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1 Present address: Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, 165 Cambridge Street, Suite 810, Boston, MA 02114.
Anthony Gebran
Footnotes
1 Present address: Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, 165 Cambridge Street, Suite 810, Boston, MA 02114.
Affiliations
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA, USA
1 Present address: Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, 165 Cambridge Street, Suite 810, Boston, MA 02114.
Ander Dorken-Gallastegi
Footnotes
1 Present address: Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, 165 Cambridge Street, Suite 810, Boston, MA 02114.
Affiliations
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA, USA
Corresponding author. Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, 165 Cambridge Street, Suite 810, Boston, MA 02114.
1 Present address: Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, 165 Cambridge Street, Suite 810, Boston, MA 02114.
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. 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.
More severe GI complications ranging from ileus to life-threatening mesenteric ischemia arise in 74% to 86% of critically ill patients with COVID-19 during their frequently lengthy hospitalization.
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 due to 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.
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 gallbladder epithelial cells and bile could indicate a more specific causal role of the virus.
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.
Antibiotics and percutaneous cholecystostomy should be attempted first in the management of acute cholecystitis among critically ill patients with COVID-19.
Clinical approach to patients admitted to the emergency room due to acute cholecystitis during the COVID-19 pandemic and percutaneous cholecystostomy experience.
In a study conducted by the COVIDSurg Collaborative during the early phases of the pandemic, 145 patients with COVID-19 who underwent cholecystectomy had a 30-day mortality of 10.3%, despite most not being critically ill preoperatively. Mortality risk was particularly exacerbated among patients who had preoperative respiratory signs or symptoms of COVID-19 as compared with those who did not (19.2% vs 0.0%, P < 0.001).
Ogilvie syndrome or acute colonic pseudoobstruction 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.
The exact cause of acute colonic pseudoobstruction in critically ill patients with COVID-19 is unknown. Previously reported effects of SARS-CoV2 on the nervous system (eg, Guillain-Barré syndrome, transverse myelitis, encephalitis) suggest that a similar impact of the virus on mesenteric nerves could be the cause. Specifically, acute colonic pseudoobstruction might be caused by a loss of parasympathetic regulation of bowels if SARS-CoV2 invades the myenteric plexus.
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 (eg, opioids, sedatives). Although 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 pseudoobstruction, 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 indicate a severe disease course.
In 2 large cohort studies from the United States, elevations in ALT and AST were detected in 29% to 63% of patients.
In a study of 2273 SARS-CoV-2-positive and 1108 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.
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).
A systematic review including 9889 confirmed cases of COVID-19 from a single country reported an incidence of liver injury of 24.7%.
Patients with severe COVID-19 were twice as likely to suffer liver injury than those with nonsevere COVID-19.
The cause of acute liver injury in patients with COVID-19 is uncertain but likely involves direct, viral-mediated damage and an indirect, immune-mediated inflammatory response.
Direct viral-induced damage could be mediated through the angiotensin-converting enzyme 2 (ACE2) receptors found in biliary and hepatic endothelial cells.
Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA | original investigation | caring for the critically ill patient.
Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. doi:10.1101/2020.02.03.931766
Indirect immune-mediated damage results from cytokine storm with severe COVID-19, as evidenced by elevated C-reactive protein, serum ferritin, interleukin-6 (IL-6), and IL-2, which can lead to multisystem organ failure.
Additional liver damage could be the result of concomitant critical illness (eg, sepsis, shock). The degree of elevation of transaminases (notably peak ALT) was shown to be an independent predictor of mortality among patients with COVID-19.
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 causes (eg, hepatitis A, B, or C virus, myositis).
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 patients with COVID-19 from 12 hospitals, the incidence of acute pancreatitis was 0.27%.
In another retrospective study of more than 63,000 patients with COVID-19 seen in the emergency department, the incidence of acute pancreatitis was reported at 0.07%.
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.
Ex-vivo and in-vivo studies as well as human autopsies have demonstrated that SARS-CoV-2 infection can target β cells of the human pancreas and lead to metabolic dysregulation.
Similar studies are needed to ascertain the association between COVID-19 and pancreatitis.
COVID-19–related acute pancreatitis is treated similarly to non–COVID-19–related acute pancreatitis. Supportive therapy with fluid resuscitation, pain control, and nutritional support is the mainstay of treatment in uncomplicated cases. Percutaneous, endoscopic, or surgical debridement may be required if necrotizing pancreatitis supervenes.
Ileus refers to obstipation and feeding intolerance resulting from disruption of normal bowel peristalsis in the absence of mechanical obstruction. Significant ileus and feeding intolerance have been reported in 46% to 56% of critically ill patients with COVID-19 admitted to an intensive care unit.
Critically ill patients with COVID-19 frequently require substantial doses of sedatives and opiates for ventilator synchrony, which can independently result in decreased intestinal function. It remains unclear whether SARS-CoV2 infection plays a direct role in causing this pathology.
Management of COVID-19–related ileus is no different from the management of ileus unassociated with COVID-19 infection. Supportive care is the mainstay of treatment and includes electrolyte replacement as necessary, maintenance of fluids, bowel rest, and intestinal decompression as needed.
Mesenteric Ischemia
Mesenteric ischemia can affect the small and/or large intestine and is caused either by a reduction in intestinal blood flow from systemic hypotension or by thromboembolic occlusion of the mesenteric vessels.
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.
The diagnosis of mesenteric ischemia is typically confirmed by imaging. Contrast-enhanced 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.
When using intravenous contrast, arterial phase imaging may reveal filling defects in the thoracoabdominal aorta or mesenteric arteries, which could indicate acute thromboembolic events.
Such findings suggest a microvascular cause of mesenteric ischemia in a significant number of patients. Fig. 1 shows the CT scan findings of a patient with COVID-19 who developed mesenteric ischemia and small bowel perforation.
Fig. 1Abdominal CT scan in a patient diagnosed with COVID-19 infection demonstrating small intestinal ischemia with perforation and loss of integrity of the small bowel wall in the right lower quadrant contiguous with a fluid and gas-containing collection.
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 nonspecific and could be present in other conditions, such as severe viral sepsis in the absence of mesenteric ischemia.
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.
Anticoagulants may play a role in treating mesenteric ischemia; however, there is no compelling evidence to support their use prophylactically. The only available data come from case reports describing a reversal of bowel ischemia in hemodynamically stable patients who were treated conservatively with anticoagulation.
A 29-year-old male construction worker from india who presented with left-sided abdominal pain due to isolated superior mesenteric vein thrombosis associated with SARS-CoV-2 infection.
On intraoperative gross examination of the bowel, many surgeons identified necrotic tissue, punctuate lesions, and/or frank perforation. Surgeons also reported peculiar findings of well-demarcated yellow discoloration with spotty or circumferential distribution on the antimesenteric side.
Pathologic specimens may demonstrate sharp demarcation between areas of mucosal necrosis and viable mucosa, transmural infarction, and fibrin thrombi in small vessels underlying areas of necrosis.
The exact pathophysiology of COVID-related GI complications is unknown. The high rate of GI complications in patients with COVID-19 makes it more likely that they are not just a manifestation of critical illness but are at least in part caused by COVID-19. A propensity score–matched analysis of 184 critically ill patients with acute respiratory distress syndrome (ARDS) 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%).
In addition, certain GI complications might manifest differently in patients with versus without COVID-19. Although mesenteric ischemia in critical illness affects watershed areas, patients with COVID-19 often present with patchy areas of necrosis throughout the entire small bowel (Fig. 2).
As a result, illness severity alone is unlikely to explain the increased rates of GI complications, and other COVID disease-specific mechanisms may occur.
Fig. 2Patchy antimesenteric bowel necrosis with bright yellow discoloration and clear demarcation in a patient diagnosed with COVID-19 infection.
(From Kaafarani HMA, el Moheb M, Hwabejire JO, et al. Gastrointestinal Complications in Critically Ill Patients With COVID-19. Ann Surg. 2020;272(2):e61-e62. https://doi.org/10.1097/SLA.0000000000004004; with permission.)
Identification of Severe Acute Respiratory Syndrome Coronavirus 2 in the Gastrointestinal Tract
SARS-CoV2 RNA or proteins have been isolated from several parts of the GI tract in patients known to have COVID-19 disease.
Several studies have reported elevated viral loads in fecal samples of patients with COVID-19 disease. In a systematic review and meta-analysis of 1636 patients with COVID-19, 43% of patients had evidence of fecal SARS-CoV-2 RNA. Patients with GI symptoms had a higher proportion of detectable fecal SARS-CoV-2 RNA as compared with those without GI symptoms (52.4% vs 25.9%; odds ratio [OR] = 2.4). The difference was most notable for patients who developed diarrhea (51.6% vs 24.0%; OR = 3.0) versus those without diarrhea. Fecal shedding also persisted longer than respiratory shedding (mean duration: 21.8 days vs 14.7 days; mean difference = 7.1 days).
High SARS-CoV2 viral loads have been documented by reverse transcription–polymerase chain reaction inside a pancreatic pseudocyst’s fluid in the setting of COVID-19 disease.
Bowel ischemia in a patient with SARS CoV-2-like illness and negative real-time reverse transcription polymerase chain reaction test results during the peak of the pandemic.
The virus could attach to the ACE2 receptors in the GI tract, translocate to the submucosal tissue, and damage the underlying tissue and vasculature, resulting in various pathologies.
Presentation can include cerebrovascular accidents, strokes, deep vein thrombosis, renal failure, and mesenteric ischemia. In the latter, SARS-CoV2 has a higher propensity toward microvasculature and often spares large mesenteric arteries. Microscopic analysis of resected intestinal tissue revealed fibrin microthrombi in capillaries beneath necrotic zones.
Although COVID-19 is primarily characterized as a respiratory infection, it has serious extrapulmonary manifestations including serious GI complications.
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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.
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Critically ill patients with COVID-19 can experience a wide range of GI complications ranging from ileus to life-threatening mesenteric ischemia.
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The cause of GI manifestations in COVID-19 is multifactorial. The propensity of the virus for ACE2 receptors and their high expression in the GI tract, viral isolation in GI tissues, and microvascular coagulopathy support a role of SARS-CoV2 in the reported GI complications.
References
El Moheb M.
Christensen M.A.
Naar L.
et al.
Comment on “‘gastrointestinal complications in critically ill patients with COVID-19’” an update.
Clinical approach to patients admitted to the emergency room due to acute cholecystitis during the COVID-19 pandemic and percutaneous cholecystostomy experience.
Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA | original investigation | caring for the critically ill patient.
Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. doi:10.1101/2020.02.03.931766
A 29-year-old male construction worker from india who presented with left-sided abdominal pain due to isolated superior mesenteric vein thrombosis associated with SARS-CoV-2 infection.
Bowel ischemia in a patient with SARS CoV-2-like illness and negative real-time reverse transcription polymerase chain reaction test results during the peak of the pandemic.
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