False Negative Tuberculin Skin Test (TST) Response in Asymptomatic HIV-1 Infected Blood Donors with Subclinical Iron Overload Developing High Incidence of Pulmonary Tuberculosis on Follow Up

Background: Tuberculin skin testing (TST) response as a predictive tool for development of pulmonary tuberculosis (PT) in Human Immunodeficiency Virus type-1 (HIV-1) infected subjects, is likely to be more valuable at early stage of illness in order to adapt timely management strategy. Earlier reports on HIV-1 infected blood donors with history of oral iron intake and biochemical evidence of iron overload documented development of high incidence of PT on follow up. Methods: A group of HIV-1 infected asymptomatic blood donors, belonging to replacement or voluntary categories, were subjected to TST and anergy testing using a commercial panel of recall antigens along with estimation of serum iron parameters, peripheral CD4+ T cell count, plasma viral load and assessment of in vitro production of interferon gamma (IFN-γ) by peripheral blood mononuclear cells (PBMC) in response to PHA, BCG and PPD. Results: The replacement category of donors showed biochemical evidence of iron overload with high proportion (60%) demonstrating negative TST response on initial testing at enrollment but positive response on repeat testing after 2-3 weeks (boosting) or after 1 year (conversion) consequent to normalization of iron parameters. However, such initial negative TST response at enrollment in donors showing boosting or conversion was not associated with evidence of anergy to recall antigens but corroborated with impaired IFN-γ production by PBMC to PPD challenge that could be reversed on addition of exogeneous recombinant interleukin 12 (rIL-12). Majority (63.6%) of replacement donors showing boosting reaction or conversion developed PT on follow up. Conclusion: Subclinical iron overload may mask TST response due to impaired production of IFN-γ by PBMC to M. tuberculosis specific antigens that could be related to inadequate cooperation of IL-12 from macrophages. Such masking of TST associated with iron overload may hamper predictive value of TST for future development of PT.