Coronaviruses are positive-sense single-strand RNA viruses that infect amphibians, birds, and mammals. Coronavirus Disease 2019 (COVID-19) has become a major health problem caused by one of the coronaviruses called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread fast throughout the globe since its first identification in Wuhan, China, in December 2019. Although COVID-19 is principally defined by its respiratory symptoms, it is now clear that the virus can also affect the digestive system causing gastrointestinal (GI) symptoms like diarrhea, loss of appetite, nausea/vomiting, and abdominal pain as a major complaint. GI symptoms could be the initial signs of preceding respiratory signs, carrying a potential for slowed investigation and raised disease transmission opportunities. Various studies recognized the COVID-19 RNA in stool specimens of infected patients, and its viral receptor angiotensin-converting enzyme-2 (ACE-2) is highly expressed in GI epithelial cells. Many cases were reported negative using nasopharyngeal/oropharyngeal swabs and finally, SARS‐CoV‐2 RNA was detected in their anal/rectal swabs and stool specimens. These suggest that COVID-19 can actively infect and replicate in the GI tract. In this review, we elaborate on the close relationship between SARS-CoV-2 and the digestive system, focusing on the current status in the field of COVID-19 in gastroenterology, liver injury, endoscopy, inflammatory bowel disease, imaging, and the potential underlying mechanisms with illustrating the current epidemiological status regarding this pandemic.
Keywords: COVID-19, SARS-CoV-2, digestive system, anal swab, GI, liver, epidemiology
Coronaviruses are zoonotic, positive-sense single-strand RNA viruses. In December 2019, an outbreak of COVID-19 was caused by SARS-CoV-2 in Wuhan City, China. The World Health Organization (WHO) announced the coronavirus outbreak as a global pandemic in March 2020 (WHO, 2020).
It was indicated that SARS-CoV-2 may be transmitted between individuals by several different routes; the primary transmission mode is mainly contacted through respiratory droplets generated by breathing, coughing, sneezing, as well as direct contact with the infected subjects or indirect contact, by hand-mediated viral transfer from the contaminated fomites to the nose, mouth, or eyes (La Rosa et al., 2020).
Various researches have confirmed that the gastrointestinal (GI) tract is also a potential route. Once the coronavirus is attached to the spike protein (S), the viral genome penetrates the cells, uses human cell machinery, and creates multiple viral particles to be released to infect other cells (Aguila et al., 2020).
COVID-19 initially appeared to be primarily respiratory, presenting as fever and cough with a rapid decline requiring ventilatory support. Later, GI symptoms (nausea, vomiting, diarrhea, abdominal pain), neurologic symptoms (loss of taste and smell, stroke), and other nonspecific symptomatology have also been noted (Lin et al., 2020). However, with an expanded emphasis on reporting, this went up in some reports with even pure GI symptoms without respiratory manifestations.
In this article, we reviewed the current status of COVID-19 in gastroenterology and hepatology, imaging, and its current epidemiological level.
Wang et al. (2020) reported that there are 6 common signs and symptoms that 30 % of the patients have felt, including fever (98.5 %), fatigue (69.9 %), dry cough (59.4 %), anorexia (39.8 %), myalgia (34.8 %), dyspnea (31.1 %). Although respiratory tract manifestations are the most commonly reported symptoms in COVID-19, emerging data suggest that the gastrointestinal tract and liver might also be affected by SARS-CoV-2, on the basis that gastrointestinal epithelial cells and liver cells express angiotensin-converting enzyme 2 (ACE2), the major receptor of SARS-CoV-2 (Qi et al., 2020).
The most common GI presentation in patients with COVID-19 is diarrhea (3.8 %-34 %), followed by nausea and/or vomiting (3.9 %-10.1 %) and abdominal pain (1.1 %-2.2 %) (Grasselli et al., 2020). Other common GI symptoms reported in patients with COVID-19 are anorexia, anosmia, and dysgeusia (Giacomelli et al., 2020). Figure 1(Fig. 1) shows the incidence percentage of different GI symptoms in patients with COVID-19.
From a total of 35 studies, including 6686 patients with COVID-19, only 29 studies (n=6064) met the inclusion criteria and found GI manifestations in COVID-19 patients at investigation, and the combined prevalence of digestive marks was 15 % (95 % CI 10-21), the most common of which were nausea or vomiting, diarrhea, and anorexia (Mao et al., 2020). Nevertheless, Pan et al. (2020) found that patients with digestive symptoms were more likely to exhibit elevated liver tests, such as AST and ALT, compared with patients without digestive symptoms.
There is accumulating data that bidirectional communication is found between gut and lung, which is termed the gut-lung axis. It is thought that gastrointestinal inflammation causes lung inflammation by this communication. The specific pathway underlying this inflammatory transfer from the gut to the lung is not yet completely revealed (Hufnagl et al., 2020). Intestinal flora is supposed to significantly regulate the development and function of the innate and adaptive immune system, tune the immune cells for pro- and anti-inflammatory responses, and maintain immune homeostasis, thereby affecting the host's susceptibility to various diseases (He et al., 2020). SARS-CoV-2 directly or indirectly harms the digestive system by an inflammatory response. Alterations in the composition and role of the digestive tract flora influence the respiratory tract by the common mucosal immune system and respiratory tract flora diseases similarly affect the digestive tract by immune control. The effect is called the “gut-lung axis” (Budden et al., 2017), which may further explain why patients with COVID-19 pneumonia often have digestive symptoms.
Studies have shown that SARS-CoV-2 can be transmitted through feces (Holshue et al., 2020). Upon infection with COVID-19, it binds to the host cell's angiotensin-converting enzyme 2 (ACE2) receptor, which commonly is found in cilia of glandular epithelium in the gastrointestinal tract and cholangiocytes (Hamming et al., 2004), allows its entry into the target cell and facilitates replication (Xiao et al., 2020). Moreover, it is reported that ACE2 expression is approximately 100-fold higher in the gastrointestinal tract (particularly the colon) than in the respiratory system (Zhang et al., 2020). Therefore, it is not surprising that the digestive system, with several ACE2-expressing organs, would present a risk of being invaded by SARS-CoV-2.
Viral host receptor ACE2 stained positive mainly in the cytoplasm of gastrointestinal epithelial cells and the cilia of glandular epithelial cells but rarely is expressed in the esophageal squamous epithelial cells. Although viral RNA was also detected in the esophageal mucous tissue, the absence of viral nucleocapsid protein staining in the esophageal mucosa indicates low viral infection in the esophageal mucosa (van Doremalen et al., 2020). After viral entry, virus-specific RNA and proteins are synthesized in the cytoplasm to assemble new virions, which can be released to the gastrointestinal tract (Aguila et al., 2020) (Figure 2(Fig. 2)). Hence, clinicians should give care to GI manifestations and other atypical manifestations of COVID-19 patients to check and cure their infections.
According to the European Centre for Disease Prevention and Control (ECDC), since December 31, 2019 and throughJanuary 13, 2021, there have been 89,802,096 cases of COVID-19 including 1,940,529 deaths. Most cases in America (n = 39,844,634) were reported from: the United States (22,423,006), Brazil (8,131,612), Colombia (1,801,903), Argentina (1,730,908) and Mexico (1,541,633), followed by Europe (n = 28,291,217); most cases reported in Russia (3,425,269), United Kingdom (3,072,349), France (2,783,256), Italy (2,276,491) and Spain (2,111,782), Asia (n = 18,549,010): most cases were in India (10,466,595), Iran (1,286,406), Indonesia (828,026), Iraq (598,369) and Bangladesh (522,453), Africa (n = 3,059,974): most cases were in South Africa (1,231,597), Morocco (452,532), Tunisia (162,350), Egypt (149,792) and Ethiopia (128,616), Oceania (n = 56,556): the largest cases found in Australia (28,614), French Polynesia (17,241), Guam (7,423), New Zealand (2,222) and Papua New Guinea (811) (Figure 3(Fig. 3)). Most deaths in America (n = 925,925) were reported from the United States (374,442), Brazil (203,580), Mexico (134,368), Colombia (46,451) and Argentina (44,654), followed by Europe (n = 623,024) and most deaths were in the United Kingdom (81,431), Italy (78,755), France (67,750), Russia (62,273) and Spain (52,275), Asia (n = 317,547): most deaths were in India (151,160), Iran (56,171), Indonesia (24,129), Iraq (12,844) and Pakistan (10,676), Africa (n = 72,834): most deaths were in South Africa (33,163), Egypt (8,197), Morocco (7,743), Tunisia (5,284) and Algeria (2,807), Oceania (n = 1,193): most deaths were reported in Australia (909), Guam (124), French Polynesia (122), New Zealand (25) and Papua New Guinea (9) (ECDC, 2021).
Countries are classified in beating COVID-19 by these three groups: countries beating COVID-19, green plots (Figure 4(Fig. 4)), countries that are nearly there, yellow plots (Figure 5(Fig. 5)), and countries that need to take action red plots (Figure 6(Fig. 6)). These plots are customized for every country to better present the data (EndCoronavirus, 2021).
A recent meta-analysis composed of 60 studies with 4243 patients from China, Singapore, South Korea, the United Kingdom, and the United States showed a pooled prevalence of GI symptoms of 17.6 % including anorexia, nausea, vomiting, diarrhea, and abdominal pain (Cheung et al., 2020). Furthermore, digestive symptoms appeared to be associated with worse outcomes. Whereas about sixty percent of patients without digestive symptoms recovered and were discharged, while only 34.3 % of the patients with digestive manifestations recovered (Pan et al., 2020). Therefore, patients with GI manifestations should attract the attention of both patients and physicians. Table 1(Tab. 1) (References in Table 1: Balaphas et al., 2020; Boettler et al., 2020; Colmenero et al., 2021; Ding et al., 2004; Elli et al., 2020; Garland et al., 2020; Jothimani et al., 2020; Lee-Archer et al., 2020; Macaluso and Orlando, 2020; Monteleone and Ardizzone, 2020; Nabil et al., 2020; Onder et al., 2020; Portincasa et al., 2020; Rana, 2020; RECOVERY Collaborative Group et al., 2020; Wang et al., 2020; Wu et al., 2020; Yang et al., 2010; Yang et al., 2019; Yang et al., 2020) shows the current updated status of COVID-19 in gastroenterology, liver injury, endoscopy, inflammatory bowel diseases (IBD), and imaging.
CT scan works as the screening and diagnostic base for COVID-19: chest imaging in the initial stage presents various plaque shadows and interstitial changes, frequently observed in the peripheral lung and subpleural, and later expanded into multiple ground glass shadows and infiltration shadows in both lungs. In severe cases, lung consolidation can happen, shown as “white lung”, with unique pleural effusion and mediastinal lymph node increase (Chen et al., 2020).
There is a study reporting that 57 % of abdominopelvic CT exams performed on symptomatic COVID-positive patients had positive CT findings in the abdomen or pelvis. Abnormalities in the gastrointestinal tract were the most common (31 %), of which mural thickening was the most frequent. CT findings relating to the gallbladder and biliary system were found in 25 % of patients, including gallbladder distension, mural edema, and findings reported as possible or definite acute cholecystitis; 10 % of patients had biliary ductal dilation. Right upper quadrant ultrasound results previously reported on 37 COVID positive patients showed a similar distribution of pathology, with approximately 60 % demonstrating gallbladder sludge, 3 % demonstrating wall thickening, and 3 % showing pericholecystic fluid (Goldberg-Stein et al., 2020).
Finally, the COVID-19 pandemic is a highly infectious disease caused by the novel coronavirus SARS-CoV-2 that represents a global public health crisis. Although COVID-19 is principally defined by its respiratory symptoms, it is now clear that the virus can also affect the digestive system causing GI symptoms. ACE2-positive cells in digestive tract tissue strengthen the potential ways for SARS-CoV-2 infection. GI symptoms could be the initial manifestations preceding the respiratory one. In limited scenarios, digestive signs could be the only illness with an absence of any respiratory symptoms, harboring a danger of misdiagnosis. The correlation between the digestive system and COVID-19 deserves further investigation in future relevant studies.
Ahmed Nabil, Gamal Shiha (Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt; Tel: +20 1223280501, E-mail: firstname.lastname@example.org) and Mitsuhiro Ebara (Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1Namiki, Tsukuba, Ibaraki 305-0044, Japan; Tel: 008180-6661-5342, E-mail: EBARA.Mitsuhiro@nims.go.jp) equally contributed as corresponding authors.
All authors express their great gratitude to researchers, physicians, nurses, health care technicians, and all coworkers in the frontlines in Egypt, Japan, and any spot of the globe who spend their lives fighting this virus, hoping this work could help them in their mission.
Special thanks to Ebara Labo., NIMS, Japan research team & ELRIAH, El Mansoura, Egypt researchers, physicians, nurses, and health care technicians.
Ahmed Nabil: Resources, conceptualization, original draft writing, supervision, review & editing. Koichiro Uto: Original draft writing, review & editing. Mohamed M. Elshemy: Original draft writing, review, editing & resources. Reham Soliman: Writing, review & editing. Ayman A. Hassan: Writing & editing. Gamal Shiha: Conceptualization, original draft writing, review, editing & supervision. Mitsuhiro Ebara: Conceptualization, resources, original draft writing, supervision, review & editing.
The authors declare that they have no conflict of interest.
Figure 3: Geographic distribution of the 14-day cumulative number of reported COVID-19 cases per 100 000 population, worldwide, as of 13 January 2021 (ECDC, 2021)
[*] Corresponding Author:
Dr. Ahmed Nabil, Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1Namiki, Tsukuba, Ibaraki 305-0044, Japan; Tel: 00818035404321, (+20)1000618349, eMail: TOLBA.AhmedNabil@nims.go.jp