The vast majority of the estimated annual 9.4 million new cases of active tuberculosis and 1.7 million tuberculosis-related deaths occur in low- and middle-income countries [50
]. Because of resource constraints, public health policies have appropriately placed limited emphasis on diagnosis and treatment of LTBI in these settings. Clinical use of IGRAs, however, has expanded dramatically in recent years, especially in the private sector [13
]. Because of their high burden of disease and emerging economies, these countries (eg, India, South Africa, Brazil, and China) represent a potentially lucrative market for commercial IGRAs. Although IGRAs are intended for LTBI and not active tuberculosis disease, and although these tests cannot distinguish between latent infection and active disease, there is concern about increasing use of IGRAs for active tuberculosis in high-burden countries. In this systematic review focused on individuals living in low- and middle-income countries, the highest-quality evidence from persons with suspected tuberculosis demonstrated sensitivity of 69%–83% and specificity of 52%–61% for IGRAs in the diagnosis of active tuberculosis. Furthermore, there was no consistent evidence that either IGRA was more sensitive than the TST for active tuberculosis diagnosis.
The majority of evidence for the diagnostic accuracy of IGRAs to date has been summarized from high-income settings where active tuberculosis has been used as a surrogate reference standard for LTBI diagnosis [4
]. However, diagnostic test performance (eg, sensitivity and specificity) can be expected to vary according to disease prevalence and other population characteristics [51
]. Likewise, clinicians have been advised to base their decisions on studies that most closely match their own clinical circumstances [53
IGRAs were designed as diagnostic tests of LTBI, though the lack of an accepted gold standard for LTBI has been a significant limitation in establishing test performance. In contrast, adequate and commonly used reference standards exist for diagnosing active tuberculosis. Among studies that enrolled persons with suspected active tuberculosis (ie, patients with diagnostic uncertainty), both IGRAs demonstrated suboptimal rule-out value for active tuberculosis. In other words, approximately 1 in 4 patients with culture-confirmed active tuberculosis can be expected to have negative IGRA results in low- and middle-income countries; this has consequences for patients in terms of morbidity and mortality. Although high-quality data were limited, sensitivity of both IGRAs was lower among HIV-infected patients (60%–70%), suggesting that ~1 in 3 HIV-infected patients with active tuberculosis will have negative IGRA results. The few available comparisons between QFT-GIT and T-SPOT revealed higher sensitivity for the T-SPOT platform, although this difference did not reach statistical significance. Lastly, comparisons with pooled estimates of TST sensitivity were difficult to interpret because of substantial heterogeneity. Our results, however, suggest that neither IGRA platform may be more sensitive than the TST for active tuberculosis diagnosis in low- and middle-income countries.
IGRA specificity in diagnosing LTBI, estimated among individuals at low risk for tuberculosis exposure in settings with low tuberculosis incidence (high-income settings), is known to be high (≥98%) [4
]. In contrast, specificity for active tuberculosis diagnosis is best estimated only in studies evaluating persons with suspected tuberculosis. As expected, because of the higher background LTBI prevalence and the known inability of IGRAs to differentiate LTBI from active tuberculosis [10
], the specificity of both IGRAs for active tuberculosis was low, regardless of HIV status. These data suggest that 1 in 2 patients without active tuberculosis will have positive IGRA results; this has consequences for patients because of unnecessary therapy for tuberculosis and its attendant risks. Studies demonstrating activated T-cell IFN-γ response throughout the entire spectrum of tuberculosis, from latency to active disease [54
], lend biologic plausibility to our findings. Even in the spectrum of latent tuberculosis infection [55
], activated T-cell IFN-γ responses occur throughout each phase, with the possible exception of the innate immune response (which eliminates M. tuberculosis
without priming a T-cell immune response).
The goal of our systematic review was to critically evaluate the diagnostic accuracy of IGRAs for active tuberculosis diagnosis in low- and middle-income settings. However, there are inherent limitations to sensitivity, specificity, and predictive values as measures of test performance. These measures are unable to determine the extent to which a test may improve on readily available clinical information [56
] or the degree to which patient-important outcomes are improved by test results [26
]. Although limited, available data suggest that IGRAs may add little to the conventional diagnostic investigation for active tuberculosis in settings with low [57
] and high tuberculosis incidence [58
]. Additional work is necessary to confirm this.
Our meta-analysis has several limitations. First, as with previous systematic reviews [4
], heterogeneity was substantial for the primary outcomes of sensitivity and specificity. We used empirical random effects weighting, excluded all studies contributing <10 eligible individuals, and separately synthesized data for currently manufactured IGRAs to minimize heterogeneity. Second, World Bank income classification is an imperfect surrogate for national tuberculosis incidence. Although no standard criteria currently exist for defining countries with high tuberculosis incidence, our results were fundamentally unchanged when restricted to nations with a World Health Organization (WHO)-defined annual tuberculosis incidence of ≥50 cases/100000 population [50
]. Third, it is likely that unpublished data and ongoing studies were missed. It is also possible that studies that found poor IGRA performance were less likely to be published. Because of 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 our estimates resulting from publication bias. Fourth, our review did not include evidence on use of IGRAs in 2 patient subgroups in which conventional tests for active tuberculosis perform poorly: children and patients with suspected extrapulmonary tuberculosis. Lastly, we did not identify any studies directly measuring the impact of IGRAs on patient-important outcomes.
In conclusion, as in the case of the TST, the data suggest no role for using IGRAs for active tuberculosis diagnosis for adults living in low- and middle-income countries. These data should help inform evidence-based policies on the role of IGRAs in active tuberculosis diagnosis in low- and middle-income settings. Indeed, a WHO Expert Group considering this evidence recently recommended that IGRAs should not be used as a replacement for conventional microbiological diagnosis of pulmonary and extrapulmonary tuberculosis in low-and middle-income countries [59