Covid-19 and the Digestive System
The novel coronavirus disease (Covid-19) is causing a major pandemic. As of 23 March 2020, it has infected over 340,000 people worldwide and caused over 14,000 deaths. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virusand is taxonomically a member of the Betacoronavirus genus. Patients typically present with fever and respiratory symptoms, nevertheless, some patients also have gastrointestinal manifestations with diarrhoea, vomiting and abdominal pain1. Studies have identified the SARS-CoV-2 RNA in anal / rectal swabs 2, 3and stool specimens 4-6of Covid-19 patients, even after the clearance of the virus in the upper respiratory tract2, 3. Furthermore, the viral receptor angiotensin converting enzyme 2 (ACE2) was found to be expressed in gastrointestinal epithelial cells7, 8. Together these suggest that SARS-CoV-2 can actively infect and replicate in the gastrointestinal tract. This has important implications to the disease management, transmission, and infection control. In this article, we review the important gastrointestinal aspects of the disease
Gastrointestinal symptomsof Covid-19patients
While Covid-19patients typically present with a respiratory illness, some patients reported gastrointestinal symptoms including diarrhoea, vomiting and abdominal pain during course of the disease. In the first case of Covid-19in a 35-year-old man in the United States4, the patient presented with a 2-day history of nausea and vomiting upon hospital admission, followed by diarrhoeaand abdominal discomfort on the second day of hospitalization. The SARS-CoV-2 RNA was detected in stool of the patient by reverse-transcriptase polymerase-chain-reaction (RT-PCR) on illness day 74.Similarly, in the familial cluster of Covid-19cases during the early epidemic9, diarrhoeawas described in two young adults (aged 36 and 37 years) out of the six patients, with reported bowel openings of up to eight times a day. Subsequentcohorts have consistently reported gastrointestinal symptomsamong Covid-19 patients. In a large study that collected data from 1,099 patients from 552 hospitals in China, it reported nausea or vomiting in 55 (5.0%)and diarrhoeain 42 (3.8%)patients Several othercohorts have reportedfrequencies of diarrhoearanging 2.0-10.1%, and nausea and/or vomiting ranging 1.0-10.1% (Table 1) 11-19. In the cohort of 140 Covid-19 patients in Wuhan, gastrointestinal symptoms were described in up to 39.6% of the patients 20, including nausea in 24 (17.3%), diarrhoeain 18 (12.9%) and vomiting in 7 (5.0%) patients. Similarly, the rate of diarrhoea was up to 35.6% in a cohort of 73 patients 7. These rates were higher than some other cohorts, and highlightedthe variability of clinical presentations. On the other hand, abdominal pain or discomfortwassparingly described 4, and was reported in 2.2-5.8% in patient cohorts16, 20(Table 1).Similar to adults, gastrointestinal symptoms were observed in a cohort of 171 paediatricpatients with Covid-1914.Diarrhoealand vomiting were observed in 15 (8.8%) and 11 (6.4%) of these children, respectively. In another study that investigated viral shredding in paediatricCovid-19 patients, diarrhoeawas observed in three out of the ten infected children3. Although different clinical features, such as a milder disease course 14and less respiratory symptoms3have been proposed in Covid-19 children, the gastrointestinal symptoms appear to be similar, although more clinical data are needed to arrive at such a conclusion.It is evident that patients can present with gastrointestinal symptoms early in the disease course. For example, the first Covid-19 patient in the US had nausea and vomiting two days before going to hospital, and developeddiarrhoeaon the second day of admission 4, whereas the two young adults in the early familial Covid-19 cluster had diarrhoeaupon presentation to the hospital 9. Diarrhoeacan be one initial symptom and may even occur earlier than pyrexia or respiratory symptoms in some cases
Liver injury in Covid-19 patients
Apart from gastrointestinal symptoms, patients with Covid-19 can have liver injury with raised enzymes found in blood tests. Current dataindicated that 14.8-53.1% of Covid-19 patients had abnormal levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during the course of disease, with mostly mild elevation in serum bilirubin 10-12, 15-18, 27.In a commentary that described a cohort of 56 Covid-19 patients, gamma-glutamyl transferase (GGT) was elevated in 54% of the patients 28. Most of the liver injuries are mild and transient, although severe liver damage can occur. The proportion of liver injury was also higher in patients with severe Covid-19 disease 10, 12. In the cohort that described 99 patients in Wuhan, 43 patients had raised ALT or AST; one patient with critical Covid-19 had severe hepatitis with serum ALT increased up to 7590 U/L 11.While the mechanism of liver injury is not fully understood, the injury can be due to direct viral infection of hepatocytes,immune-related injury, or drug hepatotoxicity 29. There is also suggestion that the virus may bind to cholangiocytes through the ACE2 receptor to dysregulate the liver function 28. Notably, histological examination of the liver biopsy from a deceased Covid-19 patient showed microvesicular steatosis and mild lobular activity30. These histological changes could be caused by SARS-CoV-2 infection or drug-induced liver injury. Nevertheless, no viral inclusion was observed in the liver.It remains to be studied whether SARS-CoV-2 may target the liver in a similar manner to SARS-CoV31-33, and whether other mechanisms play an important role in the liver injury.
Mechanismsof gastrointestinal tract involvement
Evidence from previous SARS studies indicated that coronavirus has a tropism to the gastrointestinal tract. The SARS-CoVRNA could be readily detected in stool specimens of SARS patients34, andelectron microscopy on biopsy and autopsy specimens showed active viral replications in both smalland large intestines 22. Similarly, enteric infection could occur with MERS-CoV, as human intestinal epithelial cellswere highly susceptible to the virus and could sustain robust viral replication 35. This gastrointestinal tropism may explain the frequent occurrence of diarrhoea in coronavirus infection. This faecal source can lead to fomite transmission, especially when infective aerosols are generated from the toilet plume 36.Although at a lower frequency compared to SARS, some Covid-19 patients do develop diarrhoea during their disease course. This suggests the possible tropism of SARS-CoV-2 to the gastrointestinal tract.Genome sequences showed that SARS-CoV-2 shared 79.6% sequence identity to SARS-CoV, both encoding and expressing the spike (S) glycoproteins that could bind to the entry receptor ACE2 to enter human cells 37-39. The receptor binding domainon SARS-CoV-2 could bind to human ACE2with high affinity, correlating with the efficient spread of the virus among humans 40, 41. While ACE2 is highly expressed in type II alveolar cells (AT2) in the lungs, the receptor is also abundantly expressed in the gastrointestinal tract, especially in the small and large intestines 7, 8. Staining of viralnucleocapsid protein was visualized in cytoplasm of gastric, duodenal and rectal epithelium27. These data have provided valuable insights into the receptor-mediated entry into the host cells, and provided basis for its possible transmission route through the faecalcontents.
Implications to patient care and infection control
The tropism of SARS-CoV-2 to the gastrointestinal tract, itspositive detection in stool, and its associated gastrointestinal symptoms, have important implications to both patient care and infection control. Clinicians should be alert of the gastrointestinal symptomatology of Covid-19, especially as they may occur before the onset of pyrexia and respiratory symptoms.More importantly, several studies have demonstrated the presence of viral RNA in stool or anal / rectal swabs of Covid-19 patients2-6. In a study that evaluated 73 Covid-19 patients, 39 (53.4%) were tested positive for SARS-CoV-2 RNA in stool, with a duration of positive stool ranging from 1 to 12 days. Rather of concern, 17 (23.3%) patients remained positive with stool viral RNA after showing negative in their respiratory samples 7. In another study that followed 10 paediatricpatients and evaluatedtheir nasopharyngeal and rectal swabs, eight children were persistently tested positive on rectal swabs even after nasopharyngeal clearance of the virus3. Moreover, two children had positive rectal swabs, despite after clearance with two consecutive negative rectal swabs separated by at least 24 hours apart 31. In contrast to the cycle threshold (Ct)value of 36-38 on illness day 7 stool sample from the first US case4, the longitudinal Ct values in the paediatricpatients were mostly below 353. This suggested that viral shedding from the gastrointestinal tract may be abundant, and may last long after resolution of clinical symptoms. Indeed, a previous study of SARS-CoV indicated that viral RNA could still be detected after 30 days in stool of SARS patients 42. Nevertheless, the viral dynamic of SARS-CoV-2 in the gastrointestinal tract is not known, and may not follow that of SARS-CoV as observed in the respiratory tract 25, 43.The immediate implication of these data iscertainly on the disease infectivity. A recent environmentalstudy suggested that SARS-CoV-2 could remain viable in aerosols for hours, and could stay stably on plastic and stainless steel for at least 72 hours 44.While more studies are needed to demonstrate its replication-competence, its abundance in stool and stability in environment would poise SARS-CoV-2 favourablyto spread among human hosts. This faecal source can lead to viral transmission especially when aerosols are generated, as with the major outbreak caused by toilet fume in Amoy Garden during the SARS epidemics in Hong Kong 36. The gastrointestinal involvement of Covid-19 would necessitate a need to consider several clinical policies, such as incorporationof rectal swab testing before discharging patients45, as well as our preparedness for personal protective equipment in the endoscopy setting46, 47. These considerations will be important in our battle against Covid-19
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