medRxiv : the preprint server for health sciences · 2025
Cholera rapid diagnostic tests at the host-microbe interface: Key Considerations for Global Deployments.
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Ahmed S M, Sayeed Md Abu, Sriguha I, Cato E T, Creasy-Marrazzo A, Islam K, Khabir Md I Ul, Bhuiyan Md T R, Begum Y, Islam Md Taufiqul, Khan Zahid Hasan, Freeman E, Vustepalli A, Brinkley L, Kamat M, Bailey L S, Madi N, Qadri F, Shapiro B J, Leung D T, Basso K B, Sack D A, Andrews J R, Khan A I, Nelson E J
Аннотация
BACKGROUND: Effective cholera outbreak response requires accurate bedside rapid diagnostic tests (RDTs) because access to laboratories is often limited. Formative studies suggest cholera diagnostics have multiple vulnerabilities, including antibiotics and predation by bacteriophage ('phage') specific to Vibrio cholerae (Vc).
METHODS: We conducted a prospective nationwide study in Bangladesh among over 2000 patients with diarrhoeal disease to characterize how these vulnerabilities impact RDT performance. Assays included culture, qPCR and mass spectrometry.
FINDINGS: With the current gold standard of culture or qPCR Vc positivity, we found no effect of phage on RDT performance. When the diagnostic criteria were expanded to include phage, there was a small decrease in RDT sensitivity. In contrast, large increases in sensitivity and specificity were observed among patients with moderate and severe dehydration. Using the expanded definition, the odds of RDT positivity decreased among cholera patients with phage exposure. The effect was most robust among patients with severe dehydration. Antibiotic were detected in over 80% of samples by LC-MS/MS which limited testing for effects on RDTs. Applying these findings, we estimated that restricting RDT use to severe patients with no reported antibiotic exposure increases sensitivity by 50% compared to unrestricted use. If phage were a diagnostic proxy for Vc, we estimate RDT would miss an additional 17% of cholera cases.
INTERPRETATION: Cholera RDTs have critical limitations that require consideration in global deployments. Inclusion of phage detection in diagnostic criteria may improve case detection which requires further study. The impact of these findings likely extends to other diseases where diagnostics share similar vulnerabilities.
METHODS: We conducted a prospective nationwide study in Bangladesh among over 2000 patients with diarrhoeal disease to characterize how these vulnerabilities impact RDT performance. Assays included culture, qPCR and mass spectrometry.
FINDINGS: With the current gold standard of culture or qPCR Vc positivity, we found no effect of phage on RDT performance. When the diagnostic criteria were expanded to include phage, there was a small decrease in RDT sensitivity. In contrast, large increases in sensitivity and specificity were observed among patients with moderate and severe dehydration. Using the expanded definition, the odds of RDT positivity decreased among cholera patients with phage exposure. The effect was most robust among patients with severe dehydration. Antibiotic were detected in over 80% of samples by LC-MS/MS which limited testing for effects on RDTs. Applying these findings, we estimated that restricting RDT use to severe patients with no reported antibiotic exposure increases sensitivity by 50% compared to unrestricted use. If phage were a diagnostic proxy for Vc, we estimate RDT would miss an additional 17% of cholera cases.
INTERPRETATION: Cholera RDTs have critical limitations that require consideration in global deployments. Inclusion of phage detection in diagnostic criteria may improve case detection which requires further study. The impact of these findings likely extends to other diseases where diagnostics share similar vulnerabilities.