Serotherapy

SEROTHERAPY (from Latin serum—whey/serum and Greek therapeia—treatment), serum treatment. With a great variety of methods for administering therapeutic sera and differences in the types of serum preparations themselves (sera from various animal species, purified and concentrated sera, dry sera, etc.), the fundamental point characterizing serotherapy is the use of strictly specific sera obtained from the blood of artificially hyperimmunized animals. Therefore, the concept of serotherapy proper does not include the widely used application of heterogeneous sera for the purpose of protein therapy, the use of sera as a hemostatic agent, etc., since the sera used in these cases are not specifically immune and are used simply as a foreign protein. Also, the concept of serotherapy cannot include the use of so-called "inorganic sera," i.e., solutions of chemical substances (predominantly salts) administered parenterally for the purpose of general activation of the organism (for example, Truneček's "serum"). To characterize the origin of serum preparations, clarifying additions to the term "serotherapy" are used, such as: "autoserotherapy" (treatment with one's own serum or serous transudates from various cavities), "iso-" or "homoserotherapy" (treatment with the serum of another person), "heteroserotherapy" (treatment with serum obtained from other animal species), etc. Serotherapy as a specific method of treatment has existed for only about 40 years. In the 1890s, Behring, Kitasato, and Wernicke, through their experiments on the passive immunization of animals, provided the experimental foundation for serotherapy, while its practical application was developed by Behring and his colleagues, who prepared the first therapeutic specific antidiphtheritic serum in sheep in 1892 and used it for the treatment of children suffering from diphtheria. In 1894, Roux and Martin improved the method of preparing antidiphtheritic serum, tested it on several hundred sick children, and laid a solid foundation for the serotherapy of this disease. A well-developed method for manufacturing immune sera and the brilliant successes of their practical application at the patient's bedside ensured general recognition and widespread dissemination for this new type of treatment. Following the discovery of diphtheria antitoxic serum, the discovery and therapeutic application of specific sera for a number of other infections followed rapidly. In 1892, Behring and Kitasato prepared an antitetanus serum; in 1893, Calmette prepared one against snake venom; in 1895, Marmorek prepared an antistreptococcal serum, Jochmann and Flexner prepared a meningococcal serum, in 1902, Kruse prepared an antidysenteric serum, Moser prepared an antiscarlatinal serum, and so on. To date, there is not a single known pathogen of infectious diseases against which attempts have not been made to obtain a therapeutic specific antiserum. For many diseases, such sera have fully justified themselves, and their use has entered clinical practice as an obligatory therapeutic measure. In parallel with the expansion of the field of action of specific sera, their preparation has been progressively improved in the direction of improving the quality of the sera, increasing their therapeutic activity, developing methods for titrating this activity, etc. Despite the rapid development of serotherapy, far from all its aspects have been studied, and a number of questions related to serotherapy remain open for further scientific research. The doctrine of serotherapy represents a branch of immunology and is based on the laws of immunity. The specific protective properties of the sera of non-susceptible animals, first discovered by Behring, were explained by Ehrlich's school by the appearance in the serum, during the process of immunization, of special substances, so-called antibodies. Representing a great variety in their action, these presumed bodies received special names, such as: antitoxins, bacteriolysins, bactericidins, agglutinins, opsonins, precipitins, etc. These terms, as convenient working designations, have persisted to this day, despite the fact that the existence of antibodies as separate chemical substances has not yet been proven by anyone, and there are grounds to think that they do not exist as such, and that the specific action of immune serum on an antigen depends on changes in the proteins of the latter. Although it cannot be asserted that the state of non-susceptibility of an actively immunized organism is determined entirely by the immune properties of its blood (or plasma, or serum), it has been experimentally established that it is possible to obtain a state of short-term "passive" immunity in a susceptible animal by parenteral administration of blood, or serum, from an immune animal that has recovered from the given disease or has been artificially immunized against it. It is also definitely established that some sera can be successfully used for the treatment of an already developed disease. The immediate mechanism of the protective action of serum has not been clarified, and for the time being, we cannot say to what extent it acts properly therapeutically, by detaching the pathogen's poison from the cells of the organism already affected by it and restoring their normal state, and to what extent "prophylactically," i.e., by protecting them from newly arriving pathogenic agents—toxin or bacteria. In any case, far-advanced severe damage to cells by bacterial poisons (toxins) can no longer be cured even by large doses of serum. Hence, the basic prerequisite for the success of serum treatment is the earliest possible application of the serum. It is also undoubtedly true that the action of serum is strictly specific, i.e., directed only against the infection for which the given serum was prepared. A huge amount of experimental data proves this with complete clarity. As for the action of serum on the patient's own organism, it appears to be expressed only in the non-specific irritation exerted by the serum as a foreign protein. There are no grounds to assume that the specific principle of immune serum could act in any specific way on the cells of the organism itself. The processes occurring in the tissues of a sick organism are extremely complex, and the mechanism of serum action under these conditions is very difficult to clarify. It is precisely this complexity and a whole series of technical features of serum application that explain why serum treatment is not unconditionally successful in all cases of its application. There are cases of ineffectiveness of known highly active sera. The trend that questioned the value of specific serotherapy and considered the therapeutic effect of serotherapy to be the result of the non-specific action of sera on the organism was based mainly on cases of favorable therapeutic action of normal non-specific sera. These views have no experimental basis and have been definitively refuted. Even if it is impossible to theoretically completely exclude the possibility of some favorable non-specific influence of the proteins of the therapeutic serum on the organism, the main factor of serotherapy is precisely the specific action of immune serum on the pathogen and the toxin secreted by the latter. From this premise, one should proceed when resolving practical questions of serotherapy, e.g., to use exclusively strictly specific antisera (the importance of an accurate diagnosis), to prepare therapeutic specific sera by immunizing animals with local strains of the pathogen, to strive for the maximum increase in the concentration of the specific protective properties of the serum, etc. As a result of all that has been said, one could briefly define the essence of the therapeutic action of serum as a specific radical protective-therapeutic action directed at the pathogenic agent, with the addition, perhaps, of some non-specific protein effect on the cells of the organism. Sera based on various other theoretical premises have been proposed, e.g., antienzyme serum, Deitschmann's "yeast" serum, etc. The grounds for the use of these sera are different, and the degree of success of their use corresponds to the degree of correctness of the theoretical premises on which their preparation is based. Such sera are not intended for specific serotherapy. The therapeutic effect of immune sera, depending on their strictly specific action on the infectious agent (bacterium, toxin), cannot be achieved by other types of therapy; however, this by no means excludes the expediency and necessity of using other types of treatment simultaneously with serotherapy—in some cases conservative, medicinal, in others radical, surgical. Thus, it is understandable that specific serotherapy does not exclude the use of symptomatic agents and measures aimed at maintaining the functions of individual organs or eliminating specific symptoms (cardiac, narcotic, disinfectant substances, etc.). This position is revealed particularly sharply in some surgical diseases. Although here serum is an important, often decisive factor in treatment, it by no means excludes the necessity of ordinary surgical aid.

For example, in gas phlegmons and gangrenes, severe streptococcal lesions, and partly in tetanus, radical removal or opening of the focus, which by itself is far from always curing the patient, must necessarily accompany and be accompanied by serum treatment, which has the task of ridding the organism of toxins (or bacteria) that have entered the general circulation and eliminating the phenomena of poisoning. Thus, occupying the first, decisive place in the treatment of infectious diseases, Serotherapy in no way excludes any other treatment, but, on the contrary, requires the assistance of these other non-specific forms of therapy. The success of serum treatment depends to a huge extent on a whole series of technical conditions of its application. The most important of these conditions are the timing of serum application, the quality of the serum (its activity), and the closely related question of dosage, and finally—to a somewhat lesser extent—the method of serum administration. Timely, specifically the earliest possible application of serum is an indispensable and most important prerequisite for the success of its action. Numerous experimental works, as well as daily clinical observations, show that early application of serum highly favors its therapeutic efficacy and that every day and even hour of delay sharply worsens the results of its action. With early application of serum, one is dealing not so much with the treatment of the disease as with protecting the organism from the further development of the disease thanks to the passive immunity conferred by the serum. It is perfectly clear that such protection is more easily accomplished and better results are achieved by it in the sense of protecting the organism from infection than by treatment. Ideally, the application of serum should precede the development of clinical symptoms in the infected organism (as is known, the duration of passive immunity equals 15-20 days). There is a whole series of infections—tetanus, measles, botulism—in which we have an excellent effect from serum prophylaxis even with small doses of serum and negligible efficacy of this same serum when used therapeutically even in large doses. Regarding a number of sera, it is even considered useless to use them after a certain period of the disease, whereas in the first days these sera give a good therapeutic effect (scarlet fever, meningitis, etc.). The quality of the serum, i.e., its specific activity in relation to the antigen, also plays a huge role (see Sera). In very many diseases, Serotherapy was compromised in the past precisely by unsuccessful, insufficiently active preparations of the serum used (scarlet fever, pneumococcus). The dosage of serum depends primarily on its activity. Since for the success of treatment it is important to introduce certain quantities of specific antibodies, and passive fractions of serum protein that do not carry antibodies (albumins, euglobulins) play no specific role in treatment and are unnecessary, and often even harmful (causing phenomena of serum disease), when establishing the dose of serum it is necessary to be guided not so much by the volume of the serum as by the quantity of protective properties, or substances, determined experimentally and expressed in special units of "titer". It is understandable that in all respects it is advantageous to manufacture and use the most active sera possible. The economic and technical advantages of highly active sera over less active ones are very great. They are clear from the position that, by how many times a serum is more active according to experimental titration data, by that many times a smaller quantity of it is needed to achieve the same therapeutic effect. Often in the practice of Serotherapy, one can encounter sera that differ from each other in strength by 5-8 and even 10 times. For sera whose experimental titration of activity is well developed and generally recognized, the therapeutic dosage is expressed precisely by the quantity of active protective units regardless of the volume of the serum (diphtheria, tetanus, dysentery, gas gangrene, etc.). For a greater concentration of active protective substances in the serum, besides methods of more perfect hyperimmunization of the animal from which the serum is obtained, methods of artificial concentration of sera and freeing them from ballast protein fractions that do not carry immune properties (purification) are also used (see Sera). For sera with officially recognized methods of titration, many countries have established a mandatory minimum titer, below which a serum cannot be put into use. Thus, in the USSR, a minimum has been established at the present time for antidiphtheritic serum of 400 units, for antitetanus serum of 300 international (150 American) units, for antidysenteric sera of 300 units, etc. Sera that are weak in titer can be quite active in a therapeutic sense, however, they are inconvenient for practical application due to the excessively large quantities that have to be injected. As for the therapeutic dosage of sera, expressed in units of specific titer, it should be said that it is impossible to establish any firmly fixed figures applicable to all cases of diseases. Only for prophylactic use have certain doses been more or less reasonably established (3,000 AU of antitetanus serum, 1,000-2,000 units of antidiphtheritic, etc.). For therapeutic use, one should use the largest possible doses of serum, not being deterred by their physical volume. Phenomena of reaction to foreign protein (serum disease) are the only unpleasant consequence of injecting large doses; as for the results of the treatment itself, the more antibodies are introduced to the patient, the better, although there is no exact parallelism and further increase beyond certain maximums does not justify itself. (For details of dosage, see individual diseases.) The guiding considerations when prescribing a dose of serum are the timing of its application, the severity of the disease, and the age (body weight) of the patient. The later the serum is applied, the more severely the disease is expressed, and the larger the patient's organism, the correspondingly larger the dose of serum must be. In a prolonged disease that does not immediately yield to therapy, repeated day-to-day injections of serum are indicated (beware of the 9th-12th day—anaphylaxis from the first injections). The method of serum application is of less importance than the two factors described, since the fundamental tenet of Serotherapy is the parenteral administration of serum. Local application of sera is not widespread, and its efficacy is highly doubtful (gargling or spraying the throat in diphtheria, dusting wounds in tetanus). The application of serum per os is useless in view of its digestion in the gastrointestinal tract. The only firmly established method of applying sera is their parenteral administration—intramuscular, subcutaneous, intravenous, intraperitoneal. In all these cases, the difference in therapeutic terms consists exclusively in the speed of the serum's entry into the bloodstream. The fastest in this regard is the method of intravenous administration of serum; subcutaneously injected preparations are absorbed most slowly. Intravenous injection is technically more difficult, and furthermore, it has the disadvantage of the possibility of shock in case of hypersensitivity to serum (in particular, anaphylaxis). The fear of shock, exaggerated in most cases, often deters doctors from the intravenous method of administering serum. However, when there is a need for particularly rapid administration of serum (fulminant and severe forms of diseases), this method retains all its advantages and must be used. The intraperitoneal method is dangerous due to the possibility of introducing infection into the peritoneal cavity. In terms of speed of absorption, it stands in 2nd place after the intravenous one. Most often, serum is applied intramuscularly (m. glutaeus). This method ensures a fairly rapid (4-6-8 hours) entry of antibodies into the blood. Small quantities of serum are injected subcutaneously; absorption requires 12 hours. In special cases, the introduction of serum into the affected tissue is used—intraspinal administration in meningitis, infiltration of the affected area in erysipelas, etc. Recently, intraspinal administration of sera in all infectious diseases has been widely recommended by the works of Speransky, which illuminate the role of the central nervous system in infectious diseases. So far, there is still too little data to form an objective idea about the results of such treatment. Doses for intraspinal administration of serum are correspondingly small (up to 10 cm³). The disadvantages of Serotherapy are, firstly, the non-absolute therapeutic effect in all cases of application, in particular the lack of effect when applied late, and secondly, the possibility of the development of so-called serum disease (see), as well as anaphylaxis. The first complication is observed when using sera that have not been aged long enough (4-6 months).

There exists, on the one hand, a constitutional predisposition to serum disease among people, and on the other hand, an individual peculiarity of the sera of some horses to cause phenomena of serum disease. Purifying sera of passive proteins represents an extremely valuable method for mitigating and eliminating serum disease. A more severe, but fortunately much rarer, complication of serotherapy is anaphylactic phenomena, especially shock (see Anaphylaxis). In practice, such cases occur extremely rarely, which is explained by the fact that the state of anaphylaxis is acute only during a certain period; with the passage of time, it decreases, thanks to which shock is more difficult to induce. Anaphylaxis is also rare due to the comparative rarity of cases of repeated serum treatment. In everyday practice, physicians administer serum as a rule intramuscularly or subcutaneously. With this method of administration, in normal doses, slow absorption excludes the possibility of anaphylactic shock. To avoid anaphylactic shock during intravenous administration of serum, it is necessary to inject 1-2 cm³ of the same serum 1-2 hours before administering the entire intended amount of serum for desensitization of the organism. For the same purpose, it is recommended during repeated injections of serum to use sera obtained from other animal species (cattle, sheep, etc.). The diseases for which serotherapy has won a firm position as the sole and effective means of treatment are the following: diphtheria, tetanus (predominantly prophylactic use), epidemic cerebrospinal meningitis, scarlet fever (scarlatinal streptococcus), gas gangrene, dysentery (bacillary), botulism, streptococcal infections (sepsis, puerperal fever, erysipelas, surgical infections), pneumococcal diseases (type I and II lobar pneumonia), anthrax, snake poisoning. Convalescent human sera - measles, whooping cough, scarlet fever, and some others. Sera have been proposed but have not received general recognition and wide distribution: anti-typhoid, anti-gonococcal, anti-tuberculosis, anti-whooping cough (Bordet-Gengou). Details on the technique and results of application see in the articles on the corresponding diseases. In veterinary practice, sera have come into use for the following diseases: anthrax, oedema malignum, Rauschbrand, erysipelas suum, septicaemia haemorrhagica, cholera gallinarum, morbus maculosus equorum, pestis suum, adenitis equorum, tetanus.

N. Vlasievsky, E. Gogin. Serotherapy in obstetrics and in female diseases. Serotherapy in obstetrics is used for toxicosis and dermatosis of pregnancy and for puerperal diseases (see Puerperal period, Sepsis, Endometritis). Serum treatment of toxicosis of pregnancy arose relatively recently (in 1910), due to which many questions connected with it appear to be far from resolved. The justification for the use of serotherapy in clinical practice was served by a whole series of experimental and pathological-anatomical observations, which showed the presence in various organs of those who died from eclampsia of placental cells, the ability of fresh human, horse, and guinea pig blood serum to paralyze the poisonous effect of freshly squeezed placental juice, sodium oleate (soap hemolysis), etc. Not a small role in the emergence and development of serotherapy was played by the interpretation of toxicosis of pregnancy as processes of a general character and the desire conditioned by this to act on the entire organism, to help it in the fight against circulating toxins, and not to try to arrest only individual pathological manifestations (such as, for example, vomiting in pregnant women, treating the skin locally for dermatosis, a seizure in eclampsia, etc.). For the first time, serum was used in 1910 (Daunay, Lequeux) in 3 cases of albuminuria of pregnancy. They injected goat serum; noting a certain positive effect of the serum (increase in diuresis, drop in blood pressure), they nevertheless refrained from any conclusions, considering that further observations were needed for this. The father of serotherapy should be considered Freund (R. Freund), who first proved experimentally the possibility of its use in the clinic and was the first to test it in practical life (in eclampsia and other toxicosis). He used normal horse serum; shortly after this, Mayer applied with no less success the serum of a healthy pregnant woman, Franz the blood serum obtained from the umbilical cord (in a case of erythema exsudativum multiforme), Wolff the serum of a puerperal woman (in toxidermia). Recently, Lasar Vassileff (1932) applied with a positive result in 12 cases of severe vomiting the serum of a pregnant mare. Other proposed sera (serum of a pregnant woman who had previously suffered eclampsia, serum of a horse after preliminary injection of freshly squeezed placental juice or placental emulsion - Selitsky) have not yet been tested in practice. On the basis of the available rather extensive data, one can come to the conclusion that serotherapy (predominantly normal horse serum and serum of a healthy pregnant woman) at the present time occupies one of the honorable places in the therapy of toxicosis of pregnancy, gives the greatest percentage of positive results, is used by many foreign clinics, and is, contrary to the insufficiently grounded opinion of some (Stroganov), a completely harmless intervention [for additional proof of the harmlessness of serotherapy, Selitsky injected himself intravenously with N-serum of a horse (43 cm³ in 3 doses) and noted, along with its complete harmlessness, some changes produced by it in the blood]. In the USSR, serotherapy for toxicosis was used for the first time by Selitsky; subsequently, individual successfully conducted cases were published by Polonsky, Varnakov, Goberman, Shorokhova, and others. Serotherapy was used for all kinds of toxicosis of pregnancy (vomiting, intractable vomiting, chorea, sciatica, eclampsia, mild and severe jaundice, etc.) and for various dermatosis and toxidermia (impetigo herpetiformis, herpes gestationis, prurigo gestationis, dermatitis toxica simmetrica, pruritus, etc.). All authors who used one or another serum note in a number of cases an exceptional effect, observed not only in toxicosis of mild or moderate severity, but also in very severe ones, such as, for example, icterus gravis with an unconscious state, impetigo herpetiformis, herpes gestationis, etc. There is no complete exhaustive statistics of conducted cases with one or another serum at the present time. Thus, de la Pereira in his dissertation (1915) cites 31 cases (from the women's clinic Charite in Berlin and data of other authors) of various dermatosis of pregnancy and notes only one case with a negative result (a case in which the serum was injected not immediately, but after the unsuccessful use of Ringer's solution). Selitsky in 1923 reported his first 25 cases and incidentally cited 82 cases of toxicosis and dermatosis collected by him in the literature, treated with one or another serum with positive results in 91.3% (when reducing 4 cases subject to exclusion, this percentage increases to 96.3); in 1929 he published his 12 cases of dermatosis (100% cure) with N-serum of a horse and cited statistics of 76 published cases with 95.9% positive results. In recent times (1933), Sellheim, noting the favorable results of serotherapy in toxicosis of pregnancy, proposes, on the basis of cases successfully conducted by him, the use of serum of a healthy pregnant woman in threatened abortion and threatened premature birth (see figure). The mechanism of action of one or another serum, the immediate cause of the therapeutic effect, are still not sufficiently clear. It is possible to assume that one or another injected serum comes

to the aid of the weakened and toxin-overloaded organism, is an auxiliary means for neutralizing circulating toxins, restores the protective ability of the blood, and replenishes one or another loss or deficit in the organism (Sellheim interprets in the same plane the success obtained with the injection of serum of a healthy pregnant woman in cases of threatened abortion - the serum of a healthy pregnant woman, in his opinion, possesses a healing power for a pregnant woman with insufficient function).

To speak about the specificity of serotherapy in general, just as about the specificity of any individual serum, is impossible, since, as clinical observations show, an identical effect in various kinds of toxicosis was obtained with the injection of both the serum of a pregnant woman and N-serum of a horse, a pregnant mare, etc. For these same reasons, it is still difficult to speak about the special advantages of one or

Threatened premature birth in the seventh month. Contractions every 1/4-1/2 hour for half a day. After the injection of serum, in the next 10 hours, the contractions became less frequent, less strong, less prolonged, and finally ceased altogether. The lower shaded field signifies bleeding, which after the use of serum after 6 hours gave way to brown-colored discharge and then ceased altogether.

another of the sera used. Indications that the serum of a pregnant woman is the best, because it is homogeneous, require further confirmation, just as much as the opinion of Fieux that the serum of a certain stage of pregnancy is important and that supposedly the most effective is the serum of the first three months of pregnancy. The question of which of the used sera of a healthy pregnant woman [1) serum of a pregnant woman in various stages of pregnancy, both I- and II-stage, 2) serum of a parturient woman, 3) serum of a puerperal woman, 4) serum of a woman immediately after an abortion, 5) serum of blood taken from the umbilical cord] is most appropriate and whether the administration of serum of a healthy pregnant woman to a sick pregnant woman of the same stage of pregnancy can play any role, also requires clinical verification. The serum is administered intravenously, intramuscularly, subcutaneously, and intralumbally. Most often, the serum was administered intravenously and intramuscularly. Intramuscular administration of the serum in most cases is quite sufficient and in clinical practice appears simpler. The question of dosage also has not yet been finally established. Most often, the serum is administered in amounts of 10-20 cm³, and usually one injection is not enough and it has to be repeated one or two times. The serum reaction does not differ from the reaction when other sera are administered, but in general it is slight (general restlessness, somewhat difficult breathing, slight increase in pulse rate, slight rise in temperature), almost never reaches severe degrees, and often is absent altogether. The criterion for dosage and the choice of time for a repeated injection are the general condition of the body and its reaction to the first administration of serum. Published cases show that the maximum amount of serum administered was 170 cm³ (the largest single dose was 58 cm³), the smallest was 8 cm³. The amount of serum administered does not yet determine the therapeutic effect; thus, negative results were obtained with large amounts (170 cm³) and, conversely, positive results with small doses (8 cm³). Zelgeim in cases of threatened abortion administered 10 cm³ every 14 days, while in cases of threatened premature labor, a single administration of the same dose proved sufficient. In female diseases, serum (based on a series of works by Weil) is used for various types of meno- and metrorrhagias, caused by one or another violation of the ovarian-uterine cycle or being a consequence of hemorrhagic diathesis. For this purpose, either N-serum of horses or antitoxic diphtheria serum is used. The dose is 10-20 cm³, and its administration in the form of enemas or by applying tampons to the cervix is recommended (Dalche). In stubborn cases, a longer course of treatment is indicated, in which Weil never observed anaphylactic phenomena. Lapeyre was the first to use serum in metrorrhagias (fibroma, cancer, menopause), while Pruvost considers that S. should be more effective in functional menorrhagias in the pubertal period or at menopause. In a number of cases, combination of S. with hormone therapy (preparations of the thyroid gland, adrenal glands, pituitary gland - depending on the case) is indicated.

('Selitsky.')