key: cord-0694560-whyinaey authors: Shehab, M.; Alrashed, F.; Shuaibi, S.; Alajmi, D.; Barkun, A. title: Gastroenterological and Hepatic Manifestations of Patients with COVID-19, Prevalence, Mortality by Country, and Intensive Care Admission Rate: Systematic Review and Meta-analysis. date: 2020-11-03 journal: nan DOI: 10.1101/2020.10.29.20207167 sha: f4da10ee4e35806d0d4e876bbbb52e9532cd2f45 doc_id: 694560 cord_uid: whyinaey Background & Aims Patient infected with the SARS-COV2 usually report fever and respiratory symptoms. However, multiple gastrointestinal (GI) manifestations such as diarrhea and abdominal pain has been described. The aim of this study was to evaluate the prevalence of GI, liver function test (LFT) abnormalities, and mortality of COVID19 patients. Methods We performed a systematic review and meta-analysis of published studies that included cohort of patients infected with SARSCOV2 from December 1st, 2019 to July 1st, 2020. We collected data from the cohort of patients with COVID19 by conducting a literature search using PubMed, Embase, Scopus, and Cochrane according to the preferred reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines. We analyzed pooled data on the prevalence of overall and individual gastrointestinal symptoms, LFTs abnormalities and performed subanalyses to investigate the relationship between gastrointestinal symptoms, geographic location, fatality, and ICU admission. Results The available data of 17,802 positive patients for SARS-COV2 from 120 studies were included in our analysis. The most frequent manifestations were diarrhea, nauseated elevated LFTs. The overall and GI fatality were 7.2% , and 1% respectively. Subgroup analysis showed non statistically significant associations between GI symptoms/LFTs abnormalities and ICU admissions (OR=3.41, 95%). The GI mortality rate was 0.58% in China and 3.5% in the United States. Conclusion Digestive symptoms and LFTs abnormalities are common in COVID-19 patients. Our subanalysis shows that the presence of gastrointestinal and liver manifestations does not appear to affect mortality, or ICU admission rate. However, the mortality rate was higher in the United States compared to China. In December 2019 China was struck with a new strain of Coronavirus, Novel Coronavirus (2019 nCov). Within a short period of time, it soon spread to a full pandemic. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi. org/10.1101 org/10. /2020 It was first noticed by the innumerable cases of pneumonia that suddenly surged amongst local inhabitants in the Province of Wuhan. Soon, the virus was detected through sequencing leading to officially being renamed severe acute respiratory syndrome coronavirus 2 (SARS-COV2) by the International Committee on Taxonomy of Viruses [1] [2] . The disease caused by Coronavirus (SARS-COV2) was allocated the title of COVID-19 or 'Coronavirus disease' [3] . Coronaviruses in general are single stranded RNA viruses falling under the family of Coronaviridae which also include MERS (MERS Cov) and SARS (SARS Cov) [4] . By the end of May, 5,796, 257 cases of COVID-19 have officially been confirmed worldwide and as of July the number of confirmed cases passed the 12 million mark [5] . It has been established that the transmission of Coronavirus (SARS-COV2) occurs from person to person through upper airway tract (droplet infection) or direct contact [6] . The virus can also be detected in saliva, urine, gastrointestinal tract and possibly through airborne spread [7, 8] . The spectrum of symptoms attributable to SARS-COV2 include fever, cough, myalgia, fatigue, and to a lesser extent headache. Patients may also be asymptomatic [9] [10] [11] . Diarrhea, nausea and vomiting, as well as liver involvement have all been reported in the literature [12, 13] . In fact, gastrointestinal involvement is plausible given that angiotensin converting enzyme 2 (ACE2), the major human cellular receptor for the SARS-COV2, is expressed in the gastrointestinal tract as well as liver cells [14] . We thus conducted a systematic review of published gastrointestinal and liver symptoms associated with COVID-19 on the basis of disease severity, age group, and geographical region. A systematic review was conducted using Pubmed, Scopus, Cochrane, and Embase databases. Medical literature searches for human studies were performed from December 1 st , 2019 up to July 1 st , 2020. The key terms used for the literature search were (("COVID-19" OR "COVID 2019" OR "severe acute respiratory syndrome coronavirus 2" OR "severe acute respiratory syndrome coronavirus 2" OR "2019 nCoV" OR "SARS-COV2" OR "2019nCoV" OR ("severe acute respiratory syndrome coronavirus 2" OR "SARS-COV2" AND GASTROINTESTINAL AND (MANIFESTATIONS OR CLINICAL CHARACHTERISTICS) OR ("gastrointestinal tract" OR ("gastrointestinal' AND "tract") OR "gastrointestinal tract" OR ("gi" AND "tract") 5 OR ("fatality" or "Mortality"). In addition, a manual search of all review articles, editorials and retrieved original studies was also performed. All procedures used in this meta-analysis were consistent with the Preferred Reporting Items for Systematic Reviews and Meta analyses (PRISMA) guidelines and prespecified protocol, which described our method and analysis before data collection was initiated (see supplementary PRISMA check list). Data were independently abstracted based on our protocol by two investigators (MS and FA) and any discrepancies between the two authors were resolved through discussion. Inclusion and exclusion criteria were defined prior to the literature search. The inclusion criteria were (1) study type: case reports/case series (including chart reviews), prospective/retrospective cohort studies, case control studies, cross sectional studies and randomized controlled trials; (2) patients population: Adults patients with COVID-19; inpatient or outpatient setting and (3) Outcome measured: At least one GI manifestation reported and LFT abnormality, defined as any value above the normal upper limit. Exclusion criteria were (1) Review, opinion, abstracts from conferences, editorials, commentary articles, review articles and meta analyses; (2) studies without data for retrieval; (3) duplicate studies; (4) Asymptomatic patients with COVID-19: (5) studies that did not report gastrointestinal symptoms. Data extraction was performed using Microsoft excel. The following data were extracted: 1. Study: author, journal, date, country, number of patients, and study type. 2. Patients characteristics: mean age, ethnicity, gender, and comorbidities. 3. Overall fatality rate and fatality rate by country. The Methodical Index for Nonrandomized Studies (MINORS) [15] was used to assess bias risk (see table 2 ). In addition, risk of bias was assessed based on 4 domains: selection, ascertainment, causality, and reporting. An overall judgment of risk of bias was made based on factors deemed to be most critical for the systematic review (selection criteria, ascertainment of outcome, and followup duration). Our primary analysis focused on assessing the weighted pooled prevalence of GI symptoms/LFT abnormalities in patients with COVID-19 infection, occurring any time during the course of illness. We also conducted subanalyses that looked at the association between GI symptoms/LFT abnormalities and mortality as well as ICU admission. Categorical variables were described as count (%). Continuous variables were described using mean (SD) if they are normally distributed, median (IQR) if they are not. We pooled the single arm event rates using a random effects method and we measured heterogeneity within our studies using the I 2 statistic. Subanalyses were described and tested using odd ratios and 95% confidence interval to determine statistical significance. Stata 16 was used to calculate odd ratios and their respective 95% CI and create Forest and Box plots. To examine the effect of the quality of studies on our results, we performed a sensitivity analysis on the prevalence of GI symptoms and LFTs abnormalities by excluding low qualities studies. These include case reports, case series and case control studies. We also assessed selected outcomes comparing patients with versus without GI/LFTs abnormalities. Overall, 120 studies (supplementary table. S1) from 2355 potentially relevant citations were included in the analysis (Figure 1 ). Most of the included studies were single arm only, very few studies included comparator groups. Furthermore, outcome assessors in all 120 studies were not blinded. Both inpatients and outpatients studies were included. The risk of evidence imprecision 7 was rated as very serious, given that the included studies were all observational studies. Overall, all included studies were rated as having very serious risk of bias because they lacked a control group and had a high risk of confounding and selection bias. This systematic review included 120 studies with a total of 17,801 patients that tested positive for SARS-COV2 and were included in the analysis. The mean patient age was 52.6 (±14, 95% CI 48-57.3) and 47.6% of the patients were males. Most patients had several comorbidities, most common being hypertension (23.4%, 95% CI 21-27), diabetes mellites (13.4%, 95% CI, (12) (13) (14) (15) , and cardiovascular diseases (12.4%. 95% CI, (10) (11) (12) (13) (14) . GI symptoms included nausea, vomiting, and diarrhea. Heterogeneity statistic I2 is 94.5%, which signifies a significant heterogeneity among our studies. The most common GI/liver manifestations were elevated liver enzymes and diarrhea (supplementary figure.1). Specifically, GI manifestations of patients infected with SARS-COV2 are diarrhea 13.3% (95% CI 12 -16) , nausea (9.1%, 95% CI 9 -13) anorexia or loss of appetite (8.3%, 95% CI 8 -11), vomiting (6.4%, 95% CI 5 -8), abdominal pain (3%, 95% CI, 3-6), loss of taste (1.3%, 95% CI 1 -4), and elevated LFTs (23.7%, 95% CI 21 -27). The sensitivity analysis included 25 studies (supplementary: table S4). The results did not differ from our main analysis. Among the GI manifestations experienced by COVID-19 patients, diarrhea (13.1%, 95% CI, (12) (13) (14) , was still the most common symptom, followed by nausea (9.2%, 95% CI 8-11). The percentage of patients experiencing LFTs abnormalities was 24% (95% CI 21 -26). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi. org/10.1101 org/10. /2020 A total of 78 studies reported the incidence of mortality. The overall fatality rate of patients was 7% (95% CI 6 -10), (supplementary: table S5 ). The subgroup analysis included three studies [19] [20] [21] that directly compared mortality rate in patients with and without GI symptoms. In this analysis the number of patients who experienced gastrointestinal symptoms/liver test anomalies and those who did not were 227 and 326, respectively. The results showed that patients with GI manifestations//LFT abnormalities were no more likely to die compared to those who did not with a pooled odd of patients was not statistically significant 1.07 (95% CI 0.58 -1.97) ( figure 3 ). Moreover, out of the 78 studies, a total of 25 studies reported mortality in patients with GI/Liver manifestations (see figure 4) . A subanalysis of fatality rate in patients with GI symptoms based on their location showed that 27 out 4660 patients (0.58%) in China died (95% CI 0.5, 1.6), whereas 16 out 449 patients (3.5%) in the United States died (95% CI 2 -5). In addition, 3 studies from Taiwan, Korea, and Japan reported zero fatality (table.1). Only two studies [20, 21] reported differences in ICU admissions amongst patients manifesting GI symptoms/LFT abnormalities and patients without. The total number of patients with gastrointestinal problems or LFT abnormalities who were admitted in the ICU were 23 and the number of patients who did not experience gastrointestinal problems or LFT abnormalities and were admitted to the ICU were 156. No statistically significant difference in ICU admission rate was noted between those who experienced GI/LFTs abnormalities and those who did not. The This meta-analysis of 17,801 COVID-19 patients found that gastrointestinal symptoms are common in patients infected with SARS-COV2. Our study has several strengths. This is one of the more recent meta-analyses that summarizes the rapidly emerging and sometimes confusing (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.29.20207167 doi: medRxiv preprint microbiota transplant donors. Nevertheless, the unknown effect of COVID-19 on patients with preexisting gastrointestinal diseases and its influence on treatment and outcome is a cause for concern [140]. These implications warrant further investigation. The American Gastroenterological Association (AGA) and joint society recommend the use of enhanced personal protective equipment, including the use of N95 (or N99) masks instead of surgical masks, for health care workers performing upper or lower GI procedures regardless of COVID19 status [141] . It is believed that the prevalence of gastrointestinal symptoms is underestimated because the majority of studies only reported gastrointestinal symptoms on the day of admission but not throughout the disease course [142] . Furthermore, many earlier studies did not report on other gastrointestinal symptoms except for diarrhea [141, 143] . Based on these findings, clinicians must be aware that digestive symptoms, such as diarrhea, may be a presenting feature of COVID-19 that can arise before respiratory symptoms, and on rare occasions may be the only presenting manifestation of COVID-19. The analysis also found that elevated liver enzymes are a common laboratory marker of COVID-19 patients. Huang et al. showed that AST elevation was observed in 8 (62%) of 13 patients in the intensive care unit compared with only 7 (25%) of 28 patients who did not require care in an ICU [140] . On the other hand, one study from China showed that COVID-19 patients with underlying chronic hepatitis B infection did not have higher disease severity compared to the overall population [143] . Unfortunately, most studies report liver enzymes as the mean/median value of the entire cohort without cutoff values for a given institution rather than as a proportion of patients with elevated values. One aspect that remains to be determined is the impact of COVID-19 in patients with preexisting chronic liver diseases, such as viral hepatitis, and fatty liver disease. The pooled analysis showed that the overall fatality rate was 11.2%. While the finding is not statistically significant, any possible true difference in mortality may be worth further investigation among better defined COVID-19 patient subgroups with GI/LFT anomalies because one study showed that prevalence of severe disease was more common in patients who had gastrointestinal symptoms than those who did not [141] . Furthermore, a study by Wang et al found that abdominal pain was more frequent in patients who required ICU care than those who did not [142] . Although our finding was not statistically significant, the subgroup sub analysis All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; showed that patients who did not have gastrointestinal manifestations were more likely to be admitted to the ICU. This possible finding also requires additional data. Most of the studies we base our analyses on are observational, single arm cohorts. The lack of control groups and comparison arms can lead to bias due to confounding. Also, our subanalyses might have been affected by small sample sizes. Additionally, regarding fatality rate among COVID-19 patients, most of the studies did not differentiate between the GI symptoms and LFTs abnormalities when performing head to head comparison. In this meta-analysis, we summarize the recent reports of digestive symptoms/LFT anomalies among patients infected with SARS-COV2. Gastrointestinal symptoms are commonly observed in patients with COVID-19, therefore, clinicians should be aware that diarrhea and nausea can be the only manifestations of COVID-19 patients. Our sub analysis showed that patients infected with SARS-COV2 and exhibiting digestive symptoms had higher mortality rate in the United States compared to China. We also could not find statistically significant association between ICU admission in patients with GI symptoms compared to those without digestive symptoms or hepatic manifestations due to small sample size; however, further investigation is warranted to better assess this possible association. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.29.20207167 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; Hubei, China, The American Journal of Gastroenterology: 2020;115 (5) All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. 2020;10.1007/s15010-020-01432-5. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; Review and Meta-analysis. Gastroenterology. 2020;10.1053/j.gastro.2020.03.065. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; Reported GI Symptoms Abnominal_pain Diarrhea Nausea Vomiting Anorexia or loss of appetite loss of taste Elevated liver enzymes All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 4 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 3 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 8, 9, 20 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15) . Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16] ). Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; Zou L et. al. -1 1 -1 -- Table. S4 Sensitivity Analysis (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10. 1101 COVID-19) in China Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARSCoV-2): Facts and myths Coronavirus disease 2019 (COVID-19): a perspective from China Clinical characteristics of 2019 novel coronavirus infection in China Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses Methodological index for non randomized studies (minors): development and validation of a new instrument Viral loads in clinical specimens and SARS manifestations Gastrointestinal symptoms of 95 cases with SARS-COV2 infection PhD1,2; Mu, Mi MD3,4; Yang, Pengcheng MD5 PhD11 Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Effect of gastrointestinal symptoms on patients infected with COVID-19 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. China All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Supplementary figure S1 Forest plot depicting prevalence of diarrhea All rights reserved. No reuse allowed without permission.