Interferon Gamma Release Assays for Diagnosis of Pleural Tuberculosis: a Systematic Review and Meta-Analysis

Abstract

The role of interferon gamma release assays (IGRAs), although established for identifying latent tuberculosis, is still evolving in the diagnosis of active extrapulmonary tuberculosis. We systematically evaluated the diagnostic performance of blood-and pleural fluid-based IGRAs in tuberculous pleural effusion (TPE). We searched the PubMed and Embase databases for studies evaluating the use of commercially available IGRAs on blood and/or pleural fluid samples for diagnosing TPE. The quality of the studies included was assessed through the QUADAS-2 tool. The pooled estimates of sensitivity and specificity with 95% confidence intervals (95% CI) were generated using a bivariate random-effects model and examined using forest plots and hierarchical summary receiver operating characteristic (HSROC) curves. Indeterminate IGRA results were included for sensitivity calculations. Heterogeneity was explored through subgroup analysis and meta-regression based on prespecified covariates. We identified 19 studies assessing the T.SPOT.TB and/or QuantiFERON assays. There were 20 and 14 evaluations, respectively, of whole-blood and pleural fluid assays, involving 1,085 and 727 subjects, respectively. There was only one good-quality study, and five studies used nonstandard assay thresholds. The pooled sensitivity and specificity for the blood assays were 0.77 (95% CI, 0.71 to 0.83) and 0.71 (95% CI, 0.65 to 0.76), respectively. The pooled sensitivity and specificity for the pleural fluid assays were 0.72 (95% CI, 0.55 to 0.84) and 0.78 (95% CI, 0.65 to 0.87), respectively. There was considerable heterogeneity; however, multivariate meta-regression did not identify any covariate with significant influence. There was no publication bias for blood assays. We conclude that commercial IGRAs, performed either on whole-blood or pleural fluid samples, have poor diagnostic accuracy in patients suspected to have TPE.T uberculosis (TB) is a common etiology of pleural effusion, especially in developing countries (1). A definitive microbiological diagnosis is achieved by tuberculous pleural effusion (TPE) in only a few patients, and the diagnostic accuracy of other pleural fluid investigations is suboptimal (1, 2). Estimation of adenosine deaminase or interferon gamma and detection of the mycobacterial genome in pleural fluid are used as diagnostic surrogates (2). Pleural biopsies may improve the diagnostic yield; however, these procedures are invasive, require expertise, and are not free from complications (3-5).In recent years, interferon gamma release assays (IGRAs) have emerged as an immunodiagnostic tool to detect tuberculous infection. IGRAs quantify interferon gamma released by T-lymphocytes in response to stimulation by specific antigens encoded in region of difference 1 (RD1) of the Mycobacterium tuberculosis genome. An enzyme-linked immunosorbent spot (ELISpot) assay (T-SPOT.TB; Oxford Immunotec Limited, United Kingdom) and an enzyme-linked immunosorbent assay (ELISA) (QuantiFERON; Cellestis Limited, Australia) are commercially avail...

Diagnostic Performance of Xpert MTB/RIF in Tuberculous Pleural Effusion: Systematic Review and Meta-analysis

“…Obviously, GeneXpert cannot be used alone for the diagnosis of TPE, given its low sensitivity. However, unlike other tests such as pleural fluid interferon gamma release assays (IGRAs) (35), the specificity and thus the positive predictive value of GeneXpert in the diagnosis of TPE are high. In fact, among 1,000 patients with pleural effusions with pretest probabilities of TPE of 5% and 20%; the use of GeneXpert will enable detection of 26 and 103 patients, respectively (see Table S6 in the supplemental material).…”

Pleural Fluid and Tuberculosis: Are All Interferon Gamma Release Assays Equal?

“…We do not recognize this argument in clinical practice of indeterminate IGRA results in the assessment of active TB, and moreover, this is not demonstrated in the review by Aggarwal et al, as 83% (50/60) of patients with indeterminate QuantiFERON results in pleural fluid and 52% (28/54) of patients with indeterminate T-SPOT.TB results in pleural fluid have pleural tuberculosis (1). According to the assay manufacturer's instructions, an indeterminate IGRA result should not have clinical consequences in the workup for a patient with active TB and therefore should be excluded from the calculation of diagnostic accuracy.…”

“…e have read the recently published review of Aggarwal and colleagues (1) with great interest. The use of interferon gamma release assays (IGRA) in extrasanguineous body fluids as potential diagnostic tests for active tuberculosis (TB) does have our special attention.…”

“…We tried to retrieve the correct numbers from the original article, which are, if we are correct, the following: true negative, 42; false positive, 7; and indeterminate, 0 (3). We cannot determine which numbers were used in the sensitivity and specificity analyses of Aggarwal and colleagues (1).…”

Reply to “Pleural Fluid and Tuberculosis: Are All Interferon Gamma Release Assays Equal?”

“…The question whether one of these two commercial tests is clearly better than the other remains debatable, and we attempted to briefly address this issue through subgroup analysis, both graphically (Forest plots in Fig. 1 in our article [2]) and numerically (Table 2 in our article [2]). As reported in our review, the T.SPOT-TB assay had a substantially higher pooled sensitivity in pleural fluid assays, although differences between QuantiFERON and T.SPOT-TB assay sensitivities were not formally statistically tested.…”