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Molecular diagnosis of tuberculosis: the need for new diagnostic tools.

The resurgence of tuberculosis over the past decade is now a familiar story to readers of Thorax. The interaction between HIV and mycobacteria is one of the significant causes. The consequences of this interaction have been well described and have served to exacerbate the problem of confirming a diagnosis of tuberculosis. Throughout the developing world the majority of adults are infected with Mycobacterium tuberculosis which has led to tuberculosis being seen as one ofthe commonest secondary diseases associated with HIV in these societies.'2 In contrast, disease due to Mycobacterium avium is rarely seen, which has allowed sputum microscopy to retain its specificity as a diagnostic tool. Unlike many of the organisms that afflict the HIV seropositive patient, M tuberculosis is a virulent pathogen and therefore causes disease in those with minimal immunosuppression who are infected with HIV. These patients present with features indistinguishable from those seen before the HIV era. As immunosuppression deepens, tuberculosis becomes an increasingly disseminated disease and provokes a less brisk immune response. Cavitation becomes rarer, lesions are less confined to the apices, and extrapulmonary disease becomes more common.34 A consequence of these changes is that fewer patients have positive sputum smears on direct microscopy, which accords with the smaller numbers of bacilli found in sputum from HIV seropositive patients.57 HIV-related immunosuppression also leads to an increased susceptibility to disease following recent infection or reinfection.8 This may also explain the increase in numbers of cases with disease reminiscent of primary infection with pleural effusions, hilar lymphadenopathy and miliary spread, most of whom have negative sputum microscopy. In Lusaka, the capital city of Zambia, for instance, 75% of tuberculosis patients are HIV seropositive.9 In 1993 more than one third of pretreatment samples that grewM tuberculosis were negative on direct smear (G Kahenya, Chest Disease Laboratory, Lusaka, Annual Report 1993) and only 19% ofnew cases were smear positive (R Msiska, National AIDS, STD, TB and Leprosy Control Programme, Annual Report 1993), although the latter statistic may also reflect poor utilisation of the microscopy services. From a theoretical viewpoint the rise in smear negative disease does not alter the approach to tuberculosis control. The goal must still be to find smear positive cases and treat them effectively. However, it is clear that the large number of patients with tuberculosis but negative sputum smears will be a huge stress on the diagnostic and clinical services in countries where both epidemics overlap, and a new diagnostic tool that is more rapid than culture and more sensitive than microscopy, but still specific, would be a major advance. In contrast, in the industrialised world mycobacterial disease in those infected with HIV is more frequently due to M avium, particularly in those with advanced immunosuppression, and the priority here is the individual patient rather than the community. In addition to the need for rapid diagnosis in the paucibacillary case, there is also a real need to distinguish between different acid fast bacilli and traditional methods involving cultivation may take weeks.