Summary of TB research in Karonga

We have been conducting tuberculosis research in Karonga District since 1986. These studies have contributed to our understanding of tuberculosis, from natural history to control, including interactions with HIV, and immunological interactions with other mycobacterial infections. They illustrate the value of long-term community-wide studies for understanding a complex disease in a population context.

MEIRU staff are stationed at all the major health facilities in the District, where they screen inpatients and outpatients for symptoms of tuberculosis. Additionally, everyone participating in community-based studies is asked about chronic cough. Our Category 3 Chilumba laboratory processes biological samples from district tuberculosis suspects, undertaking both sputum smear microscopy and culture.

Isolates are sent to the UK for species confirmation, drug sensitivities and molecular typing. We work closely with the Malawi National TB Programme and act on its behalf in Karonga District in co-operation with the District Tuberculosis Officer, enhancing the care for tuberculosis patients in the district.

The dominant factor in determining trends has been HIV, which arrived in the district by 1982, leading to an increase in TB incidence to a peak of approximately 125 smear-positive pulmonary cases/100,000 in the mid 1990s.

Rates were already decreasing in the district before the introduction of antiretroviral therapy. HIV infection increases the risk of TB due to recent infection more than that due to past infection, and greatly increases the risk of recurrence from new infection after treatment. Mortality rates in the HIV-infected are high; treatment of HIV-positive patients with co-trimoxazole reduced mortality; immunotherapy with Mycobacterium vaccae did not improve outcomes.

Annual incidence of adult smear positive pulmonary tuberculosis 1988-2014

Tuberculin surveys indicate annual risks of M. 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.

Neither one nor two doses of BCG provides protection against adult pulmonary tuberculosis, 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%) overtime, with no association with HIV status.

Recent consortium studies (, the ILULU Consortum, African-European TB consortium have focused on immunological markers of infection, disease and protection, and on elucidating the impact of anti-retroviral therapy on TB incidence at population level.

Current studies (2012-2016)

Whole genome sequencing

The long term study in the whole population of the district, with detailed data on all patients including contact patterns and follow-up after the end of treatment, gives us an unprecedented opportunity to understand transmission dynamics and disease patterns. Our earlier studies used RFLP to define M. tuberculosis genotypes, but now, in collaboration with the Wellcome Trust Sanger Institute, we have conducted whole genome sequencing of all available isolates (>2000).

Phylogenetic tree of M.tuberculosis strains from Karonga District, 1996-2010. Lineage 1 (Indo Oceanic) is represented in dark blue, Lineage 2 (Beijing/East Asian) in light blue, Lineage 3 (East African Indian) in green, and Lineage 4 (Europe American) in red. From DOI: 10.7554/eLife.05166.003

Studies to date have shown marked differences between the M.tuberculosis lineages in transmissibility; among smear positive patients, little effect of HIV on transmissions resulting in disease; and a reduction in transmission resulting in disease in recent years, We have also confirmed our earlier findings based on RFLP that HIV increases the risk of recurrence due to recent infection, but not relapse, and that although close contact is a risk factor for tuberculosis, most tuberculosis cases do not arise from known contacts.

Tuberculosis cases, transmission networks