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THE LANCET

Australia Antigen-the Pace QuickensINTENSIVE study of the Australia antigen over the

past few years has led clinicians and epidemiologiststo revise their views about the clinical features andmethods of spread of hepatitis-virus-B infection.Concern about the problem was justifiable, butsometimes hysterical overtones have proved a night-mare to those organising haemodialysis units, blood-transfusion services, and laboratories handling bloodspecimens. Practical considerations apart, Australia

antigen provides an intriguing challenge to virologistsand a valuable opportunity for investigation of theimmunological factors in host reactions to an infectiveagent. Although the virus has not yet been cultured,there is increasing evidence based on electron-

microscopic studies of serum that the central core ofthe large Australia-antigen particle described byDANE and his colleagues is the virus itself, probablya picornavirus, which is immunologically distinctfrom its outer coat and the tubular and small sphericalforms of the antigen.2 Examination of liver tissue forviral particles by electron microscopy and forAustralia antigen by immunofluorescence gaveapparently contradictory results initially, but a

pattern is beginning to emerge which permits tentativeconclusions. NOWOSLAWSKI’S group compared thedistribution of intranuclear 20 nm. particles andimmunofluorescence localisation of antigen in post-mortem livers from patients with acute viral

hepatitis, subacute or chronic hepatitis, and carrierswithout hepatic disease. In chronic hepatitisnuclear particles and cytoplasmic localisation of

antigen were observed, predominantly in the relativelynormal tissue, but in adjacent tissue showing themost severe damage only minute amounts of antigencould be demonstrated and no nuclear particles wereseen. Furthermore, livers from patients with severeacute hepatitis had no demonstrable antigen or

nuclear particles, whereas, at the other end of thespectrum, nuclear particles and nuclear or cyto-plasmic antigen were most abundant in patients whowere chronic carriers with histologically normal livers.This dissociation between the severity of hepatocytedamage and cytoplasmic localisation of antigen is in1. Dane, D. S., Cameron, C. H., Briggs, M. Lancet, 1970, i, 695.2. Almeida, J. D., Rubenstein, D., Stott, E. J. ibid. 1971, ii, 1225.3. Krawczynski, K., Nazarewicz, T., Brzosko, W. J., Nowoslawski, A.

J. infect. Dis. 1972, 126, 372.

general agreement with the immunofluorescencework of others. 4,5 Probably the intranuclear particlesare the core of the DANE particle and Australia antigenis added by incorporation of host-derived material inthe cytoplasm of relatively normal hepatocytes.While the virulence of different strains of the virus

may prove to be important in determining the con-sequences of infection, there are several indicationsthat the host response to the core particles, or theAustralia antigen itself, may be a major factor indetermining the severity of the liver disease and inthe pathogenesis of extrahepatic lesions such as

vasculitis and arthritis. A striking feature of Aus-tralia-antigen-containing serum examined under theelectron microscope is the presence of large immunecomplexes, but, despite early evidence that the

severity and chronicity of the hepatic damage mightdepend on antigen or antibody excess,6 no consistentelectron microscopic pattern has emerged; largeparticles and tubular forms are, however, more oftenpresent in patients with chronic disease.’ Indirectevidence that immune complexes are formed in theserum is suggested by the high frequency of anti-complementary activity, 8 but studies of serum-

complement levels have been conflicting. 9,10While the role of immune complexes in producing

the liver damage remains speculative, by analogywith experimental models the Australia antigen seemsto be more convincingly implicated in the patho-genesis of certain extrahepatic lesions. Thus,Australia antigen and complement have been demon-strated in vessel walls in patients with polyarteritisnodosa 11 and in the glomeruli in a patient withglomerulonephritis. 12 Furthermore, the finding oflow serum-complement levels in patients with arthritisassociated with Australia-antigen-positive viral hepa-titis suggests that this manifestation of the disease,which resembles serum sickness, may be mediated byimmune complexes of the antigen.13,14 4An attractive hypothesis implicating a defect of

cell-mediated immunity-particularly of thymus-derived lymphocytes-in determining the severity ofthe hepatic damage and the development of chron-icity has been put forward by DUDLEY and hisassociates.15,16 Using phytoharmagglutinin-inducedlymphocyte transformation as an index of T

4. Hadziyannis, S., Vissoulis, C., Moussouros, A., Afroudakis, A.Lancet, 1972, i, 976.

5. Edgington, T. S., Ritt, D. J. J. exp. Med. 1971, 134, 871.6. Almeida, J. D., Waterson, A. P. Lancet, 1969, ii, 983.7. Wright, R. Br. med. Bull. 1972, 28, 120.8. Shulman, N. R., Barker, L. F. Science, 1969, 165, 304.9. Dudley, F. J., Fox, R. A., Sherlock, S. Lancet, 1971, ii, 1.

10. Kosmidis, J. C., Leader-Williams, L. K. Clin. exp. Immun. 1972, 11,31.

11. Gocke, D. J., Hsu, K., Morgan, C., Bombardieri, S., Lockshin, M.,Christian, C. L. J. exp. Med. 1971, 134, 330.

12. Combes, B., Stastny, P., Shorey, J., Eigenbrodt, E. H., Barrera, A.,Hull, A. R., Carter, N. W. Lancet, 1971, ii, 234.

13. Alpert, E., Isselbacher, K. J., Schur, P. H. New Engl. J. Med. 1971,285, 185.

14. Onion, D. K., Crumpacker, C. S., Gilliland, B. C. Ann. intern. Med.1971, 75, 29.

15. Dudley, F. J., Fox, R. A., Sherlock, S. Lancet, 1972, i, 723.16. Giustino, V., Dudley, F. J., Sherlock, S. ibid. 1972, ii, 850.

86

lymphocyte function, they found that patients whobecome carriers of the antigen have an impairedresponse compared with those who clear the antigenrapidly. The numbers of patients studied were, how-ever, few and adequate serial observations from acuteto chronic disease were lacking. Impaired lymphocytetransformation in response to phytohsemagglutininhas been observed previously in viral hepatitis, andundoubtedly the carrier state is associated with dis-orders in which there is impaired cellular immunity-such as lepromatous leprosy, chronic renal failure,and Down’s syndrome-but the severity of the

hepatic damage, if any, in such patients varies

widely. 17 These concepts have led POPPER andMACKAY 1g to suggest that hepatitis-B antigens maybe responsible for both Australia-antigen-positivechronic active hepatitis and antigen-negative

" auto-

immune " hepatitis; but this view is difficult to

sustain in the light of clinical, epidemiological, andimmunological distinctions between the two groups. 7Another suggestion is that Australia antigen plays animportant role in the aetiology of chronic alcoholicliver disease, based on detection of in-vitro lympho-cyte stimulation in response to Australia-antigen-containing serum in patients with this disease’-9; buthere, too, the immunological observations run so

contrary to clinical findings that much more evidenceis required. With purification of the core and coatantigens imminent, rapid advances in our under-

standing of the pathogenesis of hepatitis-B infection,including both hepatic and extrahepatic manifest-ations, can be expected. To the virologist andimmunologist in search of a human model for a virus-induced immunological disorder the discovery of theAustralia antigen may prove to be the realisation of adream.

Acute Haemorrhagic ConjunctivitisACUTE hxmorrhagic conjunctivitis (A.H.c.) broke

out in Ghana in June, 1969,20,21 and spread along thewest coast of Africa. In 1969 and 1970 it appeared inNigeria,22, 23 the Ivory Coast, Togo, Liberia, SierraLeone, Senegal,2 and Gambia, one after the other.Then it was seen on the Mediterranean coast of Africa,outbreaks being reported from Morocco and Tunisiain the early part of 1971. 25, 26 There was an unconfirmed

17. Sutnick, A. I., London, W. T., Blumberg, B. S., Gerstley, B. J. S.Am. J. clin. Path. 1972, 57, 2.

18. Popper, H., Mackay, I. R. Lancet, 1972, i, 1161.19. Pettigrew, N. M., Goudie, R. B., Russell, R. I., Chaudhuri, A. K. R.

ibid. 1972, ii, 724.20. Chatterjee, S., Quarcoopome, C. O., Apenteng, A. Ghana med. J.

1970, 9, 9.21. Chatterjee, S., Quarcoopome, C. O., Apenteng, A. Br. J. Ophthal.

1970, 54, 626.22. Akinsete, E. O. J. Nigeria med. Ass. 1970, 7, 46.23. Parrott, W. F. Practitioner, 1971, 206, 253.24. Diallo, J., Castets, M., Bassabe, S. Bull. Soc. méd. Afr. noire Lang.

fr. 1971, 16, 73.25. Tarizzo, M. L. Personal communication.26. W.H.O. Wkly epidem. Rec. 1971, 46, 530.

rumour that the disease already existed in Vietnam,Bali, and Djakarta in 1969, but there was no doubtabout the epidemic witnessed by ophthalmologists inJava and Singapore in 1970.27,28 Then, in 1971, A.H.C.spread over almost all Asia and the Indian sub-continent : the Indian outbreak started around

April 29,30 and the disease reached Japan 31 andSouth Korea 32 at the end of August or the beginningof September. In Europe there was a small outbreakfrom September to October in London. The diseasewas still prevalent in all these areas in 1972,but so far no cases have been observed in North andSouth America, Australia, or New Zealand.

KONO et al.33 reported successful isolation of anew picornavirus from conjunctival scrapings of

Japanese patients with A.H.C. It had the generalcharacteristics of an enterovirus and was tentativelydesignated A.H.C. virus. Unlike ordinary entero-

viruses, however, it was not found in the intestinebut was confined to the conjunctiva in the acute stageof the illness.34 Thus, the main source of infectionis probably eye discharge. A.H.C. virus proved to beantigenically distinct from other enteroviruses, andsimilar agents were isolated in London (Prof. B. R.JONES), Hong Kong,35 and Taiwan (Dr J. C.

HIERHOLZER) in one year. At the same time, fourfoldor greater rises in antibody against A.H.C. virus weredemonstrated in paired sera from .H.c. patients inSingapore (1971) 36 and Djakarta (1972).34 YIN-MURPHY 37 isolated an antigenically distinct picorna-virus in the Singapore outbreak of 1970, and itsrelation to the 1971 viral isolates remains to be eluci-dated. The virus was not isolated in Africa until

1971, but Dr. O. G. GAUDIN has lately recoveredseveral strains in Morocco. Comparisons of theAsian and African viruses should show whether a

single type is causing the pandemic.Another important problem is the lumbar radi-

culomyelopathy which sometimes follows the con-junctivitis.38,39 On p. 61 this week ProfessorKONO and his co-workers report that A.H.c. virus hassome degree of neurovirulence in monkeys. Since,however, no neurological complications have beenreported outside India, more work is needed on thisaspect.

27. Lim, K. H., Yin-Murphy, M. Singapore med. J. 1970, 12, 249.28. Mardiono Marsetio, Sardjito, R. Ophthal. indones. (in the press).29. Pramanik, D. D. Practitioner, 1971, 207, 805.30. Roy, I. S., Roy, S. N., Ahmed, E. Br. J. Ophthal. 1972, 56,

501.31. Mitsui, Y., Kajima, M., Matsumura, K., Shiota, H. Jap. J. Ophthal.

1972, 16, 99.32. Kim, J. H., Shin, I. N., Rhee, S. N., Lee, C. W., Kim, J. D. J.

Korean ophthal. Soc. 1972, 13, 17.33. Kono, R., Sasagawa, A., Ishii, K., Sugiura, S., Ochi, M., Matsumiya,

H., Uchida, Y., Kameyama, K., Kaneko, M., Sakurai, N. Lancet,1972, i, 1191.

34. Kono, R. Unpublished.35. Chang, W. K. Personal communication.36. Yin-Murphy, M., Lim, K. H. Lancet, 1972, ii, 857.37. Yin-Murphy, M. S. East Asian J. trop. Med. publ. Hlth, 1972, 3,

303.38. Wadia, N. H., Irani, P. F., Katrak, S. M. Lancet, 1972, ii, 970.39. Bharucha, E. P., Mondkar, V. P. ibid.