Prognostic value of a T-cell-based, interferon-gamma biomarker in children with tuberculosis contact

Abstract

Background: Enzyme-linked immunospot (ELISpot) assay is an increasingly widely used, T-cell-based, interferon-gamma-release assay for diagnosing tuberculosis infection, but whether positive results are prognostic of active tuberculosis is not known.

Objective: To determine whether ELISpot results predict the development of active tuberculosis among persons with recent tuberculosis exposure.

Design: Longitudinal cohort study of children and adolescents with tuberculosis contact recruited from October 2002 to April 2004.

Setting: Community-based contact investigations in Turkey.

Patients: 908 children and adolescents with recent household tuberculosis exposure.

Intervention: Enzyme-linked immunospot assay, incorporating early secretory antigenic target-6 and culture filtrate protein-10, and tuberculin skin test were done at baseline.

Measurements: Incidence rates ratios of progression to active tuberculosis for contacts with positive tuberculin skin test and ELISpot results, and relative incidence rates comparing contacts with positive and negative test results.

Results: Isoniazid preventive therapy was given to 688 (76%) contacts according to local guidelines. Fifteen contacts developed active tuberculosis over 1201 person-years of follow-up. Of 381 contacts with positive ELISpot results, 11 developed active tuberculosis over 536 person-years of follow-up (incidence rate, 21 per 1000 person-years [95% CI, 10.2 to 36.7 per 1000 person-years]), a statistically significant 3- to 4-fold increased risk for progression relative to ELISpot-negative contacts. Of 550 contacts with positive tuberculin skin test results, 12 developed active tuberculosis over 722 person-years of follow-up (incidence rate, 17 per 1000 person-years [CI, 8.6 to 29.0 per 1000 person-years]).

Limitation: Only 3 of the 15 incident cases were confirmed by culture.

Conclusion: Positive ELISpot results predict subsequent development of active tuberculosis in recent tuberculosis contacts. Although tuberculosis contacts with positive ELISpot results have an incidence rate of tuberculosis similar to that of contacts with positive tuberculin skin test results, ELISpot testing could allow more focused targeting of preventive therapy to fewer contacts.

Figure 1

Study flow chart Study flow chart detailing the follow-up of 908 children with complete baseline results for ELISpot and TST. ELISpot = enzyme linked immunospot, TST = tuberculin skin test ^AIndex patients and child contacts were recruited at the 7 government run tuberculosis clinics in the Anatolian side of Istanbul. ^BPediatric Infectious Disease Clinic at Marmara University Hospital, Istanbul. ^CWhen sputum microscopy and culture reports for all 443 index cases were obtained and checked, it transpired that 4 contacts had index cases who were not sputum smear positive and 2 contacts had index cases whose sputum grew non-tuberculous atypical mycobacteria. ^D2 contacts were removed due to the loss of ELISpot plates and 33 contacts were removed due to an episode of bacterial contamination of peptide pool reagents. ^E20 (5%) contacts were ELISpot-positive and 37 (7%) contacts were ELISpot-negative at recruitment ^FIsoniazid preventive therapy was administered on the basis of age and TST results interpreted in accordance with Turkish Ministry of Health guidelines (see Methods). A further 18 contacts ELISpot-positive TST-negative at recruitment and 49 contacts ELISpot-negative TST-negative at recruitment were given IPT because they converted their TST. In total, 688 contacts received IPT of whom 41 were exposed to index cases with multi-drug-resistant tuberculosis. 13 incident cases received IPT: 6 were ELISpot-positive TST-positive, 4 were ELISpot-positive TST-negative (2 of whom converted their TST) and 3 were ELISpot-negative TST-negative (2 of whom converted their TST). None of the incident cases were ELISpot-negative TST-positive. ^GIR = incidence rate per 1000 person years of follow-up