Comparative accuracy of typhoid diagnostic tools: A Bayesian latent-class network analysis

Background: Typhoid fevers are infections caused by the bacteria Salmonella enterica serovar Typhi (Salmonella Typhi) and Paratyphi A, B and C (Salmonella Paratyphi). Approximately 17.8 million incident cases of typhoid fever occur annually, and incidence is highest in children. The accuracy of current diagnostic tests of typhoid fever is poorly understood. We aimed to determine the comparative accuracy of available tests for the pediatric population. Methods: We first conducted a systematic literature review to identify studies that compared diagnostic tests for typhoid fever in children (aged ≤15 years) to blood culture results. We applied a Bayesian latent-class extension to a network meta-analysis model. We modelled known diagnostic properties of bone marrow culture and the relationship between bone marrow and blood culture as informative priors in a Bayesian framework. We tested sensitivities for the proportion of negative blood samples that were false as well as bone marrow sensitivity and specificity. Results: We found 510 comparisons from 196 studies and 57 specific to the pediatric population. IgM-based tests outperformed their IgG-based counterparts for ELISA and Typhidot tests. The lateral flow IgG test performed comparatively well with 92% sensitivity (72% to 98% across scenario analyses) and 94% specificity. The most sensitive test of those investigated for the South Asian pediatric population was the Reverse Passive Hemagglutination Assay with 99% sensitivity (98% - 100% across scenario analyses). Adding a Widal slide test to other typhoid diagnostics did not substantially improve diagnostic performance beyond the single test alone, however, a lateral flow-based IgG rapid test combined with the typhoid/paratyphoid (TPT) assay yielded improvements in sensitivity without substantial declines in specificity and was the best performing combination test in this setting. Conclusion: In the pediatric population, lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests had high diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. South Asia has the most informed set of data on typhoid diagnostic testing accuracy, and the evidence base in other important regions needs to be expanded. Author summary: Typhoid fever is an infection caused by the bacterium Salmonella Typhi. Typhoid fever is rare in developed countries but remains high in the developing world. Effective treatment is available but accurate diagnosis of typhoid fever is challenging as typhoid fever can be difficult to distinguish from other infections. Bone marrow culture is the most accurate diagnostic test for typhoid fever however is invasive and not feasible in many settings. New vaccines for typhoid and the need for improved estimates of burden increases the demand for improved understanding of diagnostic accuracy. Comparing the diagnostic accuracy of tests for typhoid fever is challenging as head-to-head studies are few. We applied newly developed methods for comparative evaluation of diagnostic tests for typhoid fever in children using statistical approaches that allowed for the proper incorporation of uncertainty and comparison of tests that had not been compared directly. The lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests all had good diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. Finally, while South Asia has the most informed set of data on typhoid diagnostic testing accuracy, the evidence base in other important regions needs to be expanded.