Putative Mechanisms of Diarrhea in COVID-19.

Dear Editor:

We read with much interest the article “Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention and Management” published by D’Amico et al in Clinical Gastroenterology and Hepatology. The article highlights the importance of gastrointestinal symptoms in coronavirus disease 2019 (COVID-19), which are increasingly being recognized. In this article, the authors report that the frequency of diarrhea in COVID-19 could be as high as 50%. They also elaborated on the role of angiotensin-converting enzyme 2 (ACE-2) receptors in severe acute respiratory syndrome–associated coronavirus 2 (SARS-CoV-2)–induced diarrhea.

We would like to discuss other putative mechanisms that could be involved in the etiopathogenesis of diarrhea in COVID-19. First, we would like to stress the importance of having a strict definition of diarrhea in COVID-19 patients, mainly because diarrhea can develop with any kind of viral illness, and it is usually short-lived (<48 hours). Hence, the term persistent diarrhea defined by at least 3 bowel movements for >48 hours might be more appropriate in this setting. The presence of viral RNA in stool samples has been noted in up to 53.4% of cases of diarrhea in COVID-19, but it is unclear whether the presence of RNA correlates with diarrheal symptoms. It is yet to be determined whether the presence of the virus in the stool sample is just a bystander/fecal shedding or due to its cytopathic effects. If the diarrhea is due to the direct cytopathic effects, then stool viral RNA is expected to be positive in significantly higher numbers in COVID-19 as compared with non-cytopathic causes. Nevertheless, the other following mechanisms could also play a role.

Severe COVID-19 is known to cause a cytokine storm with an increase in cytokine levels such as interleukins (ILs) (IL2, IL6, IL7, etc), tumor necrosis factor, and granulocyte monocyte colony-stimulating factor. These proinflammatory cytokines can alter the gut-brain axis by getting their access via the vascular/lymphatic systems. Studies showing significant gut inflammation in COVID-19 patients are limited. However, fecal calprotectin is elevated in COVID-19 patients with persistent diarrhea, which is consistent with increased gut inflammation. Interestingly, fecal calprotectin correlated with levels of IL6 but not with C-reactive protein or ferritin.

The COVID-19 patients are known to have altered gut flora, which could be due to the use of antimicrobials, concomitant infections, and the severe illness itself. The composition of gut flora could also be altered by an increase in proinflammatory mediators because of viral-induced inflammation. The use of antibiotics can have a profound effect on the gut microbiota, immune system, and antibody production, which can delay the clearance of SARS-CoV-2 from the gut. ACE-2 receptor binding has shown to have aberrant mammalian target of rapamycin activity with a decrease in antimicrobial peptides that could alter the gut flora. In addition, enteral nutrition with tube feeds is known to alter gut flora and can contribute to increased bowel output in patients with vent-dependent respiratory failure.

The COVID-19 patients are commonly treated with antibiotics because of suspicion for secondary bacterial infections. These microbial agents (such as fluoroquinolones and cephalosporins) can cause antibiotic-associated diarrhea as an adverse effect. Furthermore, antiviral agents such as ritonavir-lopinavir, hydroxychloroquine, and remdesivir are increasingly used among these patients, and diarrhea is a common side effect of these drugs. These medications are commonly being used in COVID-19 patients during the course of the disease. It remains unclear whether they play any role in the fecal clearance of SARS-CoV-2.

The diarrheal symptoms in the patients with preexisting gastrointestinal diseases such as irritable bowel syndrome, inflammatory bowel disease (IBD), and malabsorption syndromes can potentially worsen with any viral infections. The ACE-2 receptors are overexpressed in the inflamed tissue in IBD, which can theoretically increase the risk of diarrhea in IBD patients with COVID-19.

It is unclear whether the factors mentioned above play a role alone or in combination in causing diarrhea in COVID-19 patients. However, these mechanisms can, at least in part, explain the reason for negative stool RNA testing in cases of diarrhea. Future studies are needed with a strict definition of diarrhea in COVID-19 to understand its pathogenesis and role in the feco-oral transmission.