Putative Mechanisms of Diarrhea in COVID-19
Authors: Abhilash Perisetti, Mahesh Gajendran, Hemant Goyal
Journal: Clinical Gastroenterology and Hepatology (2020)

We read with much interest the article "Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention and Management" published by D'Amico et al1D'Amico F. et al.Clin Gastroenterol Hepatol. 2020; (S1542-3565(20)30481-X)Google Scholar 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.2Effenberger M. et al.Gut. 2020; (gutjnl-2020-321388)PubMed Google Scholar 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.1D'Amico F. et al.Clin Gastroenterol Hepatol. 2020; (S1542-3565(20)30481-X)Google Scholar 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.3Jose R. et al.Lancet Respir Med. 2020; (S2213-2600(20)30216-2)Google Scholar These proinflammatory cytokines can alter the gut-brain axis by getting their access via the vascular/lymphatic systems.3Jose R. et al.Lancet Respir Med. 2020; (S2213-2600(20)30216-2)Google Scholar 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.2Effenberger M. et al.Gut. 2020; (gutjnl-2020-321388)PubMed Google Scholar The COVID-19 patients are known to have altered gut flora,4Zuo T. et al.Gastroenterology. 2020; (S0016-5085(20)34701-34706)Google Scholar 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.5Wei X. et al.Clin Gastroenterol Hepatol. 2020; (S1542-3565(20)30526-30527)Google Scholar 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.6Perlot T. et al.Microbes Infect. 2013; 15: 866-873Crossref PubMed Scopus (190) Google Scholar 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.7Yang X. et al.Lancet Respir Med. 2020; 8: 475-481Abstract Full Text Full Text PDF PubMed Scopus (7052) Google Scholar 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-19.8Garg M. et al.Gut. 2020; 69: 841-851Crossref PubMed Scopus (140) Google Scholar 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. Diarrhea During COVID-19 Infection: Pathogenesis, Epidemiology, Prevention, and ManagementClinical Gastroenterology and HepatologyVol. 18Issue 8PreviewThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) pandemic is a worldwide emergency. An increasing number of diarrhea cases is reported. Here we investigate the epidemiology, clinical presentation, molecular mechanisms, management, and prevention of SARS-CoV-2 associated diarrhea. We searched on PubMed, EMBASE, and Web of Science up to March 2020 to identify studies documenting diarrhea and mechanism of intestinal inflammation in patients with confirmed diagnosis of SARS-CoV-2 infection. Full-Text PDF ReplyClinical Gastroenterology and HepatologyVol. 18Issue 13PreviewWe appreciate the thoughtful comments of Perisetti and colleagues. In line with our article they support our hypothesis that diarrhea in patients with coronavirus disease 2019 (COVID-19) may be related not only to the activity of the new coronavirus but also to the drugs used for its treatment as antibiotics and antivirals. Interestingly, they add that even the cytokine storm generated by COVID-19 may play a role in diarrhea etiopathogenesis by influencing the gut-brain axis and causing increased intestinal permeability. Full-Text PDF