Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) was declared a global pandemic by The World Health Organisation (WHO) on the 11th of March 2020 making it the fifth documented pandemic since the 1918 influenza outbreak. 1, 2 Following its rapid spread throughout the population, it has been responsible for >300 million cases and >5.5 million deaths worldwide as of 31 January 2022. 3 Human coronaviruses were first characterised in the 1960’s; making coronavirus disease 2019 (COVID-19) the seventh member of the coronavirus family to cause disease in humans and the third to be associated with disease encompassing severe acute respiratory syndrome. 2, 4 The other coronaviridae with potential to cause severe disease in humans are (SARS-CoV-1) and Middle East respiratory syndrome coronavirus(MERS-CoV). 5, 6
In addition to the better known respiratory and systemic involvement, gastrointestinal (GI) manifestations have also been reported with SARS-CoV 2. This is not unique to coronaviridae or, indeed, other respiratory viridae; GI disease is seen with SARS-Cov-1, MERS-CoV , adenovirus, influenza amongst others (7-9). Therefore, this review aims to briefly explore GI manifestations associated with previous coronavirus infections followed by exploration of the commonly reported GI manifestations of COVID-19 and the suggested underlying pathophysiology responsible.
SARS-CoV-1; Gastrointestinal Manifestations
Diarrhoea, nausea, vomiting and abdominal pain are frequently reported in many series. Diarrhoea has been described as its modal GI symptom with prevalence figures that range from 13.8% to 73%. 10-15 A retrospective analysis of GI manifestations of patients with RT-PCR confirmed SARS-Cov-2 in Hong Kong reported diarrhoea at initial presentation in 20.3% while 38.4% cumulatively had diarrhoea throughout the illness (16). Nausea and vomiting were other common manifestation with studies reporting rates of 63%, 19.4%, 11.3%, 17.2%, 19.6% (10-13, 17). Abdominal pain was reported in a small number of studies; 3.5% and 9.0%. A summary of GI manifestations associated with SARS-CoV-1 is described in Table 1.
In 2012, MERS-CoV was identified as a zoonotic disease causing a respiratory disease in humans. However, MERS-CoV infection also displayed high levels of GI involvement. In fact, GI symptoms were the most common extra-pulmonary symptoms of MERS with approximately one third of patients experiencing abdominal pain, nausea, vomiting and diarrhoea (18, 19). Mackay and colleagues described fever and gastrointestinal symptoms which formed a prodrome, followed by more severe systemic and respiratory syndrome. 20 A summary of MERS-CoV associated GI manifestations is represented by Table 2.
Pathophysiology of Gastrointestinal involvement
SARS-CoV-2 gains access to host cells via binding to angiotensin-converting enzyme 2 (ACE2) receptors found in the lungs and utilises a serine protease TMPRSS2 for S protein priming. 25 While ACE2 receptors are present in the lungs, they are also expressed in both hollow and solid intestinal organs. They are present in both the upper and lower GI tract, expressed at concentrations almost 100- fold higher compared to their respiratory counterparts.
Upon binding with the target host cell, both the ACE2 receptor and COVID-19 virus are endocytosed leading to an overall reduction in surface ACE2 concentration. 9 ACE2 receptors play particular roles in gut epithelial cells; including amino acid homeostasis maintenance, antimicrobial peptide expression and the ecology of the gut microbiome. Therefore, a reduction of surface ACE2 receptors may interrupt these processes and lead to inflammation. Digestive symptoms of COVID-19 are likely to be a result of its mechanism of action.
SARS-CoV-1 and SARS-CoV-2 possess high degrees of genomic similarity and both utilise ACE2 as means of an entry receptor (28). However, SARS-CoV-2 binding affinity to ACE2 is significantly higher (10-20 times) compared with SARS-CoV-1. 29
COVID-19 GI manifestations
Gastrointestinal manifestations are reported in a high proportion of individuals with COVID-19 infection. The majority of these include diarrhoea, nausea, vomiting, anorexia in addition to abdominal pain. A summary of articles describing these symptoms are displayed in Table 3.
Pan and colleagues found that 103 (50.5%) of participants reported a digestive problem (N=204). 30 Jin and colleagues found that 74 (11.4%) presented with at least one Gi symptom (N=651). 31 Lin and colleagues reported GI symptoms in 58 (61.1%) (N=95).32 Han et al described that of the 67 (32%) of individuals with diarrhoea, 19.4% of these experienced it as their first symptom. 34 Lin et al described that of the 58 (61.1%) of patients with GI symptoms , only 11.6% of them had symptoms on admission while the rest manifested later in the course of the illness. 32
Gut Microbiome in Covid-19
Research has demonstrated that microorganism inhabitation not only occurs in the gut, but also in the lungs. Although the concentration of microorganisms in the lungs are at lower levels compared to those found in the gut, the result is the creation of a local microbiome. 42 Since the emergence of lung microbiome research, studies have investigated the lung microbiota composition of individuals with pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic lung disease and lung cancer and compared it to the composition found in healthy individuals. 43-47
The relationship between the gut microbiota and pulmonary system is referred to as the “gut-lung axis”. This axis enables bidirectional cross-talk between GI and respiratory systems; whereby inflammation occurring in the lungs can also affect the gut microbiota. As Previously mentions, SARS-CoV-2 May be able to infect GI epithelian cells through binding to ACE2 receptors expressed there; which in turn play a role in gut microbiome regulation. This relationship raises a fascinating perspective when considering GI manifestations of COVID-19 and poses the question on whether COVID-19 infection has an impact on the gut microbiota. Segal et al. reported that there is evidence that the gut microbiota influences GI ACE2 receptor expression which in turn may influence COVID-19 infectivity and severity.
In common with many respiratory viridae, coronaviridae in general, and SARS CoV-2 in particular can infect cells of the gastrointestinal tract via the ACE2 receptor.
The majority of manifestations are mild and self-limiting. However, in a small number of cases, especially those in critical care, very serious and potentially fatal complications can arise.
References available on request.
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