MYCOBACTERIA AND AIDS munodefieieney virus infection. New EngL J. Med., 324, 289-294. Stanford, J.L., Grange, J.M. & Pozniak, A. (1991), Is Africa lost? Lancet, II, 557-558. Tckle-Haimanot, R., Frommel, D., Tadesse, T., et el. (1991), A survey of HTLV-I and HIVs in Ethiopian leprosy patients. AIDS, 5, 10g-ll0. Theuer, C.P., Hopewell, P.C., Elias, D., Schecter, G.F,, Rutherford, (3.W. & Chaisson, R.E. (1990), Human immunodeficiency virus infection in tuberculosis patients. ,/. infect. Dis., 162, 8-12. Valone, S,E., Rich, E., Wallis, R.S. & EIIner, J.J. (1988), Expression of tumor necrosis factor in vitro by hu-

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man monuclear phagocytes stimulated with whole Mycobacterium boris BCG and mycobactcrial antigens. Infect. Immun., 56, 3313-3315. Von Reyn, C.F., Falkinham, J.O., Brindle, R., Ranki, A., St. Louis, M., Arhelt, R. & O'Connor, G. (1991), The international epiderniology ofM. avium in AIDS. Abstracts of the Vllth International Conference on AIDS, Florence 2, 262. Yakrus, M.A. & Good, R.C. (1990), Geographic distribution, frequency, and specimen source of Myeobacterium avium complex serntypes isolated from patients with acquired immunodeficiency syndrome..L clin. MicrobioL, 28, 926-929.

Clinical aspects of ..-a,-,-.-,---~-h""~'*~l---,.'nfections in HIV infection R . J . C o k e r ¢n, T . J . H e l l y e r t2), I , N , B r o w n t21 i*l a n d J . N . W e b e r (1) (I) Department o f Genitourinuly Medicine end Comm!mie,~bl~ Di~eetsa% ond t21 Department o f Medieul Microbiology, St. Mary's Hospital Medical School, London W2 I N Y

Introduction Mycobacterial infection has long been associated with defective cell-mediated immunity. In the current A I D S epidemic, infection with ,~Iycobacterium tuberct*losis and Mycobacterium avium-intracellulare complex (MAC) look certain to remain dominant features. Other atypical mycobacteria are involved to a lesser extent. Effects of H I V infection on incident leprosy seem largely speculative. We shall consider the mycobaeteria in patients with H1V infection in four groups: M. tuberculosis, MAC, the other atypical rnycobacteria and M. leprae. The purpose of this article is to provide a brief overview and to highlight the experience at a major British AIDS referral hospital.

Mycobacterium tuberculosis infection Tuberculosis probably affects about one third of the world's population and the number of people dually infected with M. tuberculosis and H1V is increas-

t*) To whom coz,~demce should he addressed.

ing rapidly, particularly in countries in subsaharan Africa. It is estimated that lnor~: than 3 million people are dually infected. There are three distinct cpidemiological patterns of tuberculosis associated with H I V : 1) Reactivation of past M. tuberculosis infection in subjects subsequently infected with HIV; 2) fresh infection of H I V antibody positive individuals ; and 3) cases within the general population arising from direct contact with infectious individuals from categories (l) and (2). Evidence for an interaenon between tuberculosis and AIDS is provided by the increased number of reported cases when HIV encroaches on areas endemic for tuberculosis and the often high rates of HIV posifivity in patients admitted for tuberculosis in such areas. This evidence is well documented elsewhere and there appears to be great variation according to locality with up to 60 % patients HIV-seropositlve, e.g. in Zambia (Elliott et al., 1990). A compounding factor in developing countries may be fhe breakdown of the tuberculosis control infrastructure,

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established pre-AlDS, when tuberculosis was already a serious problem. Tllbcreniosis can present months or years prim to other clinical manifestations of HIV infection and can affect apparently immunocompetent hosts reflecting the greater virulence of M. tuberculosis over other potential opportunist pathogens. Reactivation of latent lesions are the likely source of disease in patients at this stage of HIV infection. In contrast, when tuberculosis occurs in more seriously immunocompromised HIV-infected patients, exogenous inl~ction should be considered (Sutherland, 1990). The clinical features of tuberculosis depend on the degree of immunosuppression. At early stages of HIV infection, the presentation is similar to that seen in non-HIV-infeeted patients with over 75 % patients showing exclusively pulmonary disease. At later stages, including AIDS, extrapulmonary disease predominates, although pulmonary involvement remains a common presentation with associated expectoration of smear-positive sputum. However, pulmonary cavitation is rarely seen and the classic radiological apical infiltrates in the absence of hilar or mediastinal adenopathy occurs in less than 10 % of AIDS-associated cases. Lower lobe infiltrates occur frequently. The radiographic appearance of tuberculosis in AIDS patients may he indistinguishable from primary forms of the disease seen in the immunocompetent host. Extrapulmonary disease in dually infected patients fulfils the revised Centers for Disease Control (CDC) definition of AIDS. The symptoms of tuberculosis are similar whether or not HIV is present and may be difficult to distinguish from those of other HIVrelated diseases. Patients generally present with unexplained fever and night sweats, and, where pulmonary disease is present, cough and dyspnoea may feature. The most common presentations of HIVrelated extrapulmonary tuberculosis are lymphadenitis, miliary disease and bone marrow involvement. An unusual feature is the frequent occurrence of tubercle bacteraernia which has been reported in 40 % of cases. Infection of the central nervous system may also occur. Given the extent of tuberculous involvement in many H1V-infected patients, it is perhaps surprising that bacteriological diagnosis is often found to be difficult and delayed compared to diagnosis in the non-HlV infected. One reason n,ay be the traditionat reliance on sputum specimens, which are less likely to be pc.~itive, particularly if the patients have AIDS. Several studies have suggested that a shotgun approach invo!ving lymph node biopsy material, bone marrow and stool, in addition to sputum and bronchial washings, gives better results. The fact that these patients may be less infectious through the

respiratory route than traditional tuberculous patients has important implications for their cnnicai management. Staining and culture arc still the methods most commonly used in diagnosis but have limitations. Culture is more sensitive than smear but requires time. Significant reductions can be obtained with radiometric methods, but inevitably many patients are treated on clinical suspicion alone after collection of the appropriate specimens. Clinical response then determines future management, It is claimed that the use of specific nucleic acid probes with or without amplification by the polymerase chain reaction (PCR) may overcome the limitations mentioned above, but such technology has little potential routine application in many developing countries where facilities are already fully stretched. Whether such technology would be accepted as cost effective in di~.gnosfic laboratories in developed countries with a low background prevalence of myeobacterial infection is also doubtful. There is a clear need for a direct comparison with current methods in order to establish significant benefit. Although false-negative results are common, a positive tuberculin skin test is useful for diagnosis at all stages of HIV infection, particularly in those patients who have not had BCG. Disseminated BCG disease is uncommon after vaccination of newborns in Africa, despite poorer than usual tuberculin responses in HIV-infected individuals. An important implication is that HIV-infected newborns are likely to catch tuberculosis from reactivation of maternal latent M. tuberculosis infection. It has been suggested, therefore, that the practice of BCG vaccination of asymptomatic infants in Africa should continue. Although tuberculosis in patients infected also with HIV may progress more rapidly than in other individuals, response to treatment is generally good. The recommended regimen comprises isoniazid, rifampiein and pyrazinamide and/or ethamhutol. Treatment is continued for a minimum of 9 months, and at least 6 months after culture conversion. At St. Mary's Hospital, isoniazid is continued indefinitely. Attitudes to chemoprophylaxis vary according to locality. In the USA, isoniazid treatment is advocated for H1V-positive individuals who have or give a history of a positive skin test to tuberculin. In the UK, where BCG vaccination remains widespread, the diagnostic value of the PPD tuberculin test is undetermined and the decision to offer prophylaxis depends more on an assessment of other risk factors such as demographic origin of the patient, history of tuberculous contacts, and the present domicile. In Ai¥ica, chemoprophylaxis would be of value but is largely impractical. Unlike MAC (see below), the microbiological

MYCOBACTERIA AND AIDS characterization of M, tuberculosis from H l g infected individuals has not been widely reported. This apparent lack of interest presumably reflects the general acceptance that most AIDS-related tuberculosis results from reactivation o f previously acquired infection rather than special strains of the organism. Reactivation may be the general rule in the developed countries, but the importance of exogenous infection cannot be underestimated in areas of the developing world endemic for tuberculosis. It is difficult to distinguish between disease due to reactivation and fresh infection purely on clinical grounds. Traditional microbiological methods o f discrimination a mong isolates such as drug sensitivity and phage typing have recently been supplemented by genetic characterization. Restriction fragment length polymorphism (RFLP) typing has been used to confirm nosocomial transmission of tubercle strains and may prove more widely applicable to epidemiological investigations (CDC, 1991). MAC infection

Before the emergence of AIDS, M A C was most frequently recognized as a pulmonary pathogen in middle-aged men with pre-existing lung disease including bronchiectasis, pneumoconiosis, silicosis or healed tuberculosis. Disseminated disease was rarely encountered. Today, M A C is the most c o m m o n cause of systemic bacterial infection in patients with A I D S and has been diagnosed in up to 33 % of patients before death and in over 60 V0 at autopsy. /'here have been few reports of M A C disease from developing countries, presumably reflecting inadequate hcuith care and consequent high mortality due to infection by other more virulent pathogens at earlier stages of the H I V disease progression. Diagnosis is difficult owing to the frequent occurrence of multiple infections and the non-specific nature of the clinical symptoms. The most c o m m o n clinical presentations include persistent fever, malaise and weight toss. Chronic diarrhoea, abdominal pain and malabsorption are also frequently encountered and have been directly att~;buted to severe mesenterie lymphadenopathy and villus atrophy associated with gastrointestinal infection. In contrast, there is a paucity o f pulmonary pathology, leading to the suggestion that the gastrointestinal tract is the most likely portal of entry in the majority of patients. At St. Mary's, we have isolated M A C from 44/263 (i7 ~ ) AIDS patients (Hellyer et aL, 1992, in preparation). In 37/44 (84 %) patients, the infection was considered to be clinically significant and in 30 cf these (81.1%), M A C was isolated from stool specimeos. In contrast, only 13/37 ( 3 5 . 1 % ) paticms had organisms isolated from respiratory sites. Other workers have, however, reported a higher yield from

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the respiratory tract and attempts to correlate gastrointestinal and respiratory colonization with disease dissemination have yielded conflicting results (Ellner et al., 1991). At St. Mary's Hospital, 77 % of patients with M A C disease who had culture-positive stools also had the organisms recovered from other specimens, including normally sterile sites. We have been unable to culture M A C from the stools of normal healthy individuals or H1V-infected patients preAIDS diagnosis (Hellyer et al., 1992, submitted for publication). We would therefore support the use of stool culture for early diagnosis in order that appropriate chemotherapy can be begun. Blood culture is undoubtedly ot diagnostic value if M A C disease is well advanced, but ill view of the inherent drug resistance of the organism, it may be preferable to treat at an early stage of infection. However, there is little evidence to indicate that chemotherapeutic intervention is beneficial to prognosis, although combinations of rifabutin, clofazimiue, etbambutol and isoniazid (Agiaz et al., 1989; Hoy et al., 1990) and amikacin, ciprofloxacin, ethmnbutol and rifampicin (Chin et aL, 1990) have prow.n efficaeeous in ameliorating the severity of symptoms and reducing bacillary load. There is an obvious need for randomized placebocontrolled trials to determine the most effective antibiotic regimen. However, the ability to conduct such investigations is restricted by the nature of the disease itself which manifests only in the Iatter ztages of a terminal illness when prognosis is, in any event, poor. At St. Mary's, M A C infection is diagnosed a mean of 9 months after the initial AIDS-defining diagnosis with a survival thereafter of around 7 mouths. In addition, the toxicity of many antiM A C drugs may outweigh the potential benefits to the patient in *erms of symptomatic relief and there ;., little evidence to show increased survival times among treated pat!eros. Transmission of tuberculosis within a community is by person to person spread and infection can be acquired from birth onwards. In cmttrast, MAC is widely regarded as an opportunist pathogen acquired from the environment only during late-stage HIV infection or by patients severely immunocompromised for other reasons. Evidence for earlier acquisitiou, control and reactivation Js lacking, but remains a possibility. The widespread gut involve ment is indicative of an environmental source (presumably food or water) and, in contrast to patients who have reactivated tuberculosis, specific antibody is absent (Wayne, Young and Bertram, 1986). Earlier suggestions of sexual transmission seem largely unfounded, since patients in all HIV transmission categories may develop M A C disease. the strains of M A C which infect AIDS patients may represem an exclusive subpopulation of those that are present iu the environment as a whole. In

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particular, strains with agglutination serotype ,~ and 8 have been associated with AIDS.related disease iB the U S A and UK. M A C of these serotypes also frequently possess plasmids (Hellyer et aL, 1991). In view of their widespread distribution, M A C may be isolated occasionally from healthy individuals or as contaminants in the laboratory. Characterization of clinical isolates, either genetic or phenotypie, may be of value to clinicians in deciding an appropriate course o f action and obviate unnecessary administration of cosily and toxic drugs.

Other atypical mycobacterial infections Disseminated infections caused by M . xenopi, M. kansasii, M . fortuitum, M. gordonae, M. chelonei, M. haemophilum and M. malmoense have been reported. Generally, these present in a similar fashion to M A C infection with pulmonary, gastrointestinal tract, liver and bone marrow involvement and subsequent non-specific features. However, the incidence o f opportunist myenbacterial disease caused by species other than M A C is low. In one large American study, less than 4 % of disseminated opportunist mycobaeterial disease in patients with AIDS was caused by species other than MAC, with M. kansasii involved in 2.9 % of cases (Horsburgh and Selik. 1989). It seems likely that this imbalance is not a reflection o f differences in the distribution of these species in the environment and consequent opportunities for contact. In southeast England, where M. xenopi is the predominant opportunist in the nonAIDS population (Yates et el., 1986), M A C remains the most prevalent cause of AIDS-related disease, suggesting that M A C is u~dque in its ability to exploit the immunological defects associated with AIDS. Unlike other non-tuberculous mycobaeterial species, M. kansasii is rarely a contaminant. Infection due to M. kansasii, in association with severe immunosuppression, results in pulmonary or extrapulmonary disease. The clinical features and response tO therapy of M. kansasii infection e!osely resemble those of M. tuberculosis infection in patients with AIDS. The clinical importance of infections caused by the other non-tuberculous mycobacteria is less certain and isolation may frequently occur in the absence of obvious disease.

MycobacWrium leprae infeclion The seroprevalence for HIV in areas of leprosy endemicity is high, but there is still insufficient evidence to elucidate the hehaviour of M . leprae in the

context of HIV-related immunosuppression. The question of the relationship between H I V infection and leprosy is particularly important in the context of an ongoing leprosy vaccine trim in northern Malawi. There Ixave been few reports o f leprosy in association with HIV, though the association of leprosy with a specifically impaired cell-mediated immunity has long been recognized. One study from rural Zambia revealed the possibility of serious consequences such as paralysis and neuritis (Meeran, 19891. However, data from the vaccine trial in Malawi showed no evidence for an association between incident leprosy and H I V infection, though there is a suggestion of a possible association between H1V infection and relapses (Ponnighaus et ul., 1991).

References Agins, B.D., Berman, D.S., Spicehandler, D., EI-Sadr, W., Simberkoff, M.S. & Rahal, J.J. (19891, Effect of combined therapy with ansamycin, clofazimin¢, ethambutol and isoniazld for Mycobaclerium avium infection in patients with AIDS. J. infect. Dis., 159, 784-787. Centers for Disease Control (19911, Nosocomial transmiszion of multidrug-re~i~t~n: tuberculos!s -~moog Hlvinfected persons in Florida and New York, 1988-1991. MoffaL Morbid. Weekly Rep., 40, 585-591. Chiu, J., Nussbaum, J., Bozzette, S. el aL (19901, California Collaborative T~eatment Group. Treatment of disseminated Myeobaeterium avium complex infection with amikacin, ethambutol, rifampin, and cipro,qoxaein. A~m. intern. Med.. 113, 358-361. Ellioti, A.M., Luo, N., Tembo, G. el aL (19901, impact of HIV on tuberculosis in Zambia: a cross-sectional study. Brit. reed. J., 301,412-415. Eliner, J.J., Goldberger, M.J. & Parenti, D.M. (19911, Myrobacterium avium infection and AIDS: a therapeutic dilemma in rapid evolution. J. infect. Dis., 163, 1326-i335. Hellyer, T.J., Brown, i.N., Dale, J.W. & Easmon, C.S.F. (199t), Plasmid analysis of Mycobacterium aviumintracellulare (MAI) isolated in the United Kingdom from patients with and without AIDS. J. Med. MicrubioL, 34, 225-231, Hellye,, T.J., Brown, I.N., Taylor, M.B., Allen, B.W. & Easmon, C.S.F. (1992), Gastrointestinal involvement in Mycobacterium avium-intracellulare infection of patients with HIV. ,L infect. (submitted for publication). Horsburgh, C,R. & Selik, R,M. (19891, The epidemiology of disseminated nontuberculous mycobacterial infection in the acquired immunodeficiency syndrome (AIDS). Amer. Rev. Resp. Dis., 139, 4-7, Horsbmgh, C.R., Havlik, J.A., Ellis, D.A. el aL (I991), Survival of patients with acquired immune deficiency syndrome and disseminated ~vcooacterium avium complex infection with and without antimycobacterial chemotherapy. Amer. Rev. Res,o. Dis., 144, 557-359. Hoy, J., Miich , A., Sandland, M., Grayson, L., Lucas,

MYCOBACTERIA R. & Dwyer, B. (1990), Quadruple-drug therapy for Mycobacterium avium-intracellulare baeteremia in AIDS patients, J, infect. Dis,, 161, 801-805, Meeran, K. (1989), Prevalence of ttlV infection among patients with leprosy and tuberculosisln ruralZambia, Brit, mad. J., 298, 364-365, Ponaighaus, J.M., Mwanjasi, L.J., Fine, P.E.M. et at. (1991), ls HIV infection a risk factor for leprosy? Int. J, Leprosy, 59, 221-228. Sutherland, I. (1990), The epidemiology of tuberculosis and

AND AIDS

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AIDS. PHI S Communicable Diseases Report, 90/10, 3-4. Wayne, L.G., Young, L.S, & Bertram, M, (1986), Absence of mycobacteria antibody in patients with acquired immune deficiency ~yndrome. EurotT. J. CIm. Microbiol., 5, 363-365. Yates, M.D., Grange, J.M, & Collins, C.H. (19861, The nature of mycobacterial disease in southeast England, 1977-1984..L EpMemiol. Community Health, 40, 295-300.

Antibody levels to the type-specific glyeopeptidolipid antigens of Mycobacterium avium in homosexual men: possible implications I.M. O r m e a n d D. C h a t t e r j e e Department o f Microbiology, Colorado State University, Fort Collins, C080523 (USA)

Introduction Infection caused by members of the My~bacteriu m avium complex (MAC) has emerged as the most frequent cause of bacteraemia and disseminated disease in patients with A I D S ; the infection is established clinically in 18-27 070 of AIDS patients, and is seen on autopsy in over 50 % of these indiv;duals (Ellner et aL, 1991). As therapy for other opportunistic diseases improves, the frequency of incidence of M A C infection appears to be increasing in parallel with prolonged patient survival (Horsburgh, 1991). Disseminated M A C infection appears to develop as the mean CD4 count reaches very low levels, and is most commonly associated with febrile illness involving weight loss, diarrhoea, and bacteraemia. U p o n autopsy, massive tissue invob,ement is usually seen. The aetiology of M A C infections ia AIDS patients is unknown. Beczuse massive gut invo!vement is commonly seen, and given the ubiquitous distribution of M A C in food and water, it has been suggested that colonization of the gastrointestinal tract is a maior cause o f subsequent disease (Macher et al., 1983; Chaisson and Hopewell, 1989). The role of the pulmonary tract as an additional portal of infection is less clear in view of the observation that severe pul-

monary infections are relatively uncommon (Horsburgh and Selik, 1989); however, a recent carefully designed retrospective stady (Jacobson el al., 1991) suggests that respiratory infection may he more important than previously realized. in the study described here (Lee el al., 1991), we investigated whether homosexual men under heatment for H I V infection or enrolled in an AIDS prevention program had any detectible antibodies to MAC, thus potentially indicating exposure or colonization with this organism. To our surprise, both HIVpositive and H I V negative individuals had substantially raised antibody levels to the type-specific glyeopeptido!ipid (GPL) antigens of M A C The glycopeptidolipid antigens of M. avium In this study, we exploite.! the knowledge that the GPL antigens of M A C are unique haptenic epitopes not encountered on other mycobacteriaI species (Chatterjee et al., 1987; Brennan, I989); thus, as such, they provided a very specific probe for the detection cf anti-MAC antibodies in the sera of test individuals. The basic structure of the GPL antigel3s is shown in figure I. Originally referred to as the C-mycosidcs,