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Popular Science Monthly/Volume 81/November 1912/Some Aspects of Anaphylaxis

SOME ASPECTS OF ANAPHYLAXIS
By JOHN AUER, M.D.

THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH

THE word anaphylaxis is used to designate the train of symptoms and signs which is produced by the incorporation of a foreign soluble proteid into an animal organism which has already been subjected before to the action of this same foreign proteid. The first injection need cause no obvious disturbance at all, and the injected animal seems to be perfectly normal. But if this animal be reinjected after an appropriate interval, it will answer with marked reactions, which may even end in death. Thus, for example, 5 to 6 cubic centimeters of horse serum injected intraperitoneally in a guinea-pig cause no more apparent disturbance than the same quantity of physiological salt solution; but if the same animal receive the same amount of the same horse serum intraperitoneally after two or three weeks, the animal usually dies in a short time. The first injection, therefore, though it caused no obvious change in the animal, has profoundly altered its constitution, and it reacts on second injection as if the original substance were now a violent poison. The animal, however, does not acquire this remarkable property at once; approximately ten to fourteen days must elapse before the second injection elicits marked toxic effects. If the injection is repeated earlier, slight or no symptoms will be produced. It is thus clear that the organism requires a certain length of time before the second injection can call forth toxic symptoms. The whole process, then, shows three distinct phases:

(1) Sensitization, caused by the first injection of the foreign proteid; (2) Incubation, the time which elapses before the second injection can cause a response; and (3) the state of Intoxication which this second injection causes when given to a sensitized animal.

These three stages show some interesting points which deserve to be mentioned more in detail.

Sensitization.—Any soluble proteid may be used to sensitize an animal, provided that it is of foreign nature; nor need these proteids be of animal origin; Wells has recently shown that a large number of plant proteins may be used for this purpose.

The proteid usually employed in laboratory investigation, for anaphylaxis can only be studied by animal experiment, is horse serum, and horse serum is used only because it is easily obtainable, and is not poisonous to the ordinary laboratory animals on first injection. A normal guinea-pig will easily tolerate five, a rabbit twenty and a dog one hundred cubic centimeters intravenously, without showing any obvious effect on blood-pressure or respiration. Harmlessness on first injection is, however, not an absolute essential, and animals may easily be sensitized by primarily toxic sera or poisonous animal extracts, for the amount needed to sensitize is very slight, and is only a small fraction of the lethal dose.

The amount necessary to sensitize is almost unbelievably minute; according to Rosenau and Anderson, 0.000,001 cubic centimeters of horse serum may suffice for a guinea-pig, and Wells has succeeded in sensitizing the same animal species with a still smaller quantity of pure egg albumen, 0.000,000,05 gram. These quantities are beyond the capacity of any balance or test tube to detect, and the biological reaction, as usual, is shown to be the most delicate.

The substance used for sensitization may be incorporated in a variety of ways: by subcutaneous, peritoneal or intravenous injection. Even by feeding the proteid, sensitization may be produced in the guinea-pig according to Rosenau and Anderson. The usual method employed, however, is either subcutaneous or intraperitoneal injection; both these procedures are swiftly and easily carried out, and give but slight or no discomfort to the animal.

Although not every species of animal has been tested, it seems probable that all may be sensitized. The only difference noted is that some species are more difficult to sensitize than others; the guinea-pig is most easily sensitized of all animals tested so far, and for this reason has been the classical animal for investigation. The dog and the rabbit are also rendered hypersusceptible with comparative ease. Fowl are more refractory; man also can be sensitized.

The length of time that sensitization lasts varies in the different animal species. In the guinea-pig that state persists for life, which is about three years (Rosenau and Anderson). In the rabbit the degree of sensitization diminishes after three or four weeks, but persists to a greater or less extent for many months, and in man symptoms have been noted seven years after the first injection.

The degree of sensitization varies also in the different animals and will be considered more fully later.

Incubation.—After the animal has received an unaltered foreign proteid into its circulating juices, this foreign material causes a profound change in the reactions of the host to this proteid. This change occurs gradually and reaches its maximum only after some weeks. If the animal is tested after a few days no reaction will be obtained. In guinea-pigs, for example, ten to fourteen days must elapse before an anaphylactic response can be expected with some certainty, and even with these animals it is best to allow three weeks to pass before testing.

The period of incubation, however, may be shortened if an animal is rendered passively anaphylactic. This process depends upon the fundamental observation of Gay and Southard that a normal guinea-pig may be sensitized by injecting it with the serum of another guinea-pig which is already sensitized. If a normal guinea-pig is thus injected with the serum of an animal (guinea-pig, or rabbit more usually) which was sensitized some weeks previously, this normal guinea-pig becomes fully sensitized within twenty-four hours and will respond with typical symptoms when injected with the same proteid which was used to sensitize the donor of the serum (Otto). The serum of an actively sensitized animal, that is, one sensitized by the injection of a foreign proteid, therefore contains some substance, termed a serum-rest or anaphylactin by Gay and Southard, which upon injection fully sensitizes a normal animal within a few hours.

Intoxication.—In this stage we observe how a sensitized animal responds with violent symptoms to an injection of the same proteid which it formerly tolerated with no apparent ill effect; we see the remarkable transformation of what formerly was an apparently harmless substance into a violent poison. The symptoms and signs noticeable in an animal during this stage vary with the species and with the site of injection of the toxic dose. If the injection is given subcutaneously in rabbits, an area of edema develops in the place injected; this edema may gradually lead to a circumscribed necrosis of the skin (phenomenon of Arthus). The same change may also occur in guineapigs, as Lewis has shown. If the second injection is given intravenously in rabbits, a more or less marked respiratory disturbance associated with muscular weakness and increased peristalsis develops (Arthus); if the rabbits are highly sensitized, convulsions followed by death occur in a few minutes (Arthus). In the dog, the respiratory symptoms are not prominent, but the animal shows nausea and vomiting, profound muscular weakness and often discharge of urine and feces. The animals, however, usually recover. In the guinea-pig, the stage of intoxication is dominated by respiratory symptoms. The animal makes such powerful respiratory attempts that the costal arch is drawn inwards with each inspiration; these efforts swiftly become convulsive and the animal dies a few minutes after the intravenous injection of an adequate dose (Auer and Lewis).

Anatomical and Functional Changes Found in the Stage of Intoxication.—The study of anaphylaxis from the clinical symptoms alone is unsatisfactory. The symptoms offer nothing which could not be produced by numerous drugs available to the investigator; they do not indicate why the animal shows these disturbances. For an adequate picture of the process the seat of these reactions and a finer analysis of the functional disturbances is necessary. Moreover, no rational therapeutic intervention is possible if the investigator is in the dark concerning these points. The first attempt to study anaphylaxis more thoroughly was made by Arthus in 1903. This investigator showed for the first time that anaphylaxis in rabbits is characterized by a marked drop in blood pressure. This drop in blood pressure Arthus considers the most delicate indicator of anaphylaxis. In 1910 Cesaris-Demel described the effects which were produced when the excised heart of a sensitized rabbit was perfused with a dilute solution of the same proteid which caused sensitization. He stated that such a heart rapidly decreased the amplitude of its beat and assumed a condition of greater tonus; toxic effects were also noted on normal hearts, but by no means as pronounced as in sensitized hearts. In 1911 Auer showed independently that the heart of an intact anaphylactic rabbit of sufficiently high sensitization rapidly fails to do its work, and that the animal succumbs for this reason. The functional basis for this heart failure was shown to be a complete or almost complete loss of direct irritability of the heart ventricles. On macroscopical examination of the heart muscle, the right ventricle shows a toughening of the muscle bands on its endocardial surface when scraped by the finger nail. The left ventricle does not show this toughening, except now and then on its papillary muscles. The same observer also demonstrated that these cardiac changes were obtained after section of the vagi, and after destruction of the central nervous system, thus proving that the fatal cardiac reaction was not due to central, nervous influences, but was of peripheral origin. He also noted the absence of any marked disturbance of the lungs in anaphylactic rabbits.

In dogs, Biedl and Kraus, and later Arthus, proved that the main symptom of anaphylaxis was a rapid, profound and long-lasting drop in blood pressure. Experimental evidence led Biedl and Kraus to the view that this fall was due to a paralysis of the vasomotor endings in the splanchnic area. Associated with this drop in blood pressure the same observers noted a diminution in the number of leucocytes, and an extreme loss of coagulability of the blood. Blood drawn from a dog during the anaphylactic state remained fluid for many hours, sometimes days. The respiratory function showed no noteworthy alterations. The dogs recovered as a rule.

The functional alterations produced by anaphylaxis in guinea-pigs is entirely different from those observed in rabbits and dogs. In the guinea-pig, Auer and Lewis showed that the functional interference occurs in the lungs. Within a few seconds after the intravenous injection of an adequate "second" dose the animal shows greater and greater difficulty in getting air into and out of its lungs, until finally a stage is reached where no air at all enters on inspiration and this in spite of the fact that the animal makes most violent inspiratory attempts. Three to five minutes after the injection respiration ceases and the animal dies of asphyxia. The heart keeps on beating for many minutes after all respiration has stopped. Inspection of the lungs shows a remarkable picture; on opening the thorax, the lungs do not collapse as normal lungs do, but remain fully distended and form a cast of the thoracic cavity (see Fig. 1). Their color is pale bluish pink and the lungs are light in weight. The same lung picture was obtained with equal promptness when the vagi were cut or when the central nervous system was destroyed, thus demonstrating that this lung condition was of peripheral origin and independent of the central nervous system for its production. On the basis of experimental evidence which need not be detailed here, Auer and Lewis conclude that this striking lung condition is produced by a tetanic contraction of the muscles in the finer bronchial tubes. On the basis of this, atropin was used prophylactically with good results, 72 per cent, of the treated animals recovered, while 75 per cent, of their untreated mates succumbed (Fig. 1). The blood pressure curve in these fatal cases does not resemble that seen in dogs, nor does the blood show a strongly increased coagulation time.

PSM V81 D444 Anaphylaxis and the remedial effects of atropin.png

Fig. 1. The large inflated lungs were obtained from a typical fatal case of horse-serum anaphylaxis in a guinea pig. The small collapsed lungs belonged to an anaphylactic guinea pig of the same lot which was saved by the injection of atropin. This animal seemed normal when killed. The picture shows strikingly the characteristic lung picture of anaphylaxis and the remedial effects of atropin.

The right vagus nerve had been resected in each guinea pig thirteen days before the toxic injection.

It will be observed that the important functional disturbances differ in the three species of animals which have been considered above: in the dog, the main noticeable effect is a profound, lasting drop in blood pressure associated with a great increase in the time necessary to cause coagulation; the lungs show no lasting inflation. In the rabbit, the heart stops beating and the cardiac muscle exhibits a total or almost total loss of direct irritability to mechanical and electrical stimuli; the lungs show areas of emphysema, but collapse more or less completely when the thorax is opened; the blood shows delayed coagulability, but by no means as great as that observed in a dog. The fall in blood pressure is probably secondary to the failure of the heart. In the guinea-pig, the lungs are the chief organs affected and their function is abolished by a stenosis of the finer air passages preventing in the final stage both the entrance and exit of air, so that death results from asphyxia. The anatomical sign of this condition is furnished by the large inflated lungs which do not collapse on excision from the chest cavity (Fig. 1). The heart keeps on beating after final respiratory stoppage, with no obvious loss of irritability; the blood shows only a slight delay in coagulation and the fall in blood pressure is probably due to the fatal asphyxia. These differences between the three species of animals show clearly the necessity of judging each species by the anaphylactic signs characteristic for it and not by manifestations only found in another species. This important point, that each animal species must be measured by its own yard-stick when examined in anaphylaxis, has not been realized, unfortunately, by some investigators.

Causation of Anaphylaxis.—The remarkable phenomena which characterize anaphylaxis early led investigators to search for the causative agent. Numerous theories, more or less supported by experimental facts, were advanced to explain how, for example, the originally harmless horse serum becomes toxic when injected into an animal sensitized by this substance. The pioneer work of Vaughan, Friedemann and Friedberger deals particularly with this aspect of anaphylaxis. A discussion of all the theories here, however, would lead too far and would only befog the reader. It will suffice to state that the basic idea of the chief theory is that the sensitized organism has acquired the power to split the alien serum very rapidly into its components when injected for the second time, and that these components then act as a poison. There can be no theoretical objection to this conception; it is a legitimate working hypothesis. But there are weighty objections just as soon as one substance or mixture of substance is produced from proteids in the test tube by chemical or biological processes and considered as the causative agents of anaphylaxis because when injected into normal animals they produce more or less completely the signs and symptoms which are characteristic of true anaphylaxis. The assumption may be true, but no rigid proof has so far been advanced that these substances really are produced in the animal body during anaphylaxis. The mere fact that these toxic substances produce a lesion which also occurs in true anaphylaxis, by no means justifies the conclusion that the causative agents were the same in the two processes. Take, for example, the pale, rigid, distended lungs produced in a sensitized guinea-pig which succumbs acutely to an intravenous injection of horse serum, and which are diagnostic, when properly considered, of true anaphylaxis in this animal. These lungs owe their state to a tetanic contraction of the bronchial muscles, so that the enclosed air is imprisoned in the alveolar sacs and can not escape even when the lungs are completely excised (see Fig. 1). Now, any adequate stimulus which causes an enduring contraction of these muscles while respiration goes on will produce a greater or less approximation to the lung picture of anaphylaxis. Such adequate stimuli are furnished by a large number of substances, of which we may mention muscarine, eserine, pilocarpine, digitaline, veratrine, morphine barium chloride and the salts of many heavy metals (Dixon and Brodie). Nobody, however, would state that the substances cause anaphylaxis, that they are anaphylatoxins, even though they do produce apparently a lesion of anaphylaxis, for it is perfectly obvious to every one that it is inadmissible to conclude from the identity of reaction produced (in the example chosen, the anaphylactic lung) an identity of the causative agents, as this leads to the ridiculous conclusion that eserine, muscarine, etc., are identical. The same reasoning is applicable to the degradation products obtained by chemical or biological means from proteids. It is not surprising that decomposition products of the infinitely complex proteid molecule should yield substances which are toxic to an organism, and which produce anatomical and functional changes similar to those observed in anaphylaxis, but this does not permit the conclusion that the same decomposition products are formed and exert their actions in true anaphylaxis; such reasoning commits the same error which was mentioned before. It must be insisted that an identity in the biological response caused by a variety of substances permits only the conclusion that these substances are functionally identical, not that they are chemically or so to say, morphologically identical. This confusion is widespread, and at present dominant; it is especially due to the per se valuable and interesting contributions of Friedberger and his colaborers. Friedberger is convinced that the poisonous mixture which he produces by biological methods in vitro is identical with the causative agent or agents in true anaphylaxis, and in most of his recent work the symptom complexes studied were not true anaphylaxis, but the symptoms produced on first injection by his anaphylatoxin.

The question has probably occurred to the reader why this problem was not approached directly, why, for example, the serum of animals in anaphylaxis was not examined for the presence of these degradation products which are said to play such an important rôle. The test can easily be made, for the split products of proteids which have an albumose or pepton character give the biuret reaction. But no investigator, as far as I am aware, has been able to obtain more than a very feeble or no reaction from the serum of an animal dead from true anaphylaxis, provided that the test was carried out after the total removal of all coagulable proteids, thus leaving the non-coagulable peptones and albumoses in the filtrate. This method, therefore, gives no evidence of any degradation product demonstrable by the biuret reaction (Pfeiffer and Mita).

The question was attacked in still another fashion by Abderhalden and Pincussohn. If the intoxication of anaphylaxis is produced by the rapid production of toxic cleavage products from the injected proteid, it is legitimate to assume that the serum of sensitized animals should possess ferments which rapidly accomplish this degradation of the proteid molecule. The experimental test was successful in demonstrating proteolytic ferments, but these ferments were not specific nor of very active nature; and later work by Gruber renders their relation to anaphylaxis quite doubtful.

Summing up the evidence which we have regarding the identity of proteid cleavage products and the causative agent or agents of true anaphylaxis, it must be said that while the assumption is theoretically tenable, a firm experimental basis for this assumption is yet to be laid. Moreover, investigators who unreservedly identify the disturbances caused by proteid constituents produced in vitro, with true anaphylaxis, are causing confusion in another direction. Not only is a perfectly well defined symptom-complex like anaphylaxis obscured by this extension of its scope, but a number of characteristic signs of anaphylaxis lose their significance. Before this can be discussed profitably, the original meaning of the word anaphylaxis as well as the functional disturbances and anatomical signs which characterize it, must clearly be kept in mind. On account of the importance of this, it may perhaps be permissible to give a short resume of matter already discussed.

Meaning of the Word Anaphylaxis, and Diagnostic Criteria.—What the word anaphylaxis was coined to indicate has already been stated; it means the symptoms and signs which are produced when an organism is resubjected to the action of a foreign soluble proteid. When horse serum, for example, is employed, the first injection causes no untoward effects; the second injection, however, gives outspoken and pronounced results which did not occur after the first injection, and these effects are only obtained when a proper interval has elapsed between the two administrations of horse serum. In active anaphylaxis there are three well-defined stages—sensitization, incubation and intoxication. In passive anaphylaxis, where a normal animal is sensitized by the injection of the serum of a sensitized animal, the same three stages are present, but the period of incubation is now shortened to a few hours. If, therefore, reactions are obtained in an animal after the second or so-called toxic injection which were absent when the first one was given, we are justified in speaking of the response as an undoubted reaction of anaphylaxis. The three conditions necessary for the employment of this word are fulfilled, and we are dealing with the same phenomena or group of phenomena which the older observers noted and which they called hypersensitiveness, Theobald Smith's phenomenon or anaphylaxis. If these considerations are followed a field of investigation with sharply defined borders is opened up, and every observer is enabled to judge whether or not his particular patch lies within this territory.

These criteria yield a sharply circumscribed mass of phenomena which are undoubtedly caused by the same general process, and which may now be further analyzed without any doubt, whether or not they are of anaphylactic origin. The more obvious signs and symptoms have already been established in dog, guinea-pig and rabbit, which are the animals usually employed in laboratory investigation. But it must be continually borne in mind that the characteristic anaphylactic responses of these three species are characteristic only when they are obtained after the second injection of a soluble proteid; the profound drop in blood pressure in the dog, the large immobilized pale lungs in the guinea-pig and the loss of irritability and contractility of the heart muscle in the rabbit, do not occur when a harmless soluble proteid like horse serum is injected for the first time; they only appear when the injection is repeated after the period of incubation, and this peculiarity characterizes them as anaphylactic and differentiates them at the same time from similar reactions which occur on first injection of a large number of substances.

These considerations render clear, perhaps, why it is not justified at present to admit that those cleavage products of proteids which cause a similar disturbance on first injection really produce true anaphylaxis, for as soon as this assumption is granted the three characteristic conditions of anaphylaxis which give this symptom complex an independent existence by delimiting it from similar complexes, is obliterated. Moreover, the clean and outspoken functional responses found in the three animal species in anaphylaxis lose their diagnostic character and independence, and fall back into the ruck, indistinguishable from a mass of similar reactions. This is surely a heavy price to pay for an extension of the meaning of anaphylaxis, especially as this extension is not necessary. Even when true anaphylatoxins are isolated, no such broadening of the term will be necessary, for only those substances can be considered true anaphylatoxins which are isolated biologically from the tissues and circulatory juices of a case of true anaphylaxis; and these substances must practically not be present in normal animals, but when injected into these normal animals the anaphylactic symptoms and signs characteristic for the species employed must be obtained. Such substances may be the product of proteid cleavage, but they will bear the name of anaphylatoxins legitimately, for there is no cloud regarding their origin. Such substances, with such a pedigree, have not been isolated so far. With these properly identified anaphylatoxins no confusion will be produced, for they will cause a true anaphylaxis, and the usual conception of this process will not be obscured, but, on the contrary, clarified.

This question of the causal relationship between proteid cleavage products obtained in vitro, and the symptoms and signs of true anaphylaxis has been discussed at some length because this view-point of the problem enjoys great favor; because it was necessary to point out that this view as formulated at present leads to confusion, to the useless sacrifice of a well-defined symptom complex and its characteristic anatomical and functional signs, and finally because this view is not the necessary and inevitable consequence of the experimental data at hand.

Other Manifestations of Anaphylaxis. Serum Disease.—The description given so far has dealt exclusively with the experimental analysis of the more important anaphylactic phenomena in lower animals. But similar phenomena occur in man and these have been extensively studied. Opportunity for this study was afforded shortly after therapeutic sera were generally employed to combat disease, especially diphtheria.[1] To v. Pirquet, associated in his earlier work with Schick, we owe the most thorough study of some of the reactions which the human organism may show when injected with various kinds of therapeutic sera. These reactions v. Pirquet and Schick called serumdisease. The development and course of this serum disease is as follows. The first injection of a therapeutic serum, usually obtained from an immunized horse, is tolerated by most individuals without any reaction. In those that do react, the symptoms do not develop at once, but after the lapse of eight to ten days. The chief disturbances which now occur are fever, skin eruptions, swelling of the lymph glands near the site of injection, pains in the joints and muscles and edema of the face and dependent portions of the body. In spite of this apparently formidable list of ailments the general condition of the patient is excellent, as a rule, and there is but slight danger.

When the same patient is reinjected after an interval of more than ten days, the picture is somewhat different. The period of incubation is practically absent or at least considerably shortened, and the symptoms either develop after a few hours, the "immediate reaction," or after a few days, the "accelerated reaction." As the time interval between the injections increases the "immediate reaction" no longer appears, but the "accelerated reaction" still occurs and has even been noted when the second injection followed seven years after the first. The symptoms which characterized the "accelerated" reaction are similar to those already described, with this difference that they occur suddenly, and disappear swiftly within approximately a day. The "immediate" reaction is somewhat different and characterized by a local edema at the site of injection which slowly increases and reaches its maximum within about twenty-four hours, and disappears within two to five days. Associated with this local reaction there is high fever, and the skin shows crops of transitory eruptions of varying character. In a small proportion of all cases the immediate reaction shows a grave picture, there is nausea and vomiting, and at times even collapse.

The similarity between serum disease and anaphylaxis was early noted by v. Pirquet and Schick. The specific local edema, for example, is exactly analogous to Arthus's phenomenon in rabbits; the non-fatal collapse cases also are similar to the results which Arthus obtained in rabbits where he noted a strong drop in blood pressure.

There is another class of severe reactions, fortunately rare, which occur suddenly when a patient is injected for the first time with serum. The symptoms bear a striking analogy to those observable in lethal anaphylaxis in guinea-pigs and rabbits. Some individuals show a marked respiratory distress of an asthmatic type with cyanosis, similar to guinea-pigs, and others again show symptoms where the respiratory involvement is not so pronounced, but where cardiac weakness predominates. These cases often end in death. Examination of the history of such individuals often shows that they were subject to asthma, or possessed a peculiar idiosyncrasy to the odor of horses which brought on the symptoms of hayfever and asthma. Cases of this kind are probably examples of anaphylaxis in spite of the apparent absence of any sensitizing injection, for this state of sensitization could easily be attributed to inheritance or to a gradual sensitization via the lungs or the stomach. It is well-known, for example, that a sensitized guinea-pig will transmit this property to her offspring, and we may assume that this also plays some role in human cases; moreover Rosenau and Anderson have shown that sensitization may be accomplished in guinea-pigs by feeding raw horsemeat, and more recently Rosenau and Amoss reported that they were able to sensitize guinea-pigs for human serum by injecting the infinitesimal amount of organic material found in the expired breath of human beings. These experimental facts render it quite probable that all these cases where the first injection of horse serum produced alarming symptoms or even death, were sensitized in one of the ways mentioned to this proteid. It is interesting that those individuals which recover are in a state of anti-anaphylaxis for some time afterwards, that is, they are temporarily free from attacks of asthma or hayfever, from which they suffered before.

Local Reactions of Anaphylaxis.—In 1890 Robert Koch announced that the injection of tuberculin produced a local and general reaction in tuberculous guinea-pigs, which, he said, led to an arrest of the tuberculous process and even to health. Everbody probably remembers the sensation which this statement caused. Unhappily, however, the results obtained later in clinical tests did not fulfil expectations. Nevertheless, one important fact remained: the important diagnostic value of the febrile reaction which follows the injection of tuberculin in the tuberculous individual. This reaction occurs only in subjects which are tuberculous, in other words in those who are sensitized by the proteids of the tubercle bacillus; the reaction is thus one of anaphylaxis.

The original method of injecting tuberculin was not devoid of danger, nor was it at best very agreeable to the individual with a positive reaction. In 1907 v. Pirquet described a cutaneous reaction in tuberculosis which gives accurate results and is devoid of any danger or marked discomfort to the patient, v. Pirquet noted that a very small quantity of tuberculin applied to a local scarification of the skin produced within forty-eight hours a well-marked inflammatory reaction in tuberculous subjects, which did not appear in normal individuals. This inflammatory reaction in an individual shows that he must have been sensitized by the tubercle bacillus, in other words that a tuberculous process is in existence somewhere in the organism. The value of this fact is obvious, for it gives a warning, which if properly heeded may prevent invalidism and death.

A reaction similar to that just described is the ophthalmo-reaction of "Wolff-Eisner and of Calmette. Instead of letting absorption take place from the skin these investigators instilled the tuberculin in the conjunctival sac of the eye. In tuberculous subjects a quite violent reaction follows; because of this violent response the ophthalmo-reaction has fallen into disrepute.

Phenomenon of Arthus.—The appearance of a local, massive edema and even necrosis at the site of an injection of serum in a sensitized rabbit was first noted by Arthus in 1903 and has been described before in these pages. In was the first example of a definitely recognized, experimental, local anaphylaxis.

Hayfever.—The most annoying and widespread manifestation of local anaphylaxis is hayfever. Many thousands of people suffer from it in the United States alone. In this country we have two disease periods, the so-called "spring or June cold" prevailing in June and July, and the "autumn catarrh" which begins at the end of July and lasts to October. The majority of hayfever patients suffer during the latter period, and it is quite exceptional that one individual is afflicted during both periods.

The first attack usually begins near the age of puberty and then recurs every year with such regularity that patients are able to forecast quite accurately the date of their coming illness. The duration of the sickness is approximately six weeks.

The symptoms are those of a catarrhal condition of the mucous membrane of the eyes, nose, pharynx and often of the trachea and bronchi. After a preliminary period of one to two weeks, during which there is a moderate irritation of the eyes and nose, associated with a slight discharge, the disease may reach its maximum within a few days or even hours. At this time the eyes are reddened and swollen, and tear secretion is abundant; the nasal mucous membranes are swollen and injected, causing a copious, watery discharge. In addition there are violent, explosive fits of sneezing together with an intolerable itching, and later a soreness of the nose and the eyes. Subsequently nasal breathing becomes impossible and mouth breathing is necessary. Then irritation symptoms of the larynx, trachea and bronchi develop as shown by attacks of coughing. The lung symptoms vary between a mild bronchitis and a severe asthma.

All these symptoms which make life a burden to the hayfever sufferer are caused by the inhalation of certain pollens. As early as 1831 Elliotson advanced this opinion, and later experimental researches by Blackley and especially by Dunbar placed the theory on a safe footing. Dunbar proved that the albumen fraction of certain pollens was the toxic agent by injecting or instilling this substance in predisposed individuals; under proper conditions the typical symptoms were always obtained. The reaction was specific; thus autumn catarrh patients responded typically to the proteids obtained from ragweed and goldenrod, but showed no effect when the pollen proteid of graminaceous plants was used.

Hayfever patients therefore have acquired in some fashion or another a hypersentiveness to the albumin constituent of certain pollens. When plants bearing these pollens are in bloom, the pollen is distributed by the wind, and when inhaled by susceptible individuals, the typical consequences follow. The specificity of the sensitization explains why some suffer in the spring, when pollen from the flowering grasses is in the air, while others suffer in autumn when golden-rod and ragweed distribute their pollen.

Dunbar has produced a therapeutic serum by inoculating horses with the chief pollen proteids which come into consideration. This pollantin has yielded good results when used prophylactically.

Drug Idiosyncrasies.—There are numerous individuals who react with more or less severe symptoms to drugs which cause no obvious effects in the large majority of people. Among these drugs morphine, quinine, antipyrine and the iodides may be mentioned. While the history of these eases shows a marked resemblance to anaphylaxis, there is, for most of them, no very definite experimental basis. Friedberger has recently obtained anaphylactic symptoms in guinea-pigs sensitized with an iodine-proteid compound. It would be of theoretical importance if true anaphylaxis could be experimentally produced with these substances, because they are of a non-proteid nature.

Food Idiosyncrasies.—Probably everybody is familiar with the fact that certain foods, harmless for most people, cause marked trouble in others. Certain individuals, for example, react to the ingestion of strawberries, buckwheat, clams, eggs, etc., as if a poison had been swallowed. These cases also are probably anaphylactic, but here again the experimental test is lacking to clinch the relationship between these phenomena.

Treatment of Anaphylaxis.—The treatment is not yet in a satisfactory state, but there are a number of remedies available for some of the manifestations of this protean complex. If an injection of horse serum produces respiratory symptoms of an asthmatic type in a patient, the only rational treatment is the administration of atropin, for the investigations of Auer and Lewis have shown that this asthma is due to a tetanic contraction of the finer bronchioles which hinders or prevents the entrance and exit of air in the lungs, and atropin causes a relaxation of these muscles. In a study of the prophylactic value of atropin injections in guinea-pigs, Auer was able to save 72 per cent, of his animals, while 75 per cent, of the untreated controls promptly died. These results have been corroborated by a number of observers, especially by Biedl and Kraus. The negative results which Friedberger and Mita obtained are probably due to the inadequate dose of the atropin which they administered.

If the injection of the serum, however, causes symptoms of cardiac failure with slight symptoms of asthma, there is no treatment founded on experiment. The treatment must be symptomatic only; but one class of drugs must be avoided. Auer has shown in highly sensitized rabbits that drugs of the digitalis group should not be used, because they hasten the fatal outcome by aiding the production of the same cardiac lesion which anaphylaxis itself calls forth. Moreover, the same observer has recently described changes in the cardiac muscle produced by members of the digitalis group, especially strophanthin, which are very similar to those produced in cardiac anaphylaxis. It is, therefore, clear why these cardiac stimulants must not be given, even though the weak heart would seem to demand their exhibition.

The most rational treatment is the preventive one. The utmost precaution should be observed whenever it become necessary to inject a therapeutic serum in a patient who has been injected with serum before, who is subject to asthma, hayfever, or who shows an idiosyncrasy to horses. The best treatment of this kind, in my opinion, is the vaccination procedure of Besredka. In this method a very small quantity of horse serum is given subcutaneously or even rectally and time allowed for its absorption. The amount absorbed at any time will be too small to cause serious symptoms and yet enough to produce anti-anaphylaxis. After anti-anaphylaxis has been established, and this occurs quite rapidly, the full dose may be given subcutaneously with some safety. The only objection to this procedure is that time, an hour or two, is lost. The time could be shortened probably, though at some risk. Besredka has obtained good results with the method in guinea-pigs, and it should receive a full clinical trial.

Friedberger and Mita have recently described another method by means of which they were able to protect guinea-pigs against ten times the fatal dose. This result was obtained by a slow intravenous infusion of serum so that only traces enter the circulation at one time. The time of infusion lasted fifty to sixty minutes in their experiments. It will be observed that the same principle used by Besredka, the production of anti-anaphylaxis, is here also utilized.

The treatment for hayfever has already been mentioned.

Importance of Anaphylaxis.—The phenomena of anaphylaxis which have been briefly discussed in the preceding pages are important because they have given us a deeper insight into certain interesting diseases, the so-called idiosyncrasies or predispositions whose causation was formerly inexplicable. The remarkable fact is now established that an organism may be so altered by the injection of an apparently perfectly harmless proteid, that a subsequent injection of the same proteid acts like a violent poison. Predisposition of an individual to any substance means now that this individual is sensitized to this substance. How this sensitization has been accomplished is still undecided in many instances, but the basic conceptions of anaphylaxis will be a safe guide in solving the problem.

It must be emphatically pointed out that the analysis of anaphylactic phenomena would have been impossible without animal experimentation; the chief advances have been made by the functional investigation of these disturbances in laboratory animals and not by tissue examination after death. Thus the autopsies of those early unfortunate cases where death resulted from the administration of a therapeutic serum, yielded no information whatsoever regarding the cause of exitus. The physicians stood before a riddle, the more terrible because its nature was unknown. Animal experimentation has explained this fatal enigma, partially at least, and the physician no longer stands in helpless ignorance before it. He knows the state now, and some methods to prevent or reduce its dangers have been placed at his disposal which promise a fair success.

  1. It must be stated at once that these undesirable accessory reactions which sera sometimes show in the human being form no contraindication to their employment in proper cases. In severe diphtheria, for example, the antidiphtheritic serum is the only remedy which can save the patient from death; to hesitate in its employment because it may produce more or less severe symptoms itself, would be criminal, as this action might be equivalent to throwing away the only chance of recovery the patient has.