Impact of co-infections and BCG immunisation on immune responses among household contacts of tuberculosis patients in a Ugandan cohort.
BACKGROUND
Tuberculosis 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.


METHODS
Adults 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.


RESULTS
We 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.


CONCLUSIONS
We 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.
College of Health Sciences, Makerere University, Kampala, Uganda.
Irene A
IA
Biraro
College of Health Sciences, Makerere University, Kampala, Uganda.
Moses
M
Egesa
Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Frederic
F
Toulza
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda.
Jonathan
J
Levin
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda; Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Stephen
S
Cose
College of Health Sciences, Makerere University, Kampala, Uganda.
Moses
M
Joloba
Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Steven
S
Smith
Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Hazel M
HM
Dockrell
College of Health Sciences, Makerere University, Kampala, Uganda.
Achilles
A
Katamba
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda; Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Alison M
AM
Elliott
D000293:Adolescent; D000328:Adult; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D060085:Coinfection; D016207:Cytokines; D015981:Epidemiologic Factors; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000453:epidemiology; D006373:Helminthiasis / Q000453:epidemiology; D006801:Humans; D007114:Immunization; D015994:Incidence; D055985:Latent Tuberculosis / Q000453:epidemiology; D008288:Malaria / Q000453:epidemiology; D008297:Male; D015995:Prevalence; D012307:Risk Factors; D014376:Tuberculosis / Q000453:epidemiology* / Q000276:immunology* / Q000635:transmission; D014454:Uganda / Q000453:epidemiology; D055815:Young Adult
D001500:BCG Vaccine; D016207:Cytokines