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First diagnosed in Wuhan, China, in December 2019, COVID-19 is caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2 Since its identification, questions have arisen regarding the effect of SARS-CoV-2 on the gastrointestinal (GI) tract. This brief review aims to provide practical information for gastroenterologists to use during this challenging time.
GI Symptoms
Although patients with COVID-19 are known to present with constitutional and respiratory symptoms such as fever, cough, sore throat, and shortness of breath, there is growing evidence that these patients can also experience significant GI symptoms such as nausea, vomiting, and diarrhea. At times, these symptoms can even precede respiratory symptoms.1
The pathophysiology underlying GI symptoms in the setting of COVID-19 has yet to be fully elucidated but may be related to the angiotensin-converting enzyme 2 (ACE2) receptor.1-3 The ACE2 receptor can function as the entry receptor for SARS-CoV-2 into cells within the GI tract. Viral entry leads to disruption of the lining of the GI tract, increased permeability, and an inflammatory response that results in decreased absorption and potentially diarrhea.1 Outside of direct damage to the lining of the GI tract, another possibility is that SARS-CoV-2 disrupts the gut microbiome, leading to diarrhea.
Several recent studies from China have been published that further evaluate GI symptoms in patients with COVID-19. From the limited available data, the rates of diarrhea in individuals with COVID-19 appear to range from as low as 3% to as high as 57%.4-6
Pan et al recently published a retrospective review of 204 patients in China diagnosed with SARS-CoV-2 in the American Journal of Gastroenterology.7 Approximately one-half (103/204; 50.5%) of patients experienced GI symptoms including poor appetite (39.7%), diarrhea (17%), vomiting (2%), and abdominal pain (1%). It is important to note that “poor appetite” is not necessarily specific to the GI tract. The diarrhea was typically described as mild, semi-formed (not voluminous), and occurring up to 3 times daily. The majority (97/103; 94%) of these patients with GI symptoms also had respiratory symptoms. Few (6/204; 2.9%) patients presented only with GI symptoms.
Patients with GI symptoms were found to have a significantly longer time from onset of symptoms to hospital admission vs patients without GI symptoms (9.0 vs 7.3 days, P =.013), possibly secondary to lack of recognition of what may have been considered atypical symptoms at the time. Patients with more severe disease had more pronounced GI symptoms, which could potentially be explained by direct damage caused by a higher viral load or a delay in diagnosis, as mentioned earlier. Patients with GI symptoms were more likely to receive aggressive treatments including antibiotics, interferon, and immunoglobulins vs those without GI symptoms. There was no significant difference in time to discharge, days in the intensive care unit (ICU), or mortality among those with and without GI symptoms. It is important to note that the number of patients in this study was relatively small; in addition, the investigators did not correlate GI symptoms with fecal viral RNA.
A group led by Xiao et al examined SARS-CoV-2 RNA in feces from 73 patients who were hospitalized in China with confirmed SARS-CoV-2.2 Laboratory testing revealed that approximately one-half (39/73; 53.4%) of the patients had SARS-CoV-2 RNA in their stool, with 43.6% of these patients reporting diarrhea. The duration of time to receipt of positive stool SARS-CoV-2 RNA ranged from 1 to 12 days. Approximately one-quarter (17/73; 23.3%) of these patients had positive results for SARS-CoV-2 RNA in stool after respiratory samples were reported as negative for SARS-CoV-2 RNA, which is an important takeaway. The current Centers for Disease Control and Prevention (CDC) guidelines recommend discontinuing transmission-based precautions for patients hospitalized with SARS-CoV-2 upon resolution of fever, improvement in respiratory symptoms, and with negative testing from at least 2 sequential respiratory tract specimens collected ≥24 hours apart.8 Based on this small study, it does appear that extended precautions may be necessary in patients with COVID-19, regardless of the presence of diarrhea, due to viral shedding into the stool. The authors conclude that in addition to respiratory spread, fecal-oral transmission of SARS-CoV-2 is also possible. This is imperative to know when caring for these patients as well as when considering endoscopic procedures. As respiratory testing is already limited and considered a priority, future attention to increasing access to stool testing may be warranted.
The Xiao et al study also reported on a single patient who underwent endoscopic evaluation for GI bleeding.2 Biopsies were performed of the esophagus, stomach, duodenum, and rectum, the evaluation of which showed a mild increase in lymphocytes in the esophagus and infiltrating plasma cells and lymphocytes with interstitial edema in parts of the stomach, duodenum, and rectum. Specimens from these biopsies were subsequently stained for ACE2 and were found to be most significantly positive in parts of the GI tract with glandular epithelium including the gastric, duodenal, and rectal tissue. ACE2 was rarely expressed in the esophagus, most likely based on its composition of squamous epithelial cells, compared with glandular epithelial cells found elsewhere.
GI Laboratory Findings
Several laboratory findings in patients with COVID-19 warrant consideration by gastroenterologists and hepatologists, as well as other healthcare practitioners. Pan et al found that in contrast to that seen in patients with COVID-190 but without GI symptoms, patients with COVID-19 and GI symptoms had higher mean liver enzymes and longer prothrombin times.7 The authors found no difference in complete blood count, electrolytes, or kidney function.
Guan et al extracted data from 1099 patients with laboratory-confirmed SARS-CoV-2 and found that a significant number of these patient also had elevated liver function tests including aspartate transaminase (AST; 22.2%), alanine aminotransferase (ALT; 21.3%), and total bilirubin (10.5%).4 Elevations in AST, ALT, and total bilirubin were seen more frequently in patients with severe COVID-19 vs those with nonsevere disease.
The exact mechanism to explain the elevation in liver enzymes is not fully known but could be related to the binding of SARS-CoV-2 to the ACE2 receptor, resulting in direct liver tissue injury including the intrahepatic bile ducts.7,9 In addition, the proinflammatory state induced by SARS-CoV-2 could also play a role in hepatic dysfunction in the setting of COVID-19.
It is important to note that medications currently being used to treat patients with COVID-19 — including lopinavir-ritonavir, chloroquine, hydroxychloroquine, and azithromycin — can also lead to diarrhea and elevated liver enzymes. Therefore, some of the findings in the aforementioned and other published reports may be attributable to medication side effects and not COVID-19 alone. In the Pan et al study, 184 (90.2%) and 141 (69.1%) of patients received antiviral therapy such as lopinavir-ritonavir and antibiotics, respectively, after hospital admission.7 Both medications and classes could have contributed to the reported liver abnormalities and diarrhea. Unfortunately, the authors did not communicate if patients treated with antiviral agents or antibiotics were more likely to have these findings.
As there is increased research interest in using chloroquine and hydroxychloroquine to treat COVID-19, the effect of such treatment on liver enzymes will require scrutiny as both medications can cause elevations. In addition, both chloroquine and hydroxychloroquine can also cause many of the same GI symptoms associated with COVID-19 such as nausea, vomiting, and diarrhea. If these medications are used with increasing frequency, the ability to distinguish medication side effects vs the actual disease process will be an additional clinical challenge. Remdesivir is an investigational antiviral agent that has been the subject of increased interest as well, although its effect on the GI tract is currently not known.
Thoughts Moving Forward
Moving forward from a GI perspective, it will be important to evaluate GI manifestations of SARS-CoV-2 reported from all countries and see if the results are similar to those reported herein. There does appear to be a mechanism for which SARS-CoV-2 can infiltrate the GI tract, leading to multiple symptoms. The potential for fecal-oral transmission after respiratory testing is negative needs to be considered when counselling patients. Most of the currently published data on GI effects in patients with COVID-19 are from hospitalized patients; therefore, understanding how patients in the community with COVID-19 manifest from a GI perspective is not yet known. With an increased emphasis on finding safe and effective treatments for COVID-19, gastroenterologists should be aware that many of the investigational treatments being studied have significant GI side effects.
The COVID-19 research environment remains fluid, and new studies are continuously being published. As certain studies may be fast-tracked through the data collection and publication process, new reports need to be thoroughly reviewed prior to making broad applications to all patients with COVID-19. Some studies that are being preliminarily published have not yet completed the peer-review process, which must be seriously considered when considering application of the information into daily practice. In addition to reviewing the reports of new research, it is also important to stay up to date with current national guidelines and recommendation such as those provided by the CDC, the US Surgeon General, and global gastroenterology societies.
References
1. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission [published online March 3, 2020]. Gastroenterology. doi:10.1053/j.gastro.2020.02.054
2. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2 [published online March 3, 2020]. Gastroenterology. doi:10.1053/j.gastro.2020.02.055
3. Zhang H, Kang Z, Gong H, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv website. Available at: https://www.biorxiv.org/content/10.1101/2020.01.30.927806v1. Published January 31, 2020. Accessed March 27, 2020.
4. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China [published online February 28, 2020]. N Engl J Med. doi:10.1056/NEJMoa2002032
5. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
6. Zhang Y, Zhang X, Liu L, Wang H, Zhao Q. Suggestions of infection prevention and control in digestive endoscopy during current 2019-nCoV pneumonia outbreak in Wuhan, Hubei Province, China. World Endoscopy Organization website. Available at: http://www.worldendo.org/wp-content/uploads/2020/02/Suggestions-of-Infection-Prevention-and-Control-in-Digestive-Endoscopy-During-Current-2019-nCoV-Pneumonia-Outbreak-in-Wuhan-Hubei-Province-China.pdf. Accessed March 27, 2020.
7. Pan L, Mu Mi, Yang P, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Available at: https://journals.lww.com/ajg/Documents/COVID_Digestive_Symptoms_AJG_Preproof.pdf. Published March 18, 2020. Accessed March 27, 2020.
8. Coronavirus Disease 2019 (COVID-19): Discontinuation of transmission-based precautions and disposition of patients with COVID-19 in healthcare settings (interim guidance). Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html. Updated March 23, 2020. Accessed March 27, 2020.
9. Chai XQ, Hu L, Zhang Y-Z, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv website. Available at: https://www.biorxiv.org/content/10.1101/2020.02.03.931766v1. Published February 4, 2020. Accessed March 27, 2020.
