key: cord-0774665-hffxb7bm
authors: Cheung, Ka Shing; Hung, Ivan FN.; Chan, Pierre PY.; Lung, K. C.; Tso, Eugene; Liu, Raymond; Ng, Y. Y.; Chu, Man Y.; Chung, Tom WH.; Tam, Anthony Raymond; Yip, Cyril CY.; Leung, Kit-Hang; Yim-Fong Fung, Agnes; Zhang, Ricky R.; Lin, Yansheng; Cheng, Ho Ming; Zhang, Anna JX.; To, Kelvin KW.; Chan, Kwok-H.; Yuen, Kwok-Y.; Leung, Wai K.
title: Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis
date: 2020-04-03
journal: Gastroenterology
DOI: 10.1053/j.gastro.2020.03.065
sha: 8b715b57aab3925658256a476e0b1ea50fc4ee38
doc_id: 774665
cord_uid: hffxb7bm

Abstract Background & Aims Infection with SARS-CoV-2 causes COVID-19, which has been characterized by fever, respiratory, and gastrointestinal symptoms as well as shedding of virus RNA into feces. We performed a systematic review and meta-analysis of published gastrointestinal symptoms and detection of virus in stool, and also summarized data from a cohort of patients with COVID-19 in Hong Kong. Methods We collected data from the cohort of patients with COVID-19 in Hong Kong (n=59; diagnosis from February 2 through Feb 29, 2020), and searched PubMed, Embase, Cochrane and three Chinese databases through March 11, 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We analyzed pooled data on the prevalence of overall and individual gastrointestinal symptoms (anorexia, nausea, vomiting, diarrhea, and abdominal pain or discomfort) using a random effects model. Results Among the 59 patients with COVID-19 in Hong Kong, 15 patients (25.4%) had gastrointestinal symptoms and 9 patients (15.3%) had stool that tested positive for virus RNA. Stool viral RNA was detected in 38.5% and 8.7% among those with and without diarrhea, respectively (P=.02). The median fecal viral load was 5.1 log10cpm in patients with diarrhea vs 3.9 log10cpm in patients without diarrhea (P=.06). In a meta-analysis of 60 studies, comprising 4243 patients, the pooled prevalence of all gastrointestinal symptoms was 17.6% (95% CI, 12.3%–24.5%); 11.8% of patients with non-severe COVID-19 had gastrointestinal symptoms (95% CI, 4.1%–29.1%) and 17.1% of patients with severe COVID-19 had gastrointestinal symptoms (95% CI, 6.9%–36.7%). In the meta-analysis, the pooled prevalence of stool samples that were positive for virus RNA was 48.1% (95% CI, 38.3%–57.9%); of these samples, 70.3% of those collected after loss of virus from respiratory specimens tested positive for the virus (95% CI, 49.6%–85.1%). Conclusions In an analysis of data from the Hong Kong cohort of patients with COVID-19 and a meta-analysis of findings from publications, we found that 17.6% of patients with COVID-19 had gastrointestinal symptoms. Virus RNA was detected in stool samples from 48.1% patients—even in stool collected after respiratory samples tested negative. Healthcare workers should therefore exercise caution in collecting fecal samples or performing endoscopic procedures in patients with COVID-19—even during patient recovery.

In December 2019, a cluster of unidentified form of viral pneumonia cases was first reported in Wuhan, China, which swiftly spread to the rest of China and then the rest of the world within a very short period. The virus was subsequently identified to be a novel coronavirus (CoV) that belongs to the beta-coronavirus lineage B with more than 80% resemblance to the previously reported SARS-CoV in 2003. Up until 16 March of 2020, more than 150,000 cases were reported from more than 150 countries or regions across the globe, with more than 81,000 cases in China, 21,000 cases in Italy, 12,000 cases in Iran and 8,100 cases from Korea.

Although the number of new cases seem to be declining in China, the numbers of cases are rising in an exponential manner in Europe, North America and Middle East countries. The death toll has already reached more than 5,700 globally with more than 3,000 from the Hubei Province of China, where Wuhan city is located. In response to the emerging threat posed by this virus, the World Health Organization (WHO) has declared a Public Health Emergency of International Concern on 30 January 2020, and further labelled it as a pandemic on 11 March 2020.

The disease was named as COVID-19, which was an abbreviation for coronavirus disease 2019, by the WHO and the virus was termed as the SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV). The SARS-CoV-2 is a positive-sense singlestranded RNA virus and has strong genetic similarity to bat coronaviruses but the intermediate reservoir has yet to be identified. 1 Together with the other two previously identified coronaviruses SARS-CoV and MERS-CoV that cause Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome (MERS), this is the third coronavirus identified to cause severe viral pneumonia in humans ( Table 1) . Similar to the other two coronaviruses, the SARS-CoV2 has very high infectivity as no one has immunity, resulting in an ongoing global health crisis.

Based on existing observation, the case fatality rate of COVID-19 is lower than SARS and MERS and is estimated to be about 1-2%, but is much higher in older patients. In addition to age, a high Sequential Organ Failure Assessment (SOFA) score and D-dimer level >1ug/L on admission are associated with poor prognosis. 2 Apart from respiratory symptoms, gastrointestinal manifestations are common in patients with SARS, MERS and the latest COVID-19. We previously reported the high prevalence of enteric symptoms in patients with SARS and demonstrated acute viral replication in the small intestinal mucosa of SARS patients. 3 It is estimated that 16-73% of patients had diarrhea during the course of SARS illness. Fecal shedding of SARS-CoV RNA was found in 86-100% of patients during day 6-14 of illnesses and could persist for >30 days of illness. 4, 5 It was subsequently found that SARS-CoV bind to the angiotensin-converting enzyme 2 (ACE2) receptors of the intestinal and respiratory tracts, which is the entry point for the virus to the epithelial cells. 6 Similarly, up to a quarter of patients with MERS also reported gastrointestinal symptoms such as diarrhea or abdominal pain. 7 Again, MERS-CoV could be detected in 15% of stool samples, and could persist for up to 24 days after diagnosis. 8 It was shown that the human intestinal tract including primary intestinal epithelial cells, small intestine explants, and intestinal organoids are highly susceptible to MERS-CoV. 9 Enteric manifestations of SAR-CoV2 not only pose important diagnostic challenge to clinicians when facing patients with mild COVID-19 symptoms on initial presentation, but also signify potential fecal transmission of this virus. With increasing number of reported cases of COVID-19, there is a pressing need to systemically summarize the enteric manifestations of COVID-19 and the temporal pattern of fecal shedding of the SARS-CoV-2 virus, particularly to gastroenterologists and endoscopists who may not be familiar with this disease.

This study aimed to summarize the existing data on gastrointestinal manifestations of COVID-19 and the temporal pattern of fecal shedding of SARS-CoV2 based on published data as well as the data from our recent cohort of COVID-19 patients in Hong Kong.

We included a cohort of 59 patients with virologically confirmed COVID-19 diagnosed between 2 nd and 29 th February 2020 in Hong Kong. The prevalence of gastrointestinal symptoms (including nausea/vomiting, diarrhea and abdominal pain/discomfort) and viral load in stool collected on admission was reported.

Three databases including Pubmed, Embase, and Cochrane Library were searched following the PRISMA guideline 10 

Two authors (KSC, IFH) determined the eligibility of studies independently, and dissonance was resolved by the third author (WKL). The inclusion criteria included (1) study population: COVID-19 patients (including adult or pediatric patients and pregnant women); (2) study design: case reports/case series, prospective/retrospective cohort study, case-control study, and randomized controlled trials. There was no language restriction. The exclusion criteria were (1) patients without virological proof of SARS-CoV2 infection; (2) asymptomatic patients infected with SARS-CoV2; (3) studies that did not report gastrointestinal symptoms; and (4) review articles, meta-analyses, editorials, and other forms (e.g. commentary).

If all gastrointestinal symptoms were not reported and the number of events of any individual gastrointestinal symptom was less than one, it was regarded as "not available" and excluded from the meta-analysis of all gastrointestinal symptoms. However, this study was still included in the meta-analysis of individual gastrointestinal symptom if the proportion of patients with that symptom was reported. Two additional studies 11, 12 which did not report on gastrointesitnal symptoms but provided data on stool viral RNA was included in the metaanalysis of stool viral RNA only.

For eligible articles, we recorded items including first authors, site of study, inclusion/exclusion criteria, sample size, age, sex, disease severity, any gastrointestinal symptoms (anorexia, nausea/vomiting, diarrhea, or abdominal pain), other symptoms (fever, cough, expectoration and dyspnea). Severe disease was defined according to the American Thoracic Society and Infectious Disease Society of America guidelines for communityacquired pneumonia, 13 need of intensive care unit (ICU) admission, and death.

All statistical analyses were performed using R version 3.

Computing) statistical software. Continuous variables were expressed as median (interquartile range [IQR]) or mean (± standard deviation [SD]). The prevalence of gastrointestinal symptoms was expressed as proportion and 95% confidence interval (95% CI) using the random effects model, and was presented as Forest plot. We used Cochran Q test to detect heterogeneity among studies, with a p-value <0.10 indicating significant heterogeneity.

We calculate I 2 statistic to measure the proportion of total variation in study estimates attributed to heterogeneity. I 2 values of <25%, 25-75%, and >75% indicate low, moderate, and high heterogeneity, respectively. 14 Subgroup analysis was performed according to whether studies were from China or other countries, in or outside of the Hubei province, the disease severity, and patient group (adults, pediatric patients and pregnant women). On presentation, stool viral RNA was positive in 9 (15.3%) patients, and the median viral load was 4.7 (range: 3.4-7.6) log 10 copies per mL (cpm). The proportion of patients with detectable stool viral RNA was higher among those with diarrhea than those without diarrhea Table 2 including the hospital admission period, places in which the patients were recruited, sample size, age, sex, disease severity, non-gastrointestinal symptoms (fever and respiratory symptoms) on presentation, and gastrointestinal symptoms (anorexia, nausea/vomiting, diarrhea and abdominal pain/discomfort). The median age of patients was 45.1 years (IQR: 41.0-54.8), and 57.3%

were male. Among studies that reported disease severity, severe disease accounted for 1.3-62.3%. Significant heterogeneity among studies was seen for anorexia, nausea/vomiting, and diarrhea (p<0.001; I 2 =74.6-85.2%), while the heterogeneity was less for abdominal pain/discomfort (p=0.008; I 2 =57.0%).

The pooled prevalence of all gastrointestinal symptoms was 16.1% (95% CI: 10.9-23.0) and 33 .4% (95% CI: 15.2-58.3) in studies from China and other countries, respectively ( Figure   2 ). There was no significant subgroup difference between the studies based on country origin (p=0.09). However, there was significant heterogeneity among the studies conducted in China (p=<0.001; I 2 =92.4%) but not among the studies from other countries (p=0.174;

Among studies from China, the prevalence of all gastrointestinal symptoms in the single study of 1,099 patients from 552 hospitals by Guan et al 15 was 5.0% (95% CI: 3.9-6.5).

( Figure 2 ). For studies from Hubei Province, the pooled prevalence of all gastrointestinal symptoms was 16.2% (95% CI: 9.3-26.7), whereas those from outside of Hubei Province was 18.6% (95% CI: 12.2-27.2). There was a significant subgroup difference between the studies from and outside of Hubei Province (p<0.001), and there was also significant heterogeneity among the studies (p=<0.001; I 2 =93.5% and I 2 =76.8%).

There were 11 studies that compared the prevalence of all gastrointestinal symptoms according to the severity of COVID-19 (number of patients with severe and non-severe disease was 451 and 1,731, respectively) (eTable 1). The pooled prevalence of all gastrointestinal symptoms was 17.1% (95% CI: 6.9-36.7) and 11.8% (95% CI: 4.1-29.1) in patients with severe and non-severe disease, respectively (Figure 4) . There was significant heterogeneity among the studies (p<0.001; I 2 =90.9% and I 2 =97.7%).

There were 53 studies on adults, 4 on pediatric patients, and 3 on pregnant women. The corresponding pooled prevalence of all gastrointestinal symptoms in adults, pediatric patients, and pregnant women was 16.7% (95% CI: 11.4-23.9), 24.8% (95% CI: 9.6-50.4), and 20.0% (95% CI: 4.3-58.2). There was no significant subgroup difference (p=0.717).

None of the studies tested stool viral RNA on the day of hospitalization except our current study. There were 12 studies which tested for viral RNA in stool; the study by Wang 

In this meta-analysis of 4,243 COVID-19 patients from six countries, the pooled prevalence of all gastrointestinal symptoms (including anorexia, nausea/vomiting, diarrhea or abdominal pain) was 17.6%. Anorexia was the most common gastrointestinal symptom (26.8%), followed by diarrhea (12.5%), nausea/vomiting (10.2%) and abdominal pain/discomfort (9.2%). In the Hong Kong cohort, viral RNA was detected in the stool of 15.3% of patients on presentation, including patients without any gastrointestinal symptoms. Moreover, patients with diarrhea on presentation had higher stool RNA positivity and viral load than those without diarrhea. We also noted that 48.1% of patients had detectable stool viral RNA during the course of illnesses. More importantly, prolonged shedding of viral RNA in stool rather than respiratory samples was observed in 70.3% of patients, which could be up to ≥33 days from illness onset.

Although diarrhea is one of the common gastrointestinal manifestations, the presence of constipation could not rule out COVID-19, as a case report of four patients reported that constipation was noted in two. 17 Despite the inclusion of >60 reports, the actual prevalence of any gastrointestinal symptoms could be underestimated as many earlier studies did not report other gastrointestinal symptoms except for diarrhea [18] [19] [20] [21] [22] [23] . Moreover, majority of studies only reported gastrointestinal symptoms on the day of admission but not throughout the disease course. The issue is further complicated by the difference in the criteria on diagnosing diarrhea in various hospitals. 24 With more than 80% resemblance to SARS-CoV, infection of the gastrointestinal tract by SARS-CoV-2 is not unexpected, which is proposed to be mediated via the ACE2 cell receptors. ACE2 receptors are highly expressed in the small intestine, especially in proximal and distal enterocytes, 6, 24 and the binding affinity of ACE2 receptors determines infectivity.

As ACE2 modulates intestinal inflammation, 25 Gastrointestinal manifestations were also commonly reported during the SARS and MERS outbreaks. In the previous SARS outbreak in Hong Kong, 16% patients reported diarrhea. 5 Similarly, up to a quarter of patients with MERS also reported gastrointestinal symptoms such as diarrhea or abdominal pain. 7 In our COVID-19 cohort in Hong Kong, 22% of patients reported diarrhea, which was slightly higher than our previous SARS cohort. However, many of these patients were from a large outbreak during dinner gathering in the Lunar New Year, who might contract the virus through both fecal-oral and respiratory routes, thus partly explaining the higher frequency of gastrointestinal manifestations. Previous studies during SARS demonstrated that viral load in the stool was strongly associated with presence of diarrhea. 26 In our COVID-19 cohort, patients with diarrhea also had higher prevalence of detectable stool viral RNA on presentation. Importantly, gastrointestinal manifestations may be the only initial symptoms in some COVID-19 patients. In the study by An et al, 27 Our meta-analysis showed that the prevalence of severe disease was more common in patients who had gastrointestinal symptoms than those who did not (17.1% vs 11.8%). Wang et al reported that abdominal pain was more frequent in patients who required ICU care than those who did not. 28 Healthcare professionals should be aware of the potential prognostic implications in patients with gastrointestinal symptoms, whom may require more close monitoring.

In our COVID-19 cohort in Hong Kong, we found that 15.3% of patients tested positive for stool viral RNA on the day of admission. As for the meta-analysis, we found that 48.1% of patients had stool samples ever tested positive for viral RNA during the illness. Due to the lack of systematic stool collection protocol in currently published studies, the full extent of the stool positive rate remains to be characterized, particularly the peak timing and extent of fecal shedding. It is however alarming to note that 70.3% of patients had stool viral RNA remaining positive despite negative respiratory specimens. Although it is uncertain at this moment whether these are live virus particles or just RNA fragments released from the intestinal cells, this finding could raise a serious concern on the isolation policy for the COVID-19 patients, particularly during the recovery phase. During the SARS outbreak in 2003, it was reported that the sewage system of the Amoy Gardens in Hong Kong served as the major source of infection from patients excreting coronavirus RNA. 4 The sewage concentrates of two hospitals receiving SARS patients in Beijing were also found to have SARS-CoV RNA detected at that time. 29 Intuitively, proper handling of the excreta of COVID-19 patients should still be strongly enforced despite repeatedly negative results in respiratory specimens.

Another interesting feature of COVID-19 is the recurrent infection in some patients, i.e. recurrent symptoms after apparent recovery with positive respiratory specimens for viral RNA again after initial clearance. It remains to be determined whether the persistence of viral RNA in stool may be used as surrogate monitor for the recurrent infection in some patients.

There are several strengths of our study. This is the first meta-analysis that summarized the rapidly emerging and sometimes confusing literature on COVID-19 on the prevalence of the overall and individual gastrointestinal manifestations. The comprehensive inclusion of >60 studies allows a more precise estimation of the prevalence of gastrointestinal symptoms.

Subgroup analysis found that the presence of gastrointestinal symptoms was associated with a more severe disease course, highlighting the importance of a more detailed inquiry into gastrointestinal symptoms for both diagnostic and prognostic purposes. The alarmingly high prevalence of viral shedding in stool, particularly after viral RNA negativity in respiratory specimens, prompts further research into the viral shedding dynamics in different systems, as well as the potential transmission risk via fecal-oral route, which carries significant infection control and public health implications. A few limitations of this study should be noted. As mentioned, gastrointestinal symptoms may be under-reported in some studies, which may lead to a lower pooled prevalence rate. Second, studies of large sample size on ethnic groups other than Chinese are currently lacking, precluding a more precise estimate of the prevalence of gastrointestinal manifestations in other ethnic groups.

In this study, we found that gastrointestinal symptoms were present in 17.6% of patients diagnosed with COVID-19. Moreover, viral shedding in stool was detected in 48.1% of patients, and could persist for up to ≥33 days from illness onset even after viral RNA negativity in respiratory specimens. Gastrointestinal symptoms are color coded as shown (abdominal pain/discomfort, orange; vomiting, yellow; diarrhea, green).

The details of 13 "R-S+" patients are shown in case number : 2, 5, 8, 10, 11, 14, 15, 18, 24, 26, 27, 28 and 29. Abbreviations: COVID-19, coronavirus disease 2019; D, Day of symptom onset; "R-S+", respiratory specimen negative for viral RNA but stool specimen still positive for viral RNA * Nasopharyngeal/oropharyngeal and stool samples were tested for viral RNA within 4-48 hours and 3-13 days after illness onset respectively in the study by Cai J et al; the authors did not state the exact day from illness onset on which the respiratory and stool samples were tested for individual patients; in addition, all patients were tested negative for two consecutive respiratory specimens, but the exact day on which the second consecutive respiratory specimens tested negative for viral RNA was not stated # sample size of Young BE et al was 18 (3 had diarrhea on presentation); the authors did not state which particular patient who tested for stool viral RNA (n=8) had diarrhea ^ The number of days (D) represents the days from the symptom onset (fever, cough, dyspnea, sore throat, nasal congestion, rhinorrhea, sneezing, anorexia) was not reported in the study by Zhang 

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Author names in bold designate shared co-first authorship

1 (100%) 0 * Severe disease was defined as the American Thoracic Society and Infectious Disease Society of America guidelines for community-acquired pneumonia, need of ICU admission, and death. # If all gastrointestinal symptoms were not reported and the number of events of any individual GI symptoms was less than one, it was regarded as "not available" and was excluded from the meta-analysis of all gastrointestinal symptoms. However, this study was still included in the meta-analysis of individual gastrointestinal symptom if the proportion of patients with that symptom was reported. Abbreviations: COVID-19, coronavirus disease 2019; SD, standard deviation; IQR: interquartile range; GI, gastrointestinal; C, cough; E, expectoration; D, dyspnea; n.a., not available; N: nausea; V: vomiting; ICU, intensive care unit; UK, United Kingdom; USA, United States of America What you need to know: BACKGROUND AND CONTEXT: Infection with SARS-Co-2 virus, which causes COVID-19, results in respiratory as well as gastrointestinal symptoms; virus RNA has been detected in fecal samples.

A meta-analysis of publications found that gastrointestinal symptoms have been reported in 17.6% of patients with COVID-19. Stool samples from 48.1% of patients tested positive for virus RNA; stool samples from 70.3% of these patients tested positive for virus RNA even after respiratory specimens tested negative.

This study analyzed mostly data from reported cases from China; systematic data collection was lacking for most studies.IMPACT: Gastrointestinal symptoms occur in almost 18% of patients with COVID-19. Virus RNA can be detected in fecal samples-even those collected after respiratory samples test negative.Lay Summary: Many patients with COVID-19 develop gastrointestinal symptoms. The virus can be detected in stool, so patients and caregivers should take care to avoid fecal-oral transmission of the virus.