Long-term Stability of Resistance to Latent Mycobacterium tuberculosis Infection in Highly Exposed Tuberculosis Household Contacts in Kampala, Uganda

Abstract

Resistance to LTBI, defined by repeatedly negative TST and IGRA, in adults who have had close contact with pulmonary TB patients and live in TB-endemic areas, is a stable outcome of M.tb exposure. Repeated longitudinal measurements with two different immune assays and extended follow-up provide enhanced discriminatory power to identify this resister phenotype and avoid misclassification. Resisters may use immune mechanisms to control aerosolized M.tb that differ from those used by persons who develop "classic" LTBI.

IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure

“…While there were small groups of individuals with conversions and reversions of TST and IGRAs, only HIV negative subjects who remained concordantly negative for all tests (n=82) were defined as “resisters” and used in this analysis (Supplementary Table 1). 11 By extension, HIV negative control subjects with LTBI were defined by consistently positive results at all time points by both IGRA (Extended data Figure 1A) and TST (Extended data Figure 1B and 1C), and no evidence of clinical disease. To balance for confounding factors, a representative subset (Supplementary Table 2) of “resisters” and LTBI controls were matched by age (≥ 15 years), gender and epidemiological risk score (Supplementary Table 1), representing, to our knowledge, the longest followed cohort of “resisters”.…”

“…A subset of healthy, immunocompetent individuals remain TST and IGRA negative despite persistent, high levels of exposure to Mtb 4,5 . Highly Mtb exposed but persistently TST and IGRA negative individuals have been described among health-care workers 6,7 , household contacts of TB cases 8–11 , and gold miners living and working in close quarters with individuals with active disease 12,13 . These individuals have been dubbed “resisters” related to their persistent ability to remain TST and IGRA negative 4,5 .…”

“…Here we sought to explore the immunologic basis of persistent TST and IGRA negativity. We leveraged a longitudinal cohort study in Uganda 11 to identify “resisters,” a population of household contacts who were highly exposed to Mtb yet remained persistently IGRA and TST negative over an average of 9.5 years of per-individual follow-up. “Resisters” did not possess a natural or generic anti-pathogen specific antibody profile that could account for a unique ability to handle Mtb .…”

An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa

“…who do not convert their negative IGRA or TST status, and do not develop TB, despite known high Mtb exposure are generally considered to be also resistant to active TB. These persons have been termed either "resisters" or "early clearers" [2][3][4][5] and several immune and genetic factors have been identified that contribute to this phenotype. [6][7][8][9][10].…”

Faculty Opinions recommendation of IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure.

“…A subset of healthy, immunocompetent individuals remain TST and IGRA negative despite persistent, high levels of exposure to Mtb 4,5 . Highly Mtb-exposed but persistently TST and IGRA negative individuals have been described among healthcare workers 6,7 , household contacts of patients with TB [8][9][10][11] and gold miners living and working in close quarters with individuals with active disease 12,13 . These individuals have been dubbed 'resisters' related to their persistent ability to remain TST and IGRA negative 4,5 .…”