Diagnostic Tests to Support Late-Stage Control Programs for Schistosomiasis and Soil-Transmitted Helminthiases

<div><p>Global efforts to address schistosomiasis and soil-transmitted helminthiases (STH) include deworming programs for school-aged children that are made possible by large-scale drug donations. Decisions on these mass drug administration (MDA) programs currently rely on microscopic examination of clinical specimens to determine the presence of parasite eggs. However, microscopy-based methods are not sensitive to the low-intensity infections that characterize populations that have undergone MDA. Thus, there has been increasing recognition within the schistosomiasis and STH communities of the need for improved diagnostic tools to support late-stage control program decisions, such as when to stop or reduce MDA. Failure to adequately address the need for new diagnostics could jeopardize achievement of the 2020 London Declaration goals. In this report, we assess diagnostic needs and landscape potential solutions and determine appropriate strategies to improve diagnostic testing to support control and elimination programs. Based upon literature reviews and previous input from experts in the schistosomiasis and STH communities, we prioritized two diagnostic use cases for further exploration: to inform MDA-stopping decisions and post-MDA surveillance. To this end, PATH has refined target product profiles (TPPs) for schistosomiasis and STH diagnostics that are applicable to these use cases. We evaluated the limitations of current diagnostic methods with regards to these use cases and identified candidate biomarkers and diagnostics with potential application as new tools. Based on this analysis, there is a need to develop antigen-detecting rapid diagnostic tests (RDTs) with simplified, field-deployable sample preparation for schistosomiasis. Additionally, there is a need for diagnostic tests that are more sensitive than the current methods for STH, which may include either a field-deployable molecular test or a simple, low-cost, rapid antigen-detecting test.</p></div

The steps required for gold standard microscopy in deworming programs.

<p>In the typical surveillance testing performed to assess the prevalence of helminth infection and the impact of deworming programs, stool samples (or sometimes urine for schistosomiasis) are collected and transported to a nearby laboratory space for microscopic analysis and follow-on reporting. There are numerous factors affecting each step of the process that contribute to making this analysis less than optimal.</p

Overview of STH and Schistosomaiasis (SCH) diagnostic landscapes.

<p>Overview of STH and Schistosomaiasis (SCH) diagnostic landscapes.</p

PRISMA flowchart.

<p>Study flow depicting search strategy, inclusion/exclusion criteria, and summary of systematic review.</p

Meta-analysis results by study quality.

<p>Summary diagnostic accuracies of index tests with five or more comparisons and blood culture as the reference test. Meta-analysis performed using bivariate random effects binomial regression.</p><p>¹ Could not be determined.</p><p>Meta-analysis results by study quality.</p

Constructed numerical example.

<p>Assumed sensitivity and specificity of the three tests: index test, 80% and 90%; test A, 50% and 100%; test B, 85% and 85%. Comparing the index test to a CRS = (fever) AND ((test A positive) OR (test B positive)). Fever, test A, and test B are independent conditional on disease status. Index test is independent of fever conditional on disease status.</p><p>Constructed numerical example.</p

Comparisons by reference test.

<p>Summary of the 139 papers by reference test, including 413 index/reference comparisons. Of the culture reference tests, 80% were blood culture, making up 57% of all reference tests.</p

Quality assessment of diagnostic accuracy studies.

<p>Summary of variables included in the QUADAS-2 tool assessing the quality of diagnostic accuracy studies. The criteria determined a study’s risk of bias or concern of applicability. When the domain-specific criteria were not met, the study had a high risk of bias or concern of applicability with respect to that domain. When the domain-specific criteria were all unclear, the risk of bias or concern of applicability was unclear.</p><p>¹ The currently available tests to detect typhoid fever are not sufficiently accurate; therefore, this question was problematic.</p><p>² “Unclear” = missing.</p><p>Quality assessment of diagnostic accuracy studies.</p

Meta-analysis results.

<p>Graphical illustration of sensitivities (y-axis) and specificities (x-axis) corresponding to comparisons included in the meta-analysis: PCR-based assays (A), anti-LPS assays (B), TUBEX^® assays (C), anti-<i>S</i>. <i>typhi</i> assays (D), Typhidot assays (E), Widal assays (F). Meta-analysis was performed using bivariate random effects binomial regression (STATA command: <i>metandi</i>). Sizes of individual study estimates (grey circle) represent sample size. Summary point (red square), hierarchical summary receiver operating characteristic curves (green line), 95% confidence regions (yellow dashed line), and 95% prediction regions (grey dashed line) are depicted.</p