The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic began almost 2 years ago but new and rare complications are still being reported. It is well known that COVID-19 infection is commonly accompanied by Gastrointes- tinal (GI) symptoms, including dysgeusia, nausea, vomiting, di- arrhea, and abdominal discomfort [1-3). In fact, GI symptoms may be the sole presenting concern in patients found to have COVID-19 infection and a small proportion may not experience any respiratory symptoms [4]. Many previous reviews have fo- cused on the presenting GI symptoms and relatively mild con- ditions associated with SARS-CoV-2, such as liver function test abnormalities [3,5,6]. Efforts to better understand the associa- tion and mechanism leading to GI symptoms and complications of COVID-19 are ongoing. However, it has been established that COVID-19 is able to directly infect many cells of the GI tract via the Angiotensin-Converting Enzyme 2 (ACE2) receptor and tis- sue biopsies from multiple areas of the GI tract have been posi- tive for COVID-19 RNA by PCR [7,8]. Furthermore, COVID-19 has been found in substances produced by the GI tract, including bile and stool, suggesting fecal-oral transmission of the virus is possible [9,10]. Severe GI manifestations of COVID-19 infection are less commonly described but are important causes of co- morbidity and mortality in patients with active or recently re- covered from SARS-CoV-2 infection [11]. We present a comprehensive overview of known severe manifestations of COVID-19 infection involving the GI and hepatobiliary organs that has been published in the literature to date.

      Leading gastroenterology journals were queried for articles related to severe gastrointestinal pathology from January 2020 to December 2021. Search phrases used included COVID, CO- VID-19, coronavirus, and SARS-CoV-2. Articles selected for inclu- sion were those that focused on manifestations in the GI tract that were attributed to SARS-CoV-2.

Esophagus

      Cases of esophagitis and esophageal ulcers have been re- ported in association with COVID-19 infection, as well as rare instances of hemorrhagic esophagitis and acute esophageal necrosis [4,12-14]. Esophageal mucosal biopsies showed small vessel thrombosis and mucosal necrosis [13]. COVID-19 in- fection is known to cause a pro-thrombotic state, and micro thrombi leading to mucosal necrosis has been suggested as the underlying mechanism for these cases [13]. A previous study has demonstrated that the esophageal epithelium expresses high amounts of ACE2 receptors and may explain the severe manifestations of COVID in the esophagus described above [1]. Virus-like particles have been found on electron microscopy of epithelial and endothelial cells in the esophagus [4]. Addition- ally, esophageal brushings have tested positive for SARS-CoV-2 RNA [14]. This provides strong evidence for the idea that COVID is able to directly invade the esophageal mucosa. Esophageal involvement by COVID typically presents with odynophagia, dysphagia, regurgitation of food, and signs of bleeding such as melena or hematemesis [4,12,13,15].

      SARS-CoV-2 has known neurological complications, from which the esophagus is not spared. A case of rumination syn- drome associated with COVID-19 was reported in a young man who presented with persistent regurgitation of swallowed food and weight loss. Rumination syndrome was diagnosed after negative gastric emptying study, barium swallow, esophageal pH impedance testing, and esophageal manometry [16]. In an- other case, a woman with a history of GERD status post Toupet fundoplication presented with new onset worsening heartburn not responsive to anti-reflux medications one week after test- ing positive for COVID-19. Gastric emptying study, upper GI series, and EGD were unremarkable and she was diagnosed with esophageal hypersensitivity after symptoms resolved two months later when she tested negative for SARS-CoV-2. COV- ID-19 infection of the vagus nerve leading to hypersensitivity and allodynia was suggested as a potential mechanism for her diagnosis [17].

Stomach

      Similar to the esophagus, cases of gastric ulcerations and ischemia attributed to SARS-CoV-2 infection have been report- ed [15]. Gastric ischemia in combination with COVID-19 infec- tion may present with severe abdominal pain typically accom- panied by vomiting with signs of bleeding, such as hematemesis or coffee ground emesis and less commonly melena [15,18-20]. Endoscopic evaluation of these patients showed diffuse ero- sions and oozing, gastric ulcers, and severe mucosal ischemia [15,20]. Multiple cases of gastric pneumatosis have been de- scribed in the literature. Most cases were diagnosed with Com- puted Tomography (CT) showing gastric pneumatosis and signs of ischemia. Associated findings in the abdominal vasculature  were commonly seen on imaging, ranging from thrombosis and gas in the portal system to total occlusion of the superior mes- enteric artery [18-20]. The underlying pathophysiology leading to these severe manifestations may be due to direct infection of the gastric mucosa, small vessel thrombosis, systemic hyperco- agulability, or a combination thereof. One case was attributed to macrophage activation syndrome and treated with intrave- nous immunoglobulins [21].

      One unique case describes a woman diagnosed with CO- VID-19 one month prior who presented with coffee ground emesis. CT angiography showed extensive thrombosis involving the celiac trunk, common hepatic artery, splenic and left gastric arteries, and complete splenic infarction [22]. She developed a large gastrosplenic fistula seen on imaging and EGD that was managed conservatively with a percutaneous drain. Her severe thrombotic disease was attributed to a combination of COV- ID-19 coagulopathy and Factor V Leiden heterozygosity.

      COVID-19 has also been implicated in cases of gastropare- sis. One case report describes a man with COVID-19 pneumonia who developed abdominal distention and nausea. Abdominal x-ray and CT showed gastric distention and concern for gastric outlet obstruction. His symptoms resolved after nasogastric tube decompression and promotility agents, and he was diag- nosed with acute gastroparesis [23]. This case is corroborated by a retrospective cohort study of patients with a history of CO- VID-19 who underwent a gastric emptying study and found that over half of these patients were confirmed to have gastropa- resis [24]. Although neither of these studies establish causality between COVID-19 infection and gastroparesis, an association between the two diseases is likely.

Small and large intestine

      As in the esophagus and stomach, COVID has been associ- ated with inflammation, ulceration, and ischemia of the small bowel and colon. Patients diagnosed with colitis or enteritis primarily presented with abdominal pain, diarrhea, or hemato- chezia [25]. Numerous cases of ischemic colitis associated with SARS-CoV-2 have been reported. Several cases report small or large bowel ischemia with pneumatosis intestinal is, typically diagnosed on imaging or endoscopy [25,26]. Many cases are associated with venous or arterial thrombosis suggesting hy- percoagulability induced by COVID-19 as the underlying etiol- ogy of bowel ischemia [26]. In addition, some cases of colonic ischemia associated with COVID-19 were severe enough to lead to toxic megacolon and bowel perforation [27-30]. Few of these patients had endoscopies; however, one patient with ischemic enteritis and SMA thrombosis had a small bowel resection with pathology consistent with ischemic injury and electron micros- copy showing viral particles within enterocytes [31].

      However, there are other cases of enteritis and colitis as- sociated with SARS-CoV-2 without evidence of ischemia. One patient with CT findings suggestive of acute ileitis underwent a colonoscopy with ileal mucosal biopsy positive for COVID-19 RNA [7]. Interestingly, this patient had negative prior COVID stool testing. This again suggests that direct infection of the gas- trointestinal mucosa may explain these cases of enteritis and colitis.

      COVID-19 has also been implicated in cases of colonic dys- motility and Small Bowel Obstruction (SBO) [32,33]. One pa- tient diagnosed with a partial SBO on abdominal CT underwent an exploratory laparotomy but pathology was nonspecific and inflammatory versus ischemic etiologies could not be ruled out [32]. Multiple cases of acute colonic pseudoobstruction, or Ogil- vie syndrome, have been diagnosed in patients with concurrent COVID-19 infection [11,34]. This provides further evidence that COVID-19 may cause gastrointestinal dysmotility. However, critically ill patients in intensive care units, such as those being treated for COVID ARDS, are already at an increased risk of co- lonic dysmotility from a variety of factors and makes it difficult to establish a direct relationship between COVID-19 and colonic pseudoobstruction.

      Infections, both viral and bacterial, are known triggers of Inflammatory Bowel Disease (IBD), and SARS-CoV-2 is no different [35,36]. In the published literature, there are several cases of de novo Crohn’s disease and ulcerative colitis thought to have been triggered by COVID-19 infection [37]. There was initial concern that patients with IBD would be more suscep- tible to COVID-19 than the general population, as many are on immunosuppressive medications and the ACE2 receptor was previously shown to be upregulated in IBD [38]. However, large cohort studies have shown no increased rates of COVID-19 in- fection in IBD patients [39]. In fact, it has been suggested that the COVID-19 infection rate in patients with IBD may be lower than that of the general population [40].

      However, outcomes in this patient population may be de- pendent on a variety of factors and more studies are needed to further investigate this possibility.

Pancreas

      COVID-19 infection has been associated with severe pancre- atic manifestations. Existing studies have shown that concomi- tant SARS-CoV-2 infection in patients with Acute Pancreatitis (AP) leads to more severe disease and higher mortality [41,42]. A meta-analysis showed that compared to patients without CO- VID-19, patients with acute pancreatitis and COVID-19 had three times the incidence of idiopathic pancreatitis, greater severity of AP (Bedside Index of Severity in Acute Pancreatitis (BISAP) in four studies), increased risk of pancreatic necrosis, increased intensive care unit admissions, increased need for mechanical ventilation, more persistent organ failure, and increased mor- tality [43,44]. This may be due to immune dysfunction and cy- tokine storm caused by SARS-CoV-2, but it still remains unclear if SARS-CoV-2 infection can directly cause pancreatitis [45]. ACE2 receptors are found in the pancreas, and infection of the pancreatic islet and exocrine glands may explain the pancreatic manifestations in SARS-CoV-2 infection [46].

Biliary tract

      Severe biliary tract injury resembling Sclerosing Cholangitis of Critically Ill Patients (SC-CIP) has been reported in patients with COVID-19. All reported cases occurred in severely ill pa- tients who required ICU admission and mechanical ventilation [47,48]. Patients were predominantly men with mean time to recognition over 3 months after initial COVID-19 diagnosis and the terminology “post COVID-19 cholangiopathy” has been pro- posed to describe this syndrome [47,48]. Patients have chole- static or mixed cholestatic/hepatocellular injury patterns, but the predominant feature is marked elevation in serum alkaline phosphatase levels. MRI shows bile duct inflammation with mul- tifocal stricturing and beading [47]. Biopsies in one case series showed acute/chronic large duct obstruction without obvious bile duct loss [47], while another case series showed cholangio- cyte injury, loss of bile ducts with accompanying microvascular changes, and portal/periportal fibrosis [48]. The mechanism of injury is proposed to be ischemic, related to microvascular coagulopathy and/or hypotension during severe illness. Direct virus-mediated injury to the biliary epithelium may be involved as there is widespread expression of ACE2 receptors in cholan- giocytes [47,48].

      On prolonged follow up (up to 12 months), bile duct injury appeared to be stable or worsening and patients may eventu- ally require liver transplant [47]. There have also been case reports of biliary casts which may be associated with post CO- VID-19 cholangiopathy and ERCP with removal of the casts may not lead to normalization of liver enzymes [49,50]. As seen dur- ing other severe illnesses, acalculous cholecystitis has also been described as a complication of COVID-19 infection [51].

Liver

      COVID-19 can affect the liver, causing a range of manifesta- tions from transient hepatitis to fulminant liver failure. Report- ed rates of transient transaminitis in hospitalized patients with COVID-19 ranges from 10.5 - 69% [52-56]. Additionally, one meta-analysis of twenty-two studies found that deranged liver chemistries may indicate COVID-19 severity and predict mortal- ity [57,58]. Case reports also note that fulminant liver failure can occur during COVID-19 infection in the absence of respira- tory symptoms and in patients without prior liver disease [59]. All reported cases of liver failure in the setting of COVID-19 oc- curred in patients greater than age 75. Proposed mechanisms of liver injury in COVID-19 include hypotension due to sepsis, direct viral cytotoxicity through ACE-2, drug-induced liver injury, immune-mediated damage, and passive congestion.

      Acute infection with SARS-CoV-2 often presents with gastro- intestinal symptoms such as nausea, vomiting, diarrhea, and abdominal discomfort. However, COVID-19 has also been im- plicated as the underlying etiology of gastrointestinal patholo- gies that have developed in patients both during and after their initial infection. This narrative review focused on summarizing abstracts, case reports, and case series published in gastroen- terology journals to date. Additional articles describing the myr- iad of gastrointestinal diseases and disorders associated with but not attributed to SARS-CoV-2 are important reports but are beyond the scope of this review. Furthermore, it can be difficult to delineate which manifestations can truly be attributed to CO- VID-19 and which are simply complications of critical illness and extended hospitalizations in COVID-19 patients. Many reports include pathology that supports the case as a direct result of COVID-19 infection and suggest an underlying mechanism for the manifestation, but our review ultimately relies on author analysis to determine this. Severe manifestations of COVID in the GI tract and the hepatobiliary system are important causes of morbidity and mortality that gastroenterologists and inten- sivists should be aware of as the SARS-CoV-2 pandemic contin- ues.

Author contributions

      Tavia Buysse contributed to the literature review and manu- script writing, this author has approved the final draft for sub- mission.

      Sameer Bhalla contributed to the literature review and man- uscript writing. This author has approved the final draft for sub- mission.

      Vikram Kotwal contributed to the article conception, manu- script writing, and manuscript editing. This author has approved the final draft for submission.

Financial support

      The authors have no sources of funding to declare.

      The authors do not intend to benefit financially from this publication.

Potential competing interests

      The authors have no potential conflicts of interest to dis- close.

Article guarantor

      Vikram Kotwal, MD