key: cord-0878041-we9kzreh
authors: Gupta, Sunnia; Parker, Jody; Smits, Stephanie; Underwood, Jonathan; Dolwani, Sunil
title: Persistent viral shedding of SARS-CoV-2 in faeces - a rapid review
date: 2020-04-22
journal: nan
DOI: 10.1101/2020.04.17.20069526
sha: 2f5e6026c5f4241d0636dfd05e0c230f65d58021
doc_id: 878041
cord_uid: we9kzreh

Background and aims In addition to respiratory symptoms, patients with COVID-19 can present with gastrointestinal complaints suggesting a possible faeco-oral transmission route. The primary aim of this review is to establish the incidence and timing of positive faecal samples for the SARS-CoV-2 virus in patients with COVID-19. Methods A systematic literature review was performed to identify studies describing COVID-19 patients tested for the virus in their stool. Data were extracted concerning the nature of the test, number and timing of positive samples, incidence of positive faecal tests after negative nasopharyngeal swabs and any evidence of viable faecal virus or faeco-oral transmission of the virus. Results There were 26 relevant articles identified. Combining these results demonstrated that 53.9% of those tested for faecal RNA in these studies were positive. Duration of faecal viral shedding ranged from 1 to 33 days after nasopharyngeal swab turned negative with one result remaining positive after 47 days of onset of symptoms. There was insufficient evidence to draw firm conclusions about the proportion of cases potentially transmitted through infection via faecally shed virus. Conclusions There is a relatively high rate of positive tests and persistence of the SARS-CoV-2 virus in faecal samples of selected patients with COVID-19. Further research is needed to demonstrate how much these positive tests correlate with viable virus and transmission through the faeco-oral route. This may have important implications for duration of isolation, precautions recommended in individuals undertaking a period of isolation, protective equipment for health professionals and interventional procedures involving the gastrointestinal tract.

The rapid progression of the COVID-19 pandemic has created significant challenges for the public as well as healthcare professionals around the world. Knowledge regarding virus incubation, transmission and shedding is crucial for the reduction of new cases and protection of health care professionals. Guidance regarding isolation and protective equipment has changed as evidence has increased and developed.

The high incidence of cough and fever in COVID-19 are well established. 1 Gastrointestinal symptoms are also well documented suggesting a potential faeco-oral transmission route. 2 Discharge guidelines for hospitals or declaring a COVID-19 patient recovered in the UK are largely based on time from either symptom onset or positive test depending on severity of illness and discharge destination. 3 The European Centre for Disease Prevention and Control (ECDC), on the other hand, has advocated the need for continued self-isolation and hand hygiene measures even 14 days post-discharge based on prolonged viral shedding in faeces and respiratory samples. 4 This evidence may influence the recommended duration of selfisolation as well as home sanitation practices during isolation and after discharge, and the use of protective equipment and procedures involving the gastrointestinal tract in UK. Evidence based recommendations for specialities such as gastroenterology, gastrointestinal endoscopy and gastrointestinal surgery are required where there may be an exposure risk to virus shed in faeces. Despite viral RNA being detected in the air or other surface samples like toilets, it is still unclear whether it is viable to transmit infection through this route. 5 The primary aim of this review is to assess the incidence of COVID-19 patients positive on testing of faecal samples for the virus and the timing with respect to the clinical course (onset of symptoms) when faecal tests may be positive. Our secondary aims are to establish the incidence of patients with positive faecal samples after negative respiratory swabs and any evidence to suggest faecal virus transmitted infection.

Reports of cases or studies of COVID-19 patients with evidence of the virus in faecal samples were systematically identified and full text articles reviewed for data extraction.

A comprehensive search was undertaken as per the search strategy outlined below for literature which included SARS-CoV-2 virus testing of faeces. Medline was searched to find articles published until 3 April 2020. The defined search terms were created after collaboration between the authors experienced in gastroenterology, colorectal surgery and systematic review. Search terms reflected the aim to identify studies with evidence of faecal COVID-19 and included 'clinical', 'faeces', 'gastrointestinal secretions', 'stool', 'COVID-19', 'SARS-CoV-2' and '2019-nCoV'. Additional manual searches to identify the most recent evidence were performed in the American Journal of Gastroenterology (AJG), Gastroenterology, GUT, the Lancet Gastroenterology and Hepatology, the WHO database, the Centre for Evidence Based Medicine (CEBM), the New England Journal of Medicine (NEJM), and the National Institute for Health and Care Excellence (NICE). COVID-19 preprints published until 10 April 2020 on medRxiv and bioRxiv and an independent search on social media (Twitter) by the authors (SS, SD) supplemented more articles.

Articles describing COVID-19 patients who had faecal or stool specimens tested for the virus were included. Considering the knowledge gaps existing for COVID-19 all articles were considered regardless of the number, age or gender of patients or the country of publication. Animal based studies or articles without an available full text were excluded. Foreign language articles were considered but excluded unless the necessary language expertise was available within the research group.

Articles were sorted alphabetically by author name and divided between two reviewers (SG and JP). Abstracts were reviewed and classified by the same two authors through the Rayyan Web Application 6 to identify those for full text review. The same process was used for full text articles and this data was managed through EndNote. Articles were then discussed between the same reviewers to identify the final selection of full text articles. Any conflicts were to be solved by the supervising author if necessary. Reference lists and review articles were cross referenced to identify any further original studies. All articles were categorised and described in a PRISMA flow chart.

The final data extraction was also carried by the two reviewers (JP and SG) and managed through Microsoft Excel files. The data parameters extracted from the studies are shown in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 22, 2020. . Table 1 . The final data was verified by the two reviewers (JP and SG) with conflict resolution as described previously if necessary. 1 .

Country of publication

Number and type of patients in the study

Type of sample taken (faecal sample, anal swab, RT-PCR, culture)

Number of patients having faecal samples tested and number of positive samples

Timing of positive faecal swab after symptom onset

Duration of positive faecal specimen after negative nasopharyngeal swab

Any evidence for viable faecal virus or faeco-oral transmission documented in the study Table 1 -Data parameters for extraction . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Medline searches identified 565 articles and 194 were found through other databases. An overview of the selection process is shown in the PRISMA chart in Figure 1 . There were 26 articles 7-32 included in the final analysis. An overview of the data extraction is summarised in Table 2 . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . Most studies were from China (n=20) with two from the USA and one each from Italy, Korea, Vietnam and France. The number of participants recruited in the studies ranged from 1 to 206 with ages ranging from 3 months to 87 years. Sample collection consisted of either faecal samples, anal or rectal swabs. Quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) was the test performed on all samples to detect viral RNA. The indication for faecal testing was not specified in most studies. In some the test was done in asymptomatic patients for screening after contact with an infected person or travel history to an infected area. The predominant symptoms of presentation in the studies were persistent cough, fever and breathlessness with fewer patients reporting diarrhoea or vomiting. All studies had information regarding our primary aim of reporting faecal samples for the virus in those with COVID-19. Of these, 16 7,10,11,14-19,23,24,26-30 provided information on the duration of these tests after symptom onset and evidence of positive faecal samples after symptom recovery, discharge from the hospital or negative nasopharyngeal RT-PCR. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020 A total of 824 patients were included across the studies and 540 were tested for faecal viral RNA. Positive faecal RT-PCR tests occurred in 291 (53·9%). The timing of the first positive sample was available in 21 studies and varied from day 0 of symptom onset to day 17. Late positive tests do not necessarily equate to absence of the virus earlier in the illness but may likely reflect the heterogeneity in testing patterns amongst the studies. First stool samples were often reported late after hospital admission 11 or even after discharge 28 while some were analysed from day 1 of hospitalisation or symptom onset 19, 20, 27, 29, 32 . There is a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . https://doi.org/10.1101/2020.04. 17.20069526 doi: medRxiv preprint similar discrepancy in follow up testing. Some tested until samples were found to be negative 17 while others did not 18, 29 .

Out of 199 patients who tested positive for faecal viral RNA and were followed up with stool testing, 125 (62·8%) showed persistent shedding of virus in the stool samples after a negative nasopharyngeal swab while in the individual studies it ranged from 23·3% to 100%. The duration for fecal shedding of viral RNA after clearance of respiratory samples ranged from 1 to 33 days and in 1 patient up to 47 days from symptom onset 26 .

None of the studies were designed to detect live virus in the faeces except for the study by Wang et al. 25 Out of 153 stool specimens tested in this study, 44 were PCR positive and out of 4 specimens cultured, live virus was detected in 2. 25

This rapid review demonstrates a relatively high incidence and persistence of stool positivity for SARS-CoV-2 on RT-PCR after negative nasopharyngeal swabs in faecal specimens of selected patients with COVID-19. This may have important implications regarding measures to prevent the spread of the disease, especially for precautions recommended for the public, protective equipment for health professionals involved in procedures and interventions involving the gastrointestinal tract. Similar patterns of virus isolation from stool and faeco-oral transmission were observed for other coronaviruses including SARS-CoV-1. 33 Bio-aerosol generation of viral particles as a result of flushing of toilets as well as the impact of disinfection on these have also been studied before 34, 35 along with the persistence of coronaviruses on surfaces. 36 The risk to health care professionals from patient exposure is well known, specifically in high aerosol generating procedures. Professional societies and investigator groups from countries with experience of managing COVID 19 in the context of gastrointestinal interventions 38, 39 highlight the risk to individuals in endoscopy departments and the need for necessary precautions including negative pressure rooms and personal protective equipment. This review supports the importance of these measures given the relatively high prevalence and persistence of SARS-CoV-2 virus in faeces. Isolation of live virus is confirmed by one study 25 but the proportion of cases that might be transmitted by this route is unclear due to the heterogeneity in case selection and lack of standardisation of study designs and protocols. Areas such as Care homes may be particularly vulnerable to transmission of infection by this route and recommendations must take into account this evidence to ensure the protection of health and social care providers and the general public in the meantime.

The heterogeneity of included studies was a significant limitation of this review. This was not formally assessed due to it being a rapid review but can be clearly identified on inspection of the study designs and outcomes. The variability in patient numbers and characteristics, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 22, 2020. . sample timing and follow up testing should be considered when interpreting the reliability of the results. The heterogenous nature of sampling may also affect viral detection as some studies reported faecal samples and others anal or faecal swabs. There were two foreign language articles excluded due to lack of translation resources.

The duration of viral shedding in the faeces is mostly reported as 1 to 33 days after a negative nasopharyngeal swab but can continue for up to 47 days after onset of symptoms in patients with COVID-19. These positive samples can occur after negative nasopharyngeal swabs or resolution of patient symptoms. Isolation of live virus in stool specimens in a single study of 2 cases supports the possibility of faeco-oral transmission. Further research is needed to prove if this viral shedding in stool results in a significant proportion of case transmission in the community as well as within care institutions and secondary care. Until further evidence is generated appropriate precautions should be strictly recommended for the protection of healthcare workers and patients.

1. In addition to strict adherence to hand washing recommendations, home toilet sanitary and disinfection precautions should be taken in the case of isolation or contact with a symptomatic COVID 19 case with or without gastrointestinal symptoms. This recommendation is based on limited evidence of possible viable faecal virus excretion. 2. These precautions may need to continue for longer than the period of symptoms and the current recommendations for isolation after symptoms cease. This recommendation is based on limited evidence of the duration after the onset of symptoms that a RT-PCR stool test might still be positive Implications for Healthcare professionals:

1. Professional bodies recommendations on protective equipment, endoscopic and surgical procedures for COVID-19 patients should be followed. 40-43 2. The possibility of faeco-oral transmission should be borne in mind with implications for endoscopy and theatre disinfection of surfaces in between procedures. 3. Ward areas for COVID-19 patients and Care homes or similar institutions may need to consider the implications for infection control and disinfection in light of the possibility of faeco-oral transmission 4. Screening processes for patients due to undergo investigational or interventional procedures should consider including gastrointestinal symptoms and stool testing in future pre-procedure questionnaires. 5. Healthcare teams managing patients with gastrointestinal symptoms may need to consider the possibility of COVID-19 coexisting with or worsening symptoms of underlying conditions such as Inflammatory Bowel Disease. 44 Recommendations for further research:

Future studies on viral shedding and infectivity of SARS-CoV-2 should consider standardisation of sampling methods with appropriate precautions for laboratory staff handling these samples until the situation is clearer.

2. Study designs may wish to consider repeat and parallel sampling with nasopharyngeal swabs at defined time points. This may be correlated with symptoms and serology to clarify the effect of neutralising antibodies and viable virus excretion in the stool. 3. Study designs may benefit from testing stool samples from comparable groups. This could include symptomatic, asymptomatic or recovered individuals in and out of family clusters and with or without gastrointestinal symptoms. This may improve our understanding of clinical and public health implications and potential targets for intervention in these settings.

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Acknowledgement: We would like to thank Dr SA Roberts for critical review and comments on the manuscript