Ai-Ning Zhang, Yi Zhang, Ye-Long Ji, Ke-Fan Wu, Yan Leng, Zhong-Yuan Xia

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060

Keywords:

ABSTRACT

Novel coronavirus has been officially named as Corona Virus Disease2019 (COVID-19) by the international Committee on viral taxonomy, and its pathogen has been named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[1]. Since its outbreak, this new type of pneumonia, which is far more infectious than SARS, has spread rapidly around the world, seriously threatening human life and health [2]. In view of the consequences caused by its widespread popularity in the international scope, the World Health Organization declared COVID-19 as a public health emergency of international concern. As of July 18th, the number of confirmed cases in the world has exceeded 14 million, and the cumulative number of deaths has exceeded 600,000 [4].

The most common manifestations of COVID-19 infection are fever, cough and progressive dyspnea caused by respiratory infection [5]. With the increase of the number of infected people, it has been found that not only the lungs, but also other organs may be attacked by viruses. In addition to respiratory symptoms, COVID-19 patients are often accompanied by gastrointestinal symptoms such as diarrhea, abdominal pain, vomiting and nausea, and gastrointestinal symptoms may appear earlier than respiratory symptoms [6]. This feature may lead to delay and lag in the diagnosis of diseases, improper patient management and unnecessary transmission in the process of diagnosis and treatment. Therefore, it is particularly important to study the correlation between gastrointestinal infection and symptoms, treatment and prognosis of patients.

1. Overview of SARS-CoV-2

1.1 SARS-CoV-2 and coronavirus family

Researchers from the Chinese Center for Disease Control and Prevention used the second-generation sequencing technology of metagenomics to isolate the only pathogen causing the outbreak of pneumonia from bronchoalveolar lavage fluid of two patients, namely SARS-CoV-2 in novel coronavirus [7]. This is the third severe coronavirus outbreak in less than 20 years after SARS in 2002-2003 and MERS in 2012. Although about 15% of cases caused by human coronavirus infection are common cold, SARSCoV-2 infection may have various manifestations with different severity from influenza to death [8]. Coronavirus (CoVs) family is a kind of linear single-stranded positive strand RNA virus with envelope, which can be divided into four genera:α, β, γ andδ. SARS-CoV-2 is the seventh coronavirus known to infect human, and the other six are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV[9]. RNA and RNA of coronavirus can be mutated by gene recombination. Recombination has diversity, including homologous recombination and heterologous recombination, which can make coronavirus acquire new biological characteristics in terms of virulence, host range and tissue tropism, thus increasing the pathogenicity of non-pathogenic or lowpathogenic coronavirus strains in the original host, and spreading in different species at an extremely fast speed to adapt to the new host [10].

1.2 Mechanism of SARS-CoV-2 infecting organism

All coronaviruses encode a cell surface glycoprotein, spike protein, which mediates coronaviruses to enter host cells. Spike protein is composed of S1 and S2 subunits. It first binds to the receptor on the surface of host cell through S1 subunit, and then fuses virus and host membrane through S2 subunit [11]. S1 subunit contains signal peptide, N-terminal domain and receptor binding domain (RBD). For β-CoV, RBD of spike protein mediates the interaction with host receptor. After binding to the receptor, the spike protein is cleaved by the nearby host protease and releases the signal peptide to promote the virus to enter the host cell [12,13]. Angiotensin converting enzyme 2(ACE2) and dipeptidyl peptidase 4(DPP4) are known as host receptors of SARS-CoV and MERS-CoV, respectively. Similar to SARS-CoV, SARS-CoV-2 also enters host cells through ACE2 [8]. Zhou et al. [14] confirmed that SARS-CoV-2 can infect the body by binding all cells expressing ACE2 receptor except mice. However, Wrapp et al. [15] found that although the receptors are the same, the affinity of SARS-CoV-2 to ACE2 is about 10-20 times that of SARS-CoV, which seems to explain why SARS-CoV-2 is far more infectious than SARS-CoV.

ACE2 receptor-expressing cells are susceptible to SARS-CoV-2. Although respiratory system is the main target of SARS-CoV-2, bioinformatics analysis of single cell transcriptome of lung, esophagus, stomach, ileum and colon shows that digestive system is also a potential invasion route of SARS-CoV-2, because ACE2 is highly expressed not only in type II alveolar cells and stratified epithelial cells of lung, but also in gastrointestinal tract, especially in absorptive intestinal epithelial cells of ileum and colon [16,17]. SARSCoV-2 RNA can be detected in stool samples, anal and rectal swabs of some patients, which also indicates that the virus may spread through gastrointestinal tract and infect the body [18].

2. Symptoms of digestive system infected by COVID-19

Most COVID-19 patients are accompanied by one or several symptoms of digestive system in the course of disease, and some patients take gastrointestinal symptoms such as diarrhea as the first symptom of infection [19]. The manifestations of digestive system are diverse and can not be ignored. Studies have shown that compared with patients without gastrointestinal (GI) symptoms, GI patients have more severe/critical cases, and they are more likely to receive mechanical ventilation and transfer to ICU ward, and the risk of infection and death is higher [20,21]. As one of the prominent extrapulmonary manifestations of COVID-19 infection, it is very important to identify and deal with the digestive system abnormalities of patients as early as possible.

2.1 Anorexia, nausea and vomiting

In a recent meta-analysis involving 35 studies (including gastrointestinal manifestations of 6686 SARS-CoV-2 infected patients), the comprehensive prevalence rate of all gastrointestinal symptoms was 15%, among which nausea and/or vomiting, diarrhea and anorexia were the most common three [22]. At present, various reports show that the rate of anorexia in COVID-19 patients is between 1.0% and 79%.In the research of Lin et al. [23], most COVID-19 patients suffered from anorexia during hospitalization, and a few patients suffered from anorexia at the beginning of infection. Although anorexia is the most common gastrointestinal symptom (26.8%) after comprehensive analysis of the prevalence rate, the pathogenesis of anorexia in COVID-19 patients is still unclear, and it is speculated that some of the reasons may be due to taste dysfunction and olfactory dysfunction caused by COVID-19 infection [24]. In a group of 417 mild to moderate COVID-19 patients in Europe, it was found that up to 88.0% patients had taste disorder. In addition, taste dysfunction is also significantly related to olfactory dysfunction, and the prevalence rate of olfactory dysfunction is as high as 85.6%, which may further aggravate appetite loss [25]. Viruses can enter the central nervous system and infect peripheral neurons through the cellular mechanism of active transport [26]. Human coronavirus can directly invade the olfactory bulb and destroy the central nervous system. At the same time, the cerebral cortex (pear-shaped and infralimbic cortex), basal ganglia (ventral pallidum and transverse preoptic area) and midbrain connected with the olfactory bulb can also be strongly infected with coronavirus, which spreads rapidly and indirectly infects the olfactory bulb. In transgenic mice, it has been proved that SARS-CoV can enter the brain through olfactory bulb mediated by ACE2, resulting in rapid spread of virus across neurons [27].Recent experiments by Jerome et al. [25] proved that SARS-CoV-2 virus antigen was first detected 60-66h after infection, and its content was highest in olfactory bulb. Nausea and vomiting are also common gastrointestinal symptoms of COVID-19 patients. A study by Tian et al. [28] showed that after SARS-CoV-2 infection, the incidence of vomiting was 3.6%-66.7% and the incidence of nausea was 1%-29.4%. Compared with adults, children have a higher incidence of vomiting.

2.2 Diarrhea and abdominal pain

ACE2 receptor is highly expressed in small intestinal epithelial cells. ACE2 is very important in controlling intestinal inflammation, and its destruction may lead to diarrhea [29]. Diarrhea is a common symptom when SARS broke out in 2003. About 20% of SARS patients in Hong Kong have diarrhea symptoms [31]. The average duration of diarrhea is 3.7 days, and most of them are self-limiting. The diarrhea rate during SARS infection is high. In one study, the proportion of diarrhea and abdominal pain in patients reached 73%[32-35]. The reported rate of diarrhea in COVID-19 patients ranged from 2% to 33%, and the incidence of diarrhea in different reports was quite different, which suggested that the diagnostic criteria of diarrhea in different hospitals might be different. Diarrhea is one of the main symptoms reported in the first COVID-19 case in the United States [29,36]. Although the average incidence of diarrhea in COVID-19 patients is lower than that in SARS, it is worth noting that diarrhea caused by SARS-CoV-2 may be the first symptom of COVID-19 patients [37]. Pan et al. [38] described the clinical characteristics of a group of COVID-19 infected patients from Hubei province.Among 204 patients, 99 (48.5%) complained of digestive system symptoms. Among them, 7 cases (3.4%) had only gastrointestinal symptoms, but no respiratory symptoms. These studies show that diarrhea and other digestive symptoms may be a manifestation of COVID-19 patients before respiratory symptoms, and may be the only manifestation in rare cases [39]. Therefore, clinicians must pay attention to such symptoms in patients, and patients without respiratory symptoms cannot rule out SARS-CoV-2 infection. Abdominal pain is often accompanied by diarrhea, but its average incidence is lower than that of diarrhea.

COVID-19 infection in intestinal tissue may cause diarrhea and abdominal pain. Absorbent intestinal cells can be infected and destroyed by SARS-CoV-2, which potentially leads to malabsorption, imbalance of intestinal secretion and activation of intestinal nervous system, thus leading to diarrhea and other symptoms [17]. Metabolic disorder destroys intestinal mucosal barrier and normal internal environment, and increases the absorption of harmful metabolic toxins, which will affect the function of central nervous system through intestinal-brain circulation, and then lead to dizziness and fatigue [40]. Diarrhea may also be related to the use of antibiotics during treatment. A study involving 95 confirmed patients with COVID-19 showed that during hospitalization, the use of antibiotics may lead to diarrhea, but antiviral treatment does not have this side effect and will not cause diarrhea [23].

Some studies have proved that viral RNA exists in feces or anal/rectal swabs of COVID-19 patients [41-43], and the gastrointestinal tropism of SARS-CoV-2 may explain the frequent occurrence of diarrhea in virus infection. This fecal source can lead to pathogen transmission, especially when infectious aerosols are generated from toilets [44]. However, the presence of SARS-CoV-2 RNA in feces does not necessarily mean that gastrointestinal symptoms are more serious. Lin et al. [23] discussed the relationship between gastrointestinal symptoms and SARS-CoV-2 in feces of 65 inpatients. Among them, 42 cases had gastrointestinal symptoms, 23 cases had no gastrointestinal symptoms, and 22 cases (52.4%) and 9 cases (39.1%) were positive for SARS-CoV-2 RNA in feces. There is no significant difference in the proportion of SARS-CoV-2RNA positive cases in feces between the two groups. It is worth noting that although the presence of SARS-CoV-2 in feces does not necessarily mean more gastrointestinal symptoms, the presence of SARS-CoV-2 in gastrointestinal tissues usually indicates more serious symptoms.

2.3 Liver injury

The majority of COVID-19 patients have different degrees of liver injury during the course of disease, which is characterized by abnormal liver enzyme level. Current data show that nearly 50% of COVID-19 patients have elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and most of them are accompanied by slight increase of serum bilirubin [45-47]. 2-11% of COVID-19 patients have potential chronic liver diseases, and 14-53% patients have liver insufficiency, especially in severe patients. The incidence of liver dysfunction is significantly higher in critically ill patients, which is related to poor prognosis [48]. ACE2 distribution in liver is specific. It is highly expressed in small vascular endothelial cells in liver, but not in sinusoidal endothelial cells. Chai et al. [49] sequencing data of single cell RNA from two independent cohorts showed that the expression of ACE2 receptor in bile duct cells (59.7%) was higher than that in liver cells (2.6%). The ACE2 level of bile duct cells is similar to that of alveolar type ⅱ cells, which suggests that the liver, as a potential target of SARS-CoV-2, may cause direct damage to intrahepatic bile duct. In addition to direct virus damage, the toxicity of therapeutic drugs in the process of SARS-CoV-2 infection can also cause secondary liver damage, which is mainly caused by a large intake of antiviral drugs, antibiotics and steroids and excessive immune response [50]. According to a study, a higher proportion of liver enzymes were found in patients receiving lopinavir/ritonavir antiviral treatment (56.1% vs 25%). In this population, it is not clear whether the increase of liver enzymes is due to the disease itself or the liver injury caused by drugs. In addition, COVID-19 may lead to the deterioration of potential chronic liver diseases, leading to liver decompensation, and acute aggravation leading to liver failure leading to death [51]. Cytokine storm caused by COVID-19 infection may also lead to liver dysfunction, but it does not lead to direct cytopathic effect. At present, more data are needed to determine the mode and degree of liver injury in affected patients.

2.4 Gastrointestinal bleeding

Compared with other gastrointestinal manifestations, there are fewer cases of gastrointestinal bleeding due to COVID-19 infection, but it can not be ignored. Xiao et al. [16] collected 73 confirmed patients with COVID-19, of which 10 cases had gastrointestinal bleeding during the course of disease. The pathological mechanism of gastrointestinal bleeding caused by SARS-CoV-2 has not been fully clarified, and some patients show the original basic gastrointestinal diseases, which cause gastrointestinal bleeding due to the stress of the body after infection with COVID-19. Another possible speculation is that COVID-19 infection affects the coagulation function of patients, and patients with gastrointestinal symptoms are more affected. The respiratory function of COVID-19 patients is impaired, which leads to hypoxia of tissues and cells, and activates signaling pathways dependent on transcription factors to stimulate thrombosis, resulting in abnormal coagulation function [52]. In the course of COVID-19, most patients will have prolonged prothrombin time (PT) and increased D- dimer, and some patients also have prolonged activated partial thromboplastin time (APTT) [53-55]. Abnormal coagulation function may be one of the factors that increase the risk of gastrointestinal bleeding in COVID-19 patients.

3 Principles of treatment

As gastrointestinal symptoms may be neglected as the first symptom of COVID-19 infection, in order to control the epidemic, every effort should be made to pay attention to the possible signs of COVID-19 infection, so as to diagnose the disease early and isolate patients before pulmonary symptoms appear [50]. At the same time, because SARS-CoV-2 RNA can be detected in patients' feces, the digestive system may be another infection route leading to virus transmission, especially in early contact with asymptomatic carriers or people with mild infection symptoms. Attention should be paid to the isolation of patients' digestive tract during the course of disease until the detection of SARS-CoV-2 RNA in feces turns negative [50]. Once patients with COVID-19 suspected symptoms are found, they should be required to wear a standard surgical mask and be isolated by a single person. The ideal isolation room is an airborne isolation room (negative pressure room). Tableware, tea sets and articles for daily use of suspected patients should be used and kept separately, so that they can live alone, be used exclusively for toilets, and be separated from food and drink [56]. Viral infection is often accompanied by diarrhea, followed by potential malabsorption and severe malnutrition, which is not conducive to the recovery and outcome of the disease. With the continuous expansion of the research field of intestinal flora and the use of probiotics in different disease states, probiotics have been proposed for COVID-19 infected patients, especially diarrhea patients. Various drugs used for COVID-19 (such as antibiotics and antiviral drugs) may cause changes in intestinal flora, which provides a new therapeutic target for probiotics to play a role [57]. The National Health Commission of China advocates the use of probiotics to treat patients with severe COVID-19, so as to reduce intestinal malnutrition and bacterial translocation and secondary infection [28]. In addition, patients can increase the risk of cross-infection between patients and infection of medical staff when undergoing digestive endoscopy, so we should pay attention to taking protective measures when carrying out relevant examinations, emphasizing the importance of personal protective equipment and avoiding transmission [58].

4. Summary

Although SARS-CoV-2 has been identified as a respiratory pathogen, it may cause gastrointestinal symptoms. Some patients have diarrhea, nausea, vomiting and abdominal pain, and laboratory abnormalities and liver injuries often occur, which are related to the severity of the disease. In clinical work, attention should be paid to the abnormal manifestations of digestive system in patients' course, COVID-19 infection should be identified in time, and the most effective treatment should be given to patients' clinical manifestations.