Impact of Co-Infections and BCG Immunisation on Immune Responses among Household Contacts of Tuberculosis Patients in a Ugandan Cohort

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.

Mycobacterium tuberculosis‐specific CD4+ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

“…Further studies are now needed to investigate the impact on these Treg responses on progression to TB. Although a recent study in India failed to show any effect on the rate of progression to active TB associated with filaria or hookworm infections [48], reinfection with both helminths and M. tuberculosis would be common in this setting [49]. The next question that now needs to be answered is to understand how helminths induce this population of CD4 + FoxP3 + T cells.…”

Mycobacterium tuberculosisinfection boosts B cell responses to unrelated pathogens

“…A cross-sectional study design was used to determine whether there were associations between M.tb infection status and antibody responses to heterologous pathogen recall antigens in study participants from a TB household contact study based in Uganda investigating the effect of coinfections in humans on their susceptibility to infection with M.tb (33). Individuals with APTB and their household contacts (HHCs) were recruited from the suburbs of Kampala.…”

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

“…However, the impact helminths have on vaccine efficacy and other secondary infections remains an open question. Indeed, a number of studies report a lack of correlation between intestinal worms and secondary infections (10)(11)(12)(13). In common for many of the studies describing an association between worms and increased susceptibility to secondary infection, or reduced inflammatory response in experimental autoimmune disease, is that the effects have been observed in tissue (s) in direct or close contact with the worm (14,15).…”