptly influenced by nonspecific injections, according to a number of observers. Treatment of a case of pyelonephritis has been reported by Gow, who in this instance made use of a colon-like organism for intra- venous injections. A chill was invariably produced in about 3 to 3% hours; there were nausea and headache and the temperature rise usually weL^t to 103° F. or 104° F. This organism was at first used in a dosage of 50; later 75 and 125 million were injected but the severity of the reaction diminished with successive injections. Thus when the dosage of 75 million was injected the reaction was only to 101.6° F. with some cutaneous hyperesthesia and yawning on the part of the patient. This case of pyelonephrosis made a complete recovery. In colon and staphylococcus pyelitis with concomitant bladder irritation Karo has reported very favorable results with injections of terpichin. Similarly in staphylococcus infections of the urinary tract and in the cholecystitis of children the results have been satisfactory. In cases of simple bacteriuria, however, no results were obtained. In the cystitis that accompanies enlarged prostate glands the injections were also found useful. NEURITIS Dollken has prepared an autolysate of staphylococci and bacillus prodigiosus which has been used rather extensively and is distributed commercially under the name of "vaccinurin." Dollken tried out a series of bacterial extracts, including tuberculin, and vaccines in neuritis and concluded that the combination above mentioned was followed by the best results. From his work he was led to the belief that in heterovaccination we do not deal wholly with a nonspecific plasmaactivation but that there existed a degree of selectivity in the effect of the different vaccines, that isi, they were more or less organo- tropic. In the first series of neuritic processes (51 cases) treated by him are included both trigeminal and intercostal neuralgia, sciatica, and a large number of neuritides of varying etiology — cold, professional, alcoholic, post-typhoidal, luetic, diphtheritic, pressure, facial and radial. He observes that the pressure neuralgias and the "SO-called rheumatic palsies were the ones most easily influenced. Holtzl reports the treatment of some 90 cases with vaccinurin. Of these 61 made complete recoveries and 28 were improved. The series included 25 cases of sciatica of whom 16 made prompt and com- plete recoveries. The injection was followed bya systemic effect and 218 PROTEIN THERAPY the maximum therapeutic effect was observed in about 6 hours after the injection. Cadbury has described the results obtained with typhoid vac- cines in a group of cases with neuritic pains due to a variety of causes. These included one carcinoma of the breast, in which there was temporary relief from pain; four gunshot injuries, all of which were cured; one fibroid phthisis which was relieved, 1 tic douloureux which was improved for 6 months, etc. Boyd also reports the successful treatment of neuritis with mod- erate doses of typhoid vaccine intravenously. Following nonspecific injections in neuritides a distinct focal re- action may become manifest. There may be a transient increase in the pain and other manifestations of the lesion that reaches its max- imum in from 4-8 hours, depending on the method used to elicit the reaction, followed by an analgesia which in some instances may be transient, in others permanent in character. Wishura using "vaccinurin" found that neither the focal nor the general reactions were very severe. In severe degenerative inflam- mation of nerve trunks as well as in the more common joint neuroses the injections were very successful. EAR AFFECTIONS Rauch reports the results of milk injections (5 c.c) in 41 cases of acute middle ear infections. According to his series the results were very favorable, only three of the cases requiring operative in- terference. Gomperz, on the other hand, obtained no satisfactory results and Hirsch, who used turpentine injections in cases of furuncu- losis and eczema of the meatus, as well as in acute and chronic sup- purative conditions of the ear, obtained entirely negative results. The first report on the subject was that of Alexander, who has described his results in ear diseases and sinus infections; later Lawner reported some cases of middle ear disease treated with milk injections with excellent results. MALIGNANT NEOPLASMS A number of procedures and "cures" for both carcinoma and sarcoma have been advocated during the course of more recent years which have had as the basis of their mechanism the alterations which we now recognize as due to nonspecific stimulation. I need but re- call the treatment of cancer with trypsin and amylopsin injections by Beard and the treatment of sarcoma by the injection of Coley's fluid, a bacterial autolysate; or the use of tumor autolysates or serum (Lewin) for purposes of immunization. These and all other methods that provoke a similar systemic response are followed by one of two reactions on the part of the patient. MISCELLANEOUS DISEASES 219 When the tumor is small, not necrotic or ulcerated, there may re- sult little or no temperature reaction or malaise following the in- jection and relatively little local effect. There may be a slight increase in pain at the focus and some evidence of an increased inflammatory reaction, but the size of the tumor will not alter materially. In- deed at times the rate of growth is increased. When we deal with a large tumor mass, with either central necrosis or ulceration, nonspecific injections are as a rule followed by a de- cided rise in the temperature and a feeling of malaise. The further course will be determined by the effect on the local pathology. There is usually a marked increase in the pain and evidence of inflammation, digestion takes place of the necrotic material and the tumor may be- come apparently smaller in size. The general condition of the pa- tient at this time will vary with the amount of the protein split products which are absorbed. If large in amount and but partially digested, the temperature will continue high for a period of several days; if small in amount, or if more completely digested at the focus before absorption, then the temperature reaction may fall within the limits of the provocative temperature of the nonspecific agent injected. In either case, in the period of recovery from the nonspecific re- action and from the reaction caused by the absorption of the auto- lytic tumor products, the balance swings to the reparative side and a general euphoria with increased appetite, lessened pain and ir- ritability, improved nutrition and feeling of strength may set in which will last for a variable period. If a diminution of the size of the tumor (because of the digestion of necrotic material) has oc- curred at the same time, the natural inference of curative effects are prone to further encourage both the patient and the physician. This clinical reaction has been the basis of practically all of the methods of therapy which have at various and sundry times been re- ported and it is quite possible that it takes a part in the reaction that follows after Roentgen and radium treatment, although by no means must it be held accountable for all the effect there achieved. We cannot avoid the conclusion that the nonspecific reaction has little or no effect on the rate of growth of the malignant tissue as long as it is well supplied with vascular connections. Once the tumor cells become necrotic or perhaps undergo some of the earlier de- generative changes, digestive stimulation such as that which follows nonspecific therapy has an apparent effect similar in character and range to that observed in other pathological conditions. On repeated injections the effect becomes less manifest and the reaction usually less severe, depending, of course, on the amount of necrosis present in the tumor. One finds that not only the commonly used nonspecific agents, but even iodin injections are followed by alterations in the tumor and a febrile reaction due to focal diges- tion. Moresowa has demonstrated this fact in a series of cases. 220 PROTEIN THERAPY The recent experimental work of Murphy and others dealing -with the lymphocyte as a factor in resistance to malignant infiltration is one that is not involved in the nonspecific reaction here described be- cause the lymphocytic reaction after such injections is negligible. MUller has, however, called attention to the fact that epithelial tis- sues — he observed new formed epithelial bridges covering granulation tissue — seemed particularly susceptible to the digestive changes in- duced by milk injections, etc. A different course of procedure has been adopted by Opitz and Friederich in trying to use the nonspecific reaction in conjunction with the Roentgen irradiation. While their result is merely experimental, it offers at least the possibility of development. In their studies on the treatment of carcinoma by means of Roentgen irradiation and radiiun they soon came to realize that the growth does not depend wholly on the inherent rate of the tumor cell growth but on the resistance of the tissues that were the seat of the malignant invasion. This varies not only with individuals but under certain physiological conditions as well. v. Groff, as well as Slye, have, for instance, called attention to the depression of the rate of tumor growth in mice during pregnancy, and while Slye seems to con- sider the increased metabolic demands of the maternal and fetal organisms responsible for this inhibition on the rate of tumor growth, other factors possibly enter into the mechanism. A similar depression in the rate of growth may be observed at times during the course of infectious diseases, after serum injections and other related procedures where we find an increase in the anti- ferment of the serum and a resulting tendency for the protection of connective tissue and a depression of the protein metabolism that fol- lows after all these nonspecific alterations. Of course, during the acute shock effects — either in infectious diseases or after nonspecific injec- tions, or after parturition — ^when proteolytic enzymes are mobilized, marked digestive phenomena may be observed at the site of the malignant invasions but this usually concerns the digestion of tissue already necrotic, or of connective tissue hyperplasias. Bergel has reported observations concerning the acceleration growth of bony tissue after nonspecific injections and Hoke, Doberauer and Pittroff saw a similar effect on connective tissue. Opitz and Fried- erich proceeded to make use of this principle in their work with Roentgen rays. Assuming that after irradiation the connective tissue cells were to a degree fatigued, by nonspecific injections these cells might be stimulated and the fatigue so overcome. On this basis these rejuvenated cells would then react like young cells and an atreptic im- munity would be established; the carcinoma cells would die of inani- tion, would be "strangulated" and become necrotic. While their results are not extended enough to warrant any con- clusions they state that they were encouraging. Warnekros is said MISCELLANEOUS DISEASES 221 to have combined serum injections with Roentgen rays in a similar manner of treatment. PEDIATRICS Slawik has reported on the treatment of infants with nonspecific therapy, using human milk injected intramuscularly in doses from 1 to 5 CO. usually in two-day intervals. In most cases the milk was first boiled; in a few cases he used the raw milk without encounter- ing any ill effects. Slawik found that the reaction obtained was independent of the age of the child, but was influenced by the state of nutrition, that is, the vitality of the patient, by the feeding, and to some extent by the particular disease process from which the child was suffering. There were no ill effects from the injections and when for purposes of comparison healthy infants were treated with injections of similar amounts there was no alteration in the weight curve. With repeated injections the reactions became less intense and Slawik calls atten- tion to the well-known fact that humans are normally relatively re- sistant to anaphylactic sensitization so that the danger from this source sliould not be overestimated. Among the 26 cases treated by him were the following: 3 ophthalmoblennorrhea. These were followed by a decided focal reaction; one improved at once, the others after repeated injections. 3 erysipelas. 1 improved at once, one after three weeks, the other case became chronic and later developed meningitis. 4 of multiple abscesses. These were healed in from 7 to 10 days. 1 phlegmon in a marantic child. The general condition improved after the injections and, despite the continued cachexia, the phlegmon healed. 2 marantic infants. One of these with thrush; this infant became more agile, drank better and recovered. The other was not altered. 3 with chronic exudative diathesis; they were not altered. 6 severe dysenteries, of whom 4 died. After the injections a very high agglutinin titer was observed in all the cases. In a later series Slawik injected infants parenterally with white of egg, breast milk or other substances in treatment of various pathologic conditions. The results were disappointing, probably on account of the inadequate development of the defensive forces at this age. Actual benefit was realized only with pyodermatitis and gonococcus infection. Langer has studied particularly the furunculosis of infants. He noted that after the injection of various vaccines, no matter what the clinical result, there was little or no antibody response. As a result he decided that the clinical benefit could not be a specific one 222 PROTEIN THERAPY and that he might just as well discard the old idea of a negative phase and the interval dosage as formerly used. He therefore gave large doses (500 to 1,000 million) of staphylococcus vaccine (opsonogen) intramuscularly. Injections were made daily, usually two or three injections sufficing to bring the disease process to a standstill and the recovery of the patient usually followed in a short time. When- ever phlegmons existed they were of course opened and drained. The vulvovaginitis of infants and children does not yield to non- specific therapy (collargol — Vollbrandt) . Normal horse serum has been used successfully as a stimulant in poorly developed infants by Ferreira. It seems to whip up the slug- gish metabolism and nutrition in general so that the child afterward progresses more or less normally. He injected it in three cases here described. One of the infants weighed only 3,750 gm. at the tenth month when the serotherapy was started, and the benefit was so unmistakable that it was kept up for sixteen months, the child having thus been given 2,386 gm. of the serum, and its weight showing a regular increase. He began with 2.5 c.c. but soon reached the dose of 20 c.c, repeated two or three times a week. A 3 months' babe im- proved so rapidly after the serotherapy was begun that the latter could soon be dropped, the improvement continuing thereafter. None of the three infants was entirely breast fed. Rinz has reported similar cases. Czemy and Eliasberg have used this effect of nonspecific therapy to stimulate the general condition of children ill with tuberculosis. In 26 cases so treated (daily injections of normal horse serum in doses up to 2 c.c.) 9 died; in 12 there was remarkable improvement despite the fact that some of the cases were tuberculosis of the peri- toneum and of the lungs. Valagussa has made a careful study of protein therapy in acute diseases in children and in his report reproduces the temperature curves of the various groups treated with different proteins. In 51 children from 14 months to 12 years old, all with typhoid fever, the intramuscular injection of peptone according to Nolf had a very fa- vorable influence on the course of the disease in the majority. In 31 cases of influenza in children, he injected various serums and anti- serums, and when this serotherapy was early, intense and continued, the results were excellent. There were only 3 deaths in this group of 31 severe cases of influenza. His experimental research on the au- tolysates of beer yeast in colloidal suspension confirmed their efficacy in increasing opsonins, etc., and this was sustained in 33 cases of pneu- monia or typhoid while no effect was apparent in 3 cases of whoop- ing cough. The three types of antigens represented by peptone, horse serum and organized ferments behave alike; the only difference is in the in- tensity of the phenomena induced. The yeast autolysates are the MISCELLANEOUS DISEASES 223 weakest, and slowest in their action, but all serve to reenforce the organism in its fight against the infection. There are no symptoms of anaphylaxis with the yeast, aside from the local reaction, and the effect on the temperature, and he commends this as a harmless means to activate and augment the kataphylactic powers of the organism in any and every bacterial infection. "With this extract of the cells of the saccharomyces we provide a poly-antigen therapy, and we can- not go amiss in treating a disease by augmenting the natural index of resistance and the defensive forces." The largest series of infants has been treated by Plantenga (300 cases). These included various marantic infants, usually with ali- mentary intoxication. He injected as a rule some 30 c.c of an "anti- colon" serum obtained by immunizing animals against colon bacilli. The results were quite remarkable. More recently Putzig has also described a number of cases. He found that serum injections (he used diphtheria antitoxin) in ma- rantic children caused an increase in weight and an improvement in the general condition and that this improvement was not a temporary affair (due to water retention, etc.), but was due to a stimulation of the body tissues and an actual growth of tissues. Of 7 cases 5 were appreciably improved. CHAPTER XIV TREATMENT OF GENERAL PARALYSIS, TABES, ETC. While the etiological significance of the Spirocheta pallida in its relation to tabes and general paralysis has been firmly established, the therapy of these diseases has never been very satisfactory, despite the development of our more intensive methods of mercurial treatment and the intravenous and intraspinal application of salvarsan. The damage once done the central nervous system is ir- reparable and the problem of therapy resolves itself largely in pre- venting progress of the disease rather than with the thought of re- covery. Even this modest result is seldom achieved. Remissions are of course known to occur spontaneously during the course of the disease and this fact is more often than not apt to bias the observer working with some new preparation and he ascribes therapeutic ef- fects to the procedure which are not actually due to the remedy. GENERAL PARALYSIS There seems little doubt of the clinical observation that has been made by numerous observers and for many years that intercurrent infections (malaria, typhoid, suppurative processes, etc.) are not uncommonly followed by an arrest of the disease process and even apparent improvement in the general condition of the patient suffer- ing from progressive paralysis (v. Halban, Marro and Ruata, etc.). Very early efforts to make use of this knowledge were reported. Jacobi in 1854 reported on the use of artificial abscesses in the treat- ment of general paralysis and Meyer in 1877 again took up the method. Some rather illuminating statistics have been compiled by Mat- tauschek and Pilcz in this connection. They found that in 4,134 cases of syphilis 4.7% developed general paralysis. In a group of 157 of the luetic cases there was a history of an intercurrent infection such as erysipelas, pneumonia, etc.; not a single case of general paralysis developed among these. While by no means free from criticism, they nevertheless confirm to some extent the clinical observations just alluded to. It was on this basis that v. Jauregg began the use of tuberculin in the treatment of general paralysis; tuberculin being selected as a pyrogenic agent because of its availability and the certainty of the febrile reaction, v. Jauregg had first tried a pyocyaneus vaccine in 224 TREATMENT OF GENERAL PARALYSIS, TABES, ETC. 225 a series of acute psychoses with results that encouraged him to ex- tend his experiments to other forms of mental disease. His associate, Boeck, has published the results of the treatment of cases of general paralysis in v. Jauregg's clinic. Pilcz continued the method. He gave old tuberculin in 10% solution, starting the treatment with 0.01 gm., and continuing up to 0.5 gm. Injections were made every two days. The patients re- acted with a temperature up to about 101° F. and there was an as- sociated headache and lassitude. Pilcz noted that at times there was an increase in the psychic disturbance at the time of the reaction, but this usually rapidly disappeared. In contrasting a series of 66 treated cases with 66 not treated the mortality was 20 and 39 respectively during the first year under observation. At the end of a four-year period of observation 8 of the treated group were still living, 5 of the untreated. In 1911 Pilcz published a further series of 86 cases, which were given a combined treatment of potassium iodid and tuberculin. Of these 40% did not respond to treatment; 23% were arrested, but not otherwise improved; 10% became fit to be returned to normal life; and 26% were restored to almost normal condition. In 1912 a further report was made. At this time 26 were still living, 12 of them occupationally fit, the periods of remission in 3 cases having lasted for from 4 to 5 years, in 15 cases over 1 year. These observers used tuberculin because it was convenient to ob- tain and sure in its effect. They observed that patients who seemed hypersensitive to tuberculin and reacted violently were those who derived the greatest therapeutic benefit from the method. Hudovernig, Battistessa, Dollken, Jukow and Joachim confirmed these findings. The basic theory of v. Jauregg was that the therapeutic effect in paresis was due to the increased temperature. The work of Jahnel and Weichbrodt — ^who found that in luetic rabbits subjected several times to temperatures of from 42° to 43° C. living spirocheta pallida could no longer be found (other spirochetes were not so susceptible to high temperatures)— is of particular interest in this connection. Donath had previously used salt injections, and now, with other neurologists, began the treatment of general paralysis with leuko- cytic stimulants, considering the leukocytosis thereby obtained as the important factor of benefit to the patient. Horbaczewski having called attention in the early nineties that nucleic acid (as well as pilocarpin and cinnamic acid) acted as powerful leukocytic stimu- lants, nucleins were applied by Fisher and by Donath in the treat- ment of general paralysis. Fisher's first series contained 22 cases so treated and 22 untreated 226 PROTEIN THERAPY cases as controls. The treatment consisted of injections of one-half gram nuclein in 10% solution. The average duration of life of the treated cases was 15 months, of the untreated 7 months. Later he treated a further series, this time with larger doses — from % to 3 gm. in 10% solution every 3 to 5 days. Of these ten were treated, ten tmtreated. The treated cases gave 5 remissions (three becoming progressively active again). In the ten control cases there was but one remission, that following a long continued septic condition. Donath treated 21 cases with injections every 5 or 7 days, each injection resulting in a febrile reaction that lasted for one or two days. On an average 8 injections were given the patients; the leu- kocytic reaction was quite marked, up to 61,000 in one case. Of these cases 70% showed definite evidence of improvement — in 47%' the improvement was so great that they became self-supporting. He noted that the tremor decreased, excitement diminished, there was an improvement in memory and in mental agility. The longest period of remission initiated by the therapy was 3 years. In a second series of 15, 9 showed definite improvement, of whom 3 were able to again become self-supporting. Hauber gave a combined antiluetic and nonspecific treatment to 36 patients. Of these 13 improved, but 23 showed no evidence of therapeutic effect. Szedlak treated 25 patients simply with the nucleic acid and an equal number with nucleic acid and mercury with the following re- sults: Nuc. alone. Nuc. and Hg. Marked improvement 8% 40%' Slight improvement 24% 24% No improvement 31% 16% Interrupted treatment 4% 4% Died 33% 16% In a more recent papdi V. Jauregg reported the treatment of 33 cases with staphylococcus vaccine in lieu of tuberculin formerly used. In this series 61% improved, 10 of the patients being restored to almost normal health, v. Economo reported similar results. Schacherl treated 38 cases of general paralysis (ambulatory) with a combined course of tuberculin and mercury. Of these 13 continued the course to completion. Seven of these were much improved, 5 of them were again enabled to earn their living. One developed a phlegmon after a severe eczema; this patient became lucid and was permanently cured. Of course these favorable results have not been allowed to stand unchallenged. Hiissels, Lepine, Jolowicz, Plange and Hoppe failed to find any therapeutic benefit from the use of tuberculin or the nucleins when injected. Lowenstein and Kleinberger have indeed claimed that the injections have done actual harm. Bouman, who used tuberculin, TREATMENT OF GENERAL PARALYSIS, TABES, ETC. 227 nucleinate and salvarsan, got very little results with any of them, the effect obtained being at the most transient. Brown and Ross have discussed this treatment of mental dis- eases by the production of leukocytosis, treating 9 cases by means of nuclein injections. There was not much mental improvement despite the fact that a leukocytosis of from 17,000 to 20,000 was obtained in many cases. Bruce has reported on the use of turpentine and sodium cinnamate, and collargol has also been tried by Vergueira in a dose of from 5 to 10 c.c. of a 1% solution. Friedlander has used intravenous typhoid injections; Plant tried out the effect of injections of streptococcus and of staphylococcus vac- cines without apparent results; the leukocytic response was of low grade. Recently v. Jauregg has even suggested the infection of the patient with malaria plasmodia to keep up a febrile reaction at definite intervals. Weichbrodt and Jahnel report on a number of cases so treated and Miihlens, Weygandt, and Kirschbaum have recently reported on a series of 33 cases treated by infecting the patients with the spirillum of Obermeier and malaria plasmodia. Of their series 12 were of such recent date that the end result could not be properly judged. Of the remaining 21, 4 cases died (not directly from the infection) , while 12 were markedly improved, with remissions persist- ing for a considerable time. The papers by Steiner and Pagniez are also of interest in the same connection. A review of the entire sub- ject will be found in articles by Enge and by Raecke. We are perhaps justified in assuming that the work of the Vienna school in this particular field may offer some advance in our methods of therapy which, at best, are none too satisfactory. That intercur- rent infections affect the degenerative process or at least the rate of destruction is very likely from what we know of their effect on other pathological conditions, and there is no reason why the various nonspecific procedures suggested may not at times be followed by some clinical improvement. It seems possible that in a combined ergotropic and etiotropic method some dependable results may yet be achieved. TABES Dollken has treated some cases of tabes, but a larger series has been reported by Schacherl. Schacherl used a combined specific and nonspecific method of therapy, beginning with 0.001 gr. of tuberculin and then giving 0.1 gm. of salicylate of mercury with each third dose of tuberculin. He observed that early in the course of treatment, i.e., when the patient had considerable reaction from the tuberculin, the effect of the mercury was also much more in evidence, salivation being noted much more frequently. With this method of treatment the results in 76 cases, with one 228 PROTEIN THERAPY exception, were very good. At times an initial intensification of the disease symptoms was observed with the beginning of the treatment, but later this subsided. While the ataxia was not much altered, an increase in the rapidity of transmission of sensory stimuli was ap- parent in all cases and the ability of the patient to work was greatly enhanced. An analysis of the results of treatment of the 76 cases follows: 53 were of the ataxic type — 36 were much improved, 17 were slightly improved in walking. 46 suffered from lancinating pains — 38 of these were cured, 5 were improved. 24 gastric crises — of these 23 were cured. 25 had bladder symptoms— 12 were cured, 11 improved. Miller is said to have observed that the lancinating pain disap- peared after milk injections (Boas). Wodak treated a number of tabetics with tuberculin and found that the patellar reflex was re- stored in several of his patients after the treatment. Friedlander is said to have obtained a similar result. It is to be remembered in this connection that while we may at times improve the symptoms existing in the tabetic, at other times a nonspecific injection may precipitate a gastric crisis or lancinating pains. Schmidt indeed calls attention to this possibility as a mani- festation of the focal activation so frequently observed following non- specific injections. Itten tried nonspecific therapy in the treatment of dementia prcBCOX, treating a series of 9 cases with injections of a 2% solution of nuclein (giving from 0.5 to 1.4 gm.). The cases were not improved. Dollken has treated 21 cases of whom 16 temporarily improved following in- jections of pyocyaneus and dysentery vaccines. EPILEPSY A bumber of procedures, essentially nonspecific in character, have been tried in the treatment of epilepsy, beginning with the use of serum injections by Ceni in 1903, brain extract by Lion in 1911, cerebrospinal fluid by Gordon in 1914 and immune rabbit serum by Held. Turner treated 23 cases with colloidal platinum injections and noted a diminution in the nimiber and intensity of the attacks. More recently two interesting reports have been published by Dollken and by Edgeworth. Dollken used a combined milk and luminal therapy; to the milk injections he added a small amount of vaccine (nonvirulent organisms) and injections were usually given twice a week; after therapeutic improvement took place the number of injections were decreased. TREATMENT OF GENERAL PARALYSIS, TABES, ETC. 229 Twelve cases were free from attacks for a period of 18 months, 60 for one year. As a rule from 4 to 6 months were required for treatment. In 13 cases the result was not a complete cure, but merely an improve- ment. Edgeworth's series was smaller and the course of treatment shorter. In the series of twenty-three cases a 5 per cent, solution of pep- tone was used, made up according to the prescription of Auld. It was injected. If a fortnight went by without the occurrence of an at- was 5 minims. In succeeding weeks 7, 10, 15 and 20 minims were given unless toxic symptoms occurred. No dose greater than 20 minims was injected. If a fortnight went by without the occurrence of an at- tack, the dose was not further increased. If no results were obtained after three doses of 20 minims the treatment was given up. In four cases toxic symptoms were observed, rigor, vomiting, temporary pyrexia, either as an isolated phenomenon, or in any combination. If this happened, the next dose was lessened. In such cases it was found that the dose could be increased later to the old figure or even beyond without the occurrence of any untoward symptoms. In three cases of posthemiplegic epilepsy no improvement occurred. In eleven cases of epilepsy without signs of any gross cerebral lesion no permanent arrest was produced. In four of these the fits ceased but subsequently recurred, though in lessened severity, and in two cases the frequency was lessened. The average age of the patients was 18 years, the average duration of the disease ten years, and the average frequency of attacksionce a^week. In nine cases of epilepsy without physical signs of any gross cerebral lesion the attacks ceased. This arrest has now lasted more than a month in all cases, and in, some as long as three months. Five of the patients were mentally defective^n one of these cases no mental improvement occurred, in three some improvement, and in one considerable improvement was noted. The average number of injections given was five and one-half. Geyelin has recently reported that fasting may at times be followed by the cure of epilepsy. Whether the therapeutic effect is dependent on the acidosis involved in the method, and thereby related to other nonspecific shock effects, has not been established. CHAPTER XV SKIN DISEASES "To treat skin disease wholly from without," Ravaut has recently- declared, "is as irrational as treating the skin lesions of syphilis by local applications alone. And yet the dermatologist is too apt to focus his attention exclusively on the local process. He must be a biologist, not a mere botanist." While Ravaut's statement is rather broad, there is nevertheless much value in the emphasis that he places on the fact that the dermatologist, as the result of more recent work in the general pathology and physiology of the skin, must not be satisfied with a purely local conception of the pathology or the therapy of the particular disease that may be imder consideration. Not only must we consider the fact that general systemic re- actions can profoundly alter the reactivity of the skin — both en- hancing or retarding inflammatory processes — but we must take cog- nizance of the fact that the integument seems to respond to bacterial invasion or protein injection, perhaps even to other chemical or physi- cal agents with an allergy, an alteration in reactivity which is the more remarkable in that it seems to be a definitely localized phe- nomenon, an acquired property of the individual cell. This allergy, once established, may be transplanted if the cell is transplanted, but the general organism need take no part in the alteration whatso- ever. Equally interesting is the effect of the stimulation of skin metab- olism and the effect on systemic diseases, as Heims has indicated and as Bloch and Hoffman have discussed at greater length. These have, however, been discussed in another chapter. During the past two decades a considerable munber of observa- tions concerning the effects of systemic alterations on skin diseases have been gathered, but even previously one finds isolated records that are of particular interest. One needs but recall the observation that a variety of drugs — ^thyophen, benzol, acetone, taurin and amines (Spiegler), atoxyl (Moro and Stheeman), cantharidic acids and salts (Liebreich) — would, when injected, cause a reaction at a lupus focus; that dietary faults aggravate an eczema; that intercurrent infections would favorably influence a preexisting skin lesion (Restrepo has but recently reported such a case) or that yeast therapy might influence a furunculosis. Skin diseases have afforded particularly favorable material for 230 SKIN DISEASES 231 treatment by vaccines, and the treatment of acne and of furunculosia became more or less the special field of the vaccinotherapist. Sero- logical procedures, too, such as that of autoserotherapy in psoriasis, have had their advocates. The fact that the results could be judged quite objectively has made this field one of interest and value. Linser in working with the dermatoses of pregnancy found that the injection of serum (normal) was at times followed by marked improvement and the application was extended to urticaria, purpuras, strophulus, pruritus and related conditions where vascular altera- tions might be surmised as the basis of the pathology. Zieler, Bingel, Henck, Lowenberg and others have reported results that were con- firmatory. Later psoriasis came to be selected for treatment of this kind and a number of American observers have reported their ob- servations with this method of therapy. (Lit. by Luithlen.) Quite a number of nonspecific procedures have been applied in the therapeutics of skin diseases in recent years. The use of au- togenous serum injections in psoriasis was occasionally followed by a degree of improvement, although the method was too cumbersome to come into popular use. Perry, however, substituted normal horse serum for autogenous serum with satisfactory results. From 6 to 9 injections were necessary to produce therapeutic effects. Milk injections were used shortly after their introduction by Schmidt and others. That tuberculin would cause the secondary lesions of syphilis to undergo involution was reported by Blach, while Scholz has discussed the fact that tuberculosis of the skin reacts to injections of trichophytin as well as to a variety of other substances. Engmann and McGarry began the use of typhoid vaccine in the treatment of a variety of skin diseases, among them a few syphilids, exfoliative dermatitis, lupus erythematosis and psoriasis. Engmann and McGarry made use of typhoid vaccine in dosage of from 75 to 500 million. Scully in 1917 reported on the treatment of several cases of psoriasis with injections of typhoid vaccine, 8 cases being treated with injections varying from 75 to 100 million organisms. The results were not very satisfactory; Scully noted that the effect of the injections on the temperature and leukocyte curve was not as marked in these skin cases as it had been in the cases of arthritis treated by him. Rezehde's reports show the prompt and radical cure of extensive psoriasis under "protein shock" treatment. It was in the form of 20 c.c. of normal horse serum, injected into the abdominal wall. An injection of 10 c.c. two days before had not induced an appreciable reaction, but the 20 c.c. caused fever for five days, reaching 39.6° C. (103.5° F.) the third day. By the eighth or tenth day the eruption had practically subsided. These observers used rather severe reactions; it is possible that more satisfactory results would be obtained when, with smaller doses, 232 PROTEIN THERAPY less severe reactions could be used over a longer period of time, as suggested by Van Alstyne. More recently Klingmueller has reintroduced the injection of turpentine as a method of treatment of skin diseases. Turpentine has, as it will be recalled in connection with the work of the "Fixa- tion abscess," been used before in therapy as a subcutaneous injec- tion. Khngmueller, however, has modified the procedure so that quite minute amounts are injected over a long period of time. By this method 20% tmpentine is dissolved in olive oil and injections of about 4 drops (0.01 turpentine) are made at 3-day intervals. Karc and others have improved the method by adding a minute amount of eukupin or novocain to the oil mixture in order to prevent any discomfort to the patient. Klingmueller found that the injections were followed by favorable effects not only in trichophyton infections, but in acne, acute derma- titis, eczema, salvarsan dermatitis and strophulus as well. In lupus vulgaris and in tuberculous glands he observed typical focal reactions. There was no evidence of kidney irritation following the injections. A number of observers have worked with this method. Thus Holzhauser and Werner reported excellent results in the treatment of leg ulcers and impetiginous skin conditions. Appel, too, has tried it in a series of cases. In all the staphylococcic infections (fuiuncu- losis, acne-like eruptions and pyodermia, in moist eczema, in pruritus universalis, — both essential and symptomatic — and in urticaria) Appel reports quite remarkable improvement in most cases. Lupus reacted to the injections just as it does to tuberculin. In the deeper nodules of trichophyton infection a gradual lessening of the infiltration and size of the foci was noted. Gewalt reports the treatment of pemphigus by the same method. Lowenfeld and Paulay have made a very careful study of tri- chophyton infection, treating cases with three different methods, one series on a strictly specific basis with trichon, an autolytic product* of the infecting organism; one series with a nonspecific protein — tuber- culin; the other with a nonspecific chemical agent — turpentine, recog- nizing, of course, that when injecting the turpentine it represented a form of protein therapy, in this case homologous protein from the inflanmiatory focus produced by the turpentine. There was little or no difference in the therapeutic end result whether the specific or nonspecific methods were used. The deeper nodular infiltrations were gradually absorbed under the course of the injections, the more super- ficial lesions showed less improvement. Lowenfeld and Paulay sug- gest that this result is to be expected in that the more superficial lesions, like those of favus, microsporia, pityriasis versicolor, ery- thrasma, etc., are much less susceptible to the general metabolic change that is brought about either by specific or nonspecific therapy. Fischl treated 50 cases of trichophyton infection with turpentine SKIN DISEASES 233 injections and resorcin, using resorcin as a local application and giving turpentine injections every two days. He commenced with a dose of 0.25 c.c. of the 20% turpentine in olive oil, advanced to 0.5 c.c, then followed to 0.75 and 1 c.c. doses during the course of the treat- ment. He found the treatment of great value in the deep indura- tive forms; in these, injections of trichophytin were also found use- ful. The cases were cured as a rule in about 3 weeks; the fungus dis- appeared from the lesions generally during the course of the first week. In four cases (of 30) there was some temperature reaction after the injections, one of these cases reaching 39.6° C, but Fischl does not consider the clinical effect in any way depending on the degree of temperature rise. Miiller used turpentine diluted with paraffin oil in the treatment of trichophyton infections with satisfactory results. He used no local treatment. There was no evidence of kidney irritation following the injections. Grabisch began the use of turpentine injections in the same condition and gradually extended his use of the injections to acute eczema, dermatitis, drug eruptions, gonorrheal complications, urticaria, strophulus, erythema multiforme, dermatitis herpetiformis, furunculosis, pyodermia, etc. Ruete, on the other hand, found that turpentine injections were not followed by particularly favorable results in trichophyton infection although he obtained very satisfactory results in furunculosis. Schmidt (H. E.) reached the same conclusion. Using Klingmueller's method he treated 8 superficial cases and 6 with deep seated lesions; In the latter cases the results were far better than in the superficial ones, but even these were not cured. In 5 cases of furunculosis his results were very satisfactory. Schedler's results were more satis- factory. Sachs recommends intravenous injections of hexamethylenamin (40% sol.) in the treatment of deep trichophyton infection, with large nodules. As a first dose 6 gm. (15 cm. of fluid) are injected; on the second or third day after the first injection the dose is increased to 8 gm. In one case 8 gm. were given as a first dose, which was in- creased to 12 and 14 gm. The number of injections required and the exact quantities of hexamethylenamin that will be needed cannot be definitely stated in advance. Of ten patients so treated, one was cured after a single injection of 4 gm., another after three injections of 4, 6 and 8 gm., respectively, in ten days; another patient received four injections (once 6 gm. and three times 8 gm.), and was cured in fourteen days. Singermann found turpentine injections (10%) useful in furun- culosis and in eczema, and Becker reports success in the treatment of various dermatoses. Reese used milk injections (aolan) in 175 cases of trichophyton infection. He foimd that the cases were as a rule cured in about three 234 PROTEIN THERAPY weeks, the number of injections averaging about 3. Scholz and Kraus and Miiller also report favorable results from milk and aolan injec- tions. Loeb used "leukogen," a staphylococcus vaccine of which large doses are injected, with success. Antoni found "aolan" satisfactory in trichophyton infection. Sellei, in comparing the value of milk and turpentine injections, found that the milk effect was more sustained and continuous. He obtained very satisfactory results in universal pruritus, and in superficial skin suppurations; in the deeper lesions the effect was less apparent. In eczema he obtained no results. The work of Engmann and McGarry, of Scully and of Van Alstyne in the treatment of psoriasis has already been mentioned. Cemach has used tuberculomucin in one case with favorable results, while Konte- schweller calls attention to the fact that all colloidal injections, just as vaccines and heterovaccines, act on the general system of the patient and improve his physical condition and in so far are useful in the treatment of psoriasis. It is just this fact that Sabouraud emphasizes. He considers that the treatment of psoriasis has entered on a new era of late with the discovery that certain measures which have nothing in common, except that they all give a kind of shake-up to the organism, are proving effectual in certain cases, although not in all. The list includes injection of mercurial salts, of antitoxic serums, and of emulsions of killed microbes from the patient's stools. He hopes that still more effecutal means of induc- ing the shake-up or shock may yet be found. The field of experi- mentation seems immense and almost unlimited. Sabouraud finds Danysz' enterovaccine from the stools to be harmless, and great improvement imder it seems to occur in more cases and to last longer than with any other measures yet known. In five cases that Cadbury treated with typhoid vaccine excellent temporary results were obtained but they all relapsed sooner or later. Just as furunculosis has been very satisfactorily treated with vac- cines of all kinds, so other and less specific methods of treatment have been followed by considerable clinical success. Kaiser claims results following the injection of "tebelon" (the isobutyl ester of oleic acid), Schedler used turpentine injections, Morris and Levinson col- loidal metals, and milk injections have also found extensive employ- ment. The eczemas, both the dry and exudative types, have been more or less resistant to nonspecific therapy. Spurgin tried salt infusion without apparent effects, while Cadbury treated 4 cases with typhoid vaccine and observed practically no improvement. A number of other skin lesions have given more promise of suc- cess. Schrameck reports a case of pemphigus treated successfully; Cadbury treated two cases of lichen planus with typhoid vaccine which improved and one case of erythema nodosum which was cured after two injections. Hebermann was successful in the treatment of hys- SKIN DISEASES 235 teric dermatoses. In lichen rubra Spitzer found that he obtained successful therapeutic effects with salvarsan injections provided that a typical Herxheimer reaction followed the injection, i.e., the salvarsan acted as a nonspecific agent in bringing about plasmaactivation. Ziembowski is so far the only one who has reported cases of actinomycosis treated with nonspecific injections. He used milk in three cases with excellent results. Kingsbury and Bechet have but recently called attention to the favorable influence of blood-letting on certain dermatoses. Veni- puncture, according to the researches of Luithlen, represents a non- specific method closely allied to the other and more mild methods of treatment which have their chief effect in alterations in the permeabil- ity of the capillaries. Achard and Flandin make use of the same phenomenon. They state that in conditions in which the factor of anaphylaxis is evident, the serum acquires what they call cryptotoxic properties, and can be utilized to desensitize. They give it in minute doses below the level of those inducing shock or even the hemoclastic crisis, injecting subcutaneously 0.5 c.c. of the autoserum; twelve hours later, 1 c.c. and the next day 1 or 2 c.c; 2 c.c. the following day, and then every second or third day. Recurring urticaria, angioneuro- tic edema and hay-fever yielded promptly to this treatment, but lit- tle effect was apparent in asthma. Their experience with hay-fever has been limited, but one case cured in 1918 had only very slight symptoms the following year. The effect of this treatment is not like that of ordinary serotherapy but seems to be an actual desensi- tization. CHAPTER XVI DISEASES OF THE EYE Isolated instances of successful vaccinotherapy when large doses of organisms were employed in certain cases of eye diseases have been reported during the past ten years or more, as for instance by Grey, Gorbunow, Bryan and by Allen. Romer treated hypopyon keratitis with large doses of vaccine and also used autoserotherapy with some success, using the patients' serum drawn from a blister. A large number of other observers, Darier, W. Zimmermann, Fromaget among them, successfully used diphtheria antitoxin injections, v. Szily used huge doses of gonococcus vaccine (arthogon) in the abortive treatment of ophthalmoblennorrhea with surprisingly good results, but it was not until the report of Miiller and Thanner was published that much attention was given to therapy of this nature. In fact, the use of nonspecific therapy in the treatment of eye diseases may be stated to date from their observations. Miiller and Thanner injected 5 c.c. of milk intramuscularly in 4 cases of parenchymatous keratitis, all of whom improved, as did likewise 11 cases of iritis. It was noted that when the iritis was due to gonococcus infection the improvement was not as prompt as in those of rheumatic origin or iritides of imdetermined etiology. In these the pain and photophobia disappeared in 24 hours. In nine cases of corneal opacity (without choroiditis) little improvement was ob- served, nor did they see any effect on choroiditis. Friedlander began the treatment of trachoma, using a somewhat larger dosage (10 c.c. of milk intramuscularly injected). In 42 cases so treated the results were reported to be excellent. Injections were given every 4 days. Hiihn had noted previously that trachoma cases under his care in a hospital for children improved remarkably during the course of a scarlet fever epidemic and then tried out the use of milk injections, too, in order to simulate the clinical picture of the spontaneous disease. He reports that with the milk he obtained excellent results. Rosen- stein treated trachoma with milk injections with satisfactory results; Konigstein, in a discussion at the Gesellschaft fiir Aerzte at Vienna, stated that in some thirty cases he had witnessed both increased ir- ritation and also improvement in his cases. Blatt does not believe that the method is useful. Pflugk, also using milk, obtained good results in iritis, in keratitis parenchymatosa and in adult blennorrhea. 236 DISEASES OF THE EYE 237 Heinemann and Wilke report excellent results with milk injections in adult blennorrhea and severe eye infections. Three rather extensive reports have recently been published, those of Possek, of Berneaud and of Jendralski. Possek (as well as Haab) used a typhoid vaccine, killed with phenol and made up with approxi- mately 500 million organisms to the cubic centimeter. Of this he injected from 0.6 to 1 c.c. subcutaneously the first day and 1 c.c. the second day. Following these injections there was usually a tempera- ture reaction of mild degree. This vaccine therapy was applied to a series of eye conditions of undoubted luetic origin, 52 of which were of long standing, 32 of which were recent. Of the old cases 16 were congenital lues, the balance acquired. These cases had had mercury and salvarsan treat- ment for a long time before they were treated with vaccine, but with- out apparent benefit. Possek selected the cases that had not re- sponded to the specific therapy for his experiments with vaccines. In a few cases where no luetic basis was at first suspected and non- specific treatment given without previous specific therapy, excellent results were obtained, although later the luetic nature of the trouble was established serologically. Among these cases, 4 of hereditary keratitis were markedly benefited, the inflammation of the iris re- ceded and the cornea cleared up. In several cases of retinal hemor- rhage the hemorrhage was resorbed, and in cases of turbidity of the lens, a definite clearing was observed. Good results were obtained, too, with optic neuritis. A large series of cases (500) have been reported by Berneaud. Berneaud gave over 2,000 injections of milk to these patients and his results are of considerable interest. He obtained little or no result in the treatment of glaucoma, amotio retinee, lacrymal duct inflam- mation, neuritis, neuroretinitis, multiple sclerosis, in keratitis paren- chymatosa or ophthalmoblennorrhea. On the other hand, in keratitis eczematosa and scrofulosa, and in secondary glaucoma following iritis marked improvement was noted. In 70 cases of iritis 60 were cured or markedly improved after the injection. In 24 cases of choroiditis 6 were much improved, 10 partly improved and 8 not altered. In his trachoma cases he found that the corneal ulceration was improved while the connective tissue inflamma- tion of the conjunctiva was not much influenced. Of 11 cases of gonorrheal conjunctivitis 9 responded very well. On a concomitant vulvovaginitis in some of these cases there was no apparent effect. Herpes of the cornea was also favorably influenced. Jendralski treated 100 cases of eye disease with milk injections. In phlyctenular disease some improvement was observed, more often in the subjective direction than in objective alteration. Trachoma was not altered and in corneal ulceration Jendralski urges great caution ^ lest actual pref oration may follow. In iritis the results were excellent; 238 PROTEIN THERAPY several cases of ophthalmoblennorrhea improved rapidly. In tuber- culous iridocylitis the improvement was not marked. Both Igersheimer and Kraupa obtained remarkable results in iritis and found that in gonorrheal disease the results were usually very satisfactory both in adults and in children. Jacovides treated about 221 cases oi ocular disease with nonspecific therapy. In 150 cases of ulcer of the cornea 140 were cured after 2 to 3 injections. Jickeli, using milk, treated ophthalmoblennorrhea, iritis, choroiditis and ulcers of the cornea with satisfactory results; milk therapy has found many partisans among French and Latin clinicians, and the reports of Carreras, Darier, Dimmer, Miiller, Domec, Mansilla, Arganaraz, Gaupillat, Guibert are available, while Titus and Nolf have used intravenous injections of peptone. Nolf has paid particular attention to this form of therapy in ocular complications following typhus, typhoid and septicemia. Guibert obtained his most satis- factory results in scrofulous diseases. Gaupillat obtained very satis- factory results in hypopyon keratitis and in bulbous infection. He used milk injections for subconjunctival injection in one case. Darier, one of the earliest advocates of paraspecific therapy, used milk injections together with oral administration of serum, which, as Cmnston has recently mentioned, is so frequently used as a routine by French clinicians. Darier's results in infectious ulcers of the cornea and in iritis — traimiatic as well as postoperative — ^were very satisfactory. In keratitis parenchymatosa and in trachoma he does not consider his results conclusive. Darier has been indefatigable in his advocacy of the oral ad- ministration of serum, claiming that with little reaction on the part of the patient the polyvalent serum exerts a systemic stimulation com- parable to the effect of milk, peptone or colloidal metals injected into the patient. According to Darier some diseases are affected more by one than the other of these agents so that some clinical experience must be gained before it is possible to use them with greatest success. Quite a number of observers have reported on the use of milk in- jections in the treatment of ophthalmoblennorrhea, among them Jickeli, Nassbamn, v. Liebermann, Purtcher, Miiller, Holler, Sommer, Honig and Bachsteg, all but the latter noting marked benefit following the milk injections. Liebermann undertook the treatment of a large series of cases of gonorrheal ophthalmia in adults with milk injections, but at the same time did not fail to continue the usual local treatment. He found that the effect of the injections on the symptoms was as follows: — ^The secretion usually ceased after the first or the second injection and only rarely reconamenced. The demonstration of the organism in the exudate became more and more difficult as the effect on the amount of secretion became apparent; only in exceptional cases did he obtain a positive bacterial finding after the secretion had DISEASES OF THE EYE 239 diminished. The primary effect of the injections was a chemosis after which the evidences of inflammation rapidly diminished. Ulcers of the cornea were prevented; if already present they were arrested; Liebermann observed only one corneal perforation in his entire series of about 100 cases. Liebermann made use of injections of a manganese colloid with excellent results. The most extensive treatise on the subject has been published by Uddgren at Stockholm, while other Scandinavian oculists have re- ported conflicting results — Lundsgaard, Andersen, etc. Uddgren used milk injections (sterile milk, boiled, with very little reaction on the part of the patient) in about 100 cases of eye diseases. The results were as follows: — onjunciivitis cssUvalis. Three cases. Prompt recovery. Trachoma. Three cases. Improved. Conjunctivitis phlyctenulosa. Fifteen cases. All improved, subjec- tively as well as objectively. Keratitis ■parenchymatosa. Fifteen cases. Of these twelve positively luetic, the others probably tuberculous. Results inconclusive. Keratitis profunda. Five cases. Four cured; the fifth case had a re- lapse after three months — panophthalmitis. Macula cornece. Twenty-four cases. Improved vision in some cases; in a few of these the result was not permanent. Scleritis and Sclerokeratitis. Seven cases. Without specific therapy the milk injections result in only transient improvement. Combined with specific therapy Uddgren obtained good results. Iritis and Iridocyclitis. Eight acute cases. Cured or much improved. Four subacute. Improved. Four chronic plastic type. Improved. Opacitates corp. vitr. Eleven cases. Stimulating and resorbing effect of the injections marked in some cases. Ablatio retiruB. Three cases. No permanent improvement. Ocular nerve lesions. Neuritis improved and in some cases complete cure. Atrophy of nerve not improved in single case injected. Paresis N. abducent. Two cases. Recovery accelerated. Chevallier has used collargol intravenously in cases of septic iritis and in keratitis with good results, while Boyd has reported good results by using typhoid vaccine intravenously in cases of iritis. Zimmer- mann (Chas.) has reported two cases of corneal infiltrations which improved after milk injections. Veach has recently contributed some experimental data concern- ing the value of nonspecific therapy in ocular infections due to idio- pathic origin. Reber has in his classification observed that iritis is usually due to one of 5 organisms — the spirochete, the tubercle bacil- lus, the gonococcus, the pnemnococcus and the influenza bacillus. The spirochete is responsible for some 30 to 60% of these. Assuming that we have sufficiently satisfactory therapy for all these specific in- fections, there still remain a large number in which our therapy is 240 PROTEIN THERAPY seemingly ineffectual, cases of indefinite etiology — ^rheumatic, meta- bolic, etc. It is for this group that Veach considered nonspecific therapy of utmost usefulness. Veach produced experimental iritis by injecting streptococci, both viridans and hemolyticus, and staphylococcus am-eus into the iris of rabbits. These were then treated with intramuscular milk injections. The course of the disease in the treated rabbits was definitely short- ened as compared to rabbits similarly infected but not treated with milk. Veach considers the experimental results sufficiently encourag- ing to warrant the use of this nonspecific method of therapy in clini- cal practice in all cases of iritis of uncertain origin. Stocker, instead of injecting milk intramuscularly in eye cases, has used it intraperitoneally. The method as used by him consists of injecting from 3 to 12 gm. of cow's milk (boiled for three or four minutes) into the peritoneal cavity. A fever that persists for from two to three days results. His results in eye cases have been very good. Musy pasteurizes milk for 15 minutes and injects 5 c.c. intra- gluteally every 2 to 4 days. He was amazed to observe the rapidity with which the pain, injection, photophobia and the swelling diminish under the course of such injections. In iridocy clitic processes the results were excellent; in iritis the pain subsided, the pupil dilated and corneal defects showed early vascularization; even in luetic cases with the formation of synechise, the milk injection assisted the systemic specific treatment. On the other hand, with chronic iridochoriocyclitis, in blennorrhea neonatorum and in tuberculous iridocyclitis the treatment seemed to have little effect on the course of the disease. Klingmueller reported that with turpentine injections five cases of ophthalmoblennorrhea cleared up very promptly. Peltesohn has studied in particular scrofulous diseases of the eye and their treatment by nonspecific means and by the Ponndorf method of intracutaneous tuberculin treatment. He foimd that the severe and moderately severe cases responded well to the latter method while almost hopeless cases were very favorably influenced by suitable combined treatment with the casein and the tuberculin injections. The report of Heine must finally be mentioned. Heine reports the results of his experiments with subcutaneous injections of milk in albuminuric retinitis. The dosage was from 5 to 10 c.c. If we re- gard the checking of the deterioration of vision as due in all cases to the milk injections, then out of 17 eyes, 15 were favorably affected thereby. If we consider only such cases as being favorably affected in which there was a marked improvement of vision, the favorable results numbered 11, whereas in 4 the disease process was only stayed. In m\y ^ did the disease process contmue in spite of the injections. DISEASES OF THE EYE 241 Also a series of cases of infectious retinitis and choroiditis was treated with milk injections. The primary results were often excellent, though recurrences were common. Schwarte treated a series of severe infec- tious processes with milk injections and reports that the results were very apparent, most of the cases being favorably influenced. CHAPTER XVII INFLAMMATION The studies that have been made in recent years which deal with the healing of wounds and the factors that favor or retard bacterial growth in wounds have added much to our understanding of the fundamentals of local infection and resistance. We must keep in mind the following facts. Injured tissue — con- tused — ^burned — fragmented or altered to such a degree that its cir- culation is markedly interfered with is a twofold source of intoxica- tion. As it becomes necrotic — even though sterile — it produces protein split products which are profoundly toxic to the organism and cause either a febrile reaction if relatively small in amount, or complete prostration and shock if larger in amount. Very likely the mere liberation of tissue (cell) juices without digestion can bring about similar effects; in animal experimentation the toxicity of the tissue extracts is, of course, well known, where their effect on the coagulation mechanism usually brings about an acute shock picture and death. Nageli has emphasized the importance of tissue necrosis, even when aseptic, in general pathological problems. Experimentally it has been found that the products of tissue contusion can kill an animal and the investigations on the production of shock made during the recent war by a number of American investigators have also served to focus our attention on this practical problem. Nageli, among other experi- ments, took small pieces of tissue, permitted them to autolyze for 24 hours aseptically and found that on reimplantation the animal died as a result of the absorption of the toxic split products from the auto- lyzing material. Even sterile blood (autogenous) will, when free in the tissues, cause a considerable leukocytosis (Dold), and Freund has recently published interesting studies that demonstrate the forma- tion of toxic substances from blood. Secondly, the altered tissue per- mits the establishment of bacterial invasion against which normal tissues would be amply able to protect themselves. For the first twelve or twenty-fom* hours following injury (the so-called preinflammatory stage) infecting organisms are confined to the surface of such wounds. If during this period the injured tissue is excised (debridement) we remove the potential sources of intoxica- tion as well as the opportunity for infection, and healing by primary intention is the rule. When once this pre-infiammatory stage has been passed and bac- 242 INFLAMMATION 243 teria have found lodgment and have become established, then we have to deal with the invasive power of the organisms on the one hand and the factors of resistance of the body on the other. To Wright we are considerably indebted for his contributions to this particular field and Flemming has discussed the subject in a compre- hensive manner in a recent paper. According to his view the role of antiseptics in the treatment of wound infection is problematic. Flenaming believes that all solutions that are at all effective have no appreciable bactericidal titer in the wound, but that they act as mild tissue irritants leading to increased leukocytic emigration and to more abundant flooding of the wound with normal tissue fluids, in this way hastening the separation of sloughs and the elimination of bacteria. He regards the antiseptic method of Dakin and Carrel, for instance, as fundamentally dependent on the same principles as that of the so-called physiologic method of Wright. It is quite apparent from his study that both the leukocytes as well as the enzyme-antienzyme content of the blood serum and tis- sue fluids have considerable bearing on the healing of wounds. Application of these principles was made by Wright in the use of hypertonic salt solutions (clinically not successful to the degree an- ticipated, because of the discomfort to the patient) ; the use of concen- trated sugar solutions; and the use of nonpathogenic bacteria which, when introduced into the wound, seemed to have a favorable effect on inflammation. The so-called "Reading" bacillus seems to have been one of the most successful of the bacteria of this type. This was a spore bearing anaerobe of saprophytic nature, to which the name "Reading Bacillus" was given by Donaldson. He describes it as follows: "It is highly resistant to heat and drying, and grows best in a slightly alkaline medium. It most closely resembles B. sporogenes (Metchnikoff ) . It is nonpathogenic for animals as well as for man when introduced into septic wounds. It does not attack living tis- sues. The use of salt is not necessary for the successful treatment of gunshot wounds, as was thought by those who advocated the salt- bag method. The success depends rather on the activity of this particular bacillus under conditions favorable to its growth and not on the salt. The rationale of the method depends not on inhibition by the Reading bacillus of the growth of pathogenic organisms in the wound either by reason of the formation by the bacillus of an in- hibitory organic acid, or by the production of any bacteriolytic fer- ment. It acts, however, by virtue of its proteoclastic enzymes as an organic catalyst which hydrolyzes the substrate of dead protein. It disintegrates the protein base from which pathogenic organisms oper- ate, and while so doing does not itself give rise to fresh toxic sub- stances. Not only so, but it is probably able to hydrolyze also the 244 PROTEIN THERAPY toxic degradation products of other organisms. In support of this theory, a resume is given of experiments on tetanus and other toxins, which show that the Reading bacillus, out of a series of organisms investigated, is alone able to reduce the toxicity of these toxins. There is one exception, namely, B. sporogenes (Metchnikoff) , which, how- ever, does not appear to be so potent in this direction as is the Read- ing bacillus." Donaldson suggests that this ability to modify a toxin like that of tetanus may prove to be of value as a means of differentiating various types of proteolytic organisms, while it in- troduces new ideas in regard to the biologic processes going on in septic gunshot wounds. In the discussion of the effect of nonspecific injections on the bubo, the influence of the enzyme and antienzyme changes have been fully discussed in their bearing on local inflammatory processes, so that it will not be necessary to repeat the conception of the mechanism in- volved. It should be kept in mind, however, that the effect of non- specific injections is a diphasic one: we deal at first with a peripheral leukopenia, a lowering of the antiferment titer, an increase in the pro- tease, an increase in the permeability of the capillaries, in the irritabil- ity of the nervous system, most probably an increase in the suscepti- bility to intoxication. This is the negative phase which makes its effect apparent on local inflammatory changes by an increase in the symp- tomatology. This phase is followed by a positive one in which the re- verse of all these biological alterations takes place, and usually to a de- gree measured by the intensity of the preceding negative phase. On the basis of this mechanism we can determine to a certain degree what we may expect from nonspecific therapy and what its limitations will be. If, for instance, we have existing a large inflammatory focus with much absorption of necrotic material, with a marked leukocytic re- action and a high temperature, nonspecific therapy will be abso- lutely without effect in the majority of cases because the absorption from the inflammatory focus is already doing the same thing that we would attempt artificially. In a phlegmon the treatment is siu-- gical, not expectant or nonspecific. On the other hand, in a lym- phangitis or a lymphadenitis, as Kaiser has shown, excellent results may follow nonspecific injections just as they do in the case of the bubo. Despite the fact that Gellhaus has reported favorable results in the treatment of appendicitis by means of collargol injections (in 34 cases only 6 were operated) the fact that the nonspecific injection is first followed by a negative phase with intensification of the disease process would, in my judgment, definitely exclude all such and similar acute surgical conditions from the field of its application. Gellhaus has reported on a very extended series of cellular inflam- mations (143 cases) treated with intravenous injections of small doses of collargol and seems very much impressed with the possibilities. INFLAMMATION 245 In 31 cases of cellulitis 17 healed without surgical interference. Schu- bert, on the other hand, tried turpentine injections in 80 surgical cases of all kinds, but his results were not satisfactory; Wederhake and Chiaudano have also given the method a trial, the latter with success in mastitis. On old chronic inflammation and sluggish ulcers much more can be expected and a number of favorable reports have been published. Gow, for instance, treated an old sluggish ulcer with intravenous in- jection of streptococci, using a dosage of 100 million, with good re- sults. In this case the reaction was delayed considerably as com- pared to the reaction that follows typhoid or colon injection. The pulse rate showed some change after 4 hours but the febrile rise did not begin until about 10 hours after the injection. There was some nausea and a headache which began twelve hours after the injection and persisted for 36 hours. There was practically no leukocytic re- sponse. Zalewski and Miiller have also reported on the treatment of old ulcers and more recent wounds with milk injections (aolan) and ob- tained very satisfactory results. Heterovaccination has found many adherents among French clini- cians, and in a recent discussion of the Societe de Chirurgie at Paris the treatment (especially by the method of Pierre Delbet) , particularly of carbuncles and similar surgical conditions, was taken up. Pierre Delbet combines the Pasteur method of attenuated cultures with the modern method of killed cultures. He found it possible by this means to inject a considerably larger dose, several billions of micro- organisms, at one time. Despite the massive dose, he has never ob- served any reaction analogous to that described by Wright as the negative phase, which Delbet thinks is the result of an excessive initial dose. On the contrary, certain toxic reactions were observed, often very violent, and despite their intensity, these were found to constitute a good omen. In the process of aging, the toxicity of the culture is probably attenuated though not entirely destroyed. After some attempts, Delbet fixed on 4 c.c, representing about thirteen billions of organisms, as a safe and effective dose. The vaccine is, naturally, a stock vaccine of streptococcus, staphylococcus and Bacillus pyocyaneus (the last in great abundance: eight billions). Delbet be- lieves it unnecessary to use the specific micoorganism and, like Wright, he has not only abandoned autogenous vaccines, but he even questions whether better results are not obtained with a vaccine pre- pared from cultures of a micoorganism other than that which is the causative agent in a given case. The method has been employed since 1913, since which time no case of carbuncle in Delbet's service has been treated by surgical incision ; boils, lymphangitis and erysipe- las also respond very promptly to this treatment. Renaud has used typhoid vaccines in the treatment of phlegmons. 246 PROTEIN THERAPY while Hofer found that he at times obtained very satisfactory results from milk injections in carbuncles and phlegmons. A related procedure is that of the production of a nonspecific reac- tion before some surgical procedure in order to make the patient more resistant to infection and a considerable literature of rather incon- clusive nature has been accumulated. Nucleins were the favorite agents, injections being made usually from 36 to 48 hours previous to laparotomies in order to prevent peritonitis. De Paoli and Calisti, for instance, report on two hundred cases in which such injections were made and an increased resistance against infection claimed. Experimentally they determined that apart from the leukocytosis pro- duced by such injections, bactericidal substances for colon bacilli could be demonstrated in increased amounts after the injections. Stracker used milk injections with the idea of increasing the gen- eral resistance of patients before operation and utilized reamputation cases for the purpose. He had observed that in old infected stumps subjected to reamputation, infection of the new area was almost a constant result because of the poor condition of the patient generally and because of the lowered local resistance of the tissues. To in- crease the resistance he injected 10 c.c. of sterile milk three times be- fore the operation, at two-day intervals. In fully half of the cases he observed a focal reaction at the site of the old lesion. His results were as follows: — In 43 cases of reamputation without preceding milk injections 10% healed by primary intention; in 72 cases with pre- ceding milk uijection 49% healed by primary intention. In 37% of the former cases there was suppuration, while in the "milk" series only 13% suppurated. Closely related to these observations is the observation made by Stuhl, that infected woimds heal more rapidly after typhoid inocula- tions. Perhaps the recent paper of Bier's as well as the discussion which followed its presentation at the Berlin Medical Society will be found of particular interest because it covers in a broad way the entire subject of inflanmiation and our present methods of therapy, with specific, nonspecific and physical means. CHAPTER XVIII INDICATIONS AND CONTRA-INDICATIONS Protein therapy offers a potent, perhaps the most potent, method that we have at our command of altering the current of cellular activity in two diametrically opposite directions — acceleration of function and depression of function. If the agent that we inject is very toxic and the dose large, acceleration soon gives place to fatigue, to complete exhaustion and finally to death; if relatively large doses are repeatedly given the condition of protein cachexia, observed in experimental animals, might supervene. Proper dosage, on the other hand, results in transient but well marked stimulation without clini- cally apparent fatigue, and if continued for a period of time the altera- tion of acceleration and depression of metabolic processes becomes clinically manifest in increased weight and general well being. It is apparent how far-reaching the field of application must be and how difficult to make definite rules of procedure or to advocate certain methods or preparations. The extent of usefulness of a method that is a true "plasmaactivation" in the strict sense of the term for- bids a definite delimitation to narrow confines. But despite theoretical possibilities, actual practice might perhaps reduce the clinical appli- cation to very modest dimensions. In this connection I would quote the opinion of Schmidt, who believes that we shall some day come to regard a course of protein therapy in the same light that we now do a changetin diet, a change in climate, a course of baths ; that is, apart from its usefulness in acute diseases, we shall accept protein therapy in its various modifications as one of the very first and the most com- monplace*of methods of therapy. With these considerations in mind we can intelligently apply protein therapy in infectious diseases only if we fix very firmly the concept that nonspecific therapy is purely a method of stimulation whereby all the forces of cellular and humoral resistance are for a short period of time keyed to the very highest pitch and by reason thereof, stimulation of this character is useless when the cells of the body are profoundly fatigued. As with other new therapeutic procedures there is still some un- certainty as to the proper dosage. Especially is this true because the dosage depends to some extent on the vigor of the patient, on the type of infection which is causing the disease, as well as on the stage of the disease. There is no unanimity of opinion whether it 247 248 PROTEIN THERAPY is well to give one or two fairly large injections or several smaller ones. Whatever method is used it is well to be cautious, especially when dealing with such toxic substances as vaccines. Before applying the treatment to any acute disease it would seem that prudence would demand a thorough familiarity with the range of the reaction and the degree of toxicity of the preparation it is intended to us, by first employing it in some arthritic cases. In arthritis, when we exclude alcoholics and old cardiac cases, the dangers of untoward effects from the reaction are minimal and with reasonable caution nonspecific therapy is not only without risk but indeed fre- quently followed by gratifying clinical improvement. Only in the light of experience so gained would it seem permissible for us to attempt to extend this form of therapy to other acute infections. In general it is to be kept in mind that injections must be given early in the course of the disease; that the injections should be given slowly ; that relatively small doses should be given the first time and that care must be taken, if intramuscular injections are made, that the injection is not by accident intravenous. For intravenous injections the protein split products are, for obvi- ous reasons, more satisfactory than vaccines; if a relatively mild re- action is desired the various serums are very useful. Where a mod- erate reaction (general and focal) is desired, intramuscular injections of boiled market milk are to be considered; if less general but some focal effect is desired, Uddgren believes that milk with a low bacterial count (certified milk) is to be preferred. The possibility of a certain degree of selective action of some of the agents is not to be ignored, the use of staphylococcus and pyocyaneus vaccine mixtures in the treatment of neuritis being such a case. In hemorrhagic disease the use of serums and of milk or salt solutions is to be preferred to vaccine or proteose injections, because of more marked effects in hemostasis. It should not be necessary to point out that the nonspecific method of treatment should under no circumstances be considered as a rival or a substitute for the proven specific measures that we have at our conamand. That a nonspecific factor is at times and possibly often associated with the specific reaction may be true, the more reason that both should be studied and both utilized in their proper time and place. Prom the evidence so far gathered, the use of the spe- cific measures is always in place whenever a true toxin is to be neutralized by an antitoxin; on the other hand, the nonspecific meas- ures find a field of usefulness as adjuvants of drug therapy in the treatment of syphilis, both early and late, with quinin in malaria, with salicylates in arthritis, with luminal in epilepsy, etc. Here the injections serve at least two purposes. They facilitate the diffusion and distribution of the drug and they increase the general resistance of the patient. INDICATIONS AND CONTRA-INDICATIONS 249 Apart from the early use of the nonspecific agents in the hemor- rhagic diseases, their use in methods of desensitization, not only in cases of asthma where we can find no specific cause, but in angioneu- rotic edema, urticaria and certain of the gastro-intestinal conditions to which Danysz has given particular attention, is one of consider- able importance. Finally we have to keep before use the therapeutic application of these agents in the focal reaction, where both the sharp effect of in- travenous vaccine injections (as in iritis) and the milder effect of repeated injections of turpentine have found definite spheres of use- fulness. CONTRA-INDICATIONS The effort has been made throughout this treatise to make it clear that the nonspecific reaction is a diphasic reaction, the first effect be- ing the intensification of the disease manifestation both generally and locally, the second being a constructive phase in which there occurs a general euphoria, a diminution of disease symptoms both generally and locally, with at times complete restitution to the normal. Gen- erally speaking it has been found that the more severe the first phase the greater the clinical benefit. This augmentation of the disease symptoms must be kept firmly in mind. No patient should be sub- jected to an intravenous injection normally followed by a severe reaction (typhoid or colon bacilli, protein split products, etc.) unless there is every evidence that the patient is a good clinical risk and able to bear the additional strain imposed by the injection. If non- specific therapy is desirable in the more uncertain cases some of the less severe methods can be employed with much less danger, such as intramuscular injections of milk, nucleins, turpentine, etc. An- other and equally important deduction can be drawn from the recogni- tion that the reaction is a diphasic one that depends on stimulating the cells. Therapeutic results cannot be expected when the organism is no longer capable of response to stimulation. When complete fatigue has been reached no amount of stimulation will avail and the additional burden imposed by the material injected can only harm the patient. One observes not infrequently in the American literature the use of relatively large doses of such agents as typhoid vaccine, colon vaccine and similarly toxic substances. It would appear to be not only neces- sary but quite irresponsible to subject patients to such severe methods. One can usually obtain a very satisfactory reaction with moderate dosage and this without unusual risk or inconvenience to the patient. Particular care must be observed to obtain a history of hyper- sensitiveness on the part of the patient — serum sickness — asthma — luticaria — angioneurotic edema — or of epilepsy or other grave ner- vous instability. In such cases the more active agents must not be used. 250 PROTEIN THERAPY Alcoholism, of the type that one encounters not infrequently in charity hospitals, is an absolute contra-indication. We have records of several patients who developed delirium tremens after nonspecific injections, one ending fatally. Pregnancy must be similarly regarded as an absolute contra- indication. In the various cardiac lesions great caution must be observed. We would include not only severe valvular injm-ies but cases with high blood pressure, with arteriosclerosis, myocarditis, or with evi- dences of vasomotor instability. In typhoid we have found it a good rule to exclude all cases with a pulse rate over 100; indeed, every case of acute infectious disease should be carefully gone over for evi- dence of myocardial impairment before injections are made. In well compensated valvular lesions we have injected typhoid vaccine with relatively severe general reactions without ill effects. The left heart border may be observed to extend outward for a centimeter or so, but as a rule there are no evidences of decompensation, v. Groer has fortified patients that were not in exceptionally good vascular tone by giving small doses of digitalis for about two days before injections were made. Diabetes is considered a contra-indication by Lindig who was of the impression that because of the vascular changes often associated with the diabetic condition the diabetic should be excluded. Uddgren also excludes the diabetic. In typhoid we have excluded the older cases (third week) from treatment, as well as cases that were septic or had evidence of septic or pulmonary complications. Naturally any evidence of bleeding either from the nose, stomach or bowel would exclude nonspecific therapy. The earlier workers observed several deaths from epistaxis following intravenous typhoid injections when these precautions were not observed. Neither old age nor infancy is considered a contra-indication by Uddgren. The patient does not become sensitive to the injection of hetero- vaccines or of proteoses ; on the contrary, with succeeding doses there is increased tolerance imtil several multiples of the original dose must be injected to elicit the proper reaction. Sensitization to serum is not only possible but occurs not infrequently, usually not to any degree that need cause alarm. Smith has made use of this increased sensitization to serima to obtain shock reactions and therapeutic re- sults therefrom. With milk the conditions are somewhat different. Some observers, including Bessau, Decastello and Mueller, consider the milk injection and its effect as due practically to the bacterial content, i.e., a heterobacteriotherapy. Considering the popularity of the milk injections in Europe, there have been relatively few reports INDICATIONS AND CONTRA-INDICATIONS 251 of sensitization from it, or severe collapse following after repeated doses. It has been suggested that this is due to the fact that the milk is boiled and so dedifferentiated. Hecht made intracutaneous injections of milk in patients injected previously with milk and also in noninjected patients. There was no difference in the skin response, nor was he able to demonstrate milk antibodies. When heterobacteriotherapy was first introduced and the dosage and the results were very uncertain, deaths incident to the injec- tions, such as were reported by Eggerth, Kraus and Mazza, Boral, V. Reuss and others, were perhaps excusable. Large doses of typhoid vaccines were used because of the impression that such amounts were essential to elicit the reaction. With further experience such disasters have been eliminated and less violent methods have come into use whenever the patient is not in good condition. Untoward results can no longer be attributed to a fault in the method of therapy but to the judgment of the physician. Needless to say, nonspecific therapy does require judgment, care- ful attention and bedside study on the part of the physician, perhaps in greater measure than any other therapeutic procedure. It should never be a routine; to be useful it must be an individualized therapy, with dosage and preparation and time of application varied to the dis- ease, its intensity, its duration and the resistance of the patient. So used, nonspecific therapy should prove to be one of our most use- ful measures both in acute infectious diseases and chronic inflamma- tory lesions. APPENDIX THE PROTEINS AND THEIR SPLIT PRODUCTS The nonspecific reaction, as we have seen, is elicited most fre- quently by colloidal substances, either injected therapeutically or originating in the tissues as a result of some inflammation (turpen- tine injection, burn, trauma, etc.). Luithlen has as a result used the term "Colloidal Therapy" to designate the form of treatment. Of the various colloids we find the proteins and their derived products most commonly used and it may be proper, therefore, to review very briefly the salient facts concerning their classiflcation, structure and behavior. The native proteins consist of exceedingly complex molecules which in turn are built up of combinations of amino acids. The final molecule is a large one, does not diffuse through parchment, collodion or animal membrane, frequently gives a faint opalescence in solu- tion, is usually amorphous but when in pure form can be crystallized under certain conditions. Chemically the proteins are relatively stable and inert and are amphoteric, combining with both the hydro- gen and the hydroxyl ion. They can be hydrolyzed both by acids and alkalies as well as by enzymes, yielding a series of degradation products commonly referred to as protein split products. These lat- ter vary in character, in amount, and in composition with the protein undergoing lysis, the method used in bringing about the disintegration, and the time at which the material is examined. For convenience we may use the so-called American classification of the proteins which divides them into three main classes: A. Simple proteins. B. Conjugate proteins. C. Derived proteins. The Simple (or Native) Proteins. — These are naturally occur- ring proteins which on hydrolysis yield only a-amino acids or their derivatives. Albumins. — Simple proteins, coagulable by heat, soluble in water and dilute salt solutions. Ovalbumin, serum albumin belong to this group. On injection they are followed by little or no reaction unless the organism has been previously sensitized. Globulins. — Simple proteins, heat coagulable, insoluble in water but soluble in dilute solutions of salts of strong bases or acids. Serum globulin is an example. 252 APPENDIX 253 Glutelins. — Simple proteins, heat coagulable, insoluble in water or dilute salt solutions, but soluble in very dilute acids or alkalies. Prolamins. — Simple proteins, insoluble in water but soluble in 80% alcohol. Albuminoids. — Simple proteins, insoluble in dilute acid, alkali, water or salt solution. Histons. — Simple proteins, not coagulable by heat, soluble in water and dilute acids; strongly basic. Protamins. — Simple proteins, basic, noncoagulable by heat, sol- uble in ammonia. As far as the use of these substances in nonspecific therapy is con- cerned interest has centered so far almost wholly on the native pro- teins of the serum, including serum albumin and globulin as well as fibrinogen. If the proteins used for injection include plant pro- teins, other members of this group will, of course, be involved. No study has been made dealing with the relative advantage or dis- advantage of various native proteins for therapeutic injections. The Conjugated (or Compound) Proteins. — These are compounds of some simple protein with some nonprotein group, the latter usually acid in nature. They are subdivided as follows: Chromoproteins (Hemoglobins). — These are proteins in which the nonprotein addition group is colored, as hematin in hemoglobin. Glycoproteins (Glucoproteins). — The prosthetic group in this class contains a carbohydrate radical. Mucin and cartilage are examples. Phosphoproteins. — Proteins derived from the cytoplasm. The ad- dition group contains phosphoric acid. Casein belongs to this group. Nucleoproteins. — Proteins of the nucleus, i.e., chromatin. Nucleic acid is here the added radical. Nuclein, nucleohiston, etc., are ex- amples. Lecithoproteins. — These have not been isolated in pure form. To- gether with the Lipoproteins their existence is probable, the former consisting of proteins to which lecithins or phospholipins have been attached, the latter of proteins in combination with one or more of the higher fatty acids. It is possible that the forms are easily dis- sociated and vary from loose and transient physical aggregates to relatively more stable chemical combinations. Their very lability would make them of great physiological importance in cellular processes. The conjugated proteins are of considerable importance from the point of view of nonspecific reactions. On injection they are followed in general by relatively little reaction, but the organism can become sensitized to these proteins just as to simple proteins of the first group. When the conjugated proteins are dissociated from their non- protein radicals they produce a far greater reaction than when in the conjugated form. Schittenhelm and his associates have demon- strated this with the chromoproteins. 254 PROTEIN THERAPY The phosphoproteins are of interest because casein — the isolated protein of milk — belongs in this category. This protein has been used to a great extent for the nonspecific reaction. Casein itself is followed by little or no general reaction when injected for the first time. It has been suggested that the more marked reaction obtained with milk injections is due to the bacterial content, rather than due to the protein of the milk itself. Casein is practically the only one of the native proteins which is subject to the action of erepsin, both of the enzyme of the intestinal tract and the erepsin-like enzyme occurring in the serum. The nucleoproteins occur not only in the proteins obtained from nuclei of cells, but are present in large amounts in the material ob- tained from bacterial sources in which the nucleoprotein occurs throughout the cell body. The relation of these substances to the so- called endotoxins of bacteria is still uncertain, v. Groer isolated a nucleohiston from typhoid bacilli which he used for nonspecific injections. The Derived Proteins. — ^This group is an artificial one and in- cludes all the decomposition products occurring after the action of chemical, physical or biological agents (enzymes) on the naturally occurring proteins. In the first group are included the proteins, metaproteins and coagulated proteins, that is, proteins which have undergone the first alterations following the action of heat, acids, etc. This group has no importance from the therapeutic standpoint. In the second group are included those protein derivatives com- monly called protein split products, which in turn are classified imder three groups — Proteoses, Peptones and Peptids. The Pboteoses (Albumoses). — ^These represent the first dissocia- tion products of the albumins. They are no longer heat coagulable but can be salted out by concentrations of certain salts such as am- monium sulphate, zinc sulphate, etc. They are by no means clearly defined chemical entities, the usual preparations obtained by precipi- tation including mixtures of molecules and molecular aggregates vary- ing to some extent in size. The albumoses are roughly divided into two groups, primary and secondary albumoses. Of these the primary proteoses more closely approximate the proteins from which they are derived; they are precipitated by half saturation with ammonium sulphate. The Primary Proteoses can in a general way be divided into two groups by means of dialysis, whereby the hetero-albumose becomes insoluble, or by the addition of an equal amoimt of alcohol. Hof- meister's table may be of some value in illustrating the differences in behavior of these higher split products of proteins. In general it may be stated that the primary proteoses are more toxic than the secondary proteoses, but variations occur, depending APPENDIX Hofmeister's Table 255 Precipita- tion Water sol. Ale. sol. DiffuB- ibility Biuret Primary Albumoses (Proteoses) Ppt. in from 24 to 42% Amm. Sulphate Proto- Albumose Eeadily sol. Sol. in 80% Good + Hetero- Albumose Not sol., but sol. in dil. salt sol. Insol. in 32% Poor + Deutero- 54% to 62% A. Thio- Albumose Sol. Insol. in 60%-70% + " or Secondary Albumoses (Proteoses) 70% to 95% B. Albumose Syn- Sol. Vary ,+ 100% + Acid C. C- Albumose Sol. Sol. in 67%-80% + no doubt on the chemical composition of the original protein from which the split products are derived. Kaznelson has reported observa- tions in this connection with protein split products obtained from fibrin, silk, casein, etc., and foimd that those derived from fibrin were most toxic. The Secondary Proteoses or Deutero-albumoses, have been used therapeutically by Liidke and include the protein fragments that are precipitated by complete saturation with ammonium sulphate after the primary proteoses have been removed by half saturation. The group is an indefinite one and includes a number of fragments evi- dently of different sizes which have been classified as A, B and C by Hofmeister, as Thio-albumose, Synalbumose, etc. Witte Peptone, which has been frequently studied and which Nolf, Gow and others have made use of for therapeutic injections, consists of a digestion mixture in which albumoses are abtmdantly found. It is said to be prepared by the digestion of fibrin. From it the primary and secondary proteoses can easily be prepared by salting out in proper concentrations. Peptones. — These are further hydrolytic cleavage products soluble in water, not coagulable by heat nor precipitable by ammonium sul- phate; they are easily diffusible and give biuret reactions. They differ greatly in toxicity. Peptids. — The simpler compounds of amino-acids, many of which 256 PROTEIN THERAPY have been synthetically prepared by linking two or more amino acids — di-peptids, tri-peptids, etc. They are not coagulable by heat, are easily soluble and may still give a biuret reaction. The Amino-Acids. — The amino-acids form the ultimate molecular units from which the proteins are constructed. They are grouped into five classes: — 1. The Aliphatic or Mono-amino, monocarboxylic acids, includ- ing glycocoll, alenin, valin, etc. 2. The Mono-amino, dicarboxylic acid group including aspartic acid and glutamic acid. 3. The Isocylic, amino-acids such as tyrosin and phenyl alanin. 4. The Heterocylic, amino-acids including histidin, tryptophan, prolin, etc. 5. The Diamino-monocarboxylic acid group with arginin and lysin. In general the lower split products of the proteins, including the amino acids, are relatively nontoxic and bring about little or no re- action on the part of the patient when injected; the compounds con- taining the various ring groupings of the carbon atom as well as the diamino group seem, however, to be exceptions. Considerable work has recently been reported by Dale and his associates and by Koessler and Hanke in connection with the toxicity of histamin. BIBLIOGRAPHY V. Aaron, B., Das Scticksal des intravenos verabreichten Kaseins, Ztschr. f. physiol. Chem., 1916, xcviii, 49. Abderhalden, E., Zur Kenntnis des Vorkommens der peptolytischen Fermente, Ztschr. f. physiol. Chem., 1912, Ixxviii, 344. Achard, C, and Flaudin, C, Autoserotherapy in Hay Fever, etc.. Bull, de la 8oc. Med. des Eopitaiue, Paris, 1920, xliv, Y23. Adler, Wien. med. W chnschr., 191Y, Ixvii, 509. Agazzi, Ztschr. f. Immunitatsforsch., 1909, i, 736. 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INDEX Abderhalden's reaction, 101 Abscess, fixation, of Fochier, 3, 40, 42 salt, 40 Actinomycosis, 235 Activating agents in focal reaction, 74 Activation, focal, from intracutaneous injections, 139 non-specific, 88 of skin reactivity, 129 Acute exanthemata, 139 Adnexal inflammation, 181 Albumin egg, see Ovalbumin serum, 21 Albuminoids, 253 Albumins, 252 Albuminuria, in non-specific reactions, 56 Albumoses, 25, 254 Hoffmeister's table of, 255 in influenza, 195 injection of, in typhoid fever, 158 primary, 25, 254 deutero-, 25 secondary, 255 Allergy, 130 Amino-acids, 256 Ammoniacal copper sulphate, 41 Amylopsin, 28 Anaphylactic shock, changes in coagu- lability of blood in, 216 Anemia, pernicious, 214 secondary, 213 Angina, Vincent's, 205 Angioneurotic edema, 213 Animal serum, normal, 17 Anthrax, 185 Antibacterial sera, 18 Antibodies, and the reactions, 91 in nonspecific reactions, 66 resistance, 99 Antiferments, in nonspecific reactions, 66 Antigen, of Much, 36 Antipyretics, 42 Antistreptococcus serum, in influenza, 194 Antitrypsin, in nonspecific reactions, 66 Antitoxins, 18 Antiyeast serum, 19 Aolan, 23 Arthigon, 27, 35 Arthritis, 142 gonorrheal, 171 Asthma, 210 Autolysates, tumor, 4, 29 Autoserotherapy, 16, 20 method of Gilbert, 4 Bacillary dysentery, 187, 189 Bacterial extracts and related sub- stances, 13, 36 Beard's enzyme treatment of cancer, 4, 28 Bee stings, 41 Beef serum, 17 Bibliography, 257 Bier's passive hyperemia, 21 Biological alterations, 44 Blister serum, 20 Blood, 16 coagulability of, changes in, in ana- phylactic shock, 216 Blood letting, 16 Blood pressure in nonspecific reactions, 51 Blood serums, 16 Blood sugar in nonspecific reactions, 63 Blood transfusion, 16 Blood vessels, permeability of, in non- specific reactions, 56 Buboes, 180 Carbuncles, 245 Carcinoma, 218 Beard's enzyme treatment of, 4, 28 nonspecific injections in. 111 Carriers, diphtheria, 185 typhoid, 164 Cartilage, extract from, 29 Casein, 23, 24 Caseosan, 23 Cautery, 14 Cerebral lues, 207 Cerebrospinal fluid, 21 Chicken serum, 17 Children, diseases of, 221 Chill, in nonspecific reactions, 47 Cholera vaccine, 34 Chromoproteins, 253 Classification of focal reactions, T2 Coagulability of blood, in anaphylactic shock, 216 Coley's fluid, in sarcoma, 4, 37 Collateral immunization, 33 Colloidal metals, 13, 37, 39 Colloidal therapy, 252 309 310 INDEX Colloids, metal, sensitization of skin to, 75 Colon bacillus vaccine, 33, 172 Contraindications to protein therapy, 249 Convalescent serum, 17 Counterirritants, 12, 14 Coimterirritation, 14, 15 Danysz's method, 35 Delirium in nonspecific reactions, 54 Depression immunity, 44 of skin reactivity, 128 Dermatoses, hysteric, 234 of pregnancy, 231 Detoxioation, 100 Deutero-albumoses, 25, 172, 255 dosage of, 26 Deutschmann serum, 19 Diphasic character of focal reaction, 77 Diphtheria, 185 antitoxin, 18 in influenza, 194 carriers, 185 vaccines, 34 Diphtheroid vaccines, 34 Distilled water injections, 41 Diuresis in nonspecific reactions, 56 Doellken's theory, 86, 89 Dysentery, acute, intravenous method in, 188 bacillary, 187, 189 milk injections in, 189 vaccine, 33 vaccinotherapy in old chronic cases, 188 Ear diseases and infections, 218 Eczema, 234 Edema, angioneurotic, 213 Effusions, pleural, 20 Egg albumin, see Ovalbumin Encephalitis, lethargic, 195 Endocarditis, 198 Endogenous localized inflammatory processes, 73 Enzymes, 13, 28 and the reaction, 91 in nonspecific reactions, 64 in pathological conditions, 100 in skin reactions, 131 proteolytic, 102 serum, 102 Enzyme treatment of cancer, 4, 28 Epididymitis, 174 local injection in, 178 Epilepsy, 228 Ereptase, 102 Ergotropie, 12 Erysipelas, 191 Erythema nodosum, 234 Erythrocytes in nonspecific reactions, 63 Esophylaxis, 135 Exophylaxis, 135 Extracts, tissue, 13, 29 Exudates, pleural, 20 Eye, diseases of, 236 Ferment-antiferment balance, 108 Fibrinogen in nonspecific reaction, 63 Fixation abscess of Fochier, 3, 40, 42 Focal activation from intracutaneous injections, 139 Focal reactions, 70 activating agents, 74 classification of, 72 diphasic character of, 75 in tuberculosis, 78, 79 mechanism of, 77 specificity of, 72 therapeutic applications of, 81 Fochier, fixation abscess of, 3, 40, 42 Foci, pulmonary of tuberculous origin, 72 non-tuberculous inflammatory, 73 tuberculous, 78 vascularized inflammatory, 77 Fontanelle, 14 Formalin, 41 Furunculosis, 234 Gas, mustard, 116 war, 115 Gelatin, 24 General paralysis, treatment of, 224 Glandular activity in nonspecific reac- tions, 54 Glaucoma, 237 Globulins, 252 Glucoproteins, 253 Glucose solutions, 41 Glutelins, 253 Glycoproteins, 253 Goat serum, 17 Gonococcus vaccines, 34, 171 Gonorrhea and its complications, 170 local injection in, 178 provocation reaction in, 181 Gonorrheal arthritis, 171 Gout, 147 Hay fever, 210 Headache in nonspecific reactions, 54 Heliotherapy, 43, 137 Hemoglobins, 253 Hemorrhagic diathesis, 214 Herd reaction, 70 Herpes in nonspecific reactions, 53 Heterobacteriotherapy, 8 Heterovaccination, 245 Heterovaccines in typhoid fever, 154 in parat3T)hoid fever, 154 Hetol, 41 Histamin, 27 Histones, 253 INDEX 311 Hoffmann's theory, 136 Hoffmeister's table of albumoses, 255 Horse serum, 17 Human milk, 23 serum, normal, 16 Hyperemia, Bier's, 21 Hypersensitiveness of the tuberculous, 79 Hypertonic salt solutions, 39 in influenza, 195 Hypotonic salt solutions, 39 Hysteric dermatoses, 234 Immune serum, 17 Immunity, depression, 44 Immunization, collateral, 33 nonspecific, 32 Indications for protein therapy, 247 Infections, protozoal, 206 spirochetal, 206 Inflammation, 242 adnexal, 181 local, reaction in, 113 of bacterial, origin, 116 of nonbacterial origin, reaction in, 115 Inflammatory foci, non tuberculous, 73 vascularized, 77 Inflammatory processes, localized, en- dogenous, 73 localized, traumatic, 73 Influenza, 192 albumoses in, 195 antistreptococcus serum in, 194 colloidal metals in, 192 convalescent serum in, 194 diphtheria antitoxin in, 194 fixation abscess in, 193 hypertonic salt solution in, 195 milk injection in, 194 Much's vaccine in, 195 normal serum in, 194 sera in, 194 turpentine injection in, 193 vaccines, 34, 194 Internal medicine, relation of skin to, 134 Intoxication by protein-split products, 99 Intravenous injection of typhoid vac- cine, 153 Iodides, 41 infection by, local effects of, 21 Iritis, 238, 239 Jarisch-Herxheimer reaction, 75 Joint fluid, 21 Keratitis, 236, 237, 238 Lecithoproteins, 253 Lethargic encephalitis, 195 Leukocytes in nonspecific reactions, 58 Leukocytic extracts, 28 injection of, 4 Leukocytosis, 95 Leukoproteases, 102 Light rays, 43 effect of, on skin, 136 Lipase, 64 Liproproteins, 253 Local inflammation, reaction in, 113 Local injections, in gonorrhea, 178 in epididymitis, 178 Local reactions, 70 Localized inflammatory processes, en- dogenous, 73 traumatic, 73 Lues, cerebral, 207 Lymph, concentration in nonspecific re- actions, 59 enzymes in nonspecific reactions, 64 volume in nonspecific reactions, 59 Lymphagogue effect in nonspecific re- actions, 57 Lysins, 71 Malaria, 208 activation, 208 therapy, 208 Malignant neoplasms, 218 Measles, 196 Mechanism of focal reaction, 77 Mechanism of reaction, theories of, 83 Nolf's theory, 91 Starkenstein's theory, 96 Weichardt's theory, 84 Wright's theory, 84 Meningitis, tuberculous, 203 Meningococcus vaccines, 34, 172 Menstruation, in nonspecific reactions, 53 Metallic colloids, 13, 37, 39 sensitization of skin to, 75 Milk, 54 human, 23 injections of, 22, 23 in typhoid fever, 158 Moxa, 14 Much's antigen, 36 vaccine in influenza, 195 Mustard gas, 116 Myositis, 178 Nausea, in nonspecific reactions, 53 Neoplasms, malignant, 218 Nephritis, 217 Nervous irritability, in nonspecific re- actions, 53 Neuritis, 217 Neuro-arthropathies, syphilitic, 207 Nitrogen metabolism, in nonspecific re- actions, 54 Nolf's theory of the mechanism of the reaction, 91 Nonspecific activation, 88 agents, 12 immunization, 32 312 INDEX Nonspecific injections in carcinoma, 111 Nonspecific reactions, 46 albuminuria in, 66 antibodies in, 66 antiferment in, 66 blood pressure in, 51 blood sugar in, 63 chiU in, 47 delirium in, 54 diuresis in, 56 erythroc3rtes in, 63 fibrinogen in, 63 glandular activity in, 54 headache in, 54 herpes in, 53 leukocytes in, 68 lipase in, 64 ISTnphagogue effect of, 57 menstruation in, 53 nausea in, 53 nervous irritability in, 53 nitrogen metabolism in, 54 peptidase in, 64 permeability of blood vessels in, 56 platelets in, 63 protease in, 64 pulse in, 50 serum enz3rme3 in, 64 spleen in, 63 sweating in, 52 temperature curve in, 48 thrombokinase in, 63 urticaria in, 53 vomiting in, 53 Wassennann reaction in, 69 weight of patient and, 55 Non-tuberculous inflammatory foci, 73 Normal salt solution, local effects of, 21 Normal serum, animal, 17 human, 16 Nucleic acid, 24 Nucleins, 24 Nucleohexyl, 25 Nucleoproteins, 253, 264 Omnicellular plasmaactivation, 84 Ophthalmoblenorrhea, 238 Orchitis, 196 Organotherapy, 29 Otology, 218 Ovalbumin, 21 Paralysis, general, treatment of, 224 Paraspecific serum therapy, 18 Parotitis, 196 Parat3T3hoid fever, heterovaccines in, 154 treatment of, 153, 169 Pediatrics, 221 Pemphigus, 234 Peptidase, 102 in nonspecific reactions, 64 Peptids, 255 Peptone effect, 26 Peptone shock, 26 Peptones, 265 Witte, 27, 255 Permeability of blood vessels in non- specific reactions, 56 Pernicious anemia, 214 Phlegmons, 245 Phosphoproteins, 253, 254 Photodynamic agents, 43 Phylacogens, 37 Phlyctenular disease, 237 Plant proteins, 13, 24 Plasma-activation, 12, 76, 77, 80, 84 omnicellular, 84 Plasma serum, 19 Platelets in nonspecific reactions, 63 Pleural effusions, 20 exudates, 20 transudates, 20 Pneumonia, 103, 120, 196, nonspecific reaction in, 123 therapy in, 120 Pneumococcus autolysate, 37 vaccines, 34 Pregnancy, dermatoses of, 231 Prolamines, 253 Protamines, 253 Protease, 102 in non-specific reactions, 64 Proteins, 13, 21, 252 and their split products, 252 classification of, 252 compound, 253 conjugated, 263 derived, 264 native, 21, 252 plant, 13, 24 simple, 252 Protein-split products, 13, 25 intoxication by, 99 Protein-therapy, 25 contraindications to, 249 history of, 1 indications for, 247 modem conceptions of, 7 Proteols^tic enzymes, 102 Proteoses, 25, 254 Protozoal infections, 206 Provocative reaction in gonorrhea, 181 Psoriasis, 231, 234 Puerperal infections, 196 Pulmonary foci of tuberculosis, 72 Pulse, in nonspecific reactions, 50 Purpura, 215 Pyelitis, 217 Pyelonephritis, 217 Pyocyaneus vaccines, 34 Pyretotherapy, 178, 182 INDEX 313 Radium, 43 Reaction, Abderhalden's, 101 antibodies and, 92 enzymes and, 91 focal, activating agents in, 74 in inflammations of non-bacterial origin, 115 local, 70, 113 probable mechanism of, 99 detoxication, 100 ferment-antiferment balance, 108 intoxication by protein-split prod- ucts, 99 serum enzymes, 102 thermoregulatory mechanism and, 91 Reading bacillus, 243 Relapsing fever, 206 Resistance, antibody, 100 Retinitis, 240 Roentgen rays, 43 Salt abscess, 40 Salt solutions, hypertonic, 39 hypotonic, 39 normal, effects of, 21 Sanarthrit, 29, 147 Sarcoma, 218 Coley's fluid in, 4, 37 Scarlet fever, 198 Schafer's vaccine, 37 Scurvy, 216 Secondary anemia, 213 Selective stimulation, 88 Sensitization, 130 of skin to metallic colloids, 75 Sepsis, non-specific therapy in, 125 Septicemia, 200 Serum, or Serums, 12, 16 albumin, 21 antibacterial, 18 antistreptococcus, in influenza, 194 antiyeast, 19 beef, 17 blister, 20 blood, 16 chicken, 17 concentration of, in nonspecific reac- tions, 59 convalescent, 17 in influenza, 194 Deutschmann, 19 enzymes, 102 in nonspecific reactions, 64 goat, 17 horse, 17 immune, 17 in influenza, 194 local effects of, 21 normal, animal, 17 human, 16 in influenza, 194 paraspecific, 18 plasma, 19 Serum, or Serums, sheep, 17 tuberculosis, 19 Serum therapy, paraspecific, 18 Seton, 14 Sheep serums, 17 Skin, diseases, 230 effect of light on, 136 reactions, enzymes in, 132 reactivity, 128 activation, 129 depression, 128 relation of, to internal medicine, 134 to nonspecific resistance, 128 sensitization of, to metallic colloids, 75 Smallpox, 201 Snake venom, 41 Solusin, 41 Specificity of focal reactions, 72 Spirochetal infections, 206 Spleen in nonspecific reactions, 53 Staphylococcus vaccines, 34 Starkenstein's theory of the mechan- ism of the reaction, 96 Stimulation, selective, 89 Streptococcus vaccines, 34 Sugar solutions, 41 Sweating in nonspecific reactions, 52 Syphilides, 231 Syphilis, 139, 206 cerebral, 207 Syphilitic neuro-arthropathies, 207 Tabes, treatment of, 224, 227 Tebelon, 36 Temperature curve, in nonspecific reac- tions, 48 Terpichin, 42, 180 Tetanus, 201 Therapeutic applications of focal reac- tion, 81 Thermocautery, 14 Thermoregulatory mechanism, and re- action, 90 Thrombokinase in nonspecific reac- tions, 63 Tissue extracts, 13, 29 Trachoma, 236, 237 Transfusion, blood, 16 Transudates, pleural, 20 Traumatic inflammatory processes, lo- calized, 73 Trench fever, 201 Trichophyton infection, 232 Trypsin, 28 Tryptase, 102 Tuberculin, 36 in gonorrhea, 179 reaction, 75 Tuberculosis, 202 foci of, 72, 78 serum, 19 314 INDEX Tuberculous, general hypersensitive- ness of the, 79 Tuberculous meningitis, 203 Tumor, autolysates, 4, 29 Turpentine, 42 Typhin, 36, 163 Typhoid carriers, 164 Typhoid fever, 117 albumose injections in, 158 heterovaccines in, 154 injections of milk in, 158 intravenous injections of vaccine, 153 treatment of, 153, 165 comparative results, 160 heterovaccines in, 154 intravenous injections in, 153 milk in, 158 therapeutic precautions in, 167 vaccines in, 33, 153 ulcers, 167 Typhoid ulcers, 167 vaccines, 33, 153 Typhus fever, 203 Ulcers, 245 typhoid, 167 Urticaria, in nonspecific reactions, 53 Vaccines, 13, 30 cholera, 34 colon bacillus, 33, 172 Vaccines, diphtheria, 34 diphtheroid, 34 dysentery, 33, 188 gonococcus, 34, 171 in influenza, 194, 195 meningococcus, 34, 172 mixed, 35 pneumococcus, 34 pyocyaneus, 34 staphylococcus, 34 streptococcus, 34 typhoid, 33, 153 Vaccine therapy, results of, 31 Vaccinurin, 35 Vascularized inflammatory foci, 77 Venom, snake, 41 Vincent's angina, 205 Vomiting, in nonspecific reactions, 53 War gas, 115 Wassermann reaction, effect of non- specific reactions on, 69 Weichardt's theory of plasma activa- tion, 77, 84 Weight of patient, and nonspecific re- actions, 55 Weil's disease, 207 Witte peptone, 27, 255 Wright's theory of the mechanism of the reaction, 93 Yeast, 13, 43