Abstract
BackgroundTuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic.MethodsAdults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11-plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models.ResultsWe enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39–2.66; 0.96); hookworm, 2.81 (0.56–14.14; 0.20); malaria, 1.06 (0.48–2.35; 0.87); HIV, 0.74 (0.22–2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBI-positive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNγ 0.20 (0.09–0.42), <0.0001; IL-2 0.34 (0.20–0.59), <0.0001; and TNFα 0.36 (0.16–0.79), 0.01.ConclusionsWe found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.
Highlights
Tuberculosis (TB) is a complex disease with a global burden of 8.7million (8.3–9.0million) incident cases and an annual mortality of approximately 9million deaths
A study by Mahan et al, showed higher concentrations of IFNc responses in contacts with latent tuberculosis infection (LTBI) compared to those without LTBI [50]. They focused on IFNc responses and they diagnosed LTBI using the tuberculin skin test while we assessed a range of immune responses and used the QuantiFERON-TB Gold In-Tube (QFN) test
When we assessed the effect of co-infections on cytokine responses in the household contacts (HHCs) who had LTBI, we found that malaria and HIV showed reduced cytokine responses across all cytokine families, with statistically significant associations for TNFa, in keeping with their known immune suppressive effects
Summary
Tuberculosis (TB) is a complex disease with a global burden of 8.7million (8.3–9.0million) incident cases and an annual mortality of approximately 9million deaths. There has been a particular interest in whether infections endemic to the tropics modulate host immunity, resulting in increased susceptibility to TB and thereby maintaining the TB epidemic, especially in low income countries such as Uganda [6,7]. Some of these co-infections have been well studied, in particular the role of HIV in fueling the spread of tuberculosis [8,9,10], but the relationship between TB and other coinfections such as helminths, malaria and cytomegalovirus (CMV) remains to be clearly documented. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic
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