Accuracy of line probe assays for the diagnosis of pulmonary and multidrug-resistant tuberculosis: a systematic review and meta-analysis

Abstract

Only 25% of multidrug-resistant tuberculosis (MDR-TB) cases are currently diagnosed. Line probe assays (LPAs) enable rapid drug-susceptibility testing for rifampicin (RIF) and isoniazid (INH) resistance and Mycobacterium tuberculosis detection. Genotype MTBDRplusV1 was WHO-endorsed in 2008 but newer LPAs have since been developed.This systematic review evaluated three LPAs: Hain Genotype MTBDRplusV1, MTBDRplusV2 and Nipro NTM+MDRTB. Study quality was assessed with QUADAS-2. Bivariate random-effects meta-analyses were performed for direct and indirect testing. Results for RIF and INH resistance were compared to phenotypic and composite (incorporating sequencing) reference standards. M. tuberculosis detection results were compared to culture.74 unique studies were included. For RIF resistance (21 225 samples), pooled sensitivity and specificity (with 95% confidence intervals) were 96.7% (95.6-97.5%) and 98.8% (98.2-99.2%). For INH resistance (20 954 samples), pooled sensitivity and specificity were 90.2% (88.2-91.9%) and 99.2% (98.7-99.5%). Results were similar for direct and indirect testing and across LPAs. Using a composite reference standard, specificity increased marginally. For M. tuberculosis detection (3451 samples), pooled sensitivity was 94% (89.4-99.4%) for smear-positive specimens and 44% (20.2-71.7%) for smear-negative specimens.In patients with pulmonary TB, LPAs have high sensitivity and specificity for RIF resistance and high specificity and good sensitivity for INH resistance. This meta-analysis provides evidence for policy and practice.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram of included studies. TB: tuberculosis; LPA: line probe assay.

FIGURE 2

QUADAS-2 summaries. a and c) Risk of Bias and Applicability Concerns summary about each QUADAS-2 domain presented as percentages across the 94 included datasets for rifampicin (RIF) and isoniazid (INH) resistance compared with phenotypic culture-based reference standard (of note, four datasets only contributed to RIF). The summaries for the datasets for RIF and INH compared with composite reference standard are not displayed separately since these datasets are a subset of the 94 datasets displayed below and thus the figures displayed are thought to be accordingly representative. b and d) Risk of Bias and Applicability Concerns summary about each QUADAS-2 domain presented as percentages across the six included datasets for Mycobacterium tuberculosis detection compared with a culture-based reference standard.

FIGURE 3

Hierarchical summary receiver operating characteristic graphs of summary estimates. Bivariate analysis of the sensitivity and specificity for all line probe assays for the diagnosis of drug resistance detection compared with a phenotypic reference standard for specimens tested directly for a) rifampicin resistance, b) isoniazid resistance, c) multi-drug resistance and d) the detection of Mycobacterium tuberculosis compared to a culture reference standard. In the plots below, the red squares represent the pooled summary estimates, the dashed red lines represent the 95% confidence region and the dashed green lines represent the 95% prediction region. The individual circles represent each study and the size of the circle is proportional to the total sample size.

FIGURE 4

Forest plots demonstrating the sensitivity and specificity of all line probe assays for rifampicin resistance-detection for sputum specimens tested directly compared with phenotypic drug susceptibility testing. TP: true positive; FP: false positive; FN: false negative; TN: true negative.

FIGURE 5

Forest plots demonstrating sensitivity and specificity of all line probe assays for isoniazid-resistance detection for sputum specimens tested directly compared with phenotypic drug susceptibility testing. TP: true positive; FP: false positive; FN: false negative; TN: true negative.

FIGURE 6

Forest plots demonstrating sensitivity and specificity of all line probe assays for multidrug-resistant tuberculosis detection for both specimen types compared with phenotypic drug susceptibility testing. TP: true positive; FP: false positive; FN: false negative; TN: true negative.

FIGURE 7

Forest plots demonstrating the sensitivity and specificity of all the line probe assays evaluated for the diagnosis of pulmonary Mycobacterium tuberculosis compared with culture. TP: true positive; FP: false positive; FN: false negative; TN: true negative.