·No text on this page.

·SERUM SICKNESS

·AUS DER K. K. UNIVERSITÄTS-KINDER-KLINIK
IN HIh\.
(VORSTAND PROI. ESCHERICH.)
DIE
SERUMKRANKHEIT
VOV
D C. FRH. VON PIRQUET UND D* B. SCHICK.
LEIPZIG UND VIEX.
FRANZ DEUTICKI
1906

·SERUM
SICKNESS
C FRI VON PIRQUET, N D
and
BILA SCHICK, N D
Translated by
BELA SCHICK, M
SANS
TACHE
BALTIMORE
THE WILLIAMS & WILKINS COMPANY
1951

·COPYRIGHT 1951
THE WILLIAMS & WILKINS COMPANY
Made in United States of America
COMPID AND PAINTED 27 723
WAVERLY PRESS INC
POR
Tas Y UN Tgxs COMUXT

·То Catherine

·No text on this page.

·PREFACE TO THE ENGLISH TRANSLATION Since the onginal publication of the Serum Sickness, 45 years have elapsed It took a long time before the medical world realized the fundamental value of these studies What is now called Allergy is based on ob servations published in this book However von Pirquet did not coin the term Allergy until 1906 During the last two decades many physicians have tried to acquire a copy of the original edition of Die Serumkrankheit It became more and more difficult to obtain a copy Furthermore the English speaking physicians experienced difficulties in getting correct information from the book written in German I was frequently asked where one might borrow a copy of the Serum Sickness book I often thought that it would be advisable to translate the book into English but I hesitated to do it, because translations are difficult and time consuming Such time could better be used for an original work It was not until the publishing firm, The Williams and Wilkins Company, approached me with the request for a translation that I consented to do it, influenced by the belief that I owed it to my dear friend von Pirquet that I should translate this work Thus it is now accomplished and I have the hope that it will assist in the clarification of the fundamental work upon which was founded Allergy and that it will shed light upon the greatness of Pirquet who was, all the time these studies were made, completely aware of all the ramifications that would arise from these basic observations It is a great satisfaction to me and was likewise to Parquet during his life that not only were the clinical observations complete but also that the theoretical ideas stood the test of time The theory that the interaction between antigen and antibody is responsible for the onset and course of serum sickness is still the theory best suited for its explanation That the breaking down of foreign protein by enzymatic (digestive) substances produces the toxic phase is still accepted It must be stressed that the existence and behavior of the incubation time gave the key which opened the secret lock on the closet where the solution of so many extremely interesting and important problems lay hidden Many other problems mentioned in Serum Sichness were later elaborated by Parquet, see vaccination, measles, tuberculosis, ete It is not necessary for me to say that Parquet is really the father of all skin testing The tuber culin test is a logical evolution of the ideas of the genius, Parquet All our allergy tests and almost everything what we know about allergic diseases have their origin in the observations in serum sickness which contain passive transfer and serum sickness in "reverse" YU ·Vill SERUB SICKNESS For some time I had the intention to combine a translation of Serum Sickness with discussions concerning the progress which has been attained during the 45 years since its publication It would have been a very difficult task because several thousand publications have appeared Here it is im possible to report the evolution of allergy in greater detail I wish merely to mention some other concepts concerning the theory of allergy and hyp erergic (adaphylactic) reaction One of these concepts advocated by French investigators (Villaret, Vallery Radot and others) is to the effect that the symptoms of allergy may depend upon an excess of acetylcholin or upon some disturbance in its normal breakdown by the cholin esterase Urbach contends that acetycholine and similar substances are formed as the end results and not immediately by the interaction of antigen and antibody Endotoxin and proteictoxin may likewise liberate or produce these substances from the cells Histamine may be one of the protectoxins arising during the antigen antibody interaction but not the only However histamine may be also liberated from the cells through the irritating effect of other substances produced by the antigen antibody interaction The histamine theory led to the use of anti histamine drugs (Benadryl, and Pyrıbenzamine, etc) which have been especially effective against hives Lately they are also used against "allergic colds Histamine cannot sufficiently explain all allergic reactions Doert is the outstanding champion of the "physical" theory as the basis of anaphylactic shoch He assumes that the antigens and antibodies, sub stances of high molecular weight react on the cell membrane but do not penetrate it The consequence is that physico chemical changes are insti tuted which act as an irritant to the cells According to Bronfenbrenner the interaction between antigen antibody serves to disturb the delicate ad justment of colloidal conditions existing in the serum as well as at the surface of the tissue cells Vidal looks upon anaphylactic shock as repre senting a disturbance of the colloidal balance He and his school designate the changes of the colloids in the blood as "hemoclastic crisis" and those in the tissues as "colloidoclasia " Lumière, on the contrary, explains tho nature of anaphylactic (hyperergic) phenomena on the basis of invisible flocculation occurring in the blood stream of allergic individuals as the encounter between antigen and serum antibody These various theories may have an important meaning in explaining anaphylactic (hyperergic) shock, but cannot be used as an explanation of all allergic phenomena In almost all of the theories the interaction between antigen and antibody plays a prominent role Landsteiner made an outstanding contnbution to chemical allergy when he demonstrated the attachment of simple chemical compounds to the protein of the organism, creating in this way an antigen (Forssman antigen) ·PREFACE TO THE ENGLISH TRANSLATION There are numerous publications which are helpful to physicians in their study of the later phases in the development of allergy COOKE R A Allergy in Theory and practice WB Saunders Company 1947 DOERR R Arch Derm & Syphilol 181 7 1926 Allergic Phenomena Handbook of Normal and Path Physiology 13 650 1929 Allergy and Anaphylaxy #db Path Macroorg ad31 part 2 759 1929 MAYERROFER E Parquet s Allergie begriff uad seine Entwicklung Erg Inn Med & Kind 241 271 PIRQUET « Allergy Erg Inn Med & kind I 420 1908 and V 459 1910 Klinische Studien ueber Vaccinat on und vaccinale Allergie Mu Med W 53 457 1906 RICH A R AND GREGORY TE Experimental demonstration that periarteritis nodosa 18 8 man festation of hypersensit vity Bull Johns Hopkins Hosp 72 65 1943 Experimental evidence that legions with the base characteristice of rheumatic carditis can result from anaphylactic hypersensitivity Bull Johns Hopkins Hosp 73 239 19-13 Role of hypersensitivity in periarteritis nodosa etc Bull Johns Hopkins Hoep 71 123 1942 SCRICK B Allergy and immunity Jour Mt Snai Hosp XIV 3 1947 URBACH AND GOTTLIEB Allergy Grune and Stratton New York 1943 and 1948 (With over 2260 references )

·No text on this page.

·CONTENTS Introduction 1 CHAPTER ONE CLINICAL ASPECTS OF SERUM SICKNESS General Picture of the Disease Period of Incubation Fever Exanthemata Enlargement of Lymph Glands Leukopenia Joint Symptoms Edema and Albuminuria Mucous Membranes General Condition Differential Diagnosis Therapy and Prophylaxis 6 14 18 31 39 46 50 54 61 62 64 65 CHAPTER TWO THE REINJECTION Immediate Reactivity Experimental Studies Accelerated Reactivity Clinical Symptoms 1 Immediate Local Reaction Specific Edema 2 Immediate General Reaction 3 Accelerated Reaction Diagnostic Importance of Immediate and Accelerated Reactivity 68 71 75 83 83 86 90 94 CHAPTER THREE THEORY OF SERUM SICKNESS Formation of Precipitin Antibody Reaction in Vitro 96 Clinical Symptoms of Serum Sickness as an Expression of the Vital Antibody Reaction 100 Acquired Hypereensitiveness 101 The Specific Edens 107 Acquired Immunity Hyposebsitiveness and Lack of Sensitiveness 103 Importance of Serian Sickness for General Pathology 114 Bibliography 122

·No text on this page.

·INTRODUCTION The introduction of foreign blood and foreign protein in a way other than through the gastrointestinal tract is nothing new Particularly transfusions, consisting of the transmission of blood of one individual into the circulation of another individual, were used as a therapeutic measure for some time Onginally the most varied diseases were treated with this method It can be stated with certainty that the first direct and successful transfu sion was carried out with lamb blood on June 15, 1667 by Denis, quoted by Landois in an article on Transfusion in Eulenberg Realencyclopedia 3rd Edition These transfusions with lamb blood seem to have given no outstanding results As early as 1691 Jungker said that he could not obtain satisfactory effects and in 1763 Herster found that "unfortunately only a few patients experienced the expected help and very much noise was made in the be ginning, but at present one hears very little of it' At the beginning of the last century experiments with transfusion of lamb blood were again made As prominent indications, acute anemia and poisoning were mentioned These intravenous injections of lamb blood were soon found to be very dangerous Frequently high fever up to 106° was observed half an hour after the injection Also embolic symptoms, hemorrhages, and hemoglobinuria called for caution The cause of these complications and the whole scientific basis of the doctrine of transfusions were discussed and partly clarfied only in 1873 by Landois and by Pon fick in 1875 These authors pointed out that the blood cells of animals are dissolved in the circulating blood of the recipient Naunyn and Francken showed that coagulation occurs if one brings dissolved hemoglobin into the circulation Many leukocytes are destroyed by the dissolved hemoglobin Thus generators of fibrin are set free, creating fibrin Through ex tensive coagulation death may be caused by asphyxia We do nothing further than mention these symptoms appearing immediately after transfusions of foreign blood, because they have nothing to do with serum disease as such Of much more interest to our problem is the fact that as early as about 1870 observers noted urticaria eruptions several days after the transfusion Dallera (Considerazioni e casi clinici di transfusion del sangue, Il Morgagni disp, 7: 1874) reported that a female patient suffering with "hystere mania" broke out with an urticana eruption all over her body ten days after a transfusion On that day her blood still contained the injected red cells of the animal 1 ·2 SERUY SICKNESS Neudoerfer (Contributions to Blood Transfusions, Zeitschr f Chir, Bd 6) noted that urticaria frequently appeared after a blood transfusion Landois also saw eruptions of urticana after transfusions On account of the severe damage caused by tranfusions of lamb blood, transfusions of animal blood have been almost entirely given up and we do not expect that the newly performed experiments of Dominici (Wr Med Woch, 1895) will revive the use of lamb blood After lamb blood transfusions mill transfusions were tred for a while, particularly in England This therapy soon disappearcd The final opinion of that time is best expressed by the words of Montard, Martin and Richet who say (Injections intravenouses de lait et de sucre, Soc de Biol, 26 7, 1879). As therapy milk transfusion is useless and dangerous and should therefore be absolutely condemned' Also the subcutaneous and intra peritoneal injection of blood and mill did not find any followers After the lamb blood tranfusions had been more and more replaced by infusions with sodium chloride and by transfusions with defibrinated human blood there was no reason to discuss further the danger and disad vantages of transfusion of foreign blood or serum The method and its danger were forgotten The situation changed in 1894 with the rapidly increasing use of diph theria antitonin, which was prepared by the immunization of horses with diphtheria toxin Neither red cells nor fibrin were injected Furthermore the injections were made subcutaneously rather than intravenously and the amount of the injected foreign protein was much smaller Thts was the reason why, in the majority of cases, no bad effect was noted Lublinska (An After Effect of Antitoxin in Treatment of Diphtheria," Deutsch Med Wo, 1891 45. 1847) was the first to publish a case describe ing a rash after injection of diphtheria serum As the title of the publication indicates, Lublinshi thought that the symptoms were due to the antitouin content of the serum On the second and third day of the disease an eight year old girl received three doses of 10 cc Bebring s diphtheria antitoun On the fifth day a red piammatory halo appeared around the site of injection Mine days after the last injection multa ple and very painful swellings of the joints developed accompanied by high tempera ture and a macular rash resembling an erythema ergudativum multiforme The aptensive symptoma lasted four days With the disappearance of the rash pain and awelling of the Joints receded In the very next issue of the Deutsche Medizinische Wochenschrít, Scholz described similar symptoms in two children and in a plıysician who developed urticana after & prophylactic injection The wfe of the physi cuan, also injected, suffered intensive pain in many joints ·INTRODUCTION 3 Succeeding authors were Cnyrim," Asch, Rembold,' and Treymann At this time a great number of publications appeared in rapid succession, which made it more and more certain that the unpleasant symptoms due to diphtheria serum were relatively insignificant One became accustomed to accept them without further ado Thus almost every publication con cerned with diphtheria serum ended with the mention of the occurrence of rashes and other annoying conditions As far as the cause of these symptoms was concerned, the opinion was frequently expressed that the serum may contain toxic substances At that time Heubner and Bolay expressed their suspicion that serum rashes may be due to substances in the serum of the animal different from the antitonn Johannesen proved experimentally that the agents in the horse serum which produces the sickness must be the horse serum itself, ze the foreign protein, as the same symptoms were seen in persons not suffering from diphtheria who were injected with normal horse serum In twenty-two individuals fever developed eight times, skin rashes twelve times Sévestre (Soc Med des Hopitaux, 31. 8, 196) thought that only those rashes which appeared between eight and ten days after injection were due to the serum itself The later symptoms, particularly the morbillilike rashes accompanied by high temperature, he thought were the effect of a streptococci infection However, even at that time Neler disagreed with him in the discussion, stating that also the last mentioned symptoms are due to the serum, as he saw the same symptoms when he used horse serum in cases of pneumonia and tuberculosis Sévestres theory 19 at present supported only by Marfan (Soc Méd Hop, 24: 3, '05), whereas we and all other authors share the opinion of Johannesen and Neter Monti, who at first agreed with Sévestre, retracted this opinion after he saw the same symptoms follow an injection of pure and sterle horse serum Almost all authors agreed that the damage due to serum injections was, as a whole, small This opinion prevailed in spite of the fact that from time to time severe cases of sickness and even death occurred in connection with serum injections Gottstein (Ther Monatsh, 5. 96) published, besides the famous Langerhans case, eight deaths in diphtheria patients and four deaths among other patients Since this publication only a few fatal cases have been reported Subjected to a critical examination, all these fatal cases may be differently explained These observations were not allowed to interfere with the victonous extension of the use of diphtheria antitoxin 1 Deutsche med och Nr 48 1894 * Berl klin Woch Nr 51 1894 * Deutache med och 51 1834 A cage of acute hemorrhage Nephritis following the use of diphtheria-serum of Bebring However, this case was not accepted by the critic ·SERUAR SICKNESS Among all of the symptoms following serum injections, the occurrence of rashes was so prevalent that all symptoms were named Serumeranthema Knowledge about serum exanthema was greatly advanced by the publications of Hartung (Serum Exanthema, in Diphtheria Jahrb f Kinderh, 1896, 72) and Daut (Statistics of Serum Exanthema, Jahrb ( Kinderh, Bd 44, 1897, 289) These publications appertained to the indindual symptoms and their frequency At first Harlung gave a complete survey of the literature to date From the statistics of the Kaiserl Gesundheitsamt be collected 4358 cases of serum injections and from other statistics 2661 cases Lxanthema occurred in 81% and 11 4% respectively of the cases He concluded that the frequency depends principally upon the serial numbers (that is upon the individual differences of the horses) and not upon the amount of the injected serum nor upon the amount of antitoxin Har. tung discusses the period of the incubation time extensively Its duration also seems to depend upon the sort of serum used he does not try to explain the incubation period He divdes the exanthemata into ferent groups and thoroughly discusses a number of other symptoms Daut arrives at similar results He describes 38 cases of serum exanthe mata in 339 cases injected He too obser ed that certain kinds of serum produced rashes more frequently than did other kinds He stresses the general scientific importance of the symptoms of serum exanthema Both authors point out the peculiar fact that these symptoms preferably appear on certain 80-called critical days It was ascertained that the symptoms of serum exanthema showed increasing intensity with increasing amounts of serum injected This observation was taken into consideration in the manufacture of diphtheria serum, since it was desired to attempt an increase in the concentration of the antitaxin of the serum Furthermore after Buurd called attention to the toxicity of fresh horse serum, it was recommended that only serum stored for a longer penod should be used for therapeutic measures From now on the frequency of rashes after serum injection decreased perceptibly But at the same time the interest of physicians in these symptoms lessened before the cause of the symptoms were sufficiently understood Only occasionally did publications about serum cranthema Appear, and then they were most frequently for the purpose of discussing their significance in the differential diagnosis of scarlet fever and measles In 1902 Riller lon Rittershain wrote (Jahrb f Kind, vol 55) as the first sentence of his conclusions "The serum exanthemata occur not only lesa frequently (6 45% against 22% in 1897) but have become in ciery respect less barmful" The same author reports 1221 cases of diphtheria patients injected with serum and agrecs in the main with the findings of Hartung and Daut He remarks especially about the difficulty of differentiating scarlatinform rashes of scrum eranthems from scarlet feser raskes Only in the last years has more attention been paid to serum symptoms ·INTRODUCTION This is due to the fact that serum therapy has been extended to other dis eases (sepsis, rheumatism, dysentery, scarletfever), in the treatment of which larger doses of serum were usually used Furthermore, biological research made it possible for us to investigate the fate of the injected serum and, to a certain extent, to study the changes which developed in the in jected organism F Hamburger and Moro showed (Wiener klin Wo, 1903, Nr 15) that not only animals but also human beings produce precipitins after an in- Jection of foreign serum F Hamburger studied in a further work (Artergenheit und Assimilation, Wien, Deuticke, 1903) the great difference be tween parenteral and enteral introduction of foreign protein He tried to explain why the foreign protein is assimilated if taken by the normal physiological route, whereas if introduced in the phylogenetically abnormal way of parenteral injection, it produced antibodies and reactions in the form of disease Von Dungern (The Antibodies, Jena, Verlag Fischer, 1903), Arthus (Comptes rendus de la Soc de biol, 20. 6, 1903), Kraus and Levadılı (Comptes rendus de l'academie des sciences, 5: IV, 4, 1903) and we were able to use animal experimentation in order to get an insight into the changes in the organism after serum injection As far as the symptoms in human beings are concerned the department of Scarlet Fever and Diph theria in the St Anna Children's Hopital gave us ample material for the study of serum exanthema The variety of the symptoms, which nevertheless belong all to one disease entity, deserves renewed interest, particu larly as the disease has findings which are very valuable for pathology as a whole Besides the possibility of following the fate of the injected serum and the reaction of the organism to it, we have, in the study of this disease, the further advantage that we are able to vary voluntanly the amount of the pathogenic agents We have abandoned the expression "serum exanthema" (Zur Theorie der Inkubationszeit, Wiener klin Wo, 1903, Nr 45) because We think that this name could easily lead to the idea that the rash was the most important symptoms of the disease, in its place we have proposed the name "serum disease" or "serumsickness" For justification of this change we shall bring proof Francione has already accepted this name in his last publication (La Malattia da Siero, Archivio di Brologia normale e patologia, Bd 58 Sept Okt, 1901) We are very grateful to our revered chief, Prof Escherich, and also to Doz aſoser for their great interest in the progress of our study We also thank Drs J Hertska, E Lazar, E Fromm, and v Reuss for their help in some of the investigations Vrenna Tune 1905 ·CHAPTER I CLINICAL ASPECTS OF SERUM SICKNESS GENERAL CLINICAL PICTEPE Subcutaneus Injection of serum produces smaller or larger swelling according to the amoant of serum mjected. The absorption takes more time than the absorption of the same amount of a phrological Naci solution, because the serum is more Vzxou. But eren 200 cc of serum are completely ab-orbed after 24 to 48 hours As a rule no other changes can be observed than local tendemess During the followmg days the site of mjection does not shot any reaction, the general wellbeing is not deturbed. Nothing pomts to the fact that a foreign substance is present in the erstem, which will lead to disease Vost frequently the symptoms of disease start suddenly between 8 and 12 days after the injection. Only occasionally may prodromal symtonas be found several days preceding the real onset of the disease. The skin 33 senative to sught irtation. Indetinct redness as seen at the site of the injection. The deighborhood 15 s httle red and itches The most constant prodromal symptom 13 a slight yelling of the regional lymph nodes At this time the disease proper starts with an eruption of skin tanile tations which almost aliars belong to the urticaria group Generally they are at first seen at the ate of the injection and its neighborhood The rash spreads rapidly over the body and is frequently found at the same time in symmetnical memons The erup*ing hires are partly pale, partly sur rounded by a red halo, the latter is seen particularly if the patient scratches a great deal. If the eruption of hires is very dense they may become con fuent, then the whole environment appears bfiltrated by edems The edeme may difigure the face The intensive itching makes the patient restless and unhappy All eruptions disappear quclls, the single urtica lasting only sereral hours, the whole eruption of hures rarely longer than 2 to 3 days A regular sequence in the further development of the tash, as in smallpox or measles, can not be seen. Jeanwhile the temperature has nsen to a more or less high figure, beng agn of the partiapation of the rest of the organı m. The sensorium hotever is free, the pula corresponds to the temperature, the quality of the pulse is good Besides the sequence of symptoms which makes the come "serum exanthema's & designation of the symptom complex plauzible, other symptoms appear We have already mentioned that the lymph nodes, regional to the site of the injection, become Lrger during the 6 ·CLINICAL ASPECTS OF SERUM SICKNESS 7 period of incubation This swelling increases rapidly with the onset of the temperature and the rash and may later spread to other lymph glands of the organism The swelling is painful with or without pressure The lymph nodes become smaller after the other symptoms of the disease have passed the height of their intensity The decreasing glandular swelling is, therefore, a valuable prognostic symptom, indicating that the end of the serum sickness is approaching The behavior of the kidney function and the appearance of edema deserve special attention The latter is almost always present as a typical symptom The edema is not only visible but can be ob jectively determined by taking the body weight daily, a method for the determination of edema inaugurated by Pirquet in nephritis With the onset of the disease the curve of the body weight rises in spite of fever and diminished intake of food The maximum of the weight curve coincides, as a rule, with the maximum of the symptoms of the disease If the edema reaches a certain intensity it can be seen with the naked eye or demon strated by pressure with the finger In its localization, the edema resembles more or less the nephritic edema However as there are usually no abnormal findings in the urine, even in cases of intensive edema, nothing indı cates an involvement of the kidney Only in the minorty of cases is albu men found in the urine several days after the onset of edema The amount of albumen is always small Never was it more than pro mulle The sediment is scarce Most frequently one finds only a few hyaline casts and some red blood corpuscles The amount of urme is less at the time of the rise in weight but never reaches anuria Whereas the symptoms mentioned are constant all other symptoms are less frequent Only the joint pam should be mentioned which due to its injury to the patient's general well-being was noticed from the beginning as one of the most striking symptoms We shall deal later in special chap ters with the variety of rashes, with the seldom observed symptoms on the mucous membrane and with the blood findings When the disease is of short duration the general well being is usually little disturbed and indeed is in marked contrast to the frequently high fever However there are cases which, after an injection of a large amount of serum, lasted four to five weeks In such cases severe prostration and intensive emaciation may ensue At the end of the disease convalescence sets in and with a rapid increase of weight, all symptoms of the sickness disappear No after effects are observed and one of the individual symptoms lead to a permanent damage A fatality for which the scrum could be considered the cause we never saw At most it might be considered whether or not, in an originally serious disease, where serum treatment 19 necessary, the last remnant of resistance may not have been destroyed by the addition of the serum sickness ·8 SERUM SICKNESS A description of the general picture of serum sickness affords great diffi culty not only because of the changing forms of the symptoms, but also because of the dependence of the intensity of the disease upon individual differences on the one side and on the other hand upon the kind and amount of the serum injected Cases of serum sickness which are from a practical point of view the most important because they occur most frequently, are cases of a rudimentary character showing only one or another symptom, most often fever and a rash The following two cases constitute an illustra tion that the same serum gen in the same amount with the same family disposition-with siblings-bas as a result similar symptoms G Leopold 10 years admitted on 12/9/03 on account of Pharynx D phtheris On 12/9 1000 Antitoxa unuts (8 cc) Diphtheria rerum On 12/13 the membranes Days 78 CO Leopold 39 Toteera ur 31 119 GRS Exentom 40 39 Temperaturu 37 Exanh: CHART I in the pharynx had already disappeared During the first 5 days the child had no fever On the 6th day rise in temperature to 39.5°C Pain in the shoulder joints Aspinn 05g without influence on the 7th day after the recent rise in temperature to over 40°C en eruption of urticaris appeared around the s te of the injection Pain in the shoulder joints diminishing Eighth day after a remission of the fever ta 3** in the morning & sudden rise in temperature to 40° After that no further symptoms (Chart I) On the chart the temperature induced by serum sickness is marked as a black field G Rosa 6-year old sister of Leopold also admitted with Pharynx D phtheris the fith any ) e ·CLINICAL ASPECTS OF SERUM GICKNESS 9 In axilla no lymph nodes that could be felt, in the groins they were lentıl-sized On the 9th day 37 39-37.2º temperature on that night eruption of generalized urticara with bright red halo, intensive itching appeared, otherwise patient lively inguine pea-Bized 11th day Yesterday afternoon and evening intensive eruption of bives Edema can be elicited by pressure with the finger Patient gained since the first weighing almost one kg , since yesterday about 350 g Days 78 14 15 211 175 B.Rudolf 170 Body Weight losi Temperatur No Fever Exanthema Urticaria CHART II 12th day Skia pale, edema still increasing 13th day Ederna receding 14th day Quick disappearance of edema Large amount of urine Skin pale No edema discernible In Stephan Th the symptoms of serum sickness, which consisted of a morbillous rash, fever, enlarged spleen, lasted 8 days Admitted with diphtheritic croup on 12/26/02 Injection of 1500 AU (8 cc) Diphtheria Berum On the 8th day after injection slight rise in temperature thout a rash On the 12th day with higher temperature there appeared morbillons eruptions over the whole body Temperature up to 39.59 Spleen distinctly enlarged 2 fingers breadth below the costal coargia On the 13th and 14th day post injecitonem, repeated morbilloug eruptions with temperature above 39* Oaly on the 17th day after jajection free from fever ·10 SERUM SICKNESS For the study of serum sickness it is advisable pot to use the more common, rudimentary forms, but rather cases with well-developed characteristic symptoms Therefore, although we describe'mostly serious cases as paradigma, it should not be concluded that such cases are the rule We selected intensive cases from a great number of milder cases in order to present special symptoms in their most characteristic form Between mild and severe cases there exist cases of all degrees of inteasity The table on page 11 gives a summary of the most important symptoms in their grouping and varied intensity In Chart III, five cases of serum sickness after injection of 200 to 200 ce of horse serum are depicted in such a way that the day of injection is shown as the first day on the chart The black field shows the fever due to the scrum sickness The temperature of the orginal disease (treated with serum) is shown as plain line We see an almost simultaneous onset of fever after an incubation of 8 to 9 days But after that an entirely different course of the fever us seen The duration of the fever fuctuated between one week (Case 2) three wecks (Case 5), the intensity of fever between 37 5° (Case 1) and 40 2º (Case 5) In a similar way we also see a different distribution of rashes edema, joint pain, lyraph gland swelling and albu minuti A rather exhaustive picture of all symptoms is shown in the following Case Karl L, 4 years, admitted on 11/9/03 Os 11/11, 80 cc scarlet fever serum were injected subcutaneously into the right loner side of the abdomen The inguinal lymph nodes were larger than pea-Bized 11/12 (2nd day. The site of the injection slightly edematous and tender 3rd day The tenderness disappeared Place of the injection and neighbourhood discolored light yellowish green 5th day Clanda unchanged Discolorization of the skin rodistract 6th day laguibal glands enlarged On the right side two bean sized, on the left side one bean sized gland 9th day laguinal glands protruding on the right side are smaller ones and almond sized, on the left side bean sized and some smaller odes in the region of the thighs and abdomen reddess of the skin 10th day Light redness over almost the wbole body, particularly on the parts wbere desquamation exists after scarlet fever Cheeks as if rouged The rash makes at Erst sght the impression of 2 scarlet fever rash By closer observation groups of very small to pea-bized hives are visible on different parts of the body Uripe con tains perum albumen Color of the urine is light yellow almost clear Sediment very scarce costa1210g (er hyaline casts stah na anapanaroth larga T JL ·CLINICAL ASPECTS OF SERUM SICKNESS 11 hives Many acratch effects Urine contains more albumpen but still less than 1% Hyalıpe casts 13th day No rash, the eyelids slightly edematous நர B, 27, 100 cm 8 63 200 cm IL 44 A DI TIT ni דידן T6J 100 cm +4 IT LAIT 11 INI LL LI + A. 9 J 200 RS LLL LA LLLL K 10 J 180 cm #!! Tiharlar (Dayr Marimum) Im Erentham. Precibe Joint Pain SAT MAIruna Lympl Gland Swing Oudent CHART III 14th day Temperature 39 1-33 5* Small eruption of lives on the dorsal surface of the fore arm 15th day Yesterday afternoon fresh small sized, slightly elevated exanthems on the ·12 SERUM SICKNESS 16th day Temperature 38 20-35 l", loose cough on the thighs jodistinct maculous erythema 18th day Vomited this morning up the dorsal surface of the legs brownish red maculous erythema The ingunal lymph nodes again larger than on the 16th day 19th day Temperature 38 92-38.24 Erythema like yesterday Scrotum markedly edematous Coughing less &mall amount of unne but do albumen No appetite 20th day Tempersture 39 79-37 9Afternoon prostrated, much coughing Skin desquamating strongly on the abdomen and at the inper ade of the extremities, eparcely on other parts of the body, spots of 1-2 sm diameter, brownish red slightly elevated, intensively pigmented, frequently confluent la the ingudal right region. two bean eized left greater than bean-sized lyropa glands 21st day Paie remnants of the rash on the extremites 22nd day No rash 23rd day Temperature 39 0°-37 1° Medium-sized indistinct maculous tasb on the thighs Ingwnal glands right, almond-9ized, left greater than besa-bized 24th day No fresh gerum byroptoms Pale reponants of the exanthema on the extrerouties Scrotal edema still present 26th day Temperature 39 09-37 4Indistinct medium-sized maculous erantbema on the thighs Inguinal lymph nodes As on the 23rd day 27th day Temperature 38 3-37 3º No rasa 28th day No fever, feels well 32nd day Zaguaal lymph nodes smaller than beang Rapid improvement 37th day Ingunnat lymph nodes much smaller, bigger than lentil-sized On Chart IV the main symptoms of serum sickness, fever and rash, are showa connected with the daily determination of body weight and with the number of luekocytes we see at the top of the chart the weight curve During the first 9 days the weight is stationery With the onset of the serum sickness the body weight increases almost one kilogram in 4 days This rise 19 visible clinically as edema During this penod of bigh temperature and breating down of body protein loss of weight is expected, which is indicated approximately by the basic line of the weight curve The difference between the latter and the actual weight determined by the scale is taken as edema and marked by a shaded field. The edemaa 29 slowly excreted along with the diminution of the symptoms of serum sickness on the 23rd day after the injection the convalescence starts, recognizable by the Dow real increase of body weight representing Dew tissue The cbart shows furthermore the leukocyte count taken daily in the morning at the sadde time on eropty stomach The characteristic of the count lies in the intensive diminution in the gjinber of leukocytes at the height of the disease The first drop takes place at the time of the eruption, another and more inantome the following manner The lughest peaks of the daily temperature (

·CLINICAL ASPECTS OF BERULI SICKNESS
13
temperature was taken 5 to 7 times daily) are connected. The rise in
temperature due to serum sickness is shown as a black field.
Below on the chart the number of eruptions of rashes are marked as
11/21
14 15
Days
zi 22
21
L.
I
M
Temporatur 39
38
37
Exanthema
CHART TV
spikes. The basic line connects the eruptions, which with respect to their
time of occurrence could not be separated distinctly enough
The amount of urine during the whole sickness was relatively small.
The daily amount before and after the sickness was 500 to 700 cc., during
the sickness 200 to 300 cc.

·14 SERULI SICKNESS THE PERIOD OF INCUBATION The serum sickness shares with many other diseases the peculiarity that the symptoms of the disease do not appear immediately after subcutaneous or intravenous introduction of the pathogenic agens Between the injection of the agens and the appearance of clinical symptoms, an incubation time exists In making this statement we disregard a little swelling, tenderness and redness at the site of the injection and the surrounding area which are the effect of the trauma caused by the injection (Chart V p 15) The period of incubation cannot be explained by the slowness of the absorption of the foreign serum This serum exerts its antitoxic (diphtheria, scarlet fever) effect within a few hours When Moser injected scarlet fever serum he found it easy to follow the absorption of the serum because the scarlet fever serum agglutinates scarlet fever streptococci in high dilution From the determination of the amount of agglutinın in the serum of the injected individual, the beginning and the maximum of the absorption can be ascertained Joseph R , 18 month old infant, was injected with 180 cc Moser serum, because it was a very severe case of scarlet fever Temp , 39 9° Afterwards, every 2 to 3 hours, blood was drawn from the ear lobe The serum part of this blood was tested microscopically for agglutinins in dilution from 1 4 up to 1 4000 against scarlet fever streptococci Whereas before injection no agglutinın could be found, already 2 hours later complete agglutination was present in dilution up to 1 16, incomplete up to 1 64 Now the content of agglutinins of the serum of the child rises rapidly and after 26 hours reaches complete agglutination up to 1 1000 From this height it drops slowly Parallel with the absorption the temperature falls as in a crisis As portrayed in the chart on page 15 the course of the temperature is reversed (drop shown as rise) in order to demonstrate the coincidence of the serum effect with the resorption of the serum Symptoms of the serum sickness (hives and slight fever) appeared in this case on the 6th day after injection whereas the antitoxic effect reached its maximum after 12 hours and the resorption after 26 hours Hartung has already observed that in more than half of his cases the serum symptoms did not appear until 10 days after injection Furthermore at did not escape his attention that serum sickness starts with preference on certain days which he called critical days Daut confirmed this observation Both authors would have found a greater uniformity and regularity in the length of the incubation period, if they had known the fact that persons who receive serum for the first time differ distinctly as far as the nomnd aannamod from manne who havenlready EIL. ال کا ·CLINICAL ASPECTS OF SERUM SICKNESS 15 1 Hours After Injection 5 8 12 17 21 250 1000 Completo Incompleto Agglutmation €4 250 1000 4000 Agglut na tion 2000 Curve of Resorpt on - Course of Temperature Drop produced 4 12 hours after Injection) 379 38:- 390- 2504 $42 399 12 17 21 25 21 Hours after Inject on CHART V strongly varying figures of other authors lies in the fact that the first bymptoms of the sickness which can be taken as onset of the disease are at times local, at times generalized All according to what one considers as ·16 SERUM SICKNESS 78 14 15 21 22 28 29 Days Body Weight 17h 1 1 E Elia Exanteme Kann CEART VI the beginning of the disease, the duration of the incubation period varies 1 to 2 days We prefer to take, for statistical purposes, the general reaction of the organism as the end of the incubation period In table 1 it is shown on which day after injection the serum sickness started The upper section deals with the onset of symptoms in 90 children in jected the first time, the lower with the onset in 45 reinjected cases The first heading contains the total number of cases, the second "questionable" cases in which it could not be ascertained whether they had received serum TABLE 1 Days {and 31:1415161718111011 ( 13 | 13 | 14 | 15 | 16 | 17 Onset on first injection Total 7 7 16 16 9 6 8 5 31 31 1] 1 Questionable Local ma 31 Oaset on reinjection 27 Total Questionable Local ERITE

·CLINICAL ASPECTS OF BERUL SICKNESS
17
before The third heading called "local' contains the cases which had only
local symptoms (rash, edema at the site of the injection) It can be con
2575
Days
78
14 15
21 22
28 29
4
Body Weight
Leucocytes
Irantz
z50D
CHART VII
cluded from the figures in 90 cases of children injected the first time that
the average incubation period 19 8 to 12 days All statements made in this
chapter deal with the first injection Reinjection will be discussed later in
A separate chapter
From the table it can be seen that in the case of a first injection ther

·18 SERUM SICKNESS of symptoms occurs rarely before the 6th day Such a case we report on page 85 (Gustave P) The duration of the incubation period seems to depend for the most part upon the individual disposition of the injected child It does not depend upon the amount of serum injected The vanations in the length of the incubation time, which are conditional upon the different qualities of the injected serum, are relatively insigificant when one uses horse serum We did not observe that certain kinds of serum Here combined with certain days of duration of the incubation time (Har tung) Whether the human being reacts to serum of animals other than the horse at different times were have too little experience to say Netter (Soc med des hop, 1:31, 1896) reports a child who showed, after an injection of 6 to 7 cc antipneumococcus serm of a rabbit, symptoms on the 12th day Dallera saw generalized urticaria 10 days after transfusion of lamb blood Much less frequently than in acute infectious exanthema do slight disorders of the general well being occur during the incubation period As & rule it is completely free from symptoms The onset of symptoms of disease earlier than the 8th day shall be discussed later in the chapter on "Reinjection" FEVER Since the days of TVunderlich there has been the endeavor to find a characteristic fever curve in diseases accompanied by fever Since then the course the temperature ran could be used for diagnostic purposes just as other symptoms of the disease With the varying intensity of all serum sickness symptoms we could not expect to establish a definite, unchangeable type of fever, only the following propositions can be made, particularly in regard to those cases, which received a greater amount of serum. 1 Fever is one of the most frequent symptoms of serum sickness It 18 more frequently observed than is the rash If one should want to name the disease according to the most typical symptom, one would be more correct to talk of "serum fever" than of "serum exanthema" 2 The fever lasts until the end of the clinical symptoms of serum sickness 3 The type of fever is a remittent one, the daily oscillations are 1 to 3 degrees It occurs less frequently that the temperature in the morning 13 also high Towards the end of the symptoms of serum sickness, when nor mal and subnormaal temperature are often seen in the moming, 4n intermittent type develops 4 A certain connection exists between the temperature curte and the form of exanthema The highest temperature is seen in measles like (maculo-papulous) eruption, the lowest fever is observed with pet libe erythema, whereas urticaria and scarlatiniform rashes are in between ·CLINICAL ASPECTS OF SERUM BICKNESS 19 2 5 In general the height of the temperature does not permit one to judge the duration and intensity of the disease 6 The duration and intensity of the fever depend partly upon the amount of serum injected and partly upon the individual disposition Comment 1 and 2 Our statement, that after an mjection of a large amount of serum, fever is more frequent than a rash, refers only to the fact that at the height of the serum sickness the rash may be absent, whereas the fever continues From Chart III we see clearly that fever occurs more constantly than the eruption of rashes In case II (S) perod of fever lasting 3 days exists between the first and second eruption of rashes, in case III a 4 day period In the latter case no eruptions occur from the 16th day after injection although the fever lasts more than one week longer In case 4 we see fever existing throughout 8 days without a rash Still greater differences exist in case V We lay great stress on the discussion of these facts in order to show that the term serum exanthema is not useful However we do not want to be misunderstood as far as the fever is concerned Enough cases exist where the fever is completely absent This loose relation between temperature and form of rash makes it clear that the fever is not to be considered as the effect of the exanthema Fever and rash are coordinated effects of one cause In favor of this sentence speak the facts mentioned in point 3 Comment 5 For the correctness of this statement the previous charts show examples Franz D (see p 20) shows at the beginning of the sickness a low ternperature for 3 days The physician who would have expected a mild and short duration of the disease would have been disappointed For on the 16th day fever started again, this time very intensite, lasting 10 days High temperature of short duration 19 seen frequently after an injection of a small amount of serum (Diphthena) The same observation can be made by an injection of a large amount of serum Erna E, 150 cc scarlet fever serum Incubation period 10 to 11 days Slight in crease of weight (edema 2) with high temperature The form of eruption 19 between in o A na TL L. nnn #ha whola dugA excellent pes in 9th-11th day Trousseau unchaoged 12th day Temperature 3769-37° Siace this morning disseminated over the body, indiatiact, bright red, slightly elevated lentil-811ed spots, in the left anlla a ·20 SERULI SICKNESS packet of lymph nodes more than besa sized, in inguine both sides many small 19olated lymph glands 13th day Today an intensive eruption of a serum ragh Intensively red spots elevated up to lentil size densely located on the tensor surface of the extremities, frequently confuent, fresh papules standing singly surrounded by bright halos The eruption is between erythema multiforme, urticana, and morbilli On the side of the neck just palpable lytaph nodes, in the aulla packets like yesterday The inguinal lymph nodes are somewhat tender as yesterday Temp 39 3º-33 * Muld atching General condition good 14th day The exanthema has progressed slightly Apparently the same eruption is present, it has progressed at the periphery The center of the spots 13 pigmented pale, greyish brown the periphery elevated and dusty red 15th day The same eruption present, it has progressed slowly down to the middle of the abdominal wall Beautıful multiform syri on the lips The site of the injection does not show any reaction On the old field of eruption (tensor surface of the extremities) over brownish cyanotic grouod & new eruption appears with bright halos Lymph glands in the left anlla unchanged tender Inguinal lymph nodes on the left Bide somewhat larger than on the right 16th day Temperature 39 0° 39 O® Slept well Eranthema spread to the left side of the abdomen, the rash on the extremities paler, pigmented Left eye sunken Conjunctiva both sides injected General condition good 17th day Temperature 39 99-37 69 Yesterday afternoon a sudden new eruption of Arash covering the whole abdomen Today no fresh eruption, all over greyish brownish pigmentation In spite of high fever yesterday the patient felt well 19th day Temperature 38 0°-37 6° General condition good Discharged on the 32nd day, cured Franz D Hospitalized 5/2+-7/5/01 Lymph glands Chart 7 D 17 NOM Lant Axıllar 0 0 Inguinal From palpable to lentil sized Spleen soft, 1 cm behind the costal margin Oa 5/25 intensive ecarlet fever (III) At 7 pm, 200 cc Serum 14, dated 2/12/04, was injected into the right side of the abdomen Bad day Around the site of the injection distinct swelling 7th day Lymph glands not changed 8th day Inguinal lymph nodes over lentil Bized 9th day Temperature 37 80-37 2° On the region of the upper third of the rigåt tibia bome pale hives which itch intensively Inguinal lymph nodes the Battle 10th day This morning isolated eruptions of bives, at present indistiact 11th day Temperature 384-37 2° Yesterday eruption of huyes Face somewhat swollen Fresb, mostly large-sized urticaria on the skin of the right side of the body, particularly on the cheek and on the outer side of the right thigh on the left side only a few hives and they are smaller Inguinal lymph nodes the same, but they ate hard and succulent Throat clean 15th day Na fever an erantbems 1 ce un . y - ·CLINICAL ASPECTS OF SERUB SICKNESS 21 mities, and the dorsum of the hand The maculae are isolated and elevated over the level of the akın Many ingwnal lymph nodes are lentil sized and succulent .: 11. Voctor. AAA LL. h mond ..not like design Feet On each side an nghe Axillar glands Small pea-sized Pea-sized Ingunal glands Pea-sized Below pes sized The mucous membrane of the mouth pale Spleen enlarged, palpable at the costal margin 20th day Temperature 39 7°-38 4° Yesterday repeated eruptions of rashes Today a map like rash on the face, at the border a somewhat elevated, bright red, ring The center is pale, showing normal skin On the lower lip, about in the middle, a group of herpetic vesicles Patient feels well 21st day Temperature 39 62-33 8° Also yesterday, all day, & rash Today pale remnants on the face wbich 19 edematous Maculo-papulous eruption on the lower extremities Herpes vesicles dred up Bad humor Ioguinal lymph nodes pea sized 22nd day Temperature 39 7°-37 5° Yesterday again numerous morbillous erupt1078, particularly on the calves Today the ragh 13 pigmented with a cyanotac appearance. --besides thus rash, isolated, fresh, morbillous eruptions On both fore- Arme numerous, up to lentıl sized, in the center paler, eruptions, definitely elevated, and at places, confluent Similar eruption on the thighs and in the left epigastric region Lymph nodes in inguine numerous, pea-sized, and succulent 23rd day Temperature 400-37 2° Yesterday during the height of the fever, prostrated, at night quiet Yesterday's rash faded at the border of the old eruption On the forearm and lower extremities fresh eruptions The eruptions show irregular borders The maculo-papulous spots have an elevated border are bright red, yellow 18h in the center, and sunken Throat clear 24th day Temperature 39 2° 37 4° Yesterday and today very few new eruptions T-LL tled pigmentation on the extremities 27th day Temperature 38 6º-37 2° No ragh any more 28th day Temperature 37 8º-36 8° Glands less swollen 20th day No fever 36th day Inguinal lymph nodes smaller than lentils Now we report some cases which do not exactly correspond to the above mentioned relation between fever and certain eruptions Intensive urticanis eruptions without fever were reported by us before The folloning 19 a case where urticanal and morbillous eruptions showed the same intensity of fever ·22 SERUM SICKNESS Henriette N 100 cc scarlet fever acrum No 14 on 8/19/03 On the 6th day after the injection, following a lymph gland enlargement, fever and urticaria appeared which lasted five days Traces of albumen in the urine on the 9th 10th and 11th days after injection Then a lessening of the fever, of the lymph gland swelling disappearance of the albumen from the urine Wirth & new rise of temperature lymph gland swellog and albuminuria Morbilli like rash mth small sized macula This eruption started twelve days after injection Nice weight curve, spleen 19 swollen Days 7 & 14 15 21,22 27 NC Hennote Body Weight 1 ti 39 Temperatur 38% Erantnome lihat 1 Ren 6170 CISART VIII The type of the temperature of the first symptoms of the serum sickness is that of a continua During the morbillous eruption, the intermittent character of the fever curve becomes distinctly evident The amount of urine was not substantially changed Complete Case Report (Chart VIII) Became sick on 8/17/03 with sore throat On 8/10 in the morning vomiting of mucus, then fever and scarlet fever rash Injection of 100 cc scarlet fever scrum tha 1 1 Lalande ·CLINICAL ASPECTS OF SERUM SICKNESS 23 During the first days some tenderness at the site of the injection but no other reaction 7th day Siace yesterday afternoon urticaria on the abdomen, since the evening & generalized eruption of large hives with red halos, temperature 38 99-37 6° Spleen not enlarged Lymph glands enlarged 8th day Continuing generalized eruptions of medium sized urticaria The skın 19 cyanotic, showing a design composed of small spots, at the buttocks net-like hemorrbages are visible, all over the body are scattered lentıl sized hives with broad, red halos Many effects of scratching The inguinal lymph nodes protrude very much, forming on the left side almost a date-sized packet, on the right side about bean- Bized glands, crural glands bean Bized In each a ulla a hazelnut-sized packet of enlarged glands, at the neck many glands over pes-sized, one gland at the maxillar Angle 18 bean-sized Spleen hard and firm, palpable at the costal margin The mucous membrane of the mouth 18 pale Traces of albumen in the urine Bure At the lower extremities and on the face a scarlatınıform rash Lymph glands rather smaller Spleen palpable at the cogtal margin Feels well in spite of high fever Much scratching Traces of albumen in the urine quiet than usual The eyeballs injected Trace of albumen in the urine Ilth day Skin delicate, only indistisct remnants of the rash, temperature 39 6° At night restless, apparently joint pain, but the patient denies it with great atubbornegg Lymph gladda definitely a little smaller Spleen at the costal margin On the posterior part of the skull more than pea sized lymph nodes Fine scaling on the face Lesg edema Weight decreasing 13th day Temperature 37 7º-37 3º Quiet, no ragh Joint pain less Face only a httle edematous Inguinal lymph nodes softer and emaller Throat clean and pale 14th day Yesterday afternoon a general eruption of a pale rogy red rush At night restless This morning & bright red, emall, slightly elevated fresh eruption, on the had ametrtrally bean gized In right axılla up bean-sized glands At each side of the thorax wall a lentil-81zed gland At the neck many pes-sized glands At the occiput (right ede) one pes sized, left, a lentil-sized gland Body weight decreasing Urine free of albumen 15th day Night quiet Temperature 39 6-38 6º On the calves, on both forearms, a pale red, rather dense, small, not elevated eruption, some areas showing a ring formatsop Gladds the same In the urine again traces of albumen 16th day Temperature 39 92-37 7° Yesterday new eruptions The face in spite of loss in weight 19 more edematous All Over fresh eruptions, loosely scattered some confluence produces net-like designs Most dense 19 the eruption on the tensor surface of the upper extremities, on the calves between the scapule The right occipital gland 18 tender Traces of albumen in the urine ·24 SERUL SICKNESS 17th day Temperature 39 89-37 69 Quet at night Yeaterday during the day new eruptions, morbstli like is character, especially localized on tbe csives Today pale remnants of them are visible, some new eruptions scattered over the body Face distinctły edematous Trece of albumen 18th day Temperature 393-37 8º Quiet, face less swollen On the kide wall of the thorax and on the lower extremities pale remnants of rash The spleen can be reached behind the costal margo Trace of albumen 19th day Temperature 38 4-37 2* Nonew rash Skin pale, dry edema unchanged Glands everywhere smajer sad softer The two occipstal glands hardly palpablo anymore Pendulum rhythm of the heart 20th day Temperature 37 70-37 3º Skin pale and dry Body weight decreasing Glands ia inguide on the right ade pea sized, on the left ade nearly bean-sized, others pea-Bized 23rd day Glands in inguste over pes sized tot succulent any more 25th day Out of bed on 31th day discharged Eduard G 4 years old 10/8-12/12/03 Medium severe scarlet fever, was injected with 100 cc Egmont" serum Inginal lymph node palpable 8th day No fever Juist bow fat, skin colored hrves appear loguinal glands, left ade just palpable on the right side bean sized och day Temperature 37 40-37 2° On different parts of the body lentil-and larger sized beves erupting without red halos Patient complains that he is bitten by fless Left 12 inguine pea sized right one over bean sized and several pca sized glands In the right axilla a pea-Bized gland 10ch day Still more eruption of isolated bives without balo 11th day Yesterday the patient said. These are too many animals, I won't he here anymore in bed ” Continuous eruptions of urticaria, at the rounds pes Bized and larger pale fine somewhat elevated hives, exclusively on the extremities Inguinal glaads on the right side somerhat larger than on the left No len er 12th day No fever, feeling well few pale kives on the outside of the extremities Here we tee a case with intenaive eruptions without lever The following case runs a similar course Olga L 3 years old 1/2-2/13/01 Injection of 200 cc ecazlet Sever Rerum No 4 (Fine), dated 10/7 on the right side of the abdomen injected on 1/2 mmdzight 9th day Temperature 37 5° 37 O® Skin pale only one kuve on the skin of the back 10th day Glasds bat egterged lith day Iesterday afternoon at 3 o'clock an sotensive, dense eruption of huvca on the dorsum of the hands At 10 o'clock 18 the eveniog fresh urticaria eruption at the site M the injection and surrounding area not crossiog tbe msdliae Today only one fresh have on the dorstin of the night hand otherwise over the extensor surface of the upper extremitica and on the dorsum of the hand irregularly formed red spots 83 well as scattered on the item appareatly lading bives 131h day Yesterday more eruptione ol bıyes over the whole body, of which at present only pele irregularly formed remeants are viable No fever 13th day Distinct new hiver on the nght forearm and on the doraum of the left band Some hives also aver the raper malleolus of the night 1oot 14th day No fever Yesterday some eruption of lives Comment S The fever 8 semittent in character ·CLINICAL ASPECTS OF SERUM SICKNESS 25 Io typical cases the fever almost never reaches its toiximum in one day, usually the rise to the maximum develops gradually 'The fever drops showng a steep curve with a deep remission in the morning Days 1 14 15 21 22 21 29 19 Temperatur 31 37 22 38 4 32 23 CHART IX We report the following scien cunes in Chart IX in which the fuser us represented by a design different from the previous ones, in that re marked not only the maxima but also the minima of the day Curses 2 and 3 are ·26 SERUM SICKNESS the fever chart of two injected siblings Note the similanty of the course of the fever Other types of fever also occur, but they are much rarer No characteristic fever curve can be demonstrated for rudimentary forms of the disease Through the gradual lytic drop in fever always showing a declining rise in the afternoon, the fever chart becomes as valuable a guide for the prognosis as the edema and lymph gland enlargement, uhich will be discussed later Comment 6 Daut and von Rittershain established that the incidence of serum sickness falls with the amount of injected serum In the first period of serum injections for the treatment of diphtheria when 10 to 30 cc of horse serum were used, symptoms of serum sickness developed in 22% of the cases Von Rittershain reported later a drop from this figure to 6 45% due to the fact that it had become customary to use A reduced amount of serum (6 to 15 cc) The best proof for the correctness of the statement that the incidence of serum sickness depends upon the amount of serum injected lies in the fact that, after an injection of 100 to 200 cc serum, we observed serum symptoms in 85% of the cases We can conclude that the disposition for the disease is an universal one If we increase the amount of serum still further, finally every individual would develop serum sicknesz Whether an individual develops serum sickness after injection of a small amount of serum depends upon the disposition of the individual As it was to be expected, the intensity of the symptoms also becomes decidedly stronger with an increase in the amount of the serum Symptoms of such long duration as we have seen in cases which were injected with large doses never occurred after an injection of smaller amounts of serum (Chart III) We may regard as proof of the influence of the individual disposition upon the course of the disease that sera, which otherwise only infrequently produce serum sickness, led to equal symptoms of serum sickness in sib. lings Siblings may show great uniformity even in certain anomalies of the course (as for instance, an abnormally short incubation period after a first injection), as siblings G reported on page 8 The following two cases give further proof of the similanty of the fever curve in siblings Joseph W 21 years, 10/24-12/8/03 Medium severe scarlet fever 10/24, 200 cc serum No III, dated 1077, 03, injected at 10 00 pm Glands before injection right kt Aullar Peas Peas Inguinal Small beads 2nd day Site of injection painful 4th day Glands still unchanged 8th day Tho temperature rises again to 38 99-37 9° Yesterday 8 cc diphtheria ·CLINICAL ASPECTS OF SERULI SICKNESS 27 serum was injected into the right upper arm At this site after 15 hours a local erystpelas like reaction 9th day on the stem a pale red emall- and medium-sized, slightly elevated stanthema, denge on the abdomen, acarcer on the chest Left abdominal side show, more rash than the right Yesterday's erysipelas-like redness 18 paler today surrounded by 1 cm wido, intensively red, somewhat elevated halo, the latter again shows indented and island like extension Glenda right Aullar Peas Many under bean-sized Inguinal Several bean bized One bean-sized 10th day on the stem and upper arm & rash consisting of yellowish-red, lentileized, slightly elevated maculae The areas of the previous rash on the abdomen and on the left flank show pale, confluent, redness and pigmentation, similar redness 19 seen at the site of the injection on the arm in a radius of about 8 cm At the periphery atill a bright red zone with little infiltration Glands nghe kart Axullar Peas Several under bean bized Jaguinal 2 over bead-sized bean-Byzed Crural Under bean-sized Temperature 38 92-36 8º, feeling well 11th day The whole body shows mottled pigmented remnants of the tash Spleen not palpable Lymph nodes right left Axillar Under bean-sized Inguinal Over bead-sized Bean Bized 12th day 3390-37 5° On the extremties bright red, frequently confluent, mottled, otherwise pigmented, faded, remnants on the right arm The side of the diphtheris serum injection and its neighborhood is like the site of the injection in the abdominal ekin 13th day Temperature 38.80-37 2* Fresh, bright red, shghtly elevated rash, multiform with pale center, partly flat, partly showing lentil sized maculae Cheeks rogy, as if rouged red Glands ter Axillar Many peas Bean-bized laguinal Many over bean- Bean-sized Bized ROM Spleen palpable at costal margin 14th day Skin on the thighs shows many creates Inguinal region deequamating, otherwise skin pale 15th day Since last evening a new eruption of rash, today pale to bright red, netlıke design, on the back and tensor surface of the arms Lymph glands nake Axillar Several below bean-sized Bean-eized Inguinal Bean sited, almond Several bean-sized Bized Spleen not palpable ·28 SERURI SICKNESS 16th day Tetaperature 33 72-37 2º. Yesterday afternoon and todsy fresh eruptions of bright red net-like erythema 17th day Continuous eruption of new rashes At the rounds, pale, det-like, design op many parts of the body Fresh eruption on tbe skin over the calves Skin very irritable 18th day Freshi net-like design on the back 38 438 1Glands as on the 15th day 19th day Temperature 4019-37 1“ In spite of bigh temperature yesterday, Jvely aod gay At night quiet On the back and tensor surface of the arts and lege, fresh multiform erythema Strong hemorrhages on places with pressure in the sacral region brownisk purple palm-sized discoloration composed of confluent lentil-sized 2930 Days 3.15 21 22 Body Weight w Josef 2415 Temperatur Exantheme mo CAART X muculi, which do not disappear upon pressure of hoger The skin on the jonide of the thighs, wrinkled, scaling Bronchitis Lymph glands nght and left Axillar Under bean-sized Inguinal Bean-sized 20th day Pigmented remnants of the rash of yesterday Fresh angajake bands along the right outer margin of the foot No scratch effects Bad humor Frequent loose cough 21st day Indistinct remasota of the rash No fresh eruption 40 2-37 5° Night very restless Mornings much loose coughibg Lungs rough breath sounds in the evening one stool mited with blood Microscopically mucus, red blood cells, very few white cells Serum reactiop with borse serum, 1 1, ao precipitation, with rabbit antihorse serum, distinct precipitation 22nd day Spleen at the costal margio Lymph glands ·CLINICAL ASPECTS OF SERUM BICKNESS 29 hole and left Axiller Many smaller than beads Inguinal Bean Bized Much loose coughing Breath sounds very rough particularly posteriorly Five soft stools with mucus, one almost entirely bloody 23rd day Glands nght and left Aallar Many larger than peas Inguinal Bean sized Since yesterday morning no etool and little coughing 24th day Temperature 38 9-36 7° Stool normal legg coughing and quiet at night 27th day Convalescent Patient in good apirits Little coughing Lymph nodes night Left Axular Pes sized Larger than peas Inguinal Bexa Bized Bean sized 35th day Several times net like macular red spots appeared and disappeared rapidly 45th day Nodes nose Axullar Many pea sized Inguinal Two bean sized Two smaller than beads Adolf W 4 years old 10/28-12/8/03 Severe ecarlet fever (No III) Inguinal lymph nodes on the right side larger than pea-sized On 10/20 at 3pm 200 cc Scarlet fever serum (Egmont) Temperature fell 28° 2nd day Skin of the abdomen tender 3rd day On account of positive culture for Diphtheria bacıllı 2 cc (600 A U ) Berum were injected Place of injection less tender glands unchanged 4th day Glands nghe ks Axillar Over pes Bized Pea-bized Inguinal Smaller than beas Bized (60th) 5th day Temperature 39 0° 38 0° Glands regte Axlar Several bean gized Pes-eized Inguinal Under bean sized r1 7th day Temperature 38 6-38 1° 8th and 9th day Temperature 38 70-37 1° Glands not changed 11th day Glands Axillar Over pes-rized Almond-sized Ingutnal Over ben sized Over bean sized 12th day Numerous pia point hemorrhages of the skin of diverse coloring scarce on the outside of calves and elbow very numerous ad nates and on the inner surface of the knees Otherwise the akıp 29 pale ·30 SERUM SICKNESS 13th day No new hemorrhage 14th day Temperature 38 70-37 49 Quet, bemorrhage almost disappeared Glands y and left Axillar Uoder bean-sized Inguinal Bead-sized 15th day Temperature 38 7° Night restless Since this morning a pale red small Bized, net like erythema eruption on the tensor surface of all extremities Stem free 16th day on the extremities pale brownish red pea-Bized pigmentation, as after measles Axıllar lymph nodes below bean size (both sides), inguinal glands bean Bized Doys 14 15 21 22 28 29 35 don in my 10 JY Temperatur 3 37 Ecantheme 19mmm CHART XI 17th day During right in very bad humor, at the time of tbe rounds felt better Rosy red, multiform, exanthema on the outside of the extremities Otherwise rem Dants of piginentation stem still entirely free Axillar glands right legs than bean- Bized, left bean sized, tender, inguinal glands, right, more than bean sized left, bean-sized (Chart XI) 18th day Since previous night, erythema multiforma eruption on arms and legs, garland like, pale brownish areas Outside of these areas are pea sızed, fresh red maculae Similar ones appeared on the abdomen, neck, and face Nose and forehead show confluent redness Eyelids slightly edematous Only the chest is free from a ragb At the right sogle of the mandibula, swellings that are tender 38.50-37 7 19th day Continuous new eruptions of erythema multiforme Lymph glands nght and left Allar Under pes Bized Inguinal Bean-sized Temperature 38 99-37.3* During the Dight 12 a bad humor ·CLINICAL ASPECTS OF SERUM SICKNESS 31 20th day on the outside of the extremities, scattered pea- to bean sized, bright red eruptions with a pale, pigmented center loose cough Lymph nodes nh Aullar Pea-gized Inguinal Bean Bized Below bean sized At the rounds, pale brownish, slightly elevated pea- and bean sized maculse at the outside of the extremities 23rd day No new rash Temperature 39 49-371° Before mdaight very restless 24th day Tenperature 39 8°-376° Night quiet Rapid respiration Indistinct pigmentation Lymph nodes nghe teft Axillar Palpable Palpable Inguinal Under bean-sized Been-sized 26th day Rash disappeared Serotum slightly edematous Appetite better Temperature 38 59-37 4° 30th day Yesterday and today rapidly disappearing reddish net like exanthema on several parts of the body No fever, feels well 40th day Ingunal glands less than bean gized As we have mentioned, 15% of the children treated with large doses of serum showed no clinical sign of a disease This low disposition of single individuals does however not mean a complete lack of sensitiveness It is to be assumed with certasnty that with these persons the same occurrences run therr course (in principle) the intensity of the alteration however does not reach the threshold of clinical perceptibility That the first injection alters the organism 19 a well defined manner, in spite of the absence of serum sickness, can be concluded from the fact that individuala who did not show any reaction after the first injection, behave when they are reinjected, in the same way as individuals who reacted the first time (see Chapter II) THE EXANTHEMATA This symptom which 13 80 outstanding in serum sickness reveals itself in a great multiplicity of appearance The skin is inexhaustible in its production of peculiar pictures Hartung has already classified the rashes into four groups according to their appearance I Urticaria 2 Scarlet fever like exanthemata. a) Diffuse like an erythema b) Sprouting (really similar to scarlet fever) 3 Morbil or rubella lile eruptions 4 Polymorph exanthemata, among them exudative forms Every observer will encounter cases which do not fit even in this many ·32 SERUY SICKNESS groups We think that it would be better not to set every forta of rash apart from the others because many cases show rashes which could be put, for example, either into the urticaria group or, on the other hand, also into the morbilli like group Transitional forms demonstrate that in reality Do sharp line of demarcation exists as one would assume from the aspect of typical rashes As urticaria and morbilli like rashes are not so far apart We can still find even many more transitional forms between morbill like or rubella like eruptions and exudative erythema multiforme We believe that the condition of the skin as organ determines the form of rashes more than the exciting cause In favor of this statement are observations in cases with numerous repeated and varying rashes The first sash belongs in most of the cases to the group of urticaria Frequently new eruptions of urticaria appear for days at new areas, until the whole skin becomes involved After this form of eruption has terminated and a new eruption takes its place so it is the general rule that among such rashes no urticana eruption is to be found The same can be seen when after a second eruption, a third and different rash appears To separate sharply the different forms of rasbes would be justhed only if we would make the rather unlikely assumption that in the serum different substances exist, each of them capable of eliciting different, specific rashes But then it would be necessary further to theorize that each of these substances must have a different incubation time, because almost without cxception the morbillous raskes follow the urticaria, never the reverse A further support of our opinion that the form of the rush essentially depends upon the condition of the shin, is given by the behavior of the eruptions after a reinjection We shall see that in cases of reinjection all symptoms therefore also the exanthemata, appear earlier than after the first injection, and also come to an end more rapidly If different substances were present in the serum, which could elicit different forms of exanthe mata, then after reinjection we should observe different forms of rashes simultaneously, or one quickly after the other This almost never occurs As far as generalized rashes are concemed, they almost always belong only to the urticaria group The observation of the course of rashes spreading over the skin of the body is made difficult because of the freeting character of the eruption Urticaria eruptions are frequently preceded by redness, accompanied by itching and then only does a hive appear in the center of the red area In one case we tried to follow exactly, hour by hour, how the eruption spread over the body, but we do not describe this case in detail, becrusc even here we could not discover any definite law We wish to state only the following generalizations 1 Most frequently the rash first appears at the site of injection Somo- ·CLINICAL ASPECTS OF SERUM SICKNESS 33 times this local rash is the only symptom of the disease, as far as the skin is concerned 2 The eruptions on the rest of the body are mostly symmetrical 3 The urticaria eruption 13 accompanied by intensive itching 4 The morbilli like and exudative eruptions are localized on the tensor surface of the extremities We now describe some cases where many and intensive eruptions oc curred in the case of Egon E (Chart XII page 34), we see urticama of a four days duration, after a short intermission varied rashes appear, which according to their localization and appearance, must be called multiform The onset and loss of edema is nicely shown on the curve of the body weight Egon E 10/8/03-12/6/03 At 7 pm 10/8 200 cc serum No 14 dated 9/18/03 10jected into the right side of the abdomen In axıll.1 and inguine several lymph glands up to pea-sized right and left 8th day Since yesterday evening eruption of urticaria At the rounda very large bright red areas in the center of which huves are visible (on the knees hands thighs) On the abdomen a rash which looks as if the scarlet fever rash had reappeared Inguinal lymph nodes at the right side several bean bized at the left side somewhat smaller Mucosa of the mouth pale Spleen not palpable 9th day Yesterday repeated eruptions of urticaria Today still partly macular like and confluent redness showing (particularly on the back) partly fresh urticaria eruption in the region of the right shoulder and on the tensor surface of the right knee joint intensive itching At night quiet Face decidedly edematous also the dorsum of the hand gwollen by edema The hands are slightly cyanotic The lymph glands 10 the right inguinal region are succulent over bean sized apparently some what tender On both sides the glands are protruding Conjunctiva pale Throat clean Spleen can be reached Feet cold Ana Llora Cont nously 10 L T Lw 1 - truding Ilth day Temperature 40 20 33 8° Very bad humor Skin on the stem dirty brown Extremities spotty as day before (fresh gyrı) Lymph nodeg more protruding 12th day Temperature 39 8° 38 0° Nose and upper lip slightly swollen and red dened on the lower part of the extremities fresh eruptions of erythema exsudativum multiforme On the gray livid skin lighter brick red irregularly defined areas the centers of which appear greyish blue smaller red spots with indistinct colors are distributed over the body Nearby much pigmentation in the region of the . 2 On certain areas fregh multiforme exanthemata Throat pale Lymph nodes nptt Axillar Many less than bead-sized Pea-sited Lagunal Sausage like protruding Same

·34
Day?
26 25
35 36
Ei Egon!
Body Weigh
SERUSI BICKNESS
Zymph 61
Swellirt
Temperat
Exanthe -
HL!
CHART YIL

·CLINICAL ASPECTS OF SERUS SICKNESS 35 14th day Temperature 40 0-33 5° New universal eruption of erythema multiforme, particularly intensive on the extremities Patient 19 in very bad humor 15th day Temperature 401-38 1° During night rather quiet Poor appetite Face, specially in the region of the eyelids, edematous, circa 1 20 kilograms of edema The face showg & rosy red, net bke design, a similar design within the hair area of the skull On the arms, medium sized, macular, often confluent, erythema On the thighs, similar eruption, on the calves and feet ring kke eruptions The ring appears to have an intensively purple color, which does not disappear upon pressure The center 18 livid, near by slightly elevated, brick red areas (erythema multiforme), the toes are livid Spleen not palpable, cubital glands pot palpable in the right anterior axıllar line in the height of the third intercostal space, two pea-sized lyraph nodes Lymph nodes nale Left Axillar 3 to 4 hard, pea-gized Same Inguinal Intensively protruding, A little emaller hard, sausage like bean- Bized 16th day Yesterday's emall sized rash has entirely disappeared on the extremities brownish, livid, large design (pigmentation after erythema multiforme) Feet and doraum of the band, confluent, livid brown Glands lke yesterday Temperature 40 5°-39 5º Quiet night 17th day Temperature 40 2-37 6° Appetite better Loss of weight, 1 kilogram Stem and head free from rash On the extremities, near the livid remnants, fresh eruption of erythema Glands rather larger, spleen not palpable Yesterday in spite of high fever, temperature labile 18th day Temperature 40 10-374Condition again worse Yesterday four mushy, then four brown bowel movements with mucus In the evening eighing, but reapiration not accelerated Very exhausted and tired on the extremities very widespread multiforme eruptions, the previous pigmentation has disappeared on the stem remnants of the rash No new eruption in the urine questionable trace of albumen Sediment contains no renal elements 21st day Temperature 39 3º-37 6° No rash Feels well Swelling of the glands almost gone Lyınph glands right Axıllar Less than pes-sized Same at the thorax Inguinal Bean-sized Legg than beaa Bized, Dot protruding any more 22nd day Axıllar lymph nodes hardly palpable In inguine on the left ade peasized, on the right side larger than peas Temperature 37.89-37 4 23rd day No fever (without aspirin) Edema ercreted Tired Appetite better 27th day Temperature 376-36.8° Axillar and joguinal lymph nodes pea-sized 31st day Glands the same Feels well 40th day Yesterday at 10am injection of 1 cc diphtheria serum, for immuniz9- tron, in the right lower arm (Reinjection) In tbe evening, temperature 38 14, arm ·36 SERDAL SICKNESS Bollea At rounds the right arm 19 tightly swollen from the middle of the upper arm down to the fingers, the skin is diffusely red, bot, but not very tender Carcum ference of the lower arm is 18 cm (wbereas the left aron measures 14 cm) Glands in the right arillar less than bean-sized, left pea-Bized 41&t day Yesterday from noon to evening eruption of intensively red, about leotit sized maculae particularly on the chest, face, and external surface of the thighs Today at the rounds the skin looks normal, the night arm intensively swollen like yesterday, here the skin 19 pigmented brownish greenish (at the place of yesterday's diffuse red) Temperature 39 40-37 40 Axillar lymph nodes, right bean sized, left pea sized, inguinal glands left hardly palpable 42nd day Temperature, 37 74-36 8° Still small swelling of the arm greebisb Olto D In this case & three-day urticaria period was followed by a twoday period of a morbillous eruption The duration of the sickness was short The edema was slight The snelling of the spleen and the behavior of the leukocytes was remarkable Ono D 5/23-7/5/04 Scarlet fever of medium severity Inguinal lymph nodes, right, lentil eized left, pea sized 5/24 At 3 30 pm, 200 cc berum Vienna No 4 dated 2/12/04 10jected into the right side of the abdomen 2nd day The side of the injection tender, the surrounding area of edema reaching the modine slightly edematous 3rd day The site of the injection less tender 4th day The site of the injection no longer swollen 7th day Glands uncbanged 8th day Inguinal lymph nodes right larger than leſt Many podes smaller than bean sized but not painful On right, one more than beau-szed, Dearby pen-sized glands No definite rasb 11th day Until this morning without ſever A universal eruption of iurge pebay- Bized pale lives without red halo most intensively on the forehead, Dear the site of the serum injection and on the calves Intensive itching Glands Ike yesterday Wbining disposition 12th day Temperature 38 39-37 3º Yesterday during the day more eruptions of pale urticaria Today some fresh eruptions scattered over the body 13th day Temperature 38 0°-38 4° No rash 14th day Temperature 39 6º-37 89 Tho glands in joguine up to pea size 15th day Temperature 39 42-37.8° Quiet Yesterday repeated cruptions of & morbillous rash on the cheeks and other parts of the body, mostly on the extremities Small spots are seen on the lower extremties, few on the stem, most numerous on the upper parts of the chest anteriorly Cheeks somewhat cyanotic, face intensively nal olan la larger than dea- -

·CLINICAL ASPECTS OF SERUM SICKNESS
37
16th day Temperature 38 70-37 3º Yesterday no more ragh, also today no rash,
ekin pale Face less edematous, no pain in the joigts Conjunctivitis has receded
Glands the asme Spleen a little smaller and softer
2475
Days
1
78
1 15
21 22
28 29
D, Orto
3713
Body Weight
Te
man
2
CHART XIII
17th day Temperature 38 09-37 39 Face less edematous no rasbi
18th day Temperature 37 40-37 2* Skin pale, inguinal glanda pen-sized
24th day Spleen behind the costal margin
38th day Last evening at 6 30 pm 200 Antitoxia units (1 cc Diphtheria scrum

·38 SERUM SICKNESS was injected (Reinjection) After about 11 hours & considerable swelling extending over the whole left arm Today this is still present The arm also gbows & somewhat Tajged temperature 38th day Yesterday the swelling was less today only very indistinct 39th day Swelling has disappeared Here we wish still to discuss separately two mre forms of eruptions The first group comprises the cachectic form, which is analogous to the cachectic forms of measles We find such eruptions in very debilitated patients The spots of the eruptions are then pale yellowish, washed out, particularly the hives which helong to the group are small, little elevated, the halo usually surrounding the hives 19 hardly present Going through a long duration of intensive eruptions even the skin of & strong individual becomes pretty much exhausted, so that at the end of a long lasting serum sickness, the eruption may show a type similar to the just mentioned cachectic forms Especially we wish to call attention to a state of exhaustion of the skin which is occasionally found after injection of very large amounts of serum The skin appears edematous and irregu largly pigmented on the back are streaks of hemorrhagic sulfusions produced by the pressure of the bedding By means of pressure, hemorrhages can be easily produced Baginsky talks about streaky hemorrhages Another form of eruption is a hemorrhagic rash, which is very rare Elly 1 Injected with 100 cc ecarlet fever serum On the 11th day after injection A large eruption of urticaris appeared lasting 5 days Even at that time it was strik ing that after the urticaria there remained grey pigmentation surrounded by fine red slightly elevated border on the 17th day eruptions started consisting of brownish distinctly elevated maculae of lentil Bize the center of wbuch was dark blue At the same time there was high fever On the 18th day the described eruption extended to areas 3 cm in diameter They were partly bluish red partly blackish, showing 4 narrow bright red demarcation at the margin The stem was free from Tash down to the lower part of the back while the main eruption was found on the legs-less intensive on the arms on the face only a few similar maculae were visible The general condition was relatively good From the 19th day the eruption faded The black discolorization changed to a pale yellowish color Apparently the whole affair was rather A stabis of blood and not an extravagation In this case we have to assume the existence of familjar disposition to severe rashes, because the sister of the patient also developed a very violent serum sickness after an injection of 200 cc scarlet fever serum, although without hemorrhagic eranthema Very little 19 known about pathological findings in the slın during serum sichness As far as we know, no such investigation has been made on human beings, but only on animals, which also may develop rashes after an in jection of foreign serum Beclère, Chambon and Ménard injected calves with a largo amount of ·CLINICAL ASPECTS OF SERUM BICKNESS 39 horse serum (1/100 of body weight) Four calves came down with generalized rashes and fever, one showed joint involvement Two calves injected with donkey serum showed no reaction The rashes were either like hives or like morbill. The cutis was intensively infiltrated Nothing characteristic was found by a histological examination Aronson saw not infrequently, a generalized eruption of papules after injecting horses with a foreign serum Prorkowskı injecting a horse with the blood of a syphilitic human being believed the engung rash to be a syphalıtıc eruption of papules We interpreted it in the man ner of Aronson as the result of a foreign gerum Schuetz eramined the skin of this horse and found microscopically a small cell infiltration of the epidermis and subcutis combined with the disappearance of the corny layer The tissue slits were dilated THE ENLARGEMENT OF THE LYMPH GLANDS Hitherto enlargement of the lymph glands and edema were least con sidered as symptom of serum sickness dhana 1 Finally Adolf and Hartung and later also Freyberger mention the occurrence of lymph gland swelling We attribute great significance to this symptom for two reasons (1) The swelling particularly of the regional lymph glands 19 one of the most constantly present symptoms of serum sickness (2) The stelling has great prognostic value Furthermore it is of general interest that the regional swelling informs us of which area of the skin the individual lyraph node corresponds After an injection of serum subcu taneously into the skin of the abdomen in the first place the lymph glands in inguine of the same side become enlarged If there is a more intensive involvement of the lymph glands also the axillar glands and the glands in the fogsa ovalus become enlarged From this we can conclude that the enlargement of the glands in this latter region does not always depend upon alterations in the genital region or in the lower extremities The development of the lymph gland swelling after injections of larger amounts of serum subcutaneously into the skin of the abdomen takes its course in the following manner Seven to eight days after the injection & gradual increase in the size of the inguinal lymph nodes on the side of the injection is noted The previously palpable or lentil-sized inguinal glands become pca or bean-sized more succulent and protrude so as to become easily visible if one stretches the leg in the hip joint At the time of the onset of a generalized eruption a further rapid enlargement of the glands develops They often become the size of the pit of a date and larger and ·40 SERUM BICKNESS then protrude ble a susage At this stage they are generally spontaneously tender and sensitre upon pressure During the first days of the general symptoms the swelling of the lymph nodes generally increases somewhat, also extends to other lymph gland territory and in certain cases mcreases to a generalized adenopathy As mentioned above, next the axillar and crural lymph nodes on the same side are involved, then these as well as the inguinal glands on the other side In some cases pea sized, succulent glands are felt at the side of the thorax and finally the glands at the neck and behind the ears become involved The enlargmeat of the lymph nodes continues until the disease is nearly ended, only the tenderness disappears eather When the glands become staller, softer and are less protruding We can infer that the end of the disease is near The swelling of the glands precedes the onset of the disease and starts to recede before ile termination Herein, in this behavior of the lymph glands, lies its prognostic value Only exceptionally do new enlargements of the glands develop with a reoccur Tence of symptoms of the disease Franz K 13 years old 1/5-2/20/04 Scarlet fever, medium severe (III) 1/5, 3 00 pn. 200 cc scarlet lever gerum No 8 dated 9/18/03 Glande before injection In axılla lentil-sized, in ingusne up to pea-91zed on the right ende Spleen not palpable 2nd day The side of the injection painful, some edema extending towards the back 3rd day Glands the same During the dext days nothing of importance The pain at the site of the injection disappears 8th day Inguinal glands protruding on the right side more than on the lett, og the right side two glands together date pit szed Add one bean-sized, on the left side several bean sized 9th day Azillar glands right bean sad lentil-sized, on the left side peu sited In ingine as on 1/12 10th day Temperature 37 86-37 0' Yesterday in the forenpon eruption of urticaria At first on the face, Istet spreading over the rest of the body Today almost nothing to be seen Mottled redzess on the Bexor surface of both fore arms Spleen distractly palpable 1 cm before the costal margo Glands ryghs and kent Axillar Several over pea-Bized Ioguinal Distinctly protruding two about bead-lized and geveral under bean Bized Face somewhat edematous Ilth day Temperature 37 42-37 4* Yesterday new eruptions of hures la the L Prior ogly On ·CLINICAL ASPECTS OF SERUM SICKNESS 41 14th day Temperature 3790-37 3º Yesterday pain in several joints Inguinal glands a little protruding, not so succulent anymore Crural lymph nodes, bean- Bized, still protruding 15th day. The swelling of the lymph glands subsiding 16th day Inguinal lymph glands soft, not protruding, below bean gized Face slightly edematous No edema over the tibiae 17th day Temperature 38 0°-37 3• No rash Inguinal glands soft, they and the crural glands getting smaller Spleen somewhat smaller, palpable below the costal margin 571 Days 11 16 LS 21 22 21 23 Body Weigrº 40 39 Temperatur 38 31 Exantheme CHART XIV 19th day Spleen a little behind the costal margin Ingupal glands below beanezzed, solt 23rd day No fever loguinal glands soft, rather long Barrow in the right axilla lentil gized, glands on the left side palpable The glands at the side of the thorax not palpable anymore Feeling well In this case the prognostic value of the swelling of the lymph glands is evident, because 24 hours before the eruption a rapid increase in their size was noted, as was a decrease before the end of the fever and edema, also here, as in the previous case, the acute enlargement of the spleen us found to run parallel with the swelling of the glands ·SERUN SICKNESS Bfarie A 9 years old, 4/18-6/5/04 Scarlet fever medium tevere (11) Ingunst glande palpable 4/16 at 10 00 pm 200 cc acarlet lever serum No 5 subcutane. ously into the right side of the abdomen 2nd day Site of the injection somewhat swollen and tender (traumatic) 3rd day Site of the injection a little tender 4th day Síte af t&e sojection shows no reaction 8th day No lever Throat clean Right inguinal glands larger than left, shaped like & spindle and beas-sized loth day No fever Yesterday afternoon eruption of fresh hrves on the back also today some scattered on the back and around tbe site of the lajection Cheeka mottled Mild itching The same glands pot tender 1615 16/4 Days 23kg 3 Body Weight 21 22 14 33 Temperatur 38 37 Exantheme Urticaria Lyrph Gand Swelling CHART XV 17th day Temperature 37 6° 37 4" Yesterday murderous lives on the face sad extremties Today only a few fresh brves on the lower extremities 12th day Inguinal glands as on the 8th day No temperature Yesterday general sred urticaria eruption today fresk eruptron mostly lentil bized bives on both free to and iber Drugbborhood larges buyes on the extenski swface of the tibia Large hives on the dorsum of both feet Intensive tcbiog Throat pale 13th day Na fever Yesterdry hives on the face stem and thighs Today fresh hives over the tensor surface of both ankle joints and on the dorsum of the hands The skin of the latter region is thickened through accompanying edema, the fingers are awollen, the motility so the finger joints as restricted 21st day No lever leolated Iures on the lower extremities from the knee joints down Und day No fevet, no caso kyrph gladd swelling has decreased ·CLINICAL ASPECTS OF SERUM SICKNESS 13 The importance of the swelling of the lymph glands as a symptom of serum sickness is demonstrated by the following case Heinrich S Scarlet fever of moderate intensity (II) On 3/6 at 600 pm 90 cc dried serum 'Hoechst" At the time of admission several lymph nodes in inguine below bean bize Injection on the right side On the 7th day the inguinal lymph nodes were still below been size 8th day In inguine on the right side bean sized protruding lymph glands The other lymph nodes unchanged 12th day The glands ia inguine a httle more succulent The lymph glands in the fosaa ovalis pea-gized right larger than left No rash 14th day Inguinal lymph nodes continue to be succulent, protruding a little over bean-sized 75 21 22 Days 14 15 28 78 . et The rich 23 姓 Lymph Glond Swelling Exantheme CHART YVI 17th day No fever glands the same No rash 19th day Tonight restless Itebing In the morning universal Tash composed of small maculo-papulous spots At the rounds this eruption was present on the back, particularly on the left side of the body and on the fletor surface of the upper ettre mities 1 ha 1 C a of & ragb 21st day Skin pale 25th day Glands in inguine been sized no longer succulent just a little promi Dent Feeling well Inferring from the time of appearance of the rash in this case the serum sickness would not have started before the 18th day after injection Te ·SERUDE SICKNESS see however that already from the 7th day after injection the lymph glands grew larger and remained bean sized for over a week, only then did eruptions of rashes and fever appear The swelling of the glands and other symptoms disappeared simultaneously This late onset of fever and rash 18 important for the problem of the incubation time Which day should be considered as the onset of the disease? Upon the beginning of the swelling of the lymph glands (7th day) or on the 18th day after injection when fever and rash appeared? This difficulty in determining the beginning of the disease partly explains the varying statements of authors concerning the duration of the incubation time Less frequent than the lymph gland swelling 13 & perceptible enlargement of the spleen, which lasts at most only a few days We refer to the cases Franz K, p 40, Ch XIV, and Jane A, p 42 Chs XIV and XVII Finally the lymph gland stelling may also be the only symptom of serum Sickness Leopold F 101 years, 5/17/04 Scarlet fever moderately severe (II) 4/10 Djection of 200 cc scarlet fever serum No 6 dated 2/10 into the right side of the abdomen Site of injection somewhat tender at the beginning Inguinal glandu a little tender upon admission, Darrow, long, spindie-formed From the 5th day on there was a awelling of the lymph glands which continued growing larger until the 11th day The swelling declines from the 14th day No fever 20 etapthema Gaslon Porz found in his study of the pathology of lymph glands in serum sickness that, along with considerable enlargement, there were al terations in the parenchyma Findings in men have not been collected as far as we know Czeczowiczka (Zeitschr f Hikde, 1903) treated rabbits with goat serum and examined the inner organs histologically T FAIT Arad 21 color was brought about by numerous granuli and scattered droplets, which were deposited into the cells (enlarged lymphocytes and swollen endothelial cells), filling them up very densely The granulı could be stained scarlet red orange red with sudan III But if osmium acid was used the results were irregular Czeczowrczka thinks that this substance belongs to the group of lipochromes As for the rest no particular findings concerning the lymph glands could be recorded Sometimes the lymph sinuses were dilated Similar accumulation of lipochrome was found by the author besides fatty degeneration in the user, particularly in preformed cavities of the intraacınous septa They may correspond to lymph spaces, whereas artenes, veins, bile ducts and liver blood capillanes have been free from such alteration In the

·28 2
35 35
41
59 SO
7 %
Day!
Body Wenght
hast
LABKI
17
TOT
Temperatur >>
CLINICAL ASPECTS OF SERUSI SICENESS
»
37
LL
Aiheme
Enlargement
of the Splus
Lymph Gland
Swelling
CHART XVII

·46
SERUHI BICKNESS
spleen Czeczowiczka found much pigment and in the region of the Alalpighi
corpuscles accumulation of lipochrome, in the kidney fatty degeneration.
11/29
Days
14 15
21 21
20.
Body Weight
Leucocytes
Total Number
Polynuclent
Venonuclear
Temperatur 18
38
32
Exanthema
CHART XVIII
The bone marrow appeared rch in cells, frequently lymphoid, in the
bone marrow cell many mitotic figures were secn
LEUKOPENIA
The importance of the leukocytes for the changes going on in a discased
organism makes it seem worth while to use at least the crude mcthod of
counting the number of leukocytes in serum sickness,

·CLINICAL ASPECTS OF SERULS SICKNESS 47 TABLE 2 Loukocytes among the Lymphocytes Days alter Djection Remarks Total tumber Absolute Dumber LA day 1 2 3 2,100 15 op 3,000 18 14,100 13,980 13,620 14,000 17,610 16,120 15,310 15,480 15,880 13,620 8,0301 12,500 13,420 6 7 8 9 10 11 12 13 14 2,800 Firet drop 3,600 27 16 17 49 5 4,6201 5,500 2,340 2,820 18 2,5801 1,639 65 Mononuclear cells, strikingly many large mononuclear cells with broad protoplasma The nucler sometimes show notches biscuit foring, here and there diffuse staining of the protoplasma (Tuerk solution) Leukopenia, relative lymphocytosis Relatively numerous large mononuclear cells, about 09% Eosinophile cells Bcanty Lymphocytosis more pronounced Among them algo larger forms with broad protoplasma which proves partly homo genous basophil The remaining cells mostly polynuclear forms with neutro phil granules Besides them mononuclear leukocytes with Deutrophil granuli and transitional forms Cosinophiles very scanty The 10crease in comparison to yeaterday came about on bas18 of cells with neutrophile gradali In the dry shde is seen that the regular polynuclear cells are present in relatively small numbers There are relatively numerous leukocytes with large pucler wica look Partly round, partly longish or kidney formed The protoplasms shows in the majority of cases, basophil, and oc- Casionally, also neutrophile gradul 19 5,840 2,240 33 5 ·48 SERUM SICKNESS TABLE 2 (Continued) Leukocytes among the Lymphocytes Day After injection Rerustks Total number Absolute humber lay day 20 7,140 2,180 30 5 The true lymphocytes are rather in the minority Numerous large and transitional forms The number of polynuclear cells has risen since yesterday The increase of the total qumber is almost entirely due to them A further increase in the leukocyte count is ex pected for tomorrow because of the presence of many young cells Among them only 50% regular polynuclear cells All other cells are mononuclear and in a less degree lymphocytes Mfostly large forms with a large round or longish nucleus Only slight polynuclear leukopenta Among the mononuclear cells lymphocytes are prevailing No large forms but still many transitional forms 21 8,820 ca 4 400 50 25 27 6 680 8,120 2,280 3 020 43 37 The authors, who up to this time counted leukocytes after an injection of serum, limited this examination to the first days after injection, that is, to the first days of the incubation period This counting was done mostly for the purpose of studying how the number of leukocytes in a disease 19 influenced through the treatment with serum We however were particularly interested to study the leukocyte curve during the height of the serum reaction Therefore we made daily leukocyte counts throughout two to three weeks For carrying out this counting we wish to thank Dr Eugene Fromm In some cases no worth while changes in the counts were found Those cases, in which any really more significant alteration in the leukocyte count occurred, showed a very uniform behavior (Chart XVIII) The leul ocyte count risez moderately during the incubation period and sud denly falls considerably wrth the onset of the symptomx of serum sickness The leukocytc curve reaches a low point from which the curve rises towards the end of the sickness to normal The course of the sickness in Karl L's case has already been described in detail on page 10 Flere we also consider the results of the leukocyte counts, which was carried out in this case by Dr lon Reuss, to whom ne express our thanks (table 2) We obserie therefore that the intensite drop in the number of leukocytes 18 ·CLINICAL ASPECTS OF SERUM SICKNESS 49 due almost exclusively to the reduction of the number of polynuclear cells The total number of luekocytes drops from 14,610 on the 7th day after injection to 891 on the 18th day The following mcrease of the total number takes place by the formation of new polynuclear cells, the reappearance of which is announced by young forms The mononuclear cells seem to be at first sight rather unchanged But upon closer examination we see that they are altered too With the onset of the relative lymphocytosis many large mononuclear cells appear with broad protoplasma as well as transitional forms, which disappear when the total number of leukocytes again rises In one case we made the peculiar observation that the leukopenia was the only objective symptom of the serum sickness Dr R Dehne Total number of the leukocytes after injection of 14 cc. antitetanus serum. Before injection Day of injection 2nd day 3rd day 4th day 3th day 7th day 8th day 9th day 10th day 11th day 12th day 13th day 14th day 15th day 16th day 17th day 8,500 9,000 8 200 7,400 5,000 7,600 8,200 4,800 5,200 5,500 5,400 2,600 2,500 Joint pain Towards evening feverish 3,300) Feeling sick 4,400 11,000 Feeling all right 9,000 Subjectively there existed simultaneously an intensive feeling of being sick, weak and exhuasted The case concerns a colleague who injected himself for experimental purposes with 14 cc tetanus antitoxin Therefore we can accept the subjective symptoms as correct This subjective symptom complex may occur especially with children more often than we can prove Whether or not the leukopenia may be the cause of the subjective symptoms we are not able to judge (Chart XX) This behavior of the curve of the leukocytes reminds us very much of the leukopenia during the stage of eruption in measles, smallpox and raccination The chart on page 52 serves to illustrate this similanty, the figures of which we have taken from the fine study of Sobotha, dealing with vaccination ·50 SERDE SICKNESS After reinjection we find the behavior of the leukocyte curve is altered (p 92) The appearance of precipitin in the blood of the injected person and the connection between formation of precipitin and serum sickness will be discussed in the last part of our study (p 97) Days 1 14-15 Leucocytes DERD. 10000 7500 SOLO 2554 CEART XIX JOINT SYMPTOMS Hartung reports among 2073 cases of serum sickness, 140 cases of joint pains contnbuting 19% Among 4358 cases of a collective study on diph theria serum, hardly 1% of the cases showed pain in the joints Therefore, joint involvement is not exactly a frequent symptom in serum sickness Likewise, "rheumatoid' pain in the muscles does not occur frequently Adults especially complain about the latter in the course of serum sickness Harlung already pointed out that frequently the factacarpophalangeal joints are involved, second in line are hand and knee joints The involiement is characterized by intensive spontaneous attacks of pain increasing

·CLINICAL ASPECTS OF SERUM SICKNESS
51
by touch and movement The intensity of the pain is in striking dispropor
tion to the entirely negative objective findings In some cases reported in
the literature, exudate was found in the joint cavity, the joints felt hot,
the patella was balloting We never observed such a case
Days After
5000 Vaccination 1
78
14 15
17
13500
10000
Leucocytes
7500
T'ers peratur
250g
CHART XX
We must conclude just from the negative objective findings that pain and
the whole joint involvement have a pathological and anatomical foundation
different from acute rheumatism As the condition is benign no anatomic
examinations exist in human beings Beclère Chambon and Ménard found
in cales neither microscopic por macroscopic changes, particularly no
swelling, in spite of the fact that the joint pain was apparently very in
tensive

·52 SERUM SICKNESS As the painfulness of the joints coincides with the eruption of rashes, so we suspected that perhaps similar pathology may develop on the synovial membrane of the joints as in the skin We never saw suppuration of a Dr Lazar studied the course of the leukocyte count after injection of horse serum into rabbits He was so kind as to gve us the results of bis counts for publication Data Day. Alter Injec tion Rabbit 28 Precipe- Rabbit 18 Precipi Leucocytes tin Leucocytes tin Rabbit 20 Rabbit 13 Precipi Leucocytes tin Preap Leucocytes to 23 4 25 4 27 4 29 4 1 5 35 9,400 9 800 9,900 10,400 10 000 6,700 5,400 5,500 7,900 7,900 OOOI + 18,600 10,200 26,400 23,000 19,600 9,400 9,100 0 0 Sp 9,700 9,100 12 200 12 000 11 800 6,500 7,400 7,000 7,500 11,000 0 0 0 0 0 + 2 4 6 7 8 9 10 11 12 14 17 8,900 13 200 9 000 13,400 5,100 5,000 5,200 3,400 6,400 4 500 3,600 6 600 4,800 7,200 + 5 5 6 5 7 5 85 9 5 11 5 14 5 14,200 14,000 9,000 10,000 11,900 7,500 7,800 7 600 12,900 8,000 10,500 Rabbits 28, 18, 13 and 20, bad three counts of leukocytes taken in order to determine their average number before injection After that each of these rabbits received on 4/28/03 Ito of their body weight of horse serum From then on about every day blood was withdrawn for counting the leukocytes and besides that the content of precipitin and of the precipitible substance was determined The last negative and the first positive result of examination for the preaence of precipitin 19 recorded next to the figures of leukocytes The drop in the number of leukocytes occurs in the rabbits earlier than in the human being in three rabbits on the 6th day, in one rabbit already on the 4th day Only rabbit 20 shows very low values (3,400), whereas rabbit 28, which gave the most regular figures, dropped from 10 000 to 5 400 The precipitın appears one to two days after the drop of the leukocyte count, & fact which indicates & connection between these two phenomena joint, also never a disturbance of function afterwards and never complications involving endo- or pericardium The painfulness of the joints makes the involvement of the joints one of the most unpleasant symptoms of serum sickness, particularly if scverni joints are involved The only consolation lies in the fact that the process 15 benign and that the symptoms disappear quickly Salicylates do not inflưence the process, one may safely forego their use Subjectively the most pleasant are cooling tret dressings with Buror's solution ·CLINICAL ASPECTS OF SERUM SICKNESS 53 The following case shotys, in the second week after the injection, a series of eruptions of urticaria which were accompanied by edema but not with fever Then on the 15th day high fever set in, at the same time the joints became painful, the involvement of the joints spread rapidly over all joints, including even the joints of the jaw so that chewing was made difficult Only an indistinct erythema accompanied the period of the in volvement of the joints Furthermore, the spleen was swollen Dags 1 TI 14 15 27 12 35 36 421 mane Temperatur 12 zumthame NOTIT Joint Paino Mandiner Left Arm Right Arm Loft Leg Right Lag CEART XXI AL Alary F 8 years, 4/18-5/29/04 Severe scarlet fever (III) 150 cc Scarlet fever Rerum No 5, Vienna, dated 2/12 was injected on 4/18 at 9 00 pm on the right side Inguinal lymph nodes on both sides bigger than millet grains Until 4/28 nothing noteworthy tin nan er nt on nf hives the left, but below lentil site 13th day Temperature 37 4' 37 3* New eruption of a few bives 14th day Isolated hives Today a fresh eruption of hives oa the forehead Pale remnants of the tash on the lower extremities 15th day Glands the same No fever Some hives on the forehead and on the face only. 16 day Yesterday afternoon sudden onset of intense paia in Joints of the hands and feet Sitting up was impossible Could not sleep at night Temperature at 7 00 PM, 39 2° Face distinctly edematous Cheeks spotty, reddened Conjunctiva 10- ·SERUBI SICKNESS jected Pain on chewing in both jaw joints Today paid in the left handsgd Enger joints, also ia the joiats of the left leg No difference in the skin temperature between right and left No visible swelling Lymph glands in inguine right less than lentil sized left palpable both sides teader On the anterior side of the chest indistinct spots Spleen distinctly palpable a little below the costal margin hard Heart action exested heart sounds clear 17th day Temperature 39 3º-38 40 Yesterday wticaria on the face and intense pain ia different forats Today no rash Pata only in the left arm The inguinal lymph nodes less tender 18th day 380-37 1° No pajn 19th day Temperature 38 0937 29 Feeling well 20th day No fever EDEMA AND ALBUMIINURIA According to custom we place these symptoms side by side without any intention of stating that we consider the edema as an effect of a kidney disease On the contrary, just in serum disease is it clear that edema and kidney symptoms represent coordinated symptoms Edema 15, in the course of serum disease, an almost regular symptom, while albuminuria is only rarely observed The localization of the edema is similar to nephritic edema It is seen above all on the face, only in the second place on the dependent parts of the body The edema is therefore certainly not an edema due to congestion The determination of the amount of edema is best carried out with a scale according to the idea of » Parquet, who at first used this same method 10 nephritis The advantage of the method lies in the possibility that one can approach the determination of the absolute amount of edema Further more, small amounts of edema włuch could escape detection by the eye, can be determined objectively The weight is taken daily at the same time every morning In order to evaluate the curve, which is composed of the separate daily weights, ne make the well justified assumption that, in case of ſever accom panied by loss of appetite a gradual loss of weight is to be expected If we see that in spite of these facts the seght increases, se ascribe this increase in weight, not to an increase in body substance, but to edema No conclusion can be drawn from only two successive figures of Beight, but the total weight curve must be considered before passiog judgment The problema will be clanbed by the following ·CLINICAL ASPECTS OF SERUM BICKNESS 55 might run, perhaps, a parallel course to the loss of weight during the first week of scarlet lever According to this assumption the body weight should have gone down to about 12 60 kg instead of that the body weight rises from 13 40 lg to 14 40 kg At the same time we find in the record of the case the note that the face, particularly the eyelids, looked very edematous for many days We now take this difference between the supposed and the actual weight curve as edems, and get in this way at least an approximate idea of its amount In this case it amounted to about 1 S0 kg 1%8 1 7,6 Day 14 15 21 22 27 IN enriette Body Weight Kg 14 Temperatur 1 Erantheme ir Ove Been Size !SM Lymph Swelli- Chart XXII With the retrogression of the serum symptoms, the body weight falls more or less rapidly to its true level The edema was excreted and was not visible anymore After having reached the lonest point the weight curse again rises This rise 19 due to a real increase of body substance (see Karl A, chart on page 46) The duration of the edema corresponds to the duration of the descase The decrease of the edema has a prognostic talue similar to the diminution of the lymph gland swelling If albuminuria appears at all as a sign of imtation of the kiddess, ·56 SERUM SICKNESS it does not set in until several days after the onset of the edema These authors, who until now occupied themselves with the much disputed problem of albuminuria after serum injection, looked for the albumen immedi ately after the injection or during the days following the injection of serum But albumen is found only at the height of the serum sickness, in the second or third week after injection In our cases the amount of albumen was never lugher than i pro mille In the sediment free red cells and hyalıne casts are found The amount of blood is always so small that it can not be detected macroscopically We never saw hemorrhagic nephritis due to serum as has been described by Freymann, Cuinon and Roufillage We are, in this respect, in agreement with all other authors Taking into consideration that serum therapy was chiefly used against diphtheria and, by us, also against scarlet fever, we must be particularly careful in judging albuminuria and edema, because both these diseases may themselves lead to serious kidney involvement The clinical observation of the symptoms can supply sufficient differential diagnostic clues, which permit us to separate them from the symptoms of diphtheria and scarlet fever Diphtheria shows no edema even with severe kidney damage Edema develops only on account of weakness of the heart, and then it presents the character of edema due to congestion (von Pur quet) The symptoms of an irritation of the kidneys in diphtheria start almost always during the first days of the disease, show only a slight forma tion of sediment and a small amount of blood, but often show & substan tially higher amount of albumen Besides, the distinction between albu minuria in serum sickness from the diphtheric form has little practical importance, because, in consequence of the small amount of serum used in the treatment of diphtheria, albuminuria due to serum hardly ever occurs The situation is different if we inject large amounts of serum as we are accustomed to do in scarlet fever Here the question more often anses whether the edema and urine findings are due to serum sickness or scarlet fever Edema with negative urine findings at the height of the serum sick ness one can almost certainly relate to the serum The simple edema of scarlet fever described by Quinke in some cachectic children is certainly very uncommon Ve did not see any such case among 500 cases of scarlet fever observed during the last two years where we carried out exact deter minations of body weight Furthermore, the edema due to serum starts about one week earlier than the edema of scarlet fever nephritis In the rare cases where we find edema together with urine symptoms, the differ ential diagnosis is facilitated by the time when the sediment appears Large amounts of albumen and blood, a mass of sediment, indicate with certainty the presence of searlet fever nephritis Likewise, uremic symp toms and intensive edema prove the scarlet fever character of the process ·CLINICAL ASPECTS OF SERUM SICKNESS 57 in question, as edems due to serum keeps within moderate limits, uremic symptoms never develop We never saw an accumulation of edema fluid in the pleura or in the peritoneum No hypertrophy of the left ventricle occurs, the blood pressure is not materially influenced We have seen some cases where, in the couse of the serum sickness and the accompanying edema and albuminuria, a true scarlet fever nephritis developed in the following case it can be shown that the onset of the nephritis is sometimes well marked (Chart XXIII) The serum sickness starts with a nse in body weight on the 10th day 12+ enn-nnnn with the naked eye The edema disappeared with the fall of temperature Suddenly on the 17th day of the scarlet fever albumen us found in the urine in large amount (more than 1 pro mille) Two days later the curve of the body weight rises sharply, so that after the elapse of one week it surpasses the minimum weight of the patient by almost three kilograms From this point on the body weight and the albumen in the unne decreases gradually Heinrich 8 10 years old, 1/4-3/13/04 Medium severe scarlet fever Moderate throat symptoms Injection of 200 cc scarlet fever serum No 12 on the 4th of Japuary at 11 00 pm into the right side of the abdomen Glands rigue lela Axillar Below lentil-sized Inguinal Pe3 sized Below bean 2nd day The region of the injection and its neighborhood swollen, very tender Towards the back and upward a half spherical swelling the size of & baby's head (poor resorption) 3rd day Temperature 40 20-38 2• The scarlet fever rash sacrenged during the day and is still today vind red and small, visible on the back Other places show an indistinct rash During the night restless, hallucinating Today fresh Throat less swollen No exudate on the tonsils The site of the injection less &wollen but tender Spleen palpable 4th day Temperature 39 0°-38 O° Night restless this morning much freaber Rash has faded, fine desquamation is starting Glands the same Throat paler, less swollen so that the space in the pharyntji twice as large compared with the width on admis bion Spleen palpable below the costal margin 5th day Temperature 33 2° 37 2° Fine desquamation, remparts of the rash 6th day laguinal lymph nodes below pes size and longish Stb day Skin pale, no fever 9th day Intensive desquamation on the inside of the left upper arm on the right yar denge eruption of bright red, somewhat both upper arms ition of medium to large vind red, distinctly elevated miculae on the left siue confluent to Isrge

·58
Days
7 8
1.11
FR
Body Wright
SERUM SICKNESS
Alturen
Trece
T
CS
اند. کامل It
Exarthamo
CHART XXIII

·CLINICAL ASPECTS OF SERUM SICKNESS 59 areas On the lower part of the back less red and more isolated maculae Lymph podes gut kit Axıllar Over pes-sized Bean gized Inguinal Many below bean-sized 1lth day Temperature 39 0°-38 · Yesterday afternoon an eruption of small, loosely arranged, vividly red, somewhat elevated maculae on the stem Densely arranged, up to lentul gized maculo-papular eruption appeared on the calves and doraum of the feet The eruption is today still very distinct and vividly red Isolated maculae also on the thighs and tengor surface of the upper arm The maculae de scribed yesterday flatter and paler Face free from rash, slightly edemalous 12th day Temperature 39 4-38 6° Body weight increased 450 grams Face dusfunctly puffy Edema of the dorsum of the hand Yesterday's maculae paler, however there are fregh eruptions (maculae) in the face Densely arranged more papular rash on the extensor surface and inder surface of the calves and the dorsum of the feet and also on the extensor surface of the arms from the middle of the upper arm down to the lower end of the forearm On many areas the rash has the appearance of An erythema exudativum multiforme, abich is brought about by the paleness of the central part of the eruption Lymph nodes night IH Axillar Several more than pea sized Hazelnut-sized Inguinal Both sides bean-sized, protruding not tender 13th day Temperature 39 40-39 2° Somewhat exhausted, no special subjective complaint, little sleep at night Yesterday new eruption of maculae which are today paler Fresh eruption of maculae on the dorsum of the hands and extensor surface of the forearm to the middle, as well as on the extensor surface of the fingers The rash 19 maculo-papular, in size from pin bead to larger than lentils Many maculae, in the center, paler and flatter similar eruption of a few spots on the skin over the patella Face looks puffed Glands the game Loss of weight 14th day Temperature 39 7-39 0° Yesterday and today more exhausted than usual Night restless Pain in the left side Yesterday new eruptions Thig morning no fresh spots Generalized desquamation Lymph glands nok Axillar Pea gized 0 Inguinal Several bean-sized Slim, larger than beans Glands everywhere less eucculent and do not protrude so much in inguine 15th day Temperature 39 0°-38 5° Night sleepless, today in the morning still tired Body weight went down no rash Face legs pury The inguinal lymph nodes softer, smaller, bardly protruding any more 16th day In bad humor Dunng the right pain in the abdomen Norash Desqus. mation less, face legg puffy The body weight 13 going down the abdomen all over 17th day Temperature 39 1-33 4º A little quieter, complains still of abdominal PAID, no rash Mucous membranes anemic Inguinal glands do longer protruding On the right side one gland less than bead-sized otherwise on both sides loogiab, emall glands, not tender 18th day Temperature 38 8-376° Towards evenisg abdominal pain agus Skin kn tender by pressure ·SERUM SICKNESS pale, no rash Face only slightly puffy Inguinal glands larger than peas goft Splcen 1 cm behind the costal margin 19th day Temperature 37 4°-37 09 Face pale, almost no puffiness 20th day Temperature 37 50-37 0° No rash, appetite better 21st day No fever Inguinal lymph glands larger than pea sized 23rd day Heart action a little arhythmic 24th day Until yesterday the urine contained traces of albumen Today urine 550 cc reddish, much sediment Patient is decidedly more exhausted No visible edema Body weight increasing Heart action arhythmic, slow Heart sounds are clear 25th day Amount of urine, 600 cc Body weight increased 550 grams Urine cloudy, shows a great deal of bloody sediment The sediment contains red blood cells, du 1 rer 27th day Yesterday small macular eruption on the face Today only pale red remnants visible on the left side Vindly red maculae on the extensor surface of both arms, also on the lower extremities Glands the same 28th day Temperature 38 50 38 40 Yesterday afternoon a mottled redoess the whole body Today skin pale 29th day Temperature 37 60-38 2° No subjective complaints Face distinctly puffy Also on other areas of the skın finger impressione persist Urine 350 cc (specific gravity 1017) Dark reddish brown sediment Keart dullness not enlarged Ileart sounds somewhat like murmur 30th day Temperature 37 6-37 5° Night very restless Complains about ab dominal pain Nose bleeding, today very tired, Dauges Very little food intake Urine 450 cc (specific gravity 1015) 31st day Yesterday during the day tired, afternoon staring look sometimes con Tused Pulse not particularly tenge Vomited once At 8 30 pm onset of uremic con pulsions, logg of consciousness The convulsiona are mostly in the right half of the body Uncoordinated movement of the eye balle The convulsions are tonic-clonic Pupils were wide, not reacting to light Pulse 150, tense All veggels visibly pulsating Immediately after the onset of the convulsions a venetection 18 performed on the 2. reddish yellow Patient is ull quite exhausted Sensorium free Heart dullness somewbut enlarged to the left Apex beat in the 5th intercostal space in the mammillar line Heart sounds clear 32nd day Temperature 38 0°-37 4° During the day happy, nights quiet Loss of body weight Urine 300 cc , contains less blood 34th day No fever 35th day Profuse diuresis 37th day Face pale plenty of urine which contains a trace of albumen 46th day Heart enlargement disappeared convalescent It is easily understood that we tried to develop an idea as to what im portance the edema plays in the course of serum sickness We are of the opinion that the edema is & primary symptom of the disease and not the ·CLINICAL ASPECTS OF SERUBI SICKNESS 61 expression of a secondary damage It is analogous to the rash and the lyraph gland swelling The edema is not due to congestion or insufficiency of the kidney Our conception is corroborated by the close relation between urticaria and edema This we see most clearly in the eruption of urticaria in the face Garnier and Sabaréanu found that at the time of the purulent dissolution of the smallpox eruption the body weight rises These two authors are of the opinion that this increase of body weight is due to a localized inflammatory edeme which belongs to the course of the reaction, and that it is necessary for the healing process We consider that the edema in serum sickness 19 in similar way a symptom accompanying the pathology created in the skin BEHAVIOR OF THE MUCOUS MEMBRANES - 1 - Mon nese E hing berum sickness from scarlet fever and measles Contrary to the hindings of Hartung, we have never seen a case of tonsillitis due to serum in spite of our attentive observation Nya reported that children who were injected with diphtheria serum against croup again showed symptoms of stenogis of the larynx during serum sickness The cause of which is the development of a subglottic edema He explains the connection with the assumption that the mucous membrane, damaged by the diphtheria process, 18 predisposed to the development of swellings We report one case of subglottic edema that came under our observation - In and had to be some /13 on . 9 per 1 child VINcomplained about pain in the fingertips and tres so0N LIVEI WLlub Lwy H1 and mathaw n annored on the legs Temperature rose to 37 9* However it was not seldom that we found simultaneously with other serum symptoms, signs of a diffuse bronchitis, and in some cases bloody diarrhea develops lasting several days As Hartung has already remarked, the causal connection between bronchitis and serum sickness cannot be ·62 SERUR SICKNESS proven, honever such a connection between bloody diarrhea and serum sickness seems to us very likely We could never relate with certainty rhinitis and conjunctivitis with serum sickness Hotever tre have twice observed, simultaneously with slin eruption, lentil seized red elevation in the conjunctive of the bulbus See Josef 1, p 33 On 21st day, Egon E, p 26 on 18th day THE GENERAL STATE OF HEALTH We have mentioned before, that in mild cases of serum sickness the general state of health is remarkably little affected The good general state of health is frequently in contrast to the high temperature Restless Dess, whining disposition, easy irritability occur very frequently, Cnyrim reports in his case symptoms of neurasthenia Vorniting is very rare Only if the sickness lasts very long does the patient become very tired, loses appetite and in the severest cases may become considerably prostrated In connection with the small intake of food such patient become emaciated, which is particularly noticeable after the disappcarance of the edema This loss of weight 19 analogous to the loss of body weight in experimental animals after repeated serum injections But even in extremely severe cases no danger to life exists The severest case of serum sickness we ob served is the following Chart XXIV, Max P Here we see fever periods in the 2nd, 4th, 5th and 7th seek after :D Jection which resemble each other Sudden onset, and rise of temperature remittent in type followed by lysis Exaotbemata and generahzed lymph gland swelling are present during the first and second periods Traces of albu men accompany the second to fourth perod Edema was observed through out the whole course of the periods At the onset of fevet interessed retention of fluid occurred The greatest intensity of edema has seen simultaneously with the fourth period of fever From then on the edema was excreted but not until the tenth week did it yield to a real gain in body substance repre senting reconvalescence In the sense of medical history we must count th24 clinical picture of a nine week duration as a chronic disease ending in recovery Thus we see that we have before us a chronic disease produced by A single injection of a substance which can not multiply The peculiarity i this case is that one injection can produce a repetition of four similar Derioris of symptoms of s disease separated from each other The principle importance of this observation is not reduced by the exceptional mnty of such cases, we do not lay any particular value on term "chronic" because we have seen all transitions from this case to & case of short duration

·CLINICAL ASPECTS OF SERULI SICKNESS
63
CHART XXIV
is the
eratur

·bLBUM BACAXES DIFFERENTIAL DIAGNOSIS The simdanty of the rashes during the serum sickness to the rashes in scarlet fever, measles and to toxic rashes often makes the consideration of differential diagnosis necessary Furthermore se often have to decide the question, whether isolated symptoms such as fever, albumen, edema are due to the serum Injections Almast alnays involve sick individuals except in cases of immunization and the primary disease is not entirely elimunsted by specific treatraent In the first place we should not make the mistake of assuming that in every case of unexplained fever at the time of scrum symptoms this fever is to be ascribed to serum From the viewpoint of differential diagnosis, scarlet feser and measleg sre the most important diseases Relative to this Baginsky, Monit and Harlung have already called attention to important characteristic distinctions of importance we consider the following symptoms whick favor the diagnosis of serum sickness 1 The time of the appearance of the rash (7-14 days after injection) 2 The first eruption at the site of injection 3 Regronal lymph gland swelling 4 Complete absence of symptoms on the mucous membrane Point 4 makes it easy to distinguish measles from serum schness the absence of Koplih spots, coryza, and conjunctivitis conststute efficient diferential features To distinguish serum sickness froin scarlet feser is most difficult, it is sometimes impossible in many cases only the spread of the disease to other children, the appearance of characterstic desquamas tion or the onset of hemorrhagie nephritis clarfies the situatson, showing that the supposed scarlatiniform rush was true scarlet fever Leiner re ported such a case Influenced by this some authors questioned the existence altogether of a scarlatindorm rush in serum sickness We have seen cases showing a scarlatinform rash, n here we could state with certainty that it belonged to serum sickness On tbe one hand children who were treated wth serum on account of scarlet fever developed in the course of serum symptoms a scarlatiform rash without any other Bign of a relapse of scarlet fever, on the other hand we observed the following two children developed a scarlatinform rash after an injection of diphtheria serum sed were for that reason transferred to the scarlet fel er ward After a few days they developed a typical scarlet fever As distinguishing features of scarlet fever in contrast to the scarlstuar formi rash in serum sickness we can cite the following 1 Vomating at the onset 2 The existence of a sore throat and inflasimatory redgess (Esaplbema) of the mucous mersbrane of the mouth at the same time as the rash 3 Very hsgh temperature ·CLINICAL ASPECTS OF SERULI SICKNESS 65 4 In a hospital the outbreak of scarlatınıform rashes at the same time or in short intervals The value of point 4 lies in the fact that scarlatınıforma Mshes are rare in serum sickness The distinction of toxic (mostly drug ) rashes from serum sickness would often be very difficult, in reality there is rarely an occasion to make such a decision The symptoms of serum sickness do not develop untul several days after injection At that time the patient is treated for his primary disease If a drug would be administered which according to experience may At times produce rashes, & repeated administration of the drug will clanfy the problem Urticana caused by alimentary disturbance has to be more frequently considered Location of bives at the site of the injection and swelling of regional lymph glands indicate serum as the cause, gastrointestinal symptoms, alimentary urticaria THERAPY AND PROPHYLAXIS The symptoms of serum sickness do not respond to etiological therapy After the foreign serum is once inside the organism, the latter is forced to go through the reactions induced by the foreign substance in order to get rid of at To interfere with the course of these reactions would be useless if not harmful If one likes to discuss therapy at all, it could only be a symptomatic therapy We apply Burow's solution on the area of the injection, if this region is tender and swollen, and on the extremities warm, local baths of long duration, which are found to be very pleasant The itching, which mainly accompanies eruptions of urticaria can be mitigated in some measure by rubbing the skin with 1 to 2% salicyl alcohol or 1% menthol Ahh fra and profuse sweating, but the effect is of very short duration As we have already mentioned, the salicylate has no influence upon the joint pains We recommend local warm packs and baths For diarrhoeic conditions, the customary styptic drugs with dietetic measures may be tried Edema and albuminuna do not allow themselves to be combatted Finally at remains for us to discuss the effort to avoid senim sickness by the removal of the etiological factor As the antitoxin as such has nothing to do with the damaging complications of serum sickness (Johannesen et al), we do not consider it necessary to further discuss the curative effect of different sera From the time that the foreign serum was recognized as the damaging cause of serum sickness, attempts were made to free the anti toxin from the toxic substances The many efforts to produce a "pure" antitoxin bave, until now, been unsuccessful As Ruffer and Daul prosed that the smaller the amounts were of injected ·66 SERUM SICKNESS horse serum, the less frequently did the serum sickness symptoms occur, therefore the aim was to produce the necessary amount of antitoxin in the smallest possible dose of horse serum The attempts to find an artificial concentration lead to no practical results The reduction of the amount of serum to be injected can only be attained by using as many horses as possible for immunization, and by selecting for therapeutic use only the sera of those horses which are capable of producing relatively large amounts of antitoxin and neutralizing large amount of toxin During the first years of serum therapy sera were used which contained only 20 to 50 antitoxin units in 1 cc, while now, by a sutable selection of horses, sera are produced, which contain up to 500 antitoxin units in 1 cc To provide, in an uncomplicated case of diphtheria of the pharynx, the 1000 antitoxin units that are necessary, previously 20 to 50 cc serum were needed, whereas to-day, with the use of serum with high antitoxın titre, only 2 cc are needed That this influenced very effectively the incidence and intensity of serum sycop toms, as seen in the statistics of Daut He found anong 74 injections where the doge was 2 to 15 cc , 5 cases of rashes or 4%, in 28 cases injected with 20 to 60 cc of serum 32, 14% We have already mentioned that when injecting 100 to 200 cc Berum, we found serum symptoms in 85% of the cases To Burund we owe another prophylactic measure He discovered that the horse serum has a highly toxic effect directly after the removal of the blood from the veins of the horse 1 PAP m On the basis of his extensive statistics, HG sickness depends mainly upon the individual Unruh believed that horse serum obtained intensive toxic and characteristic effects To what degree the explanation of Bujund could prove the statements of Harlung to be right cannot be decided because Har tung does not mention the age of the individual sera The most violent serum Bickness which we observed (P Max ) followed the in jection of 150 cc serum, which was only 14 days old At that time as an exception we used sera of 4 different horses which were bled only 14-21 days previously All 4 patients showed remarkable similar intensive symptoms of serum sickness But the toxicity of serum seems to become stabilized after several weeks We also saw severe symptoms after injecting serum stored for over six months According to the proposal of Bujuid, serum is stored a few months before it is released for commercial purposes Another technical procedure reducing the toxicity is based on the observation of Spronc! He found that serum bich is heated up to 59° Celsius produces almost no rashes In the State serotherapeutical institute (Prof Paltauf, Vienna) diphtheria seruim 13 submitted to this procedure However all cases of serum sickness in ·CLINICAL ASPECTS OF SERON SICKNESS 67 diphtheria and after immunization were produced by heated serum We also heated single doses of scarlet fever serum several times but we were not convinced of any differences in their toxic effect Only when fresh serum was used, did the heating seem to have an effect Along with the previously mentioned 4 severe cases a serum of the same age and the same source was injected after having been heated The child showed a considerably milder serum sickness Probably the heating influences that part of the toxic substance which also gradually disappears when stored It must be also mentioned that the toxic substance is not destroyed by freezing nor by drying in vacuum A method to determine the toxicity of the serum even after the injection of a very small amount of serum consists of an injection in hypersensitive persons (see p 101) In our experiments recorded on page 71 dealing with immunization, 1 to 2 cc serum of different origin was applied, but we did not find distinct differences between normal and heated serum or between serum of Hoechst and Vienna Our experiments on this bject have not been concluded In any event the prophylaxis of serum sickness consists in the first place in using the smallest possible amount of serum But even when large doses are administered severe cases of serum sickness are the exceptions The statement of v Ranke is correct that in comparison to the saving of the lives of many patients the after effect of serum can be quietly disregarded ·CELAPTER 2 THE REINJECTION TEE ABILITY FOR IMMEDIATE REACTION Those authors, who until now have studied serum sickness, did not pay special attention to the symptoms after reinjection, but dealt with them statistically and clinically in the same way as with the symptoms after the first injection Likewise it was only in the course of our observa tions that our attention was drawn to the important differences between first and reinjection, which exist, mainly in connection with the time of onset and intensity of symptoms August Sch , 31 years old admitted 10/11/02 with scarlet fever and tbc fungus of the right elbow joint On 10/11 injection of 200 cc polyvalent streptoccus gerum (Paltauf) Thereupon the patient had no fever for 8 days On 10/20, the 10th day after injection, fever and urticaria set in which lasted several days 10/24-11/3, no urticaria but 'hectic" fever which we related to tbe fungus Our experience since that time taught us to consider the symtoms as gurely due to serum sickness We wanted to find out whether the fever could again be stopped by a repetition of the Berum injection Thus we injected on 11/4, 21 days after the first injection, 100 cc of the same polyvalent streptococcus serum into the skin of the abdomen The 10- jection was made at noon, that evening the site of the injection and its neighborhood was to a wide extent edematous and showed diffuse redness Eruption of erythema algo on other parts of the body The fever, which was in the first days 38 4º, did not fall, on the contrary it roge to 39 7° We first suspected an infection but no abecess developed, on the contrary the swelling of the area of injection flattened out within a few days However five to six days afterwards urticarial and small papular eruption appeared which were very similar to the eruption which we are used to see in serum Bickness The peculianty of the case was that the same child who one month previously needed 9 days until it reacted to the serum with sickness reacted this time within a few hours Shortly afterwards another case was observed which showed the difference in the reaction between first injection and reinjection even more strikingly it IC n ·THE REINJECTION 69 Whereas the serum sickness after the first injection appeared only after an incubation time of seven days, such an incubation time was entirely missing after the second injection These two cases, just reported induced von Pirquet to construct a theory concerning the nature of the incubation time which we shall discuss on the following pages At first it was reces sary to collect more observations, which was carried out by v Prrquet at first with Joseph Hertzka, later with Schick, in order to find out whether the mentioned observations expressed a general biological law Looking over older charts of the hospital we found similar observations, the importance of which we had not recognized Heinrich , 3 years old On 6/13/02 he received 100 cc scarlet fever serum On the 8th day (6/20) onset of serum sickness lasting to the 26th day 7/17 31 days after the first injection 200 antitoxin units in 1 cc diphtheria serum were injected into the left arm On the same afternoon urticaria, edema of the lips The next morning the arm 18 extremely edematous The swelling lasted several days Alexandrine K , 9 years Og 5/28/02 received 180 cc normal horse serum which has no effect on the course of scarlet fever On 6/8 (11 days after the injection) severe serum symptoms which lasted to 6/17 During the course of gerum sickness 16 days after the first injection the child was immunized against diphtheria Again us in the previots case 1 cc diphtheria serum was injected into the right forearm On the following morning the skin at the site of the injection down to the wrist was swollen, very tender and vividly red so that we thought at first of erysipelas Redness and swelling disappeared in several days Elisabeth K , 63 years admitted with severe scarlet fever on 5/1/02 Injected 5/3 with 180 cc scarlet fever serum On 5/15 after the scarlet fever symptoms had nwaller nn tash These and painful edems developed on the skin of tbe abdomen ylilu ethuvu. genitalia and thighs and disappeared only after one week Looking over the publication of Hartung we found two cases observed in the year 1895 where serum sickness appeared rapidly after the injec tion In the history Hartung himself mentions that the child had been previously injected with serum (The interval between the two injections was in case 2, 32 days, in case 8 23 days ) We found a similar case in the publication of Denys and Leclef The dependence of the speed of the reaction upon the previous injection did not strike either of the authors Why does it happen that such a peculiar symptom was until now overlooked? If every reinjection would have been followed by immediate scrum sich- Dess one would have noticed it long ago It occurs however very frequently that children become infected several times with diphthers and are in Jected repeatedly wth serum Some sera as for instance the Tb serum of Maragliano or the Menzer serum against rheumatic fever arc injected ·70 SERUM SICKNESS every day or every week During this therapy certasnly reactions occur frequently, but they usually are not diagnosed as serum sickness but as reactions between sickness and antitoxin Aronson already declared that the reaction to Menzer's serum was not caused by the content of antitoxin, but was due to the nature of the foreign serum The most important reason for the lack of reaction is the length of the interval between first and second injection, a point which we shall have to discuss Jater Another dưference between our cases and the other above mentioned kind of rein. Jectrons is the size of the first dose of serim We inject between 100 and 200 cc serum, by using the present dosage of diphtheria serım the first dose amounts to only 5-10 cc But likewise as exanthemata etc appear after small doses of serum, so also such small amounts (1-12 cc) may provoke sensitiveness to the reinjection, as the following cases show, which were selected from a large number of remjected diphtheria cases Franz 2, admitted on 6/8/03 with measles, received for immunization 200 antitoxid units (1 cc) Discbarged OD 6/16, developed urticaria at home-the earliest on the 9th day after the first injection Op 8/2,817 Weeks later, ngaja sojected against croup with 1500 antitoxp units (5 ce deptheria aerum) Shortly afterwards gen eralized urticaria, edema of the face His sister, Frieda Z , reacted in a similar way She was immunized with 200 antitoxin units on 6/10 and again 6/26 29 she was in the hospital with measles On 8/2 admitted with croup she was injected with 5 cc diph theria serum One hour later her face became red and edemstow, The eyelids wero so much swollen that the right eye could not be opened Two hours later generalızed urticaria, temperature 38 69 Locally slight swelling and great tenderness EU: 3 , 4 months old, first rasection on 6/20/01 12cc diphtheria berun (2000 satttoxin units) against diphtheritic croup On 6/30 sudden fever up to 30 0°, at the same time urticaria eruption (10 days after injection of serum) Tbo lever lasted two days, later the rush became more morbilli-like and multiform in character and retained visible for several daya Ninteen daya sfter the first injection (7/9) was again wjected with S cc (500 antitoxin units) diphtheria serum Lecause symptoms of croup reap peared About one hour afterwards & severe general eruption of urticaria started From the site of the injection the skin of the entire abdomen became #wollen In the afterpoon the temperature rose to 39 54 there was no fever since the first reaction equent vomiting on the next day fever around 39 0° The area of injection shows nutande to the 72 were 3 Dis ver the er and rier or theria diphtheria bacilli ON 24/24 Iuell Bue #14 LU gerum (300 antitorin units) 27 days after the first injection One hour after this in jectroa distidet swelling of the right hand, wbich later extended over the whole forearm Trrenty four hours later still distinct edema from the elbow joint down In the neighborhood of the injection distinct discoforization, small sized, indistinct pale rosy-red 729h above the area of the injection up to the elbow joint ·THE REINJECTION 71 All 8 cases have in common that after the first injection of horse serım berum sickness developed at the normal time between the 8th-13th day But when the same individuals were reinjected with horse serum after an interval of 16-42 days symptoms of serum sickness appeared immediatelythat means at once or or at least rapidly within 24 hours EXPERIMENTAL STUDIES About the single cases reported until now the objection is possible that by chance a kind of serum was used for reinjection which produces more vehement symptoms and in a shorter time In order to counteract this objection ne took advantage of an opportunity which offered itself to inject all children at the same time with the same serum when a case suspected of diphtheria occurred on the general ward and to observe closely its course in children injected for the first time and in those who had been previously injected I Immunization on 2/11/03 At 6 00 pm injection of 15 cc diphtheria serum into the skin of the forearm Three children were previously injected 1 Johanna J 180 cc scarlet fever serum 31 days previously No definite symptoms of serum sickness 2 Emile K circa 8 -c diphtheria serum 6 years ago and the same dose 36 days ago 3 Dr P 200 cc scarlet fever serum 9 months ago, 8 days later urticaria and Numbers 4, 5, 6, 7 were children not injected before 1 and 2 showed identical joint pain .L I be half an hour itching, after one hour alightly red swelling of a radius of 2 cm reaction of Dr P 18 not an absolutely specific reinjection reaction such slight redness and dwelling are also often seen after the first injection But the bard edema of the srm in cases 1 and 3 18 specific 11 Immunization on 3/7/03 Each patient received 11 cc diphtheria serum 1 Barbara T 46 days previously injected with 100 cc Serum sicknesg started after the first injection on the 10th day and lasted to the 23d day 2 Karl D previously injected with 6 cc diphtheria serum on 2/7 and 200 cc scarlet fever Berum on 2/15 He was still suffering with gerum sickness on 3/7 3. Rudolf J Injected 4 days before with 200 cc scarlet fever gerum Serum sickbess Started only on 3/14 So the reinjection occurred therefore within tbe incubation time 4 5, 6, not previously injected Only Number 1 showed a typical sensitive reaction after 5 hours, analogous to cades 1 and 2 of the first series Among those not previously injected, to showed exanthemata but only 10 and 11 days respectively síter Injection i e starting at the Dorinal time Number 4 3/17 In the evening indistinct erythema 3/18 universal, multiform erythema, temp 33 %* Number 5 On 3/18 erythema mith large spots ·72 SERUBI SICKNESS These cases demonstrate clearly that the same serum has different effects, depending upon whether or not it is acting on a previously treated organism In the previously treated system it creates an immediate and violent reaction, in a person not previously treated either no reaction (Case 6) or a reaction at the pormal time of serum sickness (case 4 and 5) Thus the objection is removed that the rapid onset of symptoms could be due to the use of a certain kind of serum for reinjection But why do Cases 2 and 3 not react who were also previously treated with serum? For case 3 the explanation lies in the interval between the first and second injection In all cases reported up to now which showed specific reactions two to six weeks had elapsed when the second injection was performed, but in case 3 the interval was only 4 days We shall discuss this point more thoroughly later However in case 2 all conditions were present mtensive preparatory treatment suffic interval, and in spite of it no symptoms On the basis of the results of later experimental studies we shall see that this case 18 an exception to the rule for which se have no explanation III Immunization on 10/30/03, each child received 1 cc diphtheria serum 1 case previous injection 150 cc serum interval 36 days 2 case previous injection 150 cc serum interval 32 days 3 case previous injection 200 cc serum interval 6 days 4 case previous injection 200 co serum interval 4 days 5 case previous injection 200 cc serum interval 1 day 6 case previous injection 200 cc serum interval 1 day 7-12 not previously injected cases as control Result Among the Bir control cages one showed local hives on the 7th day Cases 1 and 2 developed typical immediate infiltrations on the forearm Cases 4, 5, and 6 did not show any reaction Only case 3 developed on the day of injection a local erysipelag like redness of 3 cm radius, a reaction which may not be specific The experiment reveals that 32-36 days after the previous injection of serum, specific sensitiviness was present, but is not yet present 1-6 days after the first injection IV Immunization on 7/19/03 1 cc diphtheria gerum into the skin of the forearia 3 previously injected cases i Gisela H 200 cc scarlet fever Berum 39 days ago 2 Karl B 140 cc scarlet fever serum beated according to Spronck to bye Celsius 56 days ago 3 Johann S 100 cc scarlet fever gerum 6 days before 4-10 not previously treated cases (controls) Result Not one of the 6 control cases showed any reaction nor did egge 3 Case 1 That CASA ! Teak rg ·THE REINJECTION So we see again that 39 days after the first injection of a large dose specific sensitiveness is present, but is not yet present after an interval of 6 days V Immunization on 11/15/03 each child received 1 cc diphtheria serum Nome Amount of Beruna laterval de the 1 injected 1 Franz T 2 Paul, E 3 Egon E 4 Eduard G Anna R 210 316 200 100 200 Day of onset of derung Bickness efter the 1 injection day Sth 13th 8th 9th 7th 6 months 41 days 38 38 20 6 AL The circumference of the left forearm 19 cm of the right 16 cm Ut the left upper af 17cm of the night 16 cm Temperature 37 5° In the left axılly one bean sized node In the right axılla just palpable glands - - gland swelling on the same aide later co symptoms Case 1 No immediate local reaction but instead on the 7th day a mottled erythema ertending over the whole external surfare of the left arm Slight swelling of the aullar glands Result The specific local reaction 19 present after an interval of 20 to 4 days after the first injection It 19 absent when six months have elapsed after the first injection (Case 1) Let us now summarize the results of the 5 experiments Among 30 children who had previously never recensed serum, only six (20%) developed distinct serum syraptoms after an injection of 10 to 15 cc diphthena serum but not earlier than on the oth day an immediate reaction Nocal) comparable to previously desenbed reactions de not appear Only in one child was after 21 hours a slight infiltration at the site of the injection still discernible

·74
org
Days
28 29
35 36
24
upaten
Body Weight
SERUNE SICKNESS
Lymph Gland
Swelling
st
Temperatur 38
»?
awayiuexz
1
CHARY EX

·THE REINJECTION 75 The 20 previously injected cases can be divided into three groups according to the length of the interval between the first and second injec tion 1 Intemal of 1-6 days sir case: No immediate local reaction with one exception (III/3) The child showed an erysipelas-like redness with a radius of 3 cm on the day of the injection The interval was 6 days 2 Interval from 6-9 months 2 cases One child (I/3) showed a light swelling of 2 cm radius one hour after the injection, a symptom which can also be een in some cases after a first injection The other one (V/1) showed no immediate reaction, but an erythema on the 7th day 3 Internal between 8-8 weeks Among the 12 children belonging to this group eleven developed an immediate local reaction Several hours after the injection a more or less intensive tender swelling of the injected arm was observed Only one case (11/2) was entirely negative One case (V/3) showed, besides a local swelling an immediate general eruption of a rash which reappeared on the 6th day Regarding the series of our investigation and the eight previously mentioned cases, which showed the differ ence in the tune of onset of the serum sickness after the first and second injection we can make the following statements Due to a single injection of horse serum a change takes place in the reaction of the human organism to the reintroduction of the same substance, which obeys a definite law 1 The serum sickness which usually starts after the first injection after an incubation time of set eral days appcars within a few hours The incubation time is lost eranthema 2 Besides this difference in the time of the reaction a gradual change 18 observed The reinjected indivdual as hypersensitue He reacts more frequently even after an injection of small amounts (in the experiments 90% in contrast to 20%) and more intensely the reaction consists mainly of an intensie edema in the area of the injection, less frequently of fever and generalized 3 This altered reaction is obseried regularly, if at the first injection large amounts of serum are used and if there is an interval of 2-3 weeks between the first and second injection (reinjection) THE ACCELERATED REACTIOV Until now we have devoted our attention only to the immediate reactron But one case of the experimental group (V) could have already at that time called our attention to the fact that the symptoms after rein Jection are not exhausted with the immediate reaction Egon E (V/3) First injection of 200 cc Onset of the first serum sickness on the 8th day After an interval of 38 days resnjection of 1 ce serum Immediate swelling, ·76 BERUM SICKNESS universalevanthema In the next d338 no dey symptoms On the 6th day reappearance of generalized urticaria (Chart XXVI) The following cases ran a similar course Theodor II admitted with croup on 2/14/97 received on successive days (From 2/14 -2/17) altogether c3 32 cc diphtheria serum 2/14-3/6 (16 days after injection) erup tion of urticart On 4/4/97, 49 days after the first injection, again injection of 1500 AU Immediately after the injection universal urticaria, 38 8° On the 6th day after rojection (4/9) fever starts, lasting to 4/12 On 4/10 urticana Mana K On 9/19/02 1500 A U Serum rash after discharge (ca 12 days after 10- jection) Then an interval of 4 months Os 1/27/03 1000 A U 10 8 cc serum Around the site of injection partly mottled, partly confluent redness and a few hires 2/3 (6th day) urticaria, 38 2º, joint pain Anna Q January 1903 injected in the Franz Josef's hospital against diphtheria Interval 2 moaths On 3/14/03 200 cc scarlet fever serum Local urticaria, edems at Days 1 7 8 13 H Theodor Reinjection 40 Terrrperatur ** Exartheme CRART XXVI the site of the injection 9/18 (5th day) universal urticaria On the 10th-13th days joint pain, intensive edema again universal edema on the 12th day This case will be discussed later more thoroughly (page 93) Franz K 7 years admitted on Jan 1, 1901 with scarlet fever 1/4/01 cc diphtheria serum On 1/5 200 A V scarlet fever serum On 1/13 onset of serum sickness 9 or 8 days after injection urticaris spleen enlargement, swelling of lymph glands and edema Angle of tbe weight curve marks the beginning of the convalescence (on 1/25 21 days after injection) On 2/20, transferred to the Wilhelminen hospital on account of measles, where possibly anotber propbylactic injection of serum against diphtheris 799 given h 10 m diph the ter) ibo 800 ·THE REINJECTION 77 pro till morpjog frequent vomiting sleeplessnegg, thirst 4/18 in the morning sneezing Beveral times At the round brigbtred maculae with indistinct central huves scattered all over the body Conjunctiva injected Towards evening another eruption of rash 4/19 the urme contains a trace of albumen, today for the first time Today the weight 19 at its maximum Circa 400 grams of edeme Shortly before injection and 1 3, 6, 8 and 10 days afterwards blood 18 withdrawn and tested for precipitation (microscopically) with rabbit antı horse serum and on the other hand with horse serum (1) TABLE 3 Before INJE ton 10 days alter 1 8 3 Precspitation with anti horse Berum + ++ + weak trace? ++ ++++ + eranthema) ++++ Precipitation with horse scrum What these cases have in common is that, after an immediate reaction, several days of complete latency follow, which period 18 concluded by an eruptron of new symptoms on the 6th or 6th day We encounter here again an incubation period which shows a substantial difference from the incubation time after the first injection, it is shortened Another peculiarity, which we shall discuss later more thoroughly, is revealed in the clinical picture the accelerated reaction sets in with violent, frequently stormy symptoms, and is termunated more rapidly than the normally timed reaction after a first injection A short incubation time can be observed sometimes after a first injection Fourteen cases among 90 showed the onset of generalized symptoms on the oth or 7th day after injection However in cases of rein jection, late symptoms, if they occur at all always appear on about the 6th day after injection If an individual, whom we know has already once been injected wth serum, shows no symptoms by the 7th day after injection, we need have no fear of Benim sickness If however, serum sich ness starts on the 6th day in a child whose previous history is not known, one cannot conclude with certainty from the length of the incubation period alone, that the child was previously injected Only the combination of a shortened period of incubation with a sudden onset and rapid termina tion of the disease gives the typical picture of an accelerated reaction of a Teinjected individual The double picture of the "immediate" and "accelerated reaction" leads us to a third form of reaction observed in a reinjected person, which con. sists of the accelerated reaction only The immediate reaction is left out This picture is seen after a reinjection following a long enteral Emmo Sch was admitted on 9/25/02 mth croup and received 12 cc diphtheria Serum Ru 10/12 20 symptoms 7 months later on 4/11/03 injected with co diph ·78 SERUY SICKNESS theria serum From 4/12-4/16 no fever Oa 4/17 (the 7th day) 37 89, and universal urticaria Oscar Y 11 years First injection in the beginning of 1904, 1 cc given as a prophylactic dose on account of diphtherie of his brother Second injection on 9/25 (9 months later) 10 cc (3000 A U ) On account of severe pharyar diphtheria 9/30 (5 days after injection) eruption of urticaria which quickly disappears 10/1 in the afternoon (6 days after reinjection) generalized urticaria On 10/2 in the forenoon large areas of redness with occasional lives over the entire body No fever Anna K , 3 years First injection on 9/3 against diphtheria 4500 A V (15 cc) Hospitalized 23 days, no serum sichness and injection on 3/3/05 (18 months later) 3000 A U in 12 cc serum On the next day the site of the injection is only tender but not red oor iofltrated Early on 3/9, 6 days after the injection, violent eruption of 1 Days 73 15 15 95 21 22 29 73 G Anna Body Weight 16 IS Temperatur sa 11 Exanthomo CHART XXVII urticaris on the entire body, starting from the site of injection The inguinal glands particularly dear the site of Djection, tender and enlarged the afternoon 37 5*, go further syraptong - mntame ) months 2 noun pal of 4 Inele mord ·THE REINJECTIOV 79 8 cc diphtheria serum (1000 A U ), 6/10 (7th day) eruption of large urticarja 17 the crural region, smaller on the rest of the body That is really the reason that one time an immediate reaction develops, Another time an accelerated reaction, and another time both kinds of reaction? The experience that when the injection is made after a long interval, the imediate reaction fails to appear, leads to the idea that the decisue factor 18 to be sought in the time which elapses between the first and second injechon. A chart (table 4) containing all the results of the reinjection will cor roborate this assumption In this chart only those cases are included which developed a positive reaction after the second injection The cases receiving several injections were not considered, because they would have caused complcations in the arrangement according to the duration of the interval We see that, according to the length of the interval between the first and second injections, three periods can be differentiated, tyhich overlap each other 1st interval of 12 to 40 days immediate reaction alone 2nd interval of 1 to 6 months immediate and accelerated reaction 3rd interval of over 6 months only accelerated reaction That these periods are not sharply separated, can be discerned with the first glance at the chart The gradual transition, as well as the distribution of the forms of reactions are illustrated by the spectrum shown in Chart XXVIII The immediate reactivity sets in regularly 12 days after the first injec tion and is characterized usually by local edema, less frequently by general ized symptoms Only one positive case stands out in comparison with numerous negative cases within the first 12 days This one case showed, after an interval of 6 days, erysipelas like redness at the region of the injection After an interval of 3 months and more, the immediate reaction is no longer obligatory, then gradually decreases in frequency However, Isolated cases also occur even later the longest interval after which an Inmediate reaction appeared was 3 years Marjan (Soc med 5/26/05) also reports a case of immediate reaction after a 3 year interval This restriction of the immediate reaction to a relatively short tune explains why thus obsers ation could have been over looked for so long a time Most of the cases treated with serum up tali now were diphtheria cases, of reinjections were administered they there given during the first days of treatment before the onset of scositiveness If the reinjection mas made somewhat later, at the time usual for serum Symptoms, the immediate reaction colacided with the symptoms appearing at the normal time due to the previous injection and could therefore ·TABLE 4 80 Immed ste React on Nada or No Amount 1st Inject Oaset let Berita Buckness Inter Amount of Berum Reinjection Accelerated React on Local Universal dare ++ + 7 redness + strong urticaria + strong + + very strong + very strong + 2 daya + 2 days -~-~-06880-806685- ĀS BĀRGĀTĀ BĀĀĀĀĀĀĀĀĀĀĀ + strong + weak +++ + collapse lever + 8 days + 4 days SERUM SICKNESS 1 Di Di Di 180 SC 150 SC 100 SC f OR + weak + very strong + weak + strong + strong strong + strong + strony + weak + 150 SC 200 SC ܟܒܨܝܕܝܝܝܙܝܙܚܙܝܕܒܝܚܙܘܝܨ££ strong + ទីទី៩នី strong OR + + 7th day 5th day, severo 6th day, lastiog 8 days + very strong ·Gth day you urtio weak នននខ្លួននួន គឺទីទីងទីទីទី + weak 6th day, urtic Joint pain 4th day, local ន + -Ea និង + និងទីទីទីនទីទីទីទីទីងទីង និងទី៩ទីទីទី 6 -e ទីទី៩ទីទែនទីទីនី ទីទីន័ងទី THE REINJECTION 10,63 ២២- 7th day erytheme 7th day 6th day, urticaria 7th day 5th day, local + weak oth day 8th day, violent urticaria 8th day, exanthems 6th day, fever 8th urtic L. Jose Sipe 7th day urticaria o, 7th day urt lasting2 days Jobann 6th day erythema ° 5th day festive Robert 7th day gen urtic G Johanna Sh A Valerie day very violent 5th day lasting 8 days * Severe Sc-Scarlet laver serum D:--Dyphihena serum N- Normal serum St-Polyvalent streptococcus serum Wested Frozen ៩១-១១១ ន៤ 81

·Ability of Reaction
Accelerated Reactivity
Liment
Immediate
Reactivity
ÓTTTT OZ 15. Deys
Interval Between First and Reinjection
UMIES|| DATOMI
LEED
12 Monthe is
at
Yeors
SERUM SICKNESS
CHART XXVIII

·THE REINJECTION 83 not be separated from those symptoms Later reinjections at the time of the highest sensitiveness, 20-50 days after the first hardly ever occur in diphtheria The first disease (diphtheria) 19, that time, terminated and the child is protected against a netv infection through his immunity created by the first attack of diphthena Only after loss of this immunity may reinfections with diphtheria occur occasionally At this time the organism is already in the third period, and therefore no longer reacts immediately but shows an accelerated reaction The difference between an accelerated and a normal timed reaction is all the more easily missed as the first reaction occurs not infrequently around the 6th day A comparison with an early reaction in the same individual, where we started is possible only in few cases The accelerated 1 thn annond period of accelerated reactivity Even after 7 years the accelerateu redu tion was still to be seen CLINICAL SYMPTOMS FOLLOWING REINJECTION I The Immediate Local Reaction-The Specific Edema Let us once more look over the clinical symptoms, which represent the specific signs of the reaction of a reinjected individual We must consider the immediate and accelerated serum sickness and distinguish in the im. mediate reaction local and general symptoms A very carefully observed case should illustrate the specific local reac tron Dr VP Previous injections 1902, 200 cc scarlet fever serum 1903, 5 injections togetber amounting to 20 ec diphtheria serum 1/21/05 injection of 15 cc antitetanus derum into the skin) of the left forearm The swelling produced by the injection Lot A-10 II, 19 pots Pain 37 4° The re, the skin of the cunference 33 cm Spontaneous pain less than yesterday Pain on presuwe ons ference 32 cm The length of the swelling 23 cm 30 hours after the injection Cr- 3d day Itching On the difusely red exelling appear suddenly quickly passing pale spots (indistinct buses) Circumference 31 em 4th day Itebing and hives like yesterday No general symptoms The swelling 19 ·84 SERUM SICKNESS softer, less reddened, but slightly pigmented During the following days diminution of the swelling 8th day Swelling has disappeared Slight pigmentation Daily examination of the blood for 14 days reveals no formation of precipitin We have here an individual strongly prepared with several injections of large amounts of serum who, one and a half years after the last injection, still reacted with specific edema The characterstic trait of the specific edema lies in the circumstance that the swelling produced by the injection of serum does not disappear, but gradually changes to an edema which becomes more and more intensive Notwithstanding, horse serum is ab sorbed and reaches the circulation This can be proven by testing the serum with rabbit-antihorse serum The amount of the additional accumulation of fluid in the edema can be determined by measuring the replacement of water This we did in one case The amount can be approximately determined by measuring the circumference of the forearm and the length of the swelling At the time of the maximum of the swelling (after 30 hours) the circumference of the forearm amounted to 33 cm compared to 26 5 cm before the injection, the length of the swelling was 28 cm The additional mass h (rr) which results in about 800 cc of edema in place of the injected 15 ce we find an accumulation of fluid which amounts to more than 50 tunes the volume of serum injected In H, a case which we shall describe later where the serum was injected into the thigh the difference between the two thighs was 5 cm (28 23) The length of the swelling was 20 cm The calculation gives an amount of 400 cc edema The injected 5cc increased 80 times Let us make an analogous calculation of the amount of edema in the experiment V/3 The whole arm becomes edematous after an injection of 1 cc diphtheria serum So we see that a constant proportion between the injected amount of serum and the edema does not exist That the proportion can not be a constant one is proven by the fact that in many cases the specific edema is not so intensive, but extends to the next surrounding neighborhood of the site of the injection (See the series of experiments ) The effects of two serum injections given to Dr y P will illustrate this He received on 2/21/03 8 ce diphtheria serum into the left forearm, 9 months in the reinjection T ·THE REINJECTION 85 meuted An even alder effect was produced by the previous injection on 3/11/03 after injection of 1f cc serum After an hour itching, after one hour a slightly red gwelling measuring 1 cc in radius These slight reactions cannot be distinguished in the individual cases from the slight redness and swelling as they also occur after a first injection in the neighborhood of the site of injection Such symptoms can be seen also after injection of varied substances, even after injection of physiological NaCl solution The judgment of the amount of edema is easier if after injection of a small amount of serum-as in our experimental series--1 to 2 cc-an intensive swelling develops The greater the amount of serum injected the more difficult it becomes to determine the absolute increase of the local swelling Friedrich W 16 months First injection on 11/17/03 against diphtheria Second injection on 11/29 on account of severe scarlet fever with 150 cc scarlet fever serum Interval 12 days After 14 hours the abdominal wall around the site of the injection intensively infiltrated extended 11 27 cm, with a sharply defined margin Theedema has a volume of 600 cc , if we assume that the infiltration has a height of 2 rm The volume of the injected fluid is therefore increased three times The skin over the edeml, 19 slightly yellowish Scattered over the entire body red spots appeared with pinhead sized hives After 13 d extended downwards t body In the evening injection We once saw a similar picture in a child who was never injected before (according to the statement by the parents) Gustav P 11 years Admitted on 3/16, at the hospital until 5/3/04 On 3/16 injection, due to a medium severe scarlet fever, of 150 cc scarlet fever serum into the abdominal wall Previously had never had horse serum 12 hours later the area of injection very tender and edematous The edema extends to the skin of the back and 18 surrounded by a 2 em wall like brim During the following days the infiltration flattens out, while at simultaneously extends in the width towards the thigh and back Thereby no rash develops, only a mottled, indistinct redness on the skin of the abdomen and of the back over the swollen parts and their surrounding area On 3/20 the edema has disappeared No further symptoms of serum sickness Is thus a case of specific edema in a child injected for the first time? In favor of this assumption is the fact that no late symptoms developed after the immediate reaction This would be, therefore, a case which arts primarily like a child who had been reinjected Only one circumstance prevents us from recognizing this exception unplicitly, that, namely, such a reaction was never observed in a child injected for the first time, then small doses of serum were used Further. more not one of our 30 control cases, and none of the hundreds of diph- ·86 SERDJE SICKNESS thena cases showed such an edema after an injection of a small amount of serum, thich could have been mistaken for a specific odems If one injects a large amount of serum into the abdominal wall, it is sometunes difficult to decide whether the edema 13 a specific one On this basis ve restrict our diagnosis of a specific edema only to cases which, after an injection of a small amount of serum (1-10 «C), develop a disproportionately large suelling Particularly suitable for this are cases which were injected with i cc serum in the forearma bere the edema appears 12 to 30 hours later, extending from the wrist joint to the elbow joint, and the skin is pale or slightly red As long as the swelling increases, the arm 13 exceedingly pain ful The spontaneous sensitiveness diminishes as soon as the swelling has reached its maximum The pain on pressure lasts for a longer time The swelling starts actually from the moment of injection, increases slowly, reaches its maximum about 24 hours later, and disappears entirely within 2 to 5 days Sometimes a small swelling and tenderness of the regional lymph nodes are present We separate the immediate general symptoms from the local edema, in so far as they manifest then selves by an eruption of generalized exan theraata Certain insignificant general symptoms as feeling chilly or a slight rise in temperature are always connected with intensive local edema It is very exceptional to observe local necrosis after reinjection in bumaa beings, a reaction not seldom seen in repeatedly reinjected rabbits (Arthus) An example of this is the following case Josefa Szr ist injection 11/9/94 10 cc diphtheria serum Second injection 10/13/97 Icc diphtheria serum for immunization In spite of at the child developed dupbtberis and received a third injection on 10/19 again about 8 cc diphtheria kerum (1500 AV) On the next day the area of injection on the abdomen is patalul The face 19 slightly puffy On 10/22 another injection of 8 cc (1500 A V ) Two hours afterwards a hemorrhagic area measuring 2 cm developed above the site of the injection The Burrounding skin 18 very tender and swollen in the evening the swelling exteods to the upper left side of the abdomen extremely painful Temperature 39 4* 10/23 At night very restless Pain in the abdomen zauges rapid respiration Targe 1 pallateh hrown 2 The Immediate General Reachion Ie call the appearance of fever, eranthemad and other general symptoms dereloping within the first 24 hours after reinjection, an immediate general reaction It does not exclusively occur in tesnjected persons, but in rame instances after a first injection It seems that adults show these carly symptoras after a first injection more frequently than children Amongst numerous cases of serum sickness after a first injection ne were able to find only two such cases in the children's hospital, whereas among the ·THE REINJECTION 87 adults whom Dozent Pilcz had injected with horse serum, several reacted on the first day with fever Nothing was known of a previous injection in any one of the cases On what this sensitiveness to horse serum, known as an idiosyncrasy, of an individual not previously injected depends, we are not able to ex plain It has most likely nothing to do with the sensitiveness acquired by a previous injection These exceptions do not breah the general law of the altered reactivity The cases from which we draw our conclusions are YOY A typical example of a fully developed, immediate general reaction 19 the following case L w who he was ral of a 3/23/01 the child was admitted to our diphtheria ward and was injected wilu su u pbtberia serum for immunization The interval between the previous and present Djection could not be determined Immediately after the injection the patient started to scratch At the este of the injection a hand-sized urticaria appeared other densely arranged hives with confluent balog broke out over the entire body The face was puffy Intensive itching During the course of the day the patient vomited several At 300 pm-the injection was given at 10 00 am ---no hives were any longer times viable but i still more e hemorrhagi We see here symptoms similar to the symptoms in the case Leopold H, page 68, and Heinrich K, page 69, representing the generalized immediate reaction & very acute onset of generalized urticana resembling eruptions seen in cases of diosyncrasy against chemical drugs The eruption of urticaria starts almost simultaneously at the area of injection and on the other parts of the body, accompanied by intensive Enna sen mally on the lips and Itch. T 1 a The Case & 72 and afterwards a erythematous eruption sets in of indehaite character So Tapid a change in the form of the rash is not seen in the serum sickness with & normal incubation time It makes the impression that the symptoms, which otherwise require 8-14 days for development, were condensed rato 24 hours No albuminuna xas observed during the immediate reaction ·88 SERUM SICKNESS Fever is a very frequent symptom The behavior of the temperature 18 similar to the fever of the tuberculin reaction After an injection made in the forenoon, the fever usually starts already in the same afternoon (August Sch 39 7°, Theodor H 38 8° Leopold H 38 3") If the injection is made in the afternoon the fever usually develops on the next day (Emilie K 38 8°, Herman K 392) In one instance we saw a condition resembling collapse as an immediate general reaction This collapse reminds us of those severe states of collapse leading to death, which Arthus described after intravenous reinjection of horse serum in rabbits The possibility 18 not excluded that in this case the serum was injected into a vein, the sub cutaneous hemorrhage at the site of the injection would indicate this as having occurred From this observation the general rule should be deduced that intravenous injections of serum which have often been recommended particularly in England and France can be perilous of they are given to a person previously injected with serum As we are frequently unable to exclude with certainty a previous injection of serum, we advise most urgently against the intravenous injection of serum Josef w On March 4th admitted with croup after measles received 8 cc diphtheris serum (1500 AU) discharged on March 8th On March 20th the child developed a multiform erythema On March 30th readmitted with diphtheritic croup March 31st injection of 16 cc (3000 A U ) diphtheria serum 27 days after the first injection The injection was made at 10 15 a m into the right abdominal wall 10 minutes later redness and urticaria eruption appeared around the area of injection Shortly after wards hives appeared on the face and were scattered over the body 15 to 20 minutes after the injection the child who was very well before began to vomit to roll hus eyes his extremities became cyanotic his pulse could not be felt Flow of saliva After application of stimuli and hot packs the patient gradually recovered from this collapse Until 3 o clock in the afternoon several eruptions of hives In the afternoon fever rises to 38 4° Next in & deep subcutan intravenously) The ioguinal lymph nodes protruding larger than on admission 4/2 temperature 38 0° 37 5º (2 days after reinjection) The region of the e te of injection hemorrhagic Inguinal lymph nodes as yesterday 4/3 (3 days after in jection) 37 9° 37 6° no rash Three bean bized lymph nodes in the right inguinal region and several smaller ones on the left side one bean sized and several smaller nodes distinctly swollen On admission on 3/31 the inguinal glands were pea sized 4/5 (5 days after injection) In both arguinal regions a date sized pach of lymph nodes and several smaller lymph nodes 37 5* 37 3• 4/6 (5) days after injection) 37 6° 37 8° During the night eruption of a morbilli like rash on the stem and face leaving the back free In the morging only remnants of the rash la inguine (right) three bean ha Thetber actually there has been a death among human beings due to intravenous injection of serum we do not know The fatal cases of the ·THE REINJECTION 89 literature (Gottstein etc) refer to cases injected for the first time We believe that it is impossible to ascnbe them to serum because after sub cutaneous first injections of serum of even the largest doses we never experienced syncopal symptoms The immediate general reaction is usually terminated within 24 hours of small doses are injected, however sometimes they last longer Augustine # 31 yearg Previous injections w th diphtheria serum on 9/25 and 11/1/01 On 11/30 admitted with scarlet fever on the same day (29 days after the last 30/1 Daya 1 78 14 15 14 Augustin's 4) Temperatur38! 37 Exantheme CHART XXIX injection) 150 cc scarlet fever serum Hoechst Within a few hours a dense generali ed eruption developed consisting of sl ghtly elevated pea sized maculae Da the right de of the abdomen (site of the injection) appears a very tense hard and painful Enfiltration with a slight redness of the skin ettending down to the genitalia (labia) aad down the back to the spinal column to the left to the mamullar lune Iland and finger joints painful when moved Vt re ma 35 ht day on no fever ·90 SERUM SICKNESS This case shows that local edema and immediate general reaction do not exclude each other, but may exist at the same time (See also Egon E, page 75, and the chart of reactions pages 80 and 81) When the above mentioned Georg K received another injection, the local reaction was likewise combined with a general reaction which lasted three days The boy was again reinjected on 4/9 17 days after the described reinjection, with 5 cc (1500 A U) on account of an exudate on the tonsils, which showed diphtheria bacıllı in the culture At 8 15 in the morning an injection into the left thigh At 9 o'clock a great deal of thin secretion flows from the canula Face slightly puffed cyanotic The region of the injection is more prominent than immedzately after the injection and surrounded by a palm sized redness At 12 o'clock temperature 39 30 (the boy had fever during the last days due to his larynx affection up to 383) In the afternoon an intensive swelling of the thigh develops wbich was very painful Not until the next morning (24 hours p 1 ) did an urticaria eruption start which lasted 11 days With this the general symptoms are exhausted On the other hand the local affection was present for eight days 4/10 The left thigh is pale livid, intensively edematous, as of a large bematoms of the muscles were present The circumference of the left thigh 1928 cm compared with 23 cm of the right thigh 4/12 The circumference of the thigh 27 23 cm Around the area of the injection 4 greenish suffusion measuring 6-4 cm This time a much more intensive local reaction developed than at the first time But the serum sickness was terminated with the immediate reaction whereas the first time an accelerated reaction followed, which will serve us, in what follows, as paradigma 9 The Accelerated Reaction We call a reaction accelerated, vf it appears in a reinjected ındındual 6-7 days after the reinjection This form of reaction can be distinguished on the one hand from the immediate reaction of a person injected for the first time by the shortness of its incubation period The above mentioned George K was reinjected on 3/23/01 and developed an im mediate generalized reaction This reaction was already terminated by 3/21 During the following days no symptoms On 3/27 the 5th day pi in the morning patient was etill well Temperature 37 19 At noon very weary at 400 pm 39 5º at 800 pm swelling of the face develops particularly of the lips and eyelids, at the same time urticaria on the face deck, and thighs Slight swelling of the axillar lymph nodes No albumen No further symptoms The sickness starts on the afternoon of the 5th day with a stormy aspect and is already terminated on the same evening As mentioned before this precipitated course combined with the early onset is pathognomonic for a ·THE REINJECTION 91 circa 400 grams feinjection Several times we were able to recognize only from the clinical picture of an accelerated reaction, that the patient had been previously treated with serum In the case of an accelerated reaction the same symp toms occur as in a normal reaction after a first injection fever, vanous types of rashes, joint pain, edema Anna G (Chart XXVII) ist injection Unknown amount of serum on account of diphtheria 10 weeks before 2nd 10jection on 3/14/03, 200 cc scarlet fever serum on the third day of a severe case of scarlet fever Immediate local reaction The injection was made at 11 00 a m At 4 o clock in the afternoon mettled redness appeared at the site of the injection in the evening this area 19 enormously painful urticaria on the abdominal wall After 20 hours Lotensive edema and local papulous eruption 5th day Universal urticaria which rapidly disappears 11th day Urticarie edema of the fingers 12th day Joint paing Hands, especially the fingers edemstous Gaio in weight 13th day Maximum of body weight(1200 g edema) Indistinct red spots ontbestem From now on the edema decreases rapidly and has disappeared on the 16th day NO 4/7 third injection Thirteen weeks after the first three weeks after the second Injection Patient receives 1 cc diphtheria serum (Behring) MJd specific edema which 19 stull visible after 48 hours A typical example of the course of an accelerated reaction is represented in the case of Johanna G This case is all the more remarkable as the interval between the first and the reinjection amounted to 57 years In the case of this patient we made daily leukocyte counts It was interesting to see that at the time of the accelerated reaction an intensive drop in the number of leukocytes occurs This drop corresponds to the drop of the leukocyte curve during the normally timed reaction after the first injection (Com pare Charts XXX and XXXI ) Also in the curvo of the leukocytes 15 indicated the character of the accelerated reaction of scrum sickness Acute onset at an earlier time, intensity, and rupud terınınation Albumen en las ararlet any symptoms of serum sickne 10/29/03 received at 9 308 m diphtheria serum for immunization non towards evening a rapid pulse n vomiting At 8 30 pm till ·SERUBE SICKNESS hemorrhages, caused by scratcbing On the other parts of the body indistinct rem pants of a rash One would think that one was looking at a glin devastated by & 3 10 4 day continuing erythema exudativum On the abdomen gothe small bives with large halo, Distinct swelliag of the regional lymph glands in ingude and of one thoracal lymph node Afternoon tetap 37 80 47739 29740 15 Days GJ Naina 182 tian IAL 100 Leucocytes 105010 bodna $184 10 12 9,300 CEART XXX Leukocyte count after reinjection Sth day in the moralag still 37 3* from then on Do fever, exsathema disappeared Leukocyte count 4th day 5th day 6th day 7th day 8th day 9th day 10th day 11th day 12th day 17,790 8,740! 10 360 10,220 9,180

·THE REINJECTION
93
The following case illustrates the behavior of the lymph glands during
an accelerated reaction
2575
Days
1
14 15
21 22
28 19
Body Weight
Leucocytes
rariz
1250D
10000
.
ܫܢܫܢܝܐܩܪ
1
1
CEART XXXI Leukocyte count alter first injection
Anna R 5 years 10/25-12/13/03 In the spring of 1903 d phtheria treated with
an 200 cc scarlet fever serum into the right
lands
zed right several bean-sited
Confluent in the shape of a sausage anu si gul, ku uding
5th day Inguinal glands increasug in bize

·94 SERUDI SICKNESS 6th day Inguinal glands on the right side still larger In the afternoon towards 300 an eruption rather generalized urticaria 7th day Strong desquamation of the skin, many effects of scratching, isolated pea-sized hives surrounded by red halos 8th day Inguinal lymph nodes, right bean-sized, left smaller 10th day Inguinal lymph nodes, right in a shape of a sausage, bean-sized 11th day The glands in inguine both sides less than bean-sized, not longer like a sausage 21st day Injection of 1 cc diphtheria serum Slight swelhog at the site of the injec tion and a mild swelling of the regional lymph nodes The inguinal lymph nodes are distinctly enlarged already 3 days after injection, they decrease in size from the 10th day on The large amount of serum (200 cc) was disposed of with only insignificant symptoms Similar enlargement of the glands is seen in the case of Robert L Here the interval between first and reinjection amounts to 5 years Robert L 11/21/03-1/3/04 Was in the hospital 5 years ago (April 15, 1898 for 12 days) Two to three days after discharge a morbillous exanthema On 11/22/01 injection of 10 cc scarlet fever serum into the right side of the abdomen 8th day Inguinal lymph nodes on the right side until now bean sized today they became suusage like protruding bean and larger than bean sized left bean sized Ad nates indistinct net-like erythema 9th day Temperature 37 30-37 0° Remnants of exanthema on the right side of the abdomen There is a group of fresh hives with large balos, scattered bives on different parts of the body 10th day on the right side of the abdomen pale red, separated spots No fresh hives 11th day No fever, lymph glands as they were on admission It is remarkable that in this case the incubation time after the reinjection seemed to be shortened in comparison to the rerction after the first injection of the same individual, but that its duration is nearing the normal incubation tune Whether or not the accelerated reaction persists throughout the whole hfe, or if it exists only for a limited time, we can not as yet decide, we have just a little experience as to whether the accelerated reactivity through an always increasing incubation time returns to a normally timed reaction or if the accelerated reaction later in life disappears in the same manner as We learned it happens to the immediate reaction and that instead of it the normal incubation time returns The decision of this question will only be possible after a larger number of years will have elapsed since the introduction of serum therapy DIAGNOSTIC SIGNIFICACE OF THE IMMEDIATE AND ACCELERATED REACTION We have already discussed repeatedly the characteristic form of a rese, tion of a reinjected person with the idea in mind, that from it retrospectively ·THE REINJECTION 95 We would be able to diagnose a previous treatment of the person with borse serum This conclusion is only permissible of the result of the reaction is positive If the immediate reaction does not take place one can not conclude that no previous treatment has been carried out Some individuals are not sensitive to repeated injections just as there are individuals who do not react visibly to the amount of 200 cc serum Agnes T admitted four tires to the diphtheria ward was injected on 3/22/98 after 2 years on 10/17/00, again 15 months later on 1/13/09 and finally after a one month interval on 2/22/09 no distinct reaction was observed after any of these Injections But the opposite we can tell with certainty that everybody who develops * specific local edema, or a typical rapidly appearing accelerated reac tion must have been previously injected from this the practical value of these forms of reactions becomes apparent Its significance will be enhanced by the following there are persons do not react clinically to the first injection of horse serum but who behave at the reinjection like persons who teacted after the first injection Thus finding corresponds to the behavior of rabbits. Their first serum sickness Tuins a symptomless course whercas they show the typical local edema We can conclude from this that our methods of observation are insuffi Clent to establish the exstence of the first serum sickness The disease did not reach the threshold of clinical perceptibility whereas certainly biological alterations must have occurred Accidentally in an experimental study next to other previously injected children we injected a child as control who presumably was never before injected We were surprised to see that this chid likewise showed an in mediate local reaction It was revealed later that 29 days ago this child had been immunized on account of diphtherig of his siblings after reinjection Franz W 4/7 (interva Ewell og oft ton peräisted for 2 days The possess therefore in the immediate or accelerated reactily a new CTIE for tox V of the human to revaccination The accelerated and modne ledenu Staallpox vaccine proves a previously successfully performed first vaccina tion ·CHAPTER 3 THEORY OF SERUM SICKNESS FORMATION OF PRECIPITIN IN VITRO PROVABLE ANTIBODY RCACTIOV On the preceding pages we have limited ourselves to clinical observations and have purposely avoided mingling our theories with the facts The difference in the reactivity between the first injection and the reinjection forced us to the formation of some theoretical explanations of this differ ence This difference could not be due to the antigen (10jected serum), as we have shown in our experiments since the same serum caused different kinds of and differently timed reactions depending on whether it was injected into the organism for the first time or was reinjected Thus we came to the conclusion that it was the human organism which has become specifically altered due to the first injection of a foreign serum and that it has acquired a new property in consequence of which the second reaction occurs more quickly than the first We now ask ourselves what kind of alterations developed in the organism after it was injected with a foreign serum We know from the results of biological research that specific substances are formed in the injected organism When these substances are brought in contact with the antigen in a test tube they bring about a precipitation We owe the discovery of this substance called precipitin to R. Kraus who demonstrated that the serum of an animal immunized against typhoid fever produces a precipitation when in contact with the germ free filtrate of a typhoid bacıllı culture Furthermore it as found that the serum of animals which were previously injected with the serum of a foreign animal produced a precipitation when in contact with the antigen (the serum uscd for the previous injection) Tschistoitsch observed that the serum of a rabbit previously mjected with horse or eel serum shows a precipitation of brought in contact with horse or eel serum An analogous report was made by Bordel about rabbits which had been injected with hen serum The formation of precipitin is a specific reaction similar to that of the formation of immune bodies This was made clear even in the first publica tions Bordet Uhlenhut and Wassermann used it for the forensic durer entiation of the different kinds of blood Nuttall used it for zoological differentiation Hamburger and Aforo were the first to prove that humans also forma precipitins after an injection of horse serum These authors expressed their assumption that the symptoms of serum sickness are due to the ·THEORY OF SERUS SICKNESS 97 appearance of precipitins At first they developed the supposition that the exanthemata might be produced by mechanical difficulties in circula tion, created by the formation of & precipitation brought about by the contact of precipitin with the still present horse serum at the moment that the precipitins enter the blood However they dropped this idea because Rostoshe, lichaelis, and Oppenheimer proved that no precipita tion takes place in the blood of living orgʻin sms Lately (Soc med des Hopitaux 26: 5, 1903) Trdal and Rostaine col Jected experiences from therapeutical experiments in cases of paroxysmal hemoglobinuria, which confirmed the animal experiments of the above named authors also for human organisms Vidal and Rostaine injected antı human serum of rabbits and horses, which gave abundant precipitation in the test tube subcutaneously and intravenously If coagulation would occur in the living animal or human being we would surely see very severe symptoms of sichness brought about by the plugging of capillaries Howeser the individuals behaved as if plain rabbit or horse serum had been injected The first injection showed no immediate reaction excepting in one case where a generalized urticaria developed Only if the injection was repeated local reactions occurred hich were similar to the reaction which we observed after the reinjection of normal horse serum As we shall see later it is not simple to show a causal connection betteen precipitin formation and serum sickness In most cases precipitın appear much later than the disease and even very intensive serum sickness symptoms run their course without the forma tion of precipitin Time of Appearance of Precipitin The precipitins do not appear immediately after the injection of a foreign serum but only after a longer interval, in some measure varying according to the k nd of animal and serum used 1 course of penodo cipitin 3 1 tbe following paw *,. he rise of the content of pre- The drop in antibody content The second period lasts about trso days, the third and fourth periods vary in their duration After rabbits are injected subcutaneously with horse serum, the period of latency is somershat longer When fise rabbite trere injected with 1/100 of their body weight of horse serum, the precipitin appeared in tro animals on the seventh day, in three animals on the ainth day (Hamburger and Pirquet) In one rabbit, which recensed 1/300 of its body weight, the ·98 SERUM SICKNESS precipitin did not appear until the tenth day This delay is not the con sequence of the smaller dose but of an individual difference, because in other cases the incubation time is independent of the amount of serum injected (v Dungern) Weeks IZ YUT Z 1 R 150 cm 1903 12 2 PJ 150 cm 1963 VI 123 3 PM 150 cm 1903 Viln P 300 cm 1903 V/15 A 200 cm 1903 IV 11 T 100 cm) 1903 11 13 D 200 cm 1903 IV./5 8 IT 190 cm) 1903 1V./13 1 7 28 35 42 49 Day CHART XXXII Serum sickness and precipitation The black area signifies the time of appearance of distinct serum symptoms (fever, rash, etc ) indistinct final symptoms are illustrated by points Each examination of the children s serum is marked + or -, according to whether or not they showed a precipitate with horse serum The positive results are con nected with a black line In cases 6 and 7, I means the reinjection of 1 cc serum (Immunization against diphtheria) In case 6 the reappearance of precipitin 18 observed already on the eighth day after rcinjection Human beings do not produce detectable precipitin against horse berum as easily as rabbits do Even doses of 200 cc do not always bong about 8 detectable formation of precipitin In a number of children investigated for this purpose, it has mostly at the end of the third week that precipitin was found Our investigation was made microscopically and by mixing children 8 serum math equal parts of concentrated horse serum llamburger and also Francioni found precipitin even earlier than the third cek This difícr ·THEORY OF SERUM SICKNESS 99 ence may be due either to the method used or to the amount of serum injected Further investigation will decide this question In human beings the precipitin can be observed for varying lengths of time in case 1 the curve in the chart showed a strong precipitin still in the ninth week, whereas in case 3, after a short presence, no precipitin could be observed already in the fourth week How now do these antibodies, visible in vitro, behave after reinjection? Here we can distinguish 3 possibilities First the injection during the incu. bation time, second during the stage of free antibodies, third after the disappearance of the precipitin Days 01 2 3 4 5 6 7 8 9 10 11 Large Amount Praespitin 1. Jnyektier Trace . Horse Serum -20 80 Large Amount Precipitan 2 Jnyekto Trace Horse Seyum za - Praecipitation Agglutinanon CRART XXXIII 1 The curve of the precipitins is not essentially influenced by the injection of foreign protein during the incubation period 2 If the new injection of foreign protein occurs dunng the stage of free antibodies, the amount of precipitin drops rapidly immediately after the injection (v Dungern, P 88) The intensity of this drop depends upon the amount of the nenly injected serum However, New formation of precipitin takes place during the following days, a formation which considerably passes the original height of the precipitin content This new formation already occurs after a short incubation time 3 When the injection is made after the disappearance of precipitin from the serum of the previously injected animals, the antibodies appear pot only in an increased amount, but also markedly more quickly than the first time (accelerated reactivity) Von Dungern shows several curies of such reinjected animals, which ·100 SERUM SICKNESS demonstrate that after an intravenous reinjection, the antibodies already appear after three days Hamburger and von Pirquet confirmed these findings in rabbits injected with horse serum A characteristic example is the following Chart XXXIII According to the illustration of v Dungern, the precipitin is marked above the base line, below this line the horse serum detectable in rabbits The rabbit received at the first injection (on Feb 25, 1903) 6 cc, about 1/300 of its body reight agglutinating scarlet fever streptococci serum Moser On the days immediately following, only horse serum was in the rabbit's serum, no precipitin was detectable The horse serum was determined by agglutination and also by precipitation through rabbit antiborse serum The precipitation and agglutination of streptococci could still be found with rabbit serum diluted sixty times The precipitin appears for the first time on the ninth day, does not become abundant until the eleventh day The second injection was made with the same amount of serum on March 18, 1903, twenty one days later At this time no precipitin was present any more on the fifth day it appeared suddenly in a large amount Corresponding to the more rapid appearance of the precipitins, the precipitable substance (F Hamburger) and the agglutinine disappeared more rapidly after the second injection CLINICAL SYMPTOMS OF SERUM SICKNESS AS EXPRESSION OF TRE VITU ANTIBODY REACTION Besides the formation of precipitin, after an injection of foreign protein we see another form of reaction in human beings, serum schness This is seen also in animals, but less distinctly After the first injection, senim sickness appears after an 8 to 13 day incubation period If the injection of the same foreign serum is repeated after a longer interval the reaction appears more rapidly as have been fully described in the preceding chapters The incubation period is shortened to 5 days We called thus reaction accelerated reaction” The disease follons the same law as the formation of antibodies in vitro We therefore state the theory that there exists a causal connection between the formation of antibodies and disease, whereby ve stress the point that we do not identify the term antibody sath precipitın, on the contrary we give the term antibody a much wider meaning Only as an external, prot able sign of the alteration going on inside the body is the course of the curse of precipitin of value to us The more le place the clinical symptoms into the foreground the clearer it becomes that the ·THEORY OF SERUM SICKNESS 101 vital reaction demonstrates more sensitively the changes occurring in the organism than the experiment in vitro In the clinical picture of reinjection we learned not only the accelerated reaction but we were able to prove that at a certain interval after the first injection (12 days to about 6 months) a peculiar form of reaction appears, which we called "immediate reaction" and which we sharply distinguished from the accelerated reaction If foreign serum is injected subcutaneously within this time, a local edema is formed, which in the most intensive cases increases within 24 hours to 200 times the quantity of injected Aud Besides this and at the same time general symptoms set in, which correspond to the symptoms We are accustomed to see in normally timed serum sickness urticans, fever, edema lymph gland swelling, joint pains From the identity of the symptoms we must conclude that the exciting cause for both series of symptoms must be the same If we have shown that the accelerated reaction is connected with the formation of antibodies, 60 We must also hold the antibodies responsible for the immediate reaction A new formation of antibodies in the sometimes minimal time between the injection of antigen and the eruption of symptoms cannot be accepted We must therefore assume that the immediate reaction is due to eusting antibodies The limitation of the immediate reactivity to a certain period after the first injection (12 days to 6 months) is in full accord with this supposition That the precipitin disappears sooner than the immediate reactivity can be explained in that the vital reaction is much more sensitive than the experiment in vitro The immediate reaction throws light upon the mechanism of the serum sickness Until now one could have had the conception that the formation of antibodies as such was combined with the serum symptoms, the scrum would be in this case only the releasing stimulus for the formation of antibodies But in the immediate reaction we see that the antigen plays an important part in the production of the symptoms of the disease It shows definitely that the meeting of antigen with antibodies elicits the symptoms In a certain respect the immediate reaction can be compared with what 1s happening in vitro In the stage of free antibodies the organism gives on one hand precipitin reaction on the other hand immediate reaction We should not forget that the chemistry of the formation of a precipitation 18 just as unexplained as the mechanism of the appearance of the eranthema We know only the condition under which the reactions appear Just as a precipitation occurs when tserenta que drop of horse serum to the serum containing antasies, Medieatest edema (the ·102 SERUM SICKNESS immediate reaction) develops when an individual possessing antibodies 19 injected with horse serum The reaction in vivo is just as specific as the reaction in vitro Are the antibodies of the vital reaction identical mth the precipitis) We shall see later (page 108) that in experiments with rabbits a discrepancy exists in the intensity between the sickness symptoms in reinjected persons and the formation of precipitin, likewise these discrepancies are illustrated by the results of experiments with human beings (Chart XXXII) Case 3, who exhubited the most intensive symptoms of the disease, showed only traces of precipitin during the course of a five weeks' sickness whereas in contrast case 6 with symptoms of medium intensity and of short duration a strong formation of precipitin In case 7 and 8 no precipitin was formed at all Also in cases with strong formation of precipitin the onset of the disease does not coincide with the presence of precipitin The ame discrepancy exists in the terminatio of the disease Francioni studied the relation of the formation of precipitin and serum sickness in many children In 17 cases he found formation of precipitin at the same time as the appearance of serum symptoms, in 4 cases precipitin formation without disease and in 7 cases seruma disease without precipitin formation Afarfan, to whom we shall come back later, also found no complete congruity between precipitin formation and hypersensitivity in hu man beings These findings indicate that antibodies of the vital reaction are not to be identified with the precipitin We know from the various processes of immunization that the same substance creates the production of different kinds of discernible antibodies So for example with an injection of a culture of typhoid bacıllı, besides antitoxin also agglutinines and bacteriolytic substances (antibodies) are formed, and their appearance and intensity do not necessanly parallel each other In general one may say that the vital reaction is more sensitive than the reaction in vitro, particularly as to that which appertains to the dura tion of the reactivity The precipitin regularly disappears 5-9 wecks after the first injection The immediate reactivity persists for several months and disappears only after } or of a year Even after 14 years it may be still present as the following case shows Dr v P was several times previously injected, the last time on 3/16/03 Reinjection on 1/21/05 No trace of precipitin in the blood 15 cc anti tetanus serum Within a few hours very intensive specific local reaction No new formation of precipitin The vilal reaction after reinjection 18 specific Proof for this is the following ·THEORY OF SERUM SICKNESS 103 1 Persons injected for the first time never develop the characteristic, extremely intensive local edema after a small dose of serum A very small local reaction consisting of redness and a little swelling occurs at a first injection, this finding does not destroy the value of the positive reaction just as an insignificant precipitation between sera, which have no antigen relation, does not destroy it 2 The reaction is specific for the antigen in question The experiments relating to this, which we shall report on page 108, were performed only on rabbits-not on human beings Previous injection of horse serum produces sensitiveness only to horse serum, pig serum only to pig serum That it is a specific reaction to horse serum and has nothing to do with the antitoxin content, can be concluded from the fact that all antitoxic sera, in so far as they are taken from the horse, show amongst themselves the vital reaction In our experiments we used promiscuously diphtheria, scarlet fever, tetanus and normal horse serum (Chart pages 80 and 81) The essential point of our theory is that the immediate reaction and the sensitiveness after reinjection are a vital antibody reaction But the antibodies, which are responsible for the reaction, are not identical with the precipitins in the organism which chemical interaction be vital reaction Let us now return to the explanation of the serum sickness after the first injection In it we see the appearance of sickness symptoms only after 8-12 days The antıgen needed for the reaction is present, what is missing 19 the second agens needed for the reaction--the antibody According to the commonly accepted theory, the latter is formed by the stimulation and tissues of the organism, in a way similar to that of an immediate reaction decided non on rahhia ·104 SERUM SICKNESS that the first symptoms of a normally timed reaction are very frequently seen at the place of injection Already in 1903 J Hertzka explained this local reaction as an effect of locally formed antibodies The accelerated reaction differs from the normally timed reaction in that the antibodies are reproduced more quickly and therefore the disease starts earlier The Clinical observation of the accelerated reaction shows another analogy between antibody formation and disease As the curve of Precipitin after reinjection not only starts after a shorter mcubation time but also rises more steeply and to a higher point, so the accelerated serum sickness starts not only more quickly but also more stormy ACQUIRED HYPERSENSITIVENESS On this basis a further characteristic sign of the immediate reaction can be understood, 1 e hypersensitiveness Whereas after the first injection of even a quantity of 200 cc serw there are often no visible symptoms of serum sickness yet in the case of reinjection in the stage of immediate reactivity as little as 1 cc almost always produces a distinct edema and frequently generalized symptoms In order to explain hypersensitiveness we must at first get an idea as to what factors are responsible for the intensity of serum sickness In the clinical picture of the first serum sickness we stated that the percentage of clinically manifest consequences of a serum wjection depends upon the kind and the amount of injected serum and upon the individuals disposition How can we bring these facts into accord with our theory? For the rnoment we can disregard the part played by the kind of serum as we always used horse serum in human beings, and in the experimental studies we always used the same serum for the first injection as we did for the reinjection Therefore the only factors which remain are the amount of the antigen and the individual disposition The first factor can be excluded by using the same amount of serum for the first injection as for the reinjection The second factor, the individual disposition, may be based on the one side, on a different intensity of antibody formation or on the other side on the difference in sensitiveness of the organism to the town created by the interaction between antigen and antibody vice at an interval of 29 days, received The first time there was no reaction, the second time an immediate mud formation of edema Here the kind and amount of serum are the same IVe can assume that the individual remained uniformly sensitive to the toxic substance as such For an explanation of the difference in reaction we have only the ·THEORY OF SERUM SICKNESS 105 absolute amount of toxic substance This depends upon the amount of the substances which interact at the time of the reaction The second reaction starts immediately after the injection of the foreign serum because the foreign seruni can be broken down by the existing antibodies The total amount of antigen can be at one time converted to a toxic substance Why does not serum sickness develop the first time? We must assume that in spite of the absence of clinical symptoms, also in this case antibodies entered the circulation about 8-12 days after the injection During the long time until this happens the concentration of antigen has diminished by its distribution throughout the whole body In a diluted solution reactions are slowed down The formation of the toxic substance does not take place with one stroke but 13 distributed over a longer period of titne Thus its effect does not reach the threshold of clinical detectibility Animal Experiments In the light of these clinical experiences the result of the animal experi ments becomes easily understood in animals the first injection regularly leads to no clinical symptoms Only after repeated injections at certain time intervals, are immediate reactions observed which after subcutaneous injections vary from local edema to gangrene, after intravenous injection from symptoms of collapse to acute death Similar experiments were performed by Arthus—following the investiga tions with actinia poison by Richel—and were published at about the same time as our first report (Arthus on June 16th, me on June 25th, 1903) Arthus reports no damage after the first injection of horse serum into rabbits and it was immaterial whether the horse serum tris injected subcutaneously or intravenously However if the injections are repeated every six days after about the fourth subcutaneous reinjection local symptoms develop at the site of injection, these symptoms becoming always more intensive, from a simple edematous infiltration to gangrene These local symptoms are not the effect of repeated injections at the same place, as they also appear if the first injection is made intraperitoneally and the nevy injection is made for the first time subcutaneously These symptoms are also not the effect of a summation of the serum in the organism of the rabbit, as a large quantity at once or several days in succession does not produce symptoms After an intravenous or intraperitoneal reinjection much more senous symptoms appeared A rabbit pretreated with 8 injections received 2 cc serum into the earvein Approumately one minute later the animal made movements like sneezing, became anxious and restless, lay down on its abdomen, the ·106 SERUM BICENESS breathing became rapid but not dyspneic (200-250 respirations) Many bowel movements set in, then the rabbit lay on its side, tumed the head bach, made running movements with the paws and finally remained mom tionless, respiration stopped After a short pause, when exophthalmus developed in the eyes by extinguished corneal reflexes, the rabbit made 4-5 respirations and died approximately 4 minutes after the injection In other cases all the mentioned syraptoms disappear in about 15 minutes, the animal seems to be entirely restored to health, but afterwards the animal becomes cachectic Arthus observed similar symptoms after repeated injections of skimmed milk sterilized by 100°C He concluded from this that all liquid protein substances produce a condition of "Hyper. senativeness" Arthus also knew that after repeated serum injections, human beings develop "a more or less edematous swelling of the area of injection In several points our conceptions differ markedly from Arthus, although we agree with his objective results Arthus believes the first injection has do clinical consequences ("Le serum de cheval n'est pas toxique pour le lapin") and after reinjection sees only hypersensitiveness, he overlooked the serum sickness after the first injection, and therefore the difference in incubation time between the first injection and the reinjection remained unknown to him On this difference we built our theoretical conception In contrast to human beings it is difficult to judge the serum sickness after the first injection in rabbits Moreover Arthus made the possibility of its observation difficult because without waiting for the sickness, he reinjected 5 cc serum (each time) at regular intervals of 6 days when he then observed local symptoras from the fourth injection on, which were always missing after the previous injections, it is easy to understand that he laid the empbasis upon the repetition and the total number of injections and not upon the time interval between the first injection and those which produced the local symptoms. Characteristic of this conception is the fact that he calculates the appearance of hypersensitiveness not according to daya but according to the number of injections In contrast to this we were able to prove that even one single injection creates hypersensitiveness Fron a comparison of our investigations with those of Arthus it can be shown that only the intensity of the specific reaction is increased by frequent repetition of the injections whereas for the timo element of the immediate reaction one previous injection suffices Proenment to study the onsel and duration of the local sensitueness ·THEORY OF SERUM SICKNESS 107 rabbit A, the third rabbit C was injected 15 days after A, D 20 days after A E Finally 25 days after AF On the 30th day after the injection of the first rabbit, all animals each received elmultaneously with the control animal 10 cc of the same horse serum into the skin of the abdomen The control animal bad had no previous injection of horse serum During the hours immediately following the injection, the control animal showed a soft swelling corresponding to the amount of injected serum Thug swelling decreased substantially within 24 hours In contrast to this, E developed a hard, intensive infiltration in the area of injection considerably surpassing the amount of injected berum The infiltration was, as Arthus had already pointed out, sterile and persisted for several days Ammals B and C developed less intensive infiltration (Interval 25, 20 days) F & D behaved like the control animal We see that also in rabbits one single injection is able to create sensitive ness It is not yet present after 5 days, after a 10 day interval it is clearly established Immediately before reinjection, the animals were examined for the presence of precipitin, with regard to the connection between precipitin formation and local reaction The strength the precipitin formation does not correspond to the intensity of the local reaction The animal with a 20 day interval did indeed show a strong local reaction combined with a strong formation of precipitin, the animal with a 5 day interval no local reaction combined with the existence of a trace of precipitin, in contrast the animal with a 25 day interval showed a strong local reaction, without finding precipitin in the blood Traces of precipitable substances were found in all cases A further blood examination was made 7 days after reinjection The repeatedly injected animals showed a formation of precipitin almost twice as strong as the control animal, a proof that after reinjection the antibodies appear earlier and in a greater amount THE SPECIFIC EDEMA Whereas we could describe many symptoms of serum sickness in human beings, rabbits show almost no symptoms outside of the local reaction Therefore the significance of this symptom 18 pushed into the foreground We use the outside of the earlobe as a suitable place for remjecting the rabbit It has the advantage over the abdominal skin of being easier to Watch An example will show how easily observation can be made at this place Rabbit 69, preinjected on 12/12/03 with 10 cc horse serum in the sbdominal wall In the afternoon of 1/4 (23 days later) a reinjection of 5 cc into the right ear In morning of the next day no stnking swelling, in the afternoon and increasing for 3 days a tremendous erysipelas like Infiltration of the ear The ear 13 hot and thick, hangs down As mentioned before, the skin of the forearm us the most suitable area for observing a reinjection in human beings ·108 SERUM SICKNESS Arthus furthermore proved that the vital local reaction is & specific one Cow milk creates sensitiveness only to cow's milk, horse serum only to horse serum We could also prove that the reaction is specific, using horse serum and pig serum for the pretreatment of rabbits When the injection was repeated, specific edema appeared at the place where the same antigen was injected the second time Experiments Also in human beings frequently enough symptoms appear only at the site of injection which can exlubit either merely a specific edema with a pale skin or we find it at the same time a mottled or urticarial eruption appears or erysipelas lile redress in the edematous skin Just as these First Injection on 3/4/05, second injection on 3/15/05 (after 11 days) Reglection (ear) Weight First Djection abdominal skin Right Rabbit to Ederna Left Edens 12 2710 13 0 (3 cc horse serum 69 2210 11 cc pig serum ++ 3 cc pis serum 3 321 2530 12) 3 0 3 ++ 92 431 102 3150 3000 2960 15) 15 cc horge serum 15) 3 3 3 ++ local eruptions are analogous to the generalized eruptions of persons in jected for the first time and of reinjected persons, so we put this local edema in the same category as the general edema, which accompanies the general rash of persons injected for the first time The local edema cannot be determined by a scale but by replacement of water or by measuring (See p 81) We saw, as we reported before, local edema in which the amount of injected serum produced a 50 to 200 times larger swelling In a reaction at normal time we find a similar relation hetween the amount of injected serum and the universal stelling due to this serum After an injection of 10 cc diphtheria serum in Rudolf B & universal edema develops accompanied by urticaria, the amount of which has determined, by weighing, to be 1100 grams The relation of edeme to the amount of spected serum 15 1.100 (Chart II) The discrepancy in the proportion between the amount of antigen and edema was already pointed out on page 81 It is also valid for the edcms of serum sickness at normal time ·THEORY OF SERUM SICKNESS 109 Thus Karl A (page 45) had 2000 gram edema after an injection of 200 cc serum, Franz K (page 41) with the same dose only 400 gram In many cases (Otto D, P 37) we are not even able clinically to deter mine the edema by weighing Chart XIII P 37 The great difference in various individuals in the formation of edema, with respect to local as well as universal edema, indicates that the edema is not to be conceived as a physical phenomenon which accompanies the interaction between precipitate substance and precipitin, but as an end effect of a toxic stimulus, through which the individual disposition is afforded larger room for action That it is the interaction between horse serum and antibodies which creates the touc substance we further tried to confirm by creating artı ficially the condition for the reaction in an animal not previously injected These rabbits each received 10 cc horse serum in the abdominal wall After 24 hours, when resorption can be assumed to be finished, but an active antibody could not be expected to be present, two rabbits each received 2 cc antı horse serum prepared from rabbits, one rabbit received 2 cc in the ear lobe Whereas the last showed no reaction at all, one of the first two rabbits showed a typical reaction (edema), the other slight edema of the ear Numerous experiments in order to produce specific edema have not given clear results These experiments consisted of injecting a mixture of horse serum with antı horse serum or of simultaneous injection of both substances, finally injecting with horse serum after having previously treated with antı horse serum ACQUIRED IMMUNITY, HYPOSENSITIVENESS AND LACK OF SENSITIVENESS A closely related question 19 whether the organism retains the hyper sensitiveness after repeated injection of foreign serum, or whether the hypersensitiveness changes to a condition of clinical immunity as it happens with tuberculin The results of animal experiments apparently are decidedly against this conception Animals repeatedly reinjected at intervals of 6-10 days react always more intensively with severe local reactions and after some time become marasmic and die From this Wolf drew the conclusion that serum differs in principle from those substances, against which the antitoxin is formed, and brought the serum in analogy to the endotoxins The espenences made with eel serum also are against the mentioned theory and in favor of the existence of true immunuty in these processes As early as 1902 Hamburger studied this question He injected egg white into animals and used the excretion albumen in the urine as an indication of immunity He found that the ·110 SERUM SICKNESS albuminuna, which was otherwise always observed after an injection of egg white, disappeared His experiments did not remain unopposed Our experience with humans does not permit us to make a definite decision Dr v P First injection in the spring of 1902 200 cc scarlet fever serum, serum Bickness sets in after 8 days and lasts one week 2nd injection, 2/11/03 15 ce diphtheria serum (interval 9 months) after hall an hour itching after one hour slight red swelling of 1 cm radius 3rd injection 2/21/03 (interval 10 days) 8 ce diphtheria serum Mildspecifio edema described on page 84 4th injection 2/27 (interval 6 days) 6 cc diphtheria serum Slight swelling Stk lajection 3/5 (interval 6 days) 3 cc diphtheria serum Hardly perceptible stelling 6th injection 3/16 (interval 9 days) 9 cc diphtheris serum Slight swelling The first injection ran a typical course Incubation time of 8 days, that 18 normally timed serum sickness Nine months later after an injection of a small amount of serum & minimal, not positively specific, reaction Through this injection the sensitiveness seems to have been reawakened because when ten days later a large amount was injected a specific local reaction appeared It is significant that through this repeated injection the sensitiveness appeared more quickly than after the single injection, when we do not see it until the third week It may be that this is to be explained by the accelerated new formation of antibodies The next injections seem to confirm the assumption that the organism became hyposensitive to the serum--that is, became immune But it is difficult to bring the result of the seventh injection into accord with this statement Dr v P 1/21/05 (interval 22 months) Injection of 15 cc antitetanus serum Strong specific edema, descnbed on page 83 The result is neither in accord with the supposition of an increasing immunity nor with the regular behavior of the reaction period according to chart XXXVIII, which established that at intervals of more than 9 months the immediate reaction 19 replaced by an accelerated reaction To be sure, only cases with one previous injection were used in this chart and it is possible that local sensitiveness lasts longer due to many rein jections and large doses Johanna Cz 13 years admitted on account of malignant diphthema For therapeute purposes repeated injections of diphtheria serum in short succession ·THEORY OF BERUM SICKNESS 111 Up to this point no symptoms of serum sickness appeared We are within the normal time incubation where sensitiveness is not yet established From very many reinjections during the first days we learned that re peated injections during the normal incubation time never bring about an earlier appearance of the disease All doses are summarized for one single reaction which turns out as of the total dose had been given at once on the first day This reminds us of the behavior of smallpox vaccination, where those areas which have been revaccinated dunng the incubation period reach the full reaction at the same time as the primary vaccination reaction (Sobotka et al) In the aforementioned case the sickness in accordance to this law ap peared 10 days after the first injection in the form of a general rash While the serum symptoms were still present the sixth injection on 4/3 (interval 13 days) 3 cc were given In the afternoon generalized urticaria, joint pains Seventh injection 4/6 (interval 16 days) 3 cc In the afternoon 382", morbillı lıke eruption in the skin of the epigastrium, confluent rash Pain in the hand on 4/7 and 4/8 fever, joint pain On 4/9 no fever Eighth injection 4/11 (interval 21 days, 3 cc) Half an hour after the injection edema at the area of injection Urticanal zone on the skin of the epigastrium Scattered urticaria over the entire body Ninth injection 4/17 interval 27 days 3 cc serum Immediately after the injection a local eruption of a rash In spite of the numerous injections this case is not very sutable for answering the question whether or not an immunity against serum develope The first five injections fall into the incubation period and sum up to one single reaction, which with several new eruptions lasts for one week Therefore it is not possible to judge the effect of the sixth and seventh injections which fall into the reaction period Only the eighth injection 19 undoubtedly followed by a specific immediate reaction, proven by the local edema This edema appears here for the first time after an interval of 1 dora Only A comparison of the intensity of the two last reactions reaction than the previous one From the following case one could conjecture the possibility of tolerance Johann, also repeatedly reinjected on account of malignant diphtheria Whether in former years an injection bad been given could not be ascertained one A U 18 cc serum On 2/12 (8 day) in the forenoon Observation 2nd, 3rd and 4th lojections ·112 SERUM SICKNESS insufficient in the skin of the arm Afternoon the area of injection slightly edematous, a little painful 5th injection 2/27 interval 20 days 4 cc After half an hour the area of injection red 24 hours later slightly infiltrated 6th injection 3/2 interval 23 days 3 cc injected Soon afterwards, limited swelling around the site of injection 24 hours later no reaction 7th injection 3/5 interval 26 days 3 cc No reaction well obeerved 8th injection 3/8 interval 29 days 3 cc No reaction well observed 9th injection 3/16 interval 37 days 3 cc No reaction well observed The child developed a positively established serum sickness, and after his clinical termination received eight more serum injections It cannot be stated whether a local reaction took place after the first two injections (2nd and 3d) However it is certain that after the 4th, 5th, and 6th specific edema developed and that later the reactivity diminished Lately Marfan* influenced by Arthus published many observations con cer ag hypersensitiveness to serum He reports six cases of immediate reaction The first case in which the first rash appeared after 5 days and the violent symptoms terminated after 2 days showed a great amount of precipitin as early as 8 days after the injection Judging from the rapid appearance of all symptoms it seepas probable that the child had been previously injected and shows an accelerated reaction This is also in accord with the observation that when reinjected after an interval of ten days immediate, specific edema developed Case 6 shows the peculiarity that no specific edema developed in spite of the presence of a weak precipitin reaction The accelerated reaction was unknown to Marfan and Le Play which was probably connected with the fact that in the selected interval (10-32 days) the immediate reaction is the rule and a later appearing accelerated reaction the exception The following cases of Marfan and Le Play are valuable for the con sideration of iminunity Case IV First injection 10/15/01 20 cc diphtheria serum After 6 days generalized urticaria, 39 3º temperature After 9 days weak precipitın reaction 2nd injection, interval 14 days 5 cc specific edema, 38 9º, strong precipitation 3d injection, 19 days after the first injection 5 cc specific edema, precipitation 4th injection, 23 days after the first mojection 5 cc slight swelling, weak precipitation 5th injection, 31 days after the first Djection 10 cc no edema but on the following day mild urticaria, weak precipitation 6th Injection, 40 days after the first Varfan aod LePlay, Rechercbes sur la pathogenie des accidents serothérapique (Soc med des Hopitaux 3/24, 1905) ·THEORY OF SERUR SICKNESS 113 injection 5 cc Very little edema, very weak precipitation Here the local reaction decreased visibly during the course of the first month It would have been very interesting of the entire course of the repeated injections in case VII could have been observed A six year old girl, being a difficult case of decanulement was a patient in the diphtheria ward for almost three years, received each month or every second month 5 cc diphtheria serum for passive immunization On July 15, 1901 Marfan demonstrated the girl at a meeting of the medical society as a proof that the observations of Arthus are not valid 50 40 20 40 60 8 days urtic 8 days erythem 6 days urtic 11 days urtic First injection (cc) 30 Incubation time and kind of веrу ѕуmрtоmѕ| after first in Jection 5 day urtic joint pan 39 8° Interval 10 days Amount of serum at the second in jection in cc 5 Reaction edeme lymph 9 days urtic 39 1° 11 days 39 3º 14 days 32 days 17 daye 12 days 10 20 gen urtio 39 5 edems demo 5 edema dema 5 no edema swelling Precipitio reaction ++ ++ + + ++ for human beings Up to that time the girl had received 24 injections without any symptoms being noticed after the injections It is peculiar that from now on the findings changed The 27th and 28th injection were followed by local edema and slight fever In any case it is interesting that the sensitiveness still exists after so many injections of serum That no precipitin was found after the 25th and 27th injections would have been an important phenomenon, if the erperiments had been repeated several times But it was done 0, 1 and two days after the injection It could be possible that precipitia was formed each time more mpidly but would perhaps appear only on the 4th to 6th day That no precipitia was found during the first days is no proof that it 19 not formed at all ·114 BERN SICKNESS THE IMPORTANCE OF SERUM SICKNESS IN GENERAL PATHOLOGY We consider the discovery of the immediate and accelerated reactivity in serum sickness as the two most outstanding results of our investigations Before us both forms of reaction had been overlooked Only the hyper sensitiveness which accompanied the immediate reactivity in vamous antigens was already dealt with by other authors It was only Arthus who, simultaneously with us, described the hyper sensitivity in serum sickness and realized its importance He proceeded from the investigations of Richet who observed in experiments with actinis. venom that the lethal dose for a dog 190 1-0 18 grams per kg body weight, when the dog is injected for the first time Death Dever occurred earlier than 10 hours after the injection In case of reinlection--the injection of the poison was given intravenously--the animals died in the first place after smaller doses (0 15 g was always fatal) and in the second place more quickly The following is a characteristic example For its first injection a dog receives 0 10 actinia venom per kg body werght, after which there were no distinct symptoms Twenty two days later another injection of 0 10g pro hg was made into the vena saphena, after a few seconds the respiration became labored The dog can hardly move around any more, lies down on its side, has diarrhea and hemorrhagic vomiting, dies after 25 minutes (C l'ortier and Ch Richet, Bull de la soc d biolg , 1902 p 170, Ch Richet Arch di Fisiologia, 1904, p 129, and Soc d bil, Jan 21st 1905 ) Richet extracted two different substances from the actina poison the crystalline thalassin which 23 only slightly toxic, but which already in minunal doses produces pruritus, and the albumen kongestin, which by far surpasses the original poison in toxic effect and which produces the characteristic congestive conditions in the digestive tract Richet made further experiments with kongeslin which as far as the relation of the first injection and the reinjection are concerned, gave the same results as the experiments with the actinia poison The lethal dose for the rabbit when injected the first time is 0 009 per kg , when reinjected it is less than 00033 g Richet coined the term ana-phylactic effect for the results of the first injection which produces hypersensitiveness The term was selected to express the difference from a prophylactic effect Anaphylazıs (hypersensitiveness) needs a certain amount of time for its development (hypersensitiveness 19 not yet present three to four days after the first injection) It persists for a long time and after one year is still distinct Transference of hypersensitiveness by means of serun of safected animals into another animal was not successful Richet quotes similar observations with tuberculin and tetanus ·THEORY OF SERUM SICKNESS 115 Knorr, Behring and Kıtashıma reported that guinea pigs show an in creasing sensitiveness to repeated injections of tetanus toxin (Experimental investigations about the limitation of curability of tetanus, V, 1902, 18, Berliner klin Vochenschr , 1901, p 157) Richet believes that in separating the two substances--thalassin and congestin–from the actinia venom-he had found the representative of the venom, the congestin causes the anaphylactic effect, the thalassın the prophylactic The congestin produces bypersensitiveness, thalassin leads to immunity From these experiments it may be concluded that the Congestin pos sesses anaphylactic effect in a high degree However the proof does not seem convincing that congestin could not act also as an immunizing substance and on the other hand thalassin as an anaphylactic substance Moreover it 19 unlikely that such a separation of opposite substances could be carried out similarly in other material with anaphylactic effect as horse serum tetanus toxın or tuberculin The results of Richet 8 experiments can be explained with the assump tion that the congestin is the more toxic and the thalassin the less tore part, and therefore the prophylactic effect of thalassın can become ap parent as an immunization with attenuated cultures and poisonous substances Serum and actinia venom are similar in the respect that both are substances which are unable to multiply However there is an important difference between them inasmuch as the actinja venom acts after the first injection without an incubation period whereas even a large amount of serum almost never produces symptoms immediately following the first injection As far as the serum is concerned, we could prove that it is as such not toxic, but that the toxic substance 18 created by the interaction between the organism and the antigen Other kinds of animal protein like milk (Arthus), spermatozoa (Wolff) behave in a similar way In spite of this difference in respect to the primary toxicity in both cases the previous injection brings about equal alterations in the organism, characterized clinically by hypersensitiveness It is only the accelerated reaction which can not be observed in substances like actinia senom which are toxic as such, because the integral part of the accelerated reaction (the shortened incubation time) cannot be seen as these poisons produce symptoms without an incubation penod Hypersensitiveness in tuberculosis can be explained in an Analogous way to that of actinia venom The behavior of tuberculin is being much more intensively studied, and besides hypersensitiveness there is another principle known namely the transition of this hypersensitiveness to lack of sensitiveness-Immunity ·116 SERUM SICKNESS Tuberculin is an extract which is not able to multiply, but originates from å germ which is able to multiply, and we can expect that after an infection with tubercle bacıllı, hypersensitiveness may be created in the same way as it is by injecting with extracts or with dead bacıllı Thus we reach the discussion of hypersensitiveness in infectious processes As early as 1888 Arlong had expressed his opinion that pathogenic microorganismos, particularly tubercle bacilli, excrete soluble substances, which influence the organism in such a way that the animals die more rapidly if they are later infected with the same bacıllı Courmont studied this problem extensively with tubercle bacıllı (Revue médicale, 1891, No 10, p 831, ref Zentralbl f Bact , Vol 13, p 714) Bovine tubercle bacıllı, derived in pure culture from a tubercle in the pleura, produces a generalized tuberculosis in rabbits and kills gunea pigs without macroscopically visible alterations Courmont injected anmals with soluble products derived from tubercle bacıllı by filtration of young cultures Guinea pigs and rabbits never react to these injections When animals, so prepared, are immediately afterwards infected with & pure culture, they behave like normal animals However if the animals were infected several days after they were injected with the soluble products, the results were quite different If animals, which had been injected with filtrate twenty days ago and since that time felt well, are infected subcutaneously with a tubercle taken from a guinea pig then the guinea pig dies in 15 hours, the rabbit in about 23 hours These animals die sixteen times more quickly than the control animals This predisposition exists in full strength from 4 to 20 days after injection Courmont assumed that the organism, by means of the previous injection becomes a more favorable soil for the infection It 18 exposed defenceless to the infection The essential part of Courmont s explanation lies therein, that the organism as such possesses protective substances, which wall off the infection The protective substances are elininated by the first injection of the mentioned soluble substances This theory which we shall still encounter frequently, we wish to call in short "Elimination" theory Courmont leaves unexplained why several days are necessary for the elimination The Lyonnaise school attnbutes these observations to other microorganism such as staphylococci and streptococci, barıllus pyocyaneus, etc R18 made sınılar observations with diphtheria bacıllı Strauss and Gamalera report that animals after a second injection of dead tubercle bacıllı die suddenly, whereas at the first injection large quantities are tolerated without any reaction Similar results are pube lished by Babes and Proca Contrary to the "Addation" theory of Koch, -accepted by most German ·THEORY OF SERUM SICKNESS 117 authors and likewise contrary to the "Elimination" theory of the Lyon naise school-as early as 1891 Koehler and Westphal offered a third theory concerning the effect of tuberculin These authors were of the opinion that through the combination of tuberculin wth the products of tubercle bacıllı in the tuberculous foci, a third substance was formed, which produces the clinical symptoms of the tuberculin reaction Marmorek (Society de biol 1901) has a similar conception concerning the ongin of fever during the tuberculin reaction, he believes that under the influence of tuberculin, the tubercle bacillus may secrete a pyrogen substance Bail, stimulated by the investigations of Detre Deutsch, took up the experiments of Courmont again, and made a careful study of hypersensitiveness in tuberculosis To explain the hypersensitiveness of tubercular guinea pigs to reinfection Bail developed another theory which he tubercle bacıllı, is injected into an animal which had no previous injection, this animal also dies rapidly Bail imagines that the tubercle bacillus secretes a soluble substance within the organism, which paralyzes the leukocytes He called this substance agressin The exudate obtained after reinjection contains this agressin In the experiments of transmission the agressin paralyzes the leukocytes, ie, the protective substance of the new organism The poisonous substance of the tubercle bacillus now rapidly exerts its effect This explanation corresponds, în principle to the "elimination theory" of Arloing and Courmont During the last year Wolff also studied the problem of hypersensitiveness and developed extensive theoretical considerations based on the investigations of Pfeffer dealing wth endotoxins Endotoxin can only produce its effect when the bacterial covers are dissolved through bacterolysine, ie, liberated by antibodies As soon as the endotoxin is set free it is immediately poisonous without any incubation time Pfeiffer's and Yolff a theory concerning the method hovy endotoxin exerts its toxic effect is very closely related to our theory about the nature of serum sickness Wolf also tried to include in his studies the hypersensitiveness after reinjection of dissolved protein substances, and in this respect based his work on Arthus' and our observations The theory of the endotoun, which was kberated by bactenolysine, cannot be applied to dissolved protein substances We can only accept it ·118 SERUM SICKNESS in the sense that by interaction of antibodies and antigen, a toxic substance is formed, but then Wolff has the same viewpoint as we established one and one-half years before him Where bacteriolytic antibodies play a part in bringing about the reaction we must remember that their produc tion sets in only after a certain incubation time This leads us to the question of the nature of the incubation time, the explanation of which cannot be an uniform one The long incubation penod in tetanus was made clear by the fact that, as was proven experimentally, the tetanus toxin has a long way to travel along the nerves until it comes in contact with the cells which are susceptible to the toxin In malaria it is shown that the interval between two attacks depends upon the fact that only certain phases of the development of the parasite produce symptoms of the disease A similar conception prevails for a list of other infectious diseases (as measles, varola etc) in which one considers the incubation perod as the breeding time of the inciting germ Samuel (Eulenburg s Realencyklopedia) says "The explanation of the incubation time most likely is that besides the multiplication and migra tion of the infectious germs, their further development must take place, which in this stage produces the stormy pathological effect " In Perl's General Pathology edited by Neelson, we find a similar train of thoughts "The easiest way to explain the incubation time is by the supposition that the invading parasite becomes dangerous only after it has reached a certain stage of its development" In spite of their external differences these theories have in common that they all seek the cause of the incubation time only and exclusively in the causative agens (the germ) and its metabolic products and they do not take in consideration the infected organism In their explanation of the incubation time in infectious processes Pfeiffer, Wassermann and Wolff pay more attention to the organism The role played by the organism becomes clear from the circumstance that just as there are laws of reactivity in serum sickness so they are also . ANDOQOO ated most beautifully in vacner Naturf u Aerzte Kassel, 1903) Whereas the earliest that the general reaction is seen after a first yaccination is on the seventh day, it always appears decidedly earlier after a revaccination Also the course of reaction 29 altered in the sense of a considerable shortening and diminution of symptoms The earlier the reaction appears the less intensive is the entire procese ·THEORY OF SERUM SICKNESS 119 How can we explain this finding? According to the earlier conception of incubation time and disease, that the inciting germ must multiply to a threshold of ability to elicit disease, we have to assume that the germ could develop and increase more rapidly in an organism that had been already injected than in an organism that had not been injected We have mentioned that Arloing even expressed this opinion Against this view is the fact that in tuberculosis and vaccination the incubation time is not shortened through an injection of an enormous amount of germs Beclere Chambon and Ménard have shown that when calves are vaccinated, the disease even then does not appear earlier when the calves are injected with a large amount of vaccination material The virulence of the germ cannot be responsible because one and the same vaccination material produces after a first vaccination a normally timed reaction, and after a revaccination, an accelerated reaction In a disease due to a multiplying germ, the law of accelerated and immediate reactivity and sensitiveness is also valid A related train of ideas regarding infectious diseases can be found in a study about Cure and Immunity written by Buttersack, (Virchow's Arch, Vol 142) in whuch he states that the cure is brought about through inhibition Butt by F bring about this inhibition of development more rapidly in the case of a repeated infection However we wish to explain immediately the essential differences between Buttersack's theory and ours Butlersack places the moment of inhibition of the developmentie of the action of the organusm, at the highest point of the disease, whereas we bring already the beginning of the disease in connection with the antibodies Our conception of antı bodies does not coincide with the usual term of antitown, but we use the term in a quite general way as the sum of the specific products of reaction of the organism created by the introduced antigen As an explanation of serum sickness Buttersack's theory does not suffice, because in the case of serum, which is a substance not capable of multiplying an inhibition of development cannot take place at all The conception that the antibodies, which should protect against disease, are also responsible for the disease, sounds at first absurd This has as its basis the fact that we are accustomed to see in disease only the harm done 1 ..hahaha fil A conce of immunity only by means of discase Modern medical science seeks to obtain this immunity on the basis of & ·120 SERUM SICKNESS mild disease and where possible a disease running a local course In in fectious diseases we clearly see the advantage so to speak the teleological significance of the accelerated reaction The earlier the reaction of the organism ensues (vaccination), the less time has the foreign intruder to multiply, the quicker will its development be inhibited, that much less will be the consequential damage to the whole organism On the other hand in serum sickness one has the impression that it 18 unfavorable for the organism to react more quickly after reinjection be cause the quicker the antibodies interact with the antigen the more intensive will be the disease This contradiction can perhaps be explained by the fact that an intro duction subcutaneously of a non multiplying agens relatively seldom takes place in nature (sting by insects, anakevenom) Serum sickness represents so to speak an unnatural (artificial) form of disease The usual cause of disease is in the vast majonty of cases the invasion of small amounts of germs capable of multiplication The defense mechanism of the organism is phylogenetically mobilized in accordance with this form of disease The accelerated reactivity is the permanent advantage the organism hag acquired by having overcome the first disease Immediately after the termination of the disease the organism is in the stage of free antibodies in consequence of which we observe the immediate reactivity and hypersensitiviness This phase has only a limited duration The free antibodies disappear, but in spite of it the individual is immune But the essence of this immunity does not lie anymore in the immediate reaction against the infectious germ but in an accelerated reproduction of antibodies Thereby the organism is placed in a position to wall off the reinfection more quickly, to localize it, as we were best able to recognize it as the result of revaccination This ability to localize a repeated infection does not rest on the presence 2 WY31854T one so perhaps there also exist other kinds of cellular immunity mann's observations about the adaptation of the tissue to a symbiosis with originally pathogenic microorganism, without a detectable antibody reac tion point to a different form of immunity based on a lack of sensitiveness Many diseases, as Tanola, measles, varicella rubella are characterized by the fact that one trumph over an attack of the disease grants a more or less certain protection for life They have the common clinical peculianty that after an incubation time that is long regular and independent from ·THE REINJECTION 121 the virulence of the inciting germ, the duration of the disease is very much limited in time If the organism does not succumb to the disease, so it has completely conquered the infectious agens The latter no longer cames any danger for the organism The nature of clinical immunity for this group of diseases, as their para digma we regard the vaccination, does not consist of an acquired insengibility towards the infectious germ, but in the ability of an accelerated reaction With our studies, we endeavored to revive interest in serum sickness and tre believe to have shown that this disease has great importance, not only from a clinical viewpoint but also from the standpoint of general pathology serum sickness 28 the best paradigma for a disease due to an organic cause which is unable to multiply, and is an exquisite object for the study of the changes going on in the system ·BIBLIOGRAPHY* Adolph, 100 Falle von Diphthere mit Behrings Heilseruu helandelt Deutsche med Wochenschnft 1896 \r 3 Alfoldı, Beitrag zur Wukung des Diphthere Heilserii 13 Pester medic. chirurgische Presse 1893, V 10 Altman, Über Heilserumtherapie bei Diphthentis Deutsche Vied toch 1895, p 230 *Aronson, Discussionsbemerkung zn Piorkorski : Vortrag Bert Medic Gesellschaft 7/12 1904 #Arthus, Injections répétées de seruin de cheval chez le lapin Soc de biot 1903, p 817 20/6 1903 "Aach, Zur Casanstik der Heilscrurnexantheme Berl Ki Wo 1894 Ar 01 *Babes und Proca, Untersuchungen aber die Wirkung der Tuberkelbacillen and über gegen wirkende Substanzen Ztschft f Hyg \VIII, p 331 *Baginsky A Zur Serumnbehandlung der Diphtherie Berl hl o 1831 Nr 52 Do Serumtherapie bei Diphtherie Berlin 1895, Hirschwald Diphtherie and Diphthentischer Croup (in lothnagels Handbuch) Wien 18 ) *Baginsky and latz Die erste Serie der mit Antitoxın (Aronson) behan delten Diphthenefalle Archus f hinderl 18 Bd, p 321 *BAI), Uberemphadhchkeit bei tuberculosed Thiered W Klin Mo 104 Nr 30 * Der scnte ud ion Veerschweinchen an Tuberculose Daselbst 191) Nr 16 *Harth, Die Nebenwirktingen des Diplıthoriehcilserums 1 mod Wochensch 1896, Nr 25, p 396 *Beclère, Chambon and Viégard, Etode expérimentale des aculent postsérotherapiques Annales de 1 Ingt l'asteur 1896 -- Ftudes sur timmunité vaccinale Ann de Ingt l'asfeur 1836 and 18 11 *Behring Leistungen und /iclo in der Scrumtherapic D Ved klo 18+ \r 38 * Behring and hituxhuma Über Terhinderung und Sicigerung der crerbte lufter phndlichkeit Berl Niin Wo 1901, 1r 17 *}eltantin Carbone I'ro luzjono di sostanze tossiche nel micro antinalı inoculati con singue eterogeneo Giorn delfi Raca di vel Torino 1898 Lr cuo nach antitotin Meu orabuljen XXXIX 7 18, Bell G *The papers marked with • bave been read by us is the ongipal all others 10 abstracts 122 ·BIBLIOGRAPHY 123 Berg 11 The soruin exanthemats obeerill in th: antit in itu it 110 ltt of diphtheria, their pathogenesis and possil le prestation en lich Vel Record Jun 1898 B168 H1, Somne expenences in the proluction and unif diluthern Antitoxine Med Rec 189) 20 4 *v Bókay, Dio Herleerumbehandlung gegen Duplutlcric 141 1 1 cater to fama kundlerspital H f Adh 1897 44 4 - Meine Erfolge init Behrings Diphthencheilseram 1 Slect lo hii, p 233 - Vleine Erfahrungen mit dem Vogerschen polyvalenten harlah try. kokkenserum D Ved lyoch 1902 \r 1 Bolton Ch, The complications of the seruni treatment of diphtlemu Ianut April 1899 *Bordot, Sur le mode d actor des séruins prés entifs Annals ik 1 Institut l'asteur 1896, p. 193 Brown Val, Antitoxin in the treatment of Diphtheria lleu Record 97 / 181) BUJH O, hann das Antidiphthoriescram schädlich scın? l'olme la nf Virchow. Jahrb 1897, II, P ( ) *Bulloch, Uber die Beziehungon zwischen Haeri ilyein nn 1 Bacter lain Centralblatt f Bact 1901, Nr 29 *ituttersack, Tinmunität und Heilung in Lichte der Physiologie und Holge Virchows Archiv, Bd 142, p 248 CARD. Oh the treatment of diphtherir by tho intru enous a diumstritt u of antidiphthoritic scrum Lanect 20/12 1902 Catriure, Des éruptions consécntries anx injoctions de sécum anti hphtlu ritique Res internat de mail ct do chururgie VII 381 11%) "{nvrim, 2 Fullo ron Erkrankungen nach Anwen inng des Diphitleru koru un D Mod Wo 1894, Nr 48 P 898 *cole Ubor die Aggintination verschiedener Typhusets/tchft 11vx und Inf 1904, Bd 46, und Experimenteller Bertrag yur iphusamali mitat, ebenda Cournont Etudes sur les substances solubles por clawpor inter 1 tot piti ogi ng do leurs microbes pro luctcurs (Roine de ved 1801 \r 10 ref (entralbl f Bact, B1 13 p 711 * rezowiczka ), lur honntnis xler durli totori un burk por erzeugten Vorin lerungen /tschft f Heilhan le 1"} 1nllera, Considerazione casi clinici di trufione del minket 1) Mi 1874. VII *Dune lur Statistih der Scrunculnthene Ih fhilbrilk 1 14 17 P 289 Dir. Je Anttorin in Duphtlu na Velat Recont 181,4 *1vxhne ein U 11 Amburger frju timentul interitu hungen über si bolge 1 frienteraler Finierleibring 12 1 fer leurru W7 him Ilu henxhir 1961 \r 29 * DIY et Louler Contributin uletele dun antonte type Brilancl Hay cz 18 It **)tre Doutoch Siperinfertion na Pri trifft Wr hlin 1.1 Irgebnisse der bununlfur hink ibur Inx totale 11 ** Thu Arhitus kat 1117 at it rintii \r 27 #Dont ·124 SERUM SICKNESS Dienonne, Iininnnitt, behutsimpfung und Serumther pie 1903 Barth cipais Doinici Wiener Ved Wollonachr 1893 (Fransfubiun) Drabelo, Uber las Heilserum bei Diphthene Wr Vcl Wo 1815. \r 6 und 8 *y Dungern, Die Antikörper Jena, Fischer, 1903 Engei Bey (Caruuistik) Borl hlin Wo 1895 (37-41) *Escherich Diphtheric, Croup, Serumtherapie Wion l'rolaska, 1895 - Versuche zur Immunisierung gegen Diphtheric auf le logo de los dauungetractes Wr Klin Woch 1897 *Francioni, Le Valattia (la Siero To Speruentale 1904, p 767 -- Nota intorno alla questione degli esantomi parlattınıfurmi che si presentano nel corso della difterite (Rivista di clin pediatrica Vai 1904) *Friedenthal und Levandovsky, Uber das Verhalten des threrischen Organismus gegen fromdes Blutserum Arch f Anat und Physiol 1849, Bd 5, 6, p 531 Freyberger, Uber Lyınphdrüsenschwellungen bei Diphtherio Inaug Dios, Berlin 1898 falato?, Des éruphons que surviennent 811 cours de la diphtherse traitée par le sérum de Roux These de Paris, 1903 *Ganghofner, Bebandlung der Diphthene, Handbuch der Therapie innerer Krankheiten von Ponzold und Stantzing Jena 1897 (1 Suppl -Bd) 1902 (Bd I) *Garnier und Sabareanu, Die Gewichtsveranderungen im Verlaufe der Blattorn, Revue de méd Juli 1904 Gongou, Ongine de l alexine du serutn Ann de linst Pasteur 1902, P 18 *Gerlach, Tod nach einer Antidiphthericseruminjektion Cherap Monatslıefte, April 1903, p 198 GCODIG, Bencht über de Behandlung D 263 Diphtheriekrankon mit Behring, Heilseruin im Cuslapitale zu Triest W. Klin Wo 21, 22, 1895 Gottstein, Uber Todesfallo, welche bei der Anwendung des Diphtherieholleerums beobachtet worden sind Therap Monatsh 1896, H 6 Daselbst Literaturangabe *Grawitz, Die Theorie der Schutzimpfung Virchons Archiv Bd 84, p 87 Guinon ot Roufflange, Un cas d engine inembranet180 traite par le sérum de Rour etc Sem med 1897, p 300 Habel, Kurze Vittheilung über cinen Fall von Wachwirkung ice Diphtherie. hellserume D Ved Woch 1895, Nr 1 Hagenbach (Casnistk) Schweizer Correspondenzblatt 1899 1 Hallor p K, Schncro Erscheinungen nach Injektion des Bohringschen Helserums Rugs p 151, 1893, ref Virchons Jalıb 1895 *Hamburger F, 7 ur Frage der Iiningninerung gegen Erwerb Wale Wa 1902, N: 45 *Hainburger F und Voro Uber dio biologischen nachycisbaren Verande. rungen des menschlichen Blutes nach deruminjektion We hiin Mo 1403, \r 15 *Hamburger F', arteigenheit und! 138lipulation Wien Dentiko 1903 *Hartung, Die Serenesanthenig bei Diphtheric (daselbst genano Iiteratur ragabe bss 1896) Jb ! hah 1834, p 72 ·BIBLIOGRAPHY 125 -- lealy J 8, Is the present lou mortality in diphtheria due to the up of antitonta sorit Verlical Recor! 1872314 *Itecker Erhobliche Erkrankungen nach der Anwendung der Behring mhen Diphtheroheilserning Dents ho inilit inirti leitschrift fatorg 24 181, H8 9, p 354 *II en bror, Praktische Klinke zur Behandlung der Diphtherio mit lleileerunu 9 cd Wo 1894, \ 3 + 701 - hlinische Studien ilber die Behan llung der plitheru mit dem Ih lining. Echen Heilsch Leipzig 1893 - Ulcr dc innen lung los Herteerums bei der Diphtheric II f huhulk 118 231 Hoffnor, Todesfall nach Annen:lung der Diphthericheileeruus 11 116 Presso 1896, Yr 25 *Ido Über ulic Bild ingegcachwindigkeit scrschiedener Antikörper Fortschritto der Vicdicin Vr 25 1902 *Johannonsen Uber Injeksionen mit ant Iphthorische ramen reineux Pferdescrutn D Sioul Wo 1895, Yr 51 Uber Immunizierung bei Diphthone Dontsclic Veit Wochenech 1845 11 *Jorgonsen A, Verlanfo des hurhonner, UL Phphthere Wr Klin Wo 1902, \r 43 *harlinski Beeintlaßt das Diphtherehcılscrum yrgen lwie den Stoffwech- 1 un ges inden Organismus? W: Ved Wo 1895 Ve 8 *h&stowICZ, Die Frfolge dos Diphtherichiedlecrans Ter Vonia) IRIN Kaupo, Fin Fall von Idiosynkrasio gegen Diphtherichoilacrum Borl hlin Wo 44, 1899 *Knorr, Fxperimentollo Untersuchungon aber dio Grenzen der Heilonga möglichkeit des Tetanus V 102 18 *hnöpfelmacher W, Die Herlecranibchan llung flor Diphtherm Carolinen hinderspitale in Wien Wr hlin Wo 1895 V 50 *hohler and Westphal eine neno Chcono zur Irklanung der Wirkung der Koch schon Heilmittois anf den fibcrcndacn Veneclicn1) Vec 110 1891 P 839 horsorotoff, über die Veränderung des Blutcm nn ciniger Organer I Kaninchen pach anbeatanor Injection von Ihphtheniche lucru (Ref Jahrh. f Kdh 1898) *Kraus R, Ūbor spezifische Reaktionen in keimfrcion Filtrien Ion (Tolera Wr Klin W. 1897 *-- Uber diagnostische Vorwertbarkoit der spezifischen Vicole recl låger Vodic Wochenschr 1901 *kraus R and Levadit, Coinptes rendus do iscal des scienrog 511 "rack inana, Ein Vergiftnogafall init Behring che Dy latherichrılscrum Therap Monatsh 1896, HG *kacharzewski Experimentelle Untersuchungen dher den intl 18 der Heilsera und des normalen Pferdescruins enf dan Bitt i male t'CHAD 1903, Vr 44 Kurth, Do Irgebnisse bei der allgemoinen Anwending de blithene. heilacruins in Bremen D Mod tlo 1897, Yr, 2x "Landois L, Dio franaf 1810n des Blato: Leipzig 1879 ·126 SERUM SICKNESS *Landoje, Artikel, Fransfusion“ in Fulenburgs Kralenkyclopadır 3 Auf 1900 1axelbst genaue I ateraturangabe Landonzy, Irenente du traitement par le sérut ( 17 les hopitiux \r 145 20/12 1894 *Landsteiner, /11 henptnis der spezihuh auf Blutkörperchen wirkenden Sora (entralbl f Bact, Bd 25, 1899 546 Langerhang Tod durch Merlrerum lleri hlin klo 1896, Yr 27 *Lciner, Uber dic sogenannten scarlatimformen Scruexanthono bei Diphtheric Wr hlin Wochenschrift 43, 1902 Lenhartz, Zur Heilsorumfrage bor der Vorheugung und Behandlung der Diphtherie Centralbl f hinderh 1896 p 2 *Lepta, Uber einen Fall von Urticaria haomorthegica Berl hlin 1 188, Nr 39 Lobligo018, Le diagnostic des erythemes scarlatınıformes et de la scarlatino apparaissant an cours do la diphthéno Gaz hebdoni 27/2 1903 Lohr, Uber Immunericrungs crsuche gegen Diphtherie Jb f hinderh, 43 Bu 1898, p 67 *Lublinski Uber eine Nachwzrkung des Antitoxins bei Behandlung der Diphtherio D Vied Wo 1894 r 45 p 847 Malinowski A, Die Sorumbehandlung der Diphtheriekranken tinct lekarska 1895 (ref Virch Jb ) Marcuse, Beitrag zu den schadlıchen Nebenwirkungen dos Diphtherie heilacrums D Ved No 1895, \r 35 P 577 *Warfan et Le Play, Recherche en la pathogénie des accidents déro thérapiqnes Extratt des Bulleting et Mémoires de la Sociéto médicale des Hopitaux de l'aris séance du 24 /3 u 1911 1905 Marmorek Der Streptokokkus und das Antistroptokokkenserum 1895, cut b. Hartung Vondol, Hauthaemorrhagien nach Behrings Heilserim Berlin hlin Wo, P 1088, 1894 *Vendelsohn Ludwig, Erfahrungen über die Behandlung des Scharlachs int Antistreptokokkenseruin Deutsche Med Hochensch 1905, p 451 *Vonzer, Serumbehandlung b acutein und chronischem (velenkrheuinatsomus Ztschft f klin Vted 47 1902, p 109 Michaelis und Oppenheimer, Arch f Anat und Physiologie (Physiot Abth (Supplenicnt 1902) Vorzard et Perrogous 231 cas de diphthérie traités par le séruin anti diphthentique (raz des Hopitaux 13 /22 1894 Monzard et Boncliard, Ball et Méin d 1 Soe Védıc des Hôpitaux 517 1895 Vontard, Vartin et Richet, Injections intra: eineuses de lait et de sucre Soc do Biol 26/7 1879 Monti, Beitrag zur Anssendung des lleilserui is gegen Ihphttierie, zit neck Hartung *- Zur Irage der Scrucxantheme Arch { adh 1903, p 390 *Voret p Uber die Behandlung des Sebatlacbs nut edem Scharlach Strepto kokkenserum Berlin harger 1902 Mga Sullazione fisiologica del siero antidifterico nell organismo infantile (Lo speritentaie 189, \LII Sezione clinica fase ?)

·BIBLIOGRAPHY 127 SI ya Sugli inconiementi della sieroterapii into difterica Lo sperimentale 1895, Yr 6 Hypoglottisches Odem nach Diphthericsoruhunjectionen Von itecliff hinderh 11, PJ27 (1904) Nachtergael A, Rapports entre les précipitines ct les précipitable du sérum L: Cellule XVII (31/12 1904), P 125 Neudorfer, Bertrago zur Bluttransfusion Zeitsclinift f Chiturgic 11 VI Oberwintor, Uber die nach Injection von Diphtherichcılacrum anftretenden Eranthene, insonderheit aber die Scharlachähnlichen Icutacho Seu Wochenschr 1903 17/9 #P#10 R, Beinerkungen zu den Falle son pl8tzlichem lodo cines hindes nach einer préventiven Injection von Behrings Heilserum V hlin Wo 1896, Nr 16 *Pawlowaky, Zur Frage der Lintunitat und Infection Ztechft f Hye 1900 Bd 33, D 261 *Perl, Allgemeine Pathologie, berausg Vcelson 3 ANH 'erd Inke 1891 *Phipp:02, Ricercbo sperimental sul urticaria (Crornale taliano delle malattio e della pelle 1899, p 675) Piorkowski, Zar Sypbıl ection eines Pferdce Borl Vedic Gesellschaft. 7/12 1904 von Pirquet, Congrès international d Hygi ne 1903 - Zur Theone der Vaccination, Versaminlung Deutscher Vaturf und Aryto Canal 1903 *-- Körpergewichtsbestimmungen bei Nephritis 76 Vers Deutscher Saturf und Arzte Breslau 1904 von Pirquet und Sebick, Zur Theorie der Incubationszeit, We hlin Wo 1903, Nr 26, 45 *-- Zur Frage des Agroasins, Wr Klin Wo 1905, Nr 17 Pixtor M, Erkrankung nach prophylaktischer Anwenduug von Behrings Diphthereherlaerum Deutsche Arztezeitung 24 1895 Pour Gaston, Recherches critiques et expérimentales sur le sérum anti diphtheritique Paris 1896 *Ponfick, Experimentelle Beiträge zur Lehre von der Transfusion Virchows Archiv, 1875 62 Bd, P 273 Portier et Richet, De 1 action anaphylactique de certains vening, Bull de la Soc di Biol 1902 170-172 Tray du Labor de Physiol V 1902 506-509 *Posp1schill Dionys, Voser & Scharlach Streptokokkenserun Wr hlin Wochenschr 1903, Yr 15 - Uber Rubeolao und Doppelexantheine Jahrb f hinderheilkunde 19114 Bd 59 *Preilich K und Heim P, Uber das Wesen der Tuberkulinreaction Centralbl f Bact 1902 Bd 31, p 712 "Radziewski, Untersuchungen zur Theorie der baktenellen Infection /tschaft f Hygiene 1901, p1 von Reake, Weitere Erfabrungen mit dem Diphthericheiloerun Maneb Ved Wo 1895 *Rauschep busch, Vergiftungserscheinungen infolge prophylaktischer Seruminjection you Behnngs Antston Berl klin Wo 1897, \ 32, P 691 ·128 SERUM SICKNESS *Romboldt Luc Fille ton Erkrankung nich Anuçndung des Heilscrius 1) Ved Wo 1894, dr 51, P 963 *Rhet. De lnnaphylaxie ou sensibilite croissante des organisins à des do4c9 ALICE CAM11es de pois01 Archivio di nerologia Junur 1904, p 129 *- Do la tron do 14 longostinc gut les lapins et de ses cffets and pinyinctiques Soc dc biol 21 1 1905 * Do l anaphylaxic aprus injections de congestine chez le chien Ebendi Rist, Sur la toricite de corps de bacillcs diphthériques Soc de Biol 1903 Vr 25 *Rittor von Rittorxhain, Erfahrungen siber tlic in den letzten vier Jahren bcobachteten Spruncxanthemo Jb f Kinderhih Bd 55 1902, p 54? Roger, G H Accudienti imputables à la sérothérapie (az hebdou. August 1896 - Des applications de sérii sanguin au traitement des Valadies Nancy 1896 Roger ct Josne, Influence des injuctions souscontantes du serum morial ct thérapeutique sur la moelle osscuse Comptos rendus de la xoc de Inol 1897 and La Renaino médicale 1897 Rostosk, Verb indlangon der physiol medic l Csellschaft zu 1 dryburg N FJ 33 *Samuel, Arnhet Incubation in Eulenburg, Realenus clopidic 1 Auflage 8asand HW, Plötzliche Synhopo nach Antitoxninjection be. Diphtheric 1 ho brit nodical Journal 26/4 1902 *Scholz, Bericht aber cincn alinlichen Iffcct Yon Heilscruminjectionen D Med Wo 1894, \r 46 Schatz, Discussionsbomerkning yu liorhouskus Turtrage Porl Naduc loco sollech 7/12 1914 Soibort A Sonir notoworthy toxic effects of the antitox treatment in liphtheria Vedeat Record 1899 Soubort und Scliuyzer, Dio I rsache des platrlichen Tode« nad Anti toxınınjectionen Hof Jh fkdli 1898 Soitz, Verhandlungen des Congre f Innere Medizin in Vanclien, 1819 Sciffort, Aur Anatomic lind Pathogenesc der Scrumrganthicum Verlandlungen dor Deutschen pathol Cosellschaft Ncf teslir í hillcilk 331 ), p513, 1913 *S&sestre, Der accidents calisés par le streptocoequo * la sinto den in jostiana de rerum de kont. Ball de la Sot inedir des lopiti 19/7 18"), Jarellist 31/1 1896, In medicine moderne 1891, Nr 1 Sirgort, hliniec ho und cyfferitten tell: lntersuchungen aber den lintua dc auf din scaunden und kranken Thicre Tirelots 1,-- (haupta su barlucht LE i itt lelkunde, 183 Ic Therup Tonat Lolly is Soltmann, Die Scrni bolanllung der Diphthere, Illitse ho Meu Wochenschr 1845, 4. 57 Springorum. Besicht über 206 bit Bchring, Heileerium belanleite Dipl thencetkrankmoen Vilach Ved llah 1895, \ 31 ·BIBLIOGRAPHY 129 *spronch Chaufftge du sériun anti sliphtherique Ann do l inst l'astenr VII, BOW 10 Verhandlungen des I\ (ongresses + Hygiene u H Badrd, 1900 Stanley, On diphtheria antitotin eruptions Bnt ved journ I 386 (1902) *straßmann Tod durch Heilaerum Ber! Klo 23, 1896 Strub L ct \ Gamalona, Recherches cxperimentales sur la tuberculose Arch de médic exporumentales III, Juli 1899 *lon Szontagli, En Fall von eigenthtunlicher Erkranknng nach Anwendung von Diphtherichcılscrum Arch f binderb Ba 28, 1900, p 403 * Uber die Wirkang des Antistreptokokkensertidig lr hin there peutische Wochensclinift 1902 rhibuergc, Anginc diphthériquc associéc bénigne traitée par le serum, accidents totiques Sem me lıcale 1895, p 300 Choinas A, Report of an experience with antitoxin etc Med Record 1895 15/6 Tuminor, Do Sorumtherapio hei Diphtherie im hindorkrankenhange ZIL Austerual D Ved Wo 1893, Nr 37, P 607 firard Vand Willcocks F, Ten cases of Diphtheria treated with anti toxin The Lancet 1895, 19/1 *Török und Harı, Frperut lentelle Untersuchurgen uber l'athogencsc dce Urticari Arch f Dermatot 1903, p 21 Trint Einige Arthropathion bei der Behandlung der Diphtheric mit clarıngs Heil-criun Ref Virch Jahrb 1896, 196 *Ireymann Otto Ein tall son acutcr haemorrhagischer Nephritis nach Inuendung dos Bebring schen Diplthierırheilserums D Med Wo 1894 Nr 61 952 Twelvstovutch Etude sur Ira proprietes du sang les adunaux injectés de Ratig uu li serum d unc antri cap ce anuale Arch rauges de Pathologie 18 ) ) *Ulicnuntia /ur henntnis ler giftigen Tigenschaften des Blutscrumie /tschft f Hyg Bd 26 1817, P 384 Hino Vethode zur Unterscheidung der crschiedenen 15! tarten, ins beson lore 711n differentialdiagnostischen Vachweis des Menschenblutes D Vied Wo 1901 Inrich Fiedler, Förster Schmaltz Getinther, Bericht aber die Belian llung der Diphthere it Behrings lleslserunt in den Dresdocr hrankenanstalten Jahreshencht d (rcsellsch i Aatur und Heilktinde in Dresden 1894-1897 os Died Uber 12 vt lleiler un borli enclelte apliti crickinder Ho 1847 \r 23 p 37') Tirot, Lcs ucci lentx ile la Seru atherapie Tournal de elinct thor infan tilox 18 Juli 1895 Terordt Erfahrungrn über Diphtherie ocit der Anncndung ron fchrings Julscrtim D Vec klo 1895, Vr 11, P 169 Vlajeff Sur la question de la serot sér ipio internat Congret f Int Vou Vonkaul 1897 are J Report of a case of scptre poisoning following the nuc of intitouin les lork med l'ecor! 30/3 189. *\ SNCTIan A Über natitrliche un kiostliche Immunitat 7tchft f Jyr 13 77, p 173 ·130 SERUAL SICKNESS * Heech der Infection in holic lind I SOTI HANN Handhuh der pathogon Vikroorginismen 1903 ****671471 und Schitze, Über cine neue furonsiache Victhol int Untersulcudung 100 Vlenselen und l hicrblut Berl klin Iloch 1 it Wasserland und Citron Die lowle Immunitatilor anabe und il rc prihliacho Wichtigkeit D Veel llo 1905, \ l p 17 *ll assortann 11, Pneunokokkenschntzstoffe D Ved Wo 1819 p 141 Vidal ct Rostaine, Pathogenic dos accidents sériques Soc sed do H pitaux, séance du 24 1905 von dorhofer, Uber 100 mt Bchnings Helserum behandelto Fullo son Diphtherie I)euteche Vied Wochenschrift 1895 Ve 2, p 17 Wajon GV, sperimente un Thieren intoinfachen und antidiphth Pferdeblntscruin Wratsch P 441, 1895 *Wolff A, Uber Grundgesetze der Immtinitit /entralbl für Bakteriologie 1904, Bu. 37 S 390, 566 und 184 Wolff Lewin, Uber einen Fall von Scrun Recidis nach Scrumboluandlung D Ved Wo 1894, Nr 52, p 180 liclenziger, Finige Fällo son Exanthemen nach Behandlung init Iph thenchelarnn Bentsche Vexi Wo 1895, p 575

·No text on this page.