INTRODUCTION — In February 2020, the World Health Organization designated the disease COVID-19, which stands for "coronavirus disease 2019," a pandemic. The virus that causes COVID-19 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
COVID-19 primarily manifests as a lung infection, with most symptomatic patients presenting with fever and respiratory symptoms. However, it has significant extrapulmonary complications affecting most organ systems, including the gastrointestinal tract.
This topic reviews the gastrointestinal manifestations and complications of COVID-19, including mesenteric ischemia, with a particular focus on the critically ill COVID-19 patient. Management of COVID-19 patients who have preexisting gastrointestinal or liver diseases can be found elsewhere. (See "COVID-19: Issues related to gastrointestinal disease in adults" and "COVID-19: Issues related to liver disease in adults".)
Perioperative management of patients with active or recent COVID-19 infection is discussed in another topic. (See "COVID-19: Perioperative risk assessment and anesthetic considerations, including airway management and infection control", section on 'Preoperative evaluation during the pandemic'.)
COVID-19 GASTROINTESTINAL SYMPTOMS — While most symptomatic COVID-19 patients present with fever, cough, shortness of breath, and/or loss of the sensation of taste and smell, up to one-third of patients present with gastrointestinal complaints. (See "COVID-19: Clinical features", section on 'Initial presentation'.)
●In an early meta-analysis of 60 studies comprising 4243 patients, the majority from China, the pooled prevalence of all gastrointestinal symptoms was 17.6 percent [1]. Anorexia was the most common presenting symptom (26.8 percent), followed by diarrhea (12.5 percent), nausea/vomiting (10.2 percent), and abdominal pain (9.2 percent) [1].
●A subsequent meta-analysis of more than 18,000 patients from around the world suggested that diarrhea was the most common (11.5 percent) gastrointestinal symptom, followed by nausea and vomiting (6.3 percent), then abdominal pain (2.3 percent) [2].
●In the subset of patients with the most severe SARS-CoV-2 infection presenting as acute respiratory distress syndrome (ARDS) and requiring intensive care, diarrhea is reported upon initial hospital presentation in one-third of the patients and nausea or vomiting in one-fifth of the patients [3].
In most of these early studies, the inquiry into and reporting of gastrointestinal symptoms upon presentation was not systematic, and thus, these rates are likely an underestimate of the true incidence.
GASTROINTESTINAL COMPLICATIONS IN CRITICALLY ILL COVID-19 PATIENTS — Patients with severe COVID-19 are at a particularly high risk for developing gastrointestinal complications. During their often prolonged hospitalization, 74 to 86 percent of critically ill patients with COVID-19 manifest gastrointestinal complications ranging from self-resolving transaminitis and feeding intolerance to life-threatening mesenteric ischemia [3,4].
Acute liver injury and elevated transaminases — Nearly two-thirds of patients with severe COVID-19 develop elevated liver transaminases [5], with reported mean aspartate aminotransferase (AST) and alanine aminotransferase (ALT) above 400 units per liter of serum [3]. The liver injury can progress to liver ischemia in rare instances.
The etiology of acute liver injury in COVID-19 patients remains unclear but is likely multifactorial. Several studies are suggesting that the degree of elevation of the transaminases is a marker of disease severity and an independent predictor of mortality [6-8].
The treatment of acute liver injury in COVID-19 patients is further discussed elsewhere. (See "COVID-19: Issues related to liver disease in adults", section on 'Management principles'.)
Acute cholecystitis — Acute cholecystitis has been widely reported in patients with COVID-19, especially those who are critically ill [3,4,9-13]. In most patients, the cholecystitis is acalculous, and the etiology remains largely unclear. While hypomotility of the gallbladder wall is expected in critical illness in general, a direct viral involvement in the pathophysiology in COVID-19 patients cannot be ruled out [13]. (See 'Possible etiologies of COVID-related gastrointestinal complications' below.)
In critically ill COVID-19 patients, initial management of acute cholecystitis should be with antibiotics and percutaneous cholecystostomy rather than surgery [14,15]. Cholecystectomy is reserved for those who do not respond to percutaneous drainage [13]. In a study by the COVIDSurg Collaborative, an international collaborative of more than 6000 hospitals across more than 90 countries, 1128 COVID-19 patients who underwent surgery had a perioperative mortality as high as 24.8 percent [16]. Age greater than 70, male sex, emergency surgery, and cancer or major surgery independently predict mortality.
The treatment of acalculous cholecystitis is discussed elsewhere. (See "Acalculous cholecystitis: Clinical manifestations, diagnosis, and management", section on 'Management'.)
Acute pancreatitis — Acute pancreatitis has also been widely reported in patients with COVID-19, especially in those with critical illness [3,4,11,17-21]. Progression to necrotizing pancreatitis that requires percutaneous, endoscopic, or surgical debridement has been also reported.
The hypothesis that acute pancreatitis in these cases is directly caused by SARS-CoV-2 is plausible, but the association between COVID-19 and acute pancreatitis is still not very well understood [22]. (See 'Possible etiologies of COVID-related gastrointestinal complications' below.)
Acute pancreatitis in COVID patients is managed in the same way as that in non-COVID patients. The treatment of acute pancreatitis is discussed in another topic. (See "Management of acute pancreatitis".)
Ileus and feeding intolerance — In critically ill COVID-19 patients admitted to the intensive care unit (ICU), significant ileus and feeding intolerance occur in 46 to 56 percent [3].
The etiology of the ileus is likely multifactorial, especially since these patients commonly require high doses of sedatives and opioids for ventilator synchrony, and these medications are associated with slowed intestinal function. However, the possibility of a SARS-CoV-2-specific etiology cannot be excluded. (See 'Possible etiologies of COVID-related gastrointestinal complications' below.)
The treatment of ileus is discussed elsewhere. (See "Postoperative ileus", section on 'Management'.)
Acute colonic pseudo-obstruction — Several cohort studies and case reports have reported a distinct colonic syndrome in the critically ill COVID-19 patient characterized by severe gaseous distention with no obvious distal obstruction, similar to the well-described acute colonic pseudo-obstruction, or Ogilvie's syndrome [3,23,24]. (See "Acute colonic pseudo-obstruction (Ogilvie's syndrome)".)
The etiology of acute colonic pseudo-obstruction in critically ill COVID-19 patients, and whether it is COVID-19 specific or a simple manifestation of prolonged critical illness, remains unclear. Some authors have reported hemorrhagic colitis and ischemic colitis in COVID-19 patients [25,26]. Several others have reported microangiopathy and/or infectious colitis in pathologic examinations. (See 'Possible etiologies of COVID-related gastrointestinal complications' below.)
When colonic pseudo-obstruction is encountered in the ICU, and if the patient remains stable with no evidence of worsening sepsis or shock, we recommend conservative management with electrolyte optimization, colonic decompression with a rectal tube or endoscopically, and decreasing or discontinuing any medications that could be worsening the paralytic ileus (eg, opioids, sedatives). Whether there is a role for acetylcholinesterase inhibitors such as neostigmine is unclear. (See "Acute colonic pseudo-obstruction (Ogilvie's syndrome)", section on 'Management'.)
In a small number of patients, the colonic distention, especially if not mitigated, can progress to wall necrosis and perforation, thus requiring surgical intervention. Therefore, the clinician should maintain a high clinical index of suspicion for ischemia and perforation in case of worsening clinical status.
Mesenteric ischemia — The most serious gastrointestinal complication reported in critically ill COVID-19 patients is mesenteric ischemia [3,27-45]. In cohort studies of critically ill COVID-19 patients admitted to a single institution, the incidence was reported at 3.8 to 4 percent [3,27].
Because most of these patients are sedated, requiring mechanical ventilation, and on low doses of vasopressors precluding a reliable clinical evaluation [28,29], early diagnosis based on physical exam and classic symptomatology (eg, severe abdominal pain or tenderness) is often not feasible. Instead, new feeding intolerance in the ICU, abdominal distention, increasing leukocytosis, increasing vasopressor requirements, and/or unexplained metabolic acidosis are the most common presenting signs [28-30]. Elevated lactate levels are neither sensitive nor specific in diagnosing mesenteric ischemia in these patients; thus, clinicians should not exclude bowel ischemia solely on the basis of a normal lactate level.
Abdominopelvic computed tomography (CT) imaging can demonstrate bowel wall thickening, pneumatosis, and/or portal venous air [46]. When intravenous contrast is used, arterial phase imaging occasionally shows filling defects in the thoracoabdominal aorta or mesenteric arteries suggestive of acute thromboembolic phenomena [30-33,47]. In other patients, delayed venous phase imaging can show filling defects in the inferior vena cava or portomesenteric venous system [30,33,34]. However, a significant number of patients develop mesenteric ischemia despite patent and well-perfusing proximal and mesenteric vessels on CT [3,27,28], suggesting perhaps that the pathophysiology of thrombosis involves the small intestinal vessels. (See "Nonocclusive mesenteric ischemia".)
Once mesenteric ischemia is suspected clinically and/or radiologically, operative intervention is often indicated for bowel examination and resection, if within the patient's goals of care [27,35]. When proximal arterial thromboembolic disease is suspected, endovascular or open angiography and thrombectomy is required. (See "Acute mesenteric arterial occlusion", section on 'Management'.)
On intraoperative examination of the bowel in these patients, many surgeons reported unusual findings with patchy areas of well-demarcated yellow discoloration involving the antimesenteric bowel wall (picture 1) [3,27,28]. The terminal ileum is the most commonly involved area of intestinal necrosis [3,27-29]. Occasionally, the bowel will appear pale or ischemic but not frankly necrotic. In those cases, leaving the abdomen temporarily open for a planned second-look laparotomy within 12 to 24 hours is recommended as ischemia can often quickly evolve into transmural necrosis.
The pathological examination of the resected bowel is reported to demonstrate extensive mucosal ulceration, congestion with areas of extensive transmural inflammation, and transmural infarction [3]. Fibrin microthrombi were occasionally noted in the capillaries underlying areas of necrosis, again raising the possibility of thrombosis at the submucosal vessel level [27].
Despite these observations, the pathophysiology of bowel ischemia in these critically ill patients with COVID-19 remains uncertain. It is well established that patients who are admitted to the ICU can develop mesenteric ischemia simply due to high doses of vasopressors, hemodynamic instability, and metabolic derangements that compromise intestinal blood flow. While this may contribute to the high rate of bowel ischemia observed in patients with COVID-19, the atypical features of the mesenteric ischemia and the rare involvement of the watershed areas strongly suggest alternative mechanisms that are specific to COVID-19. (See 'Possible etiologies of COVID-related gastrointestinal complications' below.)
The mortality rate of COVID-19 patients who develop mesenteric ischemia is currently reported to be as high as 40 percent, with more than 92 percent of the deaths occurring within the immediate postoperative days due to multiorgan failure or refractory septic shock [35].
POSSIBLE ETIOLOGIES OF COVID-RELATED GASTROINTESTINAL COMPLICATIONS — It is likely that the high incidence of gastrointestinal complications in COVID-19 patients is not only a general manifestation of critical illness but is at least partially attributable to COVID-19 itself.
In a propensity score matched comparison of 184 patients with acute respiratory distress syndrome (ARDS), COVID-19 patients had double the rate of gastrointestinal complications compared with patients without COVID-19 (74 versus 37 percent), and the difference was more evident after the third hospitalization day (figure 1) [48]. Specifically, more patients with COVID-19 ARDS developed elevation of liver enzymes (55 versus 27 percent), ileus (48 versus 22 percent), or bowel ischemia (4 versus 0 percent) compared with equally ill but non-COVID patients [48].
There is evidence that SARS-CoV-2 may be present in the gastrointestinal tract and that the angiotensin-converting enzyme 2 (ACE2) receptor is highly expressed throughout the gastrointestinal tract. As such, SARS-CoV-2 may enter gastrointestinal cells via ACE2 receptors to cause direct damage to the gastrointestinal organs. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Virology'.)
Evidence of SARS-CoV-2 in the gastrointestinal tract — SARS-CoV-2 RNA has been detected by reverse-transcriptase polymerase chain reaction in multiple gastrointestinal sites.
●SARS-CoV-2 RNA has been detected in stool and gastrointestinal tissue samples of patients with COVID-19.
•In a study of 65 hospitalized patients with COVID-19, SARS-CoV-2 RNA was detected in the fecal samples from more than one-half of the patients with gastrointestinal symptoms and in nearly 40 percent of patients without any overt gastrointestinal symptoms [49]. Six patients with gastrointestinal symptoms underwent endoscopy and biopsy, and SARS-CoV-2 RNA was detected in the tissue samples from the esophagus, stomach, duodenum, colon, and rectum [49].
•In a meta-analysis of 12 studies and 138 patients, the pooled prevalence of stool samples that were positive for the SARS-CoV-2 RNA was 48.1 percent. As importantly, more than 70 percent of the patients with positive stool samples had respiratory specimens that were negative for SARS-CoV-2 RNA, suggesting that the shedding of SARS-CoV-2 RNA in stool can significantly outlast the respiratory shedding, sometimes lingering for more than 30 days [1].
●SARS-CoV-2 RNA has been detected in the gallbladder wall of a few COVID-19 patients who underwent cholecystectomy [50] and in the bile of another patient with COVID-19-related gallbladder disease [51].
●SARS-CoV-2 RNA has been detected in the fluid from pancreatic pseudocysts of COVID-19 patients [52].
It is less clear whether there is active SARS-CoV-2 replication in the gastrointestinal system or the viral RNA present in the gastrointestinal tract comes from swallowed respiratory viruses. On one hand, no live SARS-CoV-2 has been isolated from stool. On the other hand, the combination of very high concentrations of virus RNA and the occasional detection of cells in stools that contain subgenomic mRNA indicate active replication in the gastrointestinal tract [53]. Viral subgenomic mRNA is transcribed only in infected cells and is not packaged into virions and therefore indicates the presence of actively infected cells in samples.
ACE2 expression in the gastrointestinal tract — One of the host receptors for SARS-CoV-2 cell entry is the ACE2 [54]. Both ACE2 mRNA and protein are highly expressed in the small intestine and colon, specifically at the enterocyte level [55-57]. ACE2 is also expressed in gallbladder epithelial cells and pancreatic ductal, acinar, and islet cells [58,59]. If there is active replication of SARS-CoV-2 in the gastrointestinal tract, such ACE2 receptor expression is likely one of the mechanisms that mediates the reported gastrointestinal symptoms and complications of COVID-19.
Microvascular coagulopathy — In COVID-19 patients, an inflammatory coagulopathy has been postulated to be associated with worse pulmonary disease, deep vein thrombosis, cerebrovascular accidents/strokes, and renal failure, and a similar mechanism may potentially contribute to mesenteric ischemia. However, there are insufficient data to recommend empiric therapeutic anticoagulation to prevent mesenteric ischemia in COVID-19 patients, even in those with elevated D-dimers. (See "COVID-19: Hypercoagulability".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics" and "Society guideline links: COVID-19 – Surgical care".)
SUMMARY AND RECOMMENDATIONS
●Although COVID-19 primarily manifests as a lung infection, it has significant extrapulmonary complications affecting most organ systems, including the gastrointestinal tract. (See 'Introduction' above.)
●Up to one-third of patients with COVID-19 initially present with gastrointestinal rather than respiratory symptoms, most commonly anorexia, diarrhea, nausea or vomiting, and abdominal pain. (See 'COVID-19 gastrointestinal symptoms' above.)
●About three-quarters of critically ill patients from COVID-19 develop gastrointestinal complications, which range from self-resolving transaminitis or intestinal/colonic ileus, to acute cholecystitis or pancreatitis, to life-threatening mesenteric ischemia. (See 'Gastrointestinal complications in critically ill COVID-19 patients' above.)
●While the pathophysiology of gastrointestinal complications in COVID-19 is likely multifactorial, it is at least partially COVID-19 specific, which may be potentially related to the virus, high levels of angiotensin-converting enzyme 2 (ACE2) receptor expression, and/or microvascular coagulopathy in the gastrointestinal tract. (See 'Possible etiologies of COVID-related gastrointestinal complications' above.)
