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      COVID-19: Don't Neglect the Gastrointestinal Tract!

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          Abstract

          Infection with SARS-CoV2 affects predominantly the upper airways and the respiratory tract, but it frequently extends to the extrapulmonary system and can show manifestation in other organ systems. A series of clinical reports released during the last weeks indicate also a significant involvement of the gastrointestinal tract by the infection with SARS-CoV2. There are 2 main aspects of concern: one being related to gastrointestinal symptoms (GIS) and their influence on the course of disease; the other being related to excretion of the virus (or its RNA fragments) in the patient's faeces and a possible role for faecal-oral transmission. Scientific assessment of both aspects is likely to provide important insights into the disease process and will emphasize the need for awareness of the involvement of the GI tract and help improve clinical management. GIS in the context of COVID-19 include loss of appetite (anorexia), nausea, vomiting, diarrhoea, and abdominal pain. Available reports show a wide range regarding the prevalence of these symptoms, best explained by the retrospective nature of these studies. The prevalence of GIS was 11.4% among 651 included patients in Hangzhou [1], but was 50% among 204 patients in Hubei [2]. Cheung et al. [3] published a meta-analysis including more than 4,000 patients, reporting a prevalence of GIS of 17%. This was different from data from their local patient cohort in Hong Kong (59 patients) in which the prevalence was 25% [3]. In less than 10% of adult patients, GIS were the initial symptoms of COVID-19, with the frequency being higher in children. Recent experience has shown that GIS are frequently associated with a more severe course of the disease. Certainly, anorexia is rated as the most common symptom, but it is also the most unspecific among GIS and may primarily be related to systemic inflammation and malaise (fatigue) induced by the viral infection rather than to a substantial pathology within the gastrointestinal tract. Diarrhoea represents the most relevant clinical aspect of gastrointestinal involvement. The prevalence of diarrhoea reported in 3 studies varied from 11 to 17% [1, 2, 3], but was as high as 31% in a group of healthcare workers with SARS-CoV2-induced pneumonia [4]. Apart from its impact on the patient's general condition, diarrhoea contributes to aggravation of the clinical course of COVID-19. Essential treatment of severe diarrhoea such as fluid and electrolyte replacement needs to be accompanied by the use of anti-diarrhoeic medication. Different mechanisms may contribute to diarrhoea in patients with COVID-19, and these have to be taken into account when choosing therapeutic measures. The latter includes stopping the administration of antibiotics (if such are administered) or switching to a different type, the administration of substances modulating the gut microbiome (e.g., probiotics and rifaximin) to help recover from dysbiosis, and the administration of conventional anti-diarrhoeic remedies to antagonize the damage to intestinal epithelia. In specific cases, the use of biologicals to modulate the immune system may also be considered. Patients with chronic inflammatory bowel disease and other autoimmune diseases in the digestive system belong to the high-risk group for COVID-19 as these patients are often on immune-suppressive or immune-modulatory treatment. The pathophysiological impact of the infection and the cellular interaction of the virus with the intestinal mucosa have recently been reviewed elsewhere [5]. The other important feature of gastrointestinal issues in COVID-19 patients is the higher proportion of stool samples that are positive for virus RNA in patients with diarrhoea than in those without [4]. Of great concern is the prolonged SARS-CoV2 excretion in faeces which may persist after throat swabs turn negative. This could lead to persistent infectiousness beyond the time point at which patients are generally considered to be no longer at risk of transmitting the infection. Studies looking into this aspect report the persistence of faecal viral RNA in 23–82% for up to 11 days after oro-pharyngeal and sputum tests became negative [6]. Some patients retain the viral RNA for more than a month. Obviously, this could have an important impact on possibilities of viral transmission and the need and extent of hygienic measures to be taken. There remains major uncertainty as to whether SARS-CoV2 is viable in faeces or if the respective analyses report non-viable viral RNA fragments shed together with intestinal epithelial cells. For now, these data are obtained in retrospective, small-scale studies and are inconclusive. Nevertheless, based on the information that is available, it is crucial to implement appropriate hygienic and medical strategies: Members of households of infected patients have to be informed about the possible routes of transmission of SARS-CoV2, in order to take special precautions such as the use of separate toilets where possible, careful and frequent hand washing, and regular washing of individual towels. Routine (elective) endoscopic examinations should be carefully planned in COVID-19 patients, and special precautions for protection of patients and the examining team should be taken. Faecal microbiota transplantation has become a very sensitive aspect in times of COVID-19. To prevent faecal SARS-CoV-2 transmission, a group of experts proposed assessing potential donors for the presence of typical COVID-19 symptoms within 30 days prior to donation. There is also the need for a detailed history including close contact with individuals with proven or suspected infection within the previous 30 days, and, most importantly, extensive and dedicated testing for SARS-CoV2 in stool and upper airways [7]. (In our opinion, the use of faecal microbiota transplantation should remain maximally restrictive with the exception of refractory cases of C. difficile colitis, not responding to all novel medical options.) Considerations should be given to medication that might potentially prolong infectiousness either by modulation of gastric pH (i.e., acid suppressants) or by interfering with mucosal immunology (i.e., antibiotics). The agenda for clinical research on COVID-19-related aspects in the gastrointestinal tract offers multiple opportunities. It certainly demands for studies on (a) the pathogenesis and impact of direct viral damage of the whole digestive system; and (b) factors contributing to COVID-19-associated diarrhoea with special emphasis on the gut microbiome and anti-diarrhoea management. A special focus should be directed on the role of the digestive system in transmitting the infection, on how to reduce the length of infectiousness, and on which precautions to be taken with regard to this matter. Disclosure Statement None of the authors have a conflict of interest. Author Contribution All authors have equally contributed in writing this editorial.

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          Most cited references 2

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          Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel

          As the outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread from China to other countries, governments and the medical community are taking steps to prevent transmission, from common sense recommendations to radical quarantine measures. 1 In that context, timely recommendations concerning the screening of donors of human cells, tissues, or cellular or tissue-based products have been released, as the potential for transmission of COVID-19 through transplant is not yet known. Several institutions have recommended interim precautions to screen new donors. The US Food and Drug Administration has suggested considering a donor's history of travel to areas of outbreak, cohabitation with infected individuals, or diagnosis or suspicion of COVID-19 within the 28 days before recovery of donor tissue. 2 Similar measures have been taken by the Global Alliance of Eye Bank Associations and by the Joint United Kingdom Blood Transfusion Services Professional Advisory Committee to rule out potential donors.3, 4 The European Society for Blood and Marrow Transplantation has recommended excluding potential donors who have been diagnosed with COVID-19, and waiting at least 21 days before donation in those with a history of high-risk travel or contact. 5 In Italy, where the COVID-19 outbreak is spreading rapidly, the national transplant centre has taken stronger measures and has recommended testing all potential tissue and stem-cell living donors, as well as dead donors, through real-time RT-PCR assays of nasopharyngeal swab samples (or bronchoalveolar lavage in deceased individuals). 6 Faecal microbiota transplantation is a novel treatment that has rapidly earned a major role in the management of recurrent Clostridioides difficile infection because of its clear advantages over antibiotics. 7 It is becoming increasingly more widespread and standardised around the world. Last year, an international expert panel, including several authors of this Comment, released recommendations on how to screen faecal microbiota transplant donors, including a medical history and blood and stool examinations. 8 Given the global COVID-19 outbreak, we, as an international group of experts in faecal microbiota transplantation and stool banking, believe that recommendations to update (at least temporarily) the screening of stool donors are urgently needed, as the risk of transmitting SARS-CoV-2 by faecal microbiota transplantation might be higher than that in other tissue transplants. Evidence has shown that the SARS-CoV-2 can be found in faeces, and that stool samples can remain positive for the virus even when it is no longer detectable in the respiratory tract, suggesting the possibility of a faecal–oral route of transmission. 9 This concept is supported by the presence of gastrointestinal symptoms in some patients affected by COVID-19. 10 Another relevant issue is that faecal microbiota transplantation is not classified in the same way worldwide, as some countries regulate these transplants as a drug (eg, the USA, the UK, and France), some as a tissue (eg, Italy), and others do not provide specific regulation (eg, Australia). 8 This discrepancy results in a confusing scenario, in which some countries will apply rules for human cells, tissues, or cellular or tissue-based products, and others will not, potentially contributing to the spread of the infection. A more alarming issue is represented by the uncontrolled practice of homemade faecal microbiota transplantation, which is widespread among patients who want to try this treatment for indications outside of clinical guidelines or clinical trials. 11 To prevent SARS-CoV-2 transmission, we propose additions to the current donor screening measures. In all countries, before each donation, physicians should screen for two main items: the presence of typical COVID-19 symptoms (including fever, fatigue, dry cough, myalgia, dyspnoea, and headache) within the previous 30 days; and the donor's history of travel to regions known to be affected by COVID-19 or close contact with individuals with proven or suspected infection, within the previous 30 days. If either of these items is positive, the potential donor should either be rejected or tested with RT-PCR assay for SARS-CoV-2. In endemic countries, the RT-PCR assay should be considered in all donors, even if they are asymptomatic or do not have a history of high-risk travel or contact. Alternatively, donor stools should be stored and quarantined for 30 days before use, and released only if the donor has not developed symptoms. Finally, stool banks should retrospectively check the health status of the donor before using frozen faeces, according to local epidemiology, to avoid further potential spreading of SARS-CoV-2. These suggestions should be tailored to local health-care organisations, and should be updated accordingly as further insight into COVID-19 and SARS-CoV-2 is gained.
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            Diarrhea is associated with prolonged symptoms and viral carriage in COVID-19

             XS Wei,  X Wang,  YR Niu (2021)
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              Author and article information

              Journal
              Dig Dis
              Dig Dis
              DDI
              Digestive Diseases (Basel, Switzerland)
              S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
              0257-2753
              1421-9875
              29 April 2020
              : 1-2
              Affiliations
              aDepartment of Medicine II, University Hospital, LMU Munich, Munich, Germany
              bDepartment of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
              cTranslational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals, Headington, Oxford, United Kingdom
              dDepartment of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
              Author notes
              *Prof. Peter Malfertheiner, Med. Klinik und Poliklinik II, Marchionini Str. 15, DE–81377 München (Germany), peter.malfertheiner@ 123456med.ovgu.de
              Article
              ddi-0001
              10.1159/000508289
              7316654
              32349002
              Copyright © 2020 by S. Karger AG, Basel

              This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

              Page count
              References: 7, Pages: 2
              Categories
              Editorial

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