key: cord-1051332-8eh4t7jk
authors: Concas, Giulia; Barone, Michele; Francavilla, Ruggiero; Cristofori, Fernanda; Dargenio, Vanessa Nadia; Giorgio, Rossella; Dargenio, Costantino; Fanos, Vassilios; Marcialis, Maria Antonietta
title: Twelve Months with COVID-19: What Gastroenterologists Need to Know
date: 2021-07-31
journal: Dig Dis Sci
DOI: 10.1007/s10620-021-07158-0
sha: 92b8ca5b20d605b9bf53186ea1a9bb8491afe382
doc_id: 1051332
cord_uid: 8eh4t7jk

Corona virus disease-19 (COVID-19) is the latest global pandemic. COVID-19 is mainly transmitted through respiratory droplets and, apart from respiratory symptoms, patients often present with gastrointestinal symptoms and liver involvement. Given the high percentage of COVID-19 patients that present with gastrointestinal symptoms (GIS), in this review, we report a practical up-to-date reference for the physician in their clinical practice with patients affected by chronic gastrointestinal (GI) diseases (inflammatory bowel disease, coeliac disease, chronic liver disease) at the time of COVID-19. First, we summarised data on the origin and pathogenetic mechanism of SARS-CoV-2. Then, we performed a literature search up to December 2020 examining clinical manifestations of GI involvement. Next, we illustrated and summarised the most recent guidelines on how to adhere to GI procedures (endoscopy, liver biopsy, faecal transplantation), maintaining social distance and how to deal with immunosuppressive treatment. Finally, we focussed on some special conditions such as faecal–oral transmission and gut microbiota. The rapid accumulation of information relating to this condition makes it particularly essential to revise the literature to take account of the most recent publications for medical consultation and patient care. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10620-021-07158-0.

82% identical to SARS-CoV human and 50% identical to MERS-CoV. Cases range across all ages, with most patients between 35 and 55 years and fewer cases among children and infants. Males are more susceptible than females (65%) [2] . Symptoms may include fever, cough, sore throat, nausea, myalgia and mild flu-like symptoms; a small percentage evolve towards respiratory failure needing ventilatory support and, in the most severe cases, multi-organ failure and death [3] .

Coronavirus spike surface glycoprotein (S-protein of SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE-2) to invade host cells. Through genomics studies, researchers have shown that SARS-CoV-2 binds to the same receptor with an affinity which is approximately 10-to 20-fold higher than SARS-CoV [4] [5] [6] . Many organs and tissues, besides the respiratory tract, have a high expression of ACE-2: heart, skin, kidney, endothelial cells of small and large vessels and fat. In the gastrointestinal tract, ACE-2 is abundantly expressed at the oesophageal level and in the small and large intestine, particularly in the ileum [7] [8] [9] [10] . From an evolutionary point of view, ACE-2 has high structural homology with collectrin, a transmembrane protein with a regulatory function in the expression of neutral amino-acid transporters at the brush border of the proximal renal tubules. The enzyme has a double function: a negative regulation on the renin-angiotensin-aldosterone system and an amino-acid transporter mainly in the small intestine. In the gut, collectrin is not expressed, and its role is performed by ACE-2, which acts as the chaperone for trafficking of an amino-acid transporter on cell membranes, B0AT1, which mediates uptake of neutral amino-acids into intestinal cells. Some studies have shown that ACE-2 knock-out mice do not express B0AT1 in the gut and have low levels of the aminoacids tryptophan, valine, threonine and tyrosine, resulting in severe intestinal inflammation and microbial imbalance. Structural modelling has suggested that the ACE2-B0AT1 complex can bind the S-protein of SARS-Cov-2 and that ACE-2 might be the viral entry point for SARS-CoV-2 in the gut [11] .

This systematic review summarises a 1-year experience in dealing with patients with COVID-19 and gastrointestinal symptoms (GIS) before the vaccination programme. We aim to highlight the prevalence and clinical significance of GIS in patients with COVID-19 and to report up-to-date, brief and practical information for gastroenterologists dealing with chronic gastrointestinal diseases (inflammatory bowel disease, coeliac disease, chronic liver disease) at the time of COVID-19.

We performed a literature search in December 2020, focussing on articles published from January 1 2020, examining data on clinical manifestations of gastrointestinal involvement. For this purpose, we performed an electronic search of the literature using the online databases Cochrane Library, PubMed, Scopus and Web of Science, entering the query terms ("SARS-CoV-2" OR "COVID-19") AND ("intestine*" OR "gastr*" OR "pancr*" OR "esopha*" OR "colon*" OR "rectum, "nausea" OR "vomit" OR "diarrhoea" OR "abdominal pain" OR "anorexia"). We eliminated a priori all experimental studies and limited our literature search to articles published in English in peer-reviewed journals. Further relevant articles were hand-searched using the references of the selected studies. Eligibility criteria were evaluations of in-patients with gastrointestinal symptoms.

Due to the presence and function of ACE-2 at the intestinal level, many authors have hypothesised that the virus may present a tropism for the enteric epithelium, causing GIS. Although initial studies indicated that GIS was not frequent in COVID-19, recent evidence has shown that this is not the case. In Table 1 and Table S1 , respectively, all studies with more than 100 and less than 100 patients found by our systematic literature search are reported, describing the most frequent GIS: anorexia, diarrhoea, nausea, vomiting and abdominal pain . A possible reason for the relatively high prevalence of diarrhoea compared to other GIS is that gut epithelial cells (especially in the ileum) have a significantly high ACE-2 expression. GIS might predispose to electrolyte disruptions, hyponatremia, which could exacerbate the disease.

A total of 318 patients with confirmed COVID-19 were included in a US multicentre cohort study. Overall, 61% of patients reported at least one GIS on admission, most specifically anorexia (35%), diarrhoea (34%) and nausea (26%). In addition, patients with GIS reported higher levels of fatigue, myalgia and odour or taste loss. In this experience, there were no variations in clinical deterioration rates between patients with and without GIS when comparing admission to intensive care unit (ICU), mechanical ventilation needs or overall mortality possibly due to the absence of ICU rooms/ ventilators at the participating hospitals [25]. A recent paper reported a correlation between the presence of GIS and the severity of respiratory symptoms, the need for ventilatory support and ICU admission [126] . COVID-19 patients with GIS experience worse respiratory symptoms (higher rates of fever, shortness of breath and headache). Moreover, severe cases of COVID-19 occur frequently in patients with GIS, as compared to those without (23% vs. 8%), consistent with the possibility that an intestinal localization might increase the release of pro-inflammatory cytokines with an impact Abdominal pain, although less frequent, has been associated with severe disease [127] . A recent meta-analysis showed that the prevalence of nausea and vomiting was 7% (95% CI 0.04-0.09), diarrhea was [128] . Thus, revaluation of GIS by SARS-COV-2 was lower than by SARS and MERS [129, 130] . Finally, with regard to GI involvement, critical intestinal ischemia has been recorded in 2-5% of patients with COVID-19, compared to no cases in ill patients with non-COVID-19 [58, 131] .

In a recent meta-analysis, data were selected from 32 articles with a total sample size of 759 children [132] . Among the most common clinical manifestations was diarrhoea (19%, 95% CI 9-28%). Another systematic review reported data from 45 paediatric studies on SARS-CoV-2 infection. Paediatric infections were found to be 2% of 44,672 cases in a Chinese paper, 1.2% of 22,512 cases in an Italian study, 5% of 4226 cases in the United States and less than 1% of cases in the United Kingdom. Infections in paediatric patients are therefore a minority; this could be due to active resistance of children to the virus, or an increased frequency of unrecognized asymptomatic cases. The clinical course in the paediatric patient appears to be very mild compared to adults [133] . However, young patients (up to 5 years) have a higher viral RNA load in their nasopharynx than older ones and adults [134] . The most common symptoms in children are fever and cough, but diarrhoea and vomiting have also been reported. Table 2 and Table S2 , respectively, show all studies with more than 100 or less than 100 children found by our search . In children, GIS are less common than in H1N1 influenza, which, according to the data, in 2009 caused diarrhoea in more than 20% of children [212] . An essential aspect to consider is that, although children show mild or no symptoms, stool samples and rectal swabs may test positive for viral RNA for several days after infection. In addition, paediatric patients seem to eliminate the virus through faeces for a longer time than adults [213, 214] . Several authors have proposed that the paediatric patient, due to the scarcity of symptoms and the prolonged elimination of the virus with faeces, could be an essential vehicle for transmission. However, the role of children in the spread of the virus has not yet been fully clarified.

Patients with COVID-19 may experience liver injury with elevated enzymes in blood tests. ACE-2 is expressed abundantly in hepatocytes and, in particular, on biliary epithelial cells, and this justifies the frequent liver involvement during SARS-COV2 infection. The incidence of liver involvement ranges from 15% to 50% of patients presenting with increased levels of transaminase with a relatively mild elevation in serum bilirubin [12, 14, 15, 77, 78] , while, in patients with severe disease, the proportion of liver injury was also higher [12, 16, 79, 213] . A recent meta-analysis calculated that up to 25% of patients would develop liver involvement (95% CI 0.16-0.33, P < 0.0001) [215] . There are several possible mechanisms of liver damage: (1) immune-mediated hepatitis, (2) direct viral cytopathic effect, (3) drug-induced liver injury secondary to medications used for the treatment of COVID-19 disease (lopinavir, ritonavir, remdesivir, chloroquine, tocilizumab, umifenovir), (4) hypoxia secondary to lung disease enhancing hepatic damage, (5) infectioninduced systemic inflammation, (6) hepatic congestion secondary to positive pressure ventilation, and (7) reactivation of pre-existing liver disease [214] .

A recent large retrospective cohort study, including 2073 Chinese patients with COVID-19, found that increased transaminases and direct bilirubin levels were independent predictors of mortality related to COVID-19 [215] . As far as acute-on-chronic liver (ACL) failure, among 192 hospitalised patients with chronic liver disease (CLD), 38% of the 84 cirrhotics developed ACL disease. However, mortality was not different when comparing CLD patients with or without cirrhosis. Moreover, mortality was similar between the CLD cohort and matched control without CLD [216] .

Theoretically, pancreatic involvement is based on the evidence that ACE-2 is usually expressed in the pancreas (exocrine glands and islets) of healthy people, indicating that SARS-CoV-2 might also cause pancreatic injury and potentially contribute to islet damage [217] . Wang et al., in a retrospective study of 52 patients with COVID-19, described such pancreatic involvement: 17% of patients showed an abnormality in amylase [115 ± 25 U/L (normal value < 90) or lipase [71 ± 34 U/L (normal value < 70)] and six had elevated levels of blood glucose suggestive of pancreatic islet damage. Patients with pancreatic injury had a higher incidence of anorexia and diarrhoea, more severe illness on admission, lower levels of CD3 + T-cell and CD4 + T-cell and higher levels of AST, GGT, creatinine, LDH and ESR. It is possible that some critically ill patients already had pancreatic damage on admission, and that this had been caused by drugs (NSAIDs and glucocorticoids) [81] . De-Madaria E. et al. replied that the definition of pancreatic injury, as referred by Wang et al., lacks specificity and does not meet Atlanta's criteria. A mild increase in blood levels of pancreatic enzymes within the threefold upper normal limits threshold can be explained by many factors other than direct viral damage, and the authors did not provide data on imaging techniques, which are crucial for diagnosing pancreatitis [218] . In another recent systematic review, cases of acute pancreatic disease associated with SARS-CoV-2 were searched to assess whether there was an association between the two. Six case reports and two retrospective cohort studies were selected but, unfortunately, the etiological factors and diagnostic criteria applied are not always well described [219] .

In conclusion, the risk of pancreatic involvement related to Covid-19 and the subsequent risk of acute pancreatitis exist. However, the clinical relevance of mildly elevated pancreatic enzymes in COVID-19 is unknown.

GIS appear to be secondary to intestinal inflammation, as evidenced by a recent study showing a strong correlation between the presence of diarrhoea and the elevation of faecal calprotectin and serum IL-6 [80] . Moreover, the examination of serum inflammatory markers showed elevated levels of procalcitonin, C reactive protein, D-dimer, ferritin tumour necrosis factor, interleukin (IL)-2R, IL-6, IL-8 and IL-10 [220] . These findings raise the question of whether the presence of the virus could be responsible for relapse in patients with inflammatory bowel disease (IBD), especially if requiring immunosuppressive drugs. ACE-2 receptor is highly expressed in inflamed IBD mucosal samples compared to controls. In addition, cytokines expressed in IBD, such as interferon-gamma, can potentially induce ACE-2 expression, consistent with the idea that mucosal inflammation can increase ACE-2 expression. These results indicate that patients with IBD might be especially vulnerable to COVID-19; nevertheless, there is no evidence that this is the case. In a recent systematic review and meta-analysis, data from 11 studies were reported to evaluate the various clinical manifestations of SARS-CoV-2 in patients with IBD [221] .

Diarrhoea was the most common GI manifestation in IBD patients (27.26%; 95% CI 19.51-36.69; I2 = 87%) per 100 persons. The pooled prevalence was 13.08% for abdominal pain (95% CI 9.24-18.19; I2 = 69%), 10.08% for nausea (95% CI 5.84-16.85; I2 = 80%) and 8.80% for vomiting (95% CI 4.43-16.70; I2 = 85%) per 100 persons. A noteworthy finding was the preponderance of abdominal pain in IBD patients, which is not common in the COVID-19-infected general population, as seen in other investigations. The current literature indicates that there is no evidence of increased risk or worsened outcomes in COVID-19 patients with IBD [222] .

Covid-19 seems to be more severe in old patients and in those with comorbidities (e.g. coronary heart disease, obesity, diabetes mellitus, malnutrition, cardiovascular disease, obstructive pulmonary disease and hypertension), severe IBD and/or needing surgery [223] . Considering the risk of flare-ups leading to a need for steroids or other potential immunosuppression or hospitalisation, the British Society of Gastroenterology, in a document addressing the needs of IBD patients, does not recommend interrupting or decreasing medications without first addressing it with the IBD team. Moreover, physicians must consider that immunosuppressive drug effects can persist for several weeks or months following cessation of treatment and that the evidence available indicates that patients with IBD do not have an elevated risk of developing COVID-19. Patients that receive immune suppressants should be closely monitored for symptoms and/or signs that indicate COVID-19. In addition, those patients over 60 years of age and/or with comorbidities who have a higher risk of SARS-CoV-2 induced pneumonia should remain at home and avoid public gatherings [224] . An international adult and paediatric registry (Surveillance Epidemiology of Coronavirus Under Research Exclusion-SECURE-IBD) is available to collect all the cases of COVID-19 in IBD patients at www. covid ibd. org. This registry will help to define the impact of COVID-19 in these patients and how factors such as age, severity, comorbidities and IBD treatments impact COVID-19 outcomes. Data on the effects of IBD medications on COVID-19 outcomes extrapolated from the registry have been recently published. The study, which includes 1439 cases from 47 countries, demonstrated that combination therapy and thiopurines may determine a worst COVID-19 outcome, while no differences were observed comparing different classes of biological drugs [225] .

To date, no research has shown that patients with celiac disease (CD) are at an elevated risk of severe COVID-19 as compared to patients without CD.

As for IBDs and also for CD patients, an international registry is currently collecting data of patients to monitor and report the outcomes of COVID-19 occurring in patients with celiac disease (SECURE-Celiac). The database encourages clinicians worldwide to report all cases of COVID-19 in celiac patients, regardless of severity (including asymptomatic patients identified through health screening). The database is accessible at https:// covid celiac. org/.

The CD Foundation Medical Advisory Board reports that patients with CD are not usually considered immunocompromised. A small number of CD patients with extreme malnutrition and weight loss, type 2 refractory CD, immunosuppressive medications or other serious illnesses may be at an elevated risk of severe COVID-19 and should consult with their physicians. CD is a chronic medical condition with a slightly elevated risk of infection, community-acquired pneumonia and worse outcomes with influenza [226] and therefore might benefit from an implementation of a vaccination programme for Streptococcus pneumonia and influenza. High-coverage vaccination programmes may help reduce the stress on the national healthcare system: e.g. avoiding being misled by diseases that can cause influenza-like symptoms in particular during the cold season during a pandemic, and also lower coinfections that could increase potential COVID-19 mortality. It is fair to hypothesise that those with CD, particularly the elderly, maybe at a slightly increased risk of worse infections with this new virus. Recently, Siniscalchi et al. surveyed 276 patients with CD using an ad hoc COVID-19 survey. He found that the lockdown had a small effect on patients' psychological health: CD patients did not think they were at excessive risk of being infected with the Sars-COV-2 virus nor worried about the shortage of gluten-free food. Elderly patients and patients with other comorbidities were the most worried, probably because they knew they were at greater risk of mortality [227] . In another recent survey of 1983 responses, improved adherence to the gluten-free diet was reported for 29% of enrolled adults and children [228] .

Based on a retrospective cohort study, another paper has been published on the management of CD in children with antitranglutaminase IgA between 5 and 10 times the upper limit of normal and positive endomysial antibodies during the COVID-19 outbreak.

The authors conclude for the possibility of temporarily reducing the antitranglutaminase IgA threshold for a biopsysparing approach, avoiding delayed diagnosis and complications. Certainly, a rigorous follow-up of illness course and serum auto-antibody levels is extremely crucial to confirm diagnoses over time [229] .

Since the pandemic began, several studies have been conducted to assess a link between underlying liver diseases and the course of SARS-CoV-2 infection. Patients that might be at increased risk of a severe course of COVID-19 are those with chronic hepatitis B and C or cirrhosis, alcoholassociated liver disease, non-alcoholic fatty liver disease or steatohepatitis that may suffer from metabolic comorbidities such as diabetes, hypertension and obesity [230, 231] .

According to the World Gastroenterology Organization, patients with chronic liver disease without cirrhosis and/ or after liver transplantation are not at an increased risk of severe COVID-19 disease. Some general approaches are strongly recommended: (1) reduce direct exposure and maintain social distance; (2) maintain care according to guidelines; (3) routine testing of liver biochemistry is not recommended for outpatients; (4) exclude viral hepatitis in patients with elevated transaminase; (5) maintain antiviral medications for B or C hepatitis; (6) delay nonurgent procedures of surveillance such as liver ultrasound and screening; (7) maintain immunosuppressive therapy if not differently prescribed; (8) use telemedicine whenever possible; (9) implement vaccination for Streptococcus pneumonia and influenza; (10) limit contact with medical personnel to a minimum; and (11) promote collaboration with local health care providers and primary care facilities. Additional recommendations for patients with decompensated liver disease include that listing for transplantation should be restricted to patients with poor short-term prognosis and that in-hospital liver transplant evaluation programmes should be maintained aiming to shorten hospital stays. A patient with chronic liver disease who results positive to COVID-19 should be admitted for in-patient care in the presence of additional risk factors for a more severe COVID-19 course like hypertension, diabetes, obesity, cirrhosis or a post-transplant status. A patient with chronic liver disease, negative to COVID-19 who needs in-patient care should be admitted to COVID-19-clean hospitals, preferably in private rooms, and specialised centres should provide easily accessible hepatology consultations [232] .

At the beginning of the Sars-Cov-2 pandemic, there was much concern about liver-transplanted patients since they were theoretically at higher risk of COVID-19 because of chronic immunosuppression. However, a prior experience of Italian patients found that none of the transplanted patients on highly intensive immunosuppression experienced a more severe disease course [233] . A more recent prospective Spanish nationwide study reported that, although liver transplant patients are chronically immunosuppressed and have an increased risk of acquiring COVID-19, their mortality rate is lower than the matched general population [234] .

At the beginning of the pandemic, multi-society guidelines recommended the postponement of non-emergency endoscopic procedures in adults and children [235] [236] [237] . Nowadays, the recommendations for diagnostic procedures are a dynamic process that needs to be updated regularly. It remains a good rule to screen with a COVID-19 questionnaire about the presence of symptoms, the history of potential exposure to infected individuals, travel to/from the containment zone and vaccination. Another suggestion is to use pre-endoscopy viral testing, although these are not routinely available everywhere. In the latter case, viral testing should be reserved for those patients at high risk of having COVID-19 infection after the questionnaire. Digestive endoscopy in COVID patients with GI symptoms showed variable results: oedema of the lamina propria (reported in two of three studies) and the presence of the virus in various levels of the GI tract [72, 78, 238] .

Recommendations can be examined based on individual risk-benefit considerations. Routine liver biopsy is not recommended in COVID-19 patients with liver test abnormalities. Liver biopsy should be deferred whenever possible in the event of non-alcoholic fatty liver disease or chronic viral hepatitis grading/staging and when the clinical indication is not urgent such as in the case of mildly elevated transaminases of unknown aetiology. Even in cases of autoimmune liver disease the biopsy should be postponed and an empiric therapy recommended. Liver biopsy should not be delayed in the event of liver masses suspected of malignancy [232] .

An international panel of experts in faecal microbiota transplantation and stool banking recommends updating the screening of stool donors, as the risk of faecal transplantation of SARS-CoV-2 may be high [239] . Faecal microbiota transplantation is not regulated in the same way worldwide: some countries control it as a drug (USA, UK, France) and some as a tissue (Italy). In contrast, others do not provide for precise regulation (Australia) [240] , and this complicates the situation, possibly leading to the spread of the infection. A more troubling concern is the unauthorised practice of homemade faecal microbiota transplantation, which is common among patients who would like to seek this treatment for reasons outside treatment protocols or clinical trials. The authors propose the screening of donors for the existence of risk factors for COVID-19: symptoms, travel history, and interaction within the previous 30 days with individuals with confirmed or suspected dangerous infections. The RT-PCR assay should be considered in all donors in endemic countries. In addition, donor stools should be processed and quarantined 30 days before use and released if symptoms do not appear in the donor. According to other authors, to ensure secure and efficient FMT to critically ill patients with persistent and refractory C. difficile infection, enhanced donor screening and validated stool tests for SARS-CoV-2 are needed [241] . However, faecal microbiota transplantation for these patients should be postponed until the pandemic is better under controlled conditions [242] .

SARS-CoV-2 belongs to viruses with intermediate respiratory and faecal-oral transmission capacity. The finding of viral RNA in faeces and anal and rectal swabs, reported in several studies, suggests the possibility of faecal-oral transmission. In the 2002-2003 SARS outbreak, SARS-CoV RNA was found in stools only after the fifth day of disease, and the proportion of stool-positive specimens steadily increased, peaking on day 11, with viral RNA still present for up to a month. It would also appear that the survival of the virus in the faeces is longer than in the respiratory tract. If this is also confirmed for SARS-CoV-2, doubts about the appropriateness of the current discharge criteria, based on the negative detection of the virus in two respiratory samples obtained 24 h apart, might arise. Table 3 reports the studies evaluating the presence of the SARS-CoV-2 in faecal specimens [60, 72-75, 78, 80, 91, 94, 96, 114, 119, 154, 155, 158, 171, 207, 210, 243-281] . No relationship has been reported between the persistence of the virus in the faeces, the severity of disease and the presence of GIS. In a recent meta-analysis, it was shown that positive faecal samples from 64% of patients remained positive for SARS-CoV-2 for an average of 12.5 days, up to a maximum of 33 days, after respiratory samples became negative for SARS-CoV-2, making faecal-oral transmission plausible [282] .

This finding is different from what has been reported with MERS, where the derangement of the gut epithelium was related to the subsequent development of pneumonia and severe disease [91] . In the United States, SARS-CoV-2 was first identified in stool samples. The possible faecal-oral transmission supports the necessity of strict measures while handling the stools of coronavirus-infected patients as well as adequate disinfection of hospital wastewater.

The lung and the gut are linked by a continuous two-way dialogue, each influencing the conditions of the other. Although the connection between these two systems is not yet fully understood, we know that the gut plays a central role, both because a break in the mucosal barrier may lead to the passage of endotoxins, bacterial metabolites and hormones in the body, and because gut microbiota are in constant communication with the immune system. During acute pulmonary disease, bacteria of intestinal origin can be found in the lungs secondary to bacterial translocation. Recent research has shown that the mucosal surfaces of the gastrointestinal and respiratory tract comprise distinct microbial species, both with overt and indirect effects on host defences against viral lung infections. Moreover, antiviral immune responses caused by acute respiratory infections, such as influenza, are associated with changes in respiratory and gastrointestinal microbiota (dysbiosis), which may affect the resulting function of the immune system [283] . As mentioned above, ACE-2 is crucial for the expression in the small intestine of some amino acid transporters, and, through this, ACE-2 can regulate intestinal microbiome composition [11] . In addition, gut microbiota could influence the action or change the expression of ACE-2.

In a recent study, Gu et al. reported a significant decrease in microbial diversity in intestinal microbiota specimens collected from COVID-19 patients in comparison with those collected from healthy controls [284] . Furthermore, they observed typical signs of dysbiosis: an increase of opportunistic pathogens and a decrease in the abundance of beneficial microbes, including microbial bacteria belonging to the Ruminococcaceae and Lachnospiraceae families. Zuo et al. showed significant alterations in the gut microbiome in COVID-19 patients [285] , and demonstrated an inverse correlation between the abundance of Faecalibacterium prausnitzii, considered a beneficial intestinal species, and SARS-COV-2 severity. Sufficient data are not yet available on the influence of the microbiota on the clinical course of COVID-19 and the onset of GI symptoms nor on the effect of COVID-19 on the integrity of the intestinal barrier or the onset of dysbiosis.

We have provided an update on the prevalence of gastrointestinal symptoms and liver injury in COVID-19 patients, showing that digestive symptoms and liver injury are not uncommon in COVID-19 patients, in particular in severe ones. Children with COVID-19 seem to have a milder course of GI and liver involvement as compared to adults. Patients with GI tract involvement as initial symptoms may have a delayed diagnosis of COVID-19. Moreover, those with digestive involvement tend to progress towards severe or critical illness and an unfortunate course of the disease. More attention should be paid to early identification of these patients. SARS-CoV-2 does not increase the risk of aggravation of disease among patients with pre-existing GI or liver-related comorbidities. However, these patients might benefit from an implementation of vaccination programmes, reducing possible direct exposure to the virus and maintaining social distance and care according to guidelines possibly through telemedicine without the need for reducing/stopping immunosuppressive treatment.

Nonetheless, limitations should be reported. First of all, the central core of researches has been written in other languages, particularly in Chinese. Then, GISs seem to be underreported because some symptoms were not taken into account or they were not considered as relevant or even more not categorised. In summary, the fast-evolving literature on this new pathological entity makes the gathering of new information highly relevant, since a better understanding and up-to-date knowledge of all available information might be useful, not only for scientific purposes but also for [73] 10 Stool 100 To et al. [74] 15 Rectal swabs 27 Wu et al. [75] 74 Stool 55 Lin et al. [78] 65 Stool 47.7 Effenberger et al. [80] 40 Stool 30 Cheung et al. [94] 59 Stool 15.3 Chen et al. [243] 28 Anal swabs 39.28 Zhang et al. [244] 14 Stool 37.5 Chen et al. [96] 42 Stool 66.67 Zhang et al. [245] 16 Anal swabs 62.5 Tan et al. [154] 10 Stool 30 Zheng et al. [91] 96 Stool 59 Xu et al. [155] 10 Rectal swabs 80 Wu et al. [246] 132 Stool/Anal swabs 9.83/10 Wang et al. [247] 153 the practical implications so as to provide the best care for our patients.

The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s10620-021-07158-0.

Author's contributions RF, MB and VF drafted the article and made critical revisions related to important intellectual content of the manuscript; GC, MAM, FC and VND made substantial contributions to the conception and design of the study, the acquisition of the data and its analysis and interpretation; RG and CD performed the literature search and data analysis. All the authors revised the manuscript and gave final approval of the version of the article to be published.

Funding Open access funding provided by Università degli Studi di Bari Aldo Moro within the CRUI-CARE Agreement. The present study did not receive any financial support.

The authors have no conflicts of interest relevant to this article to disclose.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by-nc/4. 0/. 

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Epidemiological characteristics of COVID-19 patients in convalescence period

Alterations of the Gut microbiota in patients with COVID-19 or H1N1 influenza

The role of interleukin-6 in monitoring severe case of coronavirus disease 2019

Clinical characteristics of rehospitalized patients with COVID-19 in China

Detection of SARS-CoV-2 in Fecal samples from patients with asymptomatic and mild COVID-19 in Korea

Clinical factors, preventive behaviours and temporal outcomes associated with COVID-19 infection in health professionals at a Spanish Hospital

Alterations in Fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge

Gastrointestinal involvement in COVID-19 patients: a retrospective study from a Greek COVID-19 referral hospital

Gastrointestinal symptoms and digestive comorbidities in an Italian cohort of patients with COVID-19

Patients with COVID-19 present with low plasma citrulline concentrations that associate with systemic inflammation and gastrointestinal symptoms

γ-Glutamyltransferase elevations are frequent in patients with COVID-19: a clinical epidemiologic study

Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19

Lipase elevation in patients with COVID-19

Digestive symptoms of COVID-19 and expression of ACE2 in digestive tract organs

Challenges in the management of SARS-CoV2 infection: the role of oral bacteriotherapy as complementary therapeutic strategy to avoid the progression of COVID-19

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

The spectrum of gastrointestinal symptoms in patients with Coronavirus disease-19: predictors, relationship with disease severity, and outcome

Clinical and radiographic characteristics, management and shortterm outcomes of patients with COVID-19 in Wenzhou, China

Clinical features and short-term outcomes of COVID-19 in Tehran, Iran: an analysis of mortality and hospital stay

Atypical presentation of COVID-19; an observational retrospective study

Risk factors associated with disease aggravation among 126 hospitalized patients with COVID-19 in different places in China: a retrospective observational study

Differences in the clinical and hematological characteristics of COVID-19 patients with and without type 2 diabetes

Enteric involvement in hospitalised patients with COVID-19 outside Wuhan

Gastrointestinal symptoms associated with severity of coronavirus disease 2019 (COVID-19): a pooled analysis

The prevalence of gastrointestinal symptoms, abnormal liver function, digestive system disease and liver disease in COVID-19 infection: a systematic review and meta-analysis

Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection

Severe acute respiratory syndrome: historical, epidemiologic, and clinical features

Gastrointestinal complications in critically ill patients with and without COVID-19

COVID-19 infection in children: a systematic review and meta-analysis of clinical features and laboratory findings

Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults

Age-related differences in nasopharyngeal severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) levels in patients with mild to moderate Coronavirus disease 2019 (COVID-19)

COVID-19 Pediatric network. Gastrointestinal symptoms in severe COVID-19 children

CoV-2 paediatric infection study group*. Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10

Clinical characteristics of 182 pediatric COVID-19 patients with different severities and allergic status

Epidemiology and clinical presentation of children hospitalized with SARS-CoV-2 infection in suburbs of Paris

Epidemiological and clinical features of pediatric COVID-19

Clinical manifestations of children and adolescents with covid-19: report of the first 115 cases from Sabará Hospital Infantil

COVID-19 in the paediatric population of Kazakhstan. Paediatr Int Child Health

Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy

CDC COVID-19 Response Team. Coronavirus disease 2019 in Children-United States

Severe Coronavirus disease-2019 in children and young adults in the

Chinese Pediatric Novel Coronavirus Study Team. SARS-CoV-2 infection in children

Hospital admission in children and adolescents with COVID-19

Clinical and immune features of hospitalized pediatric patients with Coronavirus disease 2019 (COVID-19) in Wuhan, China

Clincal and transmission dynamics characteristics of 406 children with coronavirus disease 2019 in China: a review

Overcoming COVID-19 Investigators CDC COVID-19 Response Team. Multisystem inflammatory syndrome in U.S. children and adolescents

California MIS-C Response Team. COVID-19-associated multisystem inflammatory syndrome in children-United States

Epidemiological and clinical features of pediatric COVID-19

Detection of Covid-19 in children in early

Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults

Epidemiologic and clinical characteristics of 10 children with coronavirus disease 2019 in Changsha

Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent Fecal viral shedding

Columbia Pediatric COVID-19 Management Group. Epidemiology, clinical features, and disease severity in patients with Coronavirus disease 2019 (COVID-19) in a Children's Hospital

Clinical and epidemiological features of 46 children <1 year old with Coronavirus disease 2019 in Wuhan, China: a descriptive study

Comparative study of the clinical characteristics and epidemiological trend of 244 COVID-19 infected children with or without GI symptoms

Childhood COVID-19: a multicentre retrospective study

Northwell Health Covid-19 research consortium. Early experience of COVID-19 in a US Children's Hospital. Pediatrics 2020

Pediatric patients with COVID-19 admitted to intensive care units in Brazil: a prospective multicenter study

Spanish Pediatric Intensive Care Society working group on SARS-CoV-2 infection. Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain

Multisystem inflammatory syndrome in children (MIS-C) during SARS-CoV-2 pandemic in Brazil: a multicenter, prospective cohort study

Multisystem inflammatory syndrome in children rose and fell with the first wave of the COVID-19 pandemic in France

SARS-CoV-2 infection in infants aged 28 days and younger. A multicentre case series. An Pediatr (Engl Ed). 2020

Screening and severity of Coronavirus disease 2019 (COVID-19) in children in Madrid

A comparative-descriptive analysis of clinical characteristics in 2019-coronavirus-infected children and adults

The clinical and immunological features of pediatric COVID-19 patients in China

Novel coronavirus infection in children outside of Wuhan, China

Multisystem inflammatory syndrome in children during the Coronavirus 2019 pandemic: a case series

Coinfection and other clinical characteristics of COVID-19 in children

Lung ultrasound in children with COVID-19

Roman Lung Ultrasound Study Team for Pediatric COVID-19 (ROMULUS COVID Team)

COVID-19 in children and the dynamics of infection in families

Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children that is related to Coronavirus disease 2019: a single center experience of 44 cases

Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment

Pediatric coronavirus disease 2019 (COVID-19): an insight from west of Iran

Beware of too aggressive approach in children with acute abdomen during COVID-19 outbreak!

SARS-CoV-2 infection in infants under 1 year of age in Wuhan City

Clinical features of pediatric patients with COVID-19: a report of two family cluster cases

Prolonged viral shedding in feces of pediatric patients with coronavirus disease 2019

Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study

SARS-CoV-2 testing and outcomes in the first 30 days after the first case of COVID-19 at an Australian children's hospital

Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic

SARS-CoV-2-induced Kawasaki-like hyperinflammatory syndrome: a novel COVID phenotype in children

Clinical characteristics of children with Coronavirus disease

COVID-19: four paediatric cases in Malaysia

Clinical characteristics of 5 COVID-19 cases with non-respiratory symptoms as the first manifestation in children

The epidemiological and clinical characteristics of 81 children with COVID-19 in a pandemic hospital in turkey: an observational cohort study

Acute myocardial injury: a novel clinical pattern in children with COVID-19

Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study

International COVID-19 PICU collaborative. Characteristics and outcomes of children with Coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian Pediatric Intensive Care Units

Coronavirus disease 2019 in children: characteristics, antimicrobial treatment, and outcomes

The severity of COVID-19 in children on immunosuppressive medication

A singlecenter, retrospective study of COVID-19 features in children: a descriptive investigation

Comparison of hospitalized patients with pneumonia caused by COVID-19 and influenza A in children under 5 years

Cardiac MRI in children with multisystem inflammatory syndrome associated with COVID-19

Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department

New York State and Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children Investigation Team. Multisystem inflammatory syndrome in children in New York State

Northwell Health Covid-19 research consortium. Early experience of COVID-19 in a US Children's Hospital

CT features of Coronavirus disease (COVID-19) in 30 pediatric patients

Clinical features of 33 cases in children infected with SARS-CoV-2 in Anhui Province

The early experiences of a single tertiary Italian emergency department treating COVID-19 in children

Epidemiology and clinical features of Coronavirus disease 2019 in Moroccan children

Characteristics of hospitalized pediatric Coronavirus disease

Epidemiological features and viral shedding in children with SARS-CoV-2 infection

SARS-CoV-2 infection in ambulatory and hospitalised Spanish children

Clinical analysis of 25 COVID-19 infections in children

Dynamic viral severe acute respiratory syndrome Coronavirus 2 RNA shedding in children: preliminary data and clinical consideration from a Italian Regional Center

Clinical and epidemiological characteristics of pediatric SARS-CoV-2 infections in China: a multicenter case series

Do children need a longer time to shed SARS-CoV-2 in stool than adults?

A comparative study on the clinical features of COVID-19 pneumonia to other pneumonias

COVID-19 and liver disease

Association of liver abnormalities with in-hospital mortality in patients with COVID-19

Risk factors and outcomes for acute-on-chronic liver failure in COVID-19: a large multi-center observational cohort study

ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection

Increased amylase and lipase in patients with COVID-19 pneumonia: don´t blame the pancreas just yet! Gastroenterology

Insufficient etiological workup of COVID-19-associated acute pancreatitis: a systematic review

Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis

Clinical presentation of COVID-19 in patients with inflammatory bowel disease: a systematic review and meta-analysis

Risk and outcomes of coronavirus disease (COVID-19) in patients with inflammatory bowel disease: a systematic review and metaanalysis. United

Covid-19 and immunomodulation in IBD

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic

Effect of IBD medications on COVID-19 outcomes: results from an international registry

Increased risk of hospital admission for influenza in patients with celiac disease: a nationwide cohort study in Sweden

COVID-19 pandemic perception in adults with celiac disease: an impulse to implement the use of telemedicine: COVID-19 and CeD. Dig Liver Dis

Adherence to the Gluten-Free diet during the lockdown for COVID-19 pandemic: a web-based survey of Italian subjects with celiac disease

biopsy-sparing" guidelines for celiac disease in children with low antitransglutaminase during COVID-19

The incidence of COVID-19 in patients with metabolic syndrome and non-alcoholic steatohepatitis: a population-based study

The clinical characteristics and risk factors of severe COVID-19

WGO guidance for the care of patients with COVID-19 and liver disease

COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy

Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients

ESGE and ESGENA position statement on gastrointestinal endoscopy and the COVID-19 pandemic

NASPGHAN Endoscopy and Procedures Committee Pediatric Endoscopy in the Era of Coronavirus disease 2019: A North American Society for pediatric gastroenterology, hepatology, and nutrition position paper

SARS-CoV-2 gastrointestinal infection causing hemorrhagic colitis: implications for detection and transmission of COVID-19 disease

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

International consensus conference on stool banking for faecal microbiota transplantation in clinical practice

Screening FMT donors during the COVID-19 pandemic: a protocol for stool SARS-CoV-2 viral quantification

Fecal microbiota transplantation for recurrent clostridioides difficile infection: the COVID-19 Era

Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity

Fecal specimen diagnosis 2019 novel coronavirus-infected pneumonia

Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes

Detection and analysis of nucleic acid in various biological samples of COVID-19 patients

Detection of SARS-CoV-2 in different types of clinical specimens

Factors associated with clinical outcomes in patients with Coronavirus disease 2019 in Guangzhou

Risk factors for redetectable positivity in recovered COVID-19 children

Value of swab types and collection time on SARS-COV-2 detection using RT-PCR assay

Environmental virus detection associated with asymptomatic SARS-CoV-2-infected individuals with positive anal swabs

Molecular and serological characterization of SARS-CoV-2 infection among COVID-19 patients

SARS-CoV-2 can be detected in urine, blood, anal swabs, and oropharyngeal swabs specimens

SARS-CoV-2 positivity in rectal swabs: implication for possible transmission

Effects of Tanreqing capsule on the negative conversion time of nucleic acid in patients with COVID-19: a retrospective cohort study

Compare the epidemiological and clinical features of imported and local COVID-19 cases in Hainan, China

Comparison of clinical characteristics between fecal/perianal swab nucleic acid-positive and -negative patients with COVID-19

Value of viral nucleic acid in sputum and feces and specific IgM/IgG in serum for the diagnosis of Coronavirus disease 2019

Nucleic acid and antibody assay results in Chinese patients with coronavirus disease 2019 (COVID-19)

Fecal viral shedding in COVID-19 patients: clinical significance, viral load dynamics and survival analysis

Clinical characteristics and factors associated with long-term viral excretion in patients with severe acute respiratory syndrome coronavirus 2 infection: a single-center 28-day study

Positive results for patients with COVID-19 discharged form hospital in Chongqing, China

A cross-sectional comparison of epidemiological and clinical features of patients with coronavirus disease (COVID-19) in Wuhan and outside Wuhan, China

US CDC realtime reverse transcription PCR panel for detection of severe acute respiratory syndrome Coronavirus 2

Outcomes and implications of diarrhea in patients with SARS-CoV-2 infection

Viral rna load in mildly symptomatic and asymptomatic children with COVID-19

Identification of the RNasebinding site of SARS-CoV-2 RNA for anchor primer-PCR detection of viral loading in 306 COVID-19 patients

Digestive symptoms in COVID-19 patients with mild disease severity: clinical presentation, stool viral RNA testing, and outcomes

Association between detectable SARS-COV-2 RNA in anal swabs and disease severity in patients with coronavirus disease 2019

Diarrhea is associated with prolonged symptoms and viral carriage in Corona virus disease 2019

Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients

SARS-CoV-2 diagnostics in the virology laboratory of a University Hospital in Rome during the lockdown period

A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features

The implications of preliminary screening and diagnosis: clinical characteristics of 33 mild patients with SARS-CoV-2 infection in Hunan

Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States

Prolonged persistence of SARS-CoV-2 RNA in body fluids

Detection and isolation of SARS-CoV-2 in serum, urine, and stool specimens of COVID-19 patients from the Republic of Korea

Singapore 2019 novel Coronavirus outbreak research team. epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore

Evaluation of SARS-CoV-2 viral RNA in fecal samples

Persistence of SARS-CoV-2 virus RNA in feces: a case series of children

Clinical and imaging findings of discharged patients with SARS-CoV-2 positive anal swab samples: a descriptive study

Systematic review with meta-analysis: SARS-CoV-2 stool testing and the potential for faecal-oral transmission

Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia

Alterations of the Gut microbiota in patients with COVID-19 or H1N1 influenza

Alterations in Gut microbiota of patients with COVID-19 during time of hospitalization

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Giulia Concas 1 · Michele Barone 2 · Ruggiero Francavilla 3 · Fernanda Cristofori 3 · Vanessa Nadia Dargenio 3 · Rossella Giorgio 3 · Costantino Dargenio 3 · Vassilios Fanos 4 · Maria Antonietta Marcialis 4