Cholera rapid diagnostic tests at the host-microbe interface: Key Considerations for Global Deployments
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Effective cholera outbreak response requires accurate bedside rapid diagnostic tests (RDTs) because access to laboratories is limited. Formative studies suggest cholera diagnostics have multiple vulnerabilities, including predation by virulent bacteriophage (‘phage’) specific to Vibrio cholerae ( Vc ). Here we conducted a prospective nationwide study in Bangladesh among over 2000 patients with diarrheal disease to characterize how these vulnerabilities impact RDT performance. Assays included culture, qPCR, metagenomics and mass spectrometry. With the current gold standard of culture or qPCR Vc positivity, we initially found no significant effect of phage on RDT performance. When the standard was expanded to include phage, there was a small decrease in RDT sensitivity. In contrast, significant increases in sensitivity and specificity were found among patients with moderate or severe dehydration. Using the expanded definition, the odds of RDT positivity among cholera patients decreased by 63% (OR 0.377; 95%CI 0.217-0.642; P <0.001) with phage exposure. The effect was most robust among patients with severe dehydration. Furthermore, the odds of RDT test positivity among those samples with phage increased by 14 times (OR 14.7; 95%CI 2.83-117) if the infecting Vc strain harbored phage resistance factors. Antibiotic exposure was common which limited interpretation. Applying these findings, we estimated that restricting RDT use to severe patients with no known antibiotic exposure increases relative sensitivity by 50% with and without the expanded case definition. Despite this maneuver, the RDT remains with limitations that require consideration when optimizing global deployment strategies. The impact of these findings likely extends to other diseases where diagnostics share similar vulnerabilities.
Summary
Effective management, control and elimination of cholera requires accurate bedside rapid diagnostic tests (RDTs) because access to laboratory diagnostics is often limited. In response, international agencies have operationalized a global RDT deployment to address this logistical problem. Unfortunately, cholera diagnostic performance, including that of RDTs, are likely vulnerable to bacteriophage (‘phage’) predation and antibiotic exposures. This vulnerability has real-world consequences for outbreak response and calls into question the value of RDTs in their current form and method of use. In response, our objective was to determine if phage and antimicrobials indeed impact RDT performance and identify ways to better deploy RDTs and interpret results. We found RDT performance was not affected overall with phage exposure. However, we discovered that performance was positively associated with disease severity, and among severely dehydrated cholera patients, phage did have a significant negative effect. Antibiotic exposure was pervasive which limited interpretation. Among cholera patients with phage, the odds of RDT test positivity increased when the pathogen ( Vc ) harbored phage resistance factors. We explored the effects on RDT performance by including phage detection as a proxy for pathogen detection. We estimate that changing to a mode of restricted use in which RDTs are performed only on dehydrated patients, who report no antibiotic exposure, improves the relative sensitivity of the test by fifty percent. However, this maneuver neglects the poor performance among patients without dehydration. The significance of these findings may extend broadly to other diseases where diagnostics share similar vulnerabilities.
