Nephron 17: 402^*06 (1976)
Prevention of Hepatitis Type B with Specific Immune Serum Globulin Bijan N ik-A khtar, M anijeh K hakpour . F irouz Panahi and A u M. H esabi Department of Medicine, School of Medicine, and School of Public Health, Section of Virology, Tehran University, Tehran
Key Words. Hemodialysis • Hepatitis • Chronic renal failure • Immunoglobulin therapy Abstract. In order to evaluate the preventive value of specific immune serum globulin against hepatitis type B, we have used this immune globulin in required doses in 12 patients (10 with AU antigen negative and 2 with AU antigen positive) with chronic renal failure who required maintenance hemodialysis for a period of 15 months, and we were able to prevent hepatitis type B in our dialysis patients.
The value of immune serum globulin for the prevention of viral hepatitis type B. has been inconsistent [1,2] in spite of the fact that its efficacy on type A has been well established [3-7]. Since Prince et al. [8] reported that special immune serum globulin containing a high titer of anti-HAA can act against Australia or hepatitis-associated antigen (HAA), and the discovery of this antigen by Blumberg et al. [9-11] made the detection of its antibody possible by passive hemagglutination (HA) [12] and radioimmunoassay (R1A) [13], and complement fixation (CF)and immunoelectrophoresis [14], more feasible. Therefore, the possibility for prevention of hepatitis type B by its antibody became more practical. Epidemics of hepatitis B occur very frequently in hemodialysis centers [15,16], and since its prevention by specific B immune serum globulin has been emphasized by some investigators [8,17] and this seemed to be an effective measure in this respect, we therefore decided to try this preventive measure in our chronic hemodialysis patients in an effort to evaluate its preventive value.
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
Received: November 10, 1975; accepted: November 24, 1975.
N ik-A khtar/K hakpour /P anam /H esabi
403
Materials and Methods Our report involves 12 patients (7 males and 5 females) who have been under chronic hemodialysis since January 1973, and whose ages ranged from 16 to 59 years. Criteria for admission to this study plan consisted of the following measures: (a) all had negative history of jaundice with normal liver function tests and negative Australia antigen and antibody, and (b) the number of transfusions during and prior to this study was determined and their blood donors were also identified as to have negative Au antigen and antibody (table I). Detection of antigen was carried out by using immunodifusion (ID), clectroimmunodiffusion, CF, and immune adherence. Anti-Au antibodies were sought by ID and clcctroimmunodifi'usion technics. In order to evaluate the preventive value of specific B immune serum globulin against hepatitis B, on September 10th 1974, we added two additional patients who had chronic renal failure, requiring maintenance hemodialysis, and incidentally developed hepatitis B due to blood transfusion from Au antigen-positive donors to this group. Prior to this study, specific y-globulin was prepared from plasma of healthy blood donors containing high titer of anti-Au antibody, and all patients were injected intramus cularly with required doses. Doses injected varied between 0.05 and 0.4 ml kg. Injections were carried out in all subjects prior to this study (except in patients No. 5 and 6) and the doses were repeated on an every 3 months basis for three successive injections (from September 10, 1974 toJune 30,1975). The recipients were followed by serial serum specimen which were obtained at every 2 weeks intervals and more often when indicated for the following tests to detect HAA and anti-HAA by ID, CF, and RIA, serum bilirubin, serum glutamic oxaloacetic transaminase (SCOT) ,and serum glutamic pyruvic transaminase (SGPT), to evaluate possible involvement fo the liver (table I).
Under the conditions of this study, all patients developed positive anti bodies without any apparent jaundice, while in case No. 7, liver function tests became transitorily impaired. Au antigen was positive in cases N o.5 and 6. In case No. 7, it became transitorily positive and disappeared 1 month later. Since antibody by passive immunization will not last too long, we therefore decided to repeat injected doses every 3 months and while antibody was detectable in all individuals, Au antigen remained negative (except in cases No. 5 and 6) throughout the course of this study. The regular interval of passive immunization did not allow us to detect antibodies product by possible contamination which can be interpreted as active immunization. We also suspect that case No. 7 developed inapparent hepatitis evidenced by disturbed liver function tests with transient positive Au antigen. It also believed that possive immunization by specific B immune serum not only
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
Results
N ik-A khtar K iiakpour/P anahi /Mrsabi
404
Tabic / Pa Names Sex Age Trans Hemo tient fusions dialysis No. during weekly, study, n n
Specific B immune serum globu lin, kg
Liver function test during study bili rubin
SGOT SGPT
Au AuJaundice antigen antibody ID positive, days after immuni zation
1 2 3 4 5
V.O. S.L. H.A.A. S. A. AH.
F F M M M
59 27 16 21 36
12 6 4 2 3
3 2 3 2 2
0.05 0.16 0.2 0.4 0.2
0.9 0.8 0.6 0.6 3.8
42 33 27 36 217
35 47 36 41 420
+
6
M.D.
M 55
4
2
0.2
4.2
316
650
+
7 8 9 10 11 12
S. A. M.E. SH.R. A.R. M.S. N. A.
M M F F F M
11 3 16 4 8 2
2 i 3 2 3 2
0.18 0.14 0.18 0.2 0.06 0.2
1.4 0.55 0.6 0.6 0.75 0.9
58 32 27 27 31 43
46 18 21 32 12 18
+ -
48 29 24 23 24 57
—
-
30 16 34 26 at the time of dialysis at the time of dialysis 48 25 14 32 19 22
_ -
— +
-
-
prevented the occurrence of clinical symptoms of hepatitis, but also actively prevented any liver damage since liver function tests in all individuals remained essentially normal. The absence of Au antigen in most of our patients con firmed the fact that either passive immunization effectively prevented its occurrence, or contamination through dialysisequipment was not as frequent as it was previously thought.
It is now apparent that preventive measures against hepatitis type B with specific immune serum globulin arc quite possible [8,17,18.21]. Solihr et al. [17] and K r u g m a n et al. [18] under repeated studies, used hepatitis B immune serum globulin in patients by active and passive immunization, which resulted in prevention of hepatitis Beven when virus was either directly introduced to the patients [18] or through accidental contamination [17]. Since epidemic hepatitis is a real hazard both to the patients and the staff of any hemodialysis center, some investigators, therefore, focussed their
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
Discussion
Prevention of Hepatitis Type B with Specific Immune Serum Globulin
405
efforts on creating some preventive measures which could either eradicate or decrease the risks of such epidemics [15,19,20], Although a careful and regular search for Au antigen in patients, staff of dialysis units, and blood donors can effectively reduce the risk of epidemics (since this virus, like particles, can also contaminate equipment used in dialysis centers), effective prevention may not be possible at all times. With the introduction ofy-globulin against hepatitis type A, it soon became appar ent that this preventive measure can not be applied for hepatitis B [3-7], Since P rin ce et al. [8] confirmed the fact that special immune globulin containing a high titer of anti-HAA can act against Au antigen, and B lumberg et al. [9-11] detected its antibody by various methods [12-14], it soon came to the attention of scientists and clinicians that serum containing antibody can be used to prevent hepatitis B. S oulier et al.[\l] have used this antibody in two separate groups of their patients through active and passive immunization and found it quite effective. Based on these observations, we used this specific B immune scrum in our hemodialysis patients prior to their contamination with contaminated pa tients, and were able to prevent hepatitis in our unit fora period of 10 months.
References 1 G rossman, E. B.; Stewart, S.C., and Stokes, J.,jr.: Post-transfusion hepatitis In battle casualties and study of its prophylaxis by means of human immune serum globulin. J. Am. med. Ass. 129: 991-994 (1945). 2 M irick , G .S .; W ard, R., and M c C ollum , R .W .: Modification o f post transfusion hepatitis by gamma-globulin. New Engl.J. Med. 273: 59-65 (1965). 3 Stokes, J., jr. and N eefe, J. R.: Prevention and attenuation of infectious hepatitis by
gamma-globulin. Preliminary note. J. Am. mol. Ass. 127: 144-145 (1942). 4 H avens, W.P., jr. and P aul, J. R.: Prevention of infectious hepatitis with gamma globulin. J. Am. med. Ass. 129: 270-272 (1945). 5 Hsia, D .Y. Y.; Lonsway, M., jr., and G ellis, S.S.: Gamma-globulin in prevention of infectious hepatitis. Studies on uses of small doses in family outbreaks. New Engl.J. Med. 250: 417-419 (1954). 6 K rugman, S.; W ard, R.; G iles, J.P., et at.: Infectious hepatitis. Studies on the effect of gamma-globulin and on the incidence of inapparent infection. J. Am. med. Ass. 174: 823 830(1960). 7 K luge, T .: Gamma-globulin in the prevention of viral hepatitis. Acta med.scand. 174:
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
469-477 (1963).
8 Prince, A.M.; Szmuness, W.: W oods, K.R., et at.: Antibody against serum-hepatitis antigen. Prevalence and potential use as immune serum globulin in prevention of serum hepatitis infections. New Engl. J. Med. 285: 933 (1971).
406
N ik-A khtar/K hakpour/P anahi /H esabi
9 Blumberg, B.S.; A lter, H.J., and Visnich, S.: A new antigen in leukemia sera. J. Am. med. Ass. 191: 541-546 ( 1965). 10 Blumberg, B.S.; G erstley, B.U.S.; H ungerford, P.A., el al.: A serum antigen
12 13
14 15 16 17 18
19
20 21
Prof. Bijan N ik-A khtar , Department of Medicine, School of Medicine, Pahlavi Medical School, Tehran University, Tehran (Iran)
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
11
(Australia antigen) in Down's syndrome, leukemia and hepatitis. Ann. intern. Med. 66: 924-931 (1967). Blumberg, B.S.; S utnick , A.I., and London , W.T.: Hepatitis and leukemia. Their relation to Australia antigen. Bull. N.Y. Acad. Med. 44: 1566-1586 (1968). Vyas, G.N. and Schulman, N .R .: Hemagglutination assay for antigen and antibody associated with viral hepatitis. Science 170: 332-333 (1970). Lander, J.J.; A lter, H.J., and P urcell, R.H.: Frequency of antibody to hepatitisassociated antigen as measured by new radioimmunoassay technique. J.lmmun. 106: 1166—1171 (1971). P urcell, R .H .: H olland, P.V.; W alsh, J.H., el al.: A complement fixation test for measuring Australia antigen and antibody. J. infect. Dis. 120: 383-386 (1969). K night , A.H.; Fox, R.A.; Billod, R.A., el al.: Hepatitis-associated antigen and antibody in hemodialysis patients and staff. Br. Med.i. Hi: 603-606 (1970). London , T.W .: D ifiglia, M.; S utnick , A.I., et a!.: An epidemic of hepatitis in a chronic unit. New Engl.J. Mcd.2S/: 571-578 (1969). Soulier, J.P.; Blatix, C.; C ourovce, A .M ., el al.: Prevention of virus B hepatitis (SH hepatitis) Am. J. Dis. Child. 123: 429-434 (1972). K rugman, S.; G iles, J.P., and H ammond, J.: Viral hepatitis type B (M s-2 strain) prevention with specific hepatitis B immune serum globulin. J. Am. med.Ass. 218: 1665-1670(1 971). N ordenfelt, E.; L indholm , T., and D ahlqui, S.T.: A hepatitis epidemic in a dialysis unit. Occurrence and persistence of Australia antigen among patients and staff. Acta path, microbiol. scand. 78: 692-700 ( 1970). J ones, P.O.; G oldsmith, H.J.; W right , F. K., el al.: Viral hepatitis, a stall' hazard in a dyalysis unit. Lancet i: 835-840 (1967). D esmytfr, J.: Bradburnf, A .F.; Vermylen, C., et al.: Hepatitis B immunoglobulin in prevention of HBS antigenemia in hemodialysis patients. Lancet ii: 377-379 (1075).
Prevention of Hepatitis Type B with Specific Immune Serum Globulin Bijan N ik-A khtar, M anijeh K hakpour . F irouz Panahi and A u M. H esabi Department of Medicine, School of Medicine, and School of Public Health, Section of Virology, Tehran University, Tehran
Key Words. Hemodialysis • Hepatitis • Chronic renal failure • Immunoglobulin therapy Abstract. In order to evaluate the preventive value of specific immune serum globulin against hepatitis type B, we have used this immune globulin in required doses in 12 patients (10 with AU antigen negative and 2 with AU antigen positive) with chronic renal failure who required maintenance hemodialysis for a period of 15 months, and we were able to prevent hepatitis type B in our dialysis patients.
The value of immune serum globulin for the prevention of viral hepatitis type B. has been inconsistent [1,2] in spite of the fact that its efficacy on type A has been well established [3-7]. Since Prince et al. [8] reported that special immune serum globulin containing a high titer of anti-HAA can act against Australia or hepatitis-associated antigen (HAA), and the discovery of this antigen by Blumberg et al. [9-11] made the detection of its antibody possible by passive hemagglutination (HA) [12] and radioimmunoassay (R1A) [13], and complement fixation (CF)and immunoelectrophoresis [14], more feasible. Therefore, the possibility for prevention of hepatitis type B by its antibody became more practical. Epidemics of hepatitis B occur very frequently in hemodialysis centers [15,16], and since its prevention by specific B immune serum globulin has been emphasized by some investigators [8,17] and this seemed to be an effective measure in this respect, we therefore decided to try this preventive measure in our chronic hemodialysis patients in an effort to evaluate its preventive value.
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
Received: November 10, 1975; accepted: November 24, 1975.
N ik-A khtar/K hakpour /P anam /H esabi
403
Materials and Methods Our report involves 12 patients (7 males and 5 females) who have been under chronic hemodialysis since January 1973, and whose ages ranged from 16 to 59 years. Criteria for admission to this study plan consisted of the following measures: (a) all had negative history of jaundice with normal liver function tests and negative Australia antigen and antibody, and (b) the number of transfusions during and prior to this study was determined and their blood donors were also identified as to have negative Au antigen and antibody (table I). Detection of antigen was carried out by using immunodifusion (ID), clectroimmunodiffusion, CF, and immune adherence. Anti-Au antibodies were sought by ID and clcctroimmunodifi'usion technics. In order to evaluate the preventive value of specific B immune serum globulin against hepatitis B, on September 10th 1974, we added two additional patients who had chronic renal failure, requiring maintenance hemodialysis, and incidentally developed hepatitis B due to blood transfusion from Au antigen-positive donors to this group. Prior to this study, specific y-globulin was prepared from plasma of healthy blood donors containing high titer of anti-Au antibody, and all patients were injected intramus cularly with required doses. Doses injected varied between 0.05 and 0.4 ml kg. Injections were carried out in all subjects prior to this study (except in patients No. 5 and 6) and the doses were repeated on an every 3 months basis for three successive injections (from September 10, 1974 toJune 30,1975). The recipients were followed by serial serum specimen which were obtained at every 2 weeks intervals and more often when indicated for the following tests to detect HAA and anti-HAA by ID, CF, and RIA, serum bilirubin, serum glutamic oxaloacetic transaminase (SCOT) ,and serum glutamic pyruvic transaminase (SGPT), to evaluate possible involvement fo the liver (table I).
Under the conditions of this study, all patients developed positive anti bodies without any apparent jaundice, while in case No. 7, liver function tests became transitorily impaired. Au antigen was positive in cases N o.5 and 6. In case No. 7, it became transitorily positive and disappeared 1 month later. Since antibody by passive immunization will not last too long, we therefore decided to repeat injected doses every 3 months and while antibody was detectable in all individuals, Au antigen remained negative (except in cases No. 5 and 6) throughout the course of this study. The regular interval of passive immunization did not allow us to detect antibodies product by possible contamination which can be interpreted as active immunization. We also suspect that case No. 7 developed inapparent hepatitis evidenced by disturbed liver function tests with transient positive Au antigen. It also believed that possive immunization by specific B immune serum not only
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
Results
N ik-A khtar K iiakpour/P anahi /Mrsabi
404
Tabic / Pa Names Sex Age Trans Hemo tient fusions dialysis No. during weekly, study, n n
Specific B immune serum globu lin, kg
Liver function test during study bili rubin
SGOT SGPT
Au AuJaundice antigen antibody ID positive, days after immuni zation
1 2 3 4 5
V.O. S.L. H.A.A. S. A. AH.
F F M M M
59 27 16 21 36
12 6 4 2 3
3 2 3 2 2
0.05 0.16 0.2 0.4 0.2
0.9 0.8 0.6 0.6 3.8
42 33 27 36 217
35 47 36 41 420
+
6
M.D.
M 55
4
2
0.2
4.2
316
650
+
7 8 9 10 11 12
S. A. M.E. SH.R. A.R. M.S. N. A.
M M F F F M
11 3 16 4 8 2
2 i 3 2 3 2
0.18 0.14 0.18 0.2 0.06 0.2
1.4 0.55 0.6 0.6 0.75 0.9
58 32 27 27 31 43
46 18 21 32 12 18
+ -
48 29 24 23 24 57
—
-
30 16 34 26 at the time of dialysis at the time of dialysis 48 25 14 32 19 22
_ -
— +
-
-
prevented the occurrence of clinical symptoms of hepatitis, but also actively prevented any liver damage since liver function tests in all individuals remained essentially normal. The absence of Au antigen in most of our patients con firmed the fact that either passive immunization effectively prevented its occurrence, or contamination through dialysisequipment was not as frequent as it was previously thought.
It is now apparent that preventive measures against hepatitis type B with specific immune serum globulin arc quite possible [8,17,18.21]. Solihr et al. [17] and K r u g m a n et al. [18] under repeated studies, used hepatitis B immune serum globulin in patients by active and passive immunization, which resulted in prevention of hepatitis Beven when virus was either directly introduced to the patients [18] or through accidental contamination [17]. Since epidemic hepatitis is a real hazard both to the patients and the staff of any hemodialysis center, some investigators, therefore, focussed their
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
Discussion
Prevention of Hepatitis Type B with Specific Immune Serum Globulin
405
efforts on creating some preventive measures which could either eradicate or decrease the risks of such epidemics [15,19,20], Although a careful and regular search for Au antigen in patients, staff of dialysis units, and blood donors can effectively reduce the risk of epidemics (since this virus, like particles, can also contaminate equipment used in dialysis centers), effective prevention may not be possible at all times. With the introduction ofy-globulin against hepatitis type A, it soon became appar ent that this preventive measure can not be applied for hepatitis B [3-7], Since P rin ce et al. [8] confirmed the fact that special immune globulin containing a high titer of anti-HAA can act against Au antigen, and B lumberg et al. [9-11] detected its antibody by various methods [12-14], it soon came to the attention of scientists and clinicians that serum containing antibody can be used to prevent hepatitis B. S oulier et al.[\l] have used this antibody in two separate groups of their patients through active and passive immunization and found it quite effective. Based on these observations, we used this specific B immune scrum in our hemodialysis patients prior to their contamination with contaminated pa tients, and were able to prevent hepatitis in our unit fora period of 10 months.
References 1 G rossman, E. B.; Stewart, S.C., and Stokes, J.,jr.: Post-transfusion hepatitis In battle casualties and study of its prophylaxis by means of human immune serum globulin. J. Am. med. Ass. 129: 991-994 (1945). 2 M irick , G .S .; W ard, R., and M c C ollum , R .W .: Modification o f post transfusion hepatitis by gamma-globulin. New Engl.J. Med. 273: 59-65 (1965). 3 Stokes, J., jr. and N eefe, J. R.: Prevention and attenuation of infectious hepatitis by
gamma-globulin. Preliminary note. J. Am. mol. Ass. 127: 144-145 (1942). 4 H avens, W.P., jr. and P aul, J. R.: Prevention of infectious hepatitis with gamma globulin. J. Am. med. Ass. 129: 270-272 (1945). 5 Hsia, D .Y. Y.; Lonsway, M., jr., and G ellis, S.S.: Gamma-globulin in prevention of infectious hepatitis. Studies on uses of small doses in family outbreaks. New Engl.J. Med. 250: 417-419 (1954). 6 K rugman, S.; W ard, R.; G iles, J.P., et at.: Infectious hepatitis. Studies on the effect of gamma-globulin and on the incidence of inapparent infection. J. Am. med. Ass. 174: 823 830(1960). 7 K luge, T .: Gamma-globulin in the prevention of viral hepatitis. Acta med.scand. 174:
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
469-477 (1963).
8 Prince, A.M.; Szmuness, W.: W oods, K.R., et at.: Antibody against serum-hepatitis antigen. Prevalence and potential use as immune serum globulin in prevention of serum hepatitis infections. New Engl. J. Med. 285: 933 (1971).
406
N ik-A khtar/K hakpour/P anahi /H esabi
9 Blumberg, B.S.; A lter, H.J., and Visnich, S.: A new antigen in leukemia sera. J. Am. med. Ass. 191: 541-546 ( 1965). 10 Blumberg, B.S.; G erstley, B.U.S.; H ungerford, P.A., el al.: A serum antigen
12 13
14 15 16 17 18
19
20 21
Prof. Bijan N ik-A khtar , Department of Medicine, School of Medicine, Pahlavi Medical School, Tehran University, Tehran (Iran)
Downloaded by: King's College London 137.73.144.138 - 10/6/2018 11:27:28 PM
11
(Australia antigen) in Down's syndrome, leukemia and hepatitis. Ann. intern. Med. 66: 924-931 (1967). Blumberg, B.S.; S utnick , A.I., and London , W.T.: Hepatitis and leukemia. Their relation to Australia antigen. Bull. N.Y. Acad. Med. 44: 1566-1586 (1968). Vyas, G.N. and Schulman, N .R .: Hemagglutination assay for antigen and antibody associated with viral hepatitis. Science 170: 332-333 (1970). Lander, J.J.; A lter, H.J., and P urcell, R.H.: Frequency of antibody to hepatitisassociated antigen as measured by new radioimmunoassay technique. J.lmmun. 106: 1166—1171 (1971). P urcell, R .H .: H olland, P.V.; W alsh, J.H., el al.: A complement fixation test for measuring Australia antigen and antibody. J. infect. Dis. 120: 383-386 (1969). K night , A.H.; Fox, R.A.; Billod, R.A., el al.: Hepatitis-associated antigen and antibody in hemodialysis patients and staff. Br. Med.i. Hi: 603-606 (1970). London , T.W .: D ifiglia, M.; S utnick , A.I., et a!.: An epidemic of hepatitis in a chronic unit. New Engl.J. Mcd.2S/: 571-578 (1969). Soulier, J.P.; Blatix, C.; C ourovce, A .M ., el al.: Prevention of virus B hepatitis (SH hepatitis) Am. J. Dis. Child. 123: 429-434 (1972). K rugman, S.; G iles, J.P., and H ammond, J.: Viral hepatitis type B (M s-2 strain) prevention with specific hepatitis B immune serum globulin. J. Am. med.Ass. 218: 1665-1670(1 971). N ordenfelt, E.; L indholm , T., and D ahlqui, S.T.: A hepatitis epidemic in a dialysis unit. Occurrence and persistence of Australia antigen among patients and staff. Acta path, microbiol. scand. 78: 692-700 ( 1970). J ones, P.O.; G oldsmith, H.J.; W right , F. K., el al.: Viral hepatitis, a stall' hazard in a dyalysis unit. Lancet i: 835-840 (1967). D esmytfr, J.: Bradburnf, A .F.; Vermylen, C., et al.: Hepatitis B immunoglobulin in prevention of HBS antigenemia in hemodialysis patients. Lancet ii: 377-379 (1075).
