- Email: [email protected]
The uses of gamma globulins in the prophylaxis of infection
J. chron. Dis. Vol. 15,pp. 589-598. Pergamon
Press Ltd. Printed in Great Britain
THE USES OF GAMMA GLOBULINS IN THE PROPHYLAXIS OF INFECTION Department
of Microbiology,
ALLANH. LEVY, M.D. The Johns Hopkins University School of Medicine, Baltimore, Md. (Received
20 February
1962)
PASSIVEimmunization has been used since the last decade of the nineteenth century when VON BEHRINGand KITASANO introduced antitoxin for the treatment of diphtheria . Several drawbacks accompanied serum therapy before gamma globulins became available. To obtain antibody concentrations of sufficient potency, it was generally necessary to employ hyperimmune animal serum which commonly caused hypersensitivity reactions to the foreign serum proteins. Serum sickness and anaphylattic shock are still frequent manifestations of treatment with tetanus and diphtheria antitoxin. When convalescent phase whole human serum was employed, there was the danger of transmitting the viruses of infectious hepatitis or serum hepatitis. These disadvantages sharply limited the usefulness of passive immunization. With the exception of the use of tetanus antitoxin for prophylaxis,* serum therapy was limited to the treatment of established life-threatening infections, and the prevention of disease could not be effectively accomplished by passive immunization. The development of efficient techniques for the fractionation of human serum by COHN and his collaborators [2] made available for the first time fractions of human serum containing antibodies concentrated to many times their original titer, and provided in gamma globulin an effective agent for the prophylaxis of many viral diseases. Also, improved virologic methods, mainly the development of tissue culture techniques, facilitated the study of poliomyelitis and other viral diseases. These studies of pathogenetic and immune mechanisms provided a firm basis for the use of gamma globulin in passive immunization against a variety of serious infections. The prolonged immunity following many viral infections is chiefly mediated by serum antibody. Many viral diseases are widely prevalent in the population, and pools of sera from normal adults will contain low levels of antibodies against these viruses. Although the concentration of antibody in normal human serum is too low for therapeutic usefulness, the increased concentration in gamma globulin fmctionated from pooled sera provides an agent with a wide range of effectiveness in prophylaxis. At present, it is known that gamma globulins have protective value against measles, infectious hepatitis, poliomyelitis and, in all probability, rubella. In addition, gamma globulins derived from hyperimmune human sera have been demonstrated to be of value in the prophylaxis and treatment of smallpox and complications of vaccinia, and in the treatment of mumps orchitis and pertussis. *One interesting exception to this, cited by KARSNER and ECKER [l], was the use of diphtheria antibacterial serum for prophylaxis in carriers. The serum was incorporated into lozenges and used locally, but was not effective.
589
590
ALLANH. LEVY
GENERAL PROPERTIES Antibodies against most viruses and bacteria are found in Fraction II of serum treated by the ethanol fractionation procedures developed by Cohn and the Harvard group. However, certain antibodies, although gamma globulins, are separated with Cohn Fraction 111-l and are not present in commercial preparations of gamma globulin, which contain proteins mainly in Fraction II. Two preparations of gamma globulins derived from normal pooled blood are presently available. One is Immune Serum Globulin, U.S.P. (Human); the other is Poliomyelitis Immune Globulin (Human). Both are similar except that batches of the latter must meet a standard established by the National Institutes of Health for Preparations contain about 165 mg of gamma Type II poliomyelitis antibody. globulin per ml of solution; this represents an approximate 25-fold increase of the gamma globulin concentration in normal serum. Gamma globulin is injected intramuscularly or subcutaneously, and should never be administered intravenously. Intravenous injection may cause cardiac arrhythmias, hypotension, and fever. Toxic reactions to gamma globulin administered intramuscularly are uncommon, and, for the most part, not serious. JANEWAY]3] has reported an incidence of side-reactions of 1.2 per cent in a series of patients receiving small intramuscular doses for the prophylaxis of measles. These include local inflammatory responses with pain and tenderness at the site of injection, and mild systemic reactions with malaise, headache, and low-grade fever. Serious reactions are uncommon; among those reported are angioneurotic edema, nephrotic syndrome, neuromyelitis optica, and anaphylactic shock [ 41. One notable advantage of gamma globulin preparations is their freedom from contamination with the hepatitis viruses. This has been demonstrated by abundant clinical data, and has been confirmed in an experimental study by MURRAYand RATNER [5]. Of fifteen volunteers inoculated parenterally with a small dose of infected plasma, four developed serum hepatitis, but no hepatitis developed in five other individuals injected with a larger dose of gamma globulin derived from the same plasma. Since the antibody content of gamma globulin reflects the distribution and concentration of antibody in the blood of the donor populations, it is not surprising that variations in antibody titer occur in different batches of gamma globulin. Gamma globulin prepared from donors in the western United States contains antibody to western, but not to eastern equine encephalomyelitis [6]. However, for measles and infectious hepatitis, the protective effect appears to be much the same in lots of gamma globulin from different geographical areas [7]. On the other hand, the varying efficacy of gamma globulin in the prophylaxis of rubella may well reflect differences in antibody levels in the gamma globulin preparations used. PRINCIPLES OF PROPHYLAXIS The effective use of gamma globulin for prophylaxis must be governed by an understanding of the pathogenesis of the disease in which passive immunization is of value. In many viral diseases especially, the events occurring during the incubation period are critical. After infection occurs, the virus first multiplies at a primary site. In poliomyelitis, this is the gastrointestinal tract; in measles, it is believed to be the
The Uses of Gamma Globulins in the Prophylaxis of Infection
591
respiratory tract. There is usually some dissemination to local lymphatics at this time, but during the early part of the incubation period, multiplication of virus at the primary site produces relatively little tissue damage, and the host is asymptomatic. Later, shortly before the onset of clinical disease, there is a viremia; during this time virus is widely disseminated in those organs where virus multiplication will produce tissue damage and cause the characteristic symptoms of the disease. In paralytic poliomyelitis, for example, virus has reached its highest titer in the central nervous system at the time when the paralytic symptoms of the disease begin. Available evidence indicates that serum antibody neutralizes the virus only when the virus particle is outside the cell and that its damaging effects on a cell are not prevented by antibody after the cell has become infected. To be effective in prophylaxis, antibody must be present in the blood in effective concentrations during the viremic stage. If virus is neutralized in the circulation, spread to distant organs may be eliminated or markedly decreased, and the clinical manifestations of disease prevented or modified. Accordingly, for prophylaxis, gamma globulin should be given early in the incubation period so that a maximum level of antibody may surround the cells at the onset of the viremia. One or two days are required for maximum serum levels to be obtained after intramuscular injection of gamma globulin. Therefore it is essential that gamma globulin be administered as soon after exposure as possible. In infections in which a given dose of gamma globulin may prevent disease, a smaller dose or one given later in the incubation period may result in a modified infection. In this situation, there is often enough replication of the infecting agent to provide a sufficient antigenic stimulus for the concurrent development of persistent active immunity; modification is often preferable to complete prevention. It should be stressed that complete prevention of the spread of virus by passive immunization is probably a rare occurrence. Although an infection may result in no outward signs of disease, there is often some secondary dissemination and minor involvement of ‘target’ organs. Recent studies of patients exposed to infectious hepatitis who received large prophylactic doses of gamma globulin showed that many of them, although completely asymptomatic, had evidence of hepatic involvement demonstrated by liver function tests [ 81. PROPHYLAXIS
OF VIRAL IMMUNE
DISEASE GLOBULIN
WITH
POOLED
Me&es. The prevaIence of measles in the population is so high that until recently, an attack has been considered to be one of the unavoidable inconveniences of childhood. However, the substantial morbidity and the not inconsequential mortality that are associated with this illness and its complications should not be overlooked. Measles encephalitis, although rare, almost always leaves serious sequelae. In debilitated individuals or in groups where proper medical care is not available, measles represents a significant threat. An
592
ALLANH. LEVY
reactions were sufficiently numerous and severe to limit the usefulness of the vaccine [ 111. Recent reports by MCCRUMBet al. [ 121, REILLY and his associates [13], and STOKESand his co-workers [ 141 indicate that the clinical manifestations caused by live measles-virus vaccine were markedly lessened by the concurrent administration of gamma globulin without reduction in active immunization and that effective resistance to naturally-occurring measles was induced in those who had been immunized with vaccine and gamma globulin [ 141. At present, using gamma globulin alone, modification rather than complete prevention should be the aim in most circumstances. Active immunity will develop following the modified illness. It is recommended that all susceptible children should receive a modifying dose of gamma globulin after exposure to measles. The modified disease is usually characterized by a prolonged incubation period and milder symptomatology than the natural illness. There is considerable variation in the modified illness; rash, conjunctivitis, headache or malaise may still occur. The incidence of complications is very much less than in the natural disease, and the incidence of measles encephalitis may be lower [ 151. Modification is most consistently achieved by a dose of 0.02 ml per pound of body weight, administered during the first six days after exposure [ 161. After the sixth day, the recommended dose for modification or prevention should be doubled. Gamma globulin sometimes has a modifying effect if administered as late as the appearance of Koplik’s spots, but is not effective after the appearance of the exanthem [ 171. The large majority of patients to whom modifying doses of gamma globulin are administered will develop active immunity similar to that following natural infection [ 181. Prevention, rather than modification, is recommended in special circumstances. Complete prevention is recommended for infants and children up to three years of age because the highest mortality occurs in this age group. Prophylaxis is also advisable for susceptible exposed pregnant women in whom measles virus infection has been reported to be associated with premature labor and abortion [19]. Preventive doses should be administered to patients with a debilitating illness and to those whose social or economic status is such that adequate care during illness cannot reasonably be anticipated. The dose for prevention is 0.1 ml per pound of body weight, administered as soon as possible after exposure. Prophylactic doses are also warranted for those with no prior history of measles who are exposed in hospital wards or in military establishments. After a case of measles is detected in a hospital ward, new patients may still be admitted if all susceptible old patients and all new patients admitted for the following three weeks are given 0.1 ml of gamma globulin per pound of body weight. If further secondary cases occur, gamma globulin should be readministered within three weeks of the first dose, and new admissions should continue to receive prophylactic injections until at least three weeks after the last case [7]. Infectious hepatitis. Since the report in 1945 by STOKESand NEEFE [20] that the clinical manifestations of infectious hepatitis could be prevented by the administration of gamma globulin, prevention of this disease has constituted one of the most important uses of this agent. A number of studies has confirmed and extended these early observations; gamma globulin has been demonstrated to be effective in controlling institutional epidemics [8] as well as sharply reducing the frequency of secondary cases in family outbreaks [ 21 I.
The Uses of Gamma Globulins in the Prophylaxis of Infection
593
Prolonged immunity against infectious hepatitis has been observed in institutionalized patients who received prophylactic doses of gamma globulin as high as 0% ml per pound of body weight [22]. In institutional epidemics, reinfection during the time of waning passive immunity might be the mechanism responsible for the development of persistent resistance. It remains to be established whether large prophylactic doses produce concurrent passive and active immunity in noninstitutionalized individuals. Some modification of hepatitis results from a dose of gamma globulin as low as 0.005 ml per pound of body weight, and individuals infected with the virus who receive this dose apparently develop active immunity. These patients will frequently develop an anicteric illness with nausea, vomiting, and chemical abnormalities of liver function. This low dose is not recommended. It is suggested by the American Academy of Pediatrics that susceptible children should receive 0.04 ml per kg of body weight after exposure [ 231. Higher doses, up to 0.1 ml per kg, may be necessary for adults, in whom infectious hepatitis often runs a more severe course. The higher dose should be used in pregnant females in whom hepatitis is likely to be particularly severe, in debilitated patients, and during military or hospital outbreaks. If a patient is re-exposed to infectious hepatitis more than 6 or 8 weeks after receiving gamma globulin prophylaxis, another dose of gamma globulin should be administered. A more definitive dosage schedule must await further epidemiologic study and the development of appropriate virologic techniques for determining infection rates and immune status. Poliomyelitis. The administration of gamma globulin during the first five to seven days after exposure to polio virus would appear to reduce the incidence and severity of paralysis [ 241. The availability of live virus and formalin-inactivated virus vaccines should lessen the need for passive immunization against this disease. However, many persons in this country are still not immunized, and local outbreaks continue to occur. Vigorous community-wide vaccination programs hlave been suggested as the most effective means of terminating such epidemics, and live virus vaccine is currently being stockpiled for this purpose.
The routine use of gamma globulin for prophylaxis against poliomyelitis is not recommended by the American Academy of Pediatrics [ 231. Passive immunization of all susceptible persons in an epidemic situation is impractical. Futhermore, although the administration of gamma globulin to family contacts of known cases of poliomyelitis may prevent an occasional secondary paralytic case [ 251, the number of individuals that will benefit is sh,arply limited. Sixty per cent of secondary cases occur within five days after the primary case; gamma globulin administered late in the incubation period will be of little value to the majority of family contacts. HAMMON[26], however, is of the opinion that susceptible contacts in institutional and summer camp outbreaks should receive gamma globulin. In addition, he suggests that non-immunized or inadequately immunized family contacts should also receive gamma globulin early in the outbreak. Pregnant women also appear to be more vulnerable to paralysis [7] and should be considered as candidates for passive immunization. When gamma globulin is administered for prophylaxis of paralytic poliomyelitis, the dose is 0.14 ml per pound of body weight.
594
AUAN H.
LEVY
The use of gamma globulin in conjunction with live virus vaccination is under investigation, and no recommendation for its use in this fashion can be made presently. Rubella. German measles, ordinarily a benign infectious disease in children, becomes a problem when it occurs during the first four months of pregnancy. It has been conclusively established that there is a high percentage of stillbirths, neonatal deaths, and congenital abnormalities in the offspring of women contracting rubella in the first four months of pregnancy [27, 281. The virus causing German measles has not been cultivated in the laboratory; therefore, rubella antibody levels in gamma globulin preparations cannot be measured. Evaluation of the efficacy of gamma globulin preparations in preventing German measles has been mainly based on epidemiologic observations, although KRUGMANand WARD [ 291 were able to demonstrate the presence of antibody in gamma globulin by its capacity to neutralize virus obtained from a known case and administered to human volunteers. Controlled studies have shown that protection after exposure can be achieved with gamma globulin, if the injection is given early in the incubation period. In one study ( 301, protection was achieved with a dose of 0.1 ml per pound of body weight. In some individuals, German measles developed within three days after gamma globulin administration, indicating failure of protection if passive immunization is withheld until late in the incubation period. The incubation period of rubella varies from ten to twenty-one days, and gamma globulin should be administered within a week after exposure. Some batches of gamma globulin have had no protective effect ]31]. This is probably due to variations in concentration of rubella antibody in different pools of blood. More satisfactory and consistent results could be expected with gamma globulin derived from serum of convalescent persons, which would provide higher and more uniform concentrations of antibody. WARD and PARKER [32], working in Australia, have reported good results with such a preparation. Hyperimmune rubella globulin is not commercially available at present. Since rubella is a benign disease except during pregnancy, gamma globulin is not indicated at other times. It has been shown by GELLIS [ 171 that a dose of 20-30 ml of gamma globulin reduces the incidence of clinically apparent German measles in pregnant women exposed to this disease. However, it must be borne in mind that lack of obvious disease in the mother is no guarantee that the fetus will be spared from infection. COFFEY and JESSOP have observed that women who were exposed to, but did not develop rubella, produced offspring with abnormalities at a rate that was 2.5 times as great as that seen in the general populaticn [33]. The extent to which gamma globulin protects the fetus from rubella is not yet definitely established; hopefully, high doses may prove to be protective to the fetus as well as the mother. Although consistent protection will not always result, it is recommended that susceptible women exposed to rubella during the first four months of pregnancy should receive 20 ml of gamma globulin as soon as possible after exposure. HYPERIMMUNE GLOBULIN PREPARATIONS In a variety of infectious diseases, gamma globulin derived from pools of normal sera has been of limited value because of insufficient antibody content. In several
The Uses of Gamma Globulins
in the Prophylaxis
of Infection
595
instances, however, gamma globulins fractionated from pooled sera of convalescent persons have been of demonstrated efficacy. Such preparations may well have wider applicability as they become more readily available. Smallpox and complications of vaccination. Gamma globulin prepared from sera of individuals bled 4-8 weeks after immunization with vaccinia has been demonstrated to be an effective adjunct to vaccination in the prevention of smallpox. Tt is also of value in the management of the serious complications of vaccination. In many individuals exposed to smallpox, initial vaccination, as well as revaccination, does not produce a rapid enough immune response to prevent the development of smallpox. However, in exposed individuals who received a combination of vaccination and vaccinia immune globulin (VIG), there was a lower incidence of smallpox and a lower mortality than in a group treated with vaccination alone. VIG did not impair the development of an active immune response. The dosage employed was 0.2 ml per pound of body weight for adults, 0.05 ml per pound for children, and 0.1-0.2 ml per pound for infants under one year of age [ 361. VIG has been demonstrated to be of value in the prevention and treatment of eczema vaccinatum [36-381. If it is imperative to vaccinate a child with eczema, the concurrent use of hyperimmune gamma globulin is recommended. VlG is also indicated when a child suffering from eczema is intimately exposed to siblings or others recently vaccinated. and when vaccination is inadvertently performed on an individual with large areas of burned or denuded skin. Recommended dosage is from 0.6 to 1.0 ml per kg of body weight. VIG has alsc been effective in halting the appearance of new lesions of generalized vaccinia [ 381. VIG is presently distributed by the American Red Gross. Because supplies are limited, a panel of consultants has been named to evaluate requests from physicians for VIG. Full details of the distribution program have been published recently 1391. Mumps. Immune globulin from pooled normal blood does not prevent mumps. However, globulin derived from serum of persons convalescing after mumps has been effective in reducing the incidence of orchitis in adult males when administered within the first day after onset of parotitis [40]. Its effectiveness in preventing mumps itself has not been shown in a controlled study. Grchitis in adult males rarely leads to sterility, but 5-7.5 ml of mumps immune globulin may be administered in an effort to prevent this complication. Except under unusual circumstances, passive immunization is not indicated in healthy children. Pertussis. A preparation of pertussis hyperimmune gamma globulin is available commercially. Although believed to be useful in the therapy of severe whooping cough, its value as a prophylactic agent is in doubt. In a controlled study, MORRIS and MCDONALD[41] showed that the incidence of disease in children exposed to pertussis was not significantly lower in those receiving hyperimmune globulin than in a control group. REPLACEMENT THERAPY IN AGAMMAGLOBULINEMIA Periodic injections of gamma globulin have been found beneficial in the prophylaxis of recurrent bacterial infection in patients suffering from either congenital or acquired agammaglobulinemia or hypogammaglobulinemia. Plasma levels should be maintained at levels no lower than 150 mg of pooled globulin per 100 ml of plasma. In initiating therapy, 0.45 ml of gamma globulin per pound of body weight
596
ALLAN
H.
LEVY
should be given and repeated a few days later. Subsequent maintenance can usually be achieved by monthly injection of 0.3 to 0.45 ml per pound of body weight. Dosage may vary considerably from patient to patient, and it is advisable to check the level with a laboratory test. In some patients gamma globulin alone is sufficient for the prophylaxis of infections; in others, a combination of gamma globulin and antibiotics may be necessary. Several articles deal in greater detail with the management of agammaglobulinemia [42-44]. OTHER
USES
OF
GAMMA
GLOBULIN
The prevention and treatment of a number of other infectious diseases have been attempted with gamma globulin from pooled normal sera. While some favorable reports have been published, there is still insufficient evidence of beneficial effect to warrant the routine use of gamma globulin for the following conditions: In chickenpax, gamma globulin was unsuccessfully employed by GROSSand his. associates [7] in an effort to control the spread of varicella in hospital wards. A favorable report [45] indicating a prophylactic effect was not the result of a controlled study, and is considered inconclusive. Gamma globulin may be of value in the treatment of severe chickenpox pneumonia, especially in adults 1461, but this has not been definitely proved. Gamma globulin has been suggested for the treatment of herpes zoster, an illness caused by a virus identical with, or closely related to, the varicella agent. In an uncontrolled study, LEA and TAYLOR [47] noted improvement in 11 of 17 patients receiving gamma globulin and were impressed with the value of this treatment. Another study [48] has indicated that gamma globulin is without effect. The evaluation of response to any treatment of herpes zoster is notoriously difficult; gamma globulin for therapy of this disease cannot be recommended. Therapy with immune globulin has been reported effective in a case of eczema herpeticum, a serious manifestation of herpes simplex infection in children [49]. It has been claimed that some infants and children with persistent or recurrent viral upper respiratory infections benefit from the use of gamma globulin [ 501, but these observations have not been verified in controlled studies. Bacterial infections. There has been suggestive evidence that gamma globulin, in combination with antibiotics, may be of value in the treatment of refractory cases of chronic osteomyelitis and chronic pyelonephritis [ 5 1] . However, as heretofore, reliance should be placed upon the use of specific antimicrobials and appropriate local measures rather than gamma globulin. SUMMARY
The gamma globulin fraction of pooled normal human -era has a wide range of usefulness in the prophylaxis of many infectious. diseases. Hyperimmune human globulin preparations ,are effective against certain other illnesses in which globulins pooled from normal sera contain insufficient antibody. In general, gamma globulins are most effective in diseases with a relatively long period of incubation. If immune globulins are administered early in the incubation period, there will be sufficiently high levels of circulating antibody to neutralize virus during the viremic phase, and dissemination of virus to distant organs will be limited, resulting in prevention or
The Uses of Gamma Globulins
in the Prophylaxis
of Infection
597
modification of the disease. Both dose and time of administration are important in determining the effect of passive immunization. In most circumstances, the optimal dose of gamma globulin is one which will modify, rather than completely prevent, the disease and will allow the concurrent development of active immunity. Active immunization with available viral vaccines provides a far more satisfactory basis for preventing infection.
REFERENCES KARSNER,H. T. and ECKER, E. E.: The Principles of Immunology,
p. 262, J. P. Lippincott, Philadelphia, 1921. 2. COHN, E. J., ONCLEY, .I. L., STRONG,L. E., HUGHES, W. L., Jr. and ARMSTRONG,S. H.: Chemical, clinical and immunologic studies on the products of human plasma fractionation. I. The characterization of the protein fractions of human plasma, J. c&z. Invest. 23, 417, 1944. Advanc. intern. Med. 3, 295, 1949. 3. JANEWAY,C. A.: Plasma fractionation, to gamma globulin: Case report, J. med. Ass. Ala. 23, 4. OWINGS, W. J. B.: Hypersensitivity 74, 1953. 5. MURRAY,R. and RATNER,F. : Safety of immune serum globulin with respect to homologous serum hepatitis, Proc. Sot. exp. Biol. N.Y. 83, 554, 1953. 6. YANKAUER, A. : Discussion of conference on therapy. Therapeutic uses of gamma globulin, Amer. J. Med 5,590, 1948. 7. GROSS, P. A. M., GITLIN, D. and JANEWAY,C. A.: The gamma globulins and their clinical significance. IV. Therapeutic uses of gamma globulin, N. Engl. J. Med. 260, 170, 1959. a. KRUGMAN, S., WARD, R., GILES, J. P. and JACOBS, A. M.: Infectious hepatitis. Studies on the effect of gamma globulin and on the incidence of inapparent infection, J. Amer. med. Ass. 174, 823, 1960. 9. ENDIXRS,J. F., KATZ, S. L., MILOVANOVIC,M. V. and HOLLOWAY,A. : Studies on attenuated measles-virus vaccine. I. Development and preparation of vaccine: Technics for assay of effects of vaccination, N. Engl. J. Med. 263, 153, 1960. 10. KRUGMAN,S., GILES, J. P. and JACOBS,A. M. : Studies of attenuated measles-virus vaccine. VI. Clinical, antigenic, and prophylactic effects of vaccine in institutionalized children, N. Engl. .I. Med. 263, 174, 1960. vaccination against measles. II. Tests of live 11. HOEKENGA, M. T. et al. : Experimental measles and live distemper vaccine in human volunteers during measles epidemic in Panama, J. Amer. med. Ass. 173, 868, 1960. measles-virus vaccine. III. 12. MCCRUMB, F. R., Jr. et al.: Studies with live attenuated Development of practical method for large-scale immunization, Amer. J. Dis. Child. 101, 1.
708, 1961.
13. 14. 15. 16. 17. 18. 19. 20. 21.
REILLY, C. M., STOKES, J., Jr., BUYNAK,E!. B., GOLDNER, H. and HILLEMAN,M. R. : Living attenuated measles-virus vaccine in early infancy: Studies of role of passive antibody in immunization, N. Engl. J. Med. 265, 165, 1961. STOKES, J., Jr. et al.: Efficacy of live, attenuated measles-virus vaccine given with human immune globulin. A preliminary report, N. Engl. J. Med. 265, 507, 1961. GREENBERG,M., PELL~~TERI,0. and EISENSTEIN, D.: Measles encephalitis. I. Prophylactic effect of gamma globulin, J. Pediar. 46,642, 1955. KRUGMAN, S. and WARD, R.: Infectious Diseases of Children, p. 161, C. V. Mosby, St. Louis, 1960. GELLIS, S. S. : Use of gamma globulin in prevention of various diseases, Mississippi Do@. 32, 65, 1954. BIVINGS, L. : Gamma globulin dosage and measles control : Report of 188 cases, J. Pediat. 43,401, 1953. pregnancy : Report of 24 cases with 3 instances of DYER, I. : Measles complicating congenital measles, Sth. med. J. (Bgham. Ala.) 33,60, 1940. STOKES, J., Jr. and NJZEFE,J. R. : The prevention and attenuation of infectious hepatitis by gamma globulin. Preliminary note, J. Amer. med. Ass. 127, 144, 1945. BROOKS, B. F., HSIA, D. Y-Y. and GELLIS, S. S. : Family outbreaks of infectious hepatitis: Prophylactic use of gamma globulin, N. Engl. J. Med. 249, 58, 1953.
ALLAN H. LEVY
598
: Infectious hepatitis. Length of protection by immune serum globulin (gamma globulin) during epidemics, J. Amer. med. Ass. 147, 714, 1951. 23. Reoort of the Committee on the Control of Infectious Diseases, American Academy of Pediatrics, pp. 22-23, 1961. agent for 24. HAMMON, W. er al.: Evaluation of Red Cross gamma globulin as prophylactic Poliomyelitis, J. Amer. med. Ass. 156,21, 1954. Evaluation of gamma 25. National Advisory Committee for Evaluation of Gamma Globulin: globulin in prophylaxis of paralytic poliomyelitis in 1953, J. Amer. med. Ass. 154, 1086, 1954. against poliomyelitis, PoZiomyeIitis, Wld Hlth Org. 26. HAMMON, W. : Passive Immunization Monogr. Ser. No. 26, 1955. Its effects upon perinatal mortality, the 27. LUNDSTROM, R.: Rubella during pregnancy: incidence of congenital abnormalities and immaturity. A preliminary report, Acta Paediut. (Uppsala) 41, 583, 1952. 28. GREENBERG, M., PELLITTERI, 0. and BARTON,J.: Frequency of defects in infants whose mothers had rubella during pregnancy, J. Amer. med. Ass. 165, 675, 1957. Demonstration of neutralizing antibody in gamma 29. KRUGMAN,S. and WARD, R.: Rubella: globulin and re-evaluation of rubella problem, New Engl. J. Med. 259, 16, 1958. 30. Committee on Public Health of New York County Medical Society. Cited by BARONDESS, J. A. : Present status of gamma globulin, Pediatrics 10, 732, 1952. 31. KORNS, R. F. : Prophylaxis of German measles with immune serum globulin, J. infect. Dis. 90, 183, 1952. 32. WARD, H. and PARKER, G. : Passive protection against rubella, Med. J. Aust. 1, 81, 1956. 33. COFFEY, V. P. and JESSOP, W. J.: Rubella and the incidence of congenital abnormalities, Irish .I. med. Sci. 397, 1, 1959. 34. SKINNER, CLIFFORD W., Jr.: The rubella problem, Amer. J. Dis. Child. 101, 78, 1961. of Children, p. 267, C. V. Mosby, St. 35. KRUGMAN, S. and WARD, R.: Infectiozrs Diseases Louis, 1960. vaccinal gamma globulin : 36. KEMPE, C. H., BERGE, T. 0. and ENGLAND,B. : Hyperimmune Source, evaluation, and use in prophylaxis and therapy, Pediatrics 18, 177, 1956. vaccinal gamma globulin 37. ETHERIDGE,J. E., Jr. and WADDELL, W. W., Jr.: Hyperimmune in the treatment and prophylaxis of eczema vaccinatum. A report of three cases, 22.
STOKES, J.,Jr. er al.
Virginia 38. 39.
40. 41. 42. 43. 44. 45.
46. 47. 48.
49. 50.
51.
med. Mth.
87, 386, 1960.
KEMPE, C. H. : Studies on smallpox and complications of smallpox vaccination, Pediawics 26, 176, 1960. Vaccinia immune globulin, Pediatrics 26, 336, 1960. GELLIS, S. S., MCGUINESS, A. C. and PJXERS, M.: A study on the prevention of mumps orchitis with gamma globulin, Amer. J. med. Sci. 210, 661, 1945. MORRIS, D. and MCDONALD, J. C.: Failure of hyperimmune gamma globulin to prevent whooping cough, Arch. Dis. Childh. 32, 163, 1957. MARTIN, C. M., BRONSTEIN,E. and DRAY, S.: Agammaglobulinemia: Clinical Staff Conference at National Institutes of Health, Ann. iniern. Med. 47, 533, 1957. JANEWAY,C. A. and CITL~N, D.: The gamma globulins, Advanc. Pediat. 9, 65, 1957. Council on Pharmacy and Chemistry: Use of immune globulin for treatment of agammaglobulinemia and hypogammaglobulinemia, J. Amer. med. Ass. 162, 117, 1956. FU~HOUSER, W. L.: The use of serum gamma globulin antibodies to control chicken pox in a convalescent hospital for children, .7. Ped&. 32, 257, 1948. HUNNICUT~,T. N., Jr. and BERLIN, I.: Varicella pneumonia, Dis. Chest 32, 101, 1957. LEA, W. A. and TAYLOR,W. B.: Gamma globulin in the treatment of herpes zoster, Texns J. Med. 54, 594, 1958. EPSTEIN, E. and ALLINGTON,H. V.: Treatment of herpes zoster, Arch. Derm. 76, 708, 1957. RUPPE, J. P., Jr., WILSON, E. F., Jr. and WOLINS, W.: Treatment of eczema herpeticum with gamma globulin, Arch. Derm. 76, 572, 1957. TURNER, J. L. and DODSON, H. L.: Use of gamma globulin in chronically ill child, Laryngoscope 67, 1286, 1957. WAISBREN, B. A.: Treatment of bacterial infections with the combination of antibiotics and gamma globulin, Antibiof. and Chemother. 7, 322, 1957.
Press Ltd. Printed in Great Britain
THE USES OF GAMMA GLOBULINS IN THE PROPHYLAXIS OF INFECTION Department
of Microbiology,
ALLANH. LEVY, M.D. The Johns Hopkins University School of Medicine, Baltimore, Md. (Received
20 February
1962)
PASSIVEimmunization has been used since the last decade of the nineteenth century when VON BEHRINGand KITASANO introduced antitoxin for the treatment of diphtheria . Several drawbacks accompanied serum therapy before gamma globulins became available. To obtain antibody concentrations of sufficient potency, it was generally necessary to employ hyperimmune animal serum which commonly caused hypersensitivity reactions to the foreign serum proteins. Serum sickness and anaphylattic shock are still frequent manifestations of treatment with tetanus and diphtheria antitoxin. When convalescent phase whole human serum was employed, there was the danger of transmitting the viruses of infectious hepatitis or serum hepatitis. These disadvantages sharply limited the usefulness of passive immunization. With the exception of the use of tetanus antitoxin for prophylaxis,* serum therapy was limited to the treatment of established life-threatening infections, and the prevention of disease could not be effectively accomplished by passive immunization. The development of efficient techniques for the fractionation of human serum by COHN and his collaborators [2] made available for the first time fractions of human serum containing antibodies concentrated to many times their original titer, and provided in gamma globulin an effective agent for the prophylaxis of many viral diseases. Also, improved virologic methods, mainly the development of tissue culture techniques, facilitated the study of poliomyelitis and other viral diseases. These studies of pathogenetic and immune mechanisms provided a firm basis for the use of gamma globulin in passive immunization against a variety of serious infections. The prolonged immunity following many viral infections is chiefly mediated by serum antibody. Many viral diseases are widely prevalent in the population, and pools of sera from normal adults will contain low levels of antibodies against these viruses. Although the concentration of antibody in normal human serum is too low for therapeutic usefulness, the increased concentration in gamma globulin fmctionated from pooled sera provides an agent with a wide range of effectiveness in prophylaxis. At present, it is known that gamma globulins have protective value against measles, infectious hepatitis, poliomyelitis and, in all probability, rubella. In addition, gamma globulins derived from hyperimmune human sera have been demonstrated to be of value in the prophylaxis and treatment of smallpox and complications of vaccinia, and in the treatment of mumps orchitis and pertussis. *One interesting exception to this, cited by KARSNER and ECKER [l], was the use of diphtheria antibacterial serum for prophylaxis in carriers. The serum was incorporated into lozenges and used locally, but was not effective.
589
590
ALLANH. LEVY
GENERAL PROPERTIES Antibodies against most viruses and bacteria are found in Fraction II of serum treated by the ethanol fractionation procedures developed by Cohn and the Harvard group. However, certain antibodies, although gamma globulins, are separated with Cohn Fraction 111-l and are not present in commercial preparations of gamma globulin, which contain proteins mainly in Fraction II. Two preparations of gamma globulins derived from normal pooled blood are presently available. One is Immune Serum Globulin, U.S.P. (Human); the other is Poliomyelitis Immune Globulin (Human). Both are similar except that batches of the latter must meet a standard established by the National Institutes of Health for Preparations contain about 165 mg of gamma Type II poliomyelitis antibody. globulin per ml of solution; this represents an approximate 25-fold increase of the gamma globulin concentration in normal serum. Gamma globulin is injected intramuscularly or subcutaneously, and should never be administered intravenously. Intravenous injection may cause cardiac arrhythmias, hypotension, and fever. Toxic reactions to gamma globulin administered intramuscularly are uncommon, and, for the most part, not serious. JANEWAY]3] has reported an incidence of side-reactions of 1.2 per cent in a series of patients receiving small intramuscular doses for the prophylaxis of measles. These include local inflammatory responses with pain and tenderness at the site of injection, and mild systemic reactions with malaise, headache, and low-grade fever. Serious reactions are uncommon; among those reported are angioneurotic edema, nephrotic syndrome, neuromyelitis optica, and anaphylactic shock [ 41. One notable advantage of gamma globulin preparations is their freedom from contamination with the hepatitis viruses. This has been demonstrated by abundant clinical data, and has been confirmed in an experimental study by MURRAYand RATNER [5]. Of fifteen volunteers inoculated parenterally with a small dose of infected plasma, four developed serum hepatitis, but no hepatitis developed in five other individuals injected with a larger dose of gamma globulin derived from the same plasma. Since the antibody content of gamma globulin reflects the distribution and concentration of antibody in the blood of the donor populations, it is not surprising that variations in antibody titer occur in different batches of gamma globulin. Gamma globulin prepared from donors in the western United States contains antibody to western, but not to eastern equine encephalomyelitis [6]. However, for measles and infectious hepatitis, the protective effect appears to be much the same in lots of gamma globulin from different geographical areas [7]. On the other hand, the varying efficacy of gamma globulin in the prophylaxis of rubella may well reflect differences in antibody levels in the gamma globulin preparations used. PRINCIPLES OF PROPHYLAXIS The effective use of gamma globulin for prophylaxis must be governed by an understanding of the pathogenesis of the disease in which passive immunization is of value. In many viral diseases especially, the events occurring during the incubation period are critical. After infection occurs, the virus first multiplies at a primary site. In poliomyelitis, this is the gastrointestinal tract; in measles, it is believed to be the
The Uses of Gamma Globulins in the Prophylaxis of Infection
591
respiratory tract. There is usually some dissemination to local lymphatics at this time, but during the early part of the incubation period, multiplication of virus at the primary site produces relatively little tissue damage, and the host is asymptomatic. Later, shortly before the onset of clinical disease, there is a viremia; during this time virus is widely disseminated in those organs where virus multiplication will produce tissue damage and cause the characteristic symptoms of the disease. In paralytic poliomyelitis, for example, virus has reached its highest titer in the central nervous system at the time when the paralytic symptoms of the disease begin. Available evidence indicates that serum antibody neutralizes the virus only when the virus particle is outside the cell and that its damaging effects on a cell are not prevented by antibody after the cell has become infected. To be effective in prophylaxis, antibody must be present in the blood in effective concentrations during the viremic stage. If virus is neutralized in the circulation, spread to distant organs may be eliminated or markedly decreased, and the clinical manifestations of disease prevented or modified. Accordingly, for prophylaxis, gamma globulin should be given early in the incubation period so that a maximum level of antibody may surround the cells at the onset of the viremia. One or two days are required for maximum serum levels to be obtained after intramuscular injection of gamma globulin. Therefore it is essential that gamma globulin be administered as soon after exposure as possible. In infections in which a given dose of gamma globulin may prevent disease, a smaller dose or one given later in the incubation period may result in a modified infection. In this situation, there is often enough replication of the infecting agent to provide a sufficient antigenic stimulus for the concurrent development of persistent active immunity; modification is often preferable to complete prevention. It should be stressed that complete prevention of the spread of virus by passive immunization is probably a rare occurrence. Although an infection may result in no outward signs of disease, there is often some secondary dissemination and minor involvement of ‘target’ organs. Recent studies of patients exposed to infectious hepatitis who received large prophylactic doses of gamma globulin showed that many of them, although completely asymptomatic, had evidence of hepatic involvement demonstrated by liver function tests [ 81. PROPHYLAXIS
OF VIRAL IMMUNE
DISEASE GLOBULIN
WITH
POOLED
Me&es. The prevaIence of measles in the population is so high that until recently, an attack has been considered to be one of the unavoidable inconveniences of childhood. However, the substantial morbidity and the not inconsequential mortality that are associated with this illness and its complications should not be overlooked. Measles encephalitis, although rare, almost always leaves serious sequelae. In debilitated individuals or in groups where proper medical care is not available, measles represents a significant threat. An
592
ALLANH. LEVY
reactions were sufficiently numerous and severe to limit the usefulness of the vaccine [ 111. Recent reports by MCCRUMBet al. [ 121, REILLY and his associates [13], and STOKESand his co-workers [ 141 indicate that the clinical manifestations caused by live measles-virus vaccine were markedly lessened by the concurrent administration of gamma globulin without reduction in active immunization and that effective resistance to naturally-occurring measles was induced in those who had been immunized with vaccine and gamma globulin [ 141. At present, using gamma globulin alone, modification rather than complete prevention should be the aim in most circumstances. Active immunity will develop following the modified illness. It is recommended that all susceptible children should receive a modifying dose of gamma globulin after exposure to measles. The modified disease is usually characterized by a prolonged incubation period and milder symptomatology than the natural illness. There is considerable variation in the modified illness; rash, conjunctivitis, headache or malaise may still occur. The incidence of complications is very much less than in the natural disease, and the incidence of measles encephalitis may be lower [ 151. Modification is most consistently achieved by a dose of 0.02 ml per pound of body weight, administered during the first six days after exposure [ 161. After the sixth day, the recommended dose for modification or prevention should be doubled. Gamma globulin sometimes has a modifying effect if administered as late as the appearance of Koplik’s spots, but is not effective after the appearance of the exanthem [ 171. The large majority of patients to whom modifying doses of gamma globulin are administered will develop active immunity similar to that following natural infection [ 181. Prevention, rather than modification, is recommended in special circumstances. Complete prevention is recommended for infants and children up to three years of age because the highest mortality occurs in this age group. Prophylaxis is also advisable for susceptible exposed pregnant women in whom measles virus infection has been reported to be associated with premature labor and abortion [19]. Preventive doses should be administered to patients with a debilitating illness and to those whose social or economic status is such that adequate care during illness cannot reasonably be anticipated. The dose for prevention is 0.1 ml per pound of body weight, administered as soon as possible after exposure. Prophylactic doses are also warranted for those with no prior history of measles who are exposed in hospital wards or in military establishments. After a case of measles is detected in a hospital ward, new patients may still be admitted if all susceptible old patients and all new patients admitted for the following three weeks are given 0.1 ml of gamma globulin per pound of body weight. If further secondary cases occur, gamma globulin should be readministered within three weeks of the first dose, and new admissions should continue to receive prophylactic injections until at least three weeks after the last case [7]. Infectious hepatitis. Since the report in 1945 by STOKESand NEEFE [20] that the clinical manifestations of infectious hepatitis could be prevented by the administration of gamma globulin, prevention of this disease has constituted one of the most important uses of this agent. A number of studies has confirmed and extended these early observations; gamma globulin has been demonstrated to be effective in controlling institutional epidemics [8] as well as sharply reducing the frequency of secondary cases in family outbreaks [ 21 I.
The Uses of Gamma Globulins in the Prophylaxis of Infection
593
Prolonged immunity against infectious hepatitis has been observed in institutionalized patients who received prophylactic doses of gamma globulin as high as 0% ml per pound of body weight [22]. In institutional epidemics, reinfection during the time of waning passive immunity might be the mechanism responsible for the development of persistent resistance. It remains to be established whether large prophylactic doses produce concurrent passive and active immunity in noninstitutionalized individuals. Some modification of hepatitis results from a dose of gamma globulin as low as 0.005 ml per pound of body weight, and individuals infected with the virus who receive this dose apparently develop active immunity. These patients will frequently develop an anicteric illness with nausea, vomiting, and chemical abnormalities of liver function. This low dose is not recommended. It is suggested by the American Academy of Pediatrics that susceptible children should receive 0.04 ml per kg of body weight after exposure [ 231. Higher doses, up to 0.1 ml per kg, may be necessary for adults, in whom infectious hepatitis often runs a more severe course. The higher dose should be used in pregnant females in whom hepatitis is likely to be particularly severe, in debilitated patients, and during military or hospital outbreaks. If a patient is re-exposed to infectious hepatitis more than 6 or 8 weeks after receiving gamma globulin prophylaxis, another dose of gamma globulin should be administered. A more definitive dosage schedule must await further epidemiologic study and the development of appropriate virologic techniques for determining infection rates and immune status. Poliomyelitis. The administration of gamma globulin during the first five to seven days after exposure to polio virus would appear to reduce the incidence and severity of paralysis [ 241. The availability of live virus and formalin-inactivated virus vaccines should lessen the need for passive immunization against this disease. However, many persons in this country are still not immunized, and local outbreaks continue to occur. Vigorous community-wide vaccination programs hlave been suggested as the most effective means of terminating such epidemics, and live virus vaccine is currently being stockpiled for this purpose.
The routine use of gamma globulin for prophylaxis against poliomyelitis is not recommended by the American Academy of Pediatrics [ 231. Passive immunization of all susceptible persons in an epidemic situation is impractical. Futhermore, although the administration of gamma globulin to family contacts of known cases of poliomyelitis may prevent an occasional secondary paralytic case [ 251, the number of individuals that will benefit is sh,arply limited. Sixty per cent of secondary cases occur within five days after the primary case; gamma globulin administered late in the incubation period will be of little value to the majority of family contacts. HAMMON[26], however, is of the opinion that susceptible contacts in institutional and summer camp outbreaks should receive gamma globulin. In addition, he suggests that non-immunized or inadequately immunized family contacts should also receive gamma globulin early in the outbreak. Pregnant women also appear to be more vulnerable to paralysis [7] and should be considered as candidates for passive immunization. When gamma globulin is administered for prophylaxis of paralytic poliomyelitis, the dose is 0.14 ml per pound of body weight.
594
AUAN H.
LEVY
The use of gamma globulin in conjunction with live virus vaccination is under investigation, and no recommendation for its use in this fashion can be made presently. Rubella. German measles, ordinarily a benign infectious disease in children, becomes a problem when it occurs during the first four months of pregnancy. It has been conclusively established that there is a high percentage of stillbirths, neonatal deaths, and congenital abnormalities in the offspring of women contracting rubella in the first four months of pregnancy [27, 281. The virus causing German measles has not been cultivated in the laboratory; therefore, rubella antibody levels in gamma globulin preparations cannot be measured. Evaluation of the efficacy of gamma globulin preparations in preventing German measles has been mainly based on epidemiologic observations, although KRUGMANand WARD [ 291 were able to demonstrate the presence of antibody in gamma globulin by its capacity to neutralize virus obtained from a known case and administered to human volunteers. Controlled studies have shown that protection after exposure can be achieved with gamma globulin, if the injection is given early in the incubation period. In one study ( 301, protection was achieved with a dose of 0.1 ml per pound of body weight. In some individuals, German measles developed within three days after gamma globulin administration, indicating failure of protection if passive immunization is withheld until late in the incubation period. The incubation period of rubella varies from ten to twenty-one days, and gamma globulin should be administered within a week after exposure. Some batches of gamma globulin have had no protective effect ]31]. This is probably due to variations in concentration of rubella antibody in different pools of blood. More satisfactory and consistent results could be expected with gamma globulin derived from serum of convalescent persons, which would provide higher and more uniform concentrations of antibody. WARD and PARKER [32], working in Australia, have reported good results with such a preparation. Hyperimmune rubella globulin is not commercially available at present. Since rubella is a benign disease except during pregnancy, gamma globulin is not indicated at other times. It has been shown by GELLIS [ 171 that a dose of 20-30 ml of gamma globulin reduces the incidence of clinically apparent German measles in pregnant women exposed to this disease. However, it must be borne in mind that lack of obvious disease in the mother is no guarantee that the fetus will be spared from infection. COFFEY and JESSOP have observed that women who were exposed to, but did not develop rubella, produced offspring with abnormalities at a rate that was 2.5 times as great as that seen in the general populaticn [33]. The extent to which gamma globulin protects the fetus from rubella is not yet definitely established; hopefully, high doses may prove to be protective to the fetus as well as the mother. Although consistent protection will not always result, it is recommended that susceptible women exposed to rubella during the first four months of pregnancy should receive 20 ml of gamma globulin as soon as possible after exposure. HYPERIMMUNE GLOBULIN PREPARATIONS In a variety of infectious diseases, gamma globulin derived from pools of normal sera has been of limited value because of insufficient antibody content. In several
The Uses of Gamma Globulins
in the Prophylaxis
of Infection
595
instances, however, gamma globulins fractionated from pooled sera of convalescent persons have been of demonstrated efficacy. Such preparations may well have wider applicability as they become more readily available. Smallpox and complications of vaccination. Gamma globulin prepared from sera of individuals bled 4-8 weeks after immunization with vaccinia has been demonstrated to be an effective adjunct to vaccination in the prevention of smallpox. Tt is also of value in the management of the serious complications of vaccination. In many individuals exposed to smallpox, initial vaccination, as well as revaccination, does not produce a rapid enough immune response to prevent the development of smallpox. However, in exposed individuals who received a combination of vaccination and vaccinia immune globulin (VIG), there was a lower incidence of smallpox and a lower mortality than in a group treated with vaccination alone. VIG did not impair the development of an active immune response. The dosage employed was 0.2 ml per pound of body weight for adults, 0.05 ml per pound for children, and 0.1-0.2 ml per pound for infants under one year of age [ 361. VIG has been demonstrated to be of value in the prevention and treatment of eczema vaccinatum [36-381. If it is imperative to vaccinate a child with eczema, the concurrent use of hyperimmune gamma globulin is recommended. VlG is also indicated when a child suffering from eczema is intimately exposed to siblings or others recently vaccinated. and when vaccination is inadvertently performed on an individual with large areas of burned or denuded skin. Recommended dosage is from 0.6 to 1.0 ml per kg of body weight. VIG has alsc been effective in halting the appearance of new lesions of generalized vaccinia [ 381. VIG is presently distributed by the American Red Gross. Because supplies are limited, a panel of consultants has been named to evaluate requests from physicians for VIG. Full details of the distribution program have been published recently 1391. Mumps. Immune globulin from pooled normal blood does not prevent mumps. However, globulin derived from serum of persons convalescing after mumps has been effective in reducing the incidence of orchitis in adult males when administered within the first day after onset of parotitis [40]. Its effectiveness in preventing mumps itself has not been shown in a controlled study. Grchitis in adult males rarely leads to sterility, but 5-7.5 ml of mumps immune globulin may be administered in an effort to prevent this complication. Except under unusual circumstances, passive immunization is not indicated in healthy children. Pertussis. A preparation of pertussis hyperimmune gamma globulin is available commercially. Although believed to be useful in the therapy of severe whooping cough, its value as a prophylactic agent is in doubt. In a controlled study, MORRIS and MCDONALD[41] showed that the incidence of disease in children exposed to pertussis was not significantly lower in those receiving hyperimmune globulin than in a control group. REPLACEMENT THERAPY IN AGAMMAGLOBULINEMIA Periodic injections of gamma globulin have been found beneficial in the prophylaxis of recurrent bacterial infection in patients suffering from either congenital or acquired agammaglobulinemia or hypogammaglobulinemia. Plasma levels should be maintained at levels no lower than 150 mg of pooled globulin per 100 ml of plasma. In initiating therapy, 0.45 ml of gamma globulin per pound of body weight
596
ALLAN
H.
LEVY
should be given and repeated a few days later. Subsequent maintenance can usually be achieved by monthly injection of 0.3 to 0.45 ml per pound of body weight. Dosage may vary considerably from patient to patient, and it is advisable to check the level with a laboratory test. In some patients gamma globulin alone is sufficient for the prophylaxis of infections; in others, a combination of gamma globulin and antibiotics may be necessary. Several articles deal in greater detail with the management of agammaglobulinemia [42-44]. OTHER
USES
OF
GAMMA
GLOBULIN
The prevention and treatment of a number of other infectious diseases have been attempted with gamma globulin from pooled normal sera. While some favorable reports have been published, there is still insufficient evidence of beneficial effect to warrant the routine use of gamma globulin for the following conditions: In chickenpax, gamma globulin was unsuccessfully employed by GROSSand his. associates [7] in an effort to control the spread of varicella in hospital wards. A favorable report [45] indicating a prophylactic effect was not the result of a controlled study, and is considered inconclusive. Gamma globulin may be of value in the treatment of severe chickenpox pneumonia, especially in adults 1461, but this has not been definitely proved. Gamma globulin has been suggested for the treatment of herpes zoster, an illness caused by a virus identical with, or closely related to, the varicella agent. In an uncontrolled study, LEA and TAYLOR [47] noted improvement in 11 of 17 patients receiving gamma globulin and were impressed with the value of this treatment. Another study [48] has indicated that gamma globulin is without effect. The evaluation of response to any treatment of herpes zoster is notoriously difficult; gamma globulin for therapy of this disease cannot be recommended. Therapy with immune globulin has been reported effective in a case of eczema herpeticum, a serious manifestation of herpes simplex infection in children [49]. It has been claimed that some infants and children with persistent or recurrent viral upper respiratory infections benefit from the use of gamma globulin [ 501, but these observations have not been verified in controlled studies. Bacterial infections. There has been suggestive evidence that gamma globulin, in combination with antibiotics, may be of value in the treatment of refractory cases of chronic osteomyelitis and chronic pyelonephritis [ 5 1] . However, as heretofore, reliance should be placed upon the use of specific antimicrobials and appropriate local measures rather than gamma globulin. SUMMARY
The gamma globulin fraction of pooled normal human -era has a wide range of usefulness in the prophylaxis of many infectious. diseases. Hyperimmune human globulin preparations ,are effective against certain other illnesses in which globulins pooled from normal sera contain insufficient antibody. In general, gamma globulins are most effective in diseases with a relatively long period of incubation. If immune globulins are administered early in the incubation period, there will be sufficiently high levels of circulating antibody to neutralize virus during the viremic phase, and dissemination of virus to distant organs will be limited, resulting in prevention or
The Uses of Gamma Globulins
in the Prophylaxis
of Infection
597
modification of the disease. Both dose and time of administration are important in determining the effect of passive immunization. In most circumstances, the optimal dose of gamma globulin is one which will modify, rather than completely prevent, the disease and will allow the concurrent development of active immunity. Active immunization with available viral vaccines provides a far more satisfactory basis for preventing infection.
REFERENCES KARSNER,H. T. and ECKER, E. E.: The Principles of Immunology,
p. 262, J. P. Lippincott, Philadelphia, 1921. 2. COHN, E. J., ONCLEY, .I. L., STRONG,L. E., HUGHES, W. L., Jr. and ARMSTRONG,S. H.: Chemical, clinical and immunologic studies on the products of human plasma fractionation. I. The characterization of the protein fractions of human plasma, J. c&z. Invest. 23, 417, 1944. Advanc. intern. Med. 3, 295, 1949. 3. JANEWAY,C. A.: Plasma fractionation, to gamma globulin: Case report, J. med. Ass. Ala. 23, 4. OWINGS, W. J. B.: Hypersensitivity 74, 1953. 5. MURRAY,R. and RATNER,F. : Safety of immune serum globulin with respect to homologous serum hepatitis, Proc. Sot. exp. Biol. N.Y. 83, 554, 1953. 6. YANKAUER, A. : Discussion of conference on therapy. Therapeutic uses of gamma globulin, Amer. J. Med 5,590, 1948. 7. GROSS, P. A. M., GITLIN, D. and JANEWAY,C. A.: The gamma globulins and their clinical significance. IV. Therapeutic uses of gamma globulin, N. Engl. J. Med. 260, 170, 1959. a. KRUGMAN, S., WARD, R., GILES, J. P. and JACOBS, A. M.: Infectious hepatitis. Studies on the effect of gamma globulin and on the incidence of inapparent infection, J. Amer. med. Ass. 174, 823, 1960. 9. ENDIXRS,J. F., KATZ, S. L., MILOVANOVIC,M. V. and HOLLOWAY,A. : Studies on attenuated measles-virus vaccine. I. Development and preparation of vaccine: Technics for assay of effects of vaccination, N. Engl. J. Med. 263, 153, 1960. 10. KRUGMAN,S., GILES, J. P. and JACOBS,A. M. : Studies of attenuated measles-virus vaccine. VI. Clinical, antigenic, and prophylactic effects of vaccine in institutionalized children, N. Engl. .I. Med. 263, 174, 1960. vaccination against measles. II. Tests of live 11. HOEKENGA, M. T. et al. : Experimental measles and live distemper vaccine in human volunteers during measles epidemic in Panama, J. Amer. med. Ass. 173, 868, 1960. measles-virus vaccine. III. 12. MCCRUMB, F. R., Jr. et al.: Studies with live attenuated Development of practical method for large-scale immunization, Amer. J. Dis. Child. 101, 1.
708, 1961.
13. 14. 15. 16. 17. 18. 19. 20. 21.
REILLY, C. M., STOKES, J., Jr., BUYNAK,E!. B., GOLDNER, H. and HILLEMAN,M. R. : Living attenuated measles-virus vaccine in early infancy: Studies of role of passive antibody in immunization, N. Engl. J. Med. 265, 165, 1961. STOKES, J., Jr. et al.: Efficacy of live, attenuated measles-virus vaccine given with human immune globulin. A preliminary report, N. Engl. J. Med. 265, 507, 1961. GREENBERG,M., PELL~~TERI,0. and EISENSTEIN, D.: Measles encephalitis. I. Prophylactic effect of gamma globulin, J. Pediar. 46,642, 1955. KRUGMAN, S. and WARD, R.: Infectious Diseases of Children, p. 161, C. V. Mosby, St. Louis, 1960. GELLIS, S. S. : Use of gamma globulin in prevention of various diseases, Mississippi Do@. 32, 65, 1954. BIVINGS, L. : Gamma globulin dosage and measles control : Report of 188 cases, J. Pediat. 43,401, 1953. pregnancy : Report of 24 cases with 3 instances of DYER, I. : Measles complicating congenital measles, Sth. med. J. (Bgham. Ala.) 33,60, 1940. STOKES, J., Jr. and NJZEFE,J. R. : The prevention and attenuation of infectious hepatitis by gamma globulin. Preliminary note, J. Amer. med. Ass. 127, 144, 1945. BROOKS, B. F., HSIA, D. Y-Y. and GELLIS, S. S. : Family outbreaks of infectious hepatitis: Prophylactic use of gamma globulin, N. Engl. J. Med. 249, 58, 1953.
ALLAN H. LEVY
598
: Infectious hepatitis. Length of protection by immune serum globulin (gamma globulin) during epidemics, J. Amer. med. Ass. 147, 714, 1951. 23. Reoort of the Committee on the Control of Infectious Diseases, American Academy of Pediatrics, pp. 22-23, 1961. agent for 24. HAMMON, W. er al.: Evaluation of Red Cross gamma globulin as prophylactic Poliomyelitis, J. Amer. med. Ass. 156,21, 1954. Evaluation of gamma 25. National Advisory Committee for Evaluation of Gamma Globulin: globulin in prophylaxis of paralytic poliomyelitis in 1953, J. Amer. med. Ass. 154, 1086, 1954. against poliomyelitis, PoZiomyeIitis, Wld Hlth Org. 26. HAMMON, W. : Passive Immunization Monogr. Ser. No. 26, 1955. Its effects upon perinatal mortality, the 27. LUNDSTROM, R.: Rubella during pregnancy: incidence of congenital abnormalities and immaturity. A preliminary report, Acta Paediut. (Uppsala) 41, 583, 1952. 28. GREENBERG, M., PELLITTERI, 0. and BARTON,J.: Frequency of defects in infants whose mothers had rubella during pregnancy, J. Amer. med. Ass. 165, 675, 1957. Demonstration of neutralizing antibody in gamma 29. KRUGMAN,S. and WARD, R.: Rubella: globulin and re-evaluation of rubella problem, New Engl. J. Med. 259, 16, 1958. 30. Committee on Public Health of New York County Medical Society. Cited by BARONDESS, J. A. : Present status of gamma globulin, Pediatrics 10, 732, 1952. 31. KORNS, R. F. : Prophylaxis of German measles with immune serum globulin, J. infect. Dis. 90, 183, 1952. 32. WARD, H. and PARKER, G. : Passive protection against rubella, Med. J. Aust. 1, 81, 1956. 33. COFFEY, V. P. and JESSOP, W. J.: Rubella and the incidence of congenital abnormalities, Irish .I. med. Sci. 397, 1, 1959. 34. SKINNER, CLIFFORD W., Jr.: The rubella problem, Amer. J. Dis. Child. 101, 78, 1961. of Children, p. 267, C. V. Mosby, St. 35. KRUGMAN, S. and WARD, R.: Infectiozrs Diseases Louis, 1960. vaccinal gamma globulin : 36. KEMPE, C. H., BERGE, T. 0. and ENGLAND,B. : Hyperimmune Source, evaluation, and use in prophylaxis and therapy, Pediatrics 18, 177, 1956. vaccinal gamma globulin 37. ETHERIDGE,J. E., Jr. and WADDELL, W. W., Jr.: Hyperimmune in the treatment and prophylaxis of eczema vaccinatum. A report of three cases, 22.
STOKES, J.,Jr. er al.
Virginia 38. 39.
40. 41. 42. 43. 44. 45.
46. 47. 48.
49. 50.
51.
med. Mth.
87, 386, 1960.
KEMPE, C. H. : Studies on smallpox and complications of smallpox vaccination, Pediawics 26, 176, 1960. Vaccinia immune globulin, Pediatrics 26, 336, 1960. GELLIS, S. S., MCGUINESS, A. C. and PJXERS, M.: A study on the prevention of mumps orchitis with gamma globulin, Amer. J. med. Sci. 210, 661, 1945. MORRIS, D. and MCDONALD, J. C.: Failure of hyperimmune gamma globulin to prevent whooping cough, Arch. Dis. Childh. 32, 163, 1957. MARTIN, C. M., BRONSTEIN,E. and DRAY, S.: Agammaglobulinemia: Clinical Staff Conference at National Institutes of Health, Ann. iniern. Med. 47, 533, 1957. JANEWAY,C. A. and CITL~N, D.: The gamma globulins, Advanc. Pediat. 9, 65, 1957. Council on Pharmacy and Chemistry: Use of immune globulin for treatment of agammaglobulinemia and hypogammaglobulinemia, J. Amer. med. Ass. 162, 117, 1956. FU~HOUSER, W. L.: The use of serum gamma globulin antibodies to control chicken pox in a convalescent hospital for children, .7. Ped&. 32, 257, 1948. HUNNICUT~,T. N., Jr. and BERLIN, I.: Varicella pneumonia, Dis. Chest 32, 101, 1957. LEA, W. A. and TAYLOR,W. B.: Gamma globulin in the treatment of herpes zoster, Texns J. Med. 54, 594, 1958. EPSTEIN, E. and ALLINGTON,H. V.: Treatment of herpes zoster, Arch. Derm. 76, 708, 1957. RUPPE, J. P., Jr., WILSON, E. F., Jr. and WOLINS, W.: Treatment of eczema herpeticum with gamma globulin, Arch. Derm. 76, 572, 1957. TURNER, J. L. and DODSON, H. L.: Use of gamma globulin in chronically ill child, Laryngoscope 67, 1286, 1957. WAISBREN, B. A.: Treatment of bacterial infections with the combination of antibiotics and gamma globulin, Antibiof. and Chemother. 7, 322, 1957.