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A Surgical Perspective of Gastrointestinal Manifestations and Complications of COVID-19 Infection

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread over the world since December 2019. COVID-19 is a systemic disease that can affect various organs throughout the body. Gastrointestinal (GI) symptoms have been reported in 16% to 33% of all COVID-19 patients and in 75% of critically ill patients. This chapter reviews the GI manifestations of COVID-19 as well as their diagnostic and treatment modalities.


INTRODUCTION
The coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread over the world since December 2019.
The most common symptoms of COVID-19 disease include fever, cough, dyspnea, fatigue, and myalgia. However, COVID-19 is a systemic disease that can affect various organs throughout the body. Gastrointestinal (GI) symptoms have been reported in 16% to 33% of all COVID-19 patients and in 75% of critically ill patients. 1,2 This chapter reviews the GI manifestations of COVID-19 as well as their diagnostic and treatment modalities from a surgical perspective.

GASTROINTESTINAL MANIFESTATIONS
The most common presenting GI symptoms of COVID-19 disease include nausea, vomiting, diarrhea, and abdominal pain. 3 More severe GI complications ranging from ileus to lifethreatening mesenteric ischemia arise in 74% to 86% of critically ill COVID-19 patients during their frequently lengthy hospitalization. 2,4 These complications might be preceded by warning signs such as increasing abdominal distension and new or increasing vasopressor requirements.
Acute cholecystitis Acute cholecystitis refers to acute inflammation of the gallbladder, either due to obstruction of the cystic duct by a gallstone (calculous), or dysfunction of gallbladder emptying in the absence of stones (acalculous). Acute cholecystitis is one possible complication of COVID-19 infection, particularly among critically ill patients. 2,[4][5][6][7][8] When it occurs, acute cholecystitis is usually acalculous and the causal mechanism is unclear. Gallbladder wall hypomotility is common in critical illness; however, the identification of SARS-CoV2 RNA in J o u r n a l P r e -p r o o f gallbladder epithelial cells and bile could indicate a more specific causal role of the virus. 9-11 Few case reports have detailed the occurrence of gangrenous cholecystitis leading to perforation. In one case this was possibly due to the increased risk of thrombosis and organ ischemia associated with COVID-19. 12,13 Antibiotics and percutaneous cholecystostomy should be attempted first in the management of acute cholecystitis among critically ill COVID-19 patients. 14 Acute colonic pseudo-obstruction Ogilvie's syndrome or acute colonic pseudo-obstruction refers to colonic distension in the absence of mechanical obstruction and it is most commonly caused by infection, electrolyte imbalance, and opioids. Several cases of acute colonic pseudoobstruction have been reported among critically ill COVID-19 patients. 2,[18][19][20][21][22] The exact etiology of acute colonic pseudo-obstruction in critically ill COVID-19 patients is unknown. Previously reported effects of SARS-CoV2 on the nervous system (e.g. Guillain-Barré syndrome, transverse myelitis, encephalitis) suggest that a similar impact of the virus on mesenteric nerves could be the etiology. Specifically, acute colonic pseudo-obstruction might be caused by a loss of parasympathetic regulation of bowels if SARS-CoV2 invades the myenteric plexus.

J o u r n a l P r e -p r o o f
In a stable patient without evident sepsis or shock, conservative management should be attempted first. This should include bowel rest, colonic decompression with a rectal tube or by colonoscopy, electrolyte replacement, administration of intravenous fluids, treatment of an underlying infection, and discontinuation of any drugs that could worsen the paralytic ileus (e.g. opioids, sedatives). While there have been some reports of clinical improvement with the use of acetylcholinesterase inhibitors such as neostigmine, the evidence supporting its use remains weak.
Surgery is reserved for cases that failed conservative management especially if there is progression to intestinal wall necrosis and perforation. Therefore, early diagnosis and appropriate management is essential for acute colonic pseudo-obstruction, while maintaining a high index of suspicion for ischemia and perforation in case of clinical deterioration.

Acute liver injury and transaminitis
Acute liver injury, defined as an elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, is a common complication of COVID-19 disease and can be indicative of a severe disease course.
In two large cohort studies from the United States, elevations in ALT and AST were detected in 29-63% of patients. 23,24 In a study of 2,273 SARS-CoV-2-positive and 1,108 SARS-CoV-2-negative hospitalized patients, SARS-CoV-2-positive patients had greater initial and peak ALT than those who had a similar clinical presentation but tested negative for SARS-CoV2. 25 Overall, 45% of SARS-CoV2-positive patients had mild liver injury (peak ALT <2 times the upper limit of normal [ULN]), 22% had moderate liver injury (peak ALT 2-5 times the ULN), and 6% had severe liver injury (peak ALT >5 times the ULN).

J o u r n a l P r e -p r o o f
A systematic review including 9,889 confirmed cases of COVID-19 from a single country, reported an incidence of liver injury of 24.7%. 26 Patients with severe COVID-19 were twice as likely to suffer liver injury than those with non-severe COVID-19.
The etiology of acute liver injury in COVID-19 patients is uncertain but likely involves direct, viral-mediated damage and an indirect, immune-mediated inflammatory response. 27 Direct viral-induced damage could be mediated through the angiotensin-converting enzyme 2 (ACE2) receptors found in biliary and hepatic endothelial cells. [28][29][30] Indirect immune-mediated damage results from cytokine storm with severe COVID-19, as evidenced by elevated C-reactive protein (CRP), serum ferritin, interleukin (IL)-6, and IL-2, which can lead to multisystem organ failure. 31,32 Additional liver damage could be the result of concomitant critical illness (e.g. sepsis, shock). The degree of elevation of transaminases (notably peak ALT) was shown to be an independent predictor of mortality among COVID-19 patients. 25 Some studies have supported regular testing of liver transaminases in COVID-19 patients. 33 The American Association for the Study of Liver Diseases (AASLD) recommends nonetheless keeping a broad differential when dealing with elevated transaminase levels in the setting of COVID-19 and exploring other etiologies (e.g. hepatitis A, B, or C virus, myositis). 34

Acute pancreatitis
Acute pancreatitis is a complex disease resulting from inappropriate activation of digestive enzymes leading to autodigestion of the pancreas. Acute pancreatitis is an uncommon complication of COVID-19. According to a large cohort study of 11,883 hospitalized COVID-19 patients from 12 hospitals, the incidence of acute pancreatitis was 0.27%. 35 In another retrospective study of more than 63,000 COVID-19 patients seen in the emergency department, the incidence of acute pancreatitis was reported at 0.07%. 36 J o u r n a l P r e -p r o o f It remains unclear whether acute pancreatitis that develops in the setting of COVID-19 disease is a direct result of SARS-CoV2 infection. 37 The presence of ACE2 receptors in pancreatic ductal, acinar, and islet cells as well as the isolation of SARS-CoV2 from a pancreatic pseudocyst point to a possible association. 38 occlusion of the mesenteric vessels. 44 Its incidence was reported to be 3.8% to 4% in cohort studies of critically ill COVID-19 patients admitted to one institution. 1,2 Although the coagulopathy caused by COVID-19 is not fully understood, several studies show an association between SARS-CoV2 infection and mesenteric ischemia. Following matching based on baseline characteristics and clinical condition, critically ill patients with COVID-19 were significantly more likely to develop mesenteric ischemia than similarly ill patients without COVID-19. 45 The diagnosis of mesenteric ischemia is typically confirmed by imaging. Contrastenhanced Computed Tomography (CT) scan of the abdomen plays an important role in the detection of this disease and should be considered early on in the management of critically ill patients who exhibit GI symptoms. 46 Ischemic bowel should be suspected if pneumatosis intestinalis, thick edematous intestine, and/or portal venous gas are present. 47 When using intravenous contrast, arterial phase imaging may reveal filling defects in the thoracoabdominal aorta or mesenteric arteries, which could indicate acute thromboembolic events. [48][49][50][51][52] Alternatively, delayed venous phase imaging may reveal filling defects in the mesenteric and/or portal veins. 46,48,51 Finally, a considerable number of patients develop mesenteric ischemia despite having patent and well-perfusing mesenteric vessels on imaging. 1,2,53 Such findings suggest a microvascular etiology of mesenteric ischemia in a significant number of patients. Figure 1 shows the CT scan findings of a patient with COVID-19 who developed mesenteric ischemia and small bowel perforation.

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Laboratory findings can include increasing lactate, elevated D-dimers, leukocytosis, and unexplained metabolic acidosis; however, such laboratory tests might be normal early on before metabolic alterations occur. Those findings are also non-specific and could be present in other conditions, such as severe viral sepsis in the absence of mesenteric ischemia. 54 Surgical resection of any necrotic bowel is the mainstay treatment of mesenteric ischemia in the setting of COVID-19 disease. When there is evidence of proximal arterial thromboembolic disease, endovascular thrombectomy can be used to reopen blocked mesenteric arteries and restore blood flow to the intestines. 48,55 Anticoagulants may play a role in treating mesenteric ischemia; however, there is no compelling evidence to support their use prophylactically. The only available data comes from case reports describing a reversal of bowel ischemia in hemodynamically stable patients who were treated conservatively with anticoagulation. 56,57 On intraoperative gross examination of the bowel, many surgeons identified necrotic tissue, punctuate lesions, and/or frank perforation. Surgeons also reported peculiar findings of welldemarcated yellow discoloration with spotty or circumferential distribution on the antimesenteric side. 53  showed that more patients with COVID-19 ARDS developed mesenteric ischemia (4% vs. 0%), elevated liver enzymes (55% vs. 27%), and ileus (48% vs. 22%). 61 In addition, certain GI complications might manifest differently in COVID-19 versus non-COVID-19 patients. While mesenteric ischemia in critical illness affects watershed areas, patients with COVID-19 often present with patchy areas of necrosis throughout the entire small bowel (Figure 2). 1,2,53 As a result, illness severity alone is unlikely to explain the increased rates of GI complications, and other COVID disease-specific mechanisms may occur.

SUMMARY
• While COVID-19 is primarily characterized as a respiratory infection, it has serious extrapulmonary manifestations including serious GI complications.
• Diarrhea, nausea, vomiting, and abdominal pain are the most common GI manifestations seen in patients with COVID-19, accounting for up to one-third of early symptoms.
• Critically ill COVID-19 patients can experience a wide range of GI complications ranging from ileus to life-threatening mesenteric ischemia.