Indication - Cholera
Vibrio cholerae antigen
First added in 2019
Changed in 2020
For initial detection or exclusion of a cholera outbreak (Not for use in case management)
Stool Rectal swab
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 1A00
Summary of evidence evaluation
A review of the development and evaluation of cholera diagnostics since 1990 (6) included a systematic search for studies, an analysis of methodological challenges in the studies and limited details of evaluation studies; however, the quality of the studies was not assessed, and a meta-analysis was not undertaken. Many methodological limitations and variations in accuracy among test kits were identified. Five tests were considered promising, with a sensitivity that may exceed 90% and a specificity of about 80%, although there is considerable uncertainty and variation among tests.
Summary of SAGE IVD deliberations
Cholera outbreaks must be detected and monitored for rapid control. As they often occur in low-resource settings or in emergency situations, diagnostic tests that are simple to use at primary care level must be available. RDTs for cholera have been evaluated in many studies. Current cholera RDTs are intended for use in primary care settings for surveillance. They increase the specificity of the clinical diagnosis of cholera and permit triage of specimens for laboratory confirmation. Cholera RDTs may be used for early outbreak detection, for an initial alert and for monitoring outbreaks and seasonal peaks in highly endemic areas. In areas in which confirmed cholera cases have not recently been reported, positive RDT results for one or more patients with clinically suspected cholera are sufficient to launch a cholera alert, send stool specimens to a reference laboratory for confirmation by culture and initiate response measures (e.g. inform authorities and mobilize resources and material). In areas with ongoing outbreaks, positive RDTs can be used to select stool specimens from suspected cases for culture. Any positive RDT result must be confirmed by culture or PCR as soon as possible before the alert is confirmed and a cholera outbreak declared.
SAGE IVD recommendation
The SAGE IVD recommended inclusion on the EDL of the rapid antigen test for V. cholerae in the detection and monitoring of cholera epidemics at primary care level and for ruling out outbreaks. The Group noted that the test is rapid and easy to use, with acceptable diagnostic accuracy for the purpose. SAGE IVD noted, however, that, in view of its high cost and the variation among studies, studies of its impact would be useful to demonstrate its utility.
Details of submission from 2020
Disease condition and impact on patients: Cholera is an acute diarrhoeal disease caused by infection of the intestine with the bacterium V. cholerae, type O1 or O139, at any age. About 20% of people infected with V. cholerae have acute, watery diarrhoea, and approximately 20% have severe watery diarrhoea, many with vomiting. If these patients are not promptly and adequately treated, loss of fluid and salts can lead to severe dehydration and death within hours, with a case-fatality rate of 30–50%. Treatment (rehydration) is straightforward, and, if it is provided rapidly and appropriately, the case-fatality rate should remain < 1%. Cholera is transmitted by ingestion of faecally contaminated water or food and remains an ever-present risk in many countries. New outbreaks can occur in any part of the world where the water supply, sanitation, food safety and hygiene are inadequate. The risk is considerably increased in humanitarian emergencies, when there is significant population movement and crowding and frequent disruption of or inadequate access to health care services, clean water, sanitation and hygiene. The malnutrition status and health conditions of displaced populations can also lead to higher mortality. As the incubation period of cholera is short (2 h to 5 days), the numbers of cases and deaths can rise quickly, thus leading to an acute public health problem (1–3). Does this test meet a medical need? The test is used to screen stool samples for detection of toxigenic V. cholerae O1 or O139 from patients presenting with the clinical symptoms of cholera. It is used at primary care level for early detection of new cases and establishment of a cholera outbreak alert. How the test is used: Current cholera RDTs are lateral flow devices to detect the lipopolysaccharide of V. cholerae O1 and O139 in ICTs. They are intended for use in primary care settings for surveillance purposes. The RDTs increase the specificity of the clinical diagnosis of cholera and improve its positive predictive value by permitting triage of specimens for laboratory confirmation. Cholera RDTs may be used for early outbreak detection, for an initial alert and for monitoring outbreaks and seasonal peaks in highly endemic areas. In all situations, the tests should be used only for clinically suspected cholera cases. In areas in which confirmed cholera cases have not recently been reported, positive RDT results for one or more patients with clinically suspected cholera are sufficient to launch a cholera alert, send stool specimens to a reference laboratory for confirmation by culture and initiate response measures (e.g. inform authorities and mobilize resources and material). In areas with ongoing outbreaks, positive RDTs can be used to select stool specimens from suspected cases for culture. If all the results are negative, cholera should be ruled out. RDTs are not a substitute for stool culture: any positive RDT result must be confirmed by culture or PCR as soon as possible before the alert is confirmed and a cholera outbreak declared. Culture or molecular testing allows not only identification but also characterization and genotyping of circulating strains, which is useful for epidemiological purposes.
Public health relevance
Prevalence: In 2016, 38 countries reported a total of 132 121 cases of cholera and 2420 deaths to WHO. The global burden of cholera is, however, largely unknown, because most cases are not reported owing to limited capacity for epidemiological surveillance and laboratory testing and also social, political and economic disincentives for reporting. Epidemiological reporting and spatial regression modelling indicate that there are 2.86 million cases of cholera annually and 95 000 deaths in 69 endemic countries. Socioeconomic impact: Cholera often occurs in large explosive outbreaks that spread rapidly. From a public health perspective, the management of cholera outbreaks requires immediate identification, because of the pathogen’s potential for spread and the devastating consequences of epidemics. The economic impact of outbreaks has been estimated to be a loss of 1–2% of GDP in each outbreak year. WHO has estimated that US$ 26 billion will be lost each year in the next 10 years if the global cholera burden is not addressed.
WHO or other clinical guidelines relevant to the test
Global Task Force on Cholera Control. Interim technical note. The use of cholera RDTs. November 2016 (4); and Global Task Force on Cholera Control. Interim guidance document on cholera surveillance. June 2017 (5).
Evidence for clinical usefulness and impact
No direct studies of the impact of use of cholera RDTs have been reported. According to expert opinion, use of a point-of-care test for cholera can provide an initial indication of toxigenic V. cholerae transmission and thus reduce the danger of a nascent cholera epidemic. In the contexts in which cholera is most common, laboratory capacity and availability tend to be limited, and standard methods for cholera detection (culture and biochemical tests) are either unavailable or are available only after several days. As cholera outbreaks are explosive, the only realistic means of extinguishing an outbreak before it spreads is to raise an alert and begin a rapid response as soon as an RDT shows a positive result in an area known to be endemic for cholera.
Evidence for economic impact and/or cost–effectiveness
As is the case for other RDTs, the costs include that of the test (US$ 2) and of the supply chain system for monitoring and replacing stocks. In addition, although laboratory personnel are not required to perform the test, front-line health care workers should have a session of training and job aids for use, interpretation and follow-up of results. Cholera RDTs are not meant for individual diagnosis but rather to detect possible toxigenic cholera transmission in an endemic community and monitoring of the outbreak during its course. Thus, annual use in terms of the number of tests per year in an identified cholera hotspot (per 200 000 population) has been estimated at 50–100 tests. The cost per person living in an area at risk of cholera is estimated to be less than US$ 0.01 per year. Quality control and assurance and surveillance of proper RDT use must be included to ensure the most effective use of the test in a cholera surveillance system.
Ethical issues, equity and human rights issues
Consent is required to obtain a faecal sample. As the test is intended for points of care in peripheral health centres and even for community health workers, the wide availability of cholera RDTs would improve equity in communities by providing evidence of an impending cholera outbreak for rapid protective measures. At present, the benefit is at community rather than individual level.
1. Clemens JD, Nair GB, Ahmed T, Qadri F, Holmgren J. Cholera. Lancet 2017;390:1539–49. 2. Ali M, Nelson AR, Lopez AL, Sack DA. Updated global burden of cholera in endemic countries. PLoS Negl Trop Dis. 2015;9(6):e0003832. 3. Keddy KH, Sooka A, Parsons MB, Njanpop-Lafourcade BM, Fitchet K, Smith AM. Diagnosis of Vibrio cholerae O1 infection in Africa. J. Infect Dis. 2013;208(Suppl.1):S23–31. 4. Interim technical note. The use of cholera rapid diagnostic tests. Geneva: World Health Organization, Surveillance Laboratory Working Group, Global Task Force on Cholera Control; 2016 (https://www.who.int/cholera/task_force/Interim-guidance-cholera-RDT.pdf?ua=1, accessed April 2019). 5. Interim guidance document on cholera surveillance. Geneva: World Health Organization, GTFCC Surveillance Laboratory Working Group, Global Task Force on Cholera Control; 2017 (https:// www.who.int/cholera/task_force/GTFCC-Guidance-cholera-surveillance.pdf?ua=1, accessed May 2019). 6. Dick MH, Guillerm M, Moussy F, Chaignat CL. Review of two decades of cholera diagnostics – how far have we really come? PLoS Negl Trop Dis. 2012;6(10):e1845.