Molecular testing in suspected infectious diarrhoea—the value of negative results

Molecular testing for the detection of gastrointestinal pathogens is not new, and yet its potential to benefit patient management remains underexplored. The multiplicity of tests and varied numbers of target pathogens complicates their assessment. Molecular tests are rapid (results usually in 1–4 h), typically expand the range of detectable potential pathogens, can be laboratory-based or near-to-patient, but are relatively costly because of consumable and equipment needs. Culture-based results are much slower (at least the day after a sample reaches the laboratory) and require skilled expertise to process, so increasing their overall cost. Molecular testing of diarrhoeal samples still needs to be supplemented with other tests; for example, toxin detection to accurately diagnose Clostridioides difficile infection,1Planche TD Davies KA Coen PG et al.Differences in outcome according to Clostridium difficile testing method: a prospective multicentre diagnostic validation study of C difficile infection.Lancet Infect Dis. 2013; 13: 936-945Summary Full Text Full Text PDF PubMed Scopus (338) Google Scholar and typing or fingerprinting tests to enable tracking of pathogens of public health importance. These pros and cons underpin the debate about whether to switch from culture-based to molecular-based testing and, crucially, potential advantages to patient management. A crucial tenet of infection prevention and control is the prompt isolation of patients with new-onset diarrhoea, rather than after identifying an infective cause. Appropriate contact or enteric precautions are also required particularly for health-care workers who have contact with a symptomatic patient or their immediate environment to minimise the risk of pathogen spread. These needs are relatively easy to deliver in hospitals with most beds provided in single rooms. However, only about one in five beds in the NHS are in single occupancy rooms (SORs), and even fewer in many acute medical or surgical units. Given the considerable pressure on the use of SORs, rapid testing to identify patients who are isolated unnecessarily, without a transmissible pathogen, could be valuable. The key test parameter here is the negative predictive value (ie, the accuracy to rule out an enteric pathogen in a patient with acute diarrhoea). Nathan J Brendish and colleagues in The Lancet Infectious Diseases have established in a randomised, single-centre, and non-blinded trial whether the negative predictive value of a rapid molecular point-of-care test (mPOCT) can improve on the use of SORs.2Brendish NJ Beard KR Malachira AK et al.Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trial.Lancet Infect Dis. 2023; (published online April 25.)https://doi.org/10.1016/S1473-3099(23)00066-XSummary Full Text Full Text PDF PubMed Scopus (1) Google Scholar This mPOCT uses rectal swabs to detect 22 gastrointestinal pathogens with results available in about 1 h, and had a negative predictive value in the trial of 91% (95% CI 80–97). Despite a very large reduction in the time to obtaining a result with mPOCT versus conventional testing (median 1·7 vs 44·7 h, p<0·0001), the overall mean reduction in time spent in a SOR was much more modest (1·8 vs 2·6 days, p=0·0017). There was no effect on the total length of stay. If this approximately 30% reduction in so-called unnecessary single-occupancy room use is generally translatable, there is considerable potential for improving the use of valuable SORs and hence patient placement and flow. Presumably, a more efficient implementation of mPOCT, and review and actioning of results could increase this SOR capacity gain. Some of the measured secondary outcomes underscore the possibly unintended consequences of using a molecular test with enhanced sensitivity but not necessarily optimal specificity for infection. More patients had potential pathogens detected by mPOCT than laboratory testing (45% vs 26%, p=0·0007).2Brendish NJ Beard KR Malachira AK et al.Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trial.Lancet Infect Dis. 2023; (published online April 25.)https://doi.org/10.1016/S1473-3099(23)00066-XSummary Full Text Full Text PDF PubMed Scopus (1) Google Scholar In turn, antibiotic prescribing was more frequent in patients undergoing mPOCT compared with the control group (65% vs 47%, p=0·0028). Possibly reassuring here, although inappropriate antimicrobial prescribing was relatively common, its duration was on average about 4 days less in mPOCT recipients. Campylobacter spp infections were common and drove some of the inappropriate prescribing as not all require antibiotic treatment.3National Institute of Health and Care ExcellenceAdult gastroenteritis.https://cks.nice.org.uk/topics/gastroenteritis/management/adult-gastroenteritis/Date accessed: February 15, 2023Google Scholar There remains uncertainty about whether conventional (largely culture-based) testing is more accurate than molecular testing in gastroenteritis. In general, however, molecular tests have enhanced sensitivity.4Macfarlane-Smith LR Ahmed S Wilcox MH Molecular versus culture-based testing for gastrointestinal infection.Curr Opin Gastroenterol. 2018; 34: 19-24Crossref PubMed Scopus (7) Google Scholar, 5Freeman K Mistry H Tsertsvadze A et al.Multiplex tests to identify gastrointestinal bacteria, viruses and parasites in people with suspected infectious gastroenteritis: a systematic review and economic analysis.Health Technol Assess. 2017; 21: 1-188Crossref Scopus (58) Google Scholar A very large retrospective analysis of results from molecular-based versus culture-based testing across laboratories in Wales found that molecular-based testing significantly increased the detection rate of each of six key enteric pathogens.6Holliday LR Perry MD Network-wide analysis of the Serosep EntericBio Gastro Panel 2 for the detection of enteric pathogens in Public Health Wales microbiology laboratories.J Med Microbiol. 2022; 71001555Crossref PubMed Scopus (2) Google Scholar Although rapid molecular assays are probably more accurate than culture-based tests at ruling out an enteric or transmissible pathogen, the clinical relevance of the additional positives and potential pathogens detected by these is uncertain.4Macfarlane-Smith LR Ahmed S Wilcox MH Molecular versus culture-based testing for gastrointestinal infection.Curr Opin Gastroenterol. 2018; 34: 19-24Crossref PubMed Scopus (7) Google Scholar, 5Freeman K Mistry H Tsertsvadze A et al.Multiplex tests to identify gastrointestinal bacteria, viruses and parasites in people with suspected infectious gastroenteritis: a systematic review and economic analysis.Health Technol Assess. 2017; 21: 1-188Crossref Scopus (58) Google Scholar Such discrepancies might occur because of genuine differences in accuracy, or because molecular panel tests often include target microorganisms that are not sought in conventional testing. A systematic review and meta-analysis of the accuracy of three molecular tests showed considerable heterogeneity.5Freeman K Mistry H Tsertsvadze A et al.Multiplex tests to identify gastrointestinal bacteria, viruses and parasites in people with suspected infectious gastroenteritis: a systematic review and economic analysis.Health Technol Assess. 2017; 21: 1-188Crossref Scopus (58) Google Scholar Notably, the absence of a reference standard (benchmark tests) to validate the accuracy of molecular tests, means that the true value of the additional positive results generated by these remains unknown. Many episodes of acute onset diarrhoea are self-limiting and require supportive as opposed to directed therapy. Nevertheless, in a cohort of 172 children, results from the same molecular test as used by Brendish and colleagues,2Brendish NJ Beard KR Malachira AK et al.Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trial.Lancet Infect Dis. 2023; (published online April 25.)https://doi.org/10.1016/S1473-3099(23)00066-XSummary Full Text Full Text PDF PubMed Scopus (1) Google Scholar altered the medical management of gastroenteritis for about one in four cases.7Truong J Cointe A Le Roux E et al.Clinical impact of a gastrointestinal PCR panel in children with infectious diarrhoea.Arch Dis Child. 2022; 107: 601-605Crossref PubMed Scopus (3) Google Scholar Point-of-care tests became prevalent during the COVID-19 pandemic and should be viewed as an extension to the laboratory repertoire of tests, requiring validation, quality control, and audit. A quicker diagnosis of infection is not synonymous with a better result, but used wisely, rapid molecular tests have the potential to improve the management of acute onset diarrhoea and could be cost-effective.5Freeman K Mistry H Tsertsvadze A et al.Multiplex tests to identify gastrointestinal bacteria, viruses and parasites in people with suspected infectious gastroenteritis: a systematic review and economic analysis.Health Technol Assess. 2017; 21: 1-188Crossref Scopus (58) Google Scholar, 8Goldenberg SD Bacelar M Brazier P Bisnauthsing K Edgeworth JD A cost benefit analysis of the Luminex xTAG Gastrointestinal Pathogen Panel for detection of infectious gastroenteritis in hospitalised patients.J Infect. 2015; 70: 504-511Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 9Beal SG Tremblay EE Toffel S Velez L Rand KH A Gastrointestinal PCR Panel Improves Clinical Management and Lowers Health Care Costs.J Clin Microbiol. 2017; 56: e01457-e01517PubMed Google Scholar As shown by Brendish and colleagues, infection diagnostic studies need to be more ambitious to unleash their full potential.2Brendish NJ Beard KR Malachira AK et al.Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trial.Lancet Infect Dis. 2023; (published online April 25.)https://doi.org/10.1016/S1473-3099(23)00066-XSummary Full Text Full Text PDF PubMed Scopus (1) Google Scholar I declare no competing interests. Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trialmPOCT for gastrointestinal pathogens in patients with suspected gastroenteritis returned results more rapidly than conventional testing and was associated with a reduction in single-occupancy room use. However, these benefits need to be balanced against a potential increase in antibiotic use. Full-Text PDF Open Access