Studies included were those that evaluated the performance of the technologies of interest for the diagnosis of TB disease among adult (>15 years) with presumed TB or people with TB in LMIC.
The initial search yielded 789 citations. After full-text review of 185 papers evaluating IGRAs for the diagnosis of active TB, 22 were determined to meet eligibility criteria, covering 33 unique evaluations of one or more IGRAs (hereafter referred to as studies) in 19 published and three unpublished reports. Of the 33 studies, 10 (30%) were from low-income countries and 23 (70%) were from middle-income countries. Seventeen studies (52%) included People with HIV (n=1057), and 27 studies (82%) involved ambulatory subjects (outpatients as well as hospitalized patients).
IGRAs were performed in people suspected of having active TB in 19 studies (58%) and in people with known active TB in 14 studies (42%). Because of the focus on diagnostic accuracy for active TB and the high prevalence of TB infection in high TB burden settings, IGRA specificity was estimated exclusively among studies enrolling TB suspects where the diagnostic work-up ultimately showed no evidence of active disease.
The results demonstrated the following in LMIC:
- The sensitivity of IGRAs in detecting active TB among people suspected of having TB ranged from 73% to 83% and specificity from 49% to 58%. Therefore, one in four patients, on average, with culture-confirmed active TB could be expected to be IGRA-negative in LMIC, with serious consequences for patients in terms of morbidity and mortality.
- There was no evidence that IGRAs have added value beyond conventional microbiological tests for the diagnosis of active TB. Among studies that enrolled TB suspects (i.e. patients with diagnostic uncertainty), both IGRAs demonstrated suboptimal “rule-out” values for TB disease.
- Even though data were limited, the sensitivity of both IGRAs was lower among People with HIV (about 60–70%), suggesting that nearly one in three People with HIV with active TB would be IGRA-negative.
- There was no consistent evidence that either of the two IGRAs was more sensitive than the TST for active TB diagnosis, although comparisons with pooled estimates of TST sensitivity were difficult to interpret owing to substantial heterogeneity.
- The few available head-to-head comparisons between QFT-GIT and T-Spot demonstrated higher sensitivity for the T-Spot platform, although this difference did not reach statistical significance.
- The specificity of both IGRAs for active TB was low, regardless of HIV status, and results suggested that one in two patients without active TB would be IGRA-positive, with adverse consequences for patients because of unnecessary therapy for TB and a missed differential diagnosis.
- Two unpublished reports reported no incremental or added value of IGRA test results combined with important baseline patient characteristics (e.g. demographics, symptoms or chest radiograph findings). Thus, these reports did not support a meaningful contribution of IGRAs for the diagnosis of active TB beyond readily available patient data and conventional tests.
- The systematic review focused on the use of IGRAs to diagnose active pulmonary TB, given that data for extrapulmonary TB were lacking; nevertheless, the GDG consensus was that recommendations for pulmonary TB could reasonably be extrapolated to extrapulmonary TB.
- Industry involvement was unknown in 18% of studies and acknowledged in 27% of studies, including donation of IGRA kits as well as work or financial relationships between authors and IGRA manufacturers
Strengths and limitations of the evidence base
Strengths and limitations were as follows:
- Heterogeneity was substantial for the primary outcomes of sensitivity and specificity. Activities performed to minimize heterogeneity were empirical random-effects weighting, excluding studies contributing fewer than 10 eligible individuals, and separately synthesizing data for currently manufactured IGRAs.
- No standard criteria exist for defining high TB incidence countries, and the World Bank income classification is an imperfect surrogate for national TB incidence; nevertheless, results were fundamentally unchanged when restricted to countries with an arbitrarily chosen annual TB incidence of at least 50 per 100 000 population
- It is possible that ongoing studies were missed, despite systematic searching. It is also possible that studies that found poor IGRA performance were less likely to be published. Given the lack of statistical methods to account for publication bias in diagnostic meta-analyses, it would be prudent to assume some degree of overestimation of estimates due to publication bias.
- The systematic review focused on test accuracy (i.e. sensitivity and specificity) and indirect assessment of patient impact (false positive and false negative results). None of the studies reviewed provided information on patient-important outcomes (i.e. showing that IGRAs used in a given situation resulted in a clinically relevant improvement in patient care or outcomes). In addition, no information was available on the values and preferences of patients.
Data synthesis was structured around the preset PICO question, as outlined above. Web Annex I provides additional information on evidence synthesis and analysis.