Cholera rapid diagnostic tests at the host-microbe interface: Key Considerations for Global Deployments
Bibliographic record
Abstract
ABSTRACT 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. RESEARCH IN CONTEXT Evidence before this study We conducted two Pubmed searches for reports published after Jan 1, 2000, in all languages. The first search terms were [bacteriophage OR phage] AND [pathogen] AND [diagnostic test]. The primary search criteria identified 57 publications. A secondary criterion excluded reviews and papers on phage display technology. Among twenty remaining articles, bacteriophage were used as proxies for pathogens within diverse genera (Yersinia, Mycobacterium, Burkholderia, Staphylococcus, Salmonella, Bacillus, Escherichia, Acinetobacter, Vibrio); phage profiles were also used as biomarkers for infection. The second search terms were [rapid diagnostic test OR RDT] AND [Vibrio]. After excluding reviews, 101 papers were identified that covered immunologic (antibody-based lateral flow assays), molecular (PCR, qPCR, nl-qPCR) and mass spectrometry-based assays; only 5 articles related to vibriophage detection of which three were permutations of the same initiative. Added value of this study To our knowledge, this is the first study to investigate the vulnerabilities of RDT performance (e.g., sensitivity and specificity) to virulent bacteriophage and antibiotics in a large multi-site study. The hypothesis that antimicrobials and disease severity might impact RDT performance by decreasing or increasing the target number, respectively, is not novel. However, there is a lack of literature from large clinical studies that rigorously tests this hypothesis. Therefore, the added value of this study is a pragmatic evaluation of this hypothesis and a proof of concept for how to test these complex questions for other less tractable diseases. Implications of all the available evidence Inside the cholera field, we applied the findings by estimating that changing to a mode of restricted RDT use in which RDTs are reserved for severely dehydrated patients who report no antibiotic exposure, significantly improves the sensitivity. Furthermore, we estimate that an additional 17% of cases would be missed by RDT if the case definition were expanded to include phage detection as a proxy for the pathogen. In this context, the RDT remains with limitations that require consideration when optimizing global RDT deployments. Implications likely extend to other diseases where diagnostics share similar vulnerabilities.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.060 | 0.100 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.007 | 0.008 |
| Open science | 0.004 | 0.005 |
| Research integrity | 0.004 | 0.005 |
| Insufficient payload (model declined to judge) | 0.011 | 0.004 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".