HAMILTON AND IBER VS GINSBERG fect in p r e v e n t i n g d i s e a s e w h e r e t h e r e has b e e n a large i n o c u l u m . U n t i l m o r e c o n c l u s i v e d a t a is in, s t a n d a r d g a m m a g l o b u l i n should be u s e d o n l y in v e r y select c a s e s in w h i c h t h e r e w a s a small inoculum.
REFERENCES 1. Grady GF: Passive immunization against viral hepatitis-status and prospects. Am J Med Sci 270:36%374, 1975 2. Surgenor DMacN, Thomas CC, Conrad MF, Friedenwald WT, Grady GF, Hamilton M, Mosely JW, Prince AM, Stengle JM: Clinical trials of hepatitis B immune globulin-development of policies and materials for the 1972=1975studies sponsored by the National Heart and Lung Institute. N Engl J Med 293:1060-1062, 1975 3. Schweitzer IL: Vertical transmission of the hepatitis B surface antigen. Am J Med Sci 270:287-291, 1975 4. Discussion: Viral hepatitis epidemiology. Am J Med Sci 270:31%325, 1975 5. Kohler PF, Dalvis RJ, Menill PA, Bowes WA: Prevention of chronic neonatal hepatitis B virus infection with antibody to the hepatitis B surface antigen. N Engl J Med 291:13781380, 1974 6. Grady GF, Lee VA: Prevention of hepatitis from accidental exposure among medical workers. N Engl J Med 293:10671069, 1975 7. Seeff LB, other VA Cooperative Groups Study: Efficacy of hepatitis B immune serum globulin after accidental exposure. Lancet 2:93%941, 1975 8. Prince AM, Szmuness W, Mann MK, Vyas GN, Grady GF, et al: Hepatitis B "immune" globulin: Effectiveness in prevention of dialysis-associated hepatitis. N Engl J Med 293:1063-1067, 1975 9. Courouce-Pauty AM, Delons S, Soulier JP: Attempt to prevent hepatitis by using specific anti-HB~ immunoglobulin. Am J Med Sci 270:375-383, 1975 10. Ginsberg A: Refer to accompanying article
11. Cooperative Study: Prophylactic gamma globulin for prevention of endemic hepatitis: Effects of US gamma globulin upon the incidence of viral hepatitis and other infectious diseases in US soldiers abroad. Arch Int Med 128:723-738, 1971 12. Szmuness W, Prince AM, Goodman M, et al: Hepatitis B immune serum globulin in prevention of nonparenterally transmitted hepatitis B. N Engl J Med 290:701-706, 1974 13. Mosley JM, Edwards VM, Casey C, Redeker A, White E: Hepatitis B infection in dentists. N Engl J Med 293:72%734, 1975 14. Hoofnagle JH, Gerety RJ, Barker LF: Antibody to hepatitis B core antigen. Am J Med Sci 270:17%187, 1975 15. Gocke DJ: Extrahepatic manifestations of viral hepatitis. Am J Med Sci 270:4%52, 1975 16. Redeker AG, Mosley JW, Gocke DJ, McKee AP, Pollack W: Prophylactic hepatitis B immune globulin for spouses exposed to hepatitis B. N Engl J Med 293:1055-1059, 1975 17. Editorial: Specific immunoglobulin in prevention of hepatitis B. Lancet 2:1132-1133, 1975 18. Syndman DR, Bryan JA, Dixon RE: Prevention df nosocomial viral hepatitis', Type B (Hepatitis B). Ann Intern Med 83:838-845, 1975 19. Grady G: Passive immunizationagainst viral hepatitis. Symposium in viral hepatitis, National Academy of Science, March 17-19, 1975. Am J Med Sci (in press) 20. Bruguera M, Borsh J, et al: Familial clustering of hepatitis B antigen: A study in relatives of patients with liver disease and hepatitis B antigenemia. Br Med J 00:11-13, 1974 21. Kaboth UJ: Viral hepatitis. Clin Gastroenterol 0:3, 1974 22. Iwarson S, Ahlmen J, Eriksson E, et al: Hepatitis B immune serum globulin and standard gamma globulin in prevention of hepatitis B infection among hospital staff: A preliminary report. Am J Med Sci 270:385-389, 1975 23. Alter J, Holland PV, Purcell RH, et al: Posttransfusion hepatitis after exclusion of commercial and hepatitis B antigen positive donors. Ann Intern Med 77:691-699, 1972 24. Mosley JM: The epidemiology of viral hepatitis: An overview. Am J Med Sci 270:253-270, 1975
The Use of Standard Gamma Globulin for the Prevention of Hepatitis B A L L E N L. G I N S B E R G , M D
Assistant Professor of Medicine, George Washington University School of Medicine, Washington, D.C.
S t a n d a r d i m m u n e s e r u m g l o b u l i n (ISG) s h o u l d rout i n e l y be a d m i n i s t e r e d to h o u s e h o l d a n d i n t i m a t e c o n t a c t s of p a t i e n t s with viral hepatitis. R e c e n t studies h a v e i n d i c a t e d that s t a n d a r d I S G is likely to b e effective a g a i n s t b o t h virus A a n d v i r u s B (1). Alt h o u g h the risk of c o n t r a c t i n g h e p a t i t i s B b y p e r s o n -
404
al c o n t a c t a p p e a r s to b e less t h a n the risk of c o n t r a c t i n g h e p a t i t i s A , t h e r e is a definite risk (2--4). F u r t h e r m o r e , d e b i l i t y , c h r o n i c i t y , a n d m o r t a l i t y are all higher in i n f e c t i o n s with the h e p a t i t i s B virus. T h e p o t e n t i a l b e n e f i t for the few p a t i e n t s in w h o m clinical hepatitis B m a y b e p r e v e n t e d is great, while
DigestiveDiseases, Vol.21, No. 5 (May1976)
THE GAMMA GLOBULIN CONTROVERSY the likelihood of serious side effects from the administration o f l S G is almost nonexistent (1). The recommendations of the Public Health Service Advisory Committee on Immunization Practices state that standard ISG is not of value in the prevention of hepatitis B and should not be administered to persons exposed to hepatitis B (5). This statement does not take cognizance of the epidemiologic data derived since the association of Australia antigen (HBsAg) with hepatitis B infection (1, 6). The ramifications of this near-sighted view are dangerous. Ten years ago, household contacts of sporadic cases of viral hepatitis received ISG. Now, because of HBsAg testing, and the PHS recommendations, ISG is withheld from these same individuals. The results of this policy are illustrated in the following three true case histories. Case 1 is the roommate of a patient who was recently hospitalized for hepatitis B. Prior to the discovery of HBsAg it is likely that case 1 would have received ISG. However, in 1974, case 1 did not receive ISG on the basis of the PHS recommendations. Eight weeks after the roommate was hospitalized, case 1 also developed acute hepatitis B. Case 1 recovered, but is now a chronic carrier of HBsAg and may or may not have chronic hepatitis. The husband of case 2 was hospitalized with hepatitis B. ISG was not administered to case 2. Eight weeks later case 2 developed fulminant hepatitis and died (2). Patient 3 is a dentist. The dentist was just informed that one of his patients who had had a tooth extraction 48 hours previously was now hospitalized with hepatitis B. The dentist wishes to know whether or not he should receive ISG. The Public Health Service Advisory Committee on Immunization Practices does not recommend ISG in the prophylaxis of hepatitis B. You are the physician. You are aware that if the dentist were to become a chronic carrier of HB~Ag, the results could be catastrophic (7, 8). What should you do? The arguments and data which should allow you to arrive at an informed decision follow. For over three decades the term '~ hepatitis" has been used interchangeably with hepatitis A, while the term "serum hepatitis" has been used interchangeably with hepatitis B. The use of terms implying specific routes of virus exposure to connote particular viral strains has proved unfortunate. The development of tests for the detection of HBsAg has allowed the differentiation of virus B infection from infections with other hepatitis viruses. Digestive Diseases, Vol. 21, No. 5 (May 1976)
The use of this epidemiologic tool has established that hepatitis B is responsible for many sporadic cases of hepatitis in which the route of exposure is nonparenteral or inapparent. Three large studies have demonstrated that 22-55% of endemically derived cases of hepatitis are positive for HBsAg (1, 2, 9). There is evidence for the sexual transmission of hepatitis B (2, 3), and hepatitis B has now been implicated in at least one epidemic of "infectious hepatitis" (10). These findings are in accord with the observations that hepatitis B is endemic in some institutions for the retarded such as Wiilowbrook (New York) where good sanitation is difficult to maintain (11). It has also become apparent that many cases of posttransfusion hepatitis, in which the route of exposure is parenteral and the viral dosage massive, are caused by viruses other than the hepatitis B virus (12). Early studies demonstrated that ISG was effective in the prevention of "infectious hepatitis" and ineffective in the prevention of "serum hepatitis." On the basis of these studies it was assumed that ISG was effective against virus A and ineffective against virus B. In the light of current epidemiologic data, this assumption may not be valid. Standard 1SG is effective in the prevention or attenuation of viral hepatitis when the route of virus administration is nonparenteral or inapparent and the exposure dosage is small. This was first demonstrated by Stokes and Neefe (13) and soon confirmed by Gellis et al (14) and Havens and Paul (15). In these early studies epidemics were curtailed through the administration of ISG, and it is quite likely that these epidemics were caused by the hepatitis A viIns.
Krugman et al (16) in studies performed at Willowbrook showed that administration of standard ISG could virtually eliminate the occurrence of icteric hepatitis in newly admitted children. Of 635 newly admitted children who received 0.06 ml of ISG per pound only one case of icteric hepatitis developed during a 5-month period. This contrasted with 31 icteric cases observed in 636 control children. These data were widely interpreted as demonstrating that ISG was effective in preventing or attenuating "infectious hepatitis." The almost complete prevention of icteric hepatitis by high doses of ISG which was reported at Willowbrook where both virus A and virus B are highly endemic should suggest the probability that there was protection against both viral strains. Indeed the endemicity of hepatitis B at Willowbrook has been used as ajusti-
405
HAMILTON
AND
IBER VS GINSBERG
TABLE 1. EFFICACY OF GAMMA GLOBULIN IN HEPATITIS B
Author Ginsberg et al (1) Szmuness et al (6) Redeker et al (19)
Type o f study Endemic hepatitis B in soldiers Endemic hepatitis B in institutionalized children Sexual exposure to hepatitis B
Seeff et al (20)
Needle stick
Grady et al (21)
Needle stick
Prince et al (23)
Dialysis patients (? parenteral exposure) Dialysis staff (? nonparenteral exposure) Dialysis staff
Prince et al (23) Couroucr-Pauty (24)
Gamma globulin
Controls
Standard ISG
Albumin placebo
Yes
Std ISG
Uninoculated controls
Yes
HBIg HBIg HBIg Std ISG HBIg Std ISG HBIg Std ISG HBIg Std ISG HBIg
Placebo globulin devoid of antiHB~ None None None None Uninoculated controls
Effeetiveness
Yes Yes* ? Probable ? Probable ? Probable ? Probable Unknown? Unknown UnknownS: Unknown Yes
*Standard ISG was not evaluated. ?HBIg reduced the incidence of hepatitis B at 8 months. At 12 months, however, the differences between HBIg and Std ISG were not significant. ~/Differences between HBIg and Std ISG were not significant at either 8 or 12 months.
fication for the experimental induction of hepatitis B infection in humans at this institution (11). Numerous controlled studies to evaluate the efficacy of conventional ISG in the prevention of endemically derived hepatitis have been conducted but only two have utilized HBsAg testing. The first was a study performed in approximately 100,000 soldiers stationed in Korea(l). Soldiers received coded injections of 2, 5, or 10 ml of ISG or placebo in a random manner. The ISG used consisted of two lots with anti-HB~ titers of 1 : 10 and 1 : 160 as determined by radioimmune assay and titers of 1 : 4 and 1 : 16 as determined by passive hemagglutination (17). ISG in 5 and 10 mt doses afforded significant protection against endemically derived icteric hepatitis B for approximately 6 months. Only three patients who had received either 5 or 10 ml of gamma globulin within six months developed hepatitis B whereas there were 20 hepatitis B patients among those who were injected with the placebo solutions (P < 0.01). ISG was also effective for the same period of time in the prevention of icteric non-B hepatitis. The second study was performed in three institutions for the mentally retarded (6). In this study a lower incidence of anicteric hepatitis B was ob-
406
served in children receiving either conventional or hyperimmune globulin than in uninoculated controis. More importantly, no children receiving ISG developed persistent antigenemia, whereas 13.5% of uninoculated controls became chronic antigen carriers. There was no difference between standard and hyperimmune globulin. Iwarson et al (18) recently presented preliminary data to the National Academy of Science based on a controlled study of dialysis unit patients and personnel. In this study the incidence of clinical hepatitis B in untreated patients and personnel was compared with the incidence of hepatitis B in individuals treated with either standard or hyperimmune globulin. Both types of ISG appeared equally effective, and there were no cases of persistent antigenemia in ISG recipients. Seroconversion (the development of anti-HBs) in four recipients of standard ISG and in none of the recipients of hyperimmune globulin suggested that low levels of antibody present in standard ISG may favor passive-active immunization. Caution must be exercised in interpretation of new data evaluating hyperimmune globulin. Redeker et al (19) studied sexual contacts of patients with hepatitis B. They compared hyperimmune Digestive Diseases, Vol. 21, No. 5 (May 1976)
THE GAMMA GLOBULIN CONTROVERSY globulin to a true placebo globulin devoid of antiHBs. The placebo was manufactured by fractionation of plasma from individuals negative for antiHBs. Under the conditions of this experiment only 1 of 25 exposed individuals that received hyperimmune globulin developed hepatitis whereas 9 of 33 patients that received the placebo became infected. No information about the effectiveness of standard ISG which normally contains modest amounts of anti-HB~ can be derived from this study. In separate investigations Seeff et al (20) and Grady and Lee (21) studied individuals stuck by needles from patients positive for HB~Ag. The efficacy of hyperimmune and standard globulins was evaluated. Unfortunately there were no control groups. Of the exposed individuals, 93-95% were protected from acute hepatitis B by both globulin preparations. No recipient of either type of globulin became a chronic carrier of HB~Ag. Approximately 30% of recipients of standard ISG developed antiHBs presumably by passive-active immunization (20). The hepatitis which developed in recipients of hyperimmune globulin had a very long incubation period, and several of these individuals were thought to have been reexposed. These cases, however, cannot legitimately be excluded. There is no reason to believe that recipients of hyperimmune globulin should be more likely than recipients of standard ISG to restick themselves! In contrast to recipients of standard ISG, those that received hyperimmune globulin failed to develop long-term immunity by passive-active immunization. It is the bias of many in the medical profession that hyperimmune globulin will be more effective than standard globulin. For this reason it is imperative that new data be scrutinized with great care. Hyperimmune globulin will be costly, limited in supply, and may be no more effective than standard ISG (22). It is possible that only modest amounts of anti-HBs may be required to protect against clinical hepatitis B, when the infective dose is small. Studies will be necessary to determine optimal amounts of anti-HB~ necessary to prevent clinical disease, and standardization of ISG will then be needed to assure that all lots of ISG contain adequate amounts of this protective factor. Until well-controlled studies demonstrate either that standard ISG containing modest amounts of anti-HBs is ineffective, or that hyperimmune globulin is unequivocally more effective, it is prudent to administer conventional ISG to household and intimate contacts of all persons with viral hepatitis. (See Table 1.) Digestive Diseases, Vol. 21, No. 5 (May 1976)
REFERENCES 1. Ginsberg AL, Conrad ME, Bancroft WH, Ling CM, Overby LR: Prevention of endemic HAA positive hepatitis with gamma globulin: Use of a simple radioimmune assay to detect HAA. N Engl J Med 286:562-566, 1972 2. Lewis JH, Brandon JM, Gorenc TJ, Maxwell NG: Hepatitis B: A study of 200 cases positive for hepatitis B antigen, Am J Dig Dis 18:921-929, 1973 3. Hersh T, Melnick JL, Goyal RK, Hollinger FB: Non parenteral transmission of viral hepatitis type B. N Engl J Med 285:1363-1364, 1971 4. Koff RS, Slavin MM, Connelly LJD: The contagiousness of Acute hepatitis B: Secondary attack rates in household contacts. Gastroenterology 69:838, 1975 5. Immune serum globulin for protection against viral hepatitis: Recommendation of Public Health Service Advisory Committee on Immunization Practices. Ann Intern Med 77:427430, 1972 6. Szmuness W, Prince AM, Goodman M, Ehrich C, Pick R, Ansari M: Hepatitis B immune serum globulin in prevention of nonparenterally transmitted hepatitis B. N Engl J Med 290:701-706, 1974 7. Levin ML, Maddrey WC, Wands JR, Mendeloff AI: Hepatitis B transmission by dentists. JAMA 228:1139, 1974 8. Rimland D, Parkin WE: An outbreak of hepatitis B traced to an oral surgeon. Gastroenterology 67:822, 1974 9. Prince AM, Hargrove RL, Szmuness W, Cherubin CE, Fontana V J, Jeffries GH: Immunologic distinction between infectious and serum hepatitis. N Engl J Med 282:987-991, 1970 10. Villarejos VM, Gutierrey A, Pelon W: Identification of a type B hepatitis epidemic in Costa Rica. Am J Epidemiol 96:372-378, 1972 11. Krugman S, Giles JP, Hammond J: Infectious hepatitis: Evidence for two distinctive clinical, epidemiological and immunological types of infection. JAMA 200:365-373, 1967 12. Alter HJ, Holland PV, Purcell RH, Lander JL, Feinstone SM, Morrow AG, Schmidt PJ: Post-transfusion hepatitis after exclusion of commercial and hepatitis B antigen-positive donors. Ann Intern Med 77:691-699, 1972 13. Stokes J Jr, Neefe JR: The prevention and attenuation of infectious hepatitis by gamma globulin. JAMA 127:144-145, 1945 14 Gellis SS, Stokes J Jr, Brother, GM, Hall WM, Gilmore HR, Beyer E, Morrissey RA: The use of human immune serum globulin in infectious hepatitis in the Mediterranean Theater of Operations. JAMA 128:1062-1063, 1945 15. Havens WP, Paul JR: Prevention of infectious hepatitis with gamma globulin. JAMA 129:270-272, 1945 16. Krugman S, Ward R, Giles JP, Jacobs MA: Infectious hepatitis: Studies on the effect of gamma globulin and on the incidence ofinapparent infection. JAMA 174:823-830, 1960 17. Ginsberg AL, Conrad ME, Bancroft WH, Ling, CM, Overby LR: Antibody to Australia antigen: Detection with a simple radioimmune assay, incidence in military populations and role in the prevention of hepatitis B with gamma globulin. J Lab Clin Med 82:317-325, 1973 18. Iwarson S, Ahlmen J, Eriksson E, Hermodsson S, et al: Hepatitis B immune serum globulin and standard gamma globulin in prevention of hepatitis B infection among hospital staff: A preliminary report. Am J Med Sci 270:385-389, 1975
407
HAMILTON
19. Redeker AG, Mosley JW, Gocke DJ, McKee AP, Pollack W: Hepatitis B immune globulin as a prophylactic measure for spouses exposed to acute type B hepatitis. N Engl J Med 293:1055-1059, 1975 20. Seeff LB, Zimmerman H J, Wright EC, et al: Efficacy of hepatitis B immune serum globulin following "needlestick" exposure: a preliminary report of the Veterans Administration Cooperative Study. Lancet 2:939-941, 1975 21. Grady GF, Lee VA: Prevention of hepatitis from accidental exposure among medical workers. N Engl J Med 293:106% 1070, 1975
408
AND
IBER VS GINSBERG
22. Alter HJ, Barker LF, Holland PV: Hepatitis B immune globulin: Evaluation of clinical trials and rationale for usage. N Engl J Med 293:1093-1094, 1975 23. Prince AM, Szmuness W, Mann MK, Vyas GN, Grady GF, et al: Hepatitis B " i m m u n e " globulin: Effectiveness in prevention of dialysis-associated hepatitis. N Engl J Med 293:1063-1067, 1975 24. Couroucr-Pauty AM, Delons S, Soulier JP: Attempt to prevent hepatitis by using specific anti-HBs immunoglobulin. Am J Med Sci 270:375-383, 1975
Digestive Diseases, VoL 21, No. 5 (May 1976)
REFERENCES 1. Grady GF: Passive immunization against viral hepatitis-status and prospects. Am J Med Sci 270:36%374, 1975 2. Surgenor DMacN, Thomas CC, Conrad MF, Friedenwald WT, Grady GF, Hamilton M, Mosely JW, Prince AM, Stengle JM: Clinical trials of hepatitis B immune globulin-development of policies and materials for the 1972=1975studies sponsored by the National Heart and Lung Institute. N Engl J Med 293:1060-1062, 1975 3. Schweitzer IL: Vertical transmission of the hepatitis B surface antigen. Am J Med Sci 270:287-291, 1975 4. Discussion: Viral hepatitis epidemiology. Am J Med Sci 270:31%325, 1975 5. Kohler PF, Dalvis RJ, Menill PA, Bowes WA: Prevention of chronic neonatal hepatitis B virus infection with antibody to the hepatitis B surface antigen. N Engl J Med 291:13781380, 1974 6. Grady GF, Lee VA: Prevention of hepatitis from accidental exposure among medical workers. N Engl J Med 293:10671069, 1975 7. Seeff LB, other VA Cooperative Groups Study: Efficacy of hepatitis B immune serum globulin after accidental exposure. Lancet 2:93%941, 1975 8. Prince AM, Szmuness W, Mann MK, Vyas GN, Grady GF, et al: Hepatitis B "immune" globulin: Effectiveness in prevention of dialysis-associated hepatitis. N Engl J Med 293:1063-1067, 1975 9. Courouce-Pauty AM, Delons S, Soulier JP: Attempt to prevent hepatitis by using specific anti-HB~ immunoglobulin. Am J Med Sci 270:375-383, 1975 10. Ginsberg A: Refer to accompanying article
11. Cooperative Study: Prophylactic gamma globulin for prevention of endemic hepatitis: Effects of US gamma globulin upon the incidence of viral hepatitis and other infectious diseases in US soldiers abroad. Arch Int Med 128:723-738, 1971 12. Szmuness W, Prince AM, Goodman M, et al: Hepatitis B immune serum globulin in prevention of nonparenterally transmitted hepatitis B. N Engl J Med 290:701-706, 1974 13. Mosley JM, Edwards VM, Casey C, Redeker A, White E: Hepatitis B infection in dentists. N Engl J Med 293:72%734, 1975 14. Hoofnagle JH, Gerety RJ, Barker LF: Antibody to hepatitis B core antigen. Am J Med Sci 270:17%187, 1975 15. Gocke DJ: Extrahepatic manifestations of viral hepatitis. Am J Med Sci 270:4%52, 1975 16. Redeker AG, Mosley JW, Gocke DJ, McKee AP, Pollack W: Prophylactic hepatitis B immune globulin for spouses exposed to hepatitis B. N Engl J Med 293:1055-1059, 1975 17. Editorial: Specific immunoglobulin in prevention of hepatitis B. Lancet 2:1132-1133, 1975 18. Syndman DR, Bryan JA, Dixon RE: Prevention df nosocomial viral hepatitis', Type B (Hepatitis B). Ann Intern Med 83:838-845, 1975 19. Grady G: Passive immunizationagainst viral hepatitis. Symposium in viral hepatitis, National Academy of Science, March 17-19, 1975. Am J Med Sci (in press) 20. Bruguera M, Borsh J, et al: Familial clustering of hepatitis B antigen: A study in relatives of patients with liver disease and hepatitis B antigenemia. Br Med J 00:11-13, 1974 21. Kaboth UJ: Viral hepatitis. Clin Gastroenterol 0:3, 1974 22. Iwarson S, Ahlmen J, Eriksson E, et al: Hepatitis B immune serum globulin and standard gamma globulin in prevention of hepatitis B infection among hospital staff: A preliminary report. Am J Med Sci 270:385-389, 1975 23. Alter J, Holland PV, Purcell RH, et al: Posttransfusion hepatitis after exclusion of commercial and hepatitis B antigen positive donors. Ann Intern Med 77:691-699, 1972 24. Mosley JM: The epidemiology of viral hepatitis: An overview. Am J Med Sci 270:253-270, 1975
The Use of Standard Gamma Globulin for the Prevention of Hepatitis B A L L E N L. G I N S B E R G , M D
Assistant Professor of Medicine, George Washington University School of Medicine, Washington, D.C.
S t a n d a r d i m m u n e s e r u m g l o b u l i n (ISG) s h o u l d rout i n e l y be a d m i n i s t e r e d to h o u s e h o l d a n d i n t i m a t e c o n t a c t s of p a t i e n t s with viral hepatitis. R e c e n t studies h a v e i n d i c a t e d that s t a n d a r d I S G is likely to b e effective a g a i n s t b o t h virus A a n d v i r u s B (1). Alt h o u g h the risk of c o n t r a c t i n g h e p a t i t i s B b y p e r s o n -
404
al c o n t a c t a p p e a r s to b e less t h a n the risk of c o n t r a c t i n g h e p a t i t i s A , t h e r e is a definite risk (2--4). F u r t h e r m o r e , d e b i l i t y , c h r o n i c i t y , a n d m o r t a l i t y are all higher in i n f e c t i o n s with the h e p a t i t i s B virus. T h e p o t e n t i a l b e n e f i t for the few p a t i e n t s in w h o m clinical hepatitis B m a y b e p r e v e n t e d is great, while
DigestiveDiseases, Vol.21, No. 5 (May1976)
THE GAMMA GLOBULIN CONTROVERSY the likelihood of serious side effects from the administration o f l S G is almost nonexistent (1). The recommendations of the Public Health Service Advisory Committee on Immunization Practices state that standard ISG is not of value in the prevention of hepatitis B and should not be administered to persons exposed to hepatitis B (5). This statement does not take cognizance of the epidemiologic data derived since the association of Australia antigen (HBsAg) with hepatitis B infection (1, 6). The ramifications of this near-sighted view are dangerous. Ten years ago, household contacts of sporadic cases of viral hepatitis received ISG. Now, because of HBsAg testing, and the PHS recommendations, ISG is withheld from these same individuals. The results of this policy are illustrated in the following three true case histories. Case 1 is the roommate of a patient who was recently hospitalized for hepatitis B. Prior to the discovery of HBsAg it is likely that case 1 would have received ISG. However, in 1974, case 1 did not receive ISG on the basis of the PHS recommendations. Eight weeks after the roommate was hospitalized, case 1 also developed acute hepatitis B. Case 1 recovered, but is now a chronic carrier of HBsAg and may or may not have chronic hepatitis. The husband of case 2 was hospitalized with hepatitis B. ISG was not administered to case 2. Eight weeks later case 2 developed fulminant hepatitis and died (2). Patient 3 is a dentist. The dentist was just informed that one of his patients who had had a tooth extraction 48 hours previously was now hospitalized with hepatitis B. The dentist wishes to know whether or not he should receive ISG. The Public Health Service Advisory Committee on Immunization Practices does not recommend ISG in the prophylaxis of hepatitis B. You are the physician. You are aware that if the dentist were to become a chronic carrier of HB~Ag, the results could be catastrophic (7, 8). What should you do? The arguments and data which should allow you to arrive at an informed decision follow. For over three decades the term '~ hepatitis" has been used interchangeably with hepatitis A, while the term "serum hepatitis" has been used interchangeably with hepatitis B. The use of terms implying specific routes of virus exposure to connote particular viral strains has proved unfortunate. The development of tests for the detection of HBsAg has allowed the differentiation of virus B infection from infections with other hepatitis viruses. Digestive Diseases, Vol. 21, No. 5 (May 1976)
The use of this epidemiologic tool has established that hepatitis B is responsible for many sporadic cases of hepatitis in which the route of exposure is nonparenteral or inapparent. Three large studies have demonstrated that 22-55% of endemically derived cases of hepatitis are positive for HBsAg (1, 2, 9). There is evidence for the sexual transmission of hepatitis B (2, 3), and hepatitis B has now been implicated in at least one epidemic of "infectious hepatitis" (10). These findings are in accord with the observations that hepatitis B is endemic in some institutions for the retarded such as Wiilowbrook (New York) where good sanitation is difficult to maintain (11). It has also become apparent that many cases of posttransfusion hepatitis, in which the route of exposure is parenteral and the viral dosage massive, are caused by viruses other than the hepatitis B virus (12). Early studies demonstrated that ISG was effective in the prevention of "infectious hepatitis" and ineffective in the prevention of "serum hepatitis." On the basis of these studies it was assumed that ISG was effective against virus A and ineffective against virus B. In the light of current epidemiologic data, this assumption may not be valid. Standard 1SG is effective in the prevention or attenuation of viral hepatitis when the route of virus administration is nonparenteral or inapparent and the exposure dosage is small. This was first demonstrated by Stokes and Neefe (13) and soon confirmed by Gellis et al (14) and Havens and Paul (15). In these early studies epidemics were curtailed through the administration of ISG, and it is quite likely that these epidemics were caused by the hepatitis A viIns.
Krugman et al (16) in studies performed at Willowbrook showed that administration of standard ISG could virtually eliminate the occurrence of icteric hepatitis in newly admitted children. Of 635 newly admitted children who received 0.06 ml of ISG per pound only one case of icteric hepatitis developed during a 5-month period. This contrasted with 31 icteric cases observed in 636 control children. These data were widely interpreted as demonstrating that ISG was effective in preventing or attenuating "infectious hepatitis." The almost complete prevention of icteric hepatitis by high doses of ISG which was reported at Willowbrook where both virus A and virus B are highly endemic should suggest the probability that there was protection against both viral strains. Indeed the endemicity of hepatitis B at Willowbrook has been used as ajusti-
405
HAMILTON
AND
IBER VS GINSBERG
TABLE 1. EFFICACY OF GAMMA GLOBULIN IN HEPATITIS B
Author Ginsberg et al (1) Szmuness et al (6) Redeker et al (19)
Type o f study Endemic hepatitis B in soldiers Endemic hepatitis B in institutionalized children Sexual exposure to hepatitis B
Seeff et al (20)
Needle stick
Grady et al (21)
Needle stick
Prince et al (23)
Dialysis patients (? parenteral exposure) Dialysis staff (? nonparenteral exposure) Dialysis staff
Prince et al (23) Couroucr-Pauty (24)
Gamma globulin
Controls
Standard ISG
Albumin placebo
Yes
Std ISG
Uninoculated controls
Yes
HBIg HBIg HBIg Std ISG HBIg Std ISG HBIg Std ISG HBIg Std ISG HBIg
Placebo globulin devoid of antiHB~ None None None None Uninoculated controls
Effeetiveness
Yes Yes* ? Probable ? Probable ? Probable ? Probable Unknown? Unknown UnknownS: Unknown Yes
*Standard ISG was not evaluated. ?HBIg reduced the incidence of hepatitis B at 8 months. At 12 months, however, the differences between HBIg and Std ISG were not significant. ~/Differences between HBIg and Std ISG were not significant at either 8 or 12 months.
fication for the experimental induction of hepatitis B infection in humans at this institution (11). Numerous controlled studies to evaluate the efficacy of conventional ISG in the prevention of endemically derived hepatitis have been conducted but only two have utilized HBsAg testing. The first was a study performed in approximately 100,000 soldiers stationed in Korea(l). Soldiers received coded injections of 2, 5, or 10 ml of ISG or placebo in a random manner. The ISG used consisted of two lots with anti-HB~ titers of 1 : 10 and 1 : 160 as determined by radioimmune assay and titers of 1 : 4 and 1 : 16 as determined by passive hemagglutination (17). ISG in 5 and 10 mt doses afforded significant protection against endemically derived icteric hepatitis B for approximately 6 months. Only three patients who had received either 5 or 10 ml of gamma globulin within six months developed hepatitis B whereas there were 20 hepatitis B patients among those who were injected with the placebo solutions (P < 0.01). ISG was also effective for the same period of time in the prevention of icteric non-B hepatitis. The second study was performed in three institutions for the mentally retarded (6). In this study a lower incidence of anicteric hepatitis B was ob-
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served in children receiving either conventional or hyperimmune globulin than in uninoculated controis. More importantly, no children receiving ISG developed persistent antigenemia, whereas 13.5% of uninoculated controls became chronic antigen carriers. There was no difference between standard and hyperimmune globulin. Iwarson et al (18) recently presented preliminary data to the National Academy of Science based on a controlled study of dialysis unit patients and personnel. In this study the incidence of clinical hepatitis B in untreated patients and personnel was compared with the incidence of hepatitis B in individuals treated with either standard or hyperimmune globulin. Both types of ISG appeared equally effective, and there were no cases of persistent antigenemia in ISG recipients. Seroconversion (the development of anti-HBs) in four recipients of standard ISG and in none of the recipients of hyperimmune globulin suggested that low levels of antibody present in standard ISG may favor passive-active immunization. Caution must be exercised in interpretation of new data evaluating hyperimmune globulin. Redeker et al (19) studied sexual contacts of patients with hepatitis B. They compared hyperimmune Digestive Diseases, Vol. 21, No. 5 (May 1976)
THE GAMMA GLOBULIN CONTROVERSY globulin to a true placebo globulin devoid of antiHBs. The placebo was manufactured by fractionation of plasma from individuals negative for antiHBs. Under the conditions of this experiment only 1 of 25 exposed individuals that received hyperimmune globulin developed hepatitis whereas 9 of 33 patients that received the placebo became infected. No information about the effectiveness of standard ISG which normally contains modest amounts of anti-HB~ can be derived from this study. In separate investigations Seeff et al (20) and Grady and Lee (21) studied individuals stuck by needles from patients positive for HB~Ag. The efficacy of hyperimmune and standard globulins was evaluated. Unfortunately there were no control groups. Of the exposed individuals, 93-95% were protected from acute hepatitis B by both globulin preparations. No recipient of either type of globulin became a chronic carrier of HB~Ag. Approximately 30% of recipients of standard ISG developed antiHBs presumably by passive-active immunization (20). The hepatitis which developed in recipients of hyperimmune globulin had a very long incubation period, and several of these individuals were thought to have been reexposed. These cases, however, cannot legitimately be excluded. There is no reason to believe that recipients of hyperimmune globulin should be more likely than recipients of standard ISG to restick themselves! In contrast to recipients of standard ISG, those that received hyperimmune globulin failed to develop long-term immunity by passive-active immunization. It is the bias of many in the medical profession that hyperimmune globulin will be more effective than standard globulin. For this reason it is imperative that new data be scrutinized with great care. Hyperimmune globulin will be costly, limited in supply, and may be no more effective than standard ISG (22). It is possible that only modest amounts of anti-HBs may be required to protect against clinical hepatitis B, when the infective dose is small. Studies will be necessary to determine optimal amounts of anti-HB~ necessary to prevent clinical disease, and standardization of ISG will then be needed to assure that all lots of ISG contain adequate amounts of this protective factor. Until well-controlled studies demonstrate either that standard ISG containing modest amounts of anti-HBs is ineffective, or that hyperimmune globulin is unequivocally more effective, it is prudent to administer conventional ISG to household and intimate contacts of all persons with viral hepatitis. (See Table 1.) Digestive Diseases, Vol. 21, No. 5 (May 1976)
REFERENCES 1. Ginsberg AL, Conrad ME, Bancroft WH, Ling CM, Overby LR: Prevention of endemic HAA positive hepatitis with gamma globulin: Use of a simple radioimmune assay to detect HAA. N Engl J Med 286:562-566, 1972 2. Lewis JH, Brandon JM, Gorenc TJ, Maxwell NG: Hepatitis B: A study of 200 cases positive for hepatitis B antigen, Am J Dig Dis 18:921-929, 1973 3. Hersh T, Melnick JL, Goyal RK, Hollinger FB: Non parenteral transmission of viral hepatitis type B. N Engl J Med 285:1363-1364, 1971 4. Koff RS, Slavin MM, Connelly LJD: The contagiousness of Acute hepatitis B: Secondary attack rates in household contacts. Gastroenterology 69:838, 1975 5. Immune serum globulin for protection against viral hepatitis: Recommendation of Public Health Service Advisory Committee on Immunization Practices. Ann Intern Med 77:427430, 1972 6. Szmuness W, Prince AM, Goodman M, Ehrich C, Pick R, Ansari M: Hepatitis B immune serum globulin in prevention of nonparenterally transmitted hepatitis B. N Engl J Med 290:701-706, 1974 7. Levin ML, Maddrey WC, Wands JR, Mendeloff AI: Hepatitis B transmission by dentists. JAMA 228:1139, 1974 8. Rimland D, Parkin WE: An outbreak of hepatitis B traced to an oral surgeon. Gastroenterology 67:822, 1974 9. Prince AM, Hargrove RL, Szmuness W, Cherubin CE, Fontana V J, Jeffries GH: Immunologic distinction between infectious and serum hepatitis. N Engl J Med 282:987-991, 1970 10. Villarejos VM, Gutierrey A, Pelon W: Identification of a type B hepatitis epidemic in Costa Rica. Am J Epidemiol 96:372-378, 1972 11. Krugman S, Giles JP, Hammond J: Infectious hepatitis: Evidence for two distinctive clinical, epidemiological and immunological types of infection. JAMA 200:365-373, 1967 12. Alter HJ, Holland PV, Purcell RH, Lander JL, Feinstone SM, Morrow AG, Schmidt PJ: Post-transfusion hepatitis after exclusion of commercial and hepatitis B antigen-positive donors. Ann Intern Med 77:691-699, 1972 13. Stokes J Jr, Neefe JR: The prevention and attenuation of infectious hepatitis by gamma globulin. JAMA 127:144-145, 1945 14 Gellis SS, Stokes J Jr, Brother, GM, Hall WM, Gilmore HR, Beyer E, Morrissey RA: The use of human immune serum globulin in infectious hepatitis in the Mediterranean Theater of Operations. JAMA 128:1062-1063, 1945 15. Havens WP, Paul JR: Prevention of infectious hepatitis with gamma globulin. JAMA 129:270-272, 1945 16. Krugman S, Ward R, Giles JP, Jacobs MA: Infectious hepatitis: Studies on the effect of gamma globulin and on the incidence ofinapparent infection. JAMA 174:823-830, 1960 17. Ginsberg AL, Conrad ME, Bancroft WH, Ling, CM, Overby LR: Antibody to Australia antigen: Detection with a simple radioimmune assay, incidence in military populations and role in the prevention of hepatitis B with gamma globulin. J Lab Clin Med 82:317-325, 1973 18. Iwarson S, Ahlmen J, Eriksson E, Hermodsson S, et al: Hepatitis B immune serum globulin and standard gamma globulin in prevention of hepatitis B infection among hospital staff: A preliminary report. Am J Med Sci 270:385-389, 1975
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19. Redeker AG, Mosley JW, Gocke DJ, McKee AP, Pollack W: Hepatitis B immune globulin as a prophylactic measure for spouses exposed to acute type B hepatitis. N Engl J Med 293:1055-1059, 1975 20. Seeff LB, Zimmerman H J, Wright EC, et al: Efficacy of hepatitis B immune serum globulin following "needlestick" exposure: a preliminary report of the Veterans Administration Cooperative Study. Lancet 2:939-941, 1975 21. Grady GF, Lee VA: Prevention of hepatitis from accidental exposure among medical workers. N Engl J Med 293:106% 1070, 1975
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IBER VS GINSBERG
22. Alter HJ, Barker LF, Holland PV: Hepatitis B immune globulin: Evaluation of clinical trials and rationale for usage. N Engl J Med 293:1093-1094, 1975 23. Prince AM, Szmuness W, Mann MK, Vyas GN, Grady GF, et al: Hepatitis B " i m m u n e " globulin: Effectiveness in prevention of dialysis-associated hepatitis. N Engl J Med 293:1063-1067, 1975 24. Couroucr-Pauty AM, Delons S, Soulier JP: Attempt to prevent hepatitis by using specific anti-HBs immunoglobulin. Am J Med Sci 270:375-383, 1975
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