1365
Virus VIRUS
hepatitis
Hepatitis Updated is
one
of the most
important
infectious diseases yet to be controlled. The discovery1 in 1965 of hepatitis-B antigen led to tremendous advances in the knowledge of the disease and its prevention, and now the agent of virus-A
hepatitis) also seems to have hepatitis (infectious been identified.2 With practical methods of active and passive immunisation being reported, the time seemed right for the Committee on Virus Hepatitis of the National Research Council in Washington to organise a meeting.3 Type-A hepatitis is probably a more important worldwide problem than type-B. Clues to the of the agent first came from A. A. FERRIS and co-workers in Australia4 who found viral particles in the stools of patients with type-A hepatitis; and in 1973 R. H. PuRCELL and his colleagues at Bethesda identified 27 nm. particles, some full and some empty, in stools during the acute phase of type-A hepatitis.2 The particles were aggregated by convalescent serum. Meanwhile, F. DEINHARDT and his group in Chicago had been passaging type-A hepatitis in marmoset monkeys5 (the only other susceptible animal seems to be the chimpanzee). The livers of the infected marmosets contained the 27 nm. viral particles and these reacted with antisera raised in guineapigs immunised with type-Ahepatitis particles from fseces of patients. Antibody to type-A hepatitis appears quite early in the acute attack and tends to persist in the serum-volunteers recovering from type-A hepatitis cannot be reinfected. As might be expected, the frequency of antibody in the population increases with age. In volunteers, virus particles appear in the stools 5 days before the serum-transaminase rises.6 These disappear as the enzymes reach their peak. This confirms the clinical impression that patients with type-A hepatitis become non-infective as the disease becomes overt. As the virus disappears, so the serum-IgM rises. M. HILLEMAN3 has displayed the particles in the cytoplasm of human liver cells; and P. J. PROVOST3 has characterised the agent as an R.N.A. virus in-
nature
1.
Blumberg, B. S., Alter, H. J., Visnich, S. J. Am. med. Ass. 1965, 191,
2.
Feinstone, S. M., Kapikian, A. Z., Purcell, R. H. Science, 1973, 182,
541. 1026. 3.
Symposium on Viral Hepatitis. National Academy of Sciences, Washington, March 17-19, 1975. Am. J. med. Sci. (in the press). 4. Ferris, A. A., Kaldor, J., Gust, I. D., Cross, G. Lancet, 1970, ii, 243. 5. Deinhardt, F., Holmes, A. W., Capps, R. B., Popper, H. J. exp. Med. 1967, 125, 673. 6.
Dienstag, J. L., Feinstone, S. M., Kapikian, Lancet, April 5, 1975, p. 765.
A.
Z., Purcell, R. H.
activated by ultraviolet light, by heating to 100°C for 5 minutes, and by exposure to 1-in-4000 formalin. It seems identical with the MS1 strain described by S. KRUGMAN. At present, tests of hepatitis-A antibody and antigen depend on material prepared from marmoset liver. Marmosets are becoming scarce and their export from South America is restricted. Turning to hepatitis B, the large particle in blood described by DANEprobably represents the complete virion. Electronmicroscopic and immunofluorescent studies show that the Dane particle is composed of a core which is found in the nucleus of the liver cell and double-shelled surface particles which are formed in the cytoplasm.9 JUNE ALMEIDA and her colleagues,10 using detergent treatment of Dane particles with subsequent immune electronmicroscopy, have confirmed that the core is formed in the nucleus and the surface material added in the
cytoplasm-observations supported by immunofluorescence light microscopy.11 The core contains a D.N.A. polymerase,12 and if the core is treated with detergent circular D.N.A. is obtained. The surface antigen is the one routinely measured in blood and is termed HBsAg. The antibody to it is HBsAb. The core antigen is termed HBcAg and the core antibody HBcAb. HBcAb may be measured using material obtained from chimpanzees with type-B hepatitis. J. H. HOOFNAGLE 13 has shown that, in the acutely ill patient, the HBcAb level rises shortly after HBsAg is detected and tends to persist. HBsAb appears later. Antibody against core is unusual in a blooddonor population but is virtually constant in carriers of HBAg. Measurement of anti-core antibodies may be useful in detecting type-B hepatitis when HBgAg is negative and in monitoring infectivity of any volunteer receiving vaccine or immune globulin. If HBcAb rises, there is immunity and not primary infection. Unfortunately, reagents are too scarce for HBcAb to be tested routinely. Methods in the pipeline include radioimmunoassay using the D.N.A. polymerase reaction, a method using tritiated cores, and an immune-adherent haemagglutination reaction. A reservoir for infection exists for type-B hepatitis. J. W. MOSLEY3 estimates that 5-10% of infected persons become carriers. Person-to-person spread takes place not only by routes such as blood-transfusion but also by objects such as shared razors and toothbrushes. Sexual spread is being increasingly recognised,14 and type-B hepatitis is an important Krugman, S., Friedman, H., Lattimer, C. New Engl. J. Med. 1975, 292, 1141. 8. Dane, D. S., Cameron, C. H., Briggs, M. Lancet, 1970, i, 695. 9. Huang, S. N., Millman, I., O’Connell, A., Aronoff, A., Gault, H., Blumberg, B. S. Am. J. Path. 1972, 67, 453. 10. Almeida, J. D., Rubenstein, D., Stott, E. J. Lancet, 1971, ii, 1225. 11. Hadziyannis, S., Moussouros, A., Vissoulis, C., Afroudakis, A. ibid. 1972, i, 976. 12. Robinson, W. S., Clayton, D. A., Greenman, R. L. J. Virol. 1974, 14, 384. 13. Hoofnagle, J. H., Gerety, R. J., Ni, L. Y., Barker, L. F. New Engl. £. 7.
Med. 1974, 290, 1336. 14. Heathcote, J., Sherlock, S. Lancet, 1973, i, 1468.
1366
venereal disease, particularly among homosexuals. The prevalence of carriers seems to be modified by ethnic origin, sex, and age. In Canada 15 a high prevalence of carriers is seen in patients coming from the Mediterranean countries and the Orient. The carrier state is commoner in males than in females aud most are under 30 years of age. Family clustering of HBsAg-positive individuals has been noted. Vertical transmission-that is, from an HBSAg-positive mother to her child-is being increasingly recognised.16 40-70% of babies born to, mothers positive for HBsAg in the third trimester and the first two months post partum will develop antigenaemia and these babies have remained positive for up to 7 years. Spread may be placental or by contact after birth. 17 In Tokyo, K. NISHIOKA3 estimated that about 5000 HBSAg-positive mothers are delivered every year, and that about 3500 of their babies will The be HBsAg-positive and will continue so. neonate with mild hepatitis will remain HBsAgpositive and may later become the adult chronic (" healthy ") carrier. Immune serum globulin is of proved value in the prevention of type-A hepatitis. With type-B hepatitis the position is less certain, perhaps because the antibody titre of the globulin used may have been so low that it was ineffective. However, G. F. GRADY3 has observed, over the years, that the HBsAb titre of immune gammaglobulin obtained from volunteer blood-donations has risen from a mean of 1 in 8 in 1948-67 to 1 in 256 in 1971-73. Although controlled trials have not yet been reported, it must now be assumed that the conventional immune globulin (at least from United States blood-donors) is potent enough to protect against type-B as well as type-A hepatitis. In one trial in the United States immune globulin of known high antibody content was compared with conventional gammaglobulin for protecting hospital staff accidentally exposed to materials containing HBsAg; this trial has had to be extended owing to the low incidence of type-B hepatitis in both treatment groups. Hyperimmune globulin may be of value if ’given to neonates born to HBsAg-positive mothers.’-8 Theoretically, it could also be used to neutralise antigen given in an HBsAg-positive blood-transfusion, although very large amounts of hyperimmune globulin would be needed for this purpose. A.-M. COUROUCÉin Paris is using immune to protect staff on haemodialysis units from hepatitis. Active immunisation against type-B hepatitis is also becoming possible. R. H. PURCELL and his group3 at the National Institutes of Health have prepared a vaccine con-
sisting of subunits of hepatitis B. Dane particles are removed by differential centrifugation so that only the 22 nm. forms remain. Inactivation is by formalin. This vaccine is effective in chimpanzees challenged with hepatitis B. HILLEMAN and his group3 have made a potent vaccine by plasmapheresis of carriers positive for HBsAg. Dane particles are removed and the vaccine is effective against hepatitis B in chimpanzees. 200,000 doses of this vaccine are ready for trial. 20 (lg. is effective in chimpanzees, but 4 (lg..may be enough. There are problems with the existing vaccines. Host protein is introduced (which is undesirable); seroconversion is poor, and very sensitive methods have to be used; subtype specificity is uncertain; and finally there is a possibility that the vaccine may induce a chronic carrier state. A vaccine may eventually be used for patients and staff on oncology2 and dialysis units, and perhaps for any health workers who are heavily exposed to HBsAg. When carriers and sufferers from type-A and type-B hepatitis are identified and these diseases can be prevented, will the problem of viral hepatitis be solved ? Unfortunately there is increasing evidence that other viruses-perhaps they will be designated C, D, and so on-are responsible for a similar clinical illness.19 In blood-donors routine screening for HBsAg has reduced the incidence of transfusion hepatitis by only a quarter. M. GOLDFIELD and 3 colleagues have shown that, when blood was screened for HBsAg by radioimmunoassay, the incidence of post-transfusion hepatitis was 3 per 1000 in recipients of volunteer blood whereas it was 59 per 1000 in those receiving commercial blood. In only 2 cases was there a positive HBsAg. In the U.S.A., exclusion of the commercial blooddonors remains a most important means of reducing post-transfusion hepatitis. The present greatest need in hepatitis research is for an easier source of both type-A and type-B virus and their antibodies. Efforts must be made to find laboratory animals convenient than the marmoset and the chimpanzee ; but tissue-culture material would be better still. A. J. ZucKERMAN’s efforts 3 have not yet yielded consistent results. Meanwhile, the new hepatitis-B vaccines are being tested in volunteers, and we keenly await the outcome. more
globulin
15. Feinman, S. V., Cooter, N., Sinclair, J. C., Wrobel, D. M., Berris, B. Gastroenterology, 1975, 68, 113. 16. Stevens, C. S., Palmer Beasley, R., Tsui, J., Lee, W.-C. New Engl. J. Med. 1975, 292, 771. 17. Schweitzer, I. L., Dunn, A. E. G., Peters, R. L., Spears, R. L. Am. J. Med. 1973, 55, 762. 18. Kohler, P. F., Dubois, R. S., Merrill, D. A., Bowes, W. A. New Engl. J. Med. 1974, 291, 1378.
Tottering
Home
ANYONE who tackles the matter of outpatient . surgery in the seventies is likely to emerge in a state of confusion. There is much hearsay, more opinion for and against, and most of all there are the inbuilt prejudices of those who, having learnt their surgery at the knee of traditionalists, find it uncomfortable 19.
Feinstone, S. M., Kapikian, A. Z., Purcell, R. H., Alter, H. J., Holland, P. V. ibid. 1975, 292, 767.
Virus VIRUS
hepatitis
Hepatitis Updated is
one
of the most
important
infectious diseases yet to be controlled. The discovery1 in 1965 of hepatitis-B antigen led to tremendous advances in the knowledge of the disease and its prevention, and now the agent of virus-A
hepatitis) also seems to have hepatitis (infectious been identified.2 With practical methods of active and passive immunisation being reported, the time seemed right for the Committee on Virus Hepatitis of the National Research Council in Washington to organise a meeting.3 Type-A hepatitis is probably a more important worldwide problem than type-B. Clues to the of the agent first came from A. A. FERRIS and co-workers in Australia4 who found viral particles in the stools of patients with type-A hepatitis; and in 1973 R. H. PuRCELL and his colleagues at Bethesda identified 27 nm. particles, some full and some empty, in stools during the acute phase of type-A hepatitis.2 The particles were aggregated by convalescent serum. Meanwhile, F. DEINHARDT and his group in Chicago had been passaging type-A hepatitis in marmoset monkeys5 (the only other susceptible animal seems to be the chimpanzee). The livers of the infected marmosets contained the 27 nm. viral particles and these reacted with antisera raised in guineapigs immunised with type-Ahepatitis particles from fseces of patients. Antibody to type-A hepatitis appears quite early in the acute attack and tends to persist in the serum-volunteers recovering from type-A hepatitis cannot be reinfected. As might be expected, the frequency of antibody in the population increases with age. In volunteers, virus particles appear in the stools 5 days before the serum-transaminase rises.6 These disappear as the enzymes reach their peak. This confirms the clinical impression that patients with type-A hepatitis become non-infective as the disease becomes overt. As the virus disappears, so the serum-IgM rises. M. HILLEMAN3 has displayed the particles in the cytoplasm of human liver cells; and P. J. PROVOST3 has characterised the agent as an R.N.A. virus in-
nature
1.
Blumberg, B. S., Alter, H. J., Visnich, S. J. Am. med. Ass. 1965, 191,
2.
Feinstone, S. M., Kapikian, A. Z., Purcell, R. H. Science, 1973, 182,
541. 1026. 3.
Symposium on Viral Hepatitis. National Academy of Sciences, Washington, March 17-19, 1975. Am. J. med. Sci. (in the press). 4. Ferris, A. A., Kaldor, J., Gust, I. D., Cross, G. Lancet, 1970, ii, 243. 5. Deinhardt, F., Holmes, A. W., Capps, R. B., Popper, H. J. exp. Med. 1967, 125, 673. 6.
Dienstag, J. L., Feinstone, S. M., Kapikian, Lancet, April 5, 1975, p. 765.
A.
Z., Purcell, R. H.
activated by ultraviolet light, by heating to 100°C for 5 minutes, and by exposure to 1-in-4000 formalin. It seems identical with the MS1 strain described by S. KRUGMAN. At present, tests of hepatitis-A antibody and antigen depend on material prepared from marmoset liver. Marmosets are becoming scarce and their export from South America is restricted. Turning to hepatitis B, the large particle in blood described by DANEprobably represents the complete virion. Electronmicroscopic and immunofluorescent studies show that the Dane particle is composed of a core which is found in the nucleus of the liver cell and double-shelled surface particles which are formed in the cytoplasm.9 JUNE ALMEIDA and her colleagues,10 using detergent treatment of Dane particles with subsequent immune electronmicroscopy, have confirmed that the core is formed in the nucleus and the surface material added in the
cytoplasm-observations supported by immunofluorescence light microscopy.11 The core contains a D.N.A. polymerase,12 and if the core is treated with detergent circular D.N.A. is obtained. The surface antigen is the one routinely measured in blood and is termed HBsAg. The antibody to it is HBsAb. The core antigen is termed HBcAg and the core antibody HBcAb. HBcAb may be measured using material obtained from chimpanzees with type-B hepatitis. J. H. HOOFNAGLE 13 has shown that, in the acutely ill patient, the HBcAb level rises shortly after HBsAg is detected and tends to persist. HBsAb appears later. Antibody against core is unusual in a blooddonor population but is virtually constant in carriers of HBAg. Measurement of anti-core antibodies may be useful in detecting type-B hepatitis when HBgAg is negative and in monitoring infectivity of any volunteer receiving vaccine or immune globulin. If HBcAb rises, there is immunity and not primary infection. Unfortunately, reagents are too scarce for HBcAb to be tested routinely. Methods in the pipeline include radioimmunoassay using the D.N.A. polymerase reaction, a method using tritiated cores, and an immune-adherent haemagglutination reaction. A reservoir for infection exists for type-B hepatitis. J. W. MOSLEY3 estimates that 5-10% of infected persons become carriers. Person-to-person spread takes place not only by routes such as blood-transfusion but also by objects such as shared razors and toothbrushes. Sexual spread is being increasingly recognised,14 and type-B hepatitis is an important Krugman, S., Friedman, H., Lattimer, C. New Engl. J. Med. 1975, 292, 1141. 8. Dane, D. S., Cameron, C. H., Briggs, M. Lancet, 1970, i, 695. 9. Huang, S. N., Millman, I., O’Connell, A., Aronoff, A., Gault, H., Blumberg, B. S. Am. J. Path. 1972, 67, 453. 10. Almeida, J. D., Rubenstein, D., Stott, E. J. Lancet, 1971, ii, 1225. 11. Hadziyannis, S., Moussouros, A., Vissoulis, C., Afroudakis, A. ibid. 1972, i, 976. 12. Robinson, W. S., Clayton, D. A., Greenman, R. L. J. Virol. 1974, 14, 384. 13. Hoofnagle, J. H., Gerety, R. J., Ni, L. Y., Barker, L. F. New Engl. £. 7.
Med. 1974, 290, 1336. 14. Heathcote, J., Sherlock, S. Lancet, 1973, i, 1468.
1366
venereal disease, particularly among homosexuals. The prevalence of carriers seems to be modified by ethnic origin, sex, and age. In Canada 15 a high prevalence of carriers is seen in patients coming from the Mediterranean countries and the Orient. The carrier state is commoner in males than in females aud most are under 30 years of age. Family clustering of HBsAg-positive individuals has been noted. Vertical transmission-that is, from an HBSAg-positive mother to her child-is being increasingly recognised.16 40-70% of babies born to, mothers positive for HBsAg in the third trimester and the first two months post partum will develop antigenaemia and these babies have remained positive for up to 7 years. Spread may be placental or by contact after birth. 17 In Tokyo, K. NISHIOKA3 estimated that about 5000 HBSAg-positive mothers are delivered every year, and that about 3500 of their babies will The be HBsAg-positive and will continue so. neonate with mild hepatitis will remain HBsAgpositive and may later become the adult chronic (" healthy ") carrier. Immune serum globulin is of proved value in the prevention of type-A hepatitis. With type-B hepatitis the position is less certain, perhaps because the antibody titre of the globulin used may have been so low that it was ineffective. However, G. F. GRADY3 has observed, over the years, that the HBsAb titre of immune gammaglobulin obtained from volunteer blood-donations has risen from a mean of 1 in 8 in 1948-67 to 1 in 256 in 1971-73. Although controlled trials have not yet been reported, it must now be assumed that the conventional immune globulin (at least from United States blood-donors) is potent enough to protect against type-B as well as type-A hepatitis. In one trial in the United States immune globulin of known high antibody content was compared with conventional gammaglobulin for protecting hospital staff accidentally exposed to materials containing HBsAg; this trial has had to be extended owing to the low incidence of type-B hepatitis in both treatment groups. Hyperimmune globulin may be of value if ’given to neonates born to HBsAg-positive mothers.’-8 Theoretically, it could also be used to neutralise antigen given in an HBsAg-positive blood-transfusion, although very large amounts of hyperimmune globulin would be needed for this purpose. A.-M. COUROUCÉin Paris is using immune to protect staff on haemodialysis units from hepatitis. Active immunisation against type-B hepatitis is also becoming possible. R. H. PURCELL and his group3 at the National Institutes of Health have prepared a vaccine con-
sisting of subunits of hepatitis B. Dane particles are removed by differential centrifugation so that only the 22 nm. forms remain. Inactivation is by formalin. This vaccine is effective in chimpanzees challenged with hepatitis B. HILLEMAN and his group3 have made a potent vaccine by plasmapheresis of carriers positive for HBsAg. Dane particles are removed and the vaccine is effective against hepatitis B in chimpanzees. 200,000 doses of this vaccine are ready for trial. 20 (lg. is effective in chimpanzees, but 4 (lg..may be enough. There are problems with the existing vaccines. Host protein is introduced (which is undesirable); seroconversion is poor, and very sensitive methods have to be used; subtype specificity is uncertain; and finally there is a possibility that the vaccine may induce a chronic carrier state. A vaccine may eventually be used for patients and staff on oncology2 and dialysis units, and perhaps for any health workers who are heavily exposed to HBsAg. When carriers and sufferers from type-A and type-B hepatitis are identified and these diseases can be prevented, will the problem of viral hepatitis be solved ? Unfortunately there is increasing evidence that other viruses-perhaps they will be designated C, D, and so on-are responsible for a similar clinical illness.19 In blood-donors routine screening for HBsAg has reduced the incidence of transfusion hepatitis by only a quarter. M. GOLDFIELD and 3 colleagues have shown that, when blood was screened for HBsAg by radioimmunoassay, the incidence of post-transfusion hepatitis was 3 per 1000 in recipients of volunteer blood whereas it was 59 per 1000 in those receiving commercial blood. In only 2 cases was there a positive HBsAg. In the U.S.A., exclusion of the commercial blooddonors remains a most important means of reducing post-transfusion hepatitis. The present greatest need in hepatitis research is for an easier source of both type-A and type-B virus and their antibodies. Efforts must be made to find laboratory animals convenient than the marmoset and the chimpanzee ; but tissue-culture material would be better still. A. J. ZucKERMAN’s efforts 3 have not yet yielded consistent results. Meanwhile, the new hepatitis-B vaccines are being tested in volunteers, and we keenly await the outcome. more
globulin
15. Feinman, S. V., Cooter, N., Sinclair, J. C., Wrobel, D. M., Berris, B. Gastroenterology, 1975, 68, 113. 16. Stevens, C. S., Palmer Beasley, R., Tsui, J., Lee, W.-C. New Engl. J. Med. 1975, 292, 771. 17. Schweitzer, I. L., Dunn, A. E. G., Peters, R. L., Spears, R. L. Am. J. Med. 1973, 55, 762. 18. Kohler, P. F., Dubois, R. S., Merrill, D. A., Bowes, W. A. New Engl. J. Med. 1974, 291, 1378.
Tottering
Home
ANYONE who tackles the matter of outpatient . surgery in the seventies is likely to emerge in a state of confusion. There is much hearsay, more opinion for and against, and most of all there are the inbuilt prejudices of those who, having learnt their surgery at the knee of traditionalists, find it uncomfortable 19.
Feinstone, S. M., Kapikian, A. Z., Purcell, R. H., Alter, H. J., Holland, P. V. ibid. 1975, 292, 767.
