LitCovid-sentences  

PMC:7212965 / 2677-54682 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T23 0-863 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 864-1572 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 1573-2012 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 2013-2203 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 2204-2351 Sentence denotes Gastrointestinal (GI) symptoms, including anorexia, nausea, vomiting, abdominal pain, and/or diarrhea have been reported in patients with COVID-19.
T28 2352-2811 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 2813-2830 Sentence denotes Scope and Purpose
T30 2831-2942 Sentence denotes We seek to summarize international data on the Gl and liver manifestations of COVID-19 infection and treatment.
T31 2943-3081 Sentence denotes Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.
T32 3082-3397 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 3398-3477 Sentence denotes Table 1 provides a summary of the recommendations and best practice statements.
T34 3478-3522 Sentence denotes Table 1 Summary of Best Practice Statements:
T35 3523-3574 Sentence denotes Consultative Management of Coronavirus Disease 2019
T36 3575-3588 Sentence denotes Statement no.
T37 3589-3598 Sentence denotes Statement
T38 3599-3981 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 3982-4191 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 4192-4269 Sentence denotes In a high COVID-19 prevalence setting, COVID-19 testing should be considered.
T41 4270-4483 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 4484-4627 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 4628-4768 Sentence denotes 5 In patients (outpatients or inpatients) with elevated LFTs in context of suspected or known COVID-19, evaluate for alternative etiologies.
T44 4769-4994 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 4995-5124 Sentence denotes 7 In hospitalized patients undergoing drug treatment for COVID-19, evaluate for treatment-related Gl and hepatic adverse effects.
T46 5126-5179 Sentence denotes Panel Composition and Conflict of Interest Management
T47 5180-5304 Sentence denotes This rapid review and guideline was developed by gastroenterologists and guideline methodologists from the 2 AGA committees.
T48 5305-5474 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 5475-5569 Sentence denotes Panel members disclosed all potential conflicts of interest according to AGA Institute policy.
T50 5571-5586 Sentence denotes Target Audience
T51 5587-5728 Sentence denotes The target audience of this guideline includes gastroenterologists, advanced practice providers, nurses, and other health care professionals.
T52 5729-5797 Sentence denotes Patients as well as policy-makers can benefit from these guidelines.
T53 5798-5924 Sentence denotes These guidelines are not intended to impose a standard of care for individual institutions, health care systems, or countries.
T54 5925-6071 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 6073-6080 Sentence denotes Methods
T56 6082-6123 Sentence denotes Information Sources and Literature Search
T57 6124-6302 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 6303-6434 Sentence denotes In the setting of a pandemic with exponential increases in published and unpublished studies, our search strategy was multifaceted.
T59 6435-6610 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 6611-6749 Sentence denotes We then searched the following platforms on April 5, 2020 for additional published and unpublished studies: medRxiv, LitCovid,11 and SSRN.
T61 6750-6846 Sentence denotes An additional unpublished article under peer review was obtained through personal communication.
T62 6847-6971 Sentence denotes For studies from the United States, we continued to monitor major journals for additional publications until April 19, 2020.
T63 6973-7008 Sentence denotes Study Selection and Data Extraction
T64 7009-7157 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 7158-7266 Sentence denotes A second reviewer (O.A.) subsequently reviewed the full-text articles and identified articles for inclusion.
T66 7267-7334 Sentence denotes Any disagreements about inclusion were resolved through discussion.
T67 7335-7460 Sentence denotes We incorporated any studies (prospective or retrospective) that reported on patient characteristics and symptoms of interest.
T68 7461-7578 Sentence denotes For studies published in Chinese, we used Google translate to assess for potential inclusion and for data extraction.
T69 7579-7816 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 7817-7975 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 7976-8067 Sentence denotes The initial data extraction focused on data elements for study and patient characteristics.
T72 8068-8201 Sentence denotes Subsequently, we identified studies for full data extraction based on study location (unique hospitals) and total number of patients.
T73 8202-8436 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 8437-8525 Sentence denotes Data extraction was performed using a standardized Microsoft Excel data extraction form.
T75 8526-8739 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 8740-8934 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 8935-8988 Sentence denotes Studies with discrepancies in the data were excluded.
T78 8989-9034 Sentence denotes The following data elements were extracted:1.
T79 9035-9153 Sentence denotes Study: author, year, location (hospital name, city, province or state), dates of inclusion, and date of last follow-up
T80 9154-9156 Sentence denotes 2.
T81 9157-9461 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 9462-9464 Sentence denotes 3.
T83 9465-9562 Sentence denotes Outcomes: diarrhea, nausea, vomiting, abdominal pain, and liver function test (LFT) abnormalities
T84 9563-9565 Sentence denotes 4.
T85 9566-9820 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 9822-9848 Sentence denotes Assessment of Risk of Bias
T87 9849-9978 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 9979-10029 Sentence denotes Bias due to selection of participants in the study
T89 10030-10032 Sentence denotes 2.
T90 10033-10057 Sentence denotes Bias due to missing data
T91 10058-10060 Sentence denotes 3.
T92 10061-10096 Sentence denotes Bias in the measurement of outcomes
T93 10097-10099 Sentence denotes 4.
T94 10100-10144 Sentence denotes Bias in the selection of the reported result
T95 10145-10285 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 10287-10308 Sentence denotes Certainty of Evidence
T97 10309-10439 Sentence denotes Certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.
T98 10440-10526 Sentence denotes The certainty of evidence was categorized into 4 levels ranging from very low to high.
T99 10527-10828 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 10829-10984 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 10986-11013 Sentence denotes Data Synthesis and Analysis
T102 11014-11229 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 11230-11339 Sentence denotes We used the fixed-effects model using the Freeman-Tukey double arcsine transformation method for proportions.
T104 11340-11692 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 11693-11881 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 11883-11890 Sentence denotes Results
T107 11891-12418 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 12419-12557 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 12558-12865 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 12866-13001 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 13002-13164 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 13165-13274 Sentence denotes The studies included mainly adults, although a few studies included a small proportion of pediatric patients.
T113 13275-13442 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 13443-13475 Sentence denotes Based on our inclusion strategy:
T115 13476-13594 Sentence denotes 55 studies (96%) provided information on any GI symptom and 32 studies (56%) reported any data on liver abnormalities.
T116 13595-13669 Sentence denotes Fewer studies, 21 (37%), provided information on underlying GI conditions.
T117 13670-13732 Sentence denotes Table 2 provides a summary of the pooled prevalence estimates.
T118 13733-13824 Sentence denotes Table 2 Summary of the Pooled Prevalence Estimates of Gastrointestinal/Liver Manifestations
T119 13825-13923 Sentence denotes GI and liver manifestations All studies Studies from China Studies from countries other than China
T120 13924-14019 Sentence denotes % (95% CI) Patients/ studies, n % (95% CI) Patients/ studies, n % (95% CI) Patients/ studies, n
T121 14020-14125 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 14126-14236 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 14237-14342 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 14343-14451 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 14452-14560 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 14561-14659 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 14660-14715 Sentence denotes a Regardless of hospitalization and timing of symptoms.
T128 14717-14746 Sentence denotes Overall Certainty of Evidence
T129 14747-14801 Sentence denotes The overall certainty in the body of evidence was low.
T130 14802-15177 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 15178-15324 Sentence denotes Additionally, most of the studies were retrospective cohort series and did not specify whether consecutive patients were included in the analysis.
T132 15325-15508 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 15509-15592 Sentence denotes These factors may have contributed to the heterogeneity of findings across studies.
T134 15593-15727 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 15729-15786 Sentence denotes What are the Gastrointestinal Manifestations of COVID-19?
T136 15788-15796 Sentence denotes Diarrhea
T137 15797-16269 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 16270-16474 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 16475-16596 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 16597-16664 Sentence denotes Figure 1 Forest plot of the prevalence of diarrhea in all patients.
T141 16665-17514 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 17515-17965 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 17967-17990 Sentence denotes Description of diarrhea
T144 17991-18340 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 18341-18470 Sentence denotes Most patients developed diarrhea during the hospitalization, which may have been attributable to other treatments or medications.
T146 18471-18604 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 18605-18678 Sentence denotes The diarrhea symptoms were described as more than 3 loose stools per day.
T148 18679-18758 Sentence denotes Stool cultures were negative (including Clostridium difficile) in all patients.
T149 18759-18800 Sentence denotes There was no mention of fecal leukocytes.
T150 18801-19099 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 19101-19185 Sentence denotes Diarrhea as the only presenting symptom in the absence of upper respiratory symptoms
T152 19186-19474 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 19475-19609 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 19610-19788 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 19789-19879 Sentence denotes Notably, the majority of patients (96%) had lung infiltrates on chest computed tomography.
T156 19880-20152 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 20153-20447 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 20448-20573 Sentence denotes The authors explicitly reported that none of the 116 patients had isolated GI symptoms as the only manifestation of COVID-19.
T159 20575-20651 Sentence denotes Diarrhea as the initial presenting symptom preceding other COVID-19 symptoms
T160 20652-20835 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 20836-21002 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 21003-21220 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 21222-21237 Sentence denotes Nausea/vomiting
T164 21238-21598 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 21599-21995 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 21996-22070 Sentence denotes Figure 2 Forest plot of the prevalence of nausea/vomiting in all patients.
T167 22072-22086 Sentence denotes Abdominal pain
T168 22087-22378 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 22379-22885 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 22886-22959 Sentence denotes Figure 3 Forest plot of the prevalence of abdominal pain in all patients.
T171 22961-22975 Sentence denotes Stool shedding
T172 22976-23198 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 23199-23364 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 23365-23494 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 23495-23839 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 23840-23934 Sentence denotes In this study, 8 of 50 patients had diarrhea, and stool PCR was positive in 15 of 50 patients.
T177 23935-24013 Sentence denotes In a US study by Kujawski et al,57 stool PCR was positive in 7 of 10 patients.
T178 24014-24170 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 24171-24466 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 24467-24747 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 24748-24934 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 24935-25290 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 25292-25338 Sentence denotes What Are the Liver Manifestations of COVID-19?
T184 25339-25787 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 25788-25995 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 25996-26176 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 26177-26340 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 26341-26406 Sentence denotes All patients had confirmed COVID-19 by laboratory RT-PCR testing.
T189 26407-26554 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 26555-26660 Sentence denotes None of the remaining studies provided any information regarding the status of LFTs before the infection.
T191 26661-26834 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 26835-26973 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 26974-27147 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 27148-27282 Sentence denotes Thirteen studies reported on the association between the presence of liver injury at presentation and severity of disease or outcomes.
T195 27283-27771 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 27773-27811 Sentence denotes Rationale for Best Practice Statements
T197 27812-27814 Sentence denotes 1.
T198 27816-28196 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 28197-28199 Sentence denotes 2.
T200 28201-28408 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 28409-28486 Sentence denotes In a high COVID-19 prevalence setting, COVID-19 testing should be considered.
T202 28487-28489 Sentence denotes 3.
T203 28491-28702 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 28703-29068 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 29069-29164 Sentence denotes Therefore, the reported prevalence rates may represent either an overestimate or underestimate.
T206 29165-29284 Sentence denotes Information about the frequency and severity of diarrhea symptoms was inadequately reported in the majority of studies.
T207 29285-29455 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 29456-29593 Sentence denotes The majority of patients with diarrhea, nausea, or vomiting also presented with accompanying symptoms typically associated with COVID-19.
T209 29594-29699 Sentence denotes In a handful of studies, diarrhea and nausea preceded the development of other COVID-19–related symptoms.
T210 29700-29894 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 29895-30209 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 30210-30637 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 30638-31001 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 31002-31206 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 31208-31349 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 31350-31612 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 31613-31788 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 31790-31928 Sentence denotes In patients (outpatients or inpatients) with elevated LFTs in context of suspected or known COVID-19, evaluate for alternative etiologies.
T219 31929-31931 Sentence denotes 6.
T220 31933-32157 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 32158-32160 Sentence denotes 7.
T222 32162-32289 Sentence denotes In hospitalized patients undergoing drug treatment for COVID-19, evaluate for treatment-related Gl and hepatic adverse effects.
T223 32290-32464 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 32465-32661 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 32662-32884 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 32885-33035 Sentence denotes Furthermore, diagnostic evaluation of abnormal LFTs on admission was not performed routinely, such as testing for viral hepatitis or other etiologies.
T227 33036-33935 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 33936-34070 Sentence denotes We additionally advise that all patients with abnormal LFTs undergo an evaluation to investigate non–COVID-19 causes of liver disease.
T229 34072-34150 Sentence denotes What Are Common Gastrointestinal/Liver Adverse Effects of COVID-19 Treatments?
T230 34151-34248 Sentence denotes `There are currently no US Food and Drug Administration–approved routine treatments for COVID-19.
T231 34249-34471 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 34472-34805 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 34806-34946 Sentence denotes Medication GI-related adverse events are summarized in Supplementary Tables 1 and 2 (direct evidence sources and indirect evidence sources).
T234 34948-34972 Sentence denotes Antimalarial Medications
T235 34973-35284 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 35286-35320 Sentence denotes Chloroquine and hydroxychloroquine
T237 35321-35698 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 35699-35896 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 35897-35948 Sentence denotes This is seen less commonly with hydroxychloroquine.
T240 35949-36108 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 36109-36296 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 36297-36433 Sentence denotes In addition, cardiac conduction defects leading to clinically relevant arrhythmias are an important adverse effect of these medications.
T243 36435-36456 Sentence denotes Antiviral Medications
T244 36458-36468 Sentence denotes Remdesivir
T245 36469-36562 Sentence denotes Limited data regarding GI adverse events are available, as phase 3 trials are still underway.
T246 36563-36886 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 36887-37031 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 37032-37132 Sentence denotes Of 4 patients (8%) who discontinued treatment prematurely, 2 were due to elevated aminotransferases.
T249 37134-37153 Sentence denotes Lopinavir/ritonavir
T250 37154-37262 Sentence denotes The combination lopinavir/ritonavir is FDA-approved for the treatment of human immunodeficiency virus (HIV).
T251 37263-37317 Sentence denotes More recently, it was utilized to treat MERS and SARS.
T252 37318-37499 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 37500-37891 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 37892-38001 Sentence denotes Additionally, there were 2 serious adverse events of acute gastritis, which both led to drug discontinuation.
T255 38002-38173 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 38174-38307 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 38308-38399 Sentence denotes Table 3 Gastrointestinal Treatment Adverse Effects of Currently Utilized COVID-19 Therapies
T258 38400-38476 Sentence denotes Medication type Medication name Adverse effects Major drug–drug interactions
T259 38477-38501 Sentence denotes Gastrointestinal Hepatic
T260 38502-38641 Sentence denotes Antimalarial ChloroquineHydroxychloroquine Nausea, vomiting, abdominal pain, and diarrhea reported; frequency not defined Likelihood score:
T261 38642-38714 Sentence denotes D (possible rare cause of clinically apparent liver injury).Description:
T262 38715-38752 Sentence denotes Rare elevations in aminotransferases.
T263 38753-38838 Sentence denotes Most reactions are hypersensitivity with no known cross reactivity to hepatic injury.
T264 38839-38906 Sentence denotes If this occurs, reasonable to switch between chloroquine therapies.
T265 38907-38999 Sentence denotes Substrate for CYP2D6 and CYP3A4 substrateSame as above; also substrate for CYP3A5 and CYP2C8
T266 39000-39076 Sentence denotes Antiviral Remdesivir Not reported (limited data available) Likelihood score:
T267 39077-39100 Sentence denotes Not scored.Description:
T268 39101-39150 Sentence denotes Hepatotoxicity reported; frequency not yet known.
T269 39151-39201 Sentence denotes Not a significant inducer/inhibitor of CYP enzymes
T270 39202-39242 Sentence denotes Lopinavir/ritonavir Nausea and vomiting:
T271 39243-39270 Sentence denotes 5%–10% (higher in children:
T272 39271-39290 Sentence denotes 20%)Abdominal pain:
T273 39291-39306 Sentence denotes 1%–10%Diarrhea:
T274 39307-39372 Sentence denotes 10%–30% + dose-dependentOther: dysguesia in adults <2%, children:
T275 39373-39410 Sentence denotes 25%, increased serum amylase, lipase:
T276 39411-39417 Sentence denotes 3%–8%.
T277 39418-39435 Sentence denotes Likelihood score:
T278 39436-39509 Sentence denotes D (possible, rare cause of clinically apparent liver injury).Description:
T279 39510-39691 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 39692-39806 Sentence denotes Substrate for: CYP3A4, CYP2D6P-gpInducer for: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A1Inhibitor for: CYP3A4
T281 39807-39835 Sentence denotes Favipiravir Nausea/vomiting:
T282 39836-39851 Sentence denotes 5%–15%Diarrhea:
T283 39852-39894 Sentence denotes 5%Limited data available Likelihood score:
T284 39895-39917 Sentence denotes Not scoredDescription:
T285 39918-39956 Sentence denotes 3% prevalence, but few data available.
T286 39957-40051 Sentence denotes Inhibitor for: CYP2C8 and aldehyde oxidaseMetabolized by xanthine oxidase and aldehyde oxidase
T287 40052-40173 Sentence denotes The Cao et al89 RCT did not show a significant increase in hepatotoxicity in the treatment compared to the control group.
T288 40174-40557 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 40558-40782 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 40783-40831 Sentence denotes Acute liver failure, although reported, is rare.
T291 40832-40979 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 40981-40992 Sentence denotes Favipiravir
T293 40993-41050 Sentence denotes There are 2 published studies on favipiravir in COVID-19.
T294 41051-41291 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 41292-41385 Sentence denotes Hepatotoxicity characterized by any elevation in AST or ALT was reported in 7.76% (9 of 116).
T296 41386-41651 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 41653-41761 Sentence denotes Limitations of the Evidence on Gastrointestinal and Liver Manifestations in Patients With COVID-19 Infection
T298 41762-41827 Sentence denotes The individual studies in our analysis were at high risk of bias.
T299 41828-41969 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 41970-42171 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 42172-42262 Sentence denotes Most studies did not report on the duration of the GI symptoms preceding the presentation.
T302 42263-42467 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 42468-42586 Sentence denotes LFTs were mostly reported as the mean/median value of the entire cohort and without cutoff values for the institution.
T304 42587-42665 Sentence denotes Many of the studies did not report on underlying chronic GI or liver diseases.
T305 42666-42805 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 42806-43001 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 43002-43167 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 43168-43242 Sentence denotes There may be additional limitations of our findings based on our analysis.
T309 43243-43447 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 43448-43617 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 43618-43711 Sentence denotes As a result, this may have led to an over- or underestimation of the pooled effect estimates.
T312 43712-43920 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 43921-44022 Sentence denotes An important strength of this study is the appropriate statistical analysis used to pool proportions.
T314 44023-44264 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 44265-44491 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 44492-44777 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 44779-44847 Sentence denotes Limitations of Current Evidence on Treatment-Related Adverse Effects
T318 44848-45039 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 45040-45235 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 45236-45364 Sentence denotes As ongoing clinical trials are completed regarding efficacy of therapy, additional data regarding Gl adverse events will emerge.
T321 45366-45405 Sentence denotes Evidence Gaps and Guidance for Research
T322 45406-45622 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 45623-45962 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 45963-46084 Sentence denotes Other clinical decisions, including optimal medication management and treatment decisions, are still under investigation.
T325 46085-46200 Sentence denotes We encourage clinicians to contribute to these registries to further enhance understanding in these subpopulations.
T326 46201-46320 Sentence denotes Table 4 provides guidance for future studies of GI manifestations in patients with COVID-19 or other similar pathogens.
T327 46321-46397 Sentence denotes Table 4 Guidance and Research Considerations for Future Studies of COVID-19a
T328 46398-46617 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 46618-46980 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 46981-47149 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 47150-47332 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 47333-47438 Sentence denotes Investigators should avoid:• Undefined sampling (convenience sampling), including undefined time periods.
T333 47439-47596 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 47597-47785 Sentence denotes Investigators should consider stratification for GI comorbidities, such as inflammatory bowel disease and cirrhosisInvestigators should consider stratification by outpatients vs inpatients
T335 47786-48624 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 48625-48813 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 48814-48906 Sentence denotes • severe defined as tachypnea, oxygen saturation ≤93% at rest, or PaO2/FiO2 ratio <300 mm Hg
T338 48907-49052 Sentence denotes • critical respiratory failure requiring mechanical ventilation, septic shock, or other organ dysfunction or failure that requires intensive care
T339 49053-49129 Sentence denotes Patients can be stratified by:• Disease severity and presence of GI symptoms
T340 49130-49157 Sentence denotes • Disease severity and LFTs
T341 49158-49256 Sentence denotes Symptoms and their duration before development of a severe stage of the disease should be reported
T342 49257-49543 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 49544-49785 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 49786-49983 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 49984-50066 Sentence denotes Finally, peer-review remains critical to the process of disseminating information.
T346 50067-50378 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 50380-50386 Sentence denotes Update
T348 50387-50456 Sentence denotes Recommendations in this document may not be valid in the near future.
T349 50457-50591 Sentence denotes We will conduct periodic reviews of the literature and monitor the evidence to determine whether recommendations require modification.
T350 50592-50720 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 50722-50733 Sentence denotes Conclusions
T352 50734-50931 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 50932-51145 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 51146-51487 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 51488-51703 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 51704-51865 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 51866-52005 Sentence denotes Further research is needed to clarify the implications of SARS-CoV-2 in stool and potential impact on transmission and clinical management.