Intestines and COVID-19

Rakhmetova Venera Sametovna, Doctor of Medical Sciences, Professor of the Department of Internal Medicine with a course of nephrology, hematology, allergology and immunology

NJSC "Astana Medical University"

(010000, Republic of Kazakhstan, Nur-Sultan, 49a Beibitshilik st., E-mail: venerarakhmetova@gmail.com)

Malgazdarova Halima Daniyargyzy, intern doctor

NJSC "Astana Medical University"

(010000, Republic of Kazakhstan, Nur-Sultan, Beibitshilik street 49a, e-mail: malgazdarova.khalima93@gmail.com)

The following clinical variants and manifestations of COVID-19 exist and have been described: asymptomatic; mild (with lesions of the upper airways only); moderate (pneumonia without respiratory failure); severe (pneumonia with the development of respiratory failure) [6]. In addition to pneumonia, COVID-19 can also cause symptoms of damage to other organs and systems, including digestive organs. According to studies, digestive system manifestations include: loss of appetite (39.9% to 50.2%), diarrhea (2.0% to 49.5%), nausea (1.0% to 29.4%), vomiting (3.6% to 15.9%), abdominal pain (2.2% to 6.0) and gastrointestinal bleeding (4.0%) in severe cases [7]. There are also publications about damage to the liver [8] and pancreas in COVID-19 [9].  At the same time, researchers note that gastrointestinal symptoms were more common in severe cases of COVID-19 (23%) than in mild cases of infection (8%) [10].   

A study by scientists at the Hubrecht Institute found that the SARS-CoV-2 coronavirus that causes COVID-19 can infect and multiply in intestinal cells. Using modern human intestinal cell culture models, the scientists successfully replicated the virus in vitro and monitored cell response to the virus, providing a new cell culture model for studying COVID-19.  The researchers used human intestinal organoids, a "mini intestine" cultured in a cup, and demonstrated that SARS-CoV-2 readily replicates in enterocytes, resulting in the production of large numbers of infectious viral particles in the gut (Figure 1).  Intestinal symptoms of SARS-CoV-2 can be associated with damage to enterocytes expressing ACE2 and are accompanied by inflammation or intestinal damage. Loss of intestinal barrier integrity occurs and intestinal microbes, which can activate innate and adaptive immune cells to release proinflammatory cytokines, enter the circulatory system, leading to systemic inflammation [12]. These findings suggest that the digestive system, along with the respiratory tract, may be a potential pathway for SARS-CoV-2 infection, and may explain why some patients experience gastrointestinal symptoms [13].  

Some studies have reported an increased incidence of diarrhea in patients with coronavirus infection.  Clinical studies show that the incidence of diarrhea ranges from 2% to 50% of cases [14]. For example, in a study of 204 patients with COVID-19 in Hubei province, 103 (50.5%) patients were found to present with digestive symptoms, including lack of appetite, diarrhea, vomiting, and abdominal pain [15]. In another study of a group of 95 patients with severe acute respiratory syndrome, 58 had gastrointestinal symptoms, with diarrhea (24.2%), anorexia (17.9%), and nausea (17.9%) being the main symptoms [16]. In one meta-analysis involving 4805 patients with COVID-19, the pooled rates were 7.4% of patients reporting diarrhea and 4.6% of patients reporting nausea or vomiting [17].  If lack of appetite is excluded from the analyses (because it is less gastrointestinal specific), we can conclude that diarrhea is the most frequent complaint among gastrointestinal symptoms.  

Diarrhea associated with COVID-19 most often occurred 1-8 days after onset, and the average duration was 3 days. In some patients, diarrhea was the first symptom and lasted 1-14 days, with 34.3% of diarrhea appearing watery [7]. That is, diarrhea may precede or follow respiratory symptoms [14]. A case has been described of a 22-year-old patient hospitalized with only diarrhea and fever on admission, who was later diagnosed with bilateral pneumonia and had SARS-CoV-2 RNA in a nasopharyngeal swab [18]. Due to the fact that there is a discrepancy in the data and given that some authors draw attention to a possible association of diarrhea with antibiotic intake, more research is needed to identify the percentage of patients with COVID-19 and intestinal symptoms.  

Studies have also shown that RNA of the virus is detected in the feces of COVID-19 patients, hence the possibility of fecal-oral transmission of COVID-19 infection (not currently proven).  COVID-19 RNA was first isolated in feces on day 7 of illness in a 35-year-old US patient in 2019 who was admitted with complaints of nausea, vomiting, and subsequent diarrhea [19]. Somewhat later, a case of COVID-19 was published with a positive result for viral nucleic acid in a fecal sample and negative results on several pharyngeal and sputum samples in a 25-year-old patient with respiratory signs of the disease [20]. At the same time, there is evidence that patients with a positive stool sample did not experience gastrointestinal symptoms [21]. It should be noted that the duration of positive stool results ranges from 1 to 12 days, and viral RNA in stool can remain positive even after negative respiratory test results (23.29%) [22].  

Some patients with COVID-19 have been found to have microbial gut dysbiosis with reduced probiotics such as Lactobacillus and Bifidobacterium. This is because ACE2 regulates intestinal amino acid homeostasis, antimicrobial peptide expression, and the ecology of the gut microbiome. ACE2 deficiency leads to a significant change in the composition of the gut microbiota due to a decrease in the production of antimicrobial peptides that control the gut microbial community. It can be concluded that the microbiota plays a crucial role in gut homeostasis, and changes in its composition and functional activity are involved in local inflammation [23]. 

Patients with chronic inflammatory bowel disease and COVID-19 deserve special attention. Patients with inflammatory bowel disease may be at increased risk for SARS-CoV-2 infection, and the risk of a severe clinical course of COVID-19 may be increased in individuals with VIC receiving immunomodulatory treatment [24]. According to data in the SECURE-IBD registry as of March 23, 2020, 40 cases of COVID-19 have been reported worldwide in patients with VHD, including two deaths [4]. For example, a fatal case was described of an 80-year-old patient admitted to the department with an exacerbation of left-sided ulcerative colitis, which she had been suffering from for 3 years. Corticosteroid therapy was prescribed, which significantly improved the patient's condition, but on the 4th day the patient developed fever up to 39°C and a dry cough. Computed tomography of the chest organs confirmed bilateral pneumonia, and SARS-CoV-2 RNA was detected in a nasopharyngeal swab. Despite antiviral and corticosteroid therapy and respiratory support, the patient died on the 14th day after admission [25]. 

The official website of the Crohn's and Colitis foundation has published guidelines for patients with IBD that recommend continued treatment of IBD with aminosalicylates, antibiotics, and biologics, except for steroids, which can suppress the immune system [26]. Currently, it does not seem reasonable to recommend discontinuation of immunosuppressant treatment in patients with IBD [27]. Patients taking immunosuppressants and biologics are advised not to travel or gather in large groups.  Research on the relationship between COVID-19 and chronic inflammatory bowel disease is still ongoing, and physicians and scientists are constantly reviewing new information and revising recommendations [28].

1. Coronavirus disease 2019: A new severe acute respiratory syndrome from Wuhan in China. Y. CAO, K. CAI, L. XIONG. Acta virologica 64: 245– 250, 2020 

2. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine Wanbo Tai, Lei He, Xiujuan Zhang, Jing Pu, Denis Voronin, Shibo Jiang, Yusen Zhou and Lanying Du. Cellular & Molecular Immunology (2020) 17:613–620; https://doi.org/10.1038/s41423-020-0400-4 

3. Новая коронавирусная инфекция (COVID-19): клинико-эпидемиологические аспекты. В.В. Никифоров, Т.Г. Суранова, Т.Я. Чернобровкина, Я.Д. Янковская, С.В. Бурова. Архивъвнутреннеймедицины № 2  2020 [Novel coronavirus infection (COVID-19): clinical and epidemiological aspects. V.V. Nikiforov, T.G. Suranova, T.Ja. Chernobrovkina, Ja.D. Jankovskaja, S.V. Burova. Arhiv vnutrennej mediciny № 2  2020 (in Russ.)].  

4. Gastroenterology. 2020 May; 158(6): 1518–1519. Published online 2020 Mar. COVID-19: Gastrointestinal Manifestations and Potential Fecal–Oral Transmission. Jinyang Gu, Bing Han, and Jian Wang 

5. Relative Abundance of SARS-CoV-2 Entry Genes in the Enterocytes of the Lower Gastrointestinal Tract. Jaewon J. Lee, Scott Kopetz, Eduardo Vilar, John Paul Shen, Ken Chen and Anirban Maitra. Genes 2020 june; 11 (6): 645 

6. Коронавирусная инфекция COVID-2019. Б. К. Романов. Безопасность и риск фармакотерапии 2020. Т. 8, № 1. [Coronavirus infection COVID-2019. B. K. Romanov. Bezopasnost' i risk farmakoterapii 2020. T. 8, № 1 (in Russ.)].      

7. Gastroenterology Practis in COVID-19 Pandemic. Lu Xia, Kaichun Wu. E-WGO 

8. COVID-19 и поражение печени. Ильченко Л.Ю., Никитин И.Г., Федоров И.Г. Архивъ внутренней медицины. 2020;10(3):188-197 [COVID-19 andliverdamage. Il'chenkoL.Ju., NikitinI.G., FedorovI.G. Arhivvnutrennejmediciny. 2020;10(3):188-197  (inRuss.)].  

9. Инфекция COVID-19 и органы пищеварения. Д.С. Бордин, М.А. Кирюкова, М.И. Шенгелия,С.В. Колбасников. Эффективная фармакотерапия. 2020. Том 16. № 1 [COVID-19 infection and digestive organs. D.S. Bordin, M.A. Kirjukova, M.I. Shengelija,S.V. Kolbasnikov. Jeffektivnajafarmakoterapija. 2020. Tom 16. № 1  (inRuss.)].  

10. JinX., LianJS, HuJH, GaoJ., ZhengL., ZhangYM, HaoSR, JiaHY, CaiH., ZhangXL. Epidemiological, clinical and virological characteristics of 74 cases of the disease infected with coronavirus 2019 (COVID-19) with gastrointestinal symptoms. Intestine, 2020; 69: 1002-1009 

11. Mart M. Lamers, Joep Beumer, Jelte van der Vaart et al. SARS-CoV-2 productively infects human gut enterocyte. Science 03 Jul 2020 

12. Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome. SONIA VILLAPOL, 2020 

13. Don’t Overlook Digestive Symptoms in Patients With Novel Coronavirus Diseas (Covid-19). Shihua Luo, Xiaochun Zhang and Halido Xu. Clinical Gastroenterology and Hepatology 2020;18:1636–1637 

14. D’Amico F, Baumgart DC, Danese S, Peyrin-Biroulet L. Diarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention, and management. Clin Gastroenterol Hepatol 2020;18:1663–7 

15. Pan L, Mu M, Yang P, et al. Clinical characteristics of COVID- 19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroen- terol. 2020;115:766–73 

16. Lin L., Jiang X., Zhang Z., Huang S., Zhang Z., Fang Z., al. Gastrointestinal symptoms of 95 cases with  SARS-CoV-2 infection. Gut. 2020; 69(6):997–1001 DOI:  10.1136/gutjnl-2020-321013 

17. Parasa S, Desai M, Thoguluva Chandrasekar V, et al. Prevalence of gastrointestinal symptoms and fecal viral shed- ding in patients with Coronavirus disease 2019: a systematic review and meta-analysis. JAMA Netw Open 2020;3:e2011335 

18. Song Y., Liu P., Shi X.L., Chu J.L., Zhang J., Xia J., et al. SARS-CoV-2 induced diarrhea as onset symptom in patient with COVID-19. Gut. 2020;69(6):1143–44. DOI:  10.1136/gutjnl-2020-320891 

19. First Case of 2019 Novel Coronavirus in the United States. The New England Journal of Medicine. March 5, 2020 

20. COVID-19 Disease With Positive Fecal and Negative Pharyngeal and Sputum Viral Tests. Lijuan Chen, Jianghua Lou, Yan Bai  and Meiyun Wang. Am J Gastroenterol 2020;115:790 

21. Zhang J, Wang S, Xue Y. Fecal specimen diagnosis 2019 novel coronavirus-infected pneumonia. J Med Virol. 2020. https ://doi. org/10.1002/jmv.25742 

22. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020. https ://doi.org/10.1053/j.gastr o.2020.02.055  

23. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Tatsuo Hashimoto , Thomas Perlot. Nature 2012 Jul 25;487(7408):477-81) 

24. Viral screening before initiation of biologics in patients with inflammatory bowel disease during the COVID-19 outbreak. Published Online March 25, 2020 https://doi.org/10.1016/ S2468-1253(20)30085-6 

25. Mazza S., Sorce A., Peyvandy F., Vecchi M., Cap- rioli F. A fatal case of COVID-19 pneumonia occurring  in  a  patient  with  severe  acute  ulcerative  colitis.  Gut.  2020;69(6):1148–49. DOI: 10.1136/gutjnl-2020-321183 

26.https://www.crohnscolitisfoundation.org/coronavirus/ibd-medication 

27. Rubin D.T., Abrey M.T., Rai V., Siegel C.A. Interna- tional Organization for the Study of Inflammatory Bowel  Disease.  Management  of  Patients  with  Crohn’s  Disease  and  Ulcerative  Colitis  During  the  COVID-19  Pandemic:  Results  of  an  International  Meeting.  Gastroenterology. 2020; S0016-5085(20)30465-0. DOI: 10.1053/j.gas- tro.2020.04.002 

28.https://www.crohnscolitisfoundation.org/coronavirus/ibd-medication