Same-Day Tools, Including Xpert Ultra and IRISA-TB, for Rapid Diagnosis of Pleural Tuberculosis: a Prospective Observational Study

Abstract

The diagnosis of pleural tuberculosis (TB) is problematic. The comparative performance of newer same-day tools for pleural TB, including Xpert MTB/RIF Ultra (ULTRA), has hitherto not been comprehensively studied. Adenosine deaminase (ADA), IRISA-TB (interferon gamma ultrasensitive rapid immunosuspension assay), Xpert MTB/RIF, and ULTRA performance outcomes were evaluated in pleural fluid samples from 149 patients with suspected pleural TB. The reference standard was culture positivity (fluid, biopsy specimen, or sputum) and/or pleural biopsy histopathology (termed definite TB). Those designated as having non-TB were negative by microbiological testing and were not initiated on anti-TB treatment. To determine the effect of sample concentration, 65 samples underwent pelleting by centrifugation, followed by conventional Xpert MTB/RIF and ULTRA. Of the 149 patients, 49 had definite TB, 16 had probable TB (not definite but treated for TB), and 84 had non-TB. ULTRA sensitivity and specificity (95% confidence intervals [CI]) were similar to those of Xpert MTB/RIF [sensitivity, 37.5% (25.3 to 51.2) versus 28.6% (15.9 to 41.2), respectively; specificity, 98.8% (96.5 to 100) versus 98.8% (96.5 to 100), respectively]. Centrifugation did not significantly improve ULTRA sensitivity (29.5% versus 31.3%, respectively). Adenosine deaminase and IRISA-TB sensitivity were 84.4% (73.9 to 95.0) and 89.8% (81.3 to 98.3), respectively. However, IRISA-TB demonstrated significantly better specificity (96.4% versus 87.5% [P = 0.034]), positive predictive value (93.6% versus 80.9 [P = 0.028]), and positive likelihood ratio (25.1 versus 6.8 [P = 0.032]) than ADA. In summary, Xpert ULTRA has poor sensitivity for the diagnosis of pleural TB. Alternative assays (ADA and IRISA-TB) are significantly more sensitive, with IRISA-TB demonstrating a higher specificity and rule-in value than ADA in this high-TB-burden setting where HIV is endemic.

Keywords: IRISA-TB; Mycobacterium tuberculosis; ULTRA; Xpert MTB/RIF; adenosine deaminase; interferon gamma.

FIG 1

Study overview of patient groups, investigations performed, and tests undertaken. Superscript letters: a, no biopsy specimen taken, n = 10; b, fluid smear not requested, n = 40; c, sputum smear not requested, n = 1; d, histology not requested, n = 11; e, fluid culture not requested, n = 25; f, sputum culture not requested, n = 3; g, biopsy culture not requested, n = 66; h, ADA levels not requested, n = 25; i, contamination, n = 1; j, biopsy sample suboptimal for histology, n = 13; k, errors, n = 2; m, insufficient clinical data for final diagnosis. Participants classifications: definite TB, at least one positive M. tuberculosis culture (pleural fluid, biopsy specimen, and/or sputum) and/or caseating granulomatous inflammation suggestive of TB on histological examination of pleural biopsy tissue and with improvement on anti-TB treatment; probable TB, patients not meeting the criteria for definite TB but with clinical and radiological indicators suggestive of TB and who were initiated on and responded to anti-TB treatment; non-TB, patients with no microbiological or histological evidence of M. tuberculosis and/or an alternative diagnosis was available.

FIG 2

(A) Scatter plot of IFN-γ levels using IRISA-TB and adenosine deaminase (ADA) using pleural fluid from patients with definite TB and non-TB pleural effusions. *, P value determined by Mann-Whitney test. Receiver operator characteristic (ROC)-derived cut point of 20.5 pg/ml IFN-γ (indicated by red dotted line) for IRISA-TB and ADA cut point of 30 IU/liter (indicated by blue dashed line). (B) Area under the ROC curves for IRISA-TB and ADA. Areas under the curve were 0.94 (IRISA-TB) and 0.88 (ADA). The ROC curves where generated using the definite TB and non-TB groups, with the chosen cut point for IRISA-TB indicated with an arrow. No significant difference was observed between the two ROC curves by the Hanley and McNeil method.