The outbreak of novel coronavirus (2019-nCoV) pneumonia initially developed in one
of the largest cities, Wuhan, Hubei province of China, in early December 2019 and
has been declared the sixth public health emergency of international concern by the
World Health Organization, and subsequently named coronavirus disease 2019 (COVID-19).
As of February 20, 2020, a total of >75,000 cumulative confirmed cases and 2130 deaths
have been documented globally in 26 countries across 5 continents. Current studies
reveal that respiratory symptoms of COVID-19 such as fever, dry cough, and even dyspnea
represent the most common manifestations at presentation similar to severe acute respiratory
syndrome (SARS) in 2003 and Middle East respiratory syndrome in 2012, which is firmly
indicative of droplet transmission and contact transmission. However, the incidence
of less common features like diarrhea, nausea, vomiting, and abdominal discomfort
varies significantly among different study populations, along with an early and mild
onset frequently followed by typical respiratory symptoms.
Mounting evidence from former studies of SARS indicated that the gastrointestinal
tract (intestine) tropism of SARS coronavirus (SARS-CoV) was verified by the viral
detection in biopsy specimens and stool even in discharged patients, which may partially
provide explanations for the gastrointestinal symptoms, potential recurrence, and
transmission of SARS from persistently shedding human as well.
Notably, the first case of 2019-nCoV infection confirmed in the United States reported
a 2-day history of nausea and vomiting on admission, and then passed a loose bowel
movement on hospital day 2. The viral nucleic acids of loose stool and both respiratory
specimens later tested positive.
In addition, 2019-nCoV sequence could be also detected in the self-collected saliva
of most infected patients even not in nasopharyngeal aspirate, and serial saliva specimens
monitoring showed declines of salivary viral load after hospitalization.
Given that extrapulmonary detection of viral RNA does not mean infectious virus is
present, further positive viral culture suggests the possibility of salivary gland
infection and possible transmission.
More recently, 2 independent laboratories from China declared that they have successfully
isolated live 2019-nCoV from the stool of patients (unpublished). Taken together,
a growing number of clinical evidence reminds us that digestive system other than
respiratory system may serve as an alternative route of infection when people are
in contact with infected wild animals or sufferers, and asymptomatic carriers or individuals
with mild enteric symptoms at an early stage must have been neglected or underestimated
in previous investigations. Clinicians should be careful to promptly identify the
patients with initial gastrointestinal symptoms and explore the duration of infectivity
with delayed viral conversion.
To date, molecular modelling has revealed by the next-generation sequencing technology
that 2019-nCoV shares about 79% sequence identify with SARS-CoV, indicative of these
2 lineage B β-coronaviruses highly homologous, and angiotensin-converting enzyme II
(ACE2), previously known as an entry receptor for SARS-CoV, was exclusively confirmed
in 2019-nCoV infection despite amino acid mutations at some key receptor-binding domains.
It is widely accepted that coronavirus human transmissibility and pathogenesis mainly
depend on the interactions, including virus attachment, receptor recognition, protease
cleaving and membrane fusion, of its transmembrane spike glycoprotein (S-protein)
receptor-binding domain, specific cell receptors (ACE2), and host cellular transmembrane
serine protease (TMPRSS), with binding affinity of 2019-nCoV about 73% of SARS-CoV.
Recent bioinformatics analysis on available single-cell transcriptomes data of normal
human lung and gastrointestinal system was carried out to identify the ACE2-expressing
cell composition and proportion, and revealed that ACE2 was not only highly expressed
in the lung AT2 cells, but also in esophagus upper and stratified epithelial cells
and absorptive enterocytes from ileum and colon.
With the increasing gastrointestinal wall permeability to foreign pathogens once virus
infected, enteric symptoms like diarrhea will occur by the invaded enterocytes malabsorption,
which in theory indicated the digestive system might be vulnerable to COVID-19 infection.
In contrast, because ACE2 and TMPRSS especially TMPRSS2 are co-localized in the same
host cells and the latter exerts hydrolytic effects responsible for S-protein priming
and viral entry into target cells, further bioinformatics investigation renders additional
evidence for enteric infectivity of COVID-19 in that the high co-expression ratio
was found in absorptive enterocytes and upper epithelial cells of esophagus besides
lung AT2 cells. However, the exact mechanism of COVID-19–induced gastrointestinal
symptom largely remains elusive. Based on these considerations, ACE2-based strategies
against COVID-19 such as ACE2 fusion proteins and TMPRSS2 inhibitors should be accelerated
into clinical research and development for diagnosis, prophylaxis, or treatment.
Last, mild to moderate liver injury, including elevated aminotransferases, hypoproteinemia,
and prothrombin time prolongation, has been reported in the existing clinical investigations
of COVID-19, whereas up to 60% of patients suffering from SARS had liver impairment.
The presence of viral nucleic acids of SARS in liver tissue confirmed the coronavirus
direct infection in liver, and percutaneous liver biopsies of SARS showed conspicuous
mitoses and apoptosis along with atypical features such as acidophilic bodies, ballooning
of hepatocytes, and lobular activities without fibrin deposition or fibrosis.
It is believed that SARS-associated hepatotoxicity may be likely with viral hepatitis
or a secondary effect associated with drug toxicity owing to high-dose consumption
of antiviral medications, antibiotics, and steroids, as well as immune system overreaction.
However, little is known about 2019-nCoV infection in liver. Surprisingly, recent
single cell RNA sequencing data from 2 independent cohorts revealed a significant
enrichment of ACE2 expression in cholangiocytes (59.7% of cells) instead of hepatocytes
(2.6% of cells), suggesting that 2019-nCoV might lead to direct damage to the intrahepatic
Altogether, substantial effort should be made to be alert on the initial digestive
symptoms of COVID-19 for early detection, early diagnosis, early isolation, and early