COVID-19 GIS
During the 2002 SARS epidemic, diarrhea was reported in 16.7% of cases [56]. In the MERS epidemic, 26% of cases were reported with diarrhea, 21% with nausea-vomiting and 17% with abdominal pain [57].
In the first studies published on COVID-19, conducted in hospital centers in Wuhan (epicenter of the pandemic), nausea or vomiting was observed in 5% and diarrhea in 3.7% of the cases studied [32, 50].
Subsequently, many studies have analyzed the occurrence of GIS, showing great variability coinciding with the pooled analysis. Our analysis showed GIS in 16%, diarrhea in 8.1%, nausea-vomiting in 12%, and abdominal pain in 4%.
It is well known that the dominant clinical signs of COVID-19 are respiratory symptoms (cough, dyspnea and fever), but, as has been seen in this review, there is a significant percentage of cases with GIS from the time of patient admission (before starting treatment) and that, sometimes, may precede the respiratory symptoms [16, 30]. One study showed that up to 3% of cases may have exclusively presented with GIS [38]. The presence of these GIS has not been related to the positivity of viral RNA in stool [41].
On the other hand, there are studies showing that the presence of GIS may indicate a higher probability of a severe course [37, 42]. A higher percentage of diarrhea was observed in patients with severe disease (5.8%) than in non-severe disease (3.5%). Guan et al [42] and a significant serious course was found in patients with gastrointestinal symptoms (22.97%) than in those without gastrointestinal symptoms (8.12%) p<0.001 [37]. In another study, this difference with the presence of GIS was not observed in 37.8% of patients with non-severe disease and 42% of patients with severe disease [44].
Enteric involvement
The finding of an angiotensin-converting enzyme receptor as the entry for SARS-CoV-2 to the cell suggests that human organs with a high level of ACE2 expression, such as pulmonary alveolar epithelial cells and small intestinal enterocytes, are potentially vulnerable and a target for SARS-CoV-2 infection [28, 29, 58, 59].
The binding of SARS-CoV-2 to ACE2 has been shown to have approximately 10-20 times greater affinity than SARS-CoV via S protein, which may provide an explanation of why SARS-CoV-2 has more person-to-person spread compared with SARS-CoV [60, 61]. COVID-19 disease can affect, in addition to the respiratory and GI tract, various organs such as the kidneys, liver, musculoskeletal, cardiovascular and neurological systems. [62, 63].
In this review, we found [28, 29] articles supporting the above statement that human ACE2 is a receptor for SARS-CoV-2 expressed in gastric, intestinal and colonic cells [64, 65].
The possible infection of the GI cells was studied in tissue samples from the esophagus, stomach, duodenum and rectum, and although no significant histological alteration was observed, through staining, the presence in the cytoplasm of the cells of the ACE2 receptors and the nucleocapsid of the SARS-CoV-2 was determined. This indicates the possibility of enteric infection [29]. This enteric infection could release virions and cause possible fecal-oral transmission.
Other reports have suggested that if SARS-CoV-2 can actually infect the human intestinal epithelia, it would have significant implications for fecal-oral transmission and the containment of viral propagation [32, 42].
Infection of intestinal cells can be expressed with GIS, such as abdominal pain, vomiting and diarrhea, as demonstrated in some studies [66, 67].
One study showed that the extension in days of viral RNA elimination in stools has not been related to disease severity [41].
This reinforces the need for future studies on enteric participation and viral excretion of SARS-CoV-2 in stool and for research on whether fecal SARS-CoV-2 RNA levels correlate with disease severity and the presence or absence of GIS [18].
Fecal levels of SARS-CoV-2 viral RNA and possible fecal-oral transmission of infection
The primary transmission pathway is by inhalation of respiratory microdroplets, but there may be other mechanisms such as: conjunctival: one study showed the presence of RNA in conjunctiva [68]; fecal: another study in Singapore showed the presence of virus RNA in samples from an infected patient’s toilet and on fomites: the same study detected the virus on many surfaces of the room [70].
In this regard, it has been postulated that the dynamics of SARS-CoV-2 must be determined to study possible fecal transmission, and it is therefore important to take simultaneous respiratory and fecal samples to study the kinetics and viral load of SARS-CoV-2. The Ct values reflect, in an inversely related manner, the viral load and are suggested by some authors for expression [24, 71].
Viral kinetics in infected patients have not yet been fully determined. Viral RNA in COVID-19 has been found in stool in the early and late phase of the disease at a rate, in the most numerous series, of between one-third and one-half of the cases [22, 40, 41]. Viral RNA may remain positive in stool samples, up to an average of 11.2 days and up to a maximum of 33 days after being negative in respiratory samples, suggesting that the virus could actively replicate in the GI tract of the infected patient and that fecal-oral transmission could occur after viral clearance in the respiratory tract. [40, 41].
One German study found high viral loads in stool and the presence of subgenomic RNA sgRNA in some patients, indicating the possible viability of the virus, though it could not be cultured in stool [54].
In contrast, another study found no significant value of viral RNA in stool [37] . A study of the pediatric population showed persistent excretion of SARS-CoV-2 in the stool of children between 8-20 days after negativization in respiratory samples. This would increase the possibility of the virus being transmitted through contaminated fomites, so there is a need for massive efforts at all levels to prevent the spread of infection between children after reopening daycare centers and schools, as noted in one of the articles discussed in this review [39].
It has been suggested that the prolonged RNA presence of SARS-CoV-2 after negativization in respiratory specimens may be an infectious source of COVID-19 in the community and may represent a threat to public health, if eligibility for discharge is based on the current version of the COVID-19 Diagnosis and Treatment Plan [39, 72]. Therefore, SARS-CoV-2 RT-PCR measurement in stool would be recommended following the clearance of viral RNA in respiratory specimens from hospitalized or quarantined patients [39, 41].
High viral load in elderly patients has been associated not only with the low immunity of the elderly but also with high expression of the ACE2 receptor (the cellular entry receptor for SARS-CoV-2) in older adults, and further studies with a larger sample size are needed to clarify and understand the relationship between viral load and disease severity [73, 74].
In histological studies, some authors have suggested that if SARS-CoV-2 can actually infect the human intestinal epithelium, it would have significant implications for fecal-oral transmission and the containment of viral propagation [32, 42].
It has also been suggested that further studies are needed to elucidate the exact role of fecal-oral transmission in the spread of SARS-CoV-2 through environmental studies, and studies on viability and infectivity [18, 75].