key: cord-0997232-t3syriow
authors: Ghoshal, Uday C.; Ghoshal, Ujjala; Dhiman, Radha Krishan
title: Gastrointestinal, and hepatic involvement in Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection: A review
date: 2020-06-11
journal: J Clin Exp Hepatol
DOI: 10.1016/j.jceh.2020.06.002
sha: b3cd8877f88f8c064f047818f49022bd00c18f2e
doc_id: 997232
cord_uid: t3syriow

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection has caused a pandemic Coronavirus Disease-19 (COVID-19) that began in Wuhan city, China, in December 2019. Till 14(th) April 19,39,801 people have been affected by this virus 1,20,897 of whom died. Though respiratory symptoms are the typical manifestation of this disease, gastrointestinal (GI) symptoms such as anorexia, nausea, vomiting, loss of taste sensation, diarrhea, abdominal pain, and discomfort have been reported. The pooled prevalence of GI symptom is 17.6% (95% confidence interval [CI], 12.3%–24.5%), as indicated in a meta-analysis. A few studies suggested that the presence of GI symptoms is associated with poorer prognosis. The virus is excreted in feces during the acute disease, and even after the nasopharyngeal swab has become negative for viral ribonucleic acid (RNA). Fecal viral excretion may have clinical significance due to possible feco-oral transmission of the infection. 10.5% to 53% of patients with COVID-19, particularly those with severe disease, have been shown to have an elevation of hepatic enzymes through biochemical and clinical jaundice, are uncommon. Knowledge about this disease in general and GI involvement, in particular, is currently evolving.

On January 7 th, 2020, a novel Coronavirus was named and identified as Severe Acute

Taxonomy of Viruses (ICTV). 1 The current pandemic of Coronavirus Disease-19 (COVID- 19) began in Wuhan city, China, in December 2019. 1 Scientists from Wuhan Institute of Virology, Wuhan, China, initially identified the SARS-CoV-2 by metagenomic analysis of bronchoalveolar lavage fluid from a patient with pneumonia. 2, 3 This virus is an RNA virus belonging to the family of β coronavirus and can cause minor illnesses such as common cold, and fatal conditions like pneumonia, and severe acute respiratory syndrome (SARS). 1 The virus has been characterized, and it has three subtypes: A, B, and C. 4 'A' subtype is the ancestral type like bat coronavirus. 'A' and 'C' subtypes are found in the USA and Europe, and 'B' subtype predominant in East Asia. 4 The prevalent hypothesis suggested that this virus came from the bat, possibly through pangolins, 5 both of which are consumed in China even in undercooked states. If this hypothesis is correct, it suggests the gastrointestinal (GI) tract be a route for transmission. Subsequently, the infected patients can transmit the virus in the community through fomites and aerosol (Fig. 1) .

The Corona Virus Disease (COVID-19) outbreak has become a pandemic and has led to severe consequences to the global economy. 1 More than 1,20,897 people died of coronavirus to date in the world, and more than 19,39,801 people have been affected till 14 th April 2020. The mortality of coronavirus is currently 3% to 6%. Fig. 2 shows the countrywise number of COVID-19 patients and the number of death as of now, though it is increasing every day. Though respiratory symptoms are the most common manifestations of SARS-CoV-2, digestive system involvement is not uncommon. 1 This review attempts to give an overview of the spectrum of gastrointestinal system involvement in these patients and its clinical, epidemiological, and public health importance. It is crucial mentioning that the understanding of this disease is currently evolving; a lot is yet to be understood. COVID-19 patients: GI symptoms such as nausea, vomiting, anorexia, abdominal pain and discomfort, and diarrhea are common among patients with COVID-19, and their frequency varies widely between 1% and 98%. [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] Table 1 lists the frequency of these symptoms, as reported in the different studies. In a meta-analysis of 60 studies, including 4243 patients, the pooled prevalence of all gastrointestinal symptoms was 17.6%

(95% confidence interval [CI], 12.3%-24.5%). 15 Though a few studies suggested that the patients with GI symptoms may have more severe disease and even worse prognosis, the same was not substantiated in this meta-analysis (pooled prevalence in severe disease: 17.1%

[95% CI 6.9%-36.7%) vs. in less severe disease: 11.8% [95% CI, 4.1%-29.1%]). 15 Since SARS-CoV-2 (also called 2019-nCoV) is largely homologous to an earlier virus (SARS-CoV; 79% sequence identified by next-generation sequencing) 18 (1%), and 0 (0%), bronchoalveolar lavage fluid, sputum, nasal swabs, fiberoptic bronchoscope brush biopsy, pharyngeal swabs, feces, blood, and urine specimens, respectively. Quite a few studies showed that stool samples were more often positive for SARS-CoV-2 RNA in patients with than without diarrhea. The meta-analysis showed a pooled prevalence of stool RNA positivity 48.1% (95% CI, 38.3%-57.9%), even after respiratory specimens were negative in about 70% of patients. Viral excretion in these patients maybe even longer than its presence in the nasopharyngeal samples. 20 In a Chinese study on 74 patients in whom both fecal and nasopharyngeal samples were studied by RT-PCR, in 41/74 patients, fecal samples showed the presence of SARS-CoV-2 RNA by RT-PCR; fecal samples remained positive 11·2 ± 9·2 longer than the respiratory samples. 20 Based on the above findings that showed the presence of SARS-CoV-2 RNA in multiple clinical samples, the possibility of numerous routes transmission can not be ignored. 21 The popularly believed hypothesis that the virus initially came from the Wuhan wild animal market, suggested that the initial human infection occurred due to eating of an uncooked or undercooked bat and pangolin meat, also gave an impression of GI route of transmission and not respiratory route. Hence, multiple studies documenting fecal excretion of the virus are not unexpected. Fecal excretion may have public health importance as it may suggest possible feco-oral transmission of the virus. Moreover, prolonged fecal excretion, even in asymptomatic patients, may contribute to disease burden and potentially infectious carrier pool in the society. 22 Feco-oral transmission is well known in several human viral diseases such as poliovirus and hepatitis E virus. 23, 24 SARS-CoV-2 is also known to survive in the environment for days. 25 Hence, prolonged SARS-CoV-2 excretion in the feces may have public health consequences due to possible feco-oral transmission. 26 Another exciting aspect of the fecal excretion is the fact that in the future if attenuated virus vaccine can be developed, this may spread the attenuated virus strain in the community leading to widespread immunity against the virus in the population. Such herd immunity is one of the mechanisms by which dreaded poliomyelitis has been eradicated in India. Suggestion for such a herd immunity leading to protection against the virus and prevention of severe disease due to SARS-CoV-2 infection has already been hypothesized. However, most vaccines being developed currently against this virus are parenteral mRNA, which is unable to provide such immunity.

The data on GI tissue involvement in COVID-19 patients is scanty; it might be partly related to the fact that due to the risk of transmission of the virus, non-emergency endoscopy in these patients has been recommended to be withheld. Gastrointestinal endoscopy and multiple biopsies have been performed from the esophagus, stomach, duodenum, and rectum in one patient with COVID-19 that showed normal histology except mild lymphocytic and plasma cell infiltration and interstitial edema. 27 ACE2 was not much expressed in esophageal epithelium though it was abundant in the glandular epithelia. Nucleocapsid protein of the SARS-CoV-2 was found in the cytoplasm of gastric, duodenal, and rectum epithelium, but not in the esophagus. 27 The receptors for the entry of the virus inside the cell are host cellular transmembrane serine protease (TMPRSS) and angiotensin receptor 2 (ACE2); the latter is shown to be expressed in the esophageal, small intestinal and colonic epithelial cells in addition to the pulmonary epithelial cells. 28 As ACE2 is known to control intestinal inflammation, its involvement by the virus has been hypothesized to cause diarrhea. 29 It has been suggested that once infected by the virus, and enterocyte damage may lead to increased GI permeability and malabsorption causing entry of the pathogens resulting in diarrhea; 30 however, more studies are needed on this issue. and clinical jaundice are uncommon (total bilirubin elevated in 5 to 18% patients). A few studies also reported a reduction in serum albumin, suggesting impairment in the synthetic function of the liver. It is important to note that 2-3% of patients in these series had pre-existing liver disease. Patients with more severe COVID-19 had liver function test abnormalities more often. ACE2, to which the SARS-CoV-2 binds before entering into the host cells, is present both in the hepatocytes and cholangiocytes, more in the latter. 39 Since cholangiocytes play an essential role in hepatic regeneration and immune response, it has been hypothesized that bile duct epithelial cells may play more role in hepatic injury due to SARS-CoV-2 infection than the cholangiocytes. 40 Recently, post-mortem liver biopsy in a patient who died of COVID-19 has been reported. 41 The histology only showed moderate microvascular steatosis and mild lobular and portal activity. More studies on the mechanism of liver injury in patients with COVID-19 are needed.

GI and liver manifestations such as anorexia, dysgeusia, nausea, vomiting, diarrhea, abdominal pain, and discomfort are common among patients with COVID-19. Hepatic involvement in this condition is reflected by abnormal liver enzymes and much less frequently elevated bilirubin values. Quite a few studies showed that patients with the severe disease more often have GI symptoms and hepatic involvement. Though a few studies did suggest that GI manifestations are associated with the worst outcome, this has been refuted by other studies. SARS-CoV-2 has been detected in multiple other clinical samples, including feces, in addition to the nasopharyngeal specimens. Therefore, a possible transmission of the virus by endoscopy can not be refuted though a recent study suggested this possibility to be rather low. 42 Fecal excretion of the virus has clinical implications due to possible feco-oral transmission of the disease. 43 A few studies showed that the virus is excreted in the stool even after the nasopharyngeal specimen has become negative. Therefore, the current practice of relieving the patient from isolation after the nasopharyngeal SARS-CoV-2 has become negative as such patients may result in feco-oral transmission of the disease. Knowledge about this disease, however, is currently evolving, and hence, a lot remains to be explored. 44, 45 

The epidemiology, diagnosis and treatment of COVID-19

COVID-19-New Insights on a Rapidly Changing Epidemic

Novel Coronavirus-Important Information for Clinicians

Phylogenetic network analysis of SARS-CoV-2 genomes

Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

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

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

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First Case of 2019 Novel Coronavirus in the United States

Clinical Characteristics of Coronavirus Disease 2019 in China

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms

Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

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

Gastrointestinal Symptoms and COVID-19: Case-Control Study from the United States

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

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

A novel coronavirus outbreak of global health concern

Prolonged presence of SARS-CoV-2 viral RNA in faecal samples

Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes

Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel

Global Transmission of Live Polioviruses: Updated Dynamic Modeling of the Polio Endgame

Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible?

Evidence for Gastrointestinal Infection of SARS-CoV-2

Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding

Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus

COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission

COVID-19 in a Designated Infectious Diseases Hospital Outside Hubei Province

Clinical Features of COVID-19-Related Liver Damage

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

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Liver injury during highly pathogenic human coronavirus infections

Clinical Characteristics of Imported Cases of COVID-19 in Jiangsu Province: A Multicenter Descriptive Study

Cholangiocyte pathobiology

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

Low risk of COVID-19 transmission in GI endoscopy

Coronavirus Disease (COVID-19) and the Gastrointestinal System in Children

The 2019 novel coronavirus disease (COVID-19) pandemic: A review of the current evidence

Gastro-Intestinal and Hepatic Manifestations of COVID-19 and their Relationship to Severe Clinical Course: A Systematic Review and Meta-analysis

9) Nausea and/or vomiting 12 (10.3) Diarrhea 12 (10.3) Nausea/Vomiting

 Table 1 . Studies reporting digestive system involvement in patients with Coronavirus infection 19 (COVID 19) Author, year Total number of patients

Chan JFW, 2020 [6] 6 Diarrhea: 2 (33%) Huang C, 2020 [7] 38 Diarrhea: 1 (3%) Chen N, 2020 [8] 99 Diarrhea: 2 (2%) Nausea and vomiting: 1 (1%) Luo S, 2020 [9] 1141 Nausea 134 (73%) Vomiting 119 (65%) Abdominal pain 45 

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