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Bacteriologic, Etiologic, and Serologic Studies in Epilepsy and Schizophrenia III. Cutaneous Reactions to Intradermal Injection of Streptococccal Antibody and Antigen
Published in Postgraduate Medicine, Vol. 3, No. 5, May 1948, pp. 367-376.
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When a patient with a disease due to or associated with a streptococcus is given an intracutaneous injection of an antigenically related streptococcal preparation, there develops an immediate cutaneous erythema at the site of injection. In normal individuals or those with other illnesses little or no reaction occurs. The substance for injection may be streptococcic antiserums prepared in horses,1 streptococcal antibody prepared in vitro,2 and streptococcal antigen and solutions of polysaccharide.
The reactions resembled the erythematous antibody-antigen reaction discovered by Foshay3 in tularemia and in reverse the antigen-antibody reaction in pneumococcus pneumonia discovered by Francis.4 The transient flare in each instance is considered to be due to the union of specific antibody and specific antigen. The flare therefore following injection of antibody is considered as a measure of uncombined antigen and after injection of antigen as a measure of free antibody in skin or blood.
Methods
Cutaneous tests were made by injecting intradermally as superficially as possible, 0.03 ml. of solutions of thermal antibody and of antigen and of isotonic sodium chloride solution. The volar aspect of the forearm was used if possible. Ten per cent solutions of the euglobulin fraction of the serum of horses that had been immunized with the respective streptococci (natural antibody) were similarly injected.
Two types of thermal antibody were injected. They were given intradermally for the cutaneous tests and subcutaneously or intramuscularly for treatment. The first (or “thermal”) type consisted of the bacteria-free supernatant of sodium chloride solution suspensions containing 20,000,000,000 streptococci per ml. This had been autoclaved for ninety-six hours and then diluted with equal parts of sodium chloride solution. The second (or “thermal-hydrogen peroxide antibody”) consisted of the bacteria-free supernatant of sodium chloride solution suspensions containing 10,000,000,000 streptococci per ml. Before autoclaving for one hour, 1.5 per cent hydrogen peroxide was added.5
The streptococci had been preserved in glycerol two parts and saturated sodium chloride solution one part. The reaction of the former remained neutral or approximately at pH 6.5 while the latter became acid due to the formation of tartronic acid from the oxidation of glycerol by the hydrogen peroxide. The reaction of the latter was brought to pH 6.5 by the addition of sodium hydroxide before it was used in skin tests and for therapy.
Streptococcal antigen injected intradermally to measure antibody consisted of the bacteria-free supernatant sodium chloride solution of suspensions containing 10,000,000,000 streptococci per ml. after heating to 65° or 70°C. for one hour. Phenol (0.2 per cent) was added to the different solutions of antibody and antigen and sodium chloride solution as a preservative.
The skin over the area to be injected was gently disinfected with 95 per cent alcohol which was allowed to evaporate before injection. The Luer type of one ml. syringes with 26 gauge needles was used. A sharply demarcated white bleb about 5 mm. in diameter was taken to indicate that the correct amount was injected into the proper layer of the skin.
Since the reactions occurred almost immediately all test materials were drawn into syringes from rubber capped vials and carefully labeled before injections were begun and the series of injections made as rapidly as possible. The test and control materials were injected into the skin of comparable texture 4 to 5 cm. apart. The maximal flare was outlined with pen and ink and the area in square centimeters was determined by superimposing circles on transparent film of predetermined sizes in square centimeters.
Results
The significance of the flare following injection of natural and artificial antibody was considered in relation to that of control materials similarly injected and not merely according to its size. The erythema at the site of injection of antibody occurred almost immediately and reached its maximum in a few minutes while the flare to injections of antigen, if it occurred at all, occurred more slowly and reached its maximum in five to ten minutes. Both reactions occurred without itching or formation of pseudopodia, differing in these respects from reactions due to injection of histamine or of antigen to which persons are allergic.
The primary erythema of both disappeared promptly. There was no return of erythema following injection of thermal antibody but sometimes a local urticarial reaction occurred in a week or ten days following injection of the euglobulin of the serum of immunized horses. Slight erythema and infiltration was usually found in twenty-four to seventy-two hours at the site of injection of streptococcal antigen. Parallel injections of natural streptococcal antibody and of thermal antibody were made in persons suffering from different diseases. The cutaneous reactions in a series of patients suffering from idiopathic epilepsy, schizophrenia, dementia paralytica, involutional and alcoholic psychosis, and infectious arthritis are summarized in Table 1. It will be seen that the average size of the erythema and the per cent of reactions 5 sq. cm. or more in persons suffering from epilepsy, schizophrenia, and arthritis respectively were uniformly far greater to both natural and artificial antibodies prepared from the homologous streptococci than to antibodies which were prepared from heterologous strains.
Table 1: Erythematous Reaction in Persons Having Various Diseases to Intradermal Injection of “Natural” and in vitro Produced Streptococcal Antibodies
*These 25 patients were tested in parallel also with thermal antibody prepared with H202. The reactions were similarly specific. The average reaction in sq. cm. and the % 5 sq. cm. or more to the antibody prepared with H202 from streptococci isolated in studies of epilepsy, schizophrenia, and arthritis were 3.50, 40%; 6.58, 90%, and 1.79, 8% respectively.
Reactions in persons suffering from dementia paralytica without convulsions were minimal to both types of antibody solutions while those who had convulsions reacted maximally to both types of antibody prepared from streptococci isolated from patients with epilepsy. The group having involutional or alcoholic psychosis reacted moderately but maximally to both types of the antibodies prepared from streptococci isolated in studies of schizophrenia.
Through the kind cooperation of Dr. W. G. Murray, Superintendent of the State Hospital, Dixon, Illinois, and Dr. G. R. Roberts, Superintendent of the Ohio Hospital for Epileptics, Gallipolis, Ohio, I had the opportunity of testing a large number of persons suffering from idiopathic epilepsy. Results following injection of thermal antibodies are summarized in Table 2.
Table 2: Erythematous Reactions to Intradermal Injection of Thermal Antibody in Persons Suffering from Idiopathic Epilepsy
The average size of the reaction to intradermal injection of thermal antibody prepared from streptococci isolated in studies of epilepsy was uniformly much greater than to antibody prepared from streptococci isolated in studies of schizophrenia and far greater than to antibody prepared from streptococci isolated in studies of arthritis.
Moreover the reaction approached normal in the group that had “recovered” and was directly proportional to the severity of symptoms. It occurred in all groups of persons suffering from idiopathic epilepsy regardless of age, sex, location, whether hospitalized or not and quite regardless of type of seizures, and whether or not under medication with anticonvulsant drugs such as phenobarbital and/or dilantin. Cutaneous tests, not shown in the table, in persons diagnosed as suffering from Jacksonian epilepsy were usually negative.
The average reaction to thermal antibody prepared from streptococci isolated in studies of schizophrenia was greater in the groups of epileptics that were housed in wards with patients suffering from schizophrenia (7.08 sq. cm.) than in those remote from schizophrenia (5.80 sq. cm.).
The results of intradermal tests in relation to grand mal seizures (Figure 1) show that the reactions to thermal antibody prepared from streptococci isolated in studies of epilepsy was greatest shortly before and during seizures. Soon after seizures a sharp drop occurred and then a gradual increase for four days. Only slight reduction in reactions to antibodies prepared from streptococci isolated in studies of schizophrenia and arthritis occurred following seizures.
Figure 1. Erythematous cutaneous reactions in relation to major (grain and mal) seizures in persons suffering from idiopathic epilepsy to intradermal injection of thermal antibody prepared from alpha streptococci isolated respectively in studies of epilepsy, schizophrenia, and arthritis.
The agglutinin titer of the serum for the streptococcus isolated in studies of epilepsy (to be reported elsewhere) was consistently higher after than shortly before the seizures.
The results of cutaneous tests in persons suffering from schizophrenia, manic depressive psychosis, involutional and alcoholic psychosis, paranoia and paranoid states, dementia paralytica without and with convulsions, well persons exposed to schizophrenia, and as controls in persons suffering from arthritis are summarized in Table 3.
Table 3: Erythematous Reaction in Persons Suffering from Schizophrenia, Involutional Psychosis and Paranoia or Paranoid States, Dementia Paralytica and Arthritis, and in Well Persons Exposed to Schizophrenia to Intradermal Injection of Thermal Antibody Prepared from Streptococci Isolated in Studies of Epilepsy, Schizophrenia, and Arthritis
It will be noted: (1) That the reaction to thermal antibody prepared from streptococci isolated in studies of schizophrenia was far greater in the groups of persons suffering from schizophrenia than in persons suffering from dementia paralytica or arthritis or in well individuals or persons suffering from other non-neurologic diseases; (2) That reactions to thermal antibody prepared from streptococci isolated in studies of arthritis was far greater in persons suffering from arthritis than in patients suffering from epilepsy, schizophrenia, or other diseases of the nervous system or in well persons (Table 4). In both arthritic and schizophrenic patients the cutaneous reaction was proportional to the severity of the disease.
Table 4: Erythematous Reactions in Well Persons or Persons Ill with Diseases Other than of the Nervous System to Intradermal Injection of Thermal Antibodies Prepared from Streptococci, Tested as Controls
Well persons exposed to schizophrenics reacted moderately to thermal antibody prepared from streptococci isolated in studies of schizophrenia. The reaction was directly proportional to the degree of exposure. Persons suffering from schizophrenia and dementia paralytica respectively and having convulsions reacted like mild epileptics to the antibody prepared from streptococci isolated in studies of epilepsy.
The results obtained in well persons and persons clinically ill with non-neurologic or non-psychiatric diseases tested as controls are summarized in Table 4. The average reactions were uniformly far less than in persons suffering from epilepsy or schizophrenia.
The results obtained in patients tested as unknowns on admission to the hospital and on “recovery” are summarized in Table 5.
Table 5: Erythematous Reactions, on Admission and on Recovery in Persons Having Mental Disorders, to Intradermal Injection of Thermal Antibody Prepared from Streptococci Isolated in Studies of Epilepsy, Schizophrenia, and Arthritis
Persons suffering from schizophrenia reacted more severely during the active stage of the disease than on recovery or remission (thermal antibody prepared from streptococci isolated in studies of schizophrenia). In sharp contrast, reactions to this antibody were relatively slight on admission and only slightly less on recovery in persons suffering from dementia paralytica or having psychosis due to arteriosclerosis. The group having psychosis due to “intoxication,” involutional psychosis, or paranoia on admission reacted to this thermal antibody similar to the group shown in Table 3.
The results obtained in persons suffering from schizophrenia and their well, blood relatives and husband or wife and of persons suffering from chronic encephalitis are summarized in Table 6. It will be seen that the well, blood relatives reacted essentially like other well persons (Table 4) to the several antibodies and that persons suffering from schizophrenia and encephalitis, respectively, reacted maximally to the antibody prepared from the corresponding streptococci and significantly, but less strongly, to the antibody prepared from closely related strains of streptococci.
Table 6: Erythematous Reaction to Intradermal Injection of Thermal Antibody in Persons Suffering from Schizophrenia, in Well Blood Relatives, and in Husband or Wife
* For of the seven that reacted 5 sq. cm. or more complained of nervousness and had been in close contact with the respective patient.
**Four of the six patients who reacted 5 sq. cm. or more had arthritis.
Patients who had dementia paralytica reacted more than the control group (Tables 3 and 4) to thermal antibody from cases of schizophrenia than to other thermal antibodies. This was partly due to the fact that they were housed in wards with schizophrenics and partly because some had symptoms resembling schizophrenia.
With these few exceptions cutaneous reactions throughout this study were usually remarkably in accord with the clinical diagnoses which were made by the attending physicians.
All of eighteen young men who had developed schizophrenia while under stress in the armed forces reacted maximally to thermal antibody (schizophrenia) and next most strongly to antibody prepared from streptococci isolated in studies of chronic encephalitis. Reactions in this group to antibodies prepared from streptococci isolated in studies of epilepsy and arthritis were of usual minimal size.
Consistent and comparable reactions were obtained regardless of how long the streptococci had been kept in the glycerine sodium chloride solution menstruum or whether prepared directly from sodium chloride solution suspensions directly from cultures. The solutions of thermal antibody used were stable. Solutions prepared in July, 1944 and kept in the refrigerator most of the time gave undiminished and specific reactions in repeated tests over a period of two years. After two years, the reactions, while somewhat less pronounced, are still highly differential or specific.
Solutions of thermal antibody were prepared from each of three pools of streptococci isolated from the nasopharynx of well persons and one each prepared from streptococci isolated from the stool of persons suffering from schizophrenia and from epilepsy. In keeping with the negative agglutination tests with these streptococci, antibody solutions caused slight, insignificant, or no cutaneous reactions.
Control solutions of sodium chloride solution or saline to which the same amount of the glycerin-sodium chloride solution menstruum had been added as in making the thermal antibody suspensions were autoclaved in parallel and then brought to pH 6.5 or 7.0. Injections were made in 280 persons representing proportional numbers in the different groups studied. There was no reaction at the site of injection in 205 of these, a reaction of 0.79 sq. cm. in 41, of 1.77 sq. cm. in 26, and of 3.14,sq. cm. in 7. Typical allergic reactions of about 19.64 sq. cm. occurred in ten minutes to all solutions to which 0.2 per cent phenol had been added in one physician who had been handling postmortem specimens preserved in phenol. No reaction occurred to injections of sodium chloride solution without phenol. In no other instance throughout these and other studies was sensitivity to phenol observed.
Cutaneous Reactions in Relation to Therapeutic Injections of Thermal Antibody and to Electro-Shock
The effects of subcutaneous injections of streptococcal thermal antibody on the clinical course of idiopathic epilepsy and schizophrenia and of electro-shock on the reactivity of the skin to intradermal injection of thermal antibody and of antigen was first studied in 1944 through the cooperation of Dr. M. C. Petersen, Superintendent of the Rochester State Hospital, Rochester, Minnesota.
The effects of a single subcutaneous injection of 2 ml. of thermal antibody obtained from 2,000,000,000 streptococci per ml. were studied in 10 persons suffering from idiopathic epilepsy and in two groups of 7 and 5 persons each, suffering from schizophrenia. In most of these a significant increase in antibody and a drop in specific streptococcal antigen occurred in six and twenty-four hours, respectively.
In a study of four groups of 10 persons suffering from schizophrenia (Figure 2), one intramuscular injection consisting of thermal antibody from 8 billion streptococci in 4 ml. of sodium chloride solution was given to each of the 10 persons in group 1. Four milliliters of sodium chloride solution were given to each of the 10 persons in group 2. Each of the 10 persons in group 3 was given electro-shock and no injections or treatments were given to the 10 persons in group 4.
Figure 2. Erythematous cutaneous reactions to intradermal injection of streptococcal antigen and thermal antibody in four groups of 10 persons each suffering from schizophrenia in relation to therapeutic injection of thermal antibody and electroshock.
A sharp average increase in erythematous reaction to intradermal injection of antigen or an increase in antibody and a corresponding decrease to intradermal injection of antibody or a decrease in antigen prepared respectively from streptococci isolated in studies of schizophrenia occurred in twenty-four hours in group 1 after intramuscular injection of the thermal antibody prepared from homologous streptococci and in twenty-four hours after electro-shock in group 3.
The increase in antibody and decrease in antigen were specific, for no change in reactions occurred in intradermal injection of thermal antibody prepared from streptococci isolated in studies of arthritis. Moreover, there was little or no change in cutaneous reaction before and twenty-four hours after intramuscular injection of sodium chloride solution in group 2 and no change in cutaneous reactions in the two tests made twenty-four hours apart in the 10 control persons in group.
The reactions to solutions of natural antibody in the euglobulin fraction of the serum of horses prepared with streptococci isolated in studies of schizophrenia paralleled closely those obtained with thermal antibody prepared from the corresponding streptococci.
Reactions to injections of comparable solutions of natural antibody prepared with heterologous streptococci isolated in studies of epilepsy and arthritis and to normal horse serum were negative or minimal.
Similar results were obtained in cutaneous tests made with both natural and thermal antibodies and the corresponding antigens in a group of 20 persons suffering from schizophrenia before, twenty-four hours after the first, and twenty-four hours and seven days after the last of two daily subcutaneous injections of thermal antibody from four billion streptococci prepared from streptococci isolated in studies of schizophrenia. Slight local reactions occurred at first but these became progressively less after repeated injection. Constitutional reactions did not occur. Several of the patients became less disturbed.
Great variations in response occurred in the cutaneous tests, but a significant average specific increase in antibody and a decrease in antigen had occurred twenty-four hours after the first and twenty-four hours and seven days after the last therapeutic injection.
Studies on the clinical application of thermal antibody were interrupted in 1944 because of lack of facilities. A further study on the nature and conditions best suited for the production of artificial antibody occurred when opportunity to study the clinical effects of thermal antibody became available at the Longview Hospital, Cincinnati, Ohio (through the cooperation of Dr. E. A. Baber, Superintendent, and Dr. Martin Fischer, Professor of physiology of the Medical College of the University of Cincinnati, and attending physicians, Drs. Stephens, Goldman, and Kastan of Longview Hospital).
The results of the earlier studies in treatment with thermal antibody have been confirmed and the effects of intramuscular injections of thermal antibody prepared with heat alone and with hydrogen peroxide and much less heat—thermal hydrogen peroxide antibody—have been studied.
Of the 18 persons who received thermal hydrogen peroxide antibody prepared from streptococci isolated in studies of schizophrenia, 12 received antibody prepared from streptococci isolated from nasopharynx, 6 antibody prepared prior to 1945, and 6 received that prepared in 1945 from streptococci isolated from infected teeth.
The results in these three groups were comparable.
There was a striking increase of specific antibody and a decrease in specific antigen to intradermal injection of the two batches of antigen and thermal antibody prepared from streptococci isolated in studies of schizophrenia and little or no change in reaction to the antigen and antibody prepared from streptococci isolated in studies of arthritis. In sharp contrast there was little or no change in cutaneous reactions to antigen or antibody prepared from streptococci isolated in studies of schizophrenia but a sharp increase in both antibody and antigen prepared from streptococci isolated in studies of arthritis in the group that received two therapeutic injections of thermal antibody prepared from streptococci isolated in studies of arthritis.
There was no significant change in cutaneous reactions to intradermal injection of the two types of antigen and antibody in the three comparable tests made in the control group that received two intramuscular injections of sodium chloride solution.
The clinical response and cutaneous reactions to repeated therapeutic subcutaneous injections of thermal antibody prepared respectively from streptococci isolated in studies of epilepsy and schizophrenia were next studied.
Striking diminution in specific streptococcal antigen and increase in antibody occurred in each of the 4 persons suffering from epilepsy following daily therapeutic injection of thermal antibody (Figure 3). Similar results occurred in 3 of the 5 persons suffering from schizophrenia while receiving adequate dosage of thermal antibody prepared from streptococci isolated in studies of schizophrenia (Figure 4). Discontinuing therapeutic injections in cases 2 and 3 or giving of adequate dosage for one or two days was followed by diminution in antibody, which again increased to former levels after two or three daily subcutaneous injections of specific thermal antibody.
Figure 3. Results of therapeutic injections of thermal antibody prepared from streptococci isolated in studies of epilepsy in relation to cutaneous antibody-antigen and antigen-antibody reactions in four persons suffering from epilepsy.
Figure 4. Results of therapeutic injections of thermal antibody prepared from streptococci isolated in studies of schizophrenia in relation to cutaneous antibody-antigen and antigen-antibody reactions in five persons suffering from schizophrenia.
The increase in antibody and decrease in antigen and improvement in symptoms did not occur during the initial week of daily injections of antibody in the patient who had had schizophrenia for thirty-one years not shown in Figure 4 nor in the control patient who received subcutaneous injections of sodium chloride solution. After injection of thermal antibody every day for a time, and then every other day for several months, symptoms improved in both of these as antibody titer increased and antigen diminished.
In cutaneous tests in a group of 12 persons suffering from schizophrenia before, six, and twenty-four hours after treatment with electro-shock there was considerable variation in cutaneous reactions in the different cases studied. A significant average increase in specific streptococcal antibody and a corresponding decrease in specific streptococcal antigen similar to those shown in Figure 2 occurred six and twenty-four hours after the electrically induced convulsive shock.
Comments and Summary
The results of a study of erythematous cutaneous reactions to intradermal injection of antigen and of natural and artificial antibodies prepared from alpha streptococci isolated in studies of idiopathic epilepsy, schizophrenia and, as a control, in arthritis, and the effects of therapeutic injections of thermal antibody in persons suffering from idiopathic epilepsy and schizophrenia are reported.
Since immediate reactions to parallel intradermal injections of natural and thermal antibodies prepared from streptococci isolated in studies of epilepsy, schizophrenia, and arthritis, respectively, were found comparable and equally specific in persons suffering from these diseases and since delayed “allergic” reactions at the site of injection of thermal antibody did not occur, the latter type of antibody was used to measure antigen in skin or blood specifically related to the streptococcus from which it was prepared.
The reactions obtained during studies of persons suffering from idiopathic epilepsy, manic depressive psychosis, schizophrenia and involutional psychosis, paranoia and paranoid states, and arthritis proved remarkably specific. They were not only maximal in persons suffering from the disease in question but were often directly proportional to the severity of symptoms and occurred regardless of geographic location, season of year, time of day, age, and sex, whether persons tested were hospitalized or not and, in the case of epilepsy, quite regardless of medication with anticonvulsant drugs. The test is not applicable in especially dark skin of Negroes.
Moreover the cutaneous test with thermal antibody served as a presumptive test for the detection of carriers among well persons and persons suffering from dementia paralytica of the streptococci isolated in studies of epilepsy and schizophrenia on exposure to persons suffering from these diseases. Reaction in well, blood relatives of persons suffering from schizophrenia, regardless of family history of this disease, to intradermal injection of thermal antibody prepared from streptococci isolated in studies of schizophrenia paralleled those obtained in well persons without hereditary taint.
Thermal antibodies prepared from alpha streptococci isolated from nasopharynx of well persons remote from epilepsy and schizophrenia and from the feces of persons suffering from epilepsy and schizophrenia and control injection of sodium chloride solution gave slight, nonspecific, or no reactions.
Repeated intradermal injections of 0.03 ml. of respective thermal antibodies caused no change in cutaneous reactivity to re-injections. However, intramuscular or subcutaneous injections in therapeutic amounts of both thermal antibody and thermal hydrogen peroxide antibody caused a diminution of specific antigen as determined by intradermal injection of thermal antibody and usually a striking increase in specific antibody as determined by intradermal injection of the corresponding streptococcal antigen and also by agglutination tests with the serum.
When respective specific streptococcal antibodies increased and specific antigen diminished following therapeutic injections of thermal hydrogen peroxide antibody and thermal antibody, repeated, at first every day, then every other day or every third day over prolonged periods of from four to seven months clinical improvement and prevention of recurring exacerbations, seemingly attributable to this form of specific therapy, sometimes occurred even in persons who had suffered from epileptic seizures or from schizophrenia for many years.
The prompt increase of respective specific streptococcal antibodies and a decrease of corresponding antigen in schizophrenia following the electrically induced convulsion during electro-shock treatment and in idiopathic epilepsy following spontaneously occurring grand mal seizures indicate the presence of specific types of subclinical streptococcal infections and that preformed, so-called sessile antibodies are mobilized during the course of the violent reactions.
The increased cutaneous reaction to intradermal injection of thermal antibody prepared from streptococci isolated in studies of schizophrenia indicating the carrier state in well persons and in persons suffering from epilepsy and from dementia paralytica on exposure to schizophrenics, indicate that more than the mere presence of specific types of streptococci is necessary to produce disease. Hereditary transmission of physical and psychical characters alone, with and without stresses of environment, also do not seemingly suffice. The presence of a low grade but specific type of streptococcal infection for prolonged periods and hereditary predisposition almost seem to be prerequisites for the production of the respective symptoms.
The question regarding the source of or reason for the presence of specific types of streptococci in epilepsy and schizophrenia, whether due to inherited susceptibility, to chance infection by the respective streptococci, or whether the inherited constitution affords the very conditions favorable for alpha streptococci normally present in the throat and elsewhere of human beings to acquire specific affinity for the respective structures in the brain remains unanswered.
The consistent isolation of alpha streptococci in studies of idiopathic epilepsy and schizophrenia, the reproduction in important respects of the disease pictures in animals, the proof of their serologic specificity by the special methods employed, and the data obtained in this study indicate: (1) that persons suffering from epilepsy and from schizophrenia harbor in nasopharynx, in pulpless teeth, and sometimes in their blood, specific types of alpha streptococci of low general but high and specific “neurotropic” virulence; (2) that the streptococci produce neurotoxins which have predilection for certain structures in the brain and thus may play a role in pathogenesis, and (3) that attempts to combat such inapparent infections specifically by passive and active immunization with the respective antigens and antibodies are indicated in addition to present day methods at prevention and cure.
Further studies on the production and nature of artificial antibodies and on their therapeutic application are in progress and will be reported.
I acknowledge with gratitude the unstinted cooperation of the many physicians and hospital superintendents and the financial aid of the donors which made these studies possible.
Editor’s note: Since the era in which this article was written, society’s understanding of respectful terminology when referring to societal and cultural groups has evolved, and some readers may be offended by references to “Negroes” and other out-of-date terminology. However, this article has been archived as a historical document, and so we have chosen to use the author’s exact words in the interest of authenticity. No disrespect to any group is intended.
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- Rosenow, E. C.: Production in vitro of substances resembling antibodies from bacteria. J. Infect. Dis. 76:163-178, 1945·
- Foshay, Lee: The nature of the bacterial-specific intradermal antiserum reaction. J. Infect. Dis. 59:330-339, 1936.
- Francis, Thomas, Jr.: The value of the skin test with type specific polysaccharide in the serum treatment of Type I pneumococcus pneumonia. J. Exper. Med. 57:617-631, 1933.
- Rosenow, E. C.: Studies on the nature of antibodies produced in vitro from bacteria with hydrogen peroxide and heat. J. Immunol. 55:219-232, 1947.