Cytomegalovirus antibody responses associated with increased risk of TB disease in Ugandan adults

BACKGROUND:Recent evidence highlights human cytomegalovirus (HCMV) and immune activation as risk factors for tuberculosis (TB) disease. It is not known whether other herpes viruses are also implicated, nor if a dose-response relationship exists between TB risk and herpes co-infection. METHODS:This nested case-control study used stored serum samples from 25 TB cases up to 10 years prior to TB diagnosis and between 3 and 6 matched non-TB controls from a rural Ugandan cohort. Samples were investigated for Epstein Barr (EBV), Herpes Simplex (HSV), and HCMV-specific IgG, serum markers of inflammation, and mycobacterial antibody levels. RESULTS:Humoral response to HCMV, but not EBV or HSV was associated with increased risk of active TB disease up to 10 years prior to diagnosis. Individuals with medium HCMV IgG were 2.8 times more likely to have TB (p=0.055), and those with high HCMV IgG 3.4 times more likely to have TB (p=0.007). Mycobacterial antibody levels were not associated with differences in odds of TB disease. IP-10 was independently associated with increased odds of TB; OR 4.2, p=0.009. CONCLUSIONS:These data provide evidence of a dose response between magnitude of HCMV IgG with risk of TB disease. An inflammatory environment, characterized by serum IP-10 and IL1α, are independently associated with increased risk of TB disease.