Relationship between IFN-gamma and skin test responsiveness to Mycobacterium tuberculosis PPD in healthy, non-BCG-vaccinated young adults in Northern Malawi.

SETTING: Rural northern Malawi, where vaccination with BCG Glaxo (1077) provides protection against leprosy but not against pulmonary tuberculosis. OBJECTIVE: To evaluate the patterns of responsiveness to purified protein derivative of Mycobacterium tuberculosis (PPD) in terms of delayed type hypersensitivity (DTH) and interferon-gamma (IFN-gamma) production. DESIGN: IFN-gamma was measured in 6 day whole blood cultures diluted 1 in 10, stimulated with PPD RT48, and the results compared to the DTH response to PPD RT23. A total of 633 individuals aged 12 to 28 years, without prior BCG vaccination, were recruited. RESULTS: Overall, 63% of subjects made a positive IFN-gamma response (defined as >62 pg/ml), and 37% gave a DTH induration of >5 mm. A strong correlation between skin test and IFN-gamma responses was observed, although with interesting exceptions: 13/270 individuals with zero DTH showed IFN-gamma responses >500 pg/ml, and 7/53 individuals with >10 mm induration showed IFN-gamma responses < or = 62 pg/ml. The prevalence of skin test responsiveness increased with age, and was higher among older males than females; age-sex patterns were less clear for IFN-gamma production. CONCLUSION: The 6 day IFN-gamma response to PPD correlates well with Mantoux skin test induration. The discordant individuals may represent important subsets in terms of protective immunity and risk of clinical tuberculosis.

Household and dwelling contact as risk factors for leprosy in northern Malawi.

Data on household and dwelling contact with known leprosy cases were available on more than 80,000 initially disease-free individuals followed up during the 1980s in a rural district of northern Malawi. A total of 331 new cases of leprosy were diagnosed among them. Individuals recorded as living in household or dwelling contact with multibacillary patients at the start of follow-up were at approximately five- to eightfold increased risk of leprosy, respectively, compared with individuals not living in such households or dwellings. Individuals living in household or dwelling contact with paucibacillary cases were both at approximately twofold increased risk. The higher risk associated with multibacillary contact and the fact that dwelling contact entailed a greater risk than household contact if the association was with multibacillary, but not with paucibacillary, disease suggest that paucibacillary cases may not themselves be sources of transmission, but rather just markers that a household has had contact with some (outside) source of infection. When household contact was considered alone, the risks of disease were appreciably higher for younger than for older contacts and for male compared with female contacts. Despite the elevated risk of leprosy associated with household or dwelling contact, only 15% of all incidence cases arose among recognized household contacts. Given the dynamic nature of household membership and consequent misclassification of contact status, the true contribution to overall incidence of contact within household or dwelling settings is likely to be much higher than this, perhaps 30% or higher. Considering the predilection of males for infectious multibacillary forms of the disease, the transmission of Mycobacterium leprae at an early age, in particular to males, may be of particular importance for the persistence of leprosy in endemic communities. Although residential contact with a multibacillary case is the strongest known determinant of leprosy risk, the vast majority of such contacts never manifest disease, which indicates a crucial role for genetic and/or environmental factors in the transmission of M. leprae infection and/or the pathogenesis of clinical 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.

Extended schooling and good housing conditions are associated with reduced risk of leprosy in rural Malawi.

Incidence rates of leprosy in Karonga District, northern Malawi, are analyzed by duration of schooling and housing conditions, controlling for age, sex, BCG scar and geographical zone of the household. There is a strong inverse relationship between the number of completed years of schooling and leprosy risk. Good housing conditions are also associated with a decreased risk of developing leprosy in this population. The effect of housing is seen most strongly in young people. It is hypothesized that schooling changes behavior and housing determines environment in ways which are relevant for the transmission of Mycobacterium leprae or for the appropriate priming of the immune system.

Incidence rates of leprosy in Karonga District, northern Malawi: patterns by age, sex, BCG status and classification.

This paper describes incidence rates by age, sex, prior BCG status and classification in Karonga District, northern Malawi. New cases (489) were identified among 83,500 individuals followed for an average of 5 years (1.12 cases per 1000 person years). Only 29 (6%) of the incident cases were multibacillary. Incidence rates generally were higher among females than males, and increased steadily with age. Although the highest incidence rates of disease were recorded among young adults without BCG scars (males 15-19; females 20-24), these peaks were less dramatic than those reported among young adults in The Philippines and Norway. In the absence of historical data and data on infection status, it is not possible to assess to what extent these peaks may reflect either greater exposure or greater susceptibility to disease among adolescents or young adults. The incidence rates of leprosy among individuals with a prior recorded BCG scar were approximately half those of individuals lacking a scar, at all ages. Since BCG had been introduced into this population only during the 1970s, this provides strong evidence for the effectiveness of BCG when given to adults. It was estimated that past vaccination of approximately 40% of the district population had reduced the overall incidence rate of leprosy by 18%, and that this impact would increase with aging of the vaccinated cohorts. A retrospective examination of the detailed records of initial examinations revealed that 62 (13%) of the incidence cases were recorded as having skin hypopigmentation or blemishes, at the site of subsequent confirmed leprosy lesions, several months or years before they were suspected of having leprosy. The nonspecificity of these lesions, some of which were probably attributable to Mycobacterium leprae infection, highlights the difficulty of diagnosing leprosy in its earliest forms.

The Karonga Prevention Trial: a leprosy and tuberculosis vaccine trial in northern Malawi. I. Methods of the vaccination phase.

In this report the methods of the Karonga Prevention Trial, a double-blind leprosy and tuberculosis vaccine trial in Karonga District, Northern Malawi, are described in detail. During a total population house-to-house survey, which lasted from November 1985 until August 1989, 121,008 people (57,892 males and 63,116 females) were vaccinated. A further 5835 people refused vaccination and 5757 were ineligible for vaccination, 2652 of them because they had a history or signs of leprosy, or because they were suspected to have early leprosy. A total of 66,145 individuals, without evidence of prior BCG vaccination, received one of the following: BCG, BCG + 5 x 10(7) killed Mycobacterium leprae, or BCG + 6 x 10(8) killed M. leprae; 54,863 individuals found with a typical or a doubtful BCG scar received either placebo or BCG, or (from mid-1987 onwards) BCG + 6 x 10(8) killed M. leprae. Side-effects were not looked for systematically, but 4 individuals self-reported with glandular abscesses, 9 with large post-vaccination ulcers (> 25 mm in diameter) and 2 with ulcers which persisted for more than 1 year. BCG vials collected from paraffin refrigerators in the field showed satisfactory concentrations of viable BCG throughout the trial. Post-vaccination skin test (RT23 and M. leprae soluble antigen) results and post-vaccination ulcer rates indicate that few mistakes were made in the field when recording the vaccine codes.

Efficacy of BCG vaccine against leprosy and tuberculosis in northern Malawi.

Protection afforded by BCG (bacillus Calmette-Guérin) vaccines against tuberculosis and leprosy varies widely between different populations. In the only controlled trial which assessed protective efficacy of BCG (Danish and Pasteur strains) against both diseases, there was slightly more protection against leprosy than against tuberculosis. We have studied the protective efficacy of BCG (Glaxo, freeze dried) vaccine against these two diseases in Karonga District, northern Malawi. BCG vaccination was introduced into this population in 1974. Prior information about BCG scar status was available for 83,455 individuals followed up between 1979 and 1989. 414 new cases of leprosy and 180 new cases of tuberculosis were found in this population over that period. Protection was estimated at 50% or greater against leprosy, and there was no evidence for lower protection against multibacillary (84%; 95% confidence interval 26% to 97%) than against paucibacillary (51%; 30% to 66%) disease. There was no statistically significant protection by BCG against tuberculosis in this population. These findings add to the evidence that BCG vaccines afford greater protection against leprosy than against tuberculosis.

Is HIV infection a risk factor for leprosy?

A case control study was undertaken during 1988 and 1989 within the framework of the LEPRA Evaluation Project (LEP)/Karonga Prevention Trail (KPT) in Karonga District, northern Malawi, to investigate whether HIV infection is a risk factor for clinical leprosy. Cases were newly ascertained, biopsy-confirmed, incident leprosy patients older than 14 years of age. Controls were selected from the computer data base on over 170,000 people who form the basis of LEP/KPT. They were matched for sex, age, and area of residence. HIV seropositivity rates were 1.8% (2/112) for incident leprosy cases and 2.4% (24/1011) for controls. The Mantel Haenszel odds ratio is 0.6 (95% confidence interval 0.1-3.3). Thus, no evidence for an association between HIV infection and leprosy incidence has been observed in this population. In a parallel investigation, an odds ratio of 7.4% (95% confidence interval 3.3-16.7) was found for 102 microscopy- and/or culture-confirmed, incident pulmonary tuberculosis cases in the same population during 1989, a result similar to those obtained elsewhere in Africa. Among leprosy relapses, 16.7% (2/12) were HIV positive.

Certainty levels in the diagnosis of leprosy.

This paper describes a procedure for grading the degree of confidence with which it can be held that a diagnosis of leprosy is in fact correct, after considering all available clinical, historical, bacteriological, and histopathological information. Individual suspects are assigned to one of four categories corresponding to different levels of overall certainty of the diagnosis. The method is illustrated using data from the Lepra Evaluation Project in Northern Malawi, and validated in the context of an analysis of BCG's protective efficacy against clinical leprosy. Although the procedures described in this paper were designed for a specific epidemiological study, the method could be adapted for use in most leprosy research or control programs.

Protective efficacy of BCG against leprosy in Northern Malawi.

The effectiveness of a BCG vaccination programme in protecting against leprosy was assessed by case-control and cohort analyses of data from the Lepra Evaluation Project in Karonga District, Northern Malawi. Results indicate that BCG provides at least 50% protection against leprosy in this population and that protection is independent of age, sex, schooling status, or location within the project area. Agreement between these findings and those from a controlled trial in Uganda indicates that BCG is sufficiently effective against leprosy in East and Central Africa to be considered an important element of leprosy control in that region.