What has Karonga taught us? Tuberculosis studied over three decades.

This paper summarises tuberculosis (TB) research over almost 30 years in Karonga District, northern Malawi, an area typical of much of rural Africa. The dominant factor has been the human immunodeficiency virus (HIV), which arrived in the district about 1980, leading to an increase in TB incidence to a peak of approximately 65 smear-positive pulmonary cases per 100000 population in 2000. Tuberculin surveys indicate annual risks of Mycobacterium tuberculosis infection of approximately 1%; thus, most of the population is uninfected and at risk of primary infection and disease. Molecular epidemiological studies demonstrate that about two thirds of TB arises from recent infection, but recognisable recent contact is responsible for only about 10% of disease. By 2001, 57% of TB was directly attributable to HIV, implying that it would have declined were it not for HIV. HIV infection increases the risk of TB most among young adults, and greatly increases the risk of recurrence from new infection after treatment. Mortality rates in the HIV-infected are high, but there is no association of HIV with drug resistance. Other risk factors with relatively smaller effects include age and sex, contact, several genetic polymorphisms and area. Neither one nor two doses of the bacille Calmette-Guérin (BCG) vaccine provides protection against adult pulmonary TB, despite protecting against leprosy. Skin test surveys, cohort studies and comparative immunological studies with the UK suggest that exposure to environmental mycobacteria provides some protection against TB and that BCG's failure is attributable partly to this widespread heterologous exposure masking effects of the vaccine. Drug resistance has remained constant (<10%) over more than 20 years. Immunotherapy with M. vaccae provided no benefits, but treatment of HIV-positive patients with cotrimoxazole reduced mortality. The Karonga programme illustrates the value of long-term population-based studies to investigate the natural history of TB and to influence TB control policy. Current studies focus on immunological markers of infection, disease and protection, and on elucidating the impact of antiretroviral treatment on TB incidence at population level.

Polymerase chain reaction of nasal swabs from tuberculosis patients and their contacts.

Previous studies have found Mycobacterium leprae in nasal swabs from leprosy patients, their contacts, and persons living in endemic areas. It might be expected that M. tuberculosis would be present on nasal mucosa of pulmonary tuberculosis patients, but whether they can be detected in patients or contacts is unknown. We used the polymerase chain reaction (PCR) technique on nasal swabs from tuberculosis patients, contacts of tuberculosis patients, leprosy patients, and London controls to look for both M. tuberculosis and M. leprae. Swabs dipped in sputum specimens from smear-positive patients were used as positive controls. The PCRs were conducted in two independent laboratories. M. tuberculosis was detected in nasal swabs from 6/16 smear-positive tuberculosis patients and from 1/10 household contacts by one of the laboratories. All of the sputum swabs were positive for M. tuberculosis, and all of the London controls were negative. M. leprae were found in nasal swabs from 2/5 leprosy patients, but one laboratory also reported M. leprae in swabs from 4/21 tuberculosis patients and from one sputum specimen. The results show that M. tuberculosis can be found in the noses of some tuberculosis patients, and suggest that the bacilli also may be detected in some household contacts. The comparisons with M. leprae and between the two laboratories give further insights into the sensitivity and specificity of the technique.

Does bacille Calmette-Guérin scar size have implications for protection against tuberculosis or leprosy?

SETTING: Total population study in Karonga District, northern Malawi, in which the overall vaccine efficacy of bacille Calmette-Guérin (BCG) has been found to be -7% against tuberculosis and 54% against leprosy. OBJECTIVE: To examine the relationship between BCG scar size and protection against tuberculosis and leprosy. DESIGN: Cohort study in which 85,134 individuals were screened for tuberculosis and 82,265 for leprosy between 1979 and 1984, and followed up between 1986 and 1989. RESULTS: Of the BCG scar positive individuals whose scars were measured, 31/3 2471 were later identified with tuberculosis and 81/31 879 with leprosy. In 19,114 individuals, of whom 17 developed tuberculosis, tuberculin induration was measured at first examination. Mean scar sizes increased with increasing tuberculin induration in all except the oldest individuals. Mean scar sizes were lowest in individuals aged < 10 years, highest in individuals aged 10-29 years and intermediate in older individuals. There was some evidence (P = 0.08) for an increase in tuberculosis risk with increasing scar size, which probably reflects the known correlation between scar size and tuberculin status at the time of vaccination. There was no clear association between BCG scar size and leprosy incidence. CONCLUSIONS: We find no evidence that increased BCG scar size is a correlate of vaccine-induced protective immunity against either tuberculosis or leprosy.

Patterns of initial and acquired antituberculosis drug resistance in Karonga District, Malawi.

There is concern that drug-resistant tuberculosis is increasing and may be concentrated among HIV-positive patients. Little information is available from developing countries, where surveillance studies are often unable to distinguish resistance in previously untreated patients (initial resistance) from resistance acquired following drug therapy, and where information on the HIV status of the patients is rare. Initial resistance patterns reflect the strains being transmitted in the community. We have studied patterns of resistance in northern Malawi, where the Lepra Evaluation Project has been collecting data on drug resistance since 1986. Initial drug sensitivity results were available for 373 new cases of tuberculosis. Initial resistance to at least one drug was found in 44 of these patients (11.8%, 95% CI 8.5-15.1): 13 were resistant to streptomycin alone, 13 to isoniazid alone, and 17 to more than one drug. Only 3 patients showed initial rifampicin resistance-1 in isolation, 1 in combination with streptomycin, and 1 with triple resistance. Drug resistance was not related to age, sex, or HIV status of the patient and there was no evidence of any increase over the period studied. There was no evidence of geographic clustering of the resistant strains, or of any increased risk of resistant strains in households with previous tuberculosis cases. Acquired resistance during follow-up was found in 5 of 329 patients with documented initially fully sensitive strains. 5 patients with initial resistance seemed to show reversion to sensitivity. The absence of an increase in drug resistance, despite an increase in tuberculosis cases over the period, is encouraging for the control programme. It emphasises the need to collect information from many areas before assuming that increases in antituberculosis drug resistance are occurring worldwide.