Abstract
RationaleHealthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial.ObjectivesTo measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion.MethodsProspective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT.ResultsOf 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters.ConclusionsTST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.
Highlights
The incidence of Tuberculosis disease (TB) caused by Mycobacterium tuberculosis (Mtb) has been declining, Mtb continues to contribute dramatically to human morbidity and mortality worldwide with 8.3 million new cases estimated in 2012, and 1.3 million deaths due to TB [1]
We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease
Limitations in our understanding of the natural history of Mtb infection have led to the presumption that all otherwise healthy Mtb-exposed individuals with evidence for Mtb-sensitization [demonstrated by a positive Tuberculin skin test (TST) or Mtb-specific interferon-gamma release assay (IGRA)] harbor a latent form of Mtb and remain at lifelong risk for Tuberculosis disease (TB) [2]
Summary
The incidence of Tuberculosis disease (TB) caused by Mycobacterium tuberculosis (Mtb) has been declining, Mtb continues to contribute dramatically to human morbidity and mortality worldwide with 8.3 million new cases estimated in 2012, and 1.3 million deaths due to TB [1]. The biology of human primary Mtb-infection is difficult to study as the majority of sensitized individuals are either uncertain when their exposure occurred, have experienced multiple lifetime or ongoing TB exposure, or have been exposed to non-tuberculosis mycobacteria (NTM) and/or the Bacillus Calmette-Guerin (BCG) vaccine that compromise TST specificity [4] These limitations complicate the interpretation of early studies of Mtb infection that relied on TST as sole marker of Mtb-sensitization [5,6,7,8,9], and in some circumstances have impeded modern studies utilizing serial IGRAs [10,11,12]. To explore this hypothesis we monitored participants of a well-established, longitudinal study of Mtb household contacts (HHC) in Uganda [13,14] who developed evidence of primary Mtb infection following enrollment, with a combination of serial TSTs and an in-house, Mtb-specific whole blood IGRA
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