key: cord-0985970-rphwb3bo authors: Kariyawasam, Jayani C; Jayarajah, Umesh; Riza, Rishdha; Abeysuriya, Visula; Seneviratne, Suranjith L title: Gastrointestinal manifestations in COVID-19 date: 2021-03-16 journal: Trans R Soc Trop Med Hyg DOI: 10.1093/trstmh/trab042 sha: 03a50406e9cc8c355902ad1ce3a91af4c089dbbf doc_id: 985970 cord_uid: rphwb3bo Coronavirus disease 2019 (COVID-19), a respiratory viral infection, has affected more than 78 million individuals worldwide as of the end of December 2020. Previous studies reported that severe acute respiratory syndrome coronavirus 1 and Middle East respiratory syndrome–related coronavirus infections may affect the gastrointestinal (GI) system. In this review we outline the important GI manifestations of COVID-19 and discuss the possible underlying pathophysiological mechanisms and their diagnosis and management. GI manifestations are reported in 11.4–61.1% of individuals with COVID-19, with variable onset and severity. The majority of COVID-19-associated GI symptoms are mild and self-limiting and include anorexia, diarrhoea, nausea, vomiting and abdominal pain/discomfort. A minority of patients present with an acute abdomen with aetiologies such as acute pancreatitis, acute appendicitis, intestinal obstruction, bowel ischaemia, haemoperitoneum or abdominal compartment syndrome. Severe acute respiratory syndrome coronavirus 2 RNA has been found in biopsies from all parts of the alimentary canal. Involvement of the GI tract may be due to direct viral injury and/or an inflammatory immune response and may lead to malabsorption, an imbalance in intestinal secretions and gut mucosal integrity and activation of the enteric nervous system. Supportive and symptomatic care is the mainstay of therapy. However, a minority may require surgical or endoscopic treatment for acute abdomen and GI bleeding. Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is currently a pandemic and as of 26 December 2020 there have been >79 million cases worldwide and >1.7 million deaths. 1 Several vaccines have been developed to control the pandemic. 2 The earliest record of coronavirus infections among animals was in the late 1920s, where acute respiratory infections occurred in domesticated chickens in North America. 3 Human coronaviruses were discovered in the 1960s 4 and presently seven strains cause disease. Human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), human coronavirus 229E (HCoV-229E) and human coronavirus NL63 (HCoV-NL63) cause mild disease, while the severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may potentially cause severe disease. [5] [6] [7] Outbreaks of SARS-CoV-1 and MERS-CoV infections occurred in 2002 and 2012, respectively. 8 SARS-CoV-2 has 70% and 40% genetic sequence similarity with SARS-CoV-1 and MERS-CoV. 9 Although fever and respiratory symptoms predominate in coronavirus infections, gastrointestinal (GI) manifestations were seen in SARS-CoV-1, MERS-CoV and SARS-CoV-2 patients (Table 1) . 8, [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] Herein we outline the important GI manifestations of COVID-19 and discuss the possible mechanisms and aspects relating to their diagnosis and management. 13 Nausea, 14% 14 Nausea, 11.7% 15 Vomiting, 8% 14 Vomiting, 3.9% 16 16% week 1 19 14% week 2 19 NA week 3 19 25% week 1 19 37.5 week 2 19 NA week 3 19 Viral load (log10 copies/mL or CT value) 6 .52 week 1 19 7.95 week 2 19 4.5 week 1 19 4 week 2 19 31.65 CT week 1 19 26.5 CT week 2 19 5.33 week 3 19 0 week 3 19 NA week 3 19 Entry receptor ACE2 receptor DPP4 receptor ACE2 receptor Pathology Intestines: no obvious pathological changes/non-specific changes; depletion of mucosal lymphoid tissue 20 Intestines: no obvious pathological changes reported Intestines: mucosal damage in oesophagus with multiple round herpetic erosions and ulcers and numerous infiltrating plasma cells and lymphocytes as well as interstitial oedema in the lamina propria of the stomach, duodenum and rectum 21, 22 CT value: cycle threshold value; DPP4: dipeptidyl peptidase-4; NA: not applicable. then the full-text article was read. Reference lists of the full-text articles were scanned to identify any additional studies. All types of research articles, including original research articles, reviews, case series, short communications and case reports were considered. A total of 244 full-text articles were assessed for eligibility and 87 were included in this review ( Figure 1 ). There are two genera of human coronaviruses: alpha (HCoV-229E and HCoV-NL63) and beta (HCoV-HKU1, HCoV-OC43, SARS-CoV-1, MERS-CoV and SARS-CoV-2). SARS-CoV-2 and SARS-CoV-1 have high degrees of genomic similarity and use angiotensin-converting enzyme 2 (ACE2) as an entry receptor. 9 There is comparatively more literature on the GI effects of SARS-CoV-1 and MERS-CoV than the other coronaviruses. This may be due to differential levels of GI involvement by these coronaviruses. Early studies found coronavirus-like particles in intestinal lesions and the stools of infants with necrotizing enterocolitis. 23 , 24 Esper et al. 25 identified HCoV-HKU1 in stool samples from children and adults with GI disease. No stool samples were positive for HCoV-NL63, HCoV-229E or HCoV-OC43. In a study by Vabret et al. 26 in France, of six HCoV-HKU1-infected individuals, three were admitted to hospital for acute enteric disease and HCoV-HKU1 was detected in stool samples in two of them. Studies done by Kanwar et al. 27 and Kumthip et al. 28 found HCoV-HKU1 caused GI symptoms (diarrhoea, vomiting, nausea and abdominal pain) in up to 57% and 38% of infected individuals, respectively. Bouvier et al. 29 noted that among otherwise healthy adolescents and adults, HCoV-HKU1-related GI symptoms tend to occur on the fourth day of illness. During the SARS-CoV-1 outbreak, 30-70% of patients had GI involvement. 17 In a small study, Srikantiah et al. 30 found vomiting and diarrhoea in 63% and 75%, respectively, of SARS-CoV-1infected patients. Hui et al. 13 found nausea/vomiting (20-35%) and diarrhoea (20-25%) to be the common GI manifestations. On day 14 of illness, the positivity rates of SARS-CoV-1 in urine, nasopharyngeal aspirate and faeces were 42%, 68% and 97%, respectively. Other studies found diarrhoea in up to 25% of patients. [31] [32] [33] Chan et al. 34 found 5.8% of their patients had fever and diarrhoea (mainly watery without blood or mucus) as the presenting symptom. MERS-CoV patients had high levels of GI involvement. 35 Zumla et al. 36 reported nausea (21%), vomiting (21-33%) and diarrhoea (26-33%) in MERS-CoV patients. Abdullah et al. 37 noted GI manifestations in 35% of patients they studied in eastern Saudi Arabia. GI manifestations are reported in 11.4-61.1% of individuals with COVID-19. The majority of COVID-19-associated GI symptoms are mild and self-limiting and include anorexia, diarrhoea, nausea, vomiting and abdominal pain/discomfort (Table 2) . 15, 16, 21, 22, In some studies, anorexia and diarrhoea were the most common GI symptoms, 61 while in others nausea and vomiting were more prominent. 44 Although Han et al. 15 found COVID-19-associated GI symptoms to be more common in females (65.7% vs 51.1%), no other studies have found such a pattern. Diarrhoea has been reported in 2-50% of cases 62 and was found to be more common in severe disease (moderate 69.2%, severe 100%). 16 Han et al. 15 found 20% of their patients experienced diarrhoea as a first symptom, while in the rest it occurred up to 10 d after the onset of respiratory symptoms. A majority of patients are reported to have had non-severe, non-dehydrating, Luo et al. 54 found high levels of nausea and vomiting following COVID-19, while the incidence was lower in most other studies. A higher incidence of nausea was associated with more severe disease. Patients presenting with nausea, vomiting and diarrhoea are more likely to have fever than those having one of the symptoms alone. 15 Neonates with COVID-19 had vomiting and milk refusal associated with the respiratory symptoms. 63 Abdominal pain is found at a lower rate than other GI symptoms but was common among patients receiving intensive care unit (ICU) care. 49 A minority of patients presenting with abdominal pain had an important abdominal cause such as acute pancreatitis, acute appendicitis, intestinal obstruction, small bowel ischaemia, sigmoid ischaemia, haemoperitoneum, haemopneumoperitoneum or abdominal compartment syndrome. Seelinger et al. 21 described seven COVID-19 patients who underwent an emergency surgical procedure due to an acute abdomen. In a meta-analysis of 60 studies, 26.8% had anorexia as the most common symptom 61 and this accounted for difficulties with enteral feeding and maintenance of adequate nutritional status. 64 Furthermore, individuals who later developed refractory pneumonia had a higher incidence of anorexia on admission. 47 Prominent GI symptoms such as bloody diarrhoea are more common in those with severe disease. 40,65 Constipation and haemorrhagic colitis are other less common GI manifestations. 65, 66 Endoscopic evaluation carried out by Lin et al. 43 in a patient presenting with GI bleeding associated with COVID-19 showed multiple round herpetic erosions and ulcers. Similarly, Seeliger et al. 21 reported ulcerative and ischaemic changes in rectosigmoidoscopy in patients with severe symptoms. The time of onset of GI symptoms is variable. In some they are present at the start of the illness (before the other clinical manifestations), while in most they develop later. Of the 61.1% of COVID-19 patients with GI symptoms reported by Lin et al., 43 only 11.6% had symptoms on admission to hospital, while the rest developed them later. Those with predominant GI symptoms had significantly later hospital admissions than those with respiratory symptoms (9 vs 7.3 d 16 and 16 vs 11.6 d 15 ). There was an associated delay in diagnosis and treatment. 16 The group of patients with predominantly GI symptoms had a significant delay in presenting to hospital and a delay in the diagnosis as well. 16 Their clinical course was stormy and there was a higher incidence of progression to severe disease (needing mechanical ventilation and ICU care) compared with their non-GI counterparts. 15, 16, 42, 49, 53 They also had a longer hospital stay, as their discharge was delayed until viral clearance was achieved. The causes for this observation may be multifactorial. While treatment delay may have played a part, studies have also found higher viral replication and viral loads in patients with GI manifestations. 67 Han et al. 15 recommended doing routine reverse transcription polymerase chain reaction (RT-PCR) testing in patients presenting with GI symptoms, as they had higher rates of faecal RT-PCR positivity than others. On the other hand, some studies have not found an association between positive PCR results and the incidence of GI symptoms or disease severity. 43, 67 Variations in GI manifestations and time of onset may be due to several factors, including ethnic/geographical differences, associated comorbidities or the use of different clinical and diagnostic criteria. 68 It is important to be aware of the range of GI manifestations in COVID-19 so as to consider this possibility at an early stage. Clinicians should have a high degree of suspicion in patients with fever and GI symptoms, as this may be the only indicator of COVID-19 and may forecast progression to severe disease and the development of complications. Apart from preexisting liver disease, there were no other predisposing factors documented for the development of GI manifestations, making the prediction of developing such symptoms challenging. 42 SARS-CoV-2 enters host cells through ACE2 receptors. 69 High cell entry efficacy is achieved in three ways: high binding affinity of the receptor-binding domain (RBD) of the spike protein, evasion of the host immune system by reduced exposure of the RBD to the outside and Furin protease activation of the virus before entry into host cells, thus reducing its dependence on target cell proteases such as transmembrane protease, serine 2 (TMPRSS2). 70 Upon viral binding, the ACE2 receptor and virus are endocytosed, leading to a reduction in cell surface ACE2 levels. The ACE2 receptor is expressed in both hollow and solid intestinal organs. ACE2 messenger RNA (mRNA) is highly expressed in the GI tract and is stabilized by the neutral amino acid transporter B0AT1 (SLC6A19), found in the intestinal epithelium. 22 In gut epithelial cells, ACE2 is needed for maintaining amino acid homeostasis, antimicrobial peptide expression and the ecology of the gut microbiome. Thus a reduction of ACE2 may interrupt these processes and increase inflammation. A study using single-cell transcriptomics found elevated ACE2 expression in the upper oesophagus. 71 However, in a different case-control study, decreased expression of ACE2 and nucleocapsid proteins were found in the oesophagus by immunohistochemistry. 22 Such discrepant results may be due to patient or assay-related variations and ACE2 mRNA expression patterns may differ from its protein expression due to post-translational modification. Oesophageal bleeding with erosions is noted in some severe COVID-19 patients and may be due to high expression of ACE2 in stratified epithelial cells. 43 SARS-CoV-2 is usually not found in the stomach and this may be because of the highly acidic environment. ACE2 expression has been noted in the lamina propria 22 and enterocytes 72 of the stomach. Thus, although the virus is able to infect cells in the stomach, the low pH may be preventing this. There is high ACE2 expression in proximal and distal enterocytes of the small intestine, 68 with the highest expression seen at the brush border of intestinal enterocytes. 72 Interestingly, ACE2 and TMPRSS2 are more highly expressed on absorptive enterocytes of the ileum and colon than in the lung. 73 Saliva SARS-CoV-2 RNA is found in saliva and may play an important role in human-to-human viral transmission. Viral loads in saliva decline with persistence of the disease. 74 Saliva may be used for viral detection during the acute phase and has some advantages over nasopharyngeal swabs such as ease of sampling, less risk to healthcare workers and lower cost. SARS-CoV-2 RNA has been found in biopsies from the oesophagus, stomach, duodenum and rectum. 43 Involvement of the GI tract during COVID-19 may be due to direct viral injury and/or an inflammatory immune response and may lead to malabsorption, an imbalance in intestinal secretions and activation of the enteric nervous system. 73 Entry of SARS-CoV-2 into host cells may trigger an inflammatory response. This leads to recruitment of T-helper cells, a cytokine storm and organ damage. Individuals with diabetes are more susceptible to cytokine storm effects of COVID-19. 75 Virus-induced diarrhoea may be due to an alteration of intestinal permeability leading to enterocyte malabsorption. 62 Anal swabs have been reported to be persistently RT-PCR positive for SARS-CoV-2, even after throat swabs become negative. 50, 76 Positivity rates are higher among asymptomatic children, and this would have implications for its transmission potential. Histology shows occasional lymphocyte infiltration in the oesophagus and partial epithelial degradation, necrosis and mucosal shedding in the stomach. There is dilation and congestion of small blood vessels and oedema of the lamina propria and submucosa of the stomach and small intestine. Immune cell (lymphocytes, monocytes and plasma cells) infiltration is observed in the stomach and intestines. 22, [77] [78] [79] In human small intestinal organoids, enterocytes are readily infected by SARS-CoV-2, as demonstrated by confocal and electron microscopy. The studies demonstrate that intestinal epithelium supports SARS-CoV-2 replication. 72 SARS-CoV-2 viral shedding may occur through faeces. Chen et al. 67 did not find an association between stool viral RNA positivity and GI symptoms. Of 42 COVID-19 patients, 66.7% had SARS-CoV-2 RNA in their faeces but only 19% had GI symptoms. However, patients presenting with digestive symptoms are more likely to be faecal viral RNA positive than those with respiratory symptoms (73.3% vs 14.3%). Patients with digestive symptoms also take longer to clear the virus from their stools. 15 Zhang et al. 80 found a higher positivity rate of the virus in faeces compared with respiratory samples (83% vs 67%). The virus was present in the stools for a longer period compared with upper respiratory specimens (22 vs 14 d). 61 Chen et al. 67 found faecal shedding to occur for 6-10 d after pharyngeal swabs became negative and a similar pattern was seen among children. 51 The presence of faecal viral RNA does not correlate with disease severity. 67 The longer positivity of viral RNA in the stools of patients with digestive symptoms compared with those with only respiratory symptoms may be due to the high viral load in such patients. It may also be due to direct viral infectivity of the GI tract. Medications such as corticosteroids affect viral clearance. Ling et al. 81 found a significant delay in the viral clearance from faeces compared with oropharyngeal swabs (20 vs 11 d) in patients who received corticosteroids. Viral proliferation in the digestive tract raises the potential of faecal-oral transmission. 82 However, the presence of viral RNA in stools does not correlate with transmissibility, as nucleic acid detection does not differentiate infective from non-infective (dead or antibody-neutralized) viruses. 83 The detection of faecal viral RNA by RT-PCR testing in COVID-19 patients at different time points may be helpful in management (especially so in patients with GI symptoms). It may help with evaluating the effectiveness of treatment and for determining when quarantine may be ended. The gut microbiome may play an important role in COVID-19. 84 As the gut microbiota is known to affect pulmonary health, it may influence the pathogenesis of SARS-CoV-2 infections. Furthermore, respiratory infections are known to cause a change in the composition of the gut microbiota. Increased mortality and morbidity from COVID-19 is associated with the elderly, those with comorbidities such as diabetes and obesity and immunocompromised individuals. These groups of individuals are known to have an impaired gut microbiome structure and function. SARS-CoV-2 infections may further disturb the commensal microbe composition in the gut and lead to gut dysbiosis. The dysbiosis may cause increased cytokine levels, systemic inflammation and exaggerated immune responses. 85 Factors released during systemic inflammation, such as C-reactive protein, are related to the severity of COVID-19. Gou et al. 86 reported that around 20 blood proteins are associated with COVID-19. A study done in Hong Kong characterised the gut microbiome alterations in COVID-19. An abundance of Coprobacillus, Clostridium ramosum and Clostridium hathewayi correlated with COVID-19 severity, while the abundance of Faecalibacterium prausnitzii (an anti-inflammatory bacterium) showed an inverse correlation. Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis and Bacteroides ovatus were associated with low faecal SARS-CoV-2 viral loads. 87 Detailed characterisation of the gut microbiome may be useful in predicting disease severity in COVID-19 and large prospective studies are needed to explore this aspect further. The use of probiotics or prebiotics may help re-establish a more normal gut microbiota. Adequate dietary intake of high-quality proteins, vitamin A and branched chain fatty acids may increase the production of antibodies. Consumption of dietary components with known anti-inflammatory and antioxidant properties (omega-3, vitamin C, vitamin E and Transactions of the Royal Society of Tropical Medicine and Hygiene phytochemicals such as carotenoids and polyphenols) may help blunt an exaggerated inflammatory response and thus prevent dysregulated immune-mediated damage. Low vitamin D levels increase susceptibility to severe disease and death. Adequate fibre intake reduces the relative risk of mortality from infectious and respiratory diseases by 20-40% and is associated with a lower risk of chronic obstructive pulmonary disease. 88 Segal et al. 89 found the gut microbiota influences GI ACE-2 receptor expression and thus may play a role in influencing COVID-19 infectivity and disease severity. A study done in India found diet plays a crucial role in modulating the gut microbiota. The authors suggested a plant-based, fibre-rich diet may be advantageous during this pandemic, as it helps replenish the host gut microbiota, leading to various health benefits including enhanced immunity. 90 Van der Lelie et al. 91 have discussed the 'gut-lung axis,' where the gut microbiota composition influences lung susceptibility to viral infections and viral infections of the lung alter the gut microbiota composition toward a proinflammatory and dysbiotic state. Such dysregulation may influence disease progression and the risk of developing complications. The gut microbiota could influence immune responses and thus affect COVID-19 disease progression. Both overactive and underactive immune responses may lead to clinical complications in COVID-19. Safe and inexpensive prebiotics and probiotics should be considered as adjunctive treatment to limit COVID-19 progression in infected patients or as a preventive strategy in noninfected persons at risk. 92 Most GI manifestations in patients with COVID-19 are mild and self-limiting. 93 In such patients, no further investigations specific to the GI system are needed. Routine endoscopy is not useful in the diagnosis of mild disease and should be performed cautiously due to the risk of exposure of healthcare workers. Mild cases have a normal endoscopy, but in one study, endoscopic biopsy showed plasma cells and lymphocytes in the lamina propria of the stomach, duodenum and rectum despite having a macroscopically normal GI epithelium. 22 Endoscopy is useful in selected patients with GI bleeding for both diagnostic and therapeutic purposes. Lin et al. 43 found multiple round herpetic erosions and ulcers in the oesophagus. Martin et al. 45 found gastric or duodenal ulcers in 80% of endoscopies for upper GI bleeding and rectal ulcers in 60% of endoscopies when there was lower GI bleeding. Mauro et al. 46 described 11 patients who had active peptic ulcers, erosive gastritis and bleeding from gastro-oesophageal varices. A summary of the reported investigation findings and treatments used are provided in Table 3 . 15, 16, 21, 22, Although stool RT-PCR, peritoneal biopsies and peritoneal fluid RNA tests have been performed, their usefulness in management is limited. Selected patients with abdominal manifestations such as acute abdomen and peritonitis should have an abdominal computed tomography scan and angiogram. The reported positive findings include small bowel volvulus, acute enterocolitis, splenic flexure contrast extravasation, acute appendicitis, haemoperitoneum and haemopneumoperitoneum. As there are no accepted protocols for investigation of GI manifestations in COVID-19, the decision should be made based on individual circumstances considering the therapeutic benefit of the intervention and the potential risk of exposure to healthcare workers. Procedures such as upper and lower GI endoscopy should follow the recommended guidelines. 94 As positive viral RNA is seen in the oesophagus, stomach, duodenum and rectum, endoscopic procedures warrant extra precautions to ensure the safety of staff and prevent cross-contamination and nosocomial outbreaks among patients. During the COVID-19 pandemic, specific infection control guidelines have been implemented in different countries for endoscopic procedures. 94 Endoscopies should be performed only after clinical discussion and should be considered when it is essential for reaching a therapeutic decision that cannot be made using other non-invasive tests. Human-to-human transmission of SARS-CoV-2 occurs mainly through the respiratory tract via infected droplets/aerosols. Contact with contaminated surfaces is another possible mode of transmission. Thus wearing proper face masks, hand hygiene and social distancing are fundamental for infection prevention. Healthcare workers should wear appropriate personal protective equipment. Since the virus is found in stools for varying lengths of time, extra precautions may be needed to avoid faecal-oral transmission. Contact with infected saliva or stools should be avoided. Appropriate infection prevention and control measures should be in place for preventing nosocomial spread. There are case reports of the detection of virus in peritoneal fluid during laparotomy. Therefore adherence to special precautionary infection control measures for preventing aerosolization of the virus during laparoscopic procedures or when using electrocautery in open procedures should be considered. 58 As most virus-induced GI manifestations are mild and selflimiting, supportive care and symptomatic treatment are usually sufficient. [95] [96] [97] [98] Supportive treatment with oxygen, optimal hydration, analgesics and anti-emetics may be necessary. 99 Although studies are limited, endoscopy in selected patients has shown ulceration and bleeding. Avoidance of non-steroidal antiinflammatory drugs (NSAIDs) and gastric acid prophylaxis should be considered in patients with GI manifestations. Those with paralytic ileus or excessive vomiting may require nasogastric tube decompression and nothing by mouth. Patients with diarrhoea need appropriate rehydration therapy and anti-diarrheal medications. Those with GI manifestations have increased rates of electrolyte disturbance 42 and thus regular monitoring and correction of electrolytes is needed and medications that may induce electrolyte imbalance should be administered with caution. Those with severe GI manifestations or acute abdomen should be managed by a specialised multidisciplinary team including a physician, critical care specialist, nutritionist, gastroenterologist and surgeon. Transactions of the Royal Society of Tropical Medicine and Hygiene To date, no specific antiviral medications have been shown to reduce mortality in COVID-19 patients. The antiviral drugs used for treatment of COVID-19 include remdesivir and lopinavirritonavir. Remdesivir was shown to reduce hospital stays in patients with severe disease. A myriad of other treatment modalities aimed at symptom control and management of complications have been used. Immunomodulatory agents including glucocorticoids, convalescent plasma and anti-cytokine therapy have been used to reduce the negative effects of the overwhelming systemic inflammatory response. 99 However, except for dexamethasone, the other agents have not shown definite therapeutic benefits, although they may be beneficial in selected subgroups. 100 Moreover, evidence on the efficacy of these agents in treating GI manifestations is limited and further studies are required. There is an ongoing debate about the use of ACE inhibitors and renin-angiotensin-aldosterone system blockers in the treatment of COVID-19. Although beneficial mechanisms such as blocking viral entry into the host cell have been proposed, the clinical significance of these agents is yet to be conclusively proven. 101 The loss of gut mucosal integrity and dysfunction of intestinal flora are important complications in severe viral illnesses, including COVID-19. The use of probiotics has been suggested to improve GI symptoms of SARS-CoV-2 infection. 101 Irrational use of broad-spectrum antibiotics should be avoided, as they cause the loss of commensal intestinal flora and alteration of gut mucosal integrity. COVID-19 treatment guidelines in China have included the use of probiotics and micro-ecological regulators for maintaining gut mucosal integrity and to minimise secondary bacterial infections. 102 Nutrition SARS-CoV-2 patients may have a reduced oral intake due to the severity of their disease or as a side effect of the medicines that are used. Enteral nutrition is important for maintaining gut mucosal integrity, especially in patients with severe disease. In patients with severe disease, specialist nutritional assessment should be done and a high-calorie, immunomodulatory diet should be administered. In patients who are mechanically ventilated, nasogastric or nasojejunal tube insertion and enteral feeding is an option. In patients who cannot tolerate enteral feeding, parenteral nutrition should be administered. However, enteral feeding should be commenced early following improvement of the clinical condition. Rarely, patients with COVID-19 may present with an acute abdomen either due to a complication of the disease or due to a coexisting pathology. Conditions such as acute pancreatitis and abdominal compartment syndrome have been reported in association with COVID-19. 57, 103 Thus such conditions should be suspected in a deteriorating SARS-CoV-2 patient with an acute abdomen. As thrombotic complications are well-described in SARS-CoV-2 patients, mesenteric thrombosis should be suspected early in a clinically deteriorating patient with acute abdomen and appropriate anticoagulation should be initiated promptly after confirming the diagnosis through imaging. 104 In patients with GI bleeding that does not settle with medical management, therapeutic endoscopy with clipping or cautery has been found to be successful. Surgical treatment has been reported for conditions such as intestinal obstruction, bowel ischaemia, acute appendicitis and haemoperitoneum/haemopneumoperitoneum in association with SARS-CoV-2 (Table 3 ). Such cases are extremely rare and require a high degree of clinical suspicion and relevant imaging to reach the diagnosis. Standard surgical procedures have been performed with appropriate personal protective equipment and infection control measures to prevent transmission of infection. 105, 106 Furthermore, in such critically ill patients, postoperative care in an ICU is necessary. 107 A number of medications used in patients with COVID-19 have documented GI side effects (Table 4 ). Antivirals Antivirals and antibiotics may cause diarrhoea and alter the gut microbiome. 131 Remdesivir has a number of GI side effects, including nausea, vomiting, gastroparesis and constipation. 132, 133 The antimalarial agents chloroquine/hydroxychloroquine and lopinavir/ritonavir cause nausea, vomiting, loss of appetite and abdominal cramps. 108, 113 Immunomodulatory agents Immunomodulatory agents such as corticosteroids can increase the risk of peptic ulceration and GI bleeding. 134 The Janus kinase inhibitor baricitinib can cause diarrhoea. 108 Immunomodulators such as tocilizumab may cause GI bleeding, nausea, vomiting and ulceration. The GI side effects of intravenous immunoglobulins are minimal (Table 4 ). The use of PPIs are a risk factor for rotavirus, influenza virus, norovirus and MERS viral infections. 135 Individuals using PPIs once or twice daily had significantly higher odds of a positive COVID-19 test compared with those not taking it. 136 A larger study done by Lee et al. 137 in 14 163 current and 6242 past PPI users with COVID-19 found SARS-CoV-2 test positivity was not associated with current or past use of PPIs. However, current use of PPIs conferred a 79% higher risk of severe clinical outcomes following SARS-CoV-2 infection. In contrast, Taştemur and Ataseven 138 hypothesised that PPI may be used for treatment and prophylaxis of COVID-19, owing to their antiinflammatory, antioxidant, immunomodulatory and antifibrotic properties. Transactions of the Royal Society of Tropical Medicine and Hygiene The presence of comorbidities (including pre-existing digestive disorders) is associated with poor clinical outcome in COVID-19. Chronic inflammatory conditions such as IBD have a theoretical risk of making an individual more susceptible to COVID-19 or to a more severe course of illness. Thus far there has not been definite evidence for either scenario. Of the patients who contracted COVID-19, the most prominent clinical manifestations were fever and cough, similar to the general population. Diarrhoea was noted in about 20% of patients, making the clinical distinction between disease flare and COVID-19 essential for further management. 139 In those who do not have COVID-19, continuation of biologic therapy for IBD is recommended. However, in those with COVID-19, the severity of the IBD needs to be considered and treatment balanced with the severity of COVID-19. 140 Bezzio et al. 141 found that active IBD leads to a negative outcome requiring longer hospitalization and assisted ventilation. Treatment did not change this, emphasizing the importance of prevention of acute flares by adherence to therapy. IBD patients >70 y of age or with other associated comorbidities were at highest risk of complications. 142 IBD patients who are pregnant may have a high risk of COVID-19. A woman in the first trimester with an acute severe ulcerative colitis and COVID-19 suffered an abortion, but the exact reason for this was not clear. Optimal management of IBD in pregnancy during the COVID-19 pandemic is yet to be defined. No or limited use of steroids and the use cyclosporine and infliximab as salvage therapy on a case-bycase basis has been suggested. 143 Symptomatic anal fistula in Crohn's disease requires proper and timely treatment. Although exploration under anaesthesia is the gold standard for diagnosis, during the COVID-19 pandemic outpatient exploration may be a more suitable option. This would minimize the number of medical personnel required and avoid higher-risk anaesthetic procedures. 144 The pandemic has affected multiple steps in the diagnosis and management of GI malignancies. 145, 146 Interruption of endoscopic services due to the increased risk of disease transmission and added cost of infection prevention measures (especially in developing countries) has caused considerable delays in the diagnosis of GI malignancies. 147 Elective cancer therapies and surgeries have been delayed to allow increased capacity for dealing with COVID-19 patients. 148, 149 Such delays may adversely impact optimal care for cancer patients and worsen long-term outcomes. A delay in surgical resection in colorectal cancer worsens the survival rate and studies have found disease progression in patients with pancreatic malignancies. 150 Patients with GI cancers needing frequent hospital visits may be at higher risk of hospital-acquired COVID-19 transmission. Yu et al. 151 studied 1524 cancer patients and found them to have a twofold increased risk of COVID-19 infection when compared with the general population. The outcomes of patients with pancreatitis, celiac disease or irritable bowel syndrome who get COVID-19 have been poorly studied. 64 Limitations of this review include the small number of studies reporting on certain GI manifestations, making it difficult to provide more definitive conclusions on such aspects. It is possible that subtle GI findings were not documented (and thus underestimated) during the early part of the pandemic. Well-conducted studies from different regions of the world will help expand the evidence base and provide better answers to the many questions at hand. Ours is a broad overview of the main reported GI manifestations in COVID-19 and their management. A more comprehensive and detailed profile of specific aspects should emerge as more data are published from different countries. During the present pandemic, testing for SARS-CoV-2 should be considered in patients with GI symptoms, irrespective of them not having the other typical symptoms of COVID-19. The longterm effects of the different GI manifestations should become better defined as more studies using GI imaging and histological findings become available. Detailed and systematically conducted histopathology and autopsy studies should shed light on aspects of pathogenesis and pathology that are still undefined. GI manifestations are an important feature in some COVID-19 patients. The findings reported so far provide us with new and important insights for understanding the GI effects of SARS-CoV-2 and their underlying pathogenesis. Further studies should help with better delineation of the many uncertain aspects of COVID-19 and the GI tract. In this review we outlined the important GI manifestations of COVID-19 and discussed the possible mechanisms and aspects relating to their diagnosis and management. Word Health Organization. Coronavirus disease (COVID-2019) situation reports. Geneva: World Health Organization COVID-19 vaccine landscape Coronaviruses, a new group of animal RNA viruses History and recent advances in coronavirus discovery Hosts and sources of endemic human coronaviruses Coronaviruses: an overview of their replication and pathogenesis Healthcare-associated atypical pneumonia Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? SARS-CoV-2 induces a more robust innate immune response and replicates less efficiently than SARS-CoV in the human intestines: an ex vivo study with implications on pathogenesis of COVID-19 Managing SARS amidst uncertainty WHO/2019-nCoV/FAQ/Virus_origin/2020.1. Geneva: World Health Organization SARS: clinical features and diagnosis Considering revision the criteria for patients under investigations for MERS-CoV infections: diarrhea or not Digestive symptoms in COVID-19 patients with mild disease severity: clinical presentation, stool viral RNA testing, and outcomes Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis Laboratory testing of SARS-CoV, MERS-CoV, and SARS-CoV-2 (2019-nCoV): current status, challenges, and countermeasures Pathology and pathogenesis of severe acute respiratory syndrome Is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present intraperitoneally in patients with coronavirus disease 2019 (COVID-19) infection undergoing emergency operations? Evidence for gastrointestinal infection of SARS-CoV-2 Intestinal lesions containing coronavirus-like particles in neonatal necrotizing enterocolitis: an ultrastructural analysis Isolation and propagation of a human enteric coronavirus Human coronaviruses are uncommon in patients with gastrointestinal illness Detection of the new human coronavirus HKU1: a report of 6 cases Human coronavirus-HKU1 infection among adults in Cleveland Enteric and non-enteric adenoviruses associated with acute gastroenteritis in pediatric patients in Thailand Species-specific clinical characteristics of human coronavirus infection among otherwise healthy adolescents and adults. Influenza Other Respir Viruses Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts Identification of severe acute respiratory syndrome in Canada SARS: clinical presentation, transmission, pathogenesis and treatment options Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus Middle East respiratory syndrome coronavirus: epidemic potential or a storm in a teacup? Hospital outbreak of Middle East respiratory syndrome coronavirus Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study The presence of SARS-CoV-2 RNA in the feces of COVID-19 patients Clinical characteristics of coronavirus disease 2019 in China Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection Don't overlook digestive symptoms in patients with 2019 novel coronavirus disease (COVID-19) Gastrointestinal bleeding in patients with coronavirus disease 2019: a matched case-control study Upper gastrointestinal bleeding in COVID-19 inpatients: incidence and management in a multicenter experience from northern Italy Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore Clinical characteristics of coronavirus disease (COVID-19) patients with gastrointestinal symptoms: a report of 164 cases Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Gastrointestinal bleeding in patients with severe SARS-CoV-2 COVID-19 presenting as acute pancreatitis SARS-CoV-2 is present in peritoneal fluid in COVID-19 patients First case of 2019 novel coronavirus in the United States SARS-CoV-2 enterocolitis with persisting to excrete the virus for approximately two weeks after recovering from diarrhea: a case report Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong cohort: systematic review and meta-analysis. Gastroenterology Diarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention, and management SARS-CoV-2 infection with gastrointestinal symptoms as the first manifestation in a neonate Gastrointestinal manifestations of COVID-19: impact on nutrition practices SARS-CoV-2 gastrointestinal infection causing hemorrhagic colitis: implications for detection and transmission of COVID-19 disease Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment The presence of SARS-CoV-2 RNA in the feces of COVID-19 patients Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus SARS-CoV-2 Cell entry depends on aCE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell entry mechanisms of SARS-CoV-2 The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes SARS-CoV-2 productively infects human gut enterocytes Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process Consistent detection of 2019 novel coronavirus in saliva The cytokine storm and COVID-19 Detection and analysis of nucleic acid in various biological samples of COVID-19 patients Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies Histopathological observations in COVID-19: a systematic review Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients COVID-19: gastrointestinal manifestations and potential fecal-oral transmission Understanding COVID-19: what does viral RNA load really mean? Gut microbiota and Covid-19-possible link and implications Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome Diabetes is a risk factor for the progression and prognosis of COVID-19 Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge Using probiotics to flatten the curve of coronavirus disease COVID-2019 pandemic The gut microbiome: an underrecognised contributor to the COVID-19 pandemic? Diet, gut microbiota and COVID-19 COVID-19 and the gut microbiome: more than a gut feeling Gut microbiota status in COVID-19: an unrecognized player? Novel coronavirus infection (COVID-19) in humans: a scoping review and metaanalysis Overview of guidance for endoscopy during the coronavirus disease 2019 pandemic Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? Pattern of dengue virus infections in adult patients from Sri Lanka Clinical and biochemical characteristics of dengue infections in children from Sri Lanka Dengue infections and the surgical patient Clinical, laboratory and radiological characteristics and outcomes of novel coronavirus (SARS-CoV-2) infection in humans: a systematic review and series of meta-analyses Dexamethasone in hospitalized patients with Covid-19 The mechanism and treatment of gastrointestinal symptoms in patients with COVID-19 Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7) Abdominal compartment syndrome in a patient suspected of coronavirus 2019 (COVID-19) Haematological abnormalities in COVID-19: a narrative review Consensus in surgical practice during the COVID-19 pandemic: an appraisal of the literature Preoperative nasopharyngeal swab testing and postoperative pulmonary complications in patients undergoing elective surgery during the SARS-CoV-2 pandemic Consensus on perioperative surgical practice during the COVID-19 pandemic: an appraisal of the literature Review of emerging pharmacotherapy for the treatment of coronavirus disease 2019 Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro A trial of remdesivir in adults with severe COVID-19. NCT04257656 111 A trial of remdesivir in adults with mild and moderate COVID-19. NCT04252664 MERS-CoV infection treated with a combination of lopinavir/ritonavir and interferon beta-1b (MIRACLE). NCT02845843. Available from Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: a retrospective cohort study Lopinavir/ritonavir, ribavirin and IFN-beta combination for nCoV treatment. NCT04276688. Available from 115 Control of COVID-19 outbreaks in long term care Role of favipiravir in the treatment of COVID-19 Is oseltamivir suitable for fighting against COVID-19: in silico assessment, in vitro and retrospective study Effectiveness of arbidol for COVID-19 prevention in health professionals Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study Baricitinib as potential treatment for 2019-nCoV acute respiratory disease COVID-19-associated ARDS treated with dexamethasone: alliance Covid-19 Brasil III (CoDEX). NCT04327401 123 Efficacy of dexamethasone treatment for patients with ARDS caused by COVID-19 (DEXA-COVID19). NCT04325061 Drug vignettes: dexamethasone Glucocorticoid therapy for COVID-19 critically ill patients with severe acute respiratory failure 126 The efficacy of different hormone doses in 2019-nCoV severe pneumonia. NCT04263402 Effects of short-term low-dose glucocorticoids for patients with mild COVID-19 Evaluation of efficacy of levamisole and formoterol+budesonide in treatment of COVID-19. NCT04331470 High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019 Efficacy of plasmapheresis and immunoglobulin replacement therapy (IVIG) on patients with COVID-19 SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19 Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States Compassionate use of remdesivir for patients with severe Covid-19 Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C Proton pump inhibitors are risk factors for viral infections: even for COVID-19? Increased risk of COVID-19 among users of proton pump inhibitors Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching Is it possible to use proton pump inhibitors in COVID-19 treatment and prophylaxis? Med Hypotheses Characteristics and prognosis of patients with inflammatory bowel disease during the SARS-CoV-2 pandemic in the Basque Country (Spain). Gastroenterology AGA clinical practice update on management of inflammatory bowel disease during the COVID-19 pandemic: expert commentary Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic Management of acute severe ulcerative colitis in a pregnant woman with COVID-19 infection: a case report and review of the literature Ambulatory management of perianal Crohn's disease during the COVID-19 pandemic Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: an international, multicenter, comparative cohort study Gastrointestinal malignancies and the COVID-19 pandemic: evidence-based triage to surgery A practical approach to the management of cancer patients during the novel coronavirus disease 2019 (COVID-19) pandemic: an international collaborative group Delaying surgery for patients with a previous SARS-CoV-2 infection Gastrointestinal malignancies and the COVID-19 pandemic: evidence-based triage to surgery SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in Wuhan, China Funding: None. Data availability: The data underlying this article are available in the article. Authors' contributions: JCK and SLS designed the study. The search was conducted by JCK, RR, VA and UJ. JCK, UJ, RR and VA wrote the first version of the manuscript and SLS performed the final editing. All the authors reviewed and approved the final version. All authors had full access to the data in the study and final responsibility for the decision to submit for publication.Competing interests: None declared.