key: cord-354216-4khdcjed
authors: Sultan, Shahnaz; Altayar, Osama; Siddique, Shazia M.; Davitkov, Perica; Feuerstein, Joseph D.; Lim, Joseph K.; Falck-Ytter, Yngve; El-Serag, Hashem B.
title: AGA Institute Rapid Review of the GI and Liver Manifestations of COVID-19, Meta-Analysis of International Data, and Recommendations for the Consultative Management of Patients with COVID-19
date: 2020-05-11
journal: Gastroenterology
DOI: 10.1053/j.gastro.2020.05.001
sha: 
doc_id: 354216
cord_uid: 4khdcjed

Abstract Background Multiple gastrointestinal (GI) symptoms including diarrhea, nausea/vomiting, and abdominal pain, as well liver enzyme abnormalities have been variably reported in patients with COVID-19. The AGA) Institute Clinical Guideline Committee and Clinical Practice Updates Committee performed a systematic review and meta-analysis of international data on GI and liver manifestations of COVID-19. Methods We performed a systematic literature search to identify published and unpublished studies using OVID Medline and pre-print servers (medRxiv, LitCovid, and SSRN) up until April 5 2020; major journal sites were monitored for US publications until April 19 2020. We analyzed the prevalence of diarrhea, nausea, vomiting, and abdominal pain as well as LFT abnormalities using a fixed effect model and assessed the certainty of evidence using GRADE. Results We identified 118 studies and used a hierarchal study selection process to identify unique cohorts. We performed a meta-analysis of 47 studies including 10,890 unique patients. Pooled prevalence estimates of GI symptoms was diarrhea 7.7% (95% CI 7.2-8.2), nausea/vomiting 7.8% (95% CI 7.1-8.5), abdominal pain 2.7% (95% CI 2.0-3.4). Most studies reported on hospitalized patients. The pooled prevalence of elevated liver abnormalities was: AST 15.0% (13.6 to 16.5) and ALT 15.0% (13.6 to 16.4). When analyzed comparing data from China to studies from countries other than China, diarrhea, nausea/vomiting, liver abnormalities were more prevalent outside of China with diarrhea reported in 18.3% (16.6 to 20.1). Isolated GI symptoms were rarely reported. We also summarized of the Gl and liver adverse effects of the most commonly utilized medications for COVID19 Conclusions GI symptoms are associated with COVID-19 in less than 10% of patients. In studies outside of China, estimates are higher. Further studies are needed with standardized GI symptoms questionnaires and LFT checks on admission to better quantify and qualify the association of these symptoms with COVID-19. Based on findings from our meta-anlaysis, we make several Best Practice Statements for the consultative management of COVID-19.

The coronavirus family has four common human coronaviruses (229E, NL63, OC43, HKU1) associated with the common cold, and three strains are associated with pneumonia, respiratory failure, and death, including SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle Eastern respiratory syndrome coronavirus), and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). 1 The novel coronavirus, SARS-CoV-2, was first described in December 2019 in patients in Wuhan, China who developed severe pneumonia, and was named coronavirus-19 disease (COVID-19) by the World Health Organization on February 11, 2020. 2 COVID-19 is estimated to have resulted in 2,896,633 cases in 185 countries with 202,832 deaths as of April 25, 2020. 3 was first reported in the United States (U.S.) on January 20, 2020 and accounted for a total number of 938,154 cases and 53,755 deaths as of April 25, 2020. In the U.S., an early analysis of the first 4,226 cases from the Centers for Disease Control and Prevention (CDC) as of March 16, 2020 , revealed estimated rates of hospitalization (20.7-31 .4%), Intensive Care Unit (ICU) admission (4.9-11.5%), and case fatality (1.8-3.4%). 4 More recent data from a cohort of 5700 hospitalized patients with COVID-19 within a large healthcare system in New York City revealed common comorbidities including hypertension (56.6%), obesity (41.7%), and diabetes (33.8%), and reported that 373 (14.2%) of patients required treatment in the intensive care unit, and 320 (12.2%) received invasive mechanical ventilation, in whom the mortality was 88.1% (282/320)]. 5 ACE2 (angiotensin converting enzyme II), believed to be the target entry receptor for SARS-coV2, is abundantly expressed in gastric, duodenal, and rectal epithelia, thereby implicating ACE2 as a vehicle for possible fecal-oral transmission. 6 Furthermore, ACE2 receptors may be expressed in hepatic cholangiocytes 7 and hepatocytes 8 , potentially permitting direct infection of hepatic cells.

Non-GI symptoms for COVID-19 include fever, cough, shortness of breath, chills, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell. Gastrointestinal (GI) symptoms, including anorexia, nausea, vomiting, abdominal pain, and/or diarrhea have been reported in patients with COVID-19. Additionally, abnormal liver enzymes are also observed. 9 However, significant heterogeneity has been observed in the reporting of GI and liver symptoms across settings. 10 The most commonly reported GI symptom in COVID-19 is diarrhea, which has been reported in 1-36% of patients. 10 An updated characterization of the GI and liver manifestations across global settings is needed to further inform clinical guidance in the management of patients with COVID-19.

We seek to summarize international data on the Gl and liver manifestations of COVID-19 infection and treatment. Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for. This rapid review document was commissioned and approved by the AGA Institute Clinical Guidelines Committee (CGC), AGA Institute Clinical Practice Updates Committee (CPUC), and the AGA Governing Board to provide timely, methodologically rigorous guidance on a topic of high clinical importance to the AGA membership and the public.

This rapid review and guideline was developed by gastroenterologists and guideline methodologists from the two AGA committees. The guideline panel worked collaboratively with the AGA Governing Board to develop the clinical questions, review the evidence profiles and develop the recommendations. Panel members disclosed all potential conflicts of interest according to the AGA Institute policy.

The target audience of this guideline includes gastroenterologists, advanced practice providers, nurses, and other health care professionals. Patients as well as policy makers may also benefit from these guidelines. These guidelines are not intended to impose a standard of care for individual institutions, healthcare systems or countries. They provide the basis for rational informed decisions for clinicians, patients and other health care professionals in the setting of a pandemic.

We conducted a systematic literature search to identify all published and unpublished studies that could be considered eligible for our review with no restrictions on languages. In the setting of a pandemic with exponential increases in published and unpublished studies, our search strategy was multifaceted. To capture relevant published articles, we electronically searched OVID Medline from inception to March 23, 2020 using the MeSH term developed for COVID-19. We then searched the following platforms on April 5th, 2020 for additional published and unpublished studies: medRxiv, LitCovid 11 , and SSRN. An additional unpublished article in peer review was obtained through personal communication. For studies from the US, we continued to monitor major journals for additional publications until April 19 th , 2020.

Independent screening of titles and abstracts was performed by one reviewer (PD, SS, JF) to identify potential studies for inclusion. A second reviewer (OA) subsequently reviewed the full-text articles and identified articles for inclusion. Any disagreements about inclusion were resolved through discussion. We incorporated any studies (prospective or retrospective) that reported on patient characteristics and symptoms of interest. For studies published in Chinese, we used Google translate to assess for potential inclusion and for data extraction.

Due to concerns about inclusion of the same patients in different publications, we used a hierarchical model of data extraction to minimize double counting of patients across similar institutions with coinciding dates of study inclusion. We aimed to identify and include data from the largest possible cohort from each location or hospital. 12 Thus, data extraction was performed using a two-step process. The initial data extraction focused on data elements for study and patient characteristics. Subsequently, we identified certainty evidence and observational studies start out as low certainty evidence but can be rated down for several reasons: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Additionally, evidence from well conducted observational studies start as low certainty evidence but can be rated up for large effects or dose-response. 14

A meta-analysis of prevalence of GI and liver abnormalities was performed using meta 4.11-0 package in R version 3.6.3 software. 15, 16 The prevalence was expressed as a proportion and 95% confidence interval (95% CI). We used the fixed effects model using the Freeman-Tukey double arcsine transformation method for proportions. This is the preferred method of transformation and avoids giving an undue larger weight to studies with very large or very small prevalence. 17, 18 The I 2 statistic was used to measure heterogeneity. 19 To explore heterogeneity, we performed subgroup analyses based on the location (region) of the study and clinical settings (inpatient versus outpatient). To assess the robustness of our results, we performed sensitivity analyses by limiting the included studies to those that clearly reported the presence of symptoms at initial presentation.

A total of 57 studies were ultimately selected for complete data extraction; 56 from our search and one additional manuscript (under review) was included to provide more data on a US cohort. See Supplement Figure 1 for PRISMA flow diagram. Of the 57 selected studies, 47 studies reported on unique patients based on hospital name (with no duplication of cohorts from the same hospital). An additional 10 studies were identified with potentially overlapping cohorts based on hospital name, but these were included if they provided unique information about a specific symptom (e.g., diarrhea at initial presentation when the larger cohort did not clearly state that it was at initial presentation). Based on our comprehensive selection process, we believe that the included 47 studies reported data on 10,890 unique COVID-19 patients. The majority of studies (70%) in our analysis were from China; these were selected out of 118 reports published or pre-published from China. See Supplement Figure 2 . The studies included mainly adults, although a few studies included a small proportion of pediatric patients. Two studies reported on outpatients only, whereas the remaining 55 studies reported on hospitalized patients, or a combination of outpatients and hospitalized patients. Based on our inclusion strategy: 55 (96%) studies provided information on any GI symptom and 32 (56%) studies reported any data on liver abnormalities. Fewer studies, 21 (37%), provided information on underlying GI conditions. 

The overall certainty in the body of evidence was low. Our confidence in the pooled estimates of prevalence was reduced because of concerns of risk of bias (selection bias, detection bias and attrition bias), heterogeneity of the tested patient populations (inconsistency), as well as issues of indirectness (the majority of studies included primarily symptomatic hospitalized patients instead of all patients with COVID-19). Additionally, most of the studies were retrospective cohort series and did not specify if consecutive patients were included in the analysis. Other limitations included inconsistent assessment of symptoms and/or laboratory tests, missing data and/or inconsistent reporting of data, and insufficient follow up of the patients. These factors may have contributed to the heterogeneity of findings across studies. The I2 statistic ranged from 77% to 98% and was not completely explained by geographic location or by outpatient versus inpatient status. 

Our study selection criteria prioritized including studies with diarrhea as a GI manifestation and avoiding overlap in populations, and therefore did not include a comprehensive set of studies reporting on stool shedding. A recently published systematic review by Cheung (29%) stool specimens were positive for viral RNA. Four specimens with high copy numbers were cultured and electron microscopy was performed to detect live virus which was observed in the stool from 2 patients who did not have diarrhea. The authors concluded that although this does not confer infectivity, it raised the possibility of fecaloral transmission. 78 The small sample size of the reports that assessed the presence of live virus in stool combined with the conflicting findings limit our certainty in the evidence and thus the question of fecal-oral transmission remains unsettled.

Based on our inclusion strategy, 32 out of the 57 studies (56%) reported any data on liver abnormalities. 20 The overall prevalence of GI symptoms in context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than previously estimated. 10 It is important to note that the majority of studies were focused on hospitalized patients with COVID-19, and the prevalence of diarrhea in patients with mild symptoms who were not hospitalized is not known. Therefore, the reported prevalence rates may represent either an overestimate or underestimate. Information about the frequency and severity of diarrhea symptoms was inadequately reported in the majority of studies.

Based on our analysis, among hospitalized patients, diarrhea as the only presenting symptom in the absence of other COVID-related symptoms was very low. The majority of patients with diarrhea, nausea or vomiting also presented with accompanying symptoms typically associated with COVID-19. In a handful of studies, diarrhea and nausea preceded the development of other COVID-19 related symptoms. In a US casecontrol study of 278 COVID-19 patients, patients with GI symptoms were more likely to have illness duration of ≥ 1 week (33%) compared to patients without GI symptoms (22%). This may have been attributable to a delay in testing. 47 Therefore, in high prevalence settings, among patients presenting with new onset diarrhea, monitoring for the development of COVID-19 symptoms and considering referring patients for COVIDtesting is reasonable especially if testing capacity is not limited.

The CDC has recently expanded the criteria for COVID-19 testing to include presence of olfactory and gustatory symptoms as triggers for testing, as these symptoms have been demonstrated to occur in up to 80% of patients. 79 Diarrhea as an initial preceding symptom of COVID-19 has not been included on the CDC symptom checklist.

To more accurately inform our understanding of the true prevalence of diarrhea, nausea and vomiting as a manifestation of COVID-19, it is critical to systematically collect information about onset of diarrhea, duration of symptoms and documentation of whether and how long symptoms of diarrhea, nausea and vomiting precede URI symptoms. Therefore, we advise health care professionals and researchers to obtain a thorough review of systems, systematically inquire about respiratory and GI symptoms and ascertain information about exposure.

There is presently inadequate evidence to support stool testing for diagnosis or monitoring of COVID-19 as part of routine clinical practice.

While stool shedding has been reported in a prior meta-analysis in 48.1% of specimens, 2 small case series showed conflicting findings about the presence of living virus in stool. 10, 32, 78 Therefore, stool infectivity and transmission have not been confirmed. Further studies are needed to determine whether isolated virus from stool specimens confers infectivity and determine the role of stool testing is in patients with COVID-19. 

Abnormal LFTs were reported in approximately 15% of patients across the pooled studies but with variable reporting of mean or median values for the whole sample of patients. While the studies used in this analysis helped us to better understand the prevalence of abnormal LFTs among hospitalized patients, LFT abnormalities were not consistently reported across studies. Also, many of the studies in this analysis did not report on how many patients had underlying liver disease and if these patients were at an elevated risk of having increased LFTs in the setting of COVID-19 infection. Furthermore, diagnostic evaluation of abnormal LFTs on admission was not routinely performed, such as testing for viral hepatitis or other etiologies. The available studies suggest that abnormal LFTs are more commonly attributable to secondary effects (e.g., systemic inflammatory response syndrome, cytokine storm, ischemic hepatitis/shock, sepsis, drug hepatotoxicity) than primary virus-mediated hepatocellular injury. 7, 9, 80 However, liver histopathology from patients with COVID-19 have revealed mild lobular and portal inflammation and microvesicular steatosis suggestive of either virally mediated or drug-induced liver injury. 81 In addition, some studies have revealed that abnormal LFTs at hospital admission may be associated with a higher risk for severe COVID-19 (OR 2.73, 95% CI 1.19-6.3). 9 Therefore, we advise checking baseline LFTs in all patients on admission and monitoring of LFTs throughout the hospitalization, particularly in patients undergoing drug therapy for COVID-19 associated with potential hepatotoxicity. We additionally advise that all patients with abnormal LFTs undergo an evaluation to investigate non-COVID-19 causes of liver disease.

There are currently no FDA-approved routine treatments for COVID-19. The FDA has issued an emergency use authorization (EUA) for three therapies: choloroquine or hydroxychloroquine, remdesivir, and convalescent plasma. 82 In China and Japan, favipiravir has been approved for the treatment of COVID-19. Numerous medications are under investigation currently; the World Health Organization is currently spearheading a multinational, multicenter trial for the five treatments highlighted below. 83 We aim to provide a summary of the Gl and liver adverse effects of the most commonly utilized medications for COVID19 at this time irrespective of their efficacy. Medication GI-related AEs are summarized in Supplement Table 1 and 2 (Direct Evidence Sources and Indirect Evidence Sources. 

Both chloroquines have reported infrequent Gl (nausea, vomiting, abdominal pain, and diarrhea) adverse effects. 84, 85 The National Institute of Health (NIH) LiverTox resource rates both drugs with Likelihood score of D (possible rare cause of clinically apparent liver injury). 86 Chloroquine is rarely linked to aminotransferase elevations or clinically apparent liver injury. In patients with acute intermittent porphyria or porphyria cutanea tarda, it can trigger a hypersensitivity attack with fever and serum aminotransferase elevations, sometimes resulting in jaundice. This is less commonly seen with hydroxychloroquine. Such reactions are felt to be hypersensitivity reactions and there is no known cross-reactivity in liver injury between hydroxychloroquine and choloroquine.

Hydroxychloroquine is known to concentrate in the liver, thus patients with hepatitis or other hepatic diseases, or patients taking other known hepatotoxic drugs should exercise caution. Moreover, cardiac conduction defects leading to clinically relevant arrhythmias are an important adverse effect of these medications.

Remdesivir Limited data regarding GI Aes are available, as phase III trials are still underway. Based on studies from Ebola, there have been reports of elevated transaminases, although the severity and incidence has not been quantified. 87 There is one published case series (n=53) on compassionate use of remdesivir in COVID-19. 88 In this study, the most common adverse effects were notably Gl and hepatotoxicity. 5/9 (9%) of patients experienced diarrhea, and 12/53 (23%) of patients had reported elevations in hepatic enzymes associated with remdesivir. Of the four patients (8%) who discontinued treatment prematurely, two of them were due to elevated aminotransferases.

The combination lopinavir/ritonavir is FDA-approved for the treatment of Human Immunodeficiency Virus (HIV). More recently, it was utilized to treat MERS and SARS. There is one trial by Cao et al which randomized 199 hospitalized patients with severe COVID-19 to receive treatment to lopinavir/ritonavir (n=99) or placebo (n=100) for 14 days 89 GI adverse events were most common among those in the treatment group, and were the primary reason for medication discontinuation; of patients receiving lopinavir/ritonavir, there were 9.5% (9/99) with nausea, 6.3% (6/99) with vomiting, 4.2% (4/99) with diarrhea, 4.2% (4/99) with abdominal discomfort, 4.2% (4/99) with reported stomach ache, and 4.2% (4/99) with diarrhea. Additionally, there were two serious adverse events of acute gastritis, which both lead to drug discontinuation. When lopinavir/ritonavir is used in patients with HIV, diarrhea is the most common GI AE (10-30%), greater prevalence among those receiving higher dose. Other GI Aes in HIV are similar to the Cao RCT, with nausea in 5-15% and vomiting in 5-10% of patients 90 See Table 3 .

The Cao et al. RCT did not show a significant increase in hepatotoxicity in the treatment compared to the control group. 89 However, in patients with HIV, there is a welldocumented known risk of hepatotoxicity, with liver injury severity ranging from mild enzyme elevations to acute liver failure. 91 Moderate-to-severe elevations in serum aminotransferases, defined as more than five times the upper limit of normal, are found in 3-10%. 91 Rates may be higher in patients with concurrent HIV and HCV co-infection. In some cases, mild, asymptomatic elevations are self-limited and can resolve with continuation of the medication, but re-challenging the medication may also lead to recurrence, and therefore, should be avoided when possible. Acute liver failure, although reported, is rare. Ritonavir has potent effects on cytochrome P450 and therefore affects drug levels of a large number of medications typically given in GI practices.

There are two published studies on favipiravir in COVID-19. 

The individual studies in our analysis were at high risk of bias. The majority of studies reported on cohorts of patients based on inclusion dates and did not specify if these were consecutive patients. There was an inconsistent assessment of symptoms and/or laboratory tests with missing data, and none of the studies reported if patients were systematically evaluated for GI symptoms on admission. Most studies did not report on the duration of the GI symptoms preceding the presentation. When GI symptoms were reported, it was difficult to discern if these were isolated symptoms or if patients had also had concurrent typical COVID-19 symptoms (e.g., fever cough, SOB). LFTs were mostly reported as the mean/median value of the entire cohort and without cut-off values for the institution. Many of the studies did not report on underlying chronic GI or liver diseases. There was a lot of heterogeneity in our pooled estimates that could not be explained by our subgroup analysis based on geographic location. Lastly, the data on prognosis was especially difficult to analyze due to insufficient follow up of the patients (the majority of the patients were still hospitalized at the time of publication). Finally, there was no stratification of GI-related symptoms and severity of COVID-19 or patient important outcomes, such as need for ICU or survival.

There may be additional limitations of our findings based on our analysis. Due to concerns about overlapping cohorts, we used a hierarchical framework to identify unique cohorts based on the number of patients and the hospitals to analyze the prevalence of GI and liver symptoms. It is possible that we excluded relevant studies that provided more granularity regarding the GI and liver manifestations or had more rigorous methodology which may lead to an over or underestimation of the pooled effect estimates. However, we have high confidence that we were able to eliminate the counting of some patients in more than one report by using our selection framework, unless they were transferred from one hospital to another. An important strength of this study is the appropriate statistical analysis used to pool proportions. We also reviewed grey literature from pre-publication repositories which allowed us to include a large number of studies that have not been published yet, with data from a total of 10,890 unique COVID-19 patients being included in this work. Lastly, we tried to narratively describe studies that informed us on (i) the type of diarrhea symptoms (ii) whether diarrhea was reported as the only presenting symptom or (iii) diarrhea as the initial symptom that preceded other symptoms. Based on our study selection process, we may have missed studies, including smaller case series that reported on this information, and studies that were published after our inclusion period, in light of the exponential number of studies in press, under review, and on pre-print servers.

Most of the information regarding Gl Aes come from indirect evidence from medications that are FDA approved for other indications, such as the chloroquines and lopinavir/ritonavir. In particular, Gl Aes are poorly understood for both favipiravir and remdesivir, including the frequency and severity of aminotransferase elevations, and incidence of Gl manifestations. As ongoing clinical trials complete regarding efficacy of therapy, additional data regarding Gl Aes will emerge.

Currently there is insufficient evidence on the impact of COVID-19 on subgroups of patients, such as patients with inflammatory bowel disease, chronic liver disease, or liver transplant recipients on chronic immunosuppression. Early data do not indicate excess risk among patients with IBD. [93] [94] [95] [96] [97] A number of international registries have been established that will provide extremely valuable information about COVID-19 in these potentially vulnerable populations (www.covidibd.org; covidcirrhosis.web.unc.edu; www.gi-covid19.org). Other clinical decisions including optimal medication management and treatment decisions are still under investigation. We encourage clinicians to contribute to these registries to further enhance understanding in these subpopulations. Table 4 provides guidance for future studies of GI manifestations in patients with COVID-19 or other similar pathogens.

Finally, peer-review remains critical to the process of disseminating information. Journals should add resources to expedite reviews by increasing the number of editors and reviewers, shorten the review process, to maintain accuracy, high quality and details of the data reported, as well as to avoid overlap in patients between studies or multiple studies being published on the same cohort. 98

Study design -A prospective inception cohort study is a favorable study design.

-Another study design that is informative especially when there is a need for rapid data evaluation is a retrospective inception cohort study.

-Enrollment of consecutive patients beginning at pandemic onset.

-Specific set of symptoms that are predictive of COVID-19 infection, all symptoms should be systematically collected on presentation and before COVID-19 diagnosis is established.

• Elicit typical URI symptoms (e.g., cough, shortness of breath, chest pain, fever)

• Inquire about less typical symptoms, such as GI specific symptoms: diarrhea, nausea, vomiting, and abdominal pain, and also other symptoms such as anosmia, dysguesia

• Describe the GI symptoms in details including initial versus late, concurrent vs.

isolated, duration and frequency, prior history, and medication initiation relating to the onset of symptoms. -Investigators should avoid:

• Undefined sampling (convenience sampling), including undefined time periods.

• Overlap of the same population with other publications, which can be done by coordinating efforts between the different departments within the institution.

-Investigators should consider stratification for GI comorbidities such as IBD, cirrhosis.

-Investigators should consider stratification by outpatients versus inpatients Laboratory -Standardized laboratory-confirmation should be based on NAT (nucleic acid testing) for SARS-CoV-2 on respiratory specimen rather than relying on radiological suspicion on imaging studies which are less specific -Liver function tests (LFTs) should be obtained on admission and followed throughout the hospitalization.

-Changes of LFTs should be reported as normal/abnormal and the cut-off for abnormal should be specified, rather than mean and median at the individual patient level.

-The pattern of LFTs abnormalities, hepatocellular vs cholestatic, should be reported as well as the evaluation performed to work-up the abnormalities.

-When available, LFTs prior to the development of the disease (baseline LFTs) should be reported, and how they changed with the diagnosis of the disease and after the resolution of it should be accounted for.

-Report stool RNA testing, when available, and presence of GI symptoms at the time of testing Disease severity -Use of standardized disease severity definitions, for example as per WHO-China Joint Mission 99 :

• mild-to-moderate: non-pneumonia and mild pneumonia • severe defined as tachypnoea2, oxygen saturation ≤93% at rest, or PaO2/FiO2 ratio <300 mm Hg • critical respiratory failure requiring mechanical ventilation, septic shock, or other organ dysfunction or failure that requires intensive care -Patients can be stratified by:

• Disease severity and presence of GI symptoms • Disease severity and LFTs -Symptoms and their duration prior to development of a severe stage of the disease should be reported.

Outcomes should focus on patient-important outcomes such as death, clinical improvement or disease worsening/ progression, hospital discharge; included reproducible clinical definitions (e.g., threshold reached for intubation); select sufficient follow up time to ensure outcome is obtainable.

Analysis should attempt to control for confounding variables; analysis of risk factors should include univariate followed by multivariate analysis to identify independent risk factors predicting more severe disease and poor outcomes *In the table, we specifically refer to COVID-19 but this guidance applies to any future pathogen similar to COVID-19 that presents as a viral illness with potential GI and liver manifestations.

Recommendations in this document may not be valid in the near future. We will conduct periodic reviews of the literature and monitor the evidence to determine if recommendations require modification. Based on the rapidly evolving nature of this pandemic, this guideline will likely need to be updated within the next few months.

The global COVID-19 pandemic due to SARS-CoV-2 infection is associated with significant morbidity and mortality due to severe pneumonia, acute respiratory distress syndrome (ARDS), and multiorgan failure. Although fever, cough, and shortness of breath remain the most common presenting complaints in affected individuals, emerging data suggest that non-pulmonary symptoms affecting the GI tract and liver may be observed. 

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

An interactive web-based dashboard to track COVID-19 in real time

Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) -United States

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the

Evidence for Gastrointestinal Infection of SARS-CoV-2

Liver injury in COVID-19: management and challenges

Liver injury during highly pathogenic human coronavirus infections

Characteristics of Liver Tests in COVID-19 Patients

Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis

Keep up with the latest coronavirus research

Editorial Concern-Possible Reporting of the Same Patients With COVID-19 in Different Reports

GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence

The AGA institute process for developing clinical practice guidelines part one: grading the evidence

How to perform a meta-analysis with R: a practical tutorial

R: A language and environment for statistical computing: R Foundation for Statistical Computing

Meta-analysis of prevalence

Methodological quality and synthesis of case series and case reports

Measuring inconsistency in meta-analyses

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Early Clinical and CT Manifestations of Coronavirus Disease 2019 (COVID-19) Pneumonia

Gastrointestinal and Hepatic Manifestations of 2019 Novel Coronavirus Disease in a Large Cohort of Infected Patients From New York: Clinical Implications for Prognosis

Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support

Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients

Analysis on the Clinical Characteristics of 36 Cases of Novel Coronavirus Pneumonia in Kunming

Medical treatment of 55 patients with COVID-19 from seven cities in northeast China who fully recovered: a single-center, retrospective, observational study

Charakteristik von 50 hospitalisierten COVID-19-Patienten mit und ohne ARDS

Covid-19 National Emergency Response Center E, Case Management Team KCfDC, Prevention. Early Epidemiological and Clinical Characteristics of 28 Cases of Coronavirus Disease in South Korea

High Prevalence of Concurrent Gastrointestinal Manifestations in Patients with SARS-CoV-2: Early Experience from California

Epidemiological and clinical features of 291 cases with coronavirus disease 2019 in areas adjacent to Hubei, China: a double-center observational study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

A report of clinical diagnosis and treatment of nine cases of coronavirus disease 2019

Hypokalemia and Clinical Implications in Patients with Coronavirus Disease

Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State

The cross-sectional study of hospitalized coronavirus disease 2019 patients in Xiangyang, Hubei province

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Detection of SARS-CoV-2 in Different Types of Clinical Specimens

Clinical Features of COVID-19-Related Liver Damage

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Food & Drug Administration

Solidarity" clinical trial for COVID-19 treatments

Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD)

Controlled Trial of Ebola Virus Disease Therapeutics

Compassionate Use of Remdesivir for Patients with Severe Covid-19

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Kaletra (lopinavir and ritonavir) tablets and oral solution [prescribing information

Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD)

Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study

The Risk of SARS-CoV-2 in Immunosuppressed IBD Patients. Crohn's &

Characteristics and prognosis of patients with inflammatory bowel disease during the SARS-CoV-2 pandemic in the Basque Country (Spain)

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease During the COVID-19 Pandemic: Expert Commentary

Management of Patients with Crohn's Disease and Ulcerative Colitis During the COVID-19 Pandemic: Results of an International Meeting

Uneventful course in IBD patients during SARS-CoV-2 outbreak in northern Italy

Will the Quality of Research Remain the Same During the COVID-19 Pandemic?

Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). Available at

33%) compared to patients without symptoms (22%)

Presence of GI symptoms (diarrhea or nausea/vomiting) was associated with a 70% increased risk of testing positive

Age: m 61 ± 18 Gender: 42.3% females GI/liver comorbidities: 1.6% IBD, 3.0% chronic liver disease, 2.4% solid organ transplant. Disease severity: NR Diarrhea: 22.1% (234) Present on admission

7% (67/768) and outpatients 8.2% (24/291). Nausea: 15.3% (168) Present on admission Inpatients 16.0% (123/768) and outpatients 15.5% (45/291). Abdominal pain: 6.6% (72)

Age: m 64 (range 48-75) Gender: 14% females GI/liver comorbidities: NR Disease severity: NR Diarrhea: 23.8% (5) Present on admission Nausea or vomiting

Survival: 2.6% died, 11.4% still hospitalized Inclusion: Inpatients (N=35) and outpatients (N=2) with COVID-19 confirmed based on rt-PCR Age: median 42 (range 2-81) Gender: 34

GI/liver comorbidities: NR Disease severity: NR

N: 295 Survival: 1.0% died Inclusion: All individuals with COVID-19 (both outpatients and inpatients) Age: M 47 (range 0-94) Gender: (approximately) 50% female Comorbidities: NR Disease severity: NR Diarrhea: 16.3% (48) Nausea/vomiting: 11

number of patients; rt-PCR, real time reverse transcription polymerase chain reaction