PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T1	0-203	Sentence	denotes	AGA Institute Rapid Review of the Gastrointestinal and Liver Manifestations of COVID-19, Meta-Analysis of International Data, and Recommendations for the Consultative Management of Patients with COVID-19
T2	205-213	Sentence	denotes	Abstract
T3	214-231	Sentence	denotes	Background & Aims
T4	232-450	Sentence	denotes	Multiple gastrointestinal (GI) symptoms, including diarrhea, nausea/vomiting, and abdominal pain, as well as liver enzyme abnormalities, have been variably reported in patients with coronavirus disease 2019 (COVID-19).
T5	451-659	Sentence	denotes	This document provides best practice statements and recommendations for consultative management based on a systematic review and meta-analysis of international data on GI and liver manifestations of COVID-19.
T6	661-668	Sentence	denotes	Methods
T7	669-929	Sentence	denotes	We performed a systematic literature search to identify published and unpublished studies using OVID Medline and preprint servers (medRxiv, LitCovid, and SSRN) up until April 5, 2020; major journal sites were monitored for US publications until April 19, 2020.
T8	930-1213	Sentence	denotes	We pooled the prevalence of diarrhea, nausea, vomiting, and abdominal pain, as well as liver function tests abnormalities, using a fixed-effect model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.
T9	1215-1222	Sentence	denotes	Results
T10	1223-1322	Sentence	denotes	We identified 118 studies and used a hierarchal study selection process to identify unique cohorts.
T11	1323-1399	Sentence	denotes	We performed a meta-analysis of 47 studies including 10,890 unique patients.
T12	1400-1603	Sentence	denotes	Pooled prevalence estimates of GI symptoms were as follows: diarrhea 7.7% (95% confidence interval [CI], 7.2%–8.2%), nausea/vomiting 7.8% (95% CI, 7.1%–8.5%), and abdominal pain 2.7% (95% CI, 2.0%–3.4%).
T13	1604-1651	Sentence	denotes	Most studies reported on hospitalized patients.
T14	1652-1837	Sentence	denotes	The pooled prevalence estimates of elevated liver abnormalities were as follows: aspartate transaminase 15.0% (95% CI, 13.6%–16.5%) and alanine transaminase 15.0% (95% CI, 13.6%–16.4%).
T15	1838-2071	Sentence	denotes	When we compared studies from China to studies from other countries in subgroup analyses, diarrhea, nausea/vomiting, and liver abnormalities were more prevalent outside of China, with diarrhea reported in 18.3% (95% CI, 16.6%–20.1%).
T16	2072-2114	Sentence	denotes	Isolated GI symptoms were reported rarely.
T17	2115-2222	Sentence	denotes	We also summarized the Gl and liver adverse effects of the most commonly utilized medications for COVID-19.
T18	2224-2235	Sentence	denotes	Conclusions
T19	2236-2297	Sentence	denotes	GI symptoms are associated with COVID-19 in <10% of patients.
T20	2298-2348	Sentence	denotes	In studies outside of China, estimates are higher.
T21	2349-2544	Sentence	denotes	Further studies are needed with standardized GI symptoms questionnaires and liver function test checks on admission to better quantify and qualify the association of these symptoms with COVID-19.
T22	2545-2675	Sentence	denotes	Based on findings from our meta-analysis, we provide several Best Practice Statements for the consultative management of COVID-19.
T23	2677-3540	Sentence	denotes	The coronavirus family has 4 common human coronaviruses (ie, 229E, NL63, OC43, and HKU1) associated with the common cold, and 3 strains that 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-2.1 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 disease 2019 (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 COVID-19 was first reported in the United States on January 20, 2020 and accounted for a total number of 938,154 cases and 53,755 deaths as of April 25, 2020.
T24	3541-4249	Sentence	denotes	In the United States, an early analysis of the first 4226 cases from the Centers for Disease Control and Prevention as of March 16, 2020 revealed estimated rates of hospitalization of 20.7%–31.4%; intensive care unit admission of 4.9%–11.5%; and case fatality of 1.8%–3.4%.4 More recent data from a cohort of 5700 hospitalized patients with COVID-19 within a large health care system in New York City revealed common comorbidities, including hypertension (56.6%), obesity (41.7%), and diabetes (33.8%), and reported that 373 patients (14.2%) required treatment in the intensive care unit, and 320 patients (12.2%) received invasive mechanical ventilation, in whom the mortality rate was 88.1% (282 of 320)].5
T25	4250-4689	Sentence	denotes	Angiotensin converting enzyme II, believed to be the target entry receptor for SARS-CoV-2, is abundantly expressed in gastric, duodenal, and rectal epithelia, thereby implicating angiotensin converting enzyme II as a vehicle for possible fecal–oral transmission.6 In addition, angiotensin converting enzyme II receptors can be expressed in hepatic cholangiocytes7 and hepatocytes,8 potentially permitting direct infection of hepatic cells.
T26	4690-4880	Sentence	denotes	Nongastrointestinal 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.
T27	4881-5028	Sentence	denotes	Gastrointestinal (GI) symptoms, including anorexia, nausea, vomiting, abdominal pain, and/or diarrhea have been reported in patients with COVID-19.
T28	5029-5488	Sentence	denotes	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.
T29	5490-5507	Sentence	denotes	Scope and Purpose
T30	5508-5619	Sentence	denotes	We seek to summarize international data on the Gl and liver manifestations of COVID-19 infection and treatment.
T31	5620-5758	Sentence	denotes	Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.
T32	5759-6074	Sentence	denotes	This rapid review document was commissioned and approved by the AGA Institute Clinical Guidelines Committee, AGA Institute Clinical Practice Updates Committee, and the AGA Governing Board to provide timely, methodologically rigorous guidance on a topic of high clinical importance to the AGA members and the public.
T33	6075-6154	Sentence	denotes	Table 1 provides a summary of the recommendations and best practice statements.
T34	6155-6199	Sentence	denotes	Table 1 Summary of Best Practice Statements:
T35	6200-6251	Sentence	denotes	Consultative Management of Coronavirus Disease 2019
T36	6252-6265	Sentence	denotes	Statement no.
T37	6266-6275	Sentence	denotes	Statement
T38	6276-6658	Sentence	denotes	1 In outpatients with new-onset diarrhea, ascertain information about high-risk contact exposure; obtain a detailed history of symptoms associated with COVID-19, including fever, cough, shortness of breath, chills, muscle pain, headache, sore throat, or new loss of taste or smell; and obtain a thorough history for other Gl symptoms, including nausea, vomiting, and abdominal pain.
T39	6659-6868	Sentence	denotes	2 In outpatients with new-onset Gl symptoms (eg, nausea, vomiting, abdominal pain, and diarrhea), monitor for symptoms associated with COVID-19, as GI symptoms may precede COVID-related symptoms by a few days.
T40	6869-6946	Sentence	denotes	In a high COVID-19 prevalence setting, COVID-19 testing should be considered.
T41	6947-7160	Sentence	denotes	3 In hospitalized patients with suspected or known COVID-19, obtain a thorough history of GI symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea), including onset, characteristics, duration, and severity.
T42	7161-7304	Sentence	denotes	4 There is presently inadequate evidence to support stool testing for diagnosis or monitoring of COVID-19 as part of routine clinical practice.
T43	7305-7445	Sentence	denotes	5 In patients (outpatients or inpatients) with elevated LFTs in context of suspected or known COVID-19, evaluate for alternative etiologies.
T44	7446-7671	Sentence	denotes	6 In hospitalized patients with suspected or known COVID-19, obtain baseline LFTs at the time of admission and consider LFT monitoring throughout the hospitalization, particularly in the context of drug treatment for COVID-19
T45	7672-7801	Sentence	denotes	7 In hospitalized patients undergoing drug treatment for COVID-19, evaluate for treatment-related Gl and hepatic adverse effects.
T46	7803-7856	Sentence	denotes	Panel Composition and Conflict of Interest Management
T47	7857-7981	Sentence	denotes	This rapid review and guideline was developed by gastroenterologists and guideline methodologists from the 2 AGA committees.
T48	7982-8151	Sentence	denotes	The guideline panel worked collaboratively with the AGA Governing Board to develop the clinical questions, review the evidence profiles, and develop the recommendations.
T49	8152-8246	Sentence	denotes	Panel members disclosed all potential conflicts of interest according to AGA Institute policy.
T50	8248-8263	Sentence	denotes	Target Audience
T51	8264-8405	Sentence	denotes	The target audience of this guideline includes gastroenterologists, advanced practice providers, nurses, and other health care professionals.
T52	8406-8474	Sentence	denotes	Patients as well as policy-makers can benefit from these guidelines.
T53	8475-8601	Sentence	denotes	These guidelines are not intended to impose a standard of care for individual institutions, health care systems, or countries.
T54	8602-8748	Sentence	denotes	They provide the basis for rational informed decisions for clinicians, patients, and other health care professionals in the setting of a pandemic.
T55	8750-8757	Sentence	denotes	Methods
T56	8759-8800	Sentence	denotes	Information Sources and Literature Search
T57	8801-8979	Sentence	denotes	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.
T58	8980-9111	Sentence	denotes	In the setting of a pandemic with exponential increases in published and unpublished studies, our search strategy was multifaceted.
T59	9112-9287	Sentence	denotes	To capture relevant published articles, we electronically searched OVID Medline from inception to March 23, 2020 using the Medical Subject Heading term developed for COVID-19.
T60	9288-9426	Sentence	denotes	We then searched the following platforms on April 5, 2020 for additional published and unpublished studies: medRxiv, LitCovid,11 and SSRN.
T61	9427-9523	Sentence	denotes	An additional unpublished article under peer review was obtained through personal communication.
T62	9524-9648	Sentence	denotes	For studies from the United States, we continued to monitor major journals for additional publications until April 19, 2020.
T63	9650-9685	Sentence	denotes	Study Selection and Data Extraction
T64	9686-9834	Sentence	denotes	Independent screening of titles and abstracts was performed by independent reviewers (P.D., S.S., J.F.) to identify potential studies for inclusion.
T65	9835-9943	Sentence	denotes	A second reviewer (O.A.) subsequently reviewed the full-text articles and identified articles for inclusion.
T66	9944-10011	Sentence	denotes	Any disagreements about inclusion were resolved through discussion.
T67	10012-10137	Sentence	denotes	We incorporated any studies (prospective or retrospective) that reported on patient characteristics and symptoms of interest.
T68	10138-10255	Sentence	denotes	For studies published in Chinese, we used Google translate to assess for potential inclusion and for data extraction.
T69	10256-10493	Sentence	denotes	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.
T70	10494-10652	Sentence	denotes	We aimed to identify and include data from the largest possible cohort from each location or hospital.12 Data extraction was performed using a 2-step process.
T71	10653-10744	Sentence	denotes	The initial data extraction focused on data elements for study and patient characteristics.
T72	10745-10878	Sentence	denotes	Subsequently, we identified studies for full data extraction based on study location (unique hospitals) and total number of patients.
T73	10879-11113	Sentence	denotes	Additionally, when a study from a specific hospital did not provide all of the necessary information for the diarrhea symptoms, the next largest study from the same hospital (when available) was selected for inclusion in our analysis.
T74	11114-11202	Sentence	denotes	Data extraction was performed using a standardized Microsoft Excel data extraction form.
T75	11203-11416	Sentence	denotes	Data extraction was performed in pairs; one study author independently extracted data while a second reviewer checked for accuracy of the data extraction (S.S., O.A., S.M.S., P.D., J.D.F., J.K.L., Y.F.Y., H.B.E.).
T76	11417-11611	Sentence	denotes	Because the reporting of the data in the primary studies was suboptimal, a third reviewer (O.A.) additionally verified the extracted data to confirm the numbers and to resolve any disagreements.
T77	11612-11665	Sentence	denotes	Studies with discrepancies in the data were excluded.
T78	11666-11711	Sentence	denotes	The following data elements were extracted:1.
T79	11712-11830	Sentence	denotes	Study: author, year, location (hospital name, city, province or state), dates of inclusion, and date of last follow-up
T80	11831-11833	Sentence	denotes	2.
T81	11834-12138	Sentence	denotes	Patient characteristics: number of patients, age (mean, median, interquartile interval or range), number of females, severity of illness, inclusion criteria (hospitalized or outpatients), GI comorbidities (pre-existing conditions, such as chronic liver disease, hepatitis, and inflammatory bowel disease)
T82	12139-12141	Sentence	denotes	3.
T83	12142-12239	Sentence	denotes	Outcomes: diarrhea, nausea, vomiting, abdominal pain, and liver function test (LFT) abnormalities
T84	12240-12242	Sentence	denotes	4.
T85	12243-12497	Sentence	denotes	Additional information: severity, characteristics, duration, timing (before or concurrent with respiratory symptoms), relationship with clinical outcomes (need for ventilator, survival, discharge, and continued hospitalization), and viral stool shedding.
T86	12499-12525	Sentence	denotes	Assessment of Risk of Bias
T87	12526-12655	Sentence	denotes	We assessed the risk of bias according to the following domains as suggested in the ROBINS-I tool for nonrandomized studies.13 1.
T88	12656-12706	Sentence	denotes	Bias due to selection of participants in the study
T89	12707-12709	Sentence	denotes	2.
T90	12710-12734	Sentence	denotes	Bias due to missing data
T91	12735-12737	Sentence	denotes	3.
T92	12738-12773	Sentence	denotes	Bias in the measurement of outcomes
T93	12774-12776	Sentence	denotes	4.
T94	12777-12821	Sentence	denotes	Bias in the selection of the reported result
T95	12822-12962	Sentence	denotes	We considered the domains for each study and then made a judgment of high or low risk of bias for the studies included in the meta-analysis.
T96	12964-12985	Sentence	denotes	Certainty of Evidence
T97	12986-13116	Sentence	denotes	Certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.
T98	13117-13203	Sentence	denotes	The certainty of evidence was categorized into 4 levels ranging from very low to high.
T99	13204-13505	Sentence	denotes	Within the GRADE framework, evidence from randomized controlled trials (RCTs) starts as high-certainty evidence and observational studies start out as low-certainty evidence, but can be rated down for the following reasons: risk of bias, inconsistency, indirectness, imprecision, and publication bias.
T100	13506-13661	Sentence	denotes	Additionally, evidence from well-conducted observational studies start as low-certainty evidence, but can be rated up for large effects or dose–response.14
T101	13663-13690	Sentence	denotes	Data Synthesis and Analysis
T102	13691-13906	Sentence	denotes	A meta-analysis of prevalence of GI and liver abnormalities was performed using meta 4.11-0 package in R software, version 3.6.3.15 , 16 The prevalence was expressed as a proportion and 95% confidence interval (CI).
T103	13907-14016	Sentence	denotes	We used the fixed-effects model using the Freeman-Tukey double arcsine transformation method for proportions.
T104	14017-14369	Sentence	denotes	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 vs outpatient).
T105	14370-14558	Sentence	denotes	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.
T106	14560-14567	Sentence	denotes	Results
T107	14568-15095	Sentence	denotes	A total of 57 studies were ultimately selected for complete data extraction; 56 from our search and 1 additional manuscript (under review) was included to provide more data on a US cohort20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76 (see Supplementary Figure 1 for Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram).
T108	15096-15234	Sentence	denotes	Of the 57 selected studies, 47 reported on unique patients based on hospital name (with no duplication of cohorts from the same hospital).
T109	15235-15542	Sentence	denotes	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 (eg, diarrhea at initial presentation when the larger cohort did not clearly state that it was at initial presentation).
T110	15543-15678	Sentence	denotes	Based on our comprehensive selection process, we believe that the included 47 studies reported data on 10,890 unique COVID-19 patients.
T111	15679-15841	Sentence	denotes	The majority of studies (70%) in our analysis were from China; these were selected from 118 reports published or prepublished from China (Supplementary Figure 2).
T112	15842-15951	Sentence	denotes	The studies included mainly adults, although a few studies included a small proportion of pediatric patients.
T113	15952-16119	Sentence	denotes	Two studies reported on outpatients only, whereas the remaining 55 studies reported on hospitalized patients or a combination of outpatients and hospitalized patients.
T114	16120-16152	Sentence	denotes	Based on our inclusion strategy:
T115	16153-16271	Sentence	denotes	55 studies (96%) provided information on any GI symptom and 32 studies (56%) reported any data on liver abnormalities.
T116	16272-16346	Sentence	denotes	Fewer studies, 21 (37%), provided information on underlying GI conditions.
T117	16347-16409	Sentence	denotes	Table 2 provides a summary of the pooled prevalence estimates.
T118	16410-16501	Sentence	denotes	Table 2 Summary of the Pooled Prevalence Estimates of Gastrointestinal/Liver Manifestations
T119	16502-16600	Sentence	denotes	GI and liver manifestations All studies Studies from China Studies from countries other than China
T120	16601-16696	Sentence	denotes	% (95% CI) Patients/ studies, n % (95% CI) Patients/ studies, n % (95% CI) Patients/ studies, n
T121	16697-16802	Sentence	denotes	Diarrhea in all patientsa 7.7 (7.2 to 8.2) 43/10,676 5.8 (5.3 to 6.4) 32/8612 18.3 (16.6 to 20.1) 11/2064
T122	16803-16913	Sentence	denotes	Nausea/vomiting in all patientsa 7.8 (7.1 to 8.5) 26/5955 5.2 (4.4 to 5.9) 19/4054 14.9 (13.3 to –16.6) 7/1901
T123	16914-17019	Sentence	denotes	Abdominal pain in all patientsa 3.6 (3.0 to 4.3) 15/4031 2.7 (2.0 to 3.4) 10/2447 5.3 (4.2 to 6.6) 5/1584
T124	17020-17128	Sentence	denotes	Patients with elevated AST 15.0 (13.6 to 16.5) 16/2514 14.9 (13.5 to 16.4) 14/2398 20.0 (12.8 to 28.1) 2/116
T125	17129-17237	Sentence	denotes	Patients with elevated ALT 15.0 (13.6 to 16.4) 17/2711 14.9 (13.5 to 16.3) 15/2595 19.0 (12.0 to 27.1) 2/116
T126	17238-17336	Sentence	denotes	Patients with elevated total bilirubin 16.7 (15.0 to 18.5) 10/1841 16.7 (15.0 to 18.5) 10/1841 — —
T127	17337-17392	Sentence	denotes	a Regardless of hospitalization and timing of symptoms.
T128	17394-17423	Sentence	denotes	Overall Certainty of Evidence
T129	17424-17478	Sentence	denotes	The overall certainty in the body of evidence was low.
T130	17479-17854	Sentence	denotes	Our confidence in the pooled estimates of prevalence was reduced because of concerns of risk of bias (ie, 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).
T131	17855-18001	Sentence	denotes	Additionally, most of the studies were retrospective cohort series and did not specify whether consecutive patients were included in the analysis.
T132	18002-18185	Sentence	denotes	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.
T133	18186-18269	Sentence	denotes	These factors may have contributed to the heterogeneity of findings across studies.
T134	18270-18404	Sentence	denotes	The I 2 statistic ranged from 77% to 98% and was not completely explained by geographic location or by outpatient vs inpatient status.
T135	18406-18463	Sentence	denotes	What are the Gastrointestinal Manifestations of COVID-19?
T136	18465-18473	Sentence	denotes	Diarrhea
T137	18474-18946	Sentence	denotes	A total of 43 studies including 10,676 COVID-19 patients (confirmed by laboratory real-time reverse transcription polymerase chain reaction [RT-PCR] testing) were included in the overall analysis.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 , 37 , 38 , 41 , 42 , 45 , 47 , 49, 50, 51, 52, 53, 54, 55 , 58 , 59 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 73 , 76 The pooled prevalence of diarrhea symptoms across these studies was 7.7% (95% CI, 7.2%–8.2%).
T138	18947-19151	Sentence	denotes	When analyzing by country (studies from China vs studies from other countries), the pooled prevalence of diarrhea in studies from countries other than China was much higher at 18.3% (95% CI, 16.6%–20.1%).
T139	19152-19273	Sentence	denotes	This is in comparison to studies from China, where the prevalence was much lower at 5.8% (95% CI, 5.3%–6.4%) (Figure 1 ).
T140	19274-19341	Sentence	denotes	Figure 1 Forest plot of the prevalence of diarrhea in all patients.
T141	19342-20191	Sentence	denotes	In hospitalized patients, across 39 studies including 8,521 patients, the pooled prevalence was slightly higher at 10.4% (95% CI, 9.4%–10.7%) compared with outpatients.20, 21, 22, 23 , 25, 26, 27, 28 , 30 , 33, 34, 35 , 38 , 41 , 42 , 44, 45, 46 , 49, 50, 51, 52, 53, 54, 55 , 60 , 62, 63, 64, 65, 66, 67, 68 , 70, 71, 72, 73, 74 , 76 In 3 studies including 1701 outpatients, the pooled prevalence was 4.0% (95% CI, 3.1%–5.1%).31 , 59 , 63 As part of the sensitivity analysis, we identified 35 studies including 9717 patients that described diarrhea, and explicitly reported that it was one of the initial presenting symptoms.20, 21, 22, 23 , 26, 27, 28 , 31 , 33, 34, 35 , 38 , 41 , 42 , 44 , 45 , 47 , 48 , 50, 51, 52, 53, 54, 55 , 60 , 63, 64, 65, 66 , 68, 69, 70, 71 , 74 , 76 The pooled prevalence in these studies was 7.9% (95% CI, 7.4%–8.6%).
T142	20192-20642	Sentence	denotes	A total of 33 studies including 8070 patients reported on hospitalized COVID-19 patients presenting with diarrhea as one of the initial symptoms of COVID-19.20, 21, 22, 23 , 26, 27, 28 , 33, 34, 35 , 38 , 41 , 42 , 44 , 45 , 48 , 50, 51, 52, 53, 54, 55 , 60 , 63, 64, 65, 66 , 68 , 70, 71, 72, 73 , 76 The pooled prevalence was 9.3% (95% CI, 8.6%–9.9%) (Supplementary Figure 3, Supplementary Figure 4, Supplementary Figure 5, Supplementary Figure 6).
T143	20644-20667	Sentence	denotes	Description of diarrhea
T144	20668-21017	Sentence	denotes	Only a handful of studies provided any details on the type and severity of diarrhea symptoms.55 , 60 , 74 In the study by Lin et al,55 23 of 95 patients (24%) reported having diarrhea (described as loose or watery stools, ranging from 2–10 bowel movements per day); however, only a small number of patients actually had diarrhea on admission (5.2%).
T145	21018-21147	Sentence	denotes	Most patients developed diarrhea during the hospitalization, which may have been attributable to other treatments or medications.
T146	21148-21281	Sentence	denotes	In the study by Jin et al60 of 651 hospitalized patients, 8.6% of patients had diarrhea on admission before receiving any treatments.
T147	21282-21355	Sentence	denotes	The diarrhea symptoms were described as more than 3 loose stools per day.
T148	21356-21435	Sentence	denotes	Stool cultures were negative (including Clostridium difficile) in all patients.
T149	21436-21477	Sentence	denotes	There was no mention of fecal leukocytes.
T150	21478-21776	Sentence	denotes	Median duration of symptoms was 4 days (range, 1–9 days) and most patients had self-limited diarrheal symptoms.60 One additional study on 175 hospitalized patients reported that 19.4% of patients had diarrhea, with an average of 6 episodes per day, with symptom duration ranging from 1 to 4 days.74
T151	21778-21862	Sentence	denotes	Diarrhea as the only presenting symptom in the absence of upper respiratory symptoms
T152	21863-22151	Sentence	denotes	In the 43 studies that informed our analysis on the prevalence of diarrhea, we extracted information on whether diarrhea was reported as the only presenting symptom.50 , 60 In only 2 studies, there was explicit reporting of diarrhea in the absence of upper respiratory infection symptoms.
T153	22152-22286	Sentence	denotes	In a study by Luo et al50 of 1141 patients, 183 patients (16%) presented with GI symptoms only in the absence of respiratory symptoms.
T154	22287-22465	Sentence	denotes	Of 1141 patients, loss of appetite (15.8%) and nausea or vomiting (11.7%) were the most common symptoms, but diarrhea was reported in 6.0% and abdominal pain in 3.9% of patients.
T155	22466-22556	Sentence	denotes	Notably, the majority of patients (96%) had lung infiltrates on chest computed tomography.
T156	22557-22829	Sentence	denotes	In the study by Jin et al60 of 651 hospitalized patients, 21 patients (3.2%) presented with GI symptoms only (and no respiratory symptoms of coughing or sputum production).60 GI symptoms were defined as at least 1 of the following symptoms: nausea, vomiting, and diarrhea.
T157	22830-23124	Sentence	denotes	Conversely, in the US study of 116 patients with COVID-19, Cholankeril et al70 reported that 31.9% of patients had GI symptoms on admission (median duration, 1 day); diarrhea was reported in 10.3% (12 of 116), nausea and/or vomiting in 10.3% (12 of 116), and abdominal pain in 8.8% (10 of 116).
T158	23125-23250	Sentence	denotes	The authors explicitly reported that none of the 116 patients had isolated GI symptoms as the only manifestation of COVID-19.
T159	23252-23328	Sentence	denotes	Diarrhea as the initial presenting symptom preceding other COVID-19 symptoms
T160	23329-23512	Sentence	denotes	Of the studies included in our review, based on our selection framework, we identified only 1 study that reported on timing of diarrhea in relation to other COVID-19–related symptoms.
T161	23513-23679	Sentence	denotes	In a study by Ai et al76 of 102 hospitalized patients, 15 patients reported diarrhea symptoms on hospital admission, and diarrhea was the first symptom in 2 patients.
T162	23680-23897	Sentence	denotes	In a study by Wang et al77 of 138 consecutive hospitalized patients, not included in our pooled analysis, a total of 14 patients presented with diarrhea and nausea 1–2 days before the development of fever and dyspnea.
T163	23899-23914	Sentence	denotes	Nausea/vomiting
T164	23915-24275	Sentence	denotes	A total of 26 studies including 5955 patients with COVID-19 (confirmed by laboratory RT-PCR testing), were included in the overall analysis for nausea and/or vomiting.20 , 22 , 23 , 25 , 27 , 29 , 34 , 37 , 41 , 45, 46, 47 , 50 , 51 , 54 , 55 , 59 , 63 , 65 , 67 , 68 , 70, 71, 72, 73 , 76 The pooled prevalence of nausea/vomiting was 7.8% (95% CI, 7.1%–8.5%).
T165	24276-24672	Sentence	denotes	A subgroup analysis of 1901 patients from 7 studies (including patients from Germany, Singapore, United States, Australia, and The Netherlands) demonstrated a higher pooled prevalence of 14.9% (95% CI, 13.3%–16.6%).37 , 46 , 47 , 59 , 63 , 68 , 70 This is in comparison to the prevalence of symptoms in studies from China, which was 5.2% (95% CI, 4.4%–5.9%) (Figure 2 and Supplementary Figure 7).
T166	24673-24747	Sentence	denotes	Figure 2 Forest plot of the prevalence of nausea/vomiting in all patients.
T167	24749-24763	Sentence	denotes	Abdominal pain
T168	24764-25055	Sentence	denotes	A total of 15 studies including 4031 COVID-19 patients (confirmed by laboratory RT-PCR testing) were included in the overall analysis for abdominal pain.21 , 23 , 27 , 37 , 50 , 54 , 55 , 59 , 63 , 69, 70, 71, 72, 73 , 76 The pooled prevalence of abdominal pain was 3.6% (95% CI, 3.0%–4.3%).
T169	25056-25562	Sentence	denotes	A subgroup analysis of 1584 patients from the United States, Australia, South Korea, and The Netherlands, demonstrated a slightly higher pooled prevalence of 5.3% (95% CI, 4.2%–6.6)% compared with studies from China 2.7% (95% CI, 2.0%–3.4%), which included 10 studies of 2447 patients.37 , 59 , 63 , 69 , 70 The symptoms were variably described as stomachache, epigastric pain, and abdominal discomfort, without further details regarding the quality or nature of pain (Figure 3 and Supplementary Figure 8).
T170	25563-25636	Sentence	denotes	Figure 3 Forest plot of the prevalence of abdominal pain in all patients.
T171	25638-25652	Sentence	denotes	Stool shedding
T172	25653-25875	Sentence	denotes	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.
T173	25876-26041	Sentence	denotes	A recently published systematic review by Cheung et al10 found a 48.1% (95% CI, 38.3%–59.7%) pooled prevalence of stool samples positive for virus RNA in 12 studies.
T174	26042-26171	Sentence	denotes	Stool RNA was positive in 70.3% of samples taken from patients after respiratory specimens were no longer positive for the virus.
T175	26172-26516	Sentence	denotes	From the 57 studies included in our analysis, 4 studies reported on presence of viral RNA in stool.24 , 32 , 57 , 68 Of these, 3 studies were published after the systematic review by Cheung et al.10 First, Dreher et al68 conducted a retrospective cohort study in Germany, stratifying patients by presence of acute respiratory distress syndrome.
T176	26517-26611	Sentence	denotes	In this study, 8 of 50 patients had diarrhea, and stool PCR was positive in 15 of 50 patients.
T177	26612-26690	Sentence	denotes	In a US study by Kujawski et al,57 stool PCR was positive in 7 of 10 patients.
T178	26691-26847	Sentence	denotes	Finally, in a case series from Germany by Wolfel et al,32 the authors not only examined stool RNA but also tried to isolate virus from laboratory specimens.
T179	26848-27143	Sentence	denotes	In this study, 2 of 9 patients had diarrhea as an initial symptom and stool PCR remained positive for up to 11 days, but notably, the authors were unable to isolate infectious virus, despite a high stool viral RNA load, even though the virus was successfully isolated from respiratory specimens.
T180	27144-27424	Sentence	denotes	The authors concluded that stool is not a primary source of spread of infection.32 Conversely, in a letter published by Wang et al,78 the authors collected 1070 specimens from 205 hospitalized patients with COVID-19 and 44 of 153 stool specimens (29%) were positive for viral RNA.
T181	27425-27611	Sentence	denotes	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.
T182	27612-27967	Sentence	denotes	The authors concluded that although this does not confer infectivity, it raised the possibility of fecal–oral 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.
T183	27969-28015	Sentence	denotes	What Are the Liver Manifestations of COVID-19?
T184	28016-28464	Sentence	denotes	Based on our inclusion strategy, 34 of the 57 studies (60%) reported any data on liver abnormalities.20, 21, 22 , 25 , 27 , 28 , 30 , 34, 35, 36 , 38 , 41, 42, 43 , 45 , 48, 49, 50, 51, 52, 53 , 55 , 57 , 60 , 61 , 63 , 65, 66, 67 , 70, 71, 72 , 75 , 76 The majority of the studies that reported data on LFTs only reported continuous summary statistics (median and interquartile range) without reporting the number of patients with abnormal levels.
T185	28465-28672	Sentence	denotes	Abnormal aspartate transaminase (AST), defined as any value above the upper limit of normal (ULN), was reported in 15.0% (95% CI, 13.6%– 16.5) of patients across 16 studies, including 2514 COVID-19 patients.
T186	28673-28853	Sentence	denotes	Abnormal alanine transaminase (ALT), defined as any value above the ULN, was reported in 15.0% (95% CI, 13.6%–16.4%) of patients across 17 studies including 2711 COVID-19 patients.
T187	28854-29017	Sentence	denotes	Abnormal bilirubin, defined as any value above the ULN, was reported in 16.7% (95% CI, 15.0%–18.5%) of patients across 10 studies including 1841 COVID-19 patients.
T188	29018-29083	Sentence	denotes	All patients had confirmed COVID-19 by laboratory RT-PCR testing.
T189	29084-29231	Sentence	denotes	The study by Cholankeril et al70 reported that 26 of 65 patients (40%) had abnormal liver enzymes and 22 of them had normal baseline liver enzymes.
T190	29232-29337	Sentence	denotes	None of the remaining studies provided any information regarding the status of LFTs before the infection.
T191	29338-29511	Sentence	denotes	One study by Fu et al65 reported summary statistics (median and interquartile range) of LFTs for 23 patients on admission and discharge with no clinically important changes.
T192	29512-29650	Sentence	denotes	However, they did not provide the number of patients who presented with normal or abnormal LFTs and how many of them improved or worsened.
T193	29651-29824	Sentence	denotes	None of the included studies reported the workup of LFTs in the settings of COVID-19 or assessed whether they were related to alternative etiologies, especially medications.
T194	29825-29959	Sentence	denotes	Thirteen studies reported on the association between the presence of liver injury at presentation and severity of disease or outcomes.
T195	29960-30448	Sentence	denotes	Most of them reported the results of univariate analyses.20 , 22 , 27 , 38 , 45 , 48 , 51 , 53 , 55 , 63 , 67 , 71 , 72 The study by Hajifathalian et al63 reported the results of multivariate analyses that included multiple variables and showed liver injury at presentation was associated with high risk for admission, as well as higher risk of intensive care unit admission and/or death as a composite outcome63 (Supplementary Figure 10, Supplementary Figure 11, Supplementary Figure 9).
T196	30450-30488	Sentence	denotes	Rationale for Best Practice Statements
T197	30489-30491	Sentence	denotes	1.
T198	30493-30873	Sentence	denotes	In outpatients with new-onset diarrhea, ascertain information about high-risk contact exposure; obtain a detailed history of symptoms associated with COVID-19, including fever, cough, shortness of breath, chills, muscle pain, headache, sore throat, or new loss of taste or smell; and obtain a thorough history for other Gl symptoms, including nausea, vomiting, and abdominal pain.
T199	30874-30876	Sentence	denotes	2.
T200	30878-31085	Sentence	denotes	In outpatients with new-onset Gl symptoms (eg, nausea, vomiting, abdominal pain, and diarrhea), monitor for symptoms associated with COVID-19, as GI symptoms may precede COVID-related symptoms by a few days.
T201	31086-31163	Sentence	denotes	In a high COVID-19 prevalence setting, COVID-19 testing should be considered.
T202	31164-31166	Sentence	denotes	3.
T203	31168-31379	Sentence	denotes	In hospitalized patients with suspected or known COVID-19, obtain a thorough history of GI symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea), including onset, characteristics, duration, and severity.
T204	31380-31745	Sentence	denotes	The overall prevalence of GI symptoms in context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously.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.
T205	31746-31841	Sentence	denotes	Therefore, the reported prevalence rates may represent either an overestimate or underestimate.
T206	31842-31961	Sentence	denotes	Information about the frequency and severity of diarrhea symptoms was inadequately reported in the majority of studies.
T207	31962-32132	Sentence	denotes	Based on our analysis, among hospitalized patients, the prevalence of diarrhea as the only presenting symptom in the absence of other COVID-related symptoms was very low.
T208	32133-32270	Sentence	denotes	The majority of patients with diarrhea, nausea, or vomiting also presented with accompanying symptoms typically associated with COVID-19.
T209	32271-32376	Sentence	denotes	In a handful of studies, diarrhea and nausea preceded the development of other COVID-19–related symptoms.
T210	32377-32571	Sentence	denotes	In a US case–control study of 278 COVID-19 patients, patients with GI symptoms were more likely to have illness duration of 1 week or longer (33%) compared to patients without GI symptoms (22%).
T211	32572-32886	Sentence	denotes	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 COVID-testing is reasonable, especially if testing capacity is not limited.
T212	32887-33314	Sentence	denotes	The Centers for Disease Control and Prevention 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 As of April 19, 2020, diarrhea as an initial preceding symptom of COVID-19 has not been included on the Centers for Disease Control and Prevention symptom checklist.
T213	33315-33678	Sentence	denotes	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 upper respiratory infection symptoms.
T214	33679-33883	Sentence	denotes	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.4.
T215	33885-34026	Sentence	denotes	There is presently inadequate evidence to support stool testing for diagnosis or monitoring of COVID-19 as part of routine clinical practice.
T216	34027-34289	Sentence	denotes	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.
T217	34290-34465	Sentence	denotes	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-19.5.
T218	34467-34605	Sentence	denotes	In patients (outpatients or inpatients) with elevated LFTs in context of suspected or known COVID-19, evaluate for alternative etiologies.
T219	34606-34608	Sentence	denotes	6.
T220	34610-34834	Sentence	denotes	In hospitalized patients with suspected or known COVID-19, obtain baseline LFTs at the time of admission and consider LFT monitoring throughout the hospitalization, particularly in the context of drug treatment for COVID-19.
T221	34835-34837	Sentence	denotes	7.
T222	34839-34966	Sentence	denotes	In hospitalized patients undergoing drug treatment for COVID-19, evaluate for treatment-related Gl and hepatic adverse effects.
T223	34967-35141	Sentence	denotes	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.
T224	35142-35338	Sentence	denotes	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.
T225	35339-35561	Sentence	denotes	Also, many of the studies in this analysis did not report on how many patients had underlying liver disease and whether these patients were at an elevated risk of having increased LFTs in the setting of COVID-19 infection.
T226	35562-35712	Sentence	denotes	Furthermore, diagnostic evaluation of abnormal LFTs on admission was not performed routinely, such as testing for viral hepatitis or other etiologies.
T227	35713-36612	Sentence	denotes	The available studies suggest that abnormal LFTs are more commonly attributable to secondary effects (eg, systemic inflammatory response syndrome, cytokine storm, ischemic hepatitis/shock, sepsis, and 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 (odds ratio, 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.
T228	36613-36747	Sentence	denotes	We additionally advise that all patients with abnormal LFTs undergo an evaluation to investigate non–COVID-19 causes of liver disease.
T229	36749-36827	Sentence	denotes	What Are Common Gastrointestinal/Liver Adverse Effects of COVID-19 Treatments?
T230	36828-36925	Sentence	denotes	`There are currently no US Food and Drug Administration–approved routine treatments for COVID-19.
T231	36926-37148	Sentence	denotes	The FDA has issued an emergency use authorization for 3 therapies: choloroquine or hydroxychloroquine, remdesivir, and convalescent plasma.82 In China and Japan, favipiravir has been approved for the treatment of COVID-19.
T232	37149-37482	Sentence	denotes	Numerous medications are under investigation; the World Health Organization is spearheading a multinational, multicenter trial for the 5 treatments highlighted below.83 We aim to provide a summary of the Gl and liver adverse effects of the most commonly utilized medications for COVID-19 at this time, irrespective of their efficacy.
T233	37483-37623	Sentence	denotes	Medication GI-related adverse events are summarized in Supplementary Tables 1 and 2 (direct evidence sources and indirect evidence sources).
T234	37625-37649	Sentence	denotes	Antimalarial Medications
T235	37650-37961	Sentence	denotes	Although efficacy and subsequent optimal dosing in COVID-19 is still under investigation, both chloroquine and hydroxychloroquine are currently FDA-approved in the United States for other indications (ie, malaria and systemic lupus erythematosus) and now have an emergency use authorization for use in COVID-19.
T236	37963-37997	Sentence	denotes	Chloroquine and hydroxychloroquine
T237	37998-38375	Sentence	denotes	Both chloroquines have reported infrequent Gl adverse effects (ie, nausea, vomiting, abdominal pain, and diarrhea).84 , 85 The National Institute of Health LiverTox resource rates both drugs with a 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.
T238	38376-38573	Sentence	denotes	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.
T239	38574-38625	Sentence	denotes	This is seen less commonly with hydroxychloroquine.
T240	38626-38785	Sentence	denotes	Such reactions are thought to be hypersensitivity reactions and there is no known cross-reactivity in liver injury between hydroxychloroquine and choloroquine.
T241	38786-38973	Sentence	denotes	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.
T242	38974-39110	Sentence	denotes	In addition, cardiac conduction defects leading to clinically relevant arrhythmias are an important adverse effect of these medications.
T243	39112-39133	Sentence	denotes	Antiviral Medications
T244	39135-39145	Sentence	denotes	Remdesivir
T245	39146-39239	Sentence	denotes	Limited data regarding GI adverse events are available, as phase 3 trials are still underway.
T246	39240-39563	Sentence	denotes	Based on studies regarding Ebola, there have been reports of elevated transaminases, although the severity and incidence have not been quantified.87 There is 1 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.
T247	39564-39708	Sentence	denotes	Five of 53 patients (9%) experienced diarrhea and 12 of 53 patients (23%) had reported elevations in hepatic enzymes associated with remdesivir.
T248	39709-39809	Sentence	denotes	Of 4 patients (8%) who discontinued treatment prematurely, 2 were due to elevated aminotransferases.
T249	39811-39830	Sentence	denotes	Lopinavir/ritonavir
T250	39831-39939	Sentence	denotes	The combination lopinavir/ritonavir is FDA-approved for the treatment of human immunodeficiency virus (HIV).
T251	39940-39994	Sentence	denotes	More recently, it was utilized to treat MERS and SARS.
T252	39995-40176	Sentence	denotes	There is 1 trial by Cao et al89 that randomized 199 hospitalized patients with severe COVID-19 to receive treatment to lopinavir/ritonavir (n = 99) or placebo (n = 100) for 14 days.
T253	40177-40568	Sentence	denotes	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 of 99) with nausea, 6.3% (6 of 99) with vomiting, 4.2% (4 of 99) with diarrhea, 4.2% (4 of 99) with abdominal discomfort, 4.2% (4 of 99) with reported stomach ache, and 4.2% (4 of 99) with diarrhea.
T254	40569-40678	Sentence	denotes	Additionally, there were 2 serious adverse events of acute gastritis, which both led to drug discontinuation.
T255	40679-40850	Sentence	denotes	When lopinavir/ritonavir is used in patients with HIV, diarrhea is the most common GI adverse events (10%–30%), with greater prevalence among those receiving higher doses.
T256	40851-40984	Sentence	denotes	Other GI adverse events in HIV are similar to Cao et al’s RCT, with nausea in 5%–15% and vomiting in 5%–10% of patients90 (Table 3 ).
T257	40985-41076	Sentence	denotes	Table 3 Gastrointestinal Treatment Adverse Effects of Currently Utilized COVID-19 Therapies
T258	41077-41153	Sentence	denotes	Medication type Medication name Adverse effects Major drug–drug interactions
T259	41154-41178	Sentence	denotes	Gastrointestinal Hepatic
T260	41179-41318	Sentence	denotes	Antimalarial ChloroquineHydroxychloroquine Nausea, vomiting, abdominal pain, and diarrhea reported; frequency not defined Likelihood score:
T261	41319-41391	Sentence	denotes	D (possible rare cause of clinically apparent liver injury).Description:
T262	41392-41429	Sentence	denotes	Rare elevations in aminotransferases.
T263	41430-41515	Sentence	denotes	Most reactions are hypersensitivity with no known cross reactivity to hepatic injury.
T264	41516-41583	Sentence	denotes	If this occurs, reasonable to switch between chloroquine therapies.
T265	41584-41676	Sentence	denotes	Substrate for CYP2D6 and CYP3A4 substrateSame as above; also substrate for CYP3A5 and CYP2C8
T266	41677-41753	Sentence	denotes	Antiviral Remdesivir Not reported (limited data available) Likelihood score:
T267	41754-41777	Sentence	denotes	Not scored.Description:
T268	41778-41827	Sentence	denotes	Hepatotoxicity reported; frequency not yet known.
T269	41828-41878	Sentence	denotes	Not a significant inducer/inhibitor of CYP enzymes
T270	41879-41919	Sentence	denotes	Lopinavir/ritonavir Nausea and vomiting:
T271	41920-41947	Sentence	denotes	5%–10% (higher in children:
T272	41948-41967	Sentence	denotes	20%)Abdominal pain:
T273	41968-41983	Sentence	denotes	1%–10%Diarrhea:
T274	41984-42049	Sentence	denotes	10%–30% + dose-dependentOther: dysguesia in adults <2%, children:
T275	42050-42087	Sentence	denotes	25%, increased serum amylase, lipase:
T276	42088-42094	Sentence	denotes	3%–8%.
T277	42095-42112	Sentence	denotes	Likelihood score:
T278	42113-42186	Sentence	denotes	D (possible, rare cause of clinically apparent liver injury).Description:
T279	42187-42368	Sentence	denotes	Hepatotoxicity ranges from mild elevations in aminotransferases to acute liver failure.Recovery takes 1–2 mo.Re-challenging may lead to recurrence and should be avoided if possible.
T280	42369-42483	Sentence	denotes	Substrate for: CYP3A4, CYP2D6P-gpInducer for: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A1Inhibitor for: CYP3A4
T281	42484-42512	Sentence	denotes	Favipiravir Nausea/vomiting:
T282	42513-42528	Sentence	denotes	5%–15%Diarrhea:
T283	42529-42571	Sentence	denotes	5%Limited data available Likelihood score:
T284	42572-42594	Sentence	denotes	Not scoredDescription:
T285	42595-42633	Sentence	denotes	3% prevalence, but few data available.
T286	42634-42728	Sentence	denotes	Inhibitor for: CYP2C8 and aldehyde oxidaseMetabolized by xanthine oxidase and aldehyde oxidase
T287	42729-42850	Sentence	denotes	The Cao et al89 RCT did not show a significant increase in hepatotoxicity in the treatment compared to the control group.
T288	42851-43234	Sentence	denotes	However, in patients with HIV, there is a well-documented 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 5 times the ULN, are found in 3%–10%.91 Rates may be higher in patients with concurrent HIV and hepatitis C virus co-infection.
T289	43235-43459	Sentence	denotes	In some cases, mild asymptomatic elevations are self-limited and can resolve with continuation of the medication, but re-challenging the medication can also lead to recurrence and, therefore, should be avoided when possible.
T290	43460-43508	Sentence	denotes	Acute liver failure, although reported, is rare.
T291	43509-43656	Sentence	denotes	Ritonavir has potent effects on cytochrome P450 and therefore affects drug levels of a large number of medications typically given in GI practices.
T292	43658-43669	Sentence	denotes	Favipiravir
T293	43670-43727	Sentence	denotes	There are 2 published studies on favipiravir in COVID-19.
T294	43728-43968	Sentence	denotes	The first is an open-label RCT for favipiravir vs arbidol conducted in Wuhan, China by Chen et al.92 This study reported digestive tract reactions, including nausea, “anti-acid,” or flatulence in 13.79% (16 of 116) of the favipiravir group.
T295	43969-44062	Sentence	denotes	Hepatotoxicity characterized by any elevation in AST or ALT was reported in 7.76% (9 of 116).
T296	44063-44328	Sentence	denotes	The second is an open-label control study of favipiravir or lopinavir/ritonavir, both used in conjunction with interferon alfa, for COVID-19 by Cai et al,93 which reported diarrhea in 5.7% (2 of 35) and liver injury in 2.9% (1 of 35) (Supplementary Tables 2 and 3).
T297	44330-44438	Sentence	denotes	Limitations of the Evidence on Gastrointestinal and Liver Manifestations in Patients With COVID-19 Infection
T298	44439-44504	Sentence	denotes	The individual studies in our analysis were at high risk of bias.
T299	44505-44646	Sentence	denotes	The majority of studies reported on cohorts of patients based on inclusion dates and did not specify whether these were consecutive patients.
T300	44647-44848	Sentence	denotes	There was an inconsistent assessment of symptoms and/or laboratory tests with missing data, and none of the studies reported whether patients were systematically evaluated for GI symptoms on admission.
T301	44849-44939	Sentence	denotes	Most studies did not report on the duration of the GI symptoms preceding the presentation.
T302	44940-45144	Sentence	denotes	When GI symptoms were reported, it was difficult to discern whether these were isolated symptoms or whether patients also had concurrent typical COVID-19 symptoms (eg, fever cough or shortness of breath).
T303	45145-45263	Sentence	denotes	LFTs were mostly reported as the mean/median value of the entire cohort and without cutoff values for the institution.
T304	45264-45342	Sentence	denotes	Many of the studies did not report on underlying chronic GI or liver diseases.
T305	45343-45482	Sentence	denotes	There was a lot of heterogeneity in our pooled estimates that could not be explained by our subgroup analysis based on geographic location.
T306	45483-45678	Sentence	denotes	Lastly, the data on prognosis were 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).
T307	45679-45844	Sentence	denotes	Finally, there was no stratification of GI-related symptoms and severity of COVID-19 or patient important outcomes, such as need for intensive care unit or survival.
T308	45845-45919	Sentence	denotes	There may be additional limitations of our findings based on our analysis.
T309	45920-46124	Sentence	denotes	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.
T310	46125-46294	Sentence	denotes	It is possible that we excluded relevant studies that provided more granularity regarding the GI and liver manifestations, or had more systematic assessment of outcomes.
T311	46295-46388	Sentence	denotes	As a result, this may have led to an over- or underestimation of the pooled effect estimates.
T312	46389-46597	Sentence	denotes	However, we have high confidence that we were able to eliminate the counting of some patients in more than 1 report by using our selection framework, unless they were transferred from one hospital to another.
T313	46598-46699	Sentence	denotes	An important strength of this study is the appropriate statistical analysis used to pool proportions.
T314	46700-46941	Sentence	denotes	We also reviewed gray literature from prepublication 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.
T315	46942-47168	Sentence	denotes	Lastly, we tried to narratively describe studies that informed us on the type of diarrhea symptoms; whether diarrhea was reported as the only presenting symptom; or diarrhea as the initial symptom that preceded other symptoms.
T316	47169-47454	Sentence	denotes	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 preprint servers.
T317	47456-47524	Sentence	denotes	Limitations of Current Evidence on Treatment-Related Adverse Effects
T318	47525-47716	Sentence	denotes	Most of the information regarding Gl adverse events come from indirect evidence from medications that are FDA-approved for other indications, such as the chloroquines and lopinavir/ritonavir.
T319	47717-47912	Sentence	denotes	In particular, Gl adverse events are poorly understood for both favipiravir and remdesivir, including the frequency and severity of aminotransferase elevations and incidence of Gl manifestations.
T320	47913-48041	Sentence	denotes	As ongoing clinical trials are completed regarding efficacy of therapy, additional data regarding Gl adverse events will emerge.
T321	48043-48082	Sentence	denotes	Evidence Gaps and Guidance for Research
T322	48083-48299	Sentence	denotes	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.
T323	48300-48639	Sentence	denotes	Early data do not indicate excess risk among patients with inflammatory bowel disease.94, 95, 96, 97, 98 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).
T324	48640-48761	Sentence	denotes	Other clinical decisions, including optimal medication management and treatment decisions, are still under investigation.
T325	48762-48877	Sentence	denotes	We encourage clinicians to contribute to these registries to further enhance understanding in these subpopulations.
T326	48878-48997	Sentence	denotes	Table 4 provides guidance for future studies of GI manifestations in patients with COVID-19 or other similar pathogens.
T327	48998-49074	Sentence	denotes	Table 4 Guidance and Research Considerations for Future Studies of COVID-19a
T328	49075-49294	Sentence	denotes	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.
T329	49295-49657	Sentence	denotes	Participants 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 upper respiratory infection symptoms (eg, cough, shortness of breath, chest pain, and fever)
T330	49658-49826	Sentence	denotes	• Inquire about less typical symptoms, such as GI-specific symptoms: diarrhea, nausea, vomiting, and abdominal pain, and also other symptoms, such as anosmia, dysguesia
T331	49827-50009	Sentence	denotes	• Describe the GI symptoms in detail, including initial vs late, concurrent vs isolated, duration and frequency, history, and medication initiation relating to the onset of symptoms.
T332	50010-50115	Sentence	denotes	Investigators should avoid:• Undefined sampling (convenience sampling), including undefined time periods.
T333	50116-50273	Sentence	denotes	• Overlap of the same population with other publications, which can be done by coordinating efforts between the different departments within the institution.
T334	50274-50462	Sentence	denotes	Investigators should consider stratification for GI comorbidities, such as inflammatory bowel disease and cirrhosisInvestigators should consider stratification by outpatients vs inpatients
T335	50463-51301	Sentence	denotes	Laboratory Standardized laboratory confirmation should be based on nucleic acid amplification testing for SARS-CoV-2 on respiratory specimen rather than relying on radiologic suspicion on imaging studies, which are less specificLFTs should be obtained on admission and followed throughout the hospitalization.Changes in LFTs should be reported as normal/abnormal and the cutoff for abnormal should be specified, rather than mean and median at the individual patient levelPattern of LFTs abnormalities, hepatocellular vs cholestatic, should be reported as well as the evaluation performed to work up the abnormalitiesBaseline LFTs (prior to developing COVID-19), changes during the duration of the disease, and after resolution should be reported.Report stool RNA testing, when available, and presence of GI symptoms at the time of testing
T336	51302-51490	Sentence	denotes	Disease severity Use of standardized disease severity definitions, for example, as per World Health Organization–China Joint Mission100:• mild-to-moderate: non-pneumonia and mild pneumonia
T337	51491-51583	Sentence	denotes	• severe defined as tachypnea, oxygen saturation ≤93% at rest, or PaO2/FiO2 ratio <300 mm Hg
T338	51584-51729	Sentence	denotes	• critical respiratory failure requiring mechanical ventilation, septic shock, or other organ dysfunction or failure that requires intensive care
T339	51730-51806	Sentence	denotes	Patients can be stratified by:• Disease severity and presence of GI symptoms
T340	51807-51834	Sentence	denotes	• Disease severity and LFTs
T341	51835-51933	Sentence	denotes	Symptoms and their duration before development of a severe stage of the disease should be reported
T342	51934-52220	Sentence	denotes	Outcomes Outcomes should focus on patient-important outcomes, such as death, clinical improvement or disease worsening/progression, hospital discharge; include clinical definitions (eg, threshold reached for intubation); select sufficient follow-up time to ensure outcome is obtainable.
T343	52221-52462	Sentence	denotes	Analysis Analysis should attempt to control for confounding variables; analysis of risk factors should include univariate followed by multivariate analyses to identify independent risk factors predicting more severe disease and poor outcomes
T344	52463-52660	Sentence	denotes	a aIn 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.
T345	52661-52743	Sentence	denotes	Finally, peer-review remains critical to the process of disseminating information.
T346	52744-53055	Sentence	denotes	Journals should add resources to expedite reviews by increasing the number of editors and reviewers to shorten the review process; 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.99
T347	53057-53063	Sentence	denotes	Update
T348	53064-53133	Sentence	denotes	Recommendations in this document may not be valid in the near future.
T349	53134-53268	Sentence	denotes	We will conduct periodic reviews of the literature and monitor the evidence to determine whether recommendations require modification.
T350	53269-53397	Sentence	denotes	Based on the rapidly evolving nature of this pandemic, this guideline will likely need to be updated within the next few months.
T351	53399-53410	Sentence	denotes	Conclusions
T352	53411-53608	Sentence	denotes	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, and multiorgan failure.
T353	53609-53822	Sentence	denotes	Although fever, cough, and shortness of breath remain the most common presenting symptoms in affected individuals, emerging data suggest that nonpulmonary symptoms affecting the GI tract and liver may be observed.
T354	53823-54164	Sentence	denotes	Based on systematic review and meta-analysis of 47 studies and 10,890 unique patients, gastrointestinal symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea) are observed in <10% of patients with COVID-19, and abnormal liver enzymes and tests (AST, ALT, and bilirubin) are observed in approximately 15%–20% of patients with COVID-19.
T355	54165-54380	Sentence	denotes	These findings inform time-sensitive clinical guidance in the context of this pandemic to pursue careful evaluation of patients with new-onset gastrointestinal symptoms for classic and atypical symptoms of COVID-19.
T356	54381-54542	Sentence	denotes	All hospitalized patients with COVID-19 may benefit from liver enzyme monitoring, particularly in the context of drug treatment with known hepatotoxic potential.
T357	54543-54682	Sentence	denotes	Further research is needed to clarify the implications of SARS-CoV-2 in stool and potential impact on transmission and clinical management.
T358	54684-54706	Sentence	denotes	Supplementary Material
T359	54707-54751	Sentence	denotes	Supplement Figure 1 PRISMA 2009 Flow Diagram
T360	54752-54831	Sentence	denotes	Supplementary Figure 2 The matrix used in the selection of the Chinese studies.
T361	54832-54866	Sentence	denotes	The X-axis represents the studies.
T362	54867-54924	Sentence	denotes	The Y axis represent the hospitals included in the study.
T363	54925-54993	Sentence	denotes	The size of the bubble reflects the number of patients in the study.
T364	54994-55183	Sentence	denotes	Two studies by Guan et al101,102 were not included in the plot as they included patients from more than 500 hospitals from 30 or more provinces without providing the names of the hospitals.
T365	55184-55311	Sentence	denotes	Supplementary Figure 3 Forest plot of the prevalence of diarrhea in all admitted patients regardless of the timing of diarrhea.
T366	55312-55461	Sentence	denotes	Supplementary Figure 4 Forest plot of the prevalence of diarrhea as one of the initial symptoms in all patients regardless of hospitalization status.
T367	55462-55583	Sentence	denotes	Supplementary Figure 5 Forest plot of the prevalence of diarrhea as one of the initial symptoms in all admitted patients.
T368	55584-55701	Sentence	denotes	Supplementary Figure 6 Forest plot of the prevalence of diarrhea in outpatients regardless of the timing of diarrhea.
T369	55702-55858	Sentence	denotes	Supplementary Figure 7 Forest plot of the prevalence of nausea/vomiting as one of the initial symptoms in all patients regardless of hospitalization status.
T370	55859-56014	Sentence	denotes	Supplementary Figure 8 Forest plot of the prevalence of abdominal pain as one of the initial symptoms in all patients regardless of hospitalization status.
T371	56015-56084	Sentence	denotes	Supplementary Figure 9 Forest plot of the prevalence of elevated AST.
T372	56085-56155	Sentence	denotes	Supplementary Figure 10 Forest plot of the prevalence of elevated ALT.
T373	56156-56238	Sentence	denotes	Supplementary Figure 11 Forest plot of the prevalence of elevated total bilirubin.
T374	56239-56288	Sentence	denotes	Supplementary Table 1 Summary of Included Studies
T375	56289-56388	Sentence	denotes	Study characteristics Patient characteristics Gastrointestinal manifestations Liver Manifestationsa
T376	56389-56410	Sentence	denotes	Hubei Province, China
T377	56411-56454	Sentence	denotes	Luo, 202050Zhongnan Hospital (Wuhan)Dates:
T378	56455-56512	Sentence	denotes	01/01/2020-02/20/2020Last follow-up: NR n = 1141Survival:
T379	56513-56558	Sentence	denotes	3.8% (7/183) death, 96.2% recoveredInclusion:
T380	56559-56605	Sentence	denotes	Inpatients with COVID-19 (throat swab RT-PCR).
T381	56606-56637	Sentence	denotes	All patients received chest CT.
T382	56638-56730	Sentence	denotes	Details only provided for the 183 patients with GI symptoms.Age: m 53.8 y (183 patients)Sex:
T383	56731-56809	Sentence	denotes	44.3% (81/183) femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:
T384	56810-56858	Sentence	denotes	6.0% (n = 68)Present on admissionAbdominal pain:
T385	56859-56899	Sentence	denotes	3.9% (n = 45)Present on admissionNausea:
T386	56900-56944	Sentence	denotes	11.7% (n = 134)Present on admissionVomiting:
T387	56945-56996	Sentence	denotes	10.4% (119)Present on admissionNausea and vomiting:
T388	56997-57145	Sentence	denotes	3.2% (n = 37)Present on admission183 patients presented with GI symptoms only (diarrhea, abdominal pain, nausea, vomiting, and/or loss of appetite).
T389	57146-57251	Sentence	denotes	96% of them had lung lesions on chest CT AST (183 patients) m 65.8 ± 12.7ALT (183 patients) m 66.4 ± 13.2
T390	57252-57297	Sentence	denotes	Zhou, 202020Jinyintan Hospital (Wuhan)Dates:
T391	57298-57334	Sentence	denotes	12/29/2019-01/31/2020Last follow-up:
T392	57335-57362	Sentence	denotes	01/31/2020 n = 191Survival:
T393	57363-57402	Sentence	denotes	28.3% death, 71.8% dischargedInclusion:
T394	57403-57480	Sentence	denotes	Inpatients with COVID-19 (confirmed with RT-PCR) who died or were discharged.
T395	57481-57531	Sentence	denotes	Patients without key information excluded (9).Age:
T396	57532-57557	Sentence	denotes	M 56 y (IQR, 46–67 y)Sex:
T397	57558-57614	Sentence	denotes	37.7% femalesGI/liver comorbidities: NRDisease severity:
T398	57615-57635	Sentence	denotes	General 28%, severe:
T399	57636-57663	Sentence	denotes	35%, critical 28% Diarrhea:
T400	57664-57735	Sentence	denotes	4.7% (9/191)Present on admission2 died and 7 dischargedNausea/vomiting:
T401	57736-57825	Sentence	denotes	3.7% (7/191)Present on admission3 died and 4 dischargedAbdominal pain: NR AST: NRALT >40:
T402	57826-57884	Sentence	denotes	31.2% (59/189)26 died and 33 dischargedTotal bilirubin: NR
T403	57885-57908	Sentence	denotes	Zhang, 202023Wuhan No.
T404	57909-57933	Sentence	denotes	7 Hospital (Wuhan)Dates:
T405	57934-58002	Sentence	denotes	1/16/2020-02/03/2020Last follow-up: NR n = 140Survival: NRInclusion:
T406	58003-58087	Sentence	denotes	Inpatient with COVID-19 (pharyngeal swab PCR) based on symptoms and chest x-ray.Age:
T407	58088-58113	Sentence	denotes	57 y (range, 25–87 y)Sex:
T408	58114-58150	Sentence	denotes	49.3% femalesGI/liver comorbidities:
T409	58151-58401	Sentence	denotes	5.7% fatty liver and abnormal liver function, 5.0% chronic gastritis and gastric ulcer, 4.3% cholelithiasis, 6.4% cholecystectomy 5.0% appendectomy, 0.7% hemorrhoidectomy, 4.3% tumor surgeryDisease severity: severe 41.4% and nonsevere 58.6% Diarrhea:
T410	58402-58485	Sentence	denotes	12.9% (18/139)Present on admission9/82 nonsevere cases and 9/57 severe casesNausea:
T411	58486-58572	Sentence	denotes	17.3% (24/139)Present on admission19/82 nonsevere cases and 5/57 severe casesVomiting:
T412	58573-58745	Sentence	denotes	5.0% (7/139)Present on admission5/82 nonsevere cases and 2/57 severe casesBelching 5.0% (7/139)Present on admission4/82 nonsevere cases and 3/57 severe casesAbdominal pain:
T413	58746-58946	Sentence	denotes	5.8% (8/139)Present on admission2/82 nonsevere cases and 6/57 severe casesOther pathogens were detected including Mycoplasma pneumoniae in 5, respiratory syncytial virus in 1, Epstein-Barr virus in 1.
T414	58947-58974	Sentence	denotes	AST, ALT, and bilirubin: NR
T415	58975-59017	Sentence	denotes	Chen, 202072Tongji Hospital (Wuhan)Dates:
T416	59018-59054	Sentence	denotes	01/13/2020-02/12/2020Last follow-up:
T417	59055-59082	Sentence	denotes	02/28/2020 n = 274Survival:
T418	59083-59121	Sentence	denotes	52.2% death, 47.8% recoveredInclusion:
T419	59122-59267	Sentence	denotes	Moderate severity, severe or critically ill COVID-19 patients (throat swab or bronchoalveolar lavage RT-PCR) who were deceased or discharged.Age:
T420	59268-59296	Sentence	denotes	M 62.0 y (IQR, 44–70 y) sex:
T421	59297-59332	Sentence	denotes	37.6% femaleGI/liver comorbidities:
T422	59333-59452	Sentence	denotes	4% hepatitis B surface antigen positivity, 1% GI diseasesDisease severity: moderate severity, severe or critically ill.
T423	59453-59462	Sentence	denotes	Diarrhea:
T424	59463-59541	Sentence	denotes	28.1% (n = 77)Present on admission27/113 deceased and 50/161 dischargedNausea:
T425	59542-59620	Sentence	denotes	8.8% (n = 24)Present on admission8/113 deceased and 16/161 dischargedVomiting:
T426	59621-59705	Sentence	denotes	5.8% (n = 16)Present on admission6/113 deceased and 10/161 dischargedAbdominal pain:
T427	59706-59784	Sentence	denotes	6.9% (n = 19)Present on admission6/113 deceased and 13/161 discharged AST >40:
T428	59785-59850	Sentence	denotes	30.7% (84)59/113 deceased and 25/161 dischargedM 30 (IQR, 22–46).
T429	59851-59918	Sentence	denotes	Deceased M 45 (IQR, 31–67) and discharged M 25 (IQR, 20–33)ALT >41:
T430	59919-59984	Sentence	denotes	21.9% (60)30/113 deceased and 30/161 dischargedM 23 (IQR, 15–38).
T431	59985-60074	Sentence	denotes	Deceased M 28 (IQR, 18–47) and discharged M 20 (IQR, 15–32)BilirubinM 0.6 (IQR, 0.4–0.8).
T432	60075-60140	Sentence	denotes	Deceased M 0.7 (IQR, 0.6–1.0) and discharged M 0.5 (IQR, 0.3–0.7)
T433	60141-60181	Sentence	denotes	Xu, 202031Tongji Hospital (Wuhan)Dates:
T434	60182-60250	Sentence	denotes	1/15/2020-2/19/2020Last follow-up: NR n = 1324Survival: NRInclusion:
T435	60251-60343	Sentence	denotes	Outpatient COVID-19 patients presenting to fever clinic, based on PCR.Age: m 48 ± 15.3 ySex:
T436	60344-60400	Sentence	denotes	50.8% femalesGI/liver comorbidities: NRDisease severity:
T437	60401-60460	Sentence	denotes	95.9% light condition, 3.8% severe, 0.3% critical Diarrhea:
T438	60461-60507	Sentence	denotes	2.1% (28)Present on admissionLoss of appetite:
T439	60508-60575	Sentence	denotes	4.2%Present on admissionNausea, vomiting, and abdominal pain: NR NR
T440	60576-60617	Sentence	denotes	Shi, 202042Renmin Hospital (Wuhan)Dates:
T441	60618-60651	Sentence	denotes	1/1/2020-2/10/2020Last follow-up:
T442	60652-60678	Sentence	denotes	2/15/2020 n = 645Survival:
T443	60679-60731	Sentence	denotes	7.3% death, 5.1% discharged (416 patients)Inclusion:
T444	60732-60785	Sentence	denotes	Inpatient laboratory-confirmed COVID-19, consecutive.
T445	60786-60855	Sentence	denotes	Detailed results reported for 416 patients with complete results.Age:
T446	60856-60886	Sentence	denotes	M 45–64 y (range, 21–95 y)Sex:
T447	60887-60922	Sentence	denotes	52.9% femaleGI/liver comorbidities:
T448	60923-60987	Sentence	denotes	1% hepatitis B infection (of 416 patients)Severity: NR Diarrhea:
T449	60988-61139	Sentence	denotes	4.5% (29)Present on admissionAbdominal pain, nausea, vomiting: NR AST (416 patients)M 30 (IQR, 22–43).ALT (416 patients)M 28 (IQR, 18–46).Bilirubin: NR
T450	61140-61177	Sentence	denotes	Han, 202062Wuhan No.1 HospitalDates:
T451	61178-61263	Sentence	denotes	1/4/2020-2/3/2020Last follow-up: NR n = 108Survival: NR death, NR recoveredInclusion:
T452	61264-61543	Sentence	denotes	Inpatients COVID-19 (confirmed by RT-PCR) with mild pneumonia, no history of other lung infection, initial CT performed.Exclusion: CT scans performed as follow-up for COVID-19 pneumonia, or chest CT image quality insufficient for image analysisAge: mean 45 y (range, 21–90 y)Sex:
T453	61544-61580	Sentence	denotes	64.8% femalesGI/liver comorbidities:
T454	61581-61624	Sentence	denotes	Not specifiedDisease severity: NR Diarrhea:
T455	61625-61701	Sentence	denotes	14% (15/108)Abdominal pain, nausea, vomiting: NR No laboratory data reported
T456	61702-61741	Sentence	denotes	Xu, 202030Union Hospital (Wuhan)Dates:
T457	61742-61776	Sentence	denotes	1/25/2020-2/20/2020Last follow-up:
T458	61777-61816	Sentence	denotes	2/20/2020 n = 355Survival: NRInclusion:
T459	61817-61873	Sentence	denotes	Inpatients with COVID-19, confirmed based on RT-PCR.Age:
T460	61874-61932	Sentence	denotes	45.1% aged <50 y, 41.7% aged 50–69 y, 13.2% aged ≥70 ySex:
T461	61933-61989	Sentence	denotes	45.6% femalesGI/liver comorbidities: NRDisease severity:
T462	61990-62038	Sentence	denotes	63.1% mild, 16.9% severe, 20% critical Diarrhea:
T463	62039-62094	Sentence	denotes	36.6% (130/355)Abdominal pain, nausea, vomiting NR AST:
T464	62095-62137	Sentence	denotes	28.7% (102/355) m 40.8 (range, 10–475)ALT:
T465	62138-62190	Sentence	denotes	25.6% (91/355) m 35.0 (range, 1–414)Total bilirubin:
T466	62191-62230	Sentence	denotes	18.6% (66/355) m 0.83 (range, 0.1–29.9)
T467	62231-62282	Sentence	denotes	Ma, 202049Wuhan Leishenshan Hospital (Wuhan)Dates:
T468	62283-62348	Sentence	denotes	3/5/2020-3/18/2020Last follow-up: NR n = 81Survival: NRInclusion:
T469	62349-62416	Sentence	denotes	Inpatients with COVID-19 (RT-PCR on nasal and pharyngeal swabs)Age:
T470	62417-62446	Sentence	denotes	M 38 y (IQR, 34.5–42.5 y)Sex:
T471	62447-62499	Sentence	denotes	0% femaleGI/liver comorbidities: NRDisease severity:
T472	62500-62554	Sentence	denotes	2.5% mild, 86.4% moderate, 8.6% severe, 2.5% critical.
T473	62555-62564	Sentence	denotes	Diarrhea:
T474	62565-62730	Sentence	denotes	7.41% (6/81)Nausea/vomiting: NRAbdominal pain: NR AST/ALT - composite report 31/81 abnormal but no thresholdAST M 23 (IQR, 12–453)ALT M 43 (IQR, 13–799)Bilirubin: NR
T475	62731-62807	Sentence	denotes	Liu, 202054General Hospital of Central Theater Command of PLA (Wuhan)Dates:
T476	62808-62949	Sentence	denotes	2/6/2020 - 2/14/2020Last follow-up: NR n = 153 (85 tested negative but had symptoms, we did not include those patients)Survival: NRInclusion:
T477	62950-63007	Sentence	denotes	Inpatients with COVID-19 (RT-PCR on pharyngeal swabs)Age:
T478	63008-63103	Sentence	denotes	M 55 y (IQR, 38.3–65 y)Sex:39.2% femaleGI/liver comorbidities: NRDisease severity: NR Diarrhea:
T479	63104-63144	Sentence	denotes	9.2% (14/153)Present on admissionNausea:
T480	63145-63186	Sentence	denotes	1.3% (2/153)Present on admissionVomiting:
T481	63187-63232	Sentence	denotes	2% (3/153)Present on admissionAbdominal pain:
T482	63233-63293	Sentence	denotes	0.4% (1/153)Present on admission AST, ALT, and bilirubin: NR
T483	63294-63349	Sentence	denotes	Huang, 202061The Fifth Hospital of Wuhan (Wuhan)Dates:
T484	63350-63384	Sentence	denotes	1/21/2020-2/10/2020Last follow-up:
T485	63385-63410	Sentence	denotes	2/14/2020 n = 36Survival:
T486	63411-63431	Sentence	denotes	100% deathInclusion:
T487	63432-63583	Sentence	denotes	Inpatients with COVID-19 (RT-PCR)Age: mean 69.22 y (SD 9.64 y; range, 50–90 y)Sex:30.56% femaleGI/liver comorbidities: NRDisease severity: NR Diarrhea:
T488	63584-63783	Sentence	denotes	8.33% (3/36)Present on admissionNausea: NRVomiting: NRAbdominal pain: NR AST: >40 58.1% (18/31)M 43 (IQR, 30–51)ALT: >50 13.3% (4/30)M 26 (IQR, 18–38)Bilirubin: >25 12.9% (4/31)M 11.2 (IQR, 7.5–19.2)
T489	63784-63824	Sentence	denotes	Mao, 202048Union Hospital (Wuhan)Dates:
T490	63825-63879	Sentence	denotes	1/16/2020-2/19/2020Last follow-up: NR n = 214Survival:
T491	63880-63920	Sentence	denotes	1 died but not fully reported.Inclusion:
T492	63921-63990	Sentence	denotes	Inpatients with COVID-19 (RT-PCR from throat)Age: m 52.7 ± 15.5 ySex:
T493	63991-64046	Sentence	denotes	59.3% femaleGI/liver comorbidities: NRDisease severity:
T494	64047-64086	Sentence	denotes	58.9% nonsevere, 41.1% severe Diarrhea:
T495	64087-64198	Sentence	denotes	19.2% (41/214)Present on admissionSevere disease 14.8% (13/88), nonsevere disease 22.2% (28/126)Abdominal pain:
T496	64199-64458	Sentence	denotes	4.7% (10/214), not included in the analysisPresent on admissionSevere disease 6.8% (6/88), nonsevere disease 3.2% (4/126)Nausea and vomiting: NR AST 26 (8–8191)Severe 34 (8–8191), non-severe 23 (9–244)ALT 26 (5–1933)Severe 32.5 (5–1933), non-severe 23 (6–261)
T497	64459-64508	Sentence	denotes	Ai, 202076Xiangyang No.1 People’s HospitalDates:
T498	64509-64556	Sentence	denotes	Cross-sectional study 2/9/2020 n = 102Survival:
T499	64557-64617	Sentence	denotes	2.9% died, 6.9% survived, 90.2% still hospitalizedInclusion:
T500	64618-64687	Sentence	denotes	Inpatients with laboratory-confirmed COVID-19Age: m 50.4 ± 16.9 ySex:

T1

Sentence

denotes

AGA Institute Rapid Review of the Gastrointestinal and Liver Manifestations of COVID-19, Meta-Analysis of International Data, and Recommendations for the Consultative Management of Patients with COVID-19

T2

205-213

Sentence

denotes

Abstract

T3

214-231

Sentence

denotes

Background & Aims

T4

232-450

Sentence

denotes

Multiple gastrointestinal (GI) symptoms, including diarrhea, nausea/vomiting, and abdominal pain, as well as liver enzyme abnormalities, have been variably reported in patients with coronavirus disease 2019 (COVID-19).

T5

451-659

Sentence

denotes

This document provides best practice statements and recommendations for consultative management based on a systematic review and meta-analysis of international data on GI and liver manifestations of COVID-19.

T6

661-668

Sentence

denotes

Methods

T7

669-929

Sentence

denotes

We performed a systematic literature search to identify published and unpublished studies using OVID Medline and preprint servers (medRxiv, LitCovid, and SSRN) up until April 5, 2020; major journal sites were monitored for US publications until April 19, 2020.

T8

930-1213

Sentence

denotes

We pooled the prevalence of diarrhea, nausea, vomiting, and abdominal pain, as well as liver function tests abnormalities, using a fixed-effect model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.

T9

1215-1222

Sentence

denotes

Results

T10

1223-1322

Sentence

denotes

We identified 118 studies and used a hierarchal study selection process to identify unique cohorts.

T11

1323-1399

Sentence

denotes

We performed a meta-analysis of 47 studies including 10,890 unique patients.

T12

1400-1603

Sentence

denotes

Pooled prevalence estimates of GI symptoms were as follows: diarrhea 7.7% (95% confidence interval [CI], 7.2%–8.2%), nausea/vomiting 7.8% (95% CI, 7.1%–8.5%), and abdominal pain 2.7% (95% CI, 2.0%–3.4%).

T13

1604-1651

Sentence

denotes

Most studies reported on hospitalized patients.

T14

1652-1837

Sentence

denotes

The pooled prevalence estimates of elevated liver abnormalities were as follows: aspartate transaminase 15.0% (95% CI, 13.6%–16.5%) and alanine transaminase 15.0% (95% CI, 13.6%–16.4%).

T15

1838-2071

Sentence

denotes

When we compared studies from China to studies from other countries in subgroup analyses, diarrhea, nausea/vomiting, and liver abnormalities were more prevalent outside of China, with diarrhea reported in 18.3% (95% CI, 16.6%–20.1%).

T16

2072-2114

Sentence

denotes

Isolated GI symptoms were reported rarely.

T17

2115-2222

Sentence

denotes

We also summarized the Gl and liver adverse effects of the most commonly utilized medications for COVID-19.

T18

2224-2235

Sentence

denotes

Conclusions

T19

2236-2297

Sentence

denotes

GI symptoms are associated with COVID-19 in <10% of patients.

T20

2298-2348

Sentence

denotes

In studies outside of China, estimates are higher.

T21

2349-2544

Sentence

denotes

Further studies are needed with standardized GI symptoms questionnaires and liver function test checks on admission to better quantify and qualify the association of these symptoms with COVID-19.

T22

2545-2675

Sentence

denotes

Based on findings from our meta-analysis, we provide several Best Practice Statements for the consultative management of COVID-19.

T23

2677-3540

Sentence

denotes

The coronavirus family has 4 common human coronaviruses (ie, 229E, NL63, OC43, and HKU1) associated with the common cold, and 3 strains that 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-2.1 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 disease 2019 (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 COVID-19 was first reported in the United States on January 20, 2020 and accounted for a total number of 938,154 cases and 53,755 deaths as of April 25, 2020.

T24

3541-4249

Sentence

denotes

In the United States, an early analysis of the first 4226 cases from the Centers for Disease Control and Prevention as of March 16, 2020 revealed estimated rates of hospitalization of 20.7%–31.4%; intensive care unit admission of 4.9%–11.5%; and case fatality of 1.8%–3.4%.4 More recent data from a cohort of 5700 hospitalized patients with COVID-19 within a large health care system in New York City revealed common comorbidities, including hypertension (56.6%), obesity (41.7%), and diabetes (33.8%), and reported that 373 patients (14.2%) required treatment in the intensive care unit, and 320 patients (12.2%) received invasive mechanical ventilation, in whom the mortality rate was 88.1% (282 of 320)].5

T25

4250-4689

Sentence

denotes

Angiotensin converting enzyme II, believed to be the target entry receptor for SARS-CoV-2, is abundantly expressed in gastric, duodenal, and rectal epithelia, thereby implicating angiotensin converting enzyme II as a vehicle for possible fecal–oral transmission.6 In addition, angiotensin converting enzyme II receptors can be expressed in hepatic cholangiocytes7 and hepatocytes,8 potentially permitting direct infection of hepatic cells.

T26

4690-4880

Sentence

denotes

Nongastrointestinal 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.

T27

4881-5028

Sentence

denotes

Gastrointestinal (GI) symptoms, including anorexia, nausea, vomiting, abdominal pain, and/or diarrhea have been reported in patients with COVID-19.

T28

5029-5488

Sentence

denotes

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.

T29

5490-5507

Sentence

denotes

Scope and Purpose

T30

5508-5619

Sentence

denotes

We seek to summarize international data on the Gl and liver manifestations of COVID-19 infection and treatment.

T31

5620-5758

Sentence

denotes

Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.

T32

5759-6074

Sentence

denotes

This rapid review document was commissioned and approved by the AGA Institute Clinical Guidelines Committee, AGA Institute Clinical Practice Updates Committee, and the AGA Governing Board to provide timely, methodologically rigorous guidance on a topic of high clinical importance to the AGA members and the public.

T33

6075-6154

Sentence

denotes

Table 1 provides a summary of the recommendations and best practice statements.

T34

6155-6199

Sentence

denotes

Table 1 Summary of Best Practice Statements:

T35

6200-6251

Sentence

denotes

Consultative Management of Coronavirus Disease 2019

T36

6252-6265

Sentence

denotes

Statement no.

T37

6266-6275

Sentence

denotes

Statement

T38

6276-6658

Sentence

denotes

1 In outpatients with new-onset diarrhea, ascertain information about high-risk contact exposure; obtain a detailed history of symptoms associated with COVID-19, including fever, cough, shortness of breath, chills, muscle pain, headache, sore throat, or new loss of taste or smell; and obtain a thorough history for other Gl symptoms, including nausea, vomiting, and abdominal pain.

T39

6659-6868

Sentence

denotes

2 In outpatients with new-onset Gl symptoms (eg, nausea, vomiting, abdominal pain, and diarrhea), monitor for symptoms associated with COVID-19, as GI symptoms may precede COVID-related symptoms by a few days.

T40

6869-6946

Sentence

denotes

In a high COVID-19 prevalence setting, COVID-19 testing should be considered.

T41

6947-7160

Sentence

denotes

3 In hospitalized patients with suspected or known COVID-19, obtain a thorough history of GI symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea), including onset, characteristics, duration, and severity.

T42

7161-7304

Sentence

denotes

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

T43

7305-7445

Sentence

denotes

5 In patients (outpatients or inpatients) with elevated LFTs in context of suspected or known COVID-19, evaluate for alternative etiologies.

T44

7446-7671

Sentence

denotes

6 In hospitalized patients with suspected or known COVID-19, obtain baseline LFTs at the time of admission and consider LFT monitoring throughout the hospitalization, particularly in the context of drug treatment for COVID-19

T45

7672-7801

Sentence

denotes

7 In hospitalized patients undergoing drug treatment for COVID-19, evaluate for treatment-related Gl and hepatic adverse effects.

T46

7803-7856

Sentence

denotes

Panel Composition and Conflict of Interest Management

T47

7857-7981

Sentence

denotes

This rapid review and guideline was developed by gastroenterologists and guideline methodologists from the 2 AGA committees.

T48

7982-8151

Sentence

denotes

The guideline panel worked collaboratively with the AGA Governing Board to develop the clinical questions, review the evidence profiles, and develop the recommendations.

T49

8152-8246

Sentence

denotes

Panel members disclosed all potential conflicts of interest according to AGA Institute policy.

T50

8248-8263

Sentence

denotes

Target Audience

T51

8264-8405

Sentence

denotes

The target audience of this guideline includes gastroenterologists, advanced practice providers, nurses, and other health care professionals.

T52

8406-8474

Sentence

denotes

Patients as well as policy-makers can benefit from these guidelines.

T53

8475-8601

Sentence

denotes

These guidelines are not intended to impose a standard of care for individual institutions, health care systems, or countries.

T54

8602-8748

Sentence

denotes

They provide the basis for rational informed decisions for clinicians, patients, and other health care professionals in the setting of a pandemic.

T55

8750-8757

Sentence

denotes

Methods

T56

8759-8800

Sentence

denotes

Information Sources and Literature Search

T57

8801-8979

Sentence

denotes

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.

T58

8980-9111

Sentence

denotes

In the setting of a pandemic with exponential increases in published and unpublished studies, our search strategy was multifaceted.

T59

9112-9287

Sentence

denotes

To capture relevant published articles, we electronically searched OVID Medline from inception to March 23, 2020 using the Medical Subject Heading term developed for COVID-19.

T60

9288-9426

Sentence

denotes

We then searched the following platforms on April 5, 2020 for additional published and unpublished studies: medRxiv, LitCovid,11 and SSRN.

T61

9427-9523

Sentence

denotes

An additional unpublished article under peer review was obtained through personal communication.

T62

9524-9648

Sentence

denotes

For studies from the United States, we continued to monitor major journals for additional publications until April 19, 2020.

T63

9650-9685

Sentence

denotes

Study Selection and Data Extraction

T64

9686-9834

Sentence

denotes

Independent screening of titles and abstracts was performed by independent reviewers (P.D., S.S., J.F.) to identify potential studies for inclusion.

T65

9835-9943

Sentence

denotes

A second reviewer (O.A.) subsequently reviewed the full-text articles and identified articles for inclusion.

T66

9944-10011

Sentence

denotes

Any disagreements about inclusion were resolved through discussion.

T67

10012-10137

Sentence

denotes

We incorporated any studies (prospective or retrospective) that reported on patient characteristics and symptoms of interest.

T68

10138-10255

Sentence

denotes

For studies published in Chinese, we used Google translate to assess for potential inclusion and for data extraction.

T69

10256-10493

Sentence

denotes

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.

T70

10494-10652

Sentence

denotes

We aimed to identify and include data from the largest possible cohort from each location or hospital.12 Data extraction was performed using a 2-step process.

T71

10653-10744

Sentence

denotes

The initial data extraction focused on data elements for study and patient characteristics.

T72

10745-10878

Sentence

denotes

Subsequently, we identified studies for full data extraction based on study location (unique hospitals) and total number of patients.

T73

10879-11113

Sentence

denotes

Additionally, when a study from a specific hospital did not provide all of the necessary information for the diarrhea symptoms, the next largest study from the same hospital (when available) was selected for inclusion in our analysis.

T74

11114-11202

Sentence

denotes

Data extraction was performed using a standardized Microsoft Excel data extraction form.

T75

11203-11416

Sentence

denotes

Data extraction was performed in pairs; one study author independently extracted data while a second reviewer checked for accuracy of the data extraction (S.S., O.A., S.M.S., P.D., J.D.F., J.K.L., Y.F.Y., H.B.E.).

T76

11417-11611

Sentence

denotes

Because the reporting of the data in the primary studies was suboptimal, a third reviewer (O.A.) additionally verified the extracted data to confirm the numbers and to resolve any disagreements.

T77

11612-11665

Sentence

denotes

Studies with discrepancies in the data were excluded.

T78

11666-11711

Sentence

denotes

The following data elements were extracted:1.

T79

11712-11830

Sentence

denotes

Study: author, year, location (hospital name, city, province or state), dates of inclusion, and date of last follow-up

T80

11831-11833

Sentence

denotes

2.

T81

11834-12138

Sentence

denotes

Patient characteristics: number of patients, age (mean, median, interquartile interval or range), number of females, severity of illness, inclusion criteria (hospitalized or outpatients), GI comorbidities (pre-existing conditions, such as chronic liver disease, hepatitis, and inflammatory bowel disease)

T82

12139-12141

Sentence

denotes

3.

T83

12142-12239

Sentence

denotes

Outcomes: diarrhea, nausea, vomiting, abdominal pain, and liver function test (LFT) abnormalities

T84

12240-12242

Sentence

denotes

4.

T85

12243-12497

Sentence

denotes

Additional information: severity, characteristics, duration, timing (before or concurrent with respiratory symptoms), relationship with clinical outcomes (need for ventilator, survival, discharge, and continued hospitalization), and viral stool shedding.

T86

12499-12525

Sentence

denotes

Assessment of Risk of Bias

T87

12526-12655

Sentence

denotes

We assessed the risk of bias according to the following domains as suggested in the ROBINS-I tool for nonrandomized studies.13 1.

T88

12656-12706

Sentence

denotes

Bias due to selection of participants in the study

T89

12707-12709

Sentence

denotes

2.

T90

12710-12734

Sentence

denotes

Bias due to missing data

T91

12735-12737

Sentence

denotes

3.

T92

12738-12773

Sentence

denotes

Bias in the measurement of outcomes

T93

12774-12776

Sentence

denotes

4.

T94

12777-12821

Sentence

denotes

Bias in the selection of the reported result

T95

12822-12962

Sentence

denotes

We considered the domains for each study and then made a judgment of high or low risk of bias for the studies included in the meta-analysis.

T96

12964-12985

Sentence

denotes

Certainty of Evidence

T97

12986-13116

Sentence

denotes

Certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.

T98

13117-13203

Sentence

denotes

The certainty of evidence was categorized into 4 levels ranging from very low to high.

T99

13204-13505

Sentence

denotes

Within the GRADE framework, evidence from randomized controlled trials (RCTs) starts as high-certainty evidence and observational studies start out as low-certainty evidence, but can be rated down for the following reasons: risk of bias, inconsistency, indirectness, imprecision, and publication bias.

T100

13506-13661

Sentence

denotes

Additionally, evidence from well-conducted observational studies start as low-certainty evidence, but can be rated up for large effects or dose–response.14

T101

13663-13690

Sentence

denotes

Data Synthesis and Analysis

T102

13691-13906

Sentence

denotes

A meta-analysis of prevalence of GI and liver abnormalities was performed using meta 4.11-0 package in R software, version 3.6.3.15 , 16 The prevalence was expressed as a proportion and 95% confidence interval (CI).

T103

13907-14016

Sentence

denotes

We used the fixed-effects model using the Freeman-Tukey double arcsine transformation method for proportions.

T104

14017-14369

Sentence

denotes

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 vs outpatient).

T105

14370-14558

Sentence

denotes

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.

T106

14560-14567

Sentence

denotes

Results

T107

14568-15095

Sentence

denotes

A total of 57 studies were ultimately selected for complete data extraction; 56 from our search and 1 additional manuscript (under review) was included to provide more data on a US cohort20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76 (see Supplementary Figure 1 for Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram).

T108

15096-15234

Sentence

denotes

Of the 57 selected studies, 47 reported on unique patients based on hospital name (with no duplication of cohorts from the same hospital).

T109

15235-15542

Sentence

denotes

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 (eg, diarrhea at initial presentation when the larger cohort did not clearly state that it was at initial presentation).

T110

15543-15678

Sentence

denotes

Based on our comprehensive selection process, we believe that the included 47 studies reported data on 10,890 unique COVID-19 patients.

T111

15679-15841

Sentence

denotes

The majority of studies (70%) in our analysis were from China; these were selected from 118 reports published or prepublished from China (Supplementary Figure 2).

T112

15842-15951

Sentence

denotes

The studies included mainly adults, although a few studies included a small proportion of pediatric patients.

T113

15952-16119

Sentence

denotes

Two studies reported on outpatients only, whereas the remaining 55 studies reported on hospitalized patients or a combination of outpatients and hospitalized patients.

T114

16120-16152

Sentence

denotes

Based on our inclusion strategy:

T115

16153-16271

Sentence

denotes

55 studies (96%) provided information on any GI symptom and 32 studies (56%) reported any data on liver abnormalities.

T116

16272-16346

Sentence

denotes

Fewer studies, 21 (37%), provided information on underlying GI conditions.

T117

16347-16409

Sentence

denotes

Table 2 provides a summary of the pooled prevalence estimates.

T118

16410-16501

Sentence

denotes

Table 2 Summary of the Pooled Prevalence Estimates of Gastrointestinal/Liver Manifestations

T119

16502-16600

Sentence

denotes

GI and liver manifestations All studies Studies from China Studies from countries other than China

T120

16601-16696

Sentence

denotes

% (95% CI) Patients/ studies, n % (95% CI) Patients/ studies, n % (95% CI) Patients/ studies, n

T121

16697-16802

Sentence

denotes

Diarrhea in all patientsa 7.7 (7.2 to 8.2) 43/10,676 5.8 (5.3 to 6.4) 32/8612 18.3 (16.6 to 20.1) 11/2064

T122

16803-16913

Sentence

denotes

Nausea/vomiting in all patientsa 7.8 (7.1 to 8.5) 26/5955 5.2 (4.4 to 5.9) 19/4054 14.9 (13.3 to –16.6) 7/1901

T123

16914-17019

Sentence

denotes

Abdominal pain in all patientsa 3.6 (3.0 to 4.3) 15/4031 2.7 (2.0 to 3.4) 10/2447 5.3 (4.2 to 6.6) 5/1584

T124

17020-17128

Sentence

denotes

Patients with elevated AST 15.0 (13.6 to 16.5) 16/2514 14.9 (13.5 to 16.4) 14/2398 20.0 (12.8 to 28.1) 2/116

T125

17129-17237

Sentence

denotes

Patients with elevated ALT 15.0 (13.6 to 16.4) 17/2711 14.9 (13.5 to 16.3) 15/2595 19.0 (12.0 to 27.1) 2/116

T126

17238-17336

Sentence

denotes

Patients with elevated total bilirubin 16.7 (15.0 to 18.5) 10/1841 16.7 (15.0 to 18.5) 10/1841 — —

T127

17337-17392

Sentence

denotes

a Regardless of hospitalization and timing of symptoms.

T128

17394-17423

Sentence

denotes

Overall Certainty of Evidence

T129

17424-17478

Sentence

denotes

The overall certainty in the body of evidence was low.

T130

17479-17854

Sentence

denotes

Our confidence in the pooled estimates of prevalence was reduced because of concerns of risk of bias (ie, 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).

T131

17855-18001

Sentence

denotes

Additionally, most of the studies were retrospective cohort series and did not specify whether consecutive patients were included in the analysis.

T132

18002-18185

Sentence

denotes

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.

T133

18186-18269

Sentence

denotes

These factors may have contributed to the heterogeneity of findings across studies.

T134

18270-18404

Sentence

denotes

The I 2 statistic ranged from 77% to 98% and was not completely explained by geographic location or by outpatient vs inpatient status.

T135

18406-18463

Sentence

denotes

What are the Gastrointestinal Manifestations of COVID-19?

T136

18465-18473

Sentence

denotes

Diarrhea

T137

18474-18946

Sentence

denotes

A total of 43 studies including 10,676 COVID-19 patients (confirmed by laboratory real-time reverse transcription polymerase chain reaction [RT-PCR] testing) were included in the overall analysis.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 , 37 , 38 , 41 , 42 , 45 , 47 , 49, 50, 51, 52, 53, 54, 55 , 58 , 59 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 73 , 76 The pooled prevalence of diarrhea symptoms across these studies was 7.7% (95% CI, 7.2%–8.2%).

T138

18947-19151

Sentence

denotes

When analyzing by country (studies from China vs studies from other countries), the pooled prevalence of diarrhea in studies from countries other than China was much higher at 18.3% (95% CI, 16.6%–20.1%).

T139

19152-19273

Sentence

denotes

This is in comparison to studies from China, where the prevalence was much lower at 5.8% (95% CI, 5.3%–6.4%) (Figure 1 ).

T140

19274-19341

Sentence

denotes

Figure 1 Forest plot of the prevalence of diarrhea in all patients.

T141

19342-20191

Sentence

denotes

In hospitalized patients, across 39 studies including 8,521 patients, the pooled prevalence was slightly higher at 10.4% (95% CI, 9.4%–10.7%) compared with outpatients.20, 21, 22, 23 , 25, 26, 27, 28 , 30 , 33, 34, 35 , 38 , 41 , 42 , 44, 45, 46 , 49, 50, 51, 52, 53, 54, 55 , 60 , 62, 63, 64, 65, 66, 67, 68 , 70, 71, 72, 73, 74 , 76 In 3 studies including 1701 outpatients, the pooled prevalence was 4.0% (95% CI, 3.1%–5.1%).31 , 59 , 63 As part of the sensitivity analysis, we identified 35 studies including 9717 patients that described diarrhea, and explicitly reported that it was one of the initial presenting symptoms.20, 21, 22, 23 , 26, 27, 28 , 31 , 33, 34, 35 , 38 , 41 , 42 , 44 , 45 , 47 , 48 , 50, 51, 52, 53, 54, 55 , 60 , 63, 64, 65, 66 , 68, 69, 70, 71 , 74 , 76 The pooled prevalence in these studies was 7.9% (95% CI, 7.4%–8.6%).

T142

20192-20642

Sentence

denotes

A total of 33 studies including 8070 patients reported on hospitalized COVID-19 patients presenting with diarrhea as one of the initial symptoms of COVID-19.20, 21, 22, 23 , 26, 27, 28 , 33, 34, 35 , 38 , 41 , 42 , 44 , 45 , 48 , 50, 51, 52, 53, 54, 55 , 60 , 63, 64, 65, 66 , 68 , 70, 71, 72, 73 , 76 The pooled prevalence was 9.3% (95% CI, 8.6%–9.9%) (Supplementary Figure 3, Supplementary Figure 4, Supplementary Figure 5, Supplementary Figure 6).

T143

20644-20667

Sentence

denotes

Description of diarrhea

T144

20668-21017

Sentence

denotes

Only a handful of studies provided any details on the type and severity of diarrhea symptoms.55 , 60 , 74 In the study by Lin et al,55 23 of 95 patients (24%) reported having diarrhea (described as loose or watery stools, ranging from 2–10 bowel movements per day); however, only a small number of patients actually had diarrhea on admission (5.2%).

T145

21018-21147

Sentence

denotes

Most patients developed diarrhea during the hospitalization, which may have been attributable to other treatments or medications.

T146

21148-21281

Sentence

denotes

In the study by Jin et al60 of 651 hospitalized patients, 8.6% of patients had diarrhea on admission before receiving any treatments.

T147

21282-21355

Sentence

denotes

The diarrhea symptoms were described as more than 3 loose stools per day.

T148

21356-21435

Sentence

denotes

Stool cultures were negative (including Clostridium difficile) in all patients.

T149

21436-21477

Sentence

denotes

There was no mention of fecal leukocytes.

T150

21478-21776

Sentence

denotes

Median duration of symptoms was 4 days (range, 1–9 days) and most patients had self-limited diarrheal symptoms.60 One additional study on 175 hospitalized patients reported that 19.4% of patients had diarrhea, with an average of 6 episodes per day, with symptom duration ranging from 1 to 4 days.74

T151

21778-21862

Sentence

denotes

Diarrhea as the only presenting symptom in the absence of upper respiratory symptoms

T152

21863-22151

Sentence

denotes

In the 43 studies that informed our analysis on the prevalence of diarrhea, we extracted information on whether diarrhea was reported as the only presenting symptom.50 , 60 In only 2 studies, there was explicit reporting of diarrhea in the absence of upper respiratory infection symptoms.

T153

22152-22286

Sentence

denotes

In a study by Luo et al50 of 1141 patients, 183 patients (16%) presented with GI symptoms only in the absence of respiratory symptoms.

T154

22287-22465

Sentence

denotes

Of 1141 patients, loss of appetite (15.8%) and nausea or vomiting (11.7%) were the most common symptoms, but diarrhea was reported in 6.0% and abdominal pain in 3.9% of patients.

T155

22466-22556

Sentence

denotes

Notably, the majority of patients (96%) had lung infiltrates on chest computed tomography.

T156

22557-22829

Sentence

denotes

In the study by Jin et al60 of 651 hospitalized patients, 21 patients (3.2%) presented with GI symptoms only (and no respiratory symptoms of coughing or sputum production).60 GI symptoms were defined as at least 1 of the following symptoms: nausea, vomiting, and diarrhea.

T157

22830-23124

Sentence

denotes

Conversely, in the US study of 116 patients with COVID-19, Cholankeril et al70 reported that 31.9% of patients had GI symptoms on admission (median duration, 1 day); diarrhea was reported in 10.3% (12 of 116), nausea and/or vomiting in 10.3% (12 of 116), and abdominal pain in 8.8% (10 of 116).

T158

23125-23250

Sentence

denotes

The authors explicitly reported that none of the 116 patients had isolated GI symptoms as the only manifestation of COVID-19.

T159

23252-23328

Sentence

denotes

Diarrhea as the initial presenting symptom preceding other COVID-19 symptoms

T160

23329-23512

Sentence

denotes

Of the studies included in our review, based on our selection framework, we identified only 1 study that reported on timing of diarrhea in relation to other COVID-19–related symptoms.

T161

23513-23679

Sentence

denotes

In a study by Ai et al76 of 102 hospitalized patients, 15 patients reported diarrhea symptoms on hospital admission, and diarrhea was the first symptom in 2 patients.

T162

23680-23897

Sentence

denotes

In a study by Wang et al77 of 138 consecutive hospitalized patients, not included in our pooled analysis, a total of 14 patients presented with diarrhea and nausea 1–2 days before the development of fever and dyspnea.

T163

23899-23914

Sentence

denotes

Nausea/vomiting

T164

23915-24275

Sentence

denotes

A total of 26 studies including 5955 patients with COVID-19 (confirmed by laboratory RT-PCR testing), were included in the overall analysis for nausea and/or vomiting.20 , 22 , 23 , 25 , 27 , 29 , 34 , 37 , 41 , 45, 46, 47 , 50 , 51 , 54 , 55 , 59 , 63 , 65 , 67 , 68 , 70, 71, 72, 73 , 76 The pooled prevalence of nausea/vomiting was 7.8% (95% CI, 7.1%–8.5%).

T165

24276-24672

Sentence

denotes

A subgroup analysis of 1901 patients from 7 studies (including patients from Germany, Singapore, United States, Australia, and The Netherlands) demonstrated a higher pooled prevalence of 14.9% (95% CI, 13.3%–16.6%).37 , 46 , 47 , 59 , 63 , 68 , 70 This is in comparison to the prevalence of symptoms in studies from China, which was 5.2% (95% CI, 4.4%–5.9%) (Figure 2 and Supplementary Figure 7).

T166

24673-24747

Sentence

denotes

Figure 2 Forest plot of the prevalence of nausea/vomiting in all patients.

T167

24749-24763

Sentence

denotes

Abdominal pain

T168

24764-25055

Sentence

denotes

A total of 15 studies including 4031 COVID-19 patients (confirmed by laboratory RT-PCR testing) were included in the overall analysis for abdominal pain.21 , 23 , 27 , 37 , 50 , 54 , 55 , 59 , 63 , 69, 70, 71, 72, 73 , 76 The pooled prevalence of abdominal pain was 3.6% (95% CI, 3.0%–4.3%).

T169

25056-25562

Sentence

denotes

A subgroup analysis of 1584 patients from the United States, Australia, South Korea, and The Netherlands, demonstrated a slightly higher pooled prevalence of 5.3% (95% CI, 4.2%–6.6)% compared with studies from China 2.7% (95% CI, 2.0%–3.4%), which included 10 studies of 2447 patients.37 , 59 , 63 , 69 , 70 The symptoms were variably described as stomachache, epigastric pain, and abdominal discomfort, without further details regarding the quality or nature of pain (Figure 3 and Supplementary Figure 8).

T170

25563-25636

Sentence

denotes

Figure 3 Forest plot of the prevalence of abdominal pain in all patients.

T171

25638-25652

Sentence

denotes

Stool shedding

T172

25653-25875

Sentence

denotes

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.

T173

25876-26041

Sentence

denotes

A recently published systematic review by Cheung et al10 found a 48.1% (95% CI, 38.3%–59.7%) pooled prevalence of stool samples positive for virus RNA in 12 studies.

T174

26042-26171

Sentence

denotes

Stool RNA was positive in 70.3% of samples taken from patients after respiratory specimens were no longer positive for the virus.

T175

26172-26516

Sentence

denotes

From the 57 studies included in our analysis, 4 studies reported on presence of viral RNA in stool.24 , 32 , 57 , 68 Of these, 3 studies were published after the systematic review by Cheung et al.10 First, Dreher et al68 conducted a retrospective cohort study in Germany, stratifying patients by presence of acute respiratory distress syndrome.

T176

26517-26611

Sentence

denotes

In this study, 8 of 50 patients had diarrhea, and stool PCR was positive in 15 of 50 patients.

T177

26612-26690

Sentence

denotes

In a US study by Kujawski et al,57 stool PCR was positive in 7 of 10 patients.

T178

26691-26847

Sentence

denotes

Finally, in a case series from Germany by Wolfel et al,32 the authors not only examined stool RNA but also tried to isolate virus from laboratory specimens.

T179

26848-27143

Sentence

denotes

In this study, 2 of 9 patients had diarrhea as an initial symptom and stool PCR remained positive for up to 11 days, but notably, the authors were unable to isolate infectious virus, despite a high stool viral RNA load, even though the virus was successfully isolated from respiratory specimens.

T180

27144-27424

Sentence

denotes

The authors concluded that stool is not a primary source of spread of infection.32 Conversely, in a letter published by Wang et al,78 the authors collected 1070 specimens from 205 hospitalized patients with COVID-19 and 44 of 153 stool specimens (29%) were positive for viral RNA.

T181

27425-27611

Sentence

denotes

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.

T182

27612-27967

Sentence

denotes

The authors concluded that although this does not confer infectivity, it raised the possibility of fecal–oral 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.

T183

27969-28015

Sentence

denotes

What Are the Liver Manifestations of COVID-19?

T184

28016-28464

Sentence

denotes

Based on our inclusion strategy, 34 of the 57 studies (60%) reported any data on liver abnormalities.20, 21, 22 , 25 , 27 , 28 , 30 , 34, 35, 36 , 38 , 41, 42, 43 , 45 , 48, 49, 50, 51, 52, 53 , 55 , 57 , 60 , 61 , 63 , 65, 66, 67 , 70, 71, 72 , 75 , 76 The majority of the studies that reported data on LFTs only reported continuous summary statistics (median and interquartile range) without reporting the number of patients with abnormal levels.

T185

28465-28672

Sentence

denotes

Abnormal aspartate transaminase (AST), defined as any value above the upper limit of normal (ULN), was reported in 15.0% (95% CI, 13.6%– 16.5) of patients across 16 studies, including 2514 COVID-19 patients.

T186

28673-28853

Sentence

denotes

Abnormal alanine transaminase (ALT), defined as any value above the ULN, was reported in 15.0% (95% CI, 13.6%–16.4%) of patients across 17 studies including 2711 COVID-19 patients.

T187

28854-29017

Sentence

denotes

Abnormal bilirubin, defined as any value above the ULN, was reported in 16.7% (95% CI, 15.0%–18.5%) of patients across 10 studies including 1841 COVID-19 patients.

T188

29018-29083

Sentence

denotes

All patients had confirmed COVID-19 by laboratory RT-PCR testing.

T189

29084-29231

Sentence

denotes

The study by Cholankeril et al70 reported that 26 of 65 patients (40%) had abnormal liver enzymes and 22 of them had normal baseline liver enzymes.

T190

29232-29337

Sentence

denotes

None of the remaining studies provided any information regarding the status of LFTs before the infection.

T191

29338-29511

Sentence

denotes

One study by Fu et al65 reported summary statistics (median and interquartile range) of LFTs for 23 patients on admission and discharge with no clinically important changes.

T192

29512-29650

Sentence

denotes

However, they did not provide the number of patients who presented with normal or abnormal LFTs and how many of them improved or worsened.

T193

29651-29824

Sentence

denotes

None of the included studies reported the workup of LFTs in the settings of COVID-19 or assessed whether they were related to alternative etiologies, especially medications.

T194

29825-29959

Sentence

denotes

Thirteen studies reported on the association between the presence of liver injury at presentation and severity of disease or outcomes.

T195

29960-30448

Sentence

denotes

Most of them reported the results of univariate analyses.20 , 22 , 27 , 38 , 45 , 48 , 51 , 53 , 55 , 63 , 67 , 71 , 72 The study by Hajifathalian et al63 reported the results of multivariate analyses that included multiple variables and showed liver injury at presentation was associated with high risk for admission, as well as higher risk of intensive care unit admission and/or death as a composite outcome63 (Supplementary Figure 10, Supplementary Figure 11, Supplementary Figure 9).

T196

30450-30488

Sentence

denotes

Rationale for Best Practice Statements

T197

30489-30491

Sentence

denotes

1.

T198

30493-30873

Sentence

denotes

In outpatients with new-onset diarrhea, ascertain information about high-risk contact exposure; obtain a detailed history of symptoms associated with COVID-19, including fever, cough, shortness of breath, chills, muscle pain, headache, sore throat, or new loss of taste or smell; and obtain a thorough history for other Gl symptoms, including nausea, vomiting, and abdominal pain.

T199

30874-30876

Sentence

denotes

2.

T200

30878-31085

Sentence

denotes

In outpatients with new-onset Gl symptoms (eg, nausea, vomiting, abdominal pain, and diarrhea), monitor for symptoms associated with COVID-19, as GI symptoms may precede COVID-related symptoms by a few days.

T201

31086-31163

Sentence

denotes

In a high COVID-19 prevalence setting, COVID-19 testing should be considered.

T202

31164-31166

Sentence

denotes

3.

T203

31168-31379

Sentence

denotes

In hospitalized patients with suspected or known COVID-19, obtain a thorough history of GI symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea), including onset, characteristics, duration, and severity.

T204

31380-31745

Sentence

denotes

The overall prevalence of GI symptoms in context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously.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.

T205

31746-31841

Sentence

denotes

Therefore, the reported prevalence rates may represent either an overestimate or underestimate.

T206

31842-31961

Sentence

denotes

Information about the frequency and severity of diarrhea symptoms was inadequately reported in the majority of studies.

T207

31962-32132

Sentence

denotes

Based on our analysis, among hospitalized patients, the prevalence of diarrhea as the only presenting symptom in the absence of other COVID-related symptoms was very low.

T208

32133-32270

Sentence

denotes

The majority of patients with diarrhea, nausea, or vomiting also presented with accompanying symptoms typically associated with COVID-19.

T209

32271-32376

Sentence

denotes

In a handful of studies, diarrhea and nausea preceded the development of other COVID-19–related symptoms.

T210

32377-32571

Sentence

denotes

In a US case–control study of 278 COVID-19 patients, patients with GI symptoms were more likely to have illness duration of 1 week or longer (33%) compared to patients without GI symptoms (22%).

T211

32572-32886

Sentence

denotes

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 COVID-testing is reasonable, especially if testing capacity is not limited.

T212

32887-33314

Sentence

denotes

The Centers for Disease Control and Prevention 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 As of April 19, 2020, diarrhea as an initial preceding symptom of COVID-19 has not been included on the Centers for Disease Control and Prevention symptom checklist.

T213

33315-33678

Sentence

denotes

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 upper respiratory infection symptoms.

T214

33679-33883

Sentence

denotes

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.4.

T215

33885-34026

Sentence

denotes

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

T216

34027-34289

Sentence

denotes

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.

T217

34290-34465

Sentence

denotes

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-19.5.

T218

34467-34605

Sentence

denotes

In patients (outpatients or inpatients) with elevated LFTs in context of suspected or known COVID-19, evaluate for alternative etiologies.

T219

34606-34608

Sentence

denotes

6.

T220

34610-34834

Sentence

denotes

In hospitalized patients with suspected or known COVID-19, obtain baseline LFTs at the time of admission and consider LFT monitoring throughout the hospitalization, particularly in the context of drug treatment for COVID-19.

T221

34835-34837

Sentence

denotes

7.

T222

34839-34966

Sentence

denotes

In hospitalized patients undergoing drug treatment for COVID-19, evaluate for treatment-related Gl and hepatic adverse effects.

T223

34967-35141

Sentence

denotes

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.

T224

35142-35338

Sentence

denotes

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.

T225

35339-35561

Sentence

denotes

Also, many of the studies in this analysis did not report on how many patients had underlying liver disease and whether these patients were at an elevated risk of having increased LFTs in the setting of COVID-19 infection.

T226

35562-35712

Sentence

denotes

Furthermore, diagnostic evaluation of abnormal LFTs on admission was not performed routinely, such as testing for viral hepatitis or other etiologies.

T227

35713-36612

Sentence

denotes

The available studies suggest that abnormal LFTs are more commonly attributable to secondary effects (eg, systemic inflammatory response syndrome, cytokine storm, ischemic hepatitis/shock, sepsis, and 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 (odds ratio, 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.

T228

36613-36747

Sentence

denotes

We additionally advise that all patients with abnormal LFTs undergo an evaluation to investigate non–COVID-19 causes of liver disease.

T229

36749-36827

Sentence

denotes

What Are Common Gastrointestinal/Liver Adverse Effects of COVID-19 Treatments?

T230

36828-36925

Sentence

denotes

`There are currently no US Food and Drug Administration–approved routine treatments for COVID-19.

T231

36926-37148

Sentence

denotes

The FDA has issued an emergency use authorization for 3 therapies: choloroquine or hydroxychloroquine, remdesivir, and convalescent plasma.82 In China and Japan, favipiravir has been approved for the treatment of COVID-19.

T232

37149-37482

Sentence

denotes

Numerous medications are under investigation; the World Health Organization is spearheading a multinational, multicenter trial for the 5 treatments highlighted below.83 We aim to provide a summary of the Gl and liver adverse effects of the most commonly utilized medications for COVID-19 at this time, irrespective of their efficacy.

T233

37483-37623

Sentence

denotes

Medication GI-related adverse events are summarized in Supplementary Tables 1 and 2 (direct evidence sources and indirect evidence sources).

T234

37625-37649

Sentence

denotes

Antimalarial Medications

T235

37650-37961

Sentence

denotes

Although efficacy and subsequent optimal dosing in COVID-19 is still under investigation, both chloroquine and hydroxychloroquine are currently FDA-approved in the United States for other indications (ie, malaria and systemic lupus erythematosus) and now have an emergency use authorization for use in COVID-19.

T236

37963-37997

Sentence

denotes

Chloroquine and hydroxychloroquine

T237

37998-38375

Sentence

denotes

Both chloroquines have reported infrequent Gl adverse effects (ie, nausea, vomiting, abdominal pain, and diarrhea).84 , 85 The National Institute of Health LiverTox resource rates both drugs with a 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.

T238

38376-38573

Sentence

denotes

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.

T239

38574-38625

Sentence

denotes

This is seen less commonly with hydroxychloroquine.

T240

38626-38785

Sentence

denotes

Such reactions are thought to be hypersensitivity reactions and there is no known cross-reactivity in liver injury between hydroxychloroquine and choloroquine.

T241

38786-38973

Sentence

denotes

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.

T242

38974-39110

Sentence

denotes

In addition, cardiac conduction defects leading to clinically relevant arrhythmias are an important adverse effect of these medications.

T243

39112-39133

Sentence

denotes

Antiviral Medications

T244

39135-39145

Sentence

denotes

Remdesivir

T245

39146-39239

Sentence

denotes

Limited data regarding GI adverse events are available, as phase 3 trials are still underway.

T246

39240-39563

Sentence

denotes

Based on studies regarding Ebola, there have been reports of elevated transaminases, although the severity and incidence have not been quantified.87 There is 1 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.

T247

39564-39708

Sentence

denotes

Five of 53 patients (9%) experienced diarrhea and 12 of 53 patients (23%) had reported elevations in hepatic enzymes associated with remdesivir.

T248

39709-39809

Sentence

denotes

Of 4 patients (8%) who discontinued treatment prematurely, 2 were due to elevated aminotransferases.

T249

39811-39830

Sentence

denotes

Lopinavir/ritonavir

T250

39831-39939

Sentence

denotes

The combination lopinavir/ritonavir is FDA-approved for the treatment of human immunodeficiency virus (HIV).

T251

39940-39994

Sentence

denotes

More recently, it was utilized to treat MERS and SARS.

T252

39995-40176

Sentence

denotes

There is 1 trial by Cao et al89 that randomized 199 hospitalized patients with severe COVID-19 to receive treatment to lopinavir/ritonavir (n = 99) or placebo (n = 100) for 14 days.

T253

40177-40568

Sentence

denotes

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 of 99) with nausea, 6.3% (6 of 99) with vomiting, 4.2% (4 of 99) with diarrhea, 4.2% (4 of 99) with abdominal discomfort, 4.2% (4 of 99) with reported stomach ache, and 4.2% (4 of 99) with diarrhea.

T254

40569-40678

Sentence

denotes

Additionally, there were 2 serious adverse events of acute gastritis, which both led to drug discontinuation.

T255

40679-40850

Sentence

denotes

When lopinavir/ritonavir is used in patients with HIV, diarrhea is the most common GI adverse events (10%–30%), with greater prevalence among those receiving higher doses.

T256

40851-40984

Sentence

denotes

Other GI adverse events in HIV are similar to Cao et al’s RCT, with nausea in 5%–15% and vomiting in 5%–10% of patients90 (Table 3 ).

T257

40985-41076

Sentence

denotes

Table 3 Gastrointestinal Treatment Adverse Effects of Currently Utilized COVID-19 Therapies

T258

41077-41153

Sentence

denotes

Medication type Medication name Adverse effects Major drug–drug interactions

T259

41154-41178

Sentence

denotes

Gastrointestinal Hepatic

T260

41179-41318

Sentence

denotes

Antimalarial ChloroquineHydroxychloroquine Nausea, vomiting, abdominal pain, and diarrhea reported; frequency not defined Likelihood score:

T261

41319-41391

Sentence

denotes

D (possible rare cause of clinically apparent liver injury).Description:

T262

41392-41429

Sentence

denotes

Rare elevations in aminotransferases.

T263

41430-41515

Sentence

denotes

Most reactions are hypersensitivity with no known cross reactivity to hepatic injury.

T264

41516-41583

Sentence

denotes

If this occurs, reasonable to switch between chloroquine therapies.

T265

41584-41676

Sentence

denotes

Substrate for CYP2D6 and CYP3A4 substrateSame as above; also substrate for CYP3A5 and CYP2C8

T266

41677-41753

Sentence

denotes

Antiviral Remdesivir Not reported (limited data available) Likelihood score:

T267

41754-41777

Sentence

denotes

Not scored.Description:

T268

41778-41827

Sentence

denotes

Hepatotoxicity reported; frequency not yet known.

T269

41828-41878

Sentence

denotes

Not a significant inducer/inhibitor of CYP enzymes

T270

41879-41919

Sentence

denotes

Lopinavir/ritonavir Nausea and vomiting:

T271

41920-41947

Sentence

denotes

5%–10% (higher in children:

T272

41948-41967

Sentence

denotes

20%)Abdominal pain:

T273

41968-41983

Sentence

denotes

1%–10%Diarrhea:

T274

41984-42049

Sentence

denotes

10%–30% + dose-dependentOther: dysguesia in adults <2%, children:

T275

42050-42087

Sentence

denotes

25%, increased serum amylase, lipase:

T276

42088-42094

Sentence

denotes

3%–8%.

T277

42095-42112

Sentence

denotes

Likelihood score:

T278

42113-42186

Sentence

denotes

D (possible, rare cause of clinically apparent liver injury).Description:

T279

42187-42368

Sentence

denotes

Hepatotoxicity ranges from mild elevations in aminotransferases to acute liver failure.Recovery takes 1–2 mo.Re-challenging may lead to recurrence and should be avoided if possible.

T280

42369-42483

Sentence

denotes

Substrate for: CYP3A4, CYP2D6P-gpInducer for: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A1Inhibitor for: CYP3A4

T281

42484-42512

Sentence

denotes

Favipiravir Nausea/vomiting:

T282

42513-42528

Sentence

denotes

5%–15%Diarrhea:

T283

42529-42571

Sentence

denotes

5%Limited data available Likelihood score:

T284

42572-42594

Sentence

denotes

Not scoredDescription:

T285

42595-42633

Sentence

denotes

3% prevalence, but few data available.

T286

42634-42728

Sentence

denotes

Inhibitor for: CYP2C8 and aldehyde oxidaseMetabolized by xanthine oxidase and aldehyde oxidase

T287

42729-42850

Sentence

denotes

The Cao et al89 RCT did not show a significant increase in hepatotoxicity in the treatment compared to the control group.

T288

42851-43234

Sentence

denotes

However, in patients with HIV, there is a well-documented 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 5 times the ULN, are found in 3%–10%.91 Rates may be higher in patients with concurrent HIV and hepatitis C virus co-infection.

T289

43235-43459

Sentence

denotes

In some cases, mild asymptomatic elevations are self-limited and can resolve with continuation of the medication, but re-challenging the medication can also lead to recurrence and, therefore, should be avoided when possible.

T290

43460-43508

Sentence

denotes

Acute liver failure, although reported, is rare.

T291

43509-43656

Sentence

denotes

Ritonavir has potent effects on cytochrome P450 and therefore affects drug levels of a large number of medications typically given in GI practices.

T292

43658-43669

Sentence

denotes

Favipiravir

T293

43670-43727

Sentence

denotes

There are 2 published studies on favipiravir in COVID-19.

T294

43728-43968

Sentence

denotes

The first is an open-label RCT for favipiravir vs arbidol conducted in Wuhan, China by Chen et al.92 This study reported digestive tract reactions, including nausea, “anti-acid,” or flatulence in 13.79% (16 of 116) of the favipiravir group.

T295

43969-44062

Sentence

denotes

Hepatotoxicity characterized by any elevation in AST or ALT was reported in 7.76% (9 of 116).

T296

44063-44328

Sentence

denotes

The second is an open-label control study of favipiravir or lopinavir/ritonavir, both used in conjunction with interferon alfa, for COVID-19 by Cai et al,93 which reported diarrhea in 5.7% (2 of 35) and liver injury in 2.9% (1 of 35) (Supplementary Tables 2 and 3).

T297

44330-44438

Sentence

denotes

Limitations of the Evidence on Gastrointestinal and Liver Manifestations in Patients With COVID-19 Infection

T298

44439-44504

Sentence

denotes

The individual studies in our analysis were at high risk of bias.

T299

44505-44646

Sentence

denotes

The majority of studies reported on cohorts of patients based on inclusion dates and did not specify whether these were consecutive patients.

T300

44647-44848

Sentence

denotes

There was an inconsistent assessment of symptoms and/or laboratory tests with missing data, and none of the studies reported whether patients were systematically evaluated for GI symptoms on admission.

T301

44849-44939

Sentence

denotes

Most studies did not report on the duration of the GI symptoms preceding the presentation.

T302

44940-45144

Sentence

denotes

When GI symptoms were reported, it was difficult to discern whether these were isolated symptoms or whether patients also had concurrent typical COVID-19 symptoms (eg, fever cough or shortness of breath).

T303

45145-45263

Sentence

denotes

LFTs were mostly reported as the mean/median value of the entire cohort and without cutoff values for the institution.

T304

45264-45342

Sentence

denotes

Many of the studies did not report on underlying chronic GI or liver diseases.

T305

45343-45482

Sentence

denotes

There was a lot of heterogeneity in our pooled estimates that could not be explained by our subgroup analysis based on geographic location.

T306

45483-45678

Sentence

denotes

Lastly, the data on prognosis were 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).

T307

45679-45844

Sentence

denotes

Finally, there was no stratification of GI-related symptoms and severity of COVID-19 or patient important outcomes, such as need for intensive care unit or survival.

T308

45845-45919

Sentence

denotes

There may be additional limitations of our findings based on our analysis.

T309

45920-46124

Sentence

denotes

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.

T310

46125-46294

Sentence

denotes

It is possible that we excluded relevant studies that provided more granularity regarding the GI and liver manifestations, or had more systematic assessment of outcomes.

T311

46295-46388

Sentence

denotes

As a result, this may have led to an over- or underestimation of the pooled effect estimates.

T312

46389-46597

Sentence

denotes

However, we have high confidence that we were able to eliminate the counting of some patients in more than 1 report by using our selection framework, unless they were transferred from one hospital to another.

T313

46598-46699

Sentence

denotes

An important strength of this study is the appropriate statistical analysis used to pool proportions.

T314

46700-46941

Sentence

denotes

We also reviewed gray literature from prepublication 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.

T315

46942-47168

Sentence

denotes

Lastly, we tried to narratively describe studies that informed us on the type of diarrhea symptoms; whether diarrhea was reported as the only presenting symptom; or diarrhea as the initial symptom that preceded other symptoms.

T316

47169-47454

Sentence

denotes

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 preprint servers.

T317

47456-47524

Sentence

denotes

Limitations of Current Evidence on Treatment-Related Adverse Effects

T318

47525-47716

Sentence

denotes

Most of the information regarding Gl adverse events come from indirect evidence from medications that are FDA-approved for other indications, such as the chloroquines and lopinavir/ritonavir.

T319

47717-47912

Sentence

denotes

In particular, Gl adverse events are poorly understood for both favipiravir and remdesivir, including the frequency and severity of aminotransferase elevations and incidence of Gl manifestations.

T320

47913-48041

Sentence

denotes

As ongoing clinical trials are completed regarding efficacy of therapy, additional data regarding Gl adverse events will emerge.

T321

48043-48082

Sentence

denotes

Evidence Gaps and Guidance for Research

T322

48083-48299

Sentence

denotes

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.

T323

48300-48639

Sentence

denotes

Early data do not indicate excess risk among patients with inflammatory bowel disease.94, 95, 96, 97, 98 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).

T324

48640-48761

Sentence

denotes

Other clinical decisions, including optimal medication management and treatment decisions, are still under investigation.

T325

48762-48877

Sentence

denotes

We encourage clinicians to contribute to these registries to further enhance understanding in these subpopulations.

T326

48878-48997

Sentence

denotes

Table 4 provides guidance for future studies of GI manifestations in patients with COVID-19 or other similar pathogens.

T327

48998-49074

Sentence

denotes

Table 4 Guidance and Research Considerations for Future Studies of COVID-19a

T328

49075-49294

Sentence

denotes

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.

T329

49295-49657

Sentence

denotes

Participants 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 upper respiratory infection symptoms (eg, cough, shortness of breath, chest pain, and fever)

T330

49658-49826

Sentence

denotes

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

T331

49827-50009

Sentence

denotes

• Describe the GI symptoms in detail, including initial vs late, concurrent vs isolated, duration and frequency, history, and medication initiation relating to the onset of symptoms.

T332

50010-50115

Sentence

denotes

Investigators should avoid:• Undefined sampling (convenience sampling), including undefined time periods.

T333

50116-50273

Sentence

denotes

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

T334

50274-50462

Sentence

denotes

Investigators should consider stratification for GI comorbidities, such as inflammatory bowel disease and cirrhosisInvestigators should consider stratification by outpatients vs inpatients

T335

50463-51301

Sentence

denotes

Laboratory Standardized laboratory confirmation should be based on nucleic acid amplification testing for SARS-CoV-2 on respiratory specimen rather than relying on radiologic suspicion on imaging studies, which are less specificLFTs should be obtained on admission and followed throughout the hospitalization.Changes in LFTs should be reported as normal/abnormal and the cutoff for abnormal should be specified, rather than mean and median at the individual patient levelPattern of LFTs abnormalities, hepatocellular vs cholestatic, should be reported as well as the evaluation performed to work up the abnormalitiesBaseline LFTs (prior to developing COVID-19), changes during the duration of the disease, and after resolution should be reported.Report stool RNA testing, when available, and presence of GI symptoms at the time of testing

T336

51302-51490

Sentence

denotes

Disease severity Use of standardized disease severity definitions, for example, as per World Health Organization–China Joint Mission100:• mild-to-moderate: non-pneumonia and mild pneumonia

T337

51491-51583

Sentence

denotes

• severe defined as tachypnea, oxygen saturation ≤93% at rest, or PaO2/FiO2 ratio <300 mm Hg

T338

51584-51729

Sentence

denotes

• critical respiratory failure requiring mechanical ventilation, septic shock, or other organ dysfunction or failure that requires intensive care

T339

51730-51806

Sentence

denotes

Patients can be stratified by:• Disease severity and presence of GI symptoms

T340

51807-51834

Sentence

denotes

• Disease severity and LFTs

T341

51835-51933

Sentence

denotes

Symptoms and their duration before development of a severe stage of the disease should be reported

T342

51934-52220

Sentence

denotes

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

T343

52221-52462

Sentence

denotes

Analysis Analysis should attempt to control for confounding variables; analysis of risk factors should include univariate followed by multivariate analyses to identify independent risk factors predicting more severe disease and poor outcomes

T344

52463-52660

Sentence

denotes

a aIn 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.

T345

52661-52743

Sentence

denotes

Finally, peer-review remains critical to the process of disseminating information.

T346

52744-53055

Sentence

denotes

Journals should add resources to expedite reviews by increasing the number of editors and reviewers to shorten the review process; 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.99

T347

53057-53063

Sentence

denotes

Update

T348

53064-53133

Sentence

denotes

Recommendations in this document may not be valid in the near future.

T349

53134-53268

Sentence

denotes

We will conduct periodic reviews of the literature and monitor the evidence to determine whether recommendations require modification.

T350

53269-53397

Sentence

denotes

Based on the rapidly evolving nature of this pandemic, this guideline will likely need to be updated within the next few months.

T351

53399-53410

Sentence

denotes

Conclusions

T352

53411-53608

Sentence

denotes

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, and multiorgan failure.

T353

53609-53822

Sentence

denotes

Although fever, cough, and shortness of breath remain the most common presenting symptoms in affected individuals, emerging data suggest that nonpulmonary symptoms affecting the GI tract and liver may be observed.

T354

53823-54164

Sentence

denotes

Based on systematic review and meta-analysis of 47 studies and 10,890 unique patients, gastrointestinal symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea) are observed in <10% of patients with COVID-19, and abnormal liver enzymes and tests (AST, ALT, and bilirubin) are observed in approximately 15%–20% of patients with COVID-19.

T355

54165-54380

Sentence

denotes

These findings inform time-sensitive clinical guidance in the context of this pandemic to pursue careful evaluation of patients with new-onset gastrointestinal symptoms for classic and atypical symptoms of COVID-19.

T356

54381-54542

Sentence

denotes

All hospitalized patients with COVID-19 may benefit from liver enzyme monitoring, particularly in the context of drug treatment with known hepatotoxic potential.

T357

54543-54682

Sentence

denotes

Further research is needed to clarify the implications of SARS-CoV-2 in stool and potential impact on transmission and clinical management.

T358

54684-54706

Sentence

denotes

Supplementary Material

T359

54707-54751

Sentence

denotes

Supplement Figure 1 PRISMA 2009 Flow Diagram

T360

54752-54831

Sentence

denotes

Supplementary Figure 2 The matrix used in the selection of the Chinese studies.

T361

54832-54866

Sentence

denotes

The X-axis represents the studies.

T362

54867-54924

Sentence

denotes

The Y axis represent the hospitals included in the study.

T363

54925-54993

Sentence

denotes

The size of the bubble reflects the number of patients in the study.

T364

54994-55183

Sentence

denotes

Two studies by Guan et al101,102 were not included in the plot as they included patients from more than 500 hospitals from 30 or more provinces without providing the names of the hospitals.

T365

55184-55311

Sentence

denotes

Supplementary Figure 3 Forest plot of the prevalence of diarrhea in all admitted patients regardless of the timing of diarrhea.

T366

55312-55461

Sentence

denotes

Supplementary Figure 4 Forest plot of the prevalence of diarrhea as one of the initial symptoms in all patients regardless of hospitalization status.

T367

55462-55583

Sentence

denotes

Supplementary Figure 5 Forest plot of the prevalence of diarrhea as one of the initial symptoms in all admitted patients.

T368

55584-55701

Sentence

denotes

Supplementary Figure 6 Forest plot of the prevalence of diarrhea in outpatients regardless of the timing of diarrhea.

T369

55702-55858

Sentence

denotes

Supplementary Figure 7 Forest plot of the prevalence of nausea/vomiting as one of the initial symptoms in all patients regardless of hospitalization status.

T370

55859-56014

Sentence

denotes

Supplementary Figure 8 Forest plot of the prevalence of abdominal pain as one of the initial symptoms in all patients regardless of hospitalization status.

T371

56015-56084

Sentence

denotes

Supplementary Figure 9 Forest plot of the prevalence of elevated AST.

T372

56085-56155

Sentence

denotes

Supplementary Figure 10 Forest plot of the prevalence of elevated ALT.

T373

56156-56238

Sentence

denotes

Supplementary Figure 11 Forest plot of the prevalence of elevated total bilirubin.

T374

56239-56288

Sentence

denotes

Supplementary Table 1 Summary of Included Studies

T375

56289-56388

Sentence

denotes

Study characteristics Patient characteristics Gastrointestinal manifestations Liver Manifestationsa

T376

56389-56410

Sentence

denotes

Hubei Province, China

T377

56411-56454

Sentence

denotes

Luo, 202050Zhongnan Hospital (Wuhan)Dates:

T378

56455-56512

Sentence

denotes

01/01/2020-02/20/2020Last follow-up: NR n = 1141Survival:

T379

56513-56558

Sentence

denotes

3.8% (7/183) death, 96.2% recoveredInclusion:

T380

56559-56605

Sentence

denotes

Inpatients with COVID-19 (throat swab RT-PCR).

T381

56606-56637

Sentence

denotes

All patients received chest CT.

T382

56638-56730

Sentence

denotes

Details only provided for the 183 patients with GI symptoms.Age: m 53.8 y (183 patients)Sex:

T383

56731-56809

Sentence

denotes

44.3% (81/183) femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T384

56810-56858

Sentence

denotes

6.0% (n = 68)Present on admissionAbdominal pain:

T385

56859-56899

Sentence

denotes

3.9% (n = 45)Present on admissionNausea:

T386

56900-56944

Sentence

denotes

11.7% (n = 134)Present on admissionVomiting:

T387

56945-56996

Sentence

denotes

10.4% (119)Present on admissionNausea and vomiting:

T388

56997-57145

Sentence

denotes

3.2% (n = 37)Present on admission183 patients presented with GI symptoms only (diarrhea, abdominal pain, nausea, vomiting, and/or loss of appetite).

T389

57146-57251

Sentence

denotes

96% of them had lung lesions on chest CT AST (183 patients) m 65.8 ± 12.7ALT (183 patients) m 66.4 ± 13.2

T390

57252-57297

Sentence

denotes

Zhou, 202020Jinyintan Hospital (Wuhan)Dates:

T391

57298-57334

Sentence

denotes

12/29/2019-01/31/2020Last follow-up:

T392

57335-57362

Sentence

denotes

01/31/2020 n = 191Survival:

T393

57363-57402

Sentence

denotes

28.3% death, 71.8% dischargedInclusion:

T394

57403-57480

Sentence

denotes

Inpatients with COVID-19 (confirmed with RT-PCR) who died or were discharged.

T395

57481-57531

Sentence

denotes

Patients without key information excluded (9).Age:

T396

57532-57557

Sentence

denotes

M 56 y (IQR, 46–67 y)Sex:

T397

57558-57614

Sentence

denotes

37.7% femalesGI/liver comorbidities: NRDisease severity:

T398

57615-57635

Sentence

denotes

General 28%, severe:

T399

57636-57663

Sentence

denotes

35%, critical 28% Diarrhea:

T400

57664-57735

Sentence

denotes

4.7% (9/191)Present on admission2 died and 7 dischargedNausea/vomiting:

T401

57736-57825

Sentence

denotes

3.7% (7/191)Present on admission3 died and 4 dischargedAbdominal pain: NR AST: NRALT >40:

T402

57826-57884

Sentence

denotes

31.2% (59/189)26 died and 33 dischargedTotal bilirubin: NR

T403

57885-57908

Sentence

denotes

Zhang, 202023Wuhan No.

T404

57909-57933

Sentence

denotes

7 Hospital (Wuhan)Dates:

T405

57934-58002

Sentence

denotes

1/16/2020-02/03/2020Last follow-up: NR n = 140Survival: NRInclusion:

T406

58003-58087

Sentence

denotes

Inpatient with COVID-19 (pharyngeal swab PCR) based on symptoms and chest x-ray.Age:

T407

58088-58113

Sentence

denotes

57 y (range, 25–87 y)Sex:

T408

58114-58150

Sentence

denotes

49.3% femalesGI/liver comorbidities:

T409

58151-58401

Sentence

denotes

5.7% fatty liver and abnormal liver function, 5.0% chronic gastritis and gastric ulcer, 4.3% cholelithiasis, 6.4% cholecystectomy 5.0% appendectomy, 0.7% hemorrhoidectomy, 4.3% tumor surgeryDisease severity: severe 41.4% and nonsevere 58.6% Diarrhea:

T410

58402-58485

Sentence

denotes

12.9% (18/139)Present on admission9/82 nonsevere cases and 9/57 severe casesNausea:

T411

58486-58572

Sentence

denotes

17.3% (24/139)Present on admission19/82 nonsevere cases and 5/57 severe casesVomiting:

T412

58573-58745

Sentence

denotes

5.0% (7/139)Present on admission5/82 nonsevere cases and 2/57 severe casesBelching 5.0% (7/139)Present on admission4/82 nonsevere cases and 3/57 severe casesAbdominal pain:

T413

58746-58946

Sentence

denotes

5.8% (8/139)Present on admission2/82 nonsevere cases and 6/57 severe casesOther pathogens were detected including Mycoplasma pneumoniae in 5, respiratory syncytial virus in 1, Epstein-Barr virus in 1.

T414

58947-58974

Sentence

denotes

AST, ALT, and bilirubin: NR

T415

58975-59017

Sentence

denotes

Chen, 202072Tongji Hospital (Wuhan)Dates:

T416

59018-59054

Sentence

denotes

01/13/2020-02/12/2020Last follow-up:

T417

59055-59082

Sentence

denotes

02/28/2020 n = 274Survival:

T418

59083-59121

Sentence

denotes

52.2% death, 47.8% recoveredInclusion:

T419

59122-59267

Sentence

denotes

Moderate severity, severe or critically ill COVID-19 patients (throat swab or bronchoalveolar lavage RT-PCR) who were deceased or discharged.Age:

T420

59268-59296

Sentence

denotes

M 62.0 y (IQR, 44–70 y) sex:

T421

59297-59332

Sentence

denotes

37.6% femaleGI/liver comorbidities:

T422

59333-59452

Sentence

denotes

4% hepatitis B surface antigen positivity, 1% GI diseasesDisease severity: moderate severity, severe or critically ill.

T423

59453-59462

Sentence

denotes

Diarrhea:

T424

59463-59541

Sentence

denotes

28.1% (n = 77)Present on admission27/113 deceased and 50/161 dischargedNausea:

T425

59542-59620

Sentence

denotes

8.8% (n = 24)Present on admission8/113 deceased and 16/161 dischargedVomiting:

T426

59621-59705

Sentence

denotes

5.8% (n = 16)Present on admission6/113 deceased and 10/161 dischargedAbdominal pain:

T427

59706-59784

Sentence

denotes

6.9% (n = 19)Present on admission6/113 deceased and 13/161 discharged AST >40:

T428

59785-59850

Sentence

denotes

30.7% (84)59/113 deceased and 25/161 dischargedM 30 (IQR, 22–46).

T429

59851-59918

Sentence

denotes

Deceased M 45 (IQR, 31–67) and discharged M 25 (IQR, 20–33)ALT >41:

T430

59919-59984

Sentence

denotes

21.9% (60)30/113 deceased and 30/161 dischargedM 23 (IQR, 15–38).

T431

59985-60074

Sentence

denotes

Deceased M 28 (IQR, 18–47) and discharged M 20 (IQR, 15–32)BilirubinM 0.6 (IQR, 0.4–0.8).

T432

60075-60140

Sentence

denotes

Deceased M 0.7 (IQR, 0.6–1.0) and discharged M 0.5 (IQR, 0.3–0.7)

T433

60141-60181

Sentence

denotes

Xu, 202031Tongji Hospital (Wuhan)Dates:

T434

60182-60250

Sentence

denotes

1/15/2020-2/19/2020Last follow-up: NR n = 1324Survival: NRInclusion:

T435

60251-60343

Sentence

denotes

Outpatient COVID-19 patients presenting to fever clinic, based on PCR.Age: m 48 ± 15.3 ySex:

T436

60344-60400

Sentence

denotes

50.8% femalesGI/liver comorbidities: NRDisease severity:

T437

60401-60460

Sentence

denotes

95.9% light condition, 3.8% severe, 0.3% critical Diarrhea:

T438

60461-60507

Sentence

denotes

2.1% (28)Present on admissionLoss of appetite:

T439

60508-60575

Sentence

denotes

4.2%Present on admissionNausea, vomiting, and abdominal pain: NR NR

T440

60576-60617

Sentence

denotes

Shi, 202042Renmin Hospital (Wuhan)Dates:

T441

60618-60651

Sentence

denotes

1/1/2020-2/10/2020Last follow-up:

T442

60652-60678

Sentence

denotes

2/15/2020 n = 645Survival:

T443

60679-60731

Sentence

denotes

7.3% death, 5.1% discharged (416 patients)Inclusion:

T444

60732-60785

Sentence

denotes

Inpatient laboratory-confirmed COVID-19, consecutive.

T445

60786-60855

Sentence

denotes

Detailed results reported for 416 patients with complete results.Age:

T446

60856-60886

Sentence

denotes

M 45–64 y (range, 21–95 y)Sex:

T447

60887-60922

Sentence

denotes

52.9% femaleGI/liver comorbidities:

T448

60923-60987

Sentence

denotes

1% hepatitis B infection (of 416 patients)Severity: NR Diarrhea:

T449

60988-61139

Sentence

denotes

4.5% (29)Present on admissionAbdominal pain, nausea, vomiting: NR AST (416 patients)M 30 (IQR, 22–43).ALT (416 patients)M 28 (IQR, 18–46).Bilirubin: NR

T450

61140-61177

Sentence

denotes

Han, 202062Wuhan No.1 HospitalDates:

T451

61178-61263

Sentence

denotes

1/4/2020-2/3/2020Last follow-up: NR n = 108Survival: NR death, NR recoveredInclusion:

T452

61264-61543

Sentence

denotes

Inpatients COVID-19 (confirmed by RT-PCR) with mild pneumonia, no history of other lung infection, initial CT performed.Exclusion: CT scans performed as follow-up for COVID-19 pneumonia, or chest CT image quality insufficient for image analysisAge: mean 45 y (range, 21–90 y)Sex:

T453

61544-61580

Sentence

denotes

64.8% femalesGI/liver comorbidities:

T454

61581-61624

Sentence

denotes

Not specifiedDisease severity: NR Diarrhea:

T455

61625-61701

Sentence

denotes

14% (15/108)Abdominal pain, nausea, vomiting: NR No laboratory data reported

T456

61702-61741

Sentence

denotes

Xu, 202030Union Hospital (Wuhan)Dates:

T457

61742-61776

Sentence

denotes

1/25/2020-2/20/2020Last follow-up:

T458

61777-61816

Sentence

denotes

2/20/2020 n = 355Survival: NRInclusion:

T459

61817-61873

Sentence

denotes

Inpatients with COVID-19, confirmed based on RT-PCR.Age:

T460

61874-61932

Sentence

denotes

45.1% aged <50 y, 41.7% aged 50–69 y, 13.2% aged ≥70 ySex:

T461

61933-61989

Sentence

denotes

45.6% femalesGI/liver comorbidities: NRDisease severity:

T462

61990-62038

Sentence

denotes

63.1% mild, 16.9% severe, 20% critical Diarrhea:

T463

62039-62094

Sentence

denotes

36.6% (130/355)Abdominal pain, nausea, vomiting NR AST:

T464

62095-62137

Sentence

denotes

28.7% (102/355) m 40.8 (range, 10–475)ALT:

T465

62138-62190

Sentence

denotes

25.6% (91/355) m 35.0 (range, 1–414)Total bilirubin:

T466

62191-62230

Sentence

denotes

18.6% (66/355) m 0.83 (range, 0.1–29.9)

T467

62231-62282

Sentence

denotes

Ma, 202049Wuhan Leishenshan Hospital (Wuhan)Dates:

T468

62283-62348

Sentence

denotes

3/5/2020-3/18/2020Last follow-up: NR n = 81Survival: NRInclusion:

T469

62349-62416

Sentence

denotes

Inpatients with COVID-19 (RT-PCR on nasal and pharyngeal swabs)Age:

T470

62417-62446

Sentence

denotes

M 38 y (IQR, 34.5–42.5 y)Sex:

T471

62447-62499

Sentence

denotes

0% femaleGI/liver comorbidities: NRDisease severity:

T472

62500-62554

Sentence

denotes

2.5% mild, 86.4% moderate, 8.6% severe, 2.5% critical.

T473

62555-62564

Sentence

denotes

Diarrhea:

T474

62565-62730

Sentence

denotes

7.41% (6/81)Nausea/vomiting: NRAbdominal pain: NR AST/ALT - composite report 31/81 abnormal but no thresholdAST M 23 (IQR, 12–453)ALT M 43 (IQR, 13–799)Bilirubin: NR

T475

62731-62807

Sentence

denotes

Liu, 202054General Hospital of Central Theater Command of PLA (Wuhan)Dates:

T476

62808-62949

Sentence

denotes

2/6/2020 - 2/14/2020Last follow-up: NR n = 153 (85 tested negative but had symptoms, we did not include those patients)Survival: NRInclusion:

T477

62950-63007

Sentence

denotes

Inpatients with COVID-19 (RT-PCR on pharyngeal swabs)Age:

T478

63008-63103

Sentence

denotes

M 55 y (IQR, 38.3–65 y)Sex:39.2% femaleGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T479

63104-63144

Sentence

denotes

9.2% (14/153)Present on admissionNausea:

T480

63145-63186

Sentence

denotes

1.3% (2/153)Present on admissionVomiting:

T481

63187-63232

Sentence

denotes

2% (3/153)Present on admissionAbdominal pain:

T482

63233-63293

Sentence

denotes

0.4% (1/153)Present on admission AST, ALT, and bilirubin: NR

T483

63294-63349

Sentence

denotes

Huang, 202061The Fifth Hospital of Wuhan (Wuhan)Dates:

T484

63350-63384

Sentence

denotes

1/21/2020-2/10/2020Last follow-up:

T485

63385-63410

Sentence

denotes

2/14/2020 n = 36Survival:

T486

63411-63431

Sentence

denotes

100% deathInclusion:

T487

63432-63583

Sentence

denotes

Inpatients with COVID-19 (RT-PCR)Age: mean 69.22 y (SD 9.64 y; range, 50–90 y)Sex:30.56% femaleGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T488

63584-63783

Sentence

denotes

8.33% (3/36)Present on admissionNausea: NRVomiting: NRAbdominal pain: NR AST: >40 58.1% (18/31)M 43 (IQR, 30–51)ALT: >50 13.3% (4/30)M 26 (IQR, 18–38)Bilirubin: >25 12.9% (4/31)M 11.2 (IQR, 7.5–19.2)

T489

63784-63824

Sentence

denotes

Mao, 202048Union Hospital (Wuhan)Dates:

T490

63825-63879

Sentence

denotes

1/16/2020-2/19/2020Last follow-up: NR n = 214Survival:

T491

63880-63920

Sentence

denotes

1 died but not fully reported.Inclusion:

T492

63921-63990

Sentence

denotes

Inpatients with COVID-19 (RT-PCR from throat)Age: m 52.7 ± 15.5 ySex:

T493

63991-64046

Sentence

denotes

59.3% femaleGI/liver comorbidities: NRDisease severity:

T494

64047-64086

Sentence

denotes

58.9% nonsevere, 41.1% severe Diarrhea:

T495

64087-64198

Sentence

denotes

19.2% (41/214)Present on admissionSevere disease 14.8% (13/88), nonsevere disease 22.2% (28/126)Abdominal pain:

T496

64199-64458

Sentence

denotes

4.7% (10/214), not included in the analysisPresent on admissionSevere disease 6.8% (6/88), nonsevere disease 3.2% (4/126)Nausea and vomiting: NR AST 26 (8–8191)Severe 34 (8–8191), non-severe 23 (9–244)ALT 26 (5–1933)Severe 32.5 (5–1933), non-severe 23 (6–261)

T497

64459-64508

Sentence

denotes

Ai, 202076Xiangyang No.1 People’s HospitalDates:

T498

64509-64556

Sentence

denotes

Cross-sectional study 2/9/2020 n = 102Survival:

T499

64557-64617

Sentence

denotes

2.9% died, 6.9% survived, 90.2% still hospitalizedInclusion:

T500

64618-64687

Sentence

denotes

Inpatients with laboratory-confirmed COVID-19Age: m 50.4 ± 16.9 ySex:

T501

64688-64757

Sentence

denotes

49.1% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T502

64758-64839

Sentence

denotes

14.3% (15)Present on admissionDiarrhea was the first symptom in 2 patientsNausea:

T503

64840-64877

Sentence

denotes

8.8% (9)Present on admissionVomiting:

T504

64878-64921

Sentence

denotes

2.0% (2)Present on admissionAbdominal pain:

T505

64922-64959

Sentence

denotes

2.9% (3)Present on admission AST >40:

T506

64960-65003

Sentence

denotes

25.5% (26/102)Mean 30.59 (SD 15.03)ALT >50:

T507

65004-65057

Sentence

denotes

19.6% (20/102)Mean 27.77 (SD 21.13)Total bilirubin NR

T508

65058-65109

Sentence

denotes

Liu, 202052Central Hospital of Wuhan (Wuhan)Dates:

T509

65110-65162

Sentence

denotes

1/2/2020-2/1/2020Last follow-up: NR n = 109Survival:

T510

65163-65197

Sentence

denotes

28.4% died, NR otherwiseInclusion:

T511

65198-65266

Sentence

denotes

Inpatient with COVID-19 confirmed based on RT-PCR on throat swabAge:

T512

65267-65297

Sentence

denotes

M 62.5 y (IQR, 47.25–65 y)Sex:

T513

65298-65367

Sentence

denotes

33.3% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T514

65368-65603

Sentence

denotes

11% (12)Present on admission6/12 with ARDS and 6/12 with no ARDSNausea, vomiting and abdominal pain: NR AST:M 30 (IQR, 21–40)No ARDS 29 (19–38); ARDS 31 (25–44)ALT:M 23 (IQR, 15–36)No ARDS 23 (14–41); ARDS 24 (16–31)Total bilirubin: NR

T515

65604-65661

Sentence

denotes

Shu, 202041Cabin Hospital of Wuhan Stadium (Wuhan)Dates:

T516

65662-65716

Sentence

denotes

2/13/2020-2/29/2020Last follow-up: NR n = 545Survival:

T517

65717-65778

Sentence

denotes

85.9% discharged, 14.1% still hospitalized, 0% diedInclusion:

T518

65779-65829

Sentence

denotes

Inpatient with COVID-19 confirmed based on RT-PCR.

T519

65830-65880

Sentence

denotes

Severe cases requiring transfer were excluded.Age:

T520

65881-65906

Sentence

denotes

M 50 y (IQR, 38–58 y)Sex:

T521

65907-65943

Sentence

denotes

51.2% femalesGI/liver comorbidities:

T522

65944-65984

Sentence

denotes

0 chronic liver diseaseDisease severity:

T523

65985-66032

Sentence

denotes

2.9% mild, 97.1% moderate, 0 severe (excluded).

T524

66033-66042

Sentence

denotes

Diarrhea:

T525

66043-66091

Sentence

denotes

8.9% (49)Present on admissionNausea or vomiting:

T526

66092-66127

Sentence

denotes

0% (0)Present on admission AST >45:

T527

66128-66168

Sentence

denotes

6.4% (35)M 32.1 (IQR, 24.5–36.4)ALT >50:

T528

66169-66216

Sentence

denotes

7.5% (41)M 34.6 (IQR, 26.2–42.3)Bilirubin >1.2:

T529

66217-66248

Sentence

denotes

34.7% (189)M 1.1 (IQR, 0.8–1.3)

T530

66249-66329

Sentence

denotes

Wei, 202034Wuhan Integrated Chinese and Western Medicine Hospital (Wuhan)Dates:

T531

66330-66383

Sentence

denotes

2/1/2020-2/28/2020Last follow-up: NR n = 100Survival:

T532

66384-66441

Sentence

denotes

3% died, 1% discharged, 96% still hospitalized.Inclusion:

T533

66442-66493

Sentence

denotes

Inpatients with COVID-19 confirmed based on RT-PCR.

T534

66494-66534

Sentence

denotes

Only mild cases.Age: m 49.1 ± 17.2 ySex:

T535

66535-66569

Sentence

denotes

60% femalesGI/liver comorbidities:

T536

66570-66637

Sentence

denotes

9% digestive system diseases, 6% chronic gastritisDisease severity:

T537

66638-66648

Sentence

denotes

100% mild.

T538

66649-66658

Sentence

denotes

Diarrhea:

T539

66659-66694

Sentence

denotes

2% (2)Present on admissionVomiting:

T540

66695-66735

Sentence

denotes

2% (2)Present on admission AST elevated:

T541

66736-66755

Sentence

denotes

5 (5%)ALT elevated:

T542

66756-66789

Sentence

denotes

17 (17%)Total bilirubin abnormal:

T543

66790-66796

Sentence

denotes

0 (0%)

T544

66797-66820

Sentence

denotes

Other Chinese Provinces

T545

66821-66938

Sentence

denotes

Chen, 202073The First Affiliated Hospital of Wanan Medical College (Wuhu)AnhuiDates: NA (Case series) n = 9Survival:

T546

66939-66964

Sentence

denotes

100% dischargedInclusion:

T547

66965-67041

Sentence

denotes

Inpatients with COVID-19 confirmed on RT-PCR via swabAge: range, 25–56 ySex:

T548

67042-67098

Sentence

denotes

44.4% femalesGI/liver comorbidities: NRDisease severity:

T549

67099-67152

Sentence

denotes

55.6% moderately ill and 44.4% severely ill Diarrhea:

T550

67153-67178

Sentence

denotes

22.2% (2)Nausea/vomiting:

T551

67179-67200

Sentence

denotes

0% (0)Abdominal pain:

T552

67201-67235

Sentence

denotes

0% (0) AST, ALT, and bilirubin: NR

T553

67236-67342

Sentence

denotes

Zhao, 202021First Affiliated Hospital of University of Science and Technology of China (Hefei)AnhuiDates:

T554

67343-67409

Sentence

denotes

1/21/2020-2/16/2020Last follow-up: NR n = 75Survival: NRInclusion:

T555

67410-67455

Sentence

denotes

Inpatients with COVID-19 based on RT-PCR.Age:

T556

67456-67481

Sentence

denotes

M 47 y (IQR, 34–55 y)Sex:

T557

67482-67573

Sentence

denotes

44% femalesGI/liver comorbidities: chronic liver disease 5.3%Disease severity: NR Diarrhea:

T558

67574-67617

Sentence

denotes

9.3% (7)Present on admissionAbdominal pain:

T559

67618-67675

Sentence

denotes

1.3% (1)Present on admissionNausea/vomiting: NR AST > 40:

T560

67676-67711

Sentence

denotes

18.7% (14)M 27 (IQR, 21–37)ALT >40:

T561

67712-67752

Sentence

denotes

20% (15)M 23 (IQR, 14–43)Bilirubin >1.2:

T562

67753-67879

Sentence

denotes

16% (12)M 0.85 (IQR, 0.65–1.06)ALT, ALT, and total bilirubin were not associated with elevated interleukin-6 (a study outcome)

T563

67880-67928

Sentence

denotes

Zhao, 202022Beijing YouAn HospitalBeijingDates:

T564

67929-67962

Sentence

denotes

1/21/2020-2/8/2020Last follow-up:

T565

67963-67988

Sentence

denotes

2/29/2020 n = 77Survival:

T566

67989-68052

Sentence

denotes

6.5% died, 83.1% discharged, 10.4% still hospitalizedInclusion:

T567

68053-68113

Sentence

denotes

Inpatients with COVID-19 based on RT-PCR.Age: m 52 ± 2 ySex:

T568

68114-68150

Sentence

denotes

55.8% femalesGI/liver comorbidities:

T569

68151-68192

Sentence

denotes

10.4% digestive diseasesDisease severity:

T570

68193-68229

Sentence

denotes

74% non-severe, 26% severe Diarrhea:

T571

68230-68307

Sentence

denotes

1.3% (1)Present on admission1/57 nonsevere and 0/20 severeNausea or vomiting:

T572

68308-68394

Sentence

denotes

7.8% (6)Present on admission3/57 nonsevere and 3/20 severeAbdominal pain: NR AST > 40:

T573

68395-68462

Sentence

denotes

26.0% (20)11/57 non-severe and 9/20 severeM 19 (IQR, 21–42)ALT >40:

T574

68463-68533

Sentence

denotes

33.8% (26)17/57 non-severe and 9/20 severeM 28 (IQR, 20–46)BilirubinNR

T575

68534-68588

Sentence

denotes

Yang, 202026Chinese PLA General HospitalBeijingDates:

T576

68589-68623

Sentence

denotes

12/272019-2/18/2020Last follow-up:

T577

68624-68649

Sentence

denotes

2/18/2020 n = 55Survival:

T578

68650-68669

Sentence

denotes

3.6% diedInclusion:

T579

68670-68722

Sentence

denotes

Inpatients with COVID-19, confirmed with RT-PCR.Age:

T580

68723-68763

Sentence

denotes

M 44 y (IQR, 34–54 y, range, 3–85 y)Sex:

T581

68764-68798

Sentence

denotes

40% femalesGI/liver comorbidities:

T582

68799-68842

Sentence

denotes

1.8% chronic liver diseaseDisease severity:

T583

68843-68909

Sentence

denotes

38.2% mild, 36.4% common, 23.6% severe, and 1.8% extremely severe.

T584

68910-68919

Sentence

denotes

Diarrhea:

T585

68920-69107

Sentence

denotes

3.6% (2)Present on admission0/21 of the patients without pneumonia on admission and 2/34 of the patients with pneumoniaNausea, vomiting, and abdominal pain: NR AST, ALT, and bilirubin: NR

T586

69108-69198

Sentence

denotes

Li, 202056The Second Affiliated Hospital of Chongqing Medical University, ChongqingDates:

T587

69199-69256

Sentence

denotes

1/2020-2/2020Last follow-up: n = 83Survival: NRInclusion:

T588

69257-69316

Sentence

denotes

Inpatients with COVID-19 and at least one abnormal CT scan.

T589

69317-69381

Sentence

denotes

Patients with normal CT were excluded (8).Age: m 45 ± 12.3 ySex:

T590

69382-69436

Sentence

denotes

47% femalesGI/liver comorbidities: NRDisease severity:

T591

69437-69507

Sentence

denotes

69.9% ordinary, and 30.1% severe/critical Diarrhea and abdominal pain:

T592

69508-69586

Sentence

denotes

8.4% (7)Present on admissionNausea or vomiting: NR AST, ALT, and bilirubin: NR

T593

69587-69738

Sentence

denotes

Qi, 202045Chongqing Public Health Medical Center, Chongqing Three Georges Central Hospital, and Qianjiang Central Hospital of ChongqingChongqingDates:

T594

69739-69773

Sentence

denotes

1/19/2020-2/16/2020Last follow-up:

T595

69774-69800

Sentence

denotes

2/16/2020 n = 267Survival:

T596

69801-69865

Sentence

denotes

1.5% died, 38.6% discharged, 59.9% still hospitalized.Inclusion:

T597

69866-69907

Sentence

denotes

Inpatients with COVID-19 based on RT-PCR.

T598

69908-69953

Sentence

denotes

Excluded patients with missing data (42).Age:

T599

69954-69979

Sentence

denotes

M 48 y (IQR, 25–65 y)Sex:

T600

69980-70050

Sentence

denotes

44.2% femalesGI/liver comorbidities: GI diseases 4.5%Disease severity:

T601

70051-70094

Sentence

denotes

81.3% non-severe and 18.7% severe Diarrhea:

T602

70095-70174

Sentence

denotes

3.7% (10)Present on admission7/217 nonsevere and 3/50 severeNausea or vomiting:

T603

70175-70243

Sentence

denotes

2.2% (6)Present on admission5/217 nonsevere and 1/50 severeAnorexia:

T604

70244-70334

Sentence

denotes

17.2% (46)Present on admission33/217 nonsevere and 13/50 severeAbdominal pain: NR AST >35:

T605

70335-70385

Sentence

denotes

7.2% (19)9/217 non-severe and 10/50 severeALT >40:

T606

70386-70444

Sentence

denotes

7.5% (20)10/217 non-severe and 10/50 severeBilirubin >1.5:

T607

70445-70485

Sentence

denotes

2.2% (6)3/217 non-severe and 3/50 severe

T608

70486-70558

Sentence

denotes

Xu, 202029Guangzhou Eighth People’s Hospital (Guangzhou)GuangdongDates:

T609

70559-70624

Sentence

denotes

1/23/2020-2/4/2020Last follow-up: NR n = 90Survival: NRInclusion:

T610

70625-70696

Sentence

denotes

Inpatients with COVID-19 based on RT-PCR who had baseline chest CT.Age:

T611

70697-70724

Sentence

denotes

M 50 y (range, 18–86 y)Sex:

T612

70725-70794

Sentence

denotes

56.7% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T613

70795-70812

Sentence

denotes

5.6% (5)Vomiting:

T614

70813-70828

Sentence

denotes

5.6% (5)Nausea:

T615

70829-70840

Sentence

denotes

2.2% (2) NR

T616

70841-70932

Sentence

denotes

Lin, 202055The Fifth Affiliated Hospital of Sun Yat-sen University (Zhuhai)GuangdongDates:

T617

70933-70967

Sentence

denotes

1/17/2020-2/15/2020Last follow-up:

T618

70968-70993

Sentence

denotes

2/15/2020 n = 95Survival:

T619

70994-71055

Sentence

denotes

0% died, 38.9% discharged, 61.1% still hospitalizedInclusion:

T620

71056-71095

Sentence

denotes

Inpatients with confirmed COVID-19.Age:

T621

71096-71113

Sentence

denotes

45.3 ± 18.3 ySex:

T622

71114-71170

Sentence

denotes

52.6% femalesGI/liver comorbidities: NRDisease severity:

T623

71171-71211

Sentence

denotes

78.9% non-severe, 21.1% severe Diarrhea:

T624

71212-71311

Sentence

denotes

24.2% (23)5.2% (5) present on admission.Loose or watery stool, 2-10 bowel movements daily.Vomiting:

T625

71312-71355

Sentence

denotes

4.2% (4)0% (0) present on admission.Nausea:

T626

71356-71411

Sentence

denotes

17.9% (17)3.2% (3) present on admission.Abdominal pain:

T627

71412-71633

Sentence

denotes

2.1% (2)0% (0) present on admission.Epigastric discomfort.11 patients with GI symptoms did not have pneumonia.Viral RNA detected in 31/65 patients including 22/42 who had GI symptoms and 9/23 who did not have GI symptoms.

T628

71634-71672

Sentence

denotes

AST >35 for females and >40 for males:

T629

71673-71719

Sentence

denotes

4.2% (4)ALT >40 for females and >50 for males:

T630

71720-71743

Sentence

denotes

5.3% (5)Bilirubin >1.5:

T631

71744-71754

Sentence

denotes

23.2% (22)

T632

71755-71799

Sentence

denotes

Wen, 202033All Shenzhen CityGuangdongDates:

T633

71800-71833

Sentence

denotes

1/1/2020-2/28/2020Last follow-up:

T634

71834-71860

Sentence

denotes

2/28/2020 n = 417Survival:

T635

71861-71925

Sentence

denotes

0.7% died, 71.7% discharged, 27.6% still hospitalized.Inclusion:

T636

71926-71984

Sentence

denotes

Inpatients with COVID-19 based on RT-PCR.Age: m 45.4 ySex:

T637

71985-72041

Sentence

denotes

52.8% femalesGI/liver comorbidities: NRDisease severity:

T638

72042-72099

Sentence

denotes

8.9% mild, 82.5% moderate, 8.6% severe/critical Diarrhea:

T639

72100-72250

Sentence

denotes

7.0% (29)Present on admission.23/381 of mild/moderates and 6/36 of severe/criticalNausea, vomiting, and abdominal pain: NR ALT, AST, and bilirubin: NR

T640

72251-72686

Sentence

denotes

Xu, 202028First Affiliated Hospital of Guangzhou Medical University (Guangzhou), Dongguan People's Hospital (Dongguan), Foshan First People's Hospital (Foshan), Huizhou Municipal Central Hospital (Huizhou), First Affiliated Hospital of Shantou University Medical College (Shantou), Affiliated Hospital of Guangdong Medical University (Zhanijiang), Zhongshan City People's Hospital (Zhongshan)GuangdongDates: ?-2/28/2020Last follow-up:

T641

72687-72778

Sentence

denotes

2/28/2020 n = 45Survival: death 0.2%, 24.4% discharged, 73.3% still hospitalized.Inclusion:

T642

72779-72851

Sentence

denotes

Critically ill patients with COVID-19 pneumonia.Age: m 56.7 ± 15.4 ySex:

T643

72852-72908

Sentence

denotes

35.6% femalesGI/liver comorbidities: NRDisease severity:

T644

72909-72932

Sentence

denotes

100% critical Diarrhea:

T645

72933-72975

Sentence

denotes

0% (0)Present on admission AST or ALT >40:

T646

72976-73092

Sentence

denotes

37.8% (17)AST (n = 44)M 27 (IQR, 22.0–39.5)ALT (n = 44)M 29 (IQR, 20.1–50.0)Bilirubin (n = 44)M 0.91 (IQR, 0.61–1.3)

T647

73093-73136

Sentence

denotes

Yan, 202027All Hainan ProvinceHainanDates:

T648

73137-73171

Sentence

denotes

1/22/2020-3/13/2020Last follow-up:

T649

73172-73198

Sentence

denotes

3/13/2020 n = 168Survival:

T650

73199-73257

Sentence

denotes

3.6%, 1.2% still hospitalized, 95.2% discharged.Inclusion:

T651

73258-73302

Sentence

denotes

Inpatient with COVID-19 based on RT-PCR.Age:

T652

73303-73328

Sentence

denotes

M 51 y (IQR, 36–62 y)Sex:

T653

73329-73365

Sentence

denotes

51.8% femalesGI/liver comorbidities:

T654

73366-73401

Sentence

denotes

3.6% chronic liver diseaseSeverity:

T655

73402-73441

Sentence

denotes

78.6% nonsevere, 21.4% severe Diarrhea:

T656

73442-73508

Sentence

denotes

7.1% (12)Present on admission8/132 nonsevere, 4/36 severeVomiting:

T657

73509-73572

Sentence

denotes

4.2% (7)Present on admission5/132 nonsevere, 2/36 severeNausea:

T658

73573-73644

Sentence

denotes

5.4% (9)Present on admission6/132 nonsevere, 3/36 severeAbdominal pain:

T659

73645-73710

Sentence

denotes

4.2% (7)Present on admission5/132 nonsevere, 2/36 severe AST >40:

T660

73711-73762

Sentence

denotes

17.3% (18/104)7/75 non-severe, 11/29 severeALT >40:

T661

73763-73818

Sentence

denotes

8.0% (9/112)5/81 non-severe, 4/31 severeBilirubin >1.5:

T662

73819-73843

Sentence

denotes

0M 0.51 (IQR, 0.37–0.78)

T663

73844-73929

Sentence

denotes

Wang, 202035First Affiliated Hospital of Zhengzhou University (Zhengzhou)HenanDates:

T664

73930-73963

Sentence

denotes

1/21/2020-2/7/2020Last follow-up:

T665

73964-73988

Sentence

denotes

2/7/2020 n = 18Survival:

T666

73989-74049

Sentence

denotes

0 died, 33.3% discharged, 66.7% still hospitalizedInclusion:

T667

74050-74078

Sentence

denotes

Inpatients with COVID-19Age:

T668

74079-74104

Sentence

denotes

M 39 y (IQR, 29–55 y)Sex:

T669

74105-74172

Sentence

denotes

50% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T670

74173-74259

Sentence

denotes

16.7% (3)Present on admissionVomiting, nausea, abdominal pain: NR AST or ALT elevated:

T671

74260-74280

Sentence

denotes

25% (4)Bilirubin: NR

T672

74281-74377

Sentence

denotes

Chen, 202071First Hospital of Changsha (Changsha) and Loudi Central Hospital (Loudi)HunanDates:

T673

74378-74412

Sentence

denotes

1/23/2020-2/14/2020Last follow-up:

T674

74413-74440

Sentence

denotes

2/202/2020 n = 291Survival:

T675

74441-74504

Sentence

denotes

0.7% died, 54.6% discharged, 44.7% still hospitalizedInclusion:

T676

74505-74549

Sentence

denotes

Inpatients with COVID-19 based on RT-PCRAge:

T677

74550-74590

Sentence

denotes

M 46 y (IQR, 34–59 y, range, 1–84 y)Sex:

T678

74591-74627

Sentence

denotes

50.2% femalesGI/liver comorbidities:

T679

74628-74671

Sentence

denotes

5.2% chronic liver diseaseDisease severity:

T680

74672-74729

Sentence

denotes

10% mild, 72.8% moderate, 17.2% severe/critical Diarrhea:

T681

74730-74826

Sentence

denotes

8.6% (25)Present on admission3/29 mild, 17/212 moderate, 5/50 severe/criticalNausea or vomiting:

T682

74827-74918

Sentence

denotes

5.8% (17)Present on admission6/29 mild, 9/212 moderate, 2/50 severe/criticalAbdominal pain:

T683

74919-75003

Sentence

denotes

0.3% (1)Present on admission0/29 mild, 0/212 moderate, 1/50 severe/critical AST >37:

T684

75004-75094

Sentence

denotes

15.1% (44)5/29 mild, 23/212 moderate, 16/50 severe/criticalM 24.7 (IQR, 19.9–31.4)ALT >42:

T685

75095-75192

Sentence

denotes

10.3% (30)4/29 mild, 16/212 moderate, 10/50 severe/criticalM 20.7 (IQR, 14.9-28.9)Bilirubin >1.2:

T686

75193-75270

Sentence

denotes

9.3% (27)4/29 mild, 17/212 moderate, 6/50 severe/criticalM 0.6 (IQR, 0.5–0.9)

T687

75271-75316

Sentence

denotes

Liu, 202053All Jiangsu ProvinceJiangsuDates:

T688

75317-75351

Sentence

denotes

1/10/2020-2/18/2020Last follow-up:

T689

75352-75378

Sentence

denotes

2/18/2020 n = 620Survival:

T690

75379-75452

Sentence

denotes

0 died, 3.2% in ICU, 56.1% still hospitalized, 40.6% dischargedInclusion:

T691

75453-75493

Sentence

denotes

Inpatient with COVID-10 based on RT-PCR.

T692

75494-75552

Sentence

denotes

Patients without records excluded.Age: m 44.5 ± 17.2 ySex:

T693

75553-75609

Sentence

denotes

47.4% femalesGI/liver comorbidities: NRDisease severity:

T694

75610-75681

Sentence

denotes

15.6% asymptomatic/mild, 75.8% moderate, 8.5% severe/critical Diarrhea:

T695

75682-76172

Sentence

denotes

8.5% (53)Present on admission4/97 asymptomatic/mild, 43/469 moderate, 6/53 severe/critically illNausea, vomiting, and abdominal pain: NR AST (387) m 23.3 ± 18.5m 27.3 ± 14.9 in mild/asymptomatic, 32.3 ± 17.5 in moderate, 42.9 ± 28.6 in severe/critically illALT (420) m 31.0 ± 22.4m 26.8 ± 21.6 in asymptomatic/mild, m 31.2 ± 21.1 in moderate, m 39.3 ± 32.5 in severe/critically illBilirubin (460) m 0.6 ± 0.4m 0.7 ± 0.5 mild/asymptomatic, m 0.6 ± 0.4 moderate, m 0.7 ± 0.4 severe/critically

T696

76173-76233

Sentence

denotes

Fan, 202067Shenyang Chest Hospital (Shenyang)LiaoningDates:

T697

76234-76287

Sentence

denotes

1/20/2020-3/15/2020Last follow-up: NR n = 55Survival:

T698

76288-76312

Sentence

denotes

100% recoveredInclusion:

T699

76313-76388

Sentence

denotes

Recovered hospitalized COVID-19 patients, based on RT-PCR.Age: m 46.8 ySex:

T700

76389-76445

Sentence

denotes

45.5% femalesGI/liver comorbidities: NRDisease severity:

T701

76446-76480

Sentence

denotes

85.4% mild, 14.5% severe Diarrhea:

T702

76481-76538

Sentence

denotes

10.9% (6)4/47 mild/moderate, 2/8 severe/criticalVomiting:

T703

76539-76744

Sentence

denotes

7.3% (4)2/47 mild/moderate, 2/8 severe/criticalAbdominal pain: NR ALT m 40.6m 27.8 in mild/moderate and m 57.1 in severe/criticalBilirubin m 19.5m 19.0 in mild/moderate and m 22.4 in severe/criticalAST: NR

T704

76745-76793

Sentence

denotes

Yao, 202025Tangdu Hospital (Xi’an)ShaanxiDates:

T705

76794-76857

Sentence

denotes

1/21/2020-2/21/2020Last follow-up: NR n = 40Survival:Inclusion:

T706

76858-76883

Sentence

denotes

Inpatients with COVID-19.

T707

76884-76953

Sentence

denotes

No baseline LFT abnormality.Age: m 53.9 ± 15.8 y (range, 22–83 y)Sex:

T708

76954-76990

Sentence

denotes

37.5% femalesGI/liver comorbidities:

T709

76991-77035

Sentence

denotes

0% liver disease or damage.Disease severity:

T710

77036-77076

Sentence

denotes

45% non-severe, and 55% severe Diarrhea:

T711

77077-77149

Sentence

denotes

7.5% (3)8 patients developed diarrhea due to lopinavir/ritonavir.Nausea:

T712

77150-77198

Sentence

denotes

7.5% (3)Vomiting and abdominal pain: NR AST >46:

T713

77199-77267

Sentence

denotes

40% (16)Occurred as early as the 4th day up to the 26th day.ALT >66:

T714

77268-77345

Sentence

denotes

52.5% (21)Occurred as early as the 4th day up to the 26th day.Bilirubin >1.2:

T715

77346-77406

Sentence

denotes

25% (10)Occurred as early as the 4th day up to the 16th day.

T716

77407-77497

Sentence

denotes

Mostly sligh increase.Liver injury occured in 17/22 critical cases 5/18 noncritical cases.

T717

77498-77656

Sentence

denotes

Tian, 202036Liaocheng Infectious Diseases Hospital (Liaocheng) and Liaocheng People’s Hospital (Liaocheng)ShandongDates: NRLast follow-up: NR n = 37Survival:

T718

77657-77682

Sentence

denotes

100% dischargedInclusion:

T719

77683-77732

Sentence

denotes

Inpatients with COVID-19.Age: m 44.3 ± 1.67 ySex:

T720

77733-77767

Sentence

denotes

54% femalesGI/liver comorbidities:

T721

77768-77812

Sentence

denotes

2.7% cirrhosis/liver cancerDisease severity:

T722

77813-77889

Sentence

denotes

13.5% mild, 81.1% moderate, 2.7% severe, 2.7% critical Diarrhea or vomiting:

T723

77890-77961

Sentence

denotes

25.8% (8/31)Present on admissionVomiting or abdominal pain: NR AST >40:

T724

77962-77979

Sentence

denotes

10.8% (4)ALT >40:

T725

77980-78001

Sentence

denotes

5.4% (2)Bilirbuin >1:

T726

78002-78012

Sentence

denotes

35.1% (13)

T727

78013-78102

Sentence

denotes

Lu, 202051Shanghai Public Health Clinical CenterShanghaiDates: ?-2/9/2020Last follow-up:

T728

78103-78128

Sentence

denotes

2/9/2020 n = 265Survival:

T729

78129-78167

Sentence

denotes

0.4% died, 17.7% discharged.Inclusion:

T730

78168-78245

Sentence

denotes

Inpatients with COVID-19 based on RT-PCRAge: NRSex: NRGI/liver comorbidities:

T731

78246-78267

Sentence

denotes

0.4%Disease severity:

T732

78268-78325

Sentence

denotes

91.7% mild/moderate, 8.3% severe/critically ill Diarrhea:

T733

78326-78419

Sentence

denotes

6.4% (17)Present on admission17/243 mild/moderate and 0/22 severe/criticalNausea or vomiting:

T734

78420-78730

Sentence

denotes

2.3% (6)Present on admission6/243 mild/moderate and 0/22 severe/criticalAbdominal pain: NR ASTM 24 (IQR, 19–33)M 24 (IQR, 19–31) in mild/moderate and M 39.5 (IQR, 29.7–53.5) in severe/criticalALTM 23 (IQR, 15–33)M 21 (IQR, 15–33) in mild/moderate and M 30 (24.5–34.5) in severe/criticalBilirubinM 0.5 (0.4–0.6)

T735

78731-78810

Sentence

denotes

Fu, 202065Chengdu Public Health Clinical Medical Center (Chengdu)SichuanDates:

T736

78811-78844

Sentence

denotes

1/1/2020-2/20/2020Last follow-up:

T737

78845-78870

Sentence

denotes

2/29/2020 n = 52Survival:

T738

78871-78929

Sentence

denotes

100% (excluded patients who were not discharged)Inclusion:

T739

78930-78975

Sentence

denotes

Inpatients with COVID-19 confirmed by RT-PCR.

T740

78976-79030

Sentence

denotes

Excluded patients who died or were not discharged.Age:

T741

79031-79062

Sentence

denotes

M 44.5 y (IQR, 33.0–56.5 y)Sex:

T742

79063-79205

Sentence

denotes

46% femalesGI/liver comorbidities: NRDisease severity: common coronavirus pneumonia type 73.1%, severe 19.2%, critically severe 7.7% Diarrhea:

T743

79206-79245

Sentence

denotes

13.5% (7/52)Present on admissionNausea:

T744

79246-79681

Sentence

denotes

1.9 % (1/52)Present on admissionVomiting and abdominal pain: NR AST M 27 (IQR, 21.2–34.0)ALT M 24 (IQR, 15.3–49)Bilirubin 85 patients M 67.3 (IQR, 63.5–71.4)Patients with laboratory results on admission and discharge n = 23ASTOn presentation M 27 (IQR, 23–35)After discharge M 25 (IQR, 19–39)ALTOn presentation M 25 (IQR, 14–41)After discharge M 31 (IQR, 15–41)BilirubinOn presentation M 66 (IQR, 60–72)After discharge M 65 (IQR, 60–69

T745

79682-79749

Sentence

denotes

Fu, 202066Third People’s Hospital of Kunming (Kunming)YunnanDates:

T746

79750-79803

Sentence

denotes

1/26/2020-2/15/2020Last follow-up: NR n = 36Survival:

T747

79804-79861

Sentence

denotes

17% discharged, 6% ICU, 78% still hospitalized.Inclusion:

T748

79862-79904

Sentence

denotes

Inpatients with COVID-19 based RT-PCR.Age:

T749

79905-79913

Sentence

denotes

45 ySex:

T750

79914-80149

Sentence

denotes

55.6% femalesGI/liver comorbidities: NRDisease severity: mild 11% (4), common 83% (30), severe, critical 6% (2) Diarrhea: % (3)Present on admissionVomiting, nausea, and abdominal pain: NR AST 11.1% (4)ALT 11.1% (4)Bilirubin 30.56% (11)

T751

80150-80256

Sentence

denotes

Jin, 202060First Affiliated Hospital of College of Medicine, Zhejiang University (Hangzhou)ZhejiangDates:

T752

80257-80292

Sentence

denotes

1/17/2020-02/08/2020Last follow-up:

T753

80293-80320

Sentence

denotes

02/08/2020 n = 651Survival:

T754

80321-80360

Sentence

denotes

0.2% death, NR for the othersInclusion:

T755

80361-80408

Sentence

denotes

Inpatients with COVID-19.Age: m 45 ± 14.4 ySex:

T756

80409-80465

Sentence

denotes

49.2% femalesGI/liver comorbidities: NRDisease severity:

T757

80466-80496

Sentence

denotes

Severe/critical 9.8% Diarrhea:

T758

80497-80588

Sentence

denotes

8.6% (56)Present on admission and prior to treatment.Defined as loose stool >3 times daily.

T759

80589-80658

Sentence

denotes

Stool cultures were performed with negative results for all patients.

T760

80659-80783

Sentence

denotes

Clostridium difficile not detected in stool and no recent antibiotic use.Median duration was 4 d (IQR, 3–6 d, range, 1–9 d).

T761

80784-80823

Sentence

denotes

Most was self-limiting.Nausea/vomiting:

T762

80824-80958

Sentence

denotes

4.3% (28)Present on admission.11 only vomiting; 10 only nausea; 3 nausea, vomiting and diarrhea; 4 nausea and vomiting.Any GI Symptom:

T763

80959-81123

Sentence

denotes

11.4 (74)Nausea, vomiting or diarrhea.21 patients lacked respiratory symptoms of coughing and sputum production, and presented only with GI symptomsSevere/critical:

T764

81124-81176

Sentence

denotes

17/74 with GI symptoms vs 47/577 without GI symptom.

T765

81177-81353

Sentence

denotes

In those with GI symptoms, risk factors for severe/critical disease were sputum production, increased lactate dehydrogenase and increased glucose on multivariate analysis.ARDS:

T766

81354-81410

Sentence

denotes

5/74 with GI symptoms vs 12/577 without GI symptomShock:

T767

81411-81473

Sentence

denotes

1/74 with GI symptoms vs 1/577 without GI symptomLiver injury:

T768

81474-81548

Sentence

denotes

13/74 with GI symptoms vs 51/577 without GI symptomMechanical ventilation:

T769

81549-81614

Sentence

denotes

5/74 with GI symptoms vs 12/577 without GI symptom ICU admission:

T770

81615-81928

Sentence

denotes

5/74 with GI symptoms vs 12/577 without GI symptom AST >40: NRGI symptoms M 29.4 (IQR, 29.9–38.6) vs no GI symptoms M 24.4 (IQR, 19.0–32.0)ALT >50: NRGI symptoms M 25.0 (IQR, 15.8–38.5) vs no GI symptoms M 21.5 (IQR, 15.0–32.8)Total bilirubinGI symptoms M 0.6 (IQR, 0.4–0.8) vs no GI symptoms M 0.6 (IQR, 0.4–0.8)

T771

81929-82200

Sentence

denotes

Qian, 202044Xiaoshan District People's Hospital (Hangzhou), Ningbo City First Hospital (Ningbo City), Ninghai County First Hospital (Ningbo City), Xiangshan County People's First Hospital (Ningbo City), Affiliated Hospital of Shaoxing University (Shaoxing)ZhejiangDates:

T772

82201-82235

Sentence

denotes

1/20/2020-2/11/2020Last follow-up:

T773

82236-82261

Sentence

denotes

2/16/2020 n = 91Survival:

T774

82262-82324

Sentence

denotes

0% died, 34.1% discharged, 65.9% still hospitalized.Inclusion:

T775

82325-82408

Sentence

denotes

Inpatients with COVID-19 (88 based on RT-PCR and 3 based on clinical diagnosis)Age:

T776

82409-82436

Sentence

denotes

M 50 y (IQR, 36.5–57 y)Sex:

T777

82437-82491

Sentence

denotes

59% femalesGI/liver comorbidities: NRDisease severity:

T778

82492-82528

Sentence

denotes

90.1% mild and 9.9% severe Diarrhea:

T779

82529-82624

Sentence

denotes

23.1% (21)Present on admissionVomiting, nausea, and abdominal pain: not extracted Not extracted

T780

82625-82735

Sentence

denotes

Chen, 202074Wenzhou Central Hospital (Wenzhou) and Sixth People’s Hospital of Wenzhou (Wenzhou)ZhejiangDates:

T781

82736-82790

Sentence

denotes

1/11/2020-2/15/2020Last follow-up: NR n = 175Survival:

T782

82791-82840

Sentence

denotes

29.7% discharge, not reported otherwiseInclusion:

T783

82841-82886

Sentence

denotes

Inpatients with COVID-19 based on RT-PCR.Age:

T784

82887-82912

Sentence

denotes

M 46 y (IQR, 34–54 y)Sex:

T785

82913-82982

Sentence

denotes

52.6% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T786

82983-83140

Sentence

denotes

19.4% (34)Present on admissionAverage of 6 episodes per day, and often ended within 1-4 daysVomiting, nausea, and abdominal pain: not extracted Not extracted

T787

83141-83190

Sentence

denotes

Kuang, 202058All Zhejiang ProvinceZhejiangDates:

T788

83191-83257

Sentence

denotes

1/1/2020-2/10/2020Last follow-up: NR n = 944Survival: NRInclusion:

T789

83258-83286

Sentence

denotes

All reported COVID-19 cases.

T790

83287-83343

Sentence

denotes

Both inpatients and outpatients.Age: m 47.4 ± 22.9 ySex:

T791

83344-83413

Sentence

denotes

49.6% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T792

83414-83465

Sentence

denotes

2.7% (21)Vomiting, nausea and abdominal pain: NR NR

T793

83466-83476

Sentence

denotes

US studies

T794

83477-83537

Sentence

denotes

Arentz, 202075Evergreen Hospital (Kirkland)WashingtonDates:

T795

83538-83571

Sentence

denotes

2/20/2020-3/5/2020Last follow-up:

T796

83572-83597

Sentence

denotes

3/17/2020 n = 21Survival:

T797

83598-83655

Sentence

denotes

52.4% died, 9.5% out of IC, 38.1% still in ICU.Inclusion:

T798

83656-83721

Sentence

denotes

Critically ill COVID-19 patients.Age: m 70 y (range, 43–92 y)Sex:

T799

83722-83756

Sentence

denotes

48% femalesGI/liver comorbidities:

T800

83757-83817

Sentence

denotes

4.8% cirrhosis, 9.5% solid organ transplantDisease severity:

T801

83818-83973

Sentence

denotes

100% critically ill Diarrhea, nausea, vomiting, and abdominal pain: NR AST m 273 (range, 14-4432)ALT m 108 (range, 11-1414)Bilirubin m 0.6 (range, 0.2-1.1)

T802

83974-84039

Sentence

denotes

Cholankeril, 202070Stanford University HospitalsCaliforniaDates:

T803

84040-84073

Sentence

denotes

3/4/2020-3/24/2020Last follow-up:

T804

84074-84100

Sentence

denotes

3/24/2020 n = 116Survival:

T805

84101-84204

Sentence

denotes

0.9% died, 86.2% discharged, 4.3% still hospitalized.Inclusion: COVID-19 confirmed based on RT-PCR.Age:

T806

84205-84230

Sentence

denotes

M 50 y (IQR, 35–67 y)Sex:

T807

84231-84267

Sentence

denotes

46.6% femalesGI/liver comorbidities:

T808

84268-84311

Sentence

denotes

2.6% chronic liver diseaseDisease severity:

T809

84312-84409

Sentence

denotes

71.6% evaluated in ED/clinic only, 20.7% admitted to the medical floor, and 7.8% admitted to ICU.

T810

84410-84419

Sentence

denotes

Diarrhea:

T811

84420-84473

Sentence

denotes

10.3% (12)Present on admissionNausea and/or vomiting:

T812

84474-84519

Sentence

denotes

10.3% (12)Present on admissionAbdominal pain:

T813

84520-84649

Sentence

denotes

8.8% (10)Present on admissionNone of the patients had isolated GI symptoms or as the initial symptoms.31.9% reported GI symptoms.

T814

84650-84702

Sentence

denotes

Median duration of GI symptoms was 1 day (IQR, 0–4).

T815

84703-85000

Sentence

denotes

AST (n = 65)M 35 (IQR, 22–58)In those with any abnormal LFT, M 64 (IQR, 24–76)ALT (n = 65)M 32 (IQR, 22–48)In those with any abnormal LFT, M 59 (IQR, 22–76)Total bilirubin (n = 65)M 0.4 (IQR, 0.3–0.7)In those with any abnormal LFT, M 0.5 (IQR, 0.3–0.7)26 patients developed liver enzyme elevation.

T816

85001-85046

Sentence

denotes

22 of them had normal baseline liver enzymes.

T817

85047-85147

Sentence

denotes

Nobel, 202047New York–Presbyterian Hospital/Columbia University Irving Medical CenterNew YorkDates:

T818

85148-85182

Sentence

denotes

3/10/2020-3/21/2020Last follow-up:

T819

85183-85221

Sentence

denotes

18 days after testing n = 278Survival:

T820

85222-85242

Sentence

denotes

3.2% died,Inclusion:

T821

85243-85402

Sentence

denotes

Patients tested for COVID-19 at clinic or emergency department for respiratory symptoms with intent to hospitalize or the same symptoms in essential personnel.

T822

85403-85449

Sentence

denotes

Excluded patients with insufficient data (42).

T823

85450-85479

Sentence

denotes

Charts randomly selected.Age:

T824

85480-85556

Sentence

denotes

11% aged 18–30 y, 25% aged 31–50 y, 37% aged 51–70 y, and 27% aged >70 ySex:

T825

85557-85611

Sentence

denotes

48% femalesGI/liver comorbidities: NRDisease severity:

T826

85612-85673

Sentence

denotes

74.5% admitted to hospital, 15.8% admitted to ICU, 3.2% died.

T827

85674-85683

Sentence

denotes

Diarrhea:

T828

85684-85793

Sentence

denotes

20.1% (56)Present on admission42/207 admitted to hospital, 11/44 admitted to ICU, 0/9 died.Vomiting/vomiting:

T829

85794-85922

Sentence

denotes

22.7% (63)Present on admission51/207 admitted to hospital, 8/44 admitted to ICU, 0/9 died.Abdominal pain: NR35% had GI symptoms.

T830

85923-86237

Sentence

denotes

Patients with GI symptoms were more likely to have illness duration of ≥1 week (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 (adjusted odds ratio 1.7; 95% CI, 1.1–2.5) AST: NRALT: NRBilirubin: NR

T831

86238-86332

Sentence

denotes

Hajifathalian, 202063NewYork-Presbytarian Hospital/Weill Cornell Medical CenterNew YorkDates:

T832

86333-86368

Sentence

denotes

3/4/2020 to 4/9/2020Last follow-up:

T833

86369-86433

Sentence

denotes

4/16/2020 n = 1059 (768 inpatients and 291 outpatients)Survival:

T834

86434-86453

Sentence

denotes

9.1% diedInclusion:

T835

86454-86523

Sentence

denotes

Adults with COVID-19, inpatients and outpatients.Age: m 61 ± 18 ySex:

T836

86524-86560

Sentence

denotes

42.3% femalesGI/liver comorbidities:

T837

86561-86657

Sentence

denotes

1.6% IBD, 3.0% chronic liver disease, 2.4% solid organ transplant.Disease severity: NR Diarrhea:

T838

86658-86756

Sentence

denotes

22.1% (234)Present on admissionInpatients 24.3% (187/768) and outpatients 16.1% (47/291).Vomiting:

T839

86757-86848

Sentence

denotes

8.3% (91)Present on admissionInpatients 8.7% (67/768) and outpatients 8.2% (24/291).Nausea:

T840

86849-86953

Sentence

denotes

15.3% (168)Present on admissionInpatients 16.0% (123/768) and outpatients 15.5% (45/291).Abdominal pain:

T841

86954-87038

Sentence

denotes

6.6% (72)Present on admissionInpatients 7.3% (56/768) and outpatients 5.5% (16/291).

T842

87039-87047

Sentence

denotes

AST ≥40:

T843

87048-87079

Sentence

denotes

56% (n = 844) m 60 ± 79ALT ≥40:

T844

87080-87118

Sentence

denotes

39% (n = 844) m 50 ± 65Bilirubin >1.2:

T845

87119-87255

Sentence

denotes

11% (n = 844) m 0.7 ± 0.6Presence of liver injury at presentation was associated with higher risk of admission on multivariate analysis.

T846

87256-87371

Sentence

denotes

Kujawski, 202057Center of Disease ControlCalifornia, Illinois, Arizona, Massachusetts, Washington, WisconsinDates:

T847

87372-87405

Sentence

denotes

1/20/2020-2/5/2020Last follow-up:

T848

87406-87431

Sentence

denotes

2/22/2020 n = 12Survival:

T849

87432-87506

Sentence

denotes

0% died, 8.3% hospitalized, 41.7% home isolation, 50% recovered.Inclusion:

T850

87507-87573

Sentence

denotes

Patients under investigation who tested positive for COVID-19.Age:

T851

87574-87601

Sentence

denotes

M 53 y (range, 21–68 y)Sex:

T852

87602-87638

Sentence

denotes

33.3% femalesGI/liver comorbidities:

T853

87639-87694

Sentence

denotes

8.3% HBV and 8.3% fatty liver disease.Disease severity:

T854

87695-87726

Sentence

denotes

5 outpatients and 7 inpatients.

T855

87727-87736

Sentence

denotes

Diarrhea:

T856

87737-87837

Sentence

denotes

33.3% (4)8.3% (1) present on admission3 while on remdesivir (1 of tham had Giardia and C difficile).

T857

87838-87909

Sentence

denotes

1 patient had symptoms for 1 day then developed fever and cough.Nausea:

T858

87910-87961

Sentence

denotes

25% (3)8.3% (1) present on admissionAbdominal pain:

T859

87962-88017

Sentence

denotes

16.7% (2)Stool PCR positive in 70% (7/10) patients AST:

T860

88018-88089

Sentence

denotes

58.3% (7)M 129 (IQR, 46–190)ALT 58.3% (7)M 136 (IQR, 66–389)BilirubinNR

T861

88090-88262

Sentence

denotes

Rubin, 202043Stanford University School of MedicineCaliforniaDates: ?-3/11/2020Last follow-up: NR n = 54Survival: NR.Inclusion: COVID-19 patients, not clear otherwise.Age:

T862

88263-88306

Sentence

denotes

M 53.5 y (IQR, 32–75 y, range, 20–91 y)Sex:

T863

88307-88343

Sentence

denotes

46.3% femalesGI/liver comorbidities:

T864

88344-88369

Sentence

denotes

1.8% HBVDisease severity:

T865

88370-88585

Sentence

denotes

33.3% inpatients and 66.7% outpatients Diarrhea, nausea, vomiting, and abdominal pain: NR ASTFemales m 73.4 ± 61.8 (9) and males m 45.1 ± 19.5 (14)ALTFemales m 69.6 ± 65.2 (9) and males m 43.9 ± 25.8 (13)BilirubinNR

T866

88586-88601

Sentence

denotes

Other countries

T867

88602-88671

Sentence

denotes

COVID-19 National Emergency Response Center, 202069South KoreaDates:

T868

88672-88738

Sentence

denotes

1/10/2020-2/14/2020Last follow-up: NR n = 28Survival: NRInclusion:

T869

88739-88811

Sentence

denotes

Inpatients or outpatient with COVID-19Age: m 42.6 y (range, 20–73 y)Sex:

T870

88812-88881

Sentence

denotes

46.1% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T871

88882-88998

Sentence

denotes

7%% (2)Present on admission1 started 2 d after fevers and chills and 1 started 2 d after muscle achesAbdominal pain:

T872

88999-89084

Sentence

denotes

4% (1)Present on admissionStomachache 2 d after muscle acheVomiting and nausea: NR NR

T873

89085-89114

Sentence

denotes

Young, 202024SingaporeDates:

T874

89115-89148

Sentence

denotes

1/23/2020-2/3/2020Last follow-up:

T875

89149-89187

Sentence

denotes

2/25/2020 n = 18Survival: NRInclusion:

T876

89188-89227

Sentence

denotes

Inpatients COVID-19 based on RT-PCRAge:

T877

89228-89255

Sentence

denotes

M 47 y (range, 31–73 y)Sex:

T878

89256-89380

Sentence

denotes

50% femalesGI/liver comorbidities: NRDisease severity: NR (12 patients uncomplicated (67%) 6 required oxygen (33%) Diarrhea:

T879

89381-89724

Sentence

denotes

17% (3)Present on admissionNone of these patients required supplemental oxygenVomiting, nausea, and abdominal pain: NRVirus detected by PCR in stool in 4/8 (50%) and in whole blood 1/12 (8%)4 of the 5 patients treated with lopinavir-ritonavir developed nausea, vomiting, and/or diarrhea, and 3 developed abnormal liver function test results NR

T880

89725-89795

Sentence

denotes

Sun, 202039The National Centre for Infectious DiseasesSingaporeDates:

T881

89796-89862

Sentence

denotes

1/26/2020-2/16/2020Last follow-up: NR n = 54Survival: NRInclusion:

T882

89863-89910

Sentence

denotes

Patients referred for testing for COVID-19.Age:

T883

89911-89936

Sentence

denotes

M 42 y (IQR, 34–54 y)Sex:

T884

89937-89971

Sentence

denotes

46% femalesGI/liver comorbidities:

T885

89972-90020

Sentence

denotes

0 liver diseaseDisease severity: NR GI symptoms:

T886

90021-90129

Sentence

denotes

37% (20/54)General GI symptoms per different models were associated with positive COVID adjusted odds ratio.

T887

90130-90182

Sentence

denotes

3.73 (95% CI, 1.23–12.45) AST, ALT, and bilirubin NR

T888

90183-90257

Sentence

denotes

Pung, 202046SingaporeDates: ?-2/15/2020Last follow-up: NR n = 17Survival:

T889

90258-90275

Sentence

denotes

0% diedInclusion:

T890

90276-90312

Sentence

denotes

Inpatients COVID-19 based on PCRAge:

T891

90313-90401

Sentence

denotes

M 40 y (36–51 y)Sex:59 % femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T892

90402-90427

Sentence

denotes

23.5% (4)Nausea/Vomiting:

T893

90428-90483

Sentence

denotes

5.9%% (1)Abdominal pain: NR AST, ALT, and bilirubin: NR

T894

90484-90533

Sentence

denotes

Tabata, 202038Diamond Princess CruiseJapanDates:

T895

90534-90588

Sentence

denotes

2/11/2020-2/25/2020Last follow-up: NR n = 104Survival:

T896

90589-90619

Sentence

denotes

0% died, NR othewiseInclusion:

T897

90620-90699

Sentence

denotes

Laboratory confirmed patients with COVID-19 on Diamond Princess Cruise shipAge:

T898

90700-90743

Sentence

denotes

M 68 y (IQR, 46.8–75 y; range, 25–93 y)Sex:

T899

90744-90800

Sentence

denotes

54.8% femalesGI/liver comorbidities: NRDisease severity:

T900

90801-90846

Sentence

denotes

31.7% asymptomatic, 41.3% mild, 26.9% severe.

T901

90847-90856

Sentence

denotes

Diarrhea:

T902

90857-90999

Sentence

denotes

9.6% (8)Present on admission.2 additional patients develop diarrhea during the hospitalizationVomiting, nausea and abdominal pain: NR AST >38:

T903

91000-91064

Sentence

denotes

17.3% (18)9/76 (11.8%) nonsevere and 9/28 (32.1%) severeALT >45:

T904

91065-91133

Sentence

denotes

16.3% (17)10/76 (13.2%) nonsevere and 7/28 (25%) severeBilirubin: NR

T905

91134-91191

Sentence

denotes

Kluytmans, 202059Breda and Tiburg, The NetherlandsDates:

T906

91192-91244

Sentence

denotes

3/7/2020-3/12/2020Last follow-up: NR n = 86Survival:

T907

91245-91298

Sentence

denotes

0 deaths, 2 required short hospitalization.Inclusion:

T908

91299-91405

Sentence

denotes

Health care workers with fever or mild respiratory symptoms more than 10 d with subsequent positive tests.

T909

91406-91422

Sentence

denotes

Outpatients.Age:

T910

91423-91450

Sentence

denotes

M 49 y (range, 22–66 y)Sex:

T911

91451-91506

Sentence

denotes

4.6% femalesGI/liver comorbidities: NRDisease severity:

T912

91507-91545

Sentence

denotes

2 hospitalized, 19 recovered Diarrhea:

T913

91546-91600

Sentence

denotes

18.6% (16)Interviewed within 7 d of onset of symptoms:

T914

91601-91649

Sentence

denotes

5/31,Interviewed after 7 d of onset of symptoms:

T915

91650-91684

Sentence

denotes

11/55Decreased appetite or nausea:

T916

91685-91739

Sentence

denotes

17.4% (15)Interviewed within 7 d of onset of symptoms:

T917

91740-91788

Sentence

denotes

1/31,Interviewed after 7 d of onset of symptoms:

T918

91789-91809

Sentence

denotes

14/55Abdominal pain:

T919

91810-91862

Sentence

denotes

5.8% (5)Interviewed within 7 d of onset of symptoms:

T920

91863-91910

Sentence

denotes

1/31Interviewed after 7 d of onset of symptoms:

T921

91911-91943

Sentence

denotes

3/55 AST, ALT, and bilirubin: NR

T922

91944-91980

Sentence

denotes

Wolfel, 202032Munich, GermanyDates:

T923

91981-92165

Sentence

denotes

1/23/2020-?Last follow-up: NR n = 9Survival: NRInclusion: lab confirmed SARS-Co-V-2 in upper respiratory specimensAge: NRSex: NRGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T924

92166-92413

Sentence

denotes

22% (2)Present on admissionDiarrhea was never the only symptomPCR was positive for up to 11 d;Authors were not able to isolate infectious virus, despite high stool RNA viral loads.Vomiting, nausea and abdominal pain: NR AST, ALT, and bilirubin: NR

T925

92414-92500

Sentence

denotes

Dreher, 202068Aachen, GermanyDates:2/1/2020-3/1/2020Last follow-up:NR n = 50Survival:

T926

92501-92559

Sentence

denotes

14% died, 16% discharged, 70% still hospitalizedInclusion:

T927

92560-92640

Sentence

denotes

Inpatients with laboratory confirmed COVID-19Age: median 65 y (IQR, 58–76 y)Sex:

T928

92641-92740

Sentence

denotes

34% femalesGI/liver comorbidities: chronic liver failure 8%, chronic hepatitis 10%Disease severity:

T929

92741-92772

Sentence

denotes

48% ARDS,52% non-ARDS Diarrhea:

T930

92773-92834

Sentence

denotes

16% (8/50)Present on admission6/24 ARDS, 2/26 non-ARDSNausea:

T931

92835-92891

Sentence

denotes

1/50Present on admission0/24 ARDS, 1/26 nonARDSVomiting:

T932

92892-93040

Sentence

denotes

2/50Present on admission1/24 ARDS, 1/26 non-ARDSStool PCR done in 15 patients and found positive in 2 patients with ARDS AST, ALT, and bilirubin: NR

T933

93041-93157

Sentence

denotes

Gritti, 202064Papa Giovanni XXIII HospitalBergamo, ItalyDates:3/11/2020-3/24/2020Last follow-up: NR n = 21Survival:

T934

93158-93196

Sentence

denotes

4.7% died, NR for the othersInclusion:

T935

93197-93276

Sentence

denotes

Inpatients with confirmed COVID-19 who receivedAge: m 64 y (range, 48–75 y)Sex:

T936

93277-93344

Sentence

denotes

14% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T937

93345-93443

Sentence

denotes

23.8% (5)Present on admissionNausea or vomiting, or abdominal pain: NR AST, ALT, and bilirubin: NR

T938

93444-93592

Sentence

denotes

Spiteri, 202040Germany, Finland, Italy, Russia, Spain, France, Sweden, and BelgiumDates:1/24/2020-2/21/2020Last follow-up:2/21/2020 n = 38Survival:

T939

93593-93638

Sentence

denotes

2.6% died, 11.4% still hospitalizedInclusion:

T940

93639-93724

Sentence

denotes

Inpatients (n = 35) and outpatients (N=2) with COVID-19 confirmed based on RT-PCRAge:

T941

93725-93749

Sentence

denotes

M 42 (range, 2–81 y)Sex:

T942

93750-93819

Sentence

denotes

34.2% femalesGI/liver comorbidities: NRDisease severity: NR Diarrhea:

T943

93820-93858

Sentence

denotes

3.2% (1/31)Present on diagnosisNausea:

T944

93859-93936

Sentence

denotes

3.2% (1/31)Present on diagnosisAbdominal pain: NR AST, ALT, and bilirubin: NR

T945

93937-94010

Sentence

denotes

COVID-19 National Incident Room Surveillance Team, 202037AustraliaDates:

T946

94011-94055

Sentence

denotes

National data until 3/14/2020Last follow-up:

T947

94056-94082

Sentence

denotes

3/14/2020 n = 295Survival:

T948

94083-94102

Sentence

denotes

1.0% diedInclusion:

T949

94103-94170

Sentence

denotes

All individuals with COVID-19 (both outpatients and inpatients)Age:

T950

94171-94271

Sentence

denotes

M 47 y (range, 0–94 y)Sex: (approximately) 50% femaleComorbidities: NRDisease severity: NR Diarrhea:

T951

94272-94298

Sentence

denotes

16.3% (48)Nausea/vomiting:

T952

94299-94324

Sentence

denotes

11.5% (34)Abdominal pain:

T953

94325-94361

Sentence

denotes

2.0% (6) No laboratory data reported

T954

94362-94566

Sentence

denotes

ARDS, acute respiratory distress syndrome; CT, computed tomography; HBV, hepatitis B virus; ICU, intensive care unit; IQR, interquartile range; M, median; m, mean; ±, standard deviation; NR, not reported.

T955

94567-94669

Sentence

denotes

a AST and ALT are reported as units per liter while bilirubin is reported as milligrams per deciliter.

T956

94670-94738

Sentence

denotes

Supplementary Table 2 Direct Evidence of Proposed COVID-19 Therapies

T957

94739-94806

Sentence

denotes

Medication class Medication Sourcea Study Design GI adverse effects

T958

94807-94870

Sentence

denotes

Nausea/vomiting Abdominal pain Diarrhea Jaundice Hepatotoxicity

T959

94871-95025

Sentence

denotes

Antiviral Favipiravir Cai, 2020109 Open-label control study (favipiravir and lopinavir/ ritonavir) for COVID-19 NR NR 2/35 (5.7%) had diarrhea 1/35 (2.9%)

T960

95026-95163

Sentence

denotes

Chen, 202092 Open-label RCT for favipiravir vs arbidol (n = 120) in COVID-19 “Digestive tract reactions” 16/116 (13.79%) NR 9/116 (7.76%)

T961

95164-95500

Sentence

denotes

Lopinavir/ritonavir Cao,89 2020 RCT in severe COVID-19 (n = 199) 10/95 with nausea + 6/96 vomiting (reported separately) vs 0/99 with nausea and 0/99 with vomiting in control 4/95 in treatment group vs 2/99 in control group 4/95 in treatment group vs 0/99 in control group 6/95 in treatment group vs. 5/99 in control group Elevated AST:

T962

95501-95559

Sentence

denotes

4/95 in treatment vs. 9/99 in control group; Elevated ALT:

T963

95560-95602

Sentence

denotes

2/95 in treatment vs 5/99 in control group

T964

95603-95724

Sentence

denotes

Remdesivir Holshue,103 2020 Case report (first COVID in United States): remdesvir given day 7; no adverse events reported

T965

95725-95875

Sentence

denotes

Antimalarial Chloroquine Cortegiani,104 2020 Systematic review on efficacy and safety in COVID-19 Not reported in systematic review or primary studies

T966

95876-95894

Sentence

denotes

Hydroxychloroquine

T967

95895-95912

Sentence

denotes

NR, not reported.

T968

95913-95974

Sentence

denotes

a Sources include existing systematic reviews where possible.

T969

95975-96020

Sentence

denotes

If not available, primary sources are listed.

T970

96021-96091

Sentence

denotes

Supplementary Table 3 Indirect Evidence of Proposed COVID-19 Therapies

T971

96092-96160

Sentence

denotes

Medication class Medication Sourcea Indirect GI adverse events Other

T972

96161-96224

Sentence

denotes

Nausea/vomiting Abdominal pain Diarrhea Jaundice Hepatotoxicity

T973

96225-96420

Sentence

denotes

Antiviral Lopinavir/ritonavir FDA/ manufacturer's label110 HIV Nausea (5%–16%); vomiting (children 21%; adults 2%–7%) Reported 1%–11% 7%–28%; greater with once-daily dosing — Increased serum ALT:

T974

96421-96472

Sentence

denotes

1%–11%; hepatitis including AST/ALT/GGT elevations:

T975

96473-96666

Sentence

denotes

4%; hyperbilirubinemia (children 3%; adults 1%) Dysgeusia (children 22%; adults <2%); hyperamylasemia (3%–8%), dyspepsia (<6%), increased lipase (3%–5%), flatulence (1-4%), gastroenteritis (3%)

T976

96667-96711

Sentence

denotes

NIH Liver Tox111 HIV Range from mild to ALF.

T977

96712-96734

Sentence

denotes

Recovery takes 1–2 mo.

T978

96735-96771

Sentence

denotes

Do not re-challenge with medication.

T979

96772-96807

Sentence

denotes

Monitor for exacerbation of HBV/HCV

T980

96808-96875

Sentence

denotes

Momattin,105 2019 MERS Prevalence of GI AEs not reported in this SR

T981

96876-96960

Sentence

denotes

Yao,106 2020 SARS/MERS AEs not reported in this SR (can check primary studies) SARS:

T982

96961-97023

Sentence

denotes

2 retrospective cohort studies (combined with steroids); MERS:

T983

97024-97152

Sentence

denotes

1 RCT combined with IFN, 1 retrospective cohort combined with IFN/ribavirin, and 2 case reports also combined with IFN/ribavirin

T984

97153-97187

Sentence

denotes

Remdesivir Al-Tawfiq,107 2020 MERS

T985

97188-97209

Sentence

denotes

Sheahan,108 2020 MERS

T986

97210-97484

Sentence

denotes

Antimalarial Chloroquine FDA/ manufacturer's label/NIH Liver Tox111,112 Malaria Reported; frequency not defined Abdominal cramps reported; frequency not defined Reported; frequency not defined Rarely linked to aminotransferase elevations or clinically apparent liver injury.

T987

97485-97697

Sentence

denotes

In patients with AIP or PCT, it can trigger an attack with fever and serum aminotransferase elevations, sometimes resulting in jaundice Minor metabolism by liver (∼30%); mostly excreted in urine Likelihood score:

T988

97698-97757

Sentence

denotes

D (possible rare cause of clinically apparent liver injury)

T989

97758-98082

Sentence

denotes

Hydroxychloroquine113 FDA / Manufacturer's label Malaria / SLE Reported; frequency not defined Reported; frequency not defined Reported; frequency not defined Same as chloroquine above; can be exchanged with chloroquine as most reactions are hypersensitivity and no known cross reactivity to hepatic injury Likelihood score:

T990

98083-98142

Sentence

denotes

D (possible rare cause of clinically apparent liver injury)

T991

98143-98444

Sentence

denotes

AE, adverse event; AIP, acute intermittent porphyria; ALF, acute liver failure; GGT, gamma-glutamyl transferase; HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; NIH, National Institutes of Health; PCT, porphyria cutanea tarda; SLE, systemic lupus erythematosus; SR, systematic review.

T992

98445-98506

Sentence

denotes

a Sources include existing systematic reviews where possible.

T993

98507-98552

Sentence

denotes

If not available, primary sources are listed.

T994

98553-98638

Sentence

denotes

Conflicts of interest All members were required to complete the disclosure statement.

T995

98639-98775

Sentence

denotes

These statements are maintained at the AGA headquarters in Bethesda, Maryland, and pertinent disclosures are published with this report.

T996

98776-98846

Sentence

denotes

None of the panel members had any conflict relevant to this guideline.

T997

98847-99111

Sentence

denotes

Funding This document represents the official recommendations of the American Gastroenterological Association (AGA) and was developed by members of the AGA Clinical Guideline Committee and Clinical Practice Update Committee and approved by the AGA Governing Board.

T998

99112-99195

Sentence

denotes

No internal or external funding was provided for the development of this guideline.

T999

99196-99212

Sentence

denotes

Expiration date:

T1000

99213-99222

Sentence

denotes

3 months.

T1001

99223-99228

Sentence

denotes

Note:

T1002

99229-99416

Sentence

denotes

To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1053/j.gastro.2020.05.001.

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