Genome-wide association study of leprosy in Malawi and Mali.

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy.

BCG re-vaccination in Malawi: 30-year follow-up of a large, randomised, double-blind, placebo-controlled trial.

Background: A large, double-blind, randomised, placebo-controlled trial of repeat BCG found 49% efficacy against leprosy but no protection against tuberculosis after 6-9 years' follow-up in 1995. We report here additional follow-up, which resulted in greatly increased tuberculosis case numbers, and allowed subgroup analysis.

Methods: Nearly 47 000 individuals of all ages living in northern Malawi with a BCG vaccine scar were randomly assigned (1:1) between 1986 and 1989 to receive a second BCG or placebo.

Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.

We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.

Investigation of the risk factors for tuberculosis: a case-control study in three countries in West Africa.

Background: Host-related and environment-related factors have been shown to play a role in the development of tuberculosis (TB), but few studies were carried out to identify their respective roles in resource-poor countries.

Methods: A multicentre case-control study was conducted in Guinée, Guinea Bissau, and The Gambia, from January 1999 to March 2001. Cases were newly detected smear positive TB patients.

Large-scale candidate gene study of tuberculosis susceptibility in the Karonga district of northern Malawi.

Twenty-seven polymorphisms from 12 genes have been investigated for association with tuberculosis (TB) in up to 514 cases and 913 controls from Karonga district, northern Malawi. Homozygosity for the complement receptor 1 (CR1) Q1022H polymorphism was associated with susceptibility to TB in this population (odds ratio [OR] = 3.12, 95% Confidence interval [CI] = 1.

Large-scale candidate gene study of leprosy susceptibility in the Karonga district of northern Malawi.

We present a large case-control candidate gene study of leprosy susceptibility. Thirty-eight polymorphic sites from 13 genes were investigated for their role in susceptibility to leprosy by comparing 270 cases with 452 controls in Karonga district, northern Malawi. Homozygotes for a silent T-->C change in codon 352 of the vitamin D receptor gene appeared to be at high risk (odds ratio [OR] = 4.

Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988-2001.

Objective: To document the changing incidence and patterns of tuberculosis (TB) in rural Africa and the extent to which they are influenced by HIV.

Methods: As part of longstanding epidemiological studies in Karonga District, Malawi, a series of case control studies of TB and HIV were conducted from 1988 onwards. Data from these studies, from a total population survey, and from the Malawi national census have been used to reconstruct the changes in the TB epidemic in the area from 1988 to 2001, examining the role of HIV.

Tuberculosis and gender: exploring the patterns in a case control study in Malawi.

Background: In many populations there is an excess of tuberculosis in young women and older men. We explored possible explanations for these patterns, concentrating on human immunodeficiency virus (HIV) status, pregnancy, smoking, cooking smoke exposure, contact with tuberculosis cases within the household or outside, and gender differences in health service usage and diagnostic delay.

Design: Case control study in Karonga District, Malawi.

Linkage analysis of susceptibility to leprosy type using an IBD regression method.

Leprosy is a chronic disease caused by infection with Mycobacterium leprae, which is manifested across a wide clinical spectrum. There is evidence that susceptibility both to leprosy per se and to the clinical type of leprosy is influenced by host genetic factors. This paper describes the application of an identity by descent regression search for genetic determinants of leprosy type among families from Karonga District, Northern Malawi.

Mycobacterial purified protein derivatives stimulate innate immunity: Malawians show enhanced tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-10 responses compared to those of adolescents in the United Kingdom.

To investigate the role of innate immunity in variable efficacy of Mycobacterium bovis BCG vaccination in Malawi and the United Kingdom, we examined 24-h tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-10 responses to mycobacterial purified protein derivatives (PPDs). The rank order in stimulatory potency for different PPDs was the same for all three cytokines. Before vaccination Malawians made higher pro- and anti-inflammatory responses than did United Kingdom subjects.

Trends and measurement of HIV prevalence in northern Malawi.

Background: Most data on HIV prevalence in Malawi come from antenatal clinic (ANC) surveillance and are, therefore, subject to bias.

Objectives: HIV prevalence and risk factors were measured using population-based data to assess the accuracy of ANC surveillance and changes in prevalence and risk factors for HIV over time.

Methods: HIV prevalence was measured in 1988-1993 and 1998-2001 in community controls from case-control studies of mycobacterial disease in Karonga District, Malawi.

Gamma interferon responses induced by a panel of recombinant and purified mycobacterial antigens in healthy, non-mycobacterium bovis BCG-vaccinated Malawian young adults.

We have previously shown that young adults living in a rural area of northern Malawi showed greater gamma interferon (IFN-gamma) responses to purified protein derivatives (PPD) prepared from environmental mycobacteria than to PPD from Mycobacterium tuberculosis. In order to define the mycobacterial species to which individuals living in a rural African population have been exposed and sensitized, we tested T-cell recognition of recombinant and purified antigens from M. tuberculosis (38 kDa, MPT64, and ESAT-6), M.

Risk factors for tuberculosis infection in sub-Saharan Africa: a contact study in The Gambia.

Few studies have investigated the risk factors for tuberculosis (TB) infection in highly endemic countries. We conducted a household study in The Gambia, in which a tuberculin skin test (TST) was performed in members of the households of 315 smear-positive pulmonary TB cases and 305 community control subjects. The risk of being TST positive (10 mm or more) was higher in contacts of cases than in contacts of control subjects.

Risk factors for tuberculosis infection in children in contact with infectious tuberculosis cases in the Gambia, West Africa.

Objective: Tuberculosis (TB) infection is highly prevalent in developing countries. As infected children represent a large proportion of the pool from which TB cases will arise, knowledge of the factors that influence TB infection in children are of importance to evaluate transmission of infection in the community and adapt TB control activities. There are limited data on the risk of infection in child populations in developing countries.

Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial.

Background: Mortality rates of HIV-infected patients treated for tuberculosis remain high. This study aimed to assess the effect on mortality of immunotherapy with single-dose SRL172 added to standard antituberculosis chemotherapy in such patients.

Methods: The double-blind trial enrolled 1229 patients aged 18-60 years, who had never received antiretroviral treatment and who presented with newly diagnosed, sputum-smear-positive pulmonary tuberculosis to referral centres in Lusaka, Zambia, and Karonga, Malawi.

BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies.

Background: The efficacy of BCG vaccines against pulmonary tuberculosis varies between populations, showing no protection in Malawi but 50-80% protection in the UK. To investigate the mechanism underlying these differences, randomised controlled studies were set up to measure vaccine-induced immune responsiveness to mycobacterial antigens in both populations.

Methods: 483 adolescents and young adults in Malawi and 180 adolescents in the UK were tested for interferon-gamma (IFN-gamma) response to M tuberculosis purified protein derivative (PPD) in a whole blood assay, and for delayed type hypersensitivity (DTH) skin test response to tuberculin PPD, before and 1 year after receiving BCG (Glaxo 1077) vaccination or placebo or no vaccine.

Comparison of two versus three smears in identifying culture-positive tuberculosis patients in a rural African setting with high HIV prevalence.

Setting: Karonga district, northern Malawi.

Objective: To compare the sensitivity and specificity of two versus three smears for the diagnosis of pulmonary tuberculosis in a setting with high HIV prevalence.

Design: A total of 1992 pulmonary tuberculosis suspects with three sputum smears taken over a 2-7 day period and at least one culture result were studied.

Environmental mycobacteria in northern Malawi: implications for the epidemiology of tuberculosis and leprosy.

More than 36000 individuals living in rural Malawi were skin tested with antigens derived from 12 different species of environmental mycobacteria. Most were simultaneously tested with RT23 tuberculin, and all were followed up for both tuberculosis and leprosy incidence. Skin test results indicated widespread sensitivity to the environmental antigens, in particular to Mycobacterium scrofulaceum, M.

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.

Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi.

Interferon (IFN)-gamma responsiveness to 12 purified protein derivative (PPD) and new tuberculin antigens from 9 species of mycobacteria was assessed, using a whole blood assay, in 616 young adults living in northern Malawi, where Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination provides no protection against pulmonary tuberculosis. The prevalence of IFN-gamma responsiveness was highest for PPDs of M. avium, M.

BCG scars in northern Malawi: sensitivity and repeatability of scar reading, and factors affecting scar size.

Setting: Karonga district, northern Malawi.

Objective: To assess the sensitivity and repeatability of BCG scar reading, and factors affecting scar size.

Design: Follow-up of individuals aged > 3 months who were recruited into a BCG vaccine trial (1986-1989), and of infants vaccinated in health centres (1989-1991), who were examined for presence and size of BCG scars in subsequent years.

Tuberculosis: associations with HIV and socioeconomic status in rural Malawi.

Tuberculosis (TB) is associated with human immunodeficiency virus (HIV) infection, increasing age and male sex, but less is known about other risk factors in developing countries. As part of the Karonga Prevention Study in northern Malawi, we conducted a retrospective cohort study in the general population to assess risk factors for the development of TB. Individuals were identified in 1986-89 and TB cases diagnosed up to 1996 were included.

Trends in antituberculosis drug resistance in Karonga District, Malawi, 1986-1998.

Setting: Karonga District, Malawi.

Objectives: To examine long term trends in initial and acquired resistance to antituberculosis drugs in a rural area of Africa.

Design: Monitoring of all patients with culture-confirmed tuberculosis 1986-1998.