Pyrosequencing for Diagnosis of Multidrug and Extensively Drug-resistant Tuberculosis: A Systemic Review and Meta-analysis

Background: Multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) pose major threats to global health. Diagnosis accuracy and delay have been the major drivers for the upsurge of M/XDR-TB. Pyrosequencing (PSQ) is a novel, real-time DNA sequencing for rapid detection of mutations associated with M/XDR-TB. We aimed to systematically synthesize the evidence on the diagnostic accuracy of PSQ for M/XDR-TB.

Methods: We conducted an electronic search of PubMed, Embase, Biosis, Web of Science, and Google Scholar up to March 2020. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool to assess the quality of studies, the BRMA (bivariate random-effects meta-analysis) model to synthesize diagnostic accuracies, and the Rev-Man 5.4 software to perform the meta-analyses. We analyzed dichotomous data using the risk ratio (RR) with a 95% confidence interval. PROSPERO Registration ID: CRD42020200817.

Results: The analysis included seven studies, with a total sample of 3,165. At 95% confidence interval, the pooled sensitivity and specificity of PSQ were 89.7 (CI: 83.5-93.8) and 97.8 (CI: 94.9-99.1) for Isoniazid, 94.6 (CI: 90.9-96.8) and 98.5 (CI: 96.5-99.3) for Rifampicin, 87.9 (CI: 81.2-92.4) and 98.8 (CI: 97.2-99.5) for Fluoroquinolone, 83.5 (CI: 72.8-90.5) and 99.4 (CI: 98.3-99.8) for Amikacin, 79 (CI: 67-8-87) and 97.9 (CI: 95.5-99) for Capreomycin, and 69.6 (CI: 57-79.8) and 98.2 (CI: 95.9-99.2) for Kanamycin. The overall pooled sensitivity and specificity were 85.8 (CI: 76.7-91.7) and 98.5 (CI: 96.5-99.3), respectively.

Conclusion: According to the pooled data, PSQ is highly sensitive and specific for detecting M/XDR-TB, both from clinical specimens and culture isolates, and within a shorter turnaround time. We suggest a continued synthesis of the evidence on the cost-effectiveness and technical feasibilities of PSQ in low-income countries context, including sub-Saharan Africa.