COVID-19-associated abdominal pain

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Javaria Anwer M.D.[2]

Synonyms and keywords: COVID-19 associated abdominal pain, COVID associated abdominal pain, COVID linked abdominal pain, COVID-19 linked abdominal pain, coronavirus associated abdominal pain, coronavirus related belly pain, abdominal pain associated with COVID-19, abdominal pain associated with SARS CoV2, SARS CoV2 related abdominal pain, SARS CoV2 linked abdomin pain, abdominal pain and COVID-19, abdominal pain and SARS CoV2 ,abdominal pain in COVID, abdomin pain in COVID, abdominal pain in nCoV, abdominal discomfort in COVID-19, abdominal discomfort in SARS CoV2.

Overview

Abdominal pain is a vast entity and sometimes a challenge due to its various potential diagnoses. Although COVID-19 is mainly a respiratory disease, abdominal pain is one of the symptoms of COVID-19 infection. A potential explanation for abdominal pain in COVID-19 is the presence of cellular ACE 2 in esophagus, ileum, colon and cholangiocytes. Patients may present with global, epigastric, ileac fossa or epigastric pain. Cases of abdominal pain associated with COVID-19 infection may present as acute appendicitis, acute pancreatitis, upper GI bleed, gut perforation. In an unexplained abdominal pain it is important to suspect coronavirus-19 infection and take nasopharyngeal RT-PCR or CXR or chest CT as positive findings of these tests have been demonstrated in patients presenting with mere abdominal symptoms. Abdominal scans may show signs of mucosal inflammation. Contact tracing is an important secondary prevention step.

Historical Perspective

• COVID-19 was first discovered in a cluster of cases of pneumonia in Wuhan, China, reported on December 30th, 2019 by Wuhan Municipal Health Commission, China.
• Three bronchoalveolar lavage samples collected from a patient with pneumonia of unknown etiology – a surveillance definition established following the SARS outbreak of 2002-2003 – in Wuhan Jinyintan Hospital, China. Real-time PCR (RT-PCR) assays on these samples were positive for pan-Betacoronavirus. Nanopore sequencing and bioinformatic analyses indicated that the virus had features typical of the coronavirus family and belonged to the Betacoronavirus 2B lineage.A novel coronavirus was eventually identified.
• The first disease outbreak news on the new virus was first published by WHO on 5th January 2020.
• COVID-19-associated abdominal pain was first described as one of the less common symptoms of COVID-19 in a retrospective, single-center case series by Wang D et al. published on Feb 7th, 2020. The patient data was derived from January 1st-Jan 28th,2020 at Zhongnan Hospital in Wuhan, China. Still COVID-19 was primarily known as a respiratory disease. In the initial phase of the pandemic, the screening criteria for COVID‐19 did not include symptoms of abdominal pain.
• On March 11th, 2020, WHO declared the COVID-19 outbreak a pandemic.
• With the increasing evidence and ongoing research, abdominal pain are now reported to be a common symptom in patients with COVID-19, and the viral infection is suspected in a patient presenting with abdominal pain. Research is underway to develop a better understanding of the etiology, risk factors, and treatment of abdominal pain associated with COVID-19 such as NCT04331509

Classification

There is no established system for the classification of abdominal pain in COVID-19. But a differentiation can be made based on the organ injury related to COVID-19 causing abdominal pain.

Pathophysiology

• The exact pathogenesis of COVID-19-associated abdominal pain is not fully understood.
• It is thought that COVID-19-associated abdominal pain is the result of either ACE 2 receptor mediated COVID-19 infectivity and direct viral damage or colonic ischemia.
• The abdominal pain can be due to direct viral infection of the gastrointestinal tract via cellular ACE 2 receptors in several abdominal organs, making them susceptible to viral infection.
• ACE 2 acts as the COVID-19 receptor for infectivity and the entrance into the cell.ACE 2 acts as the COVID-19 receptor for infectivity and the entrance into the cell.
• Research has shown ACE 2 receptors in the [oral cavity]], tongue, esophageal epithelial cells, ileal, colon enterocytes, cholangiocytes and gallbladder cells, making them vulnerable to COVID-19 infection.
• The detection of viral nucleocapsid protein in gastrointestinal epithelial cells and viral RNA in fecal specimens reflects the infectivity and chance of direct viral damage of organs.
• The entry of the virus causes disruption of the enterocytes and may lead to inflammation, impaired cell permeability, and cellular damage.
• The severe abdominal pain associated colonic ischemia leading to gut perforation is due to nociceptor stimulation with cell destruction products and pH changes due to ischemia.
• Colon being the watreshed area is susceptible to hypoperfusion probably due to hypotension or clotting or due to reperfusion injury.
• Within 3-4 hours after the onset of ischemia, the necrosis of the mucosal villi starts leading to transmural infarct in 6 hours and eventually perforation.
• In a retrospective literature review of COVID-19 patients, the autopsy of an 85-year-old COVID-19 patient showed hepatomegaly, enlarged gallbladder, dark red mucosa of the stomach with a small number of bleeding points. It is not sure if the findings are secondary to COVID-19 or a pre-existent GI ischemia.

  

  Transfection of HeLa cells with the ACE2 receptor makes them susceptible to COVID-19 infection. hACE2, human ACE2;green, ACE2;red, viral protein (N);blue, DAPI (nuclei). Scale bars, 10 μm-By Peng Zhou et al - https://www.nature.com/articles/s41586-020-2012-7, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=91229428.jpg

  
  

Causes

• Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 virus. COVID-19 associated abdominal pain may be caused by (the causes have been reported in case reports and retrospective observational studies from China, Qatar, France, Norway, and the USA):
  • COVID-19-associated diarrhea
  • COVID-19-associated hepatic injury
  • COVID-19 associated acute abdomen (acute peritonitis and gut perforation)
  • COVID-19 associated pancreatitis
  • Anxiety associated with patient condition
• The causal relationship between abdominal pain and COVID-19 has not been established. LImited observational studies and meta-analyses do indicate that COVID-19 can present with abdominal pain without respiratory symptoms.

Differentiating COVID-19 associated abdominal pain from other Diseases

• For further information about the differential diagnosis, click here.
• To view the differential diagnosis of COVID-19, click here

Epidemiology and Demographics

• Based upon the systematic review and meta-analysis including 78 observational studies (from Dec 2019 to May 7th, 2020), the Weighted Pooled Prevalence (WPP) of abdominal pain associated with COVID-19 was approximately 6.2% (2.6%-10.3%).
• A meta-analysis from the cohort of COVID-19 patients in Hong Kong (N = 59, from February 2 through February 29, 2020), 25% patients had GI symptoms with abdominal pain/discomfort prevalent in around 11.9% patients.

Age

• One retrospective observational study from Oslo, Norway (patient population= 9) demonstrating patients with COVID-19 presenting with acute abdominal pain as their main symptom, reported a mean age of 48 years.
• Another retrospective observational study from Wuhan, China (1141 patients) demonstrated the average age of COVID-19 patients having abdominal pain as one of their symptoms to be 53 years.
• A meta-analysis from the cohort of COVID-19 patients in Hong Kong (N = 59, from February 2 through February 29, 2020) the medial age was 58.5 years.

Gender

• In a retrospective observational study from Wuhan, China (1141 patients) 56% of the COVID-19 patients having abdominal pain as one of their symptoms were male.

Race

• The systematic review and meta-analysis from observational studies on 12797 patients showed a higher weighted pooled prevalence of abdominal pain associated with COVID-19 in the non-Chinese subgroup and compared to Chinese subgroup.

Risk Factors

• The most potent risk factor in the development of the COVID-19 associated abdominal pain is COVID-19 infection itself.
• The incidence of abdominal pain is higher in patients with severe COVID-19.
• The potential risk factors for COVID-19 infection in patients with Inflammatory bowel disease (IBD) include: Old age, pregnancy, underlying health conditions, such as HTN and diabetes, active-stage IBD with malnutrition, being on immunosuppressive agents, and requirement of frequent medical clinic visits.

Screening

There is insufficient evidence to recommend routine screening for COVID-19 associated abdominal pain.

Natural History, Complications and Prognosis

• The appearance of abdominal pain has no fixed pattern of appearance in the COVID-19 clinical course. Abdominal pain may be the acute presenting symptom or one of many symptoms in a COVID-19 patient with intensity ranging from mild to severe.
• A complication reported is gut perforation due to ischemia. Patients may present with gut perforation as the first sign of COVID-19 infection.
• Upper GI bleed (due to esophageal mucosal damage as seen on endoscopy) has been reported in 4% of patients with other GI symptoms such as abdominal pain related to novel coronavirus infection. It is not known whether bleeding is a complication of other entities or a separate phenomenon in COVID-19 infection but has been mentioned together with abdominal pain. The esophagus, stomach, duodenum and stool have been tested positive for viral RNA.
• Prognosis: In a meta-analysis by Mao R. et al. the odds ratio for severe disease in patients with abdominal pain as one of the gastrointestinal symptoms were 7.10.

Diagnosis

Diagnostic Criteria

• There are no established diagnostic criteria to identify the cause of abdominal pain in COVID-19 patient. Abdominal ultrasound or CT scan, and blood tests showing deranged liver functions can give a clue of possible gastrointestinal involvement.

History and Symptoms

• Based upon retrospective observational studies patient may have abdominal pain as an accompanying symptom along with other COVID-19 infection symptoms such as diarrhea, anorexia, nausea, vomiting, fever, cough, dyspnea and malaise. Very few patients present with abdominal pain as the sole symptom and high suspicion is required in order to reach the diagnosis.
• A retrospective observational study from Norway, described nine patients with COVID-19 presenting with acute abdominal pain as presenting symptom. The pain was localised as right iliac fossa, left iliac fossa, global, epigastric and umbilical pain.
• A case of COVID-19 presenting with acute pancreatitis had severe epigastric pain along with fever, diarrhea, nausea, vomiting, dry cough and progressive dyspnea.
• A case series of COVID-19 patients presenting with acute abdomen had sudden abdominal pain along with aforementioned accompanying GI symptoms.
• Gradually progressive, generalised abdominal pain, moderate in severity has been described in a case report for COVID-19 presenting with hyponatraemia.

Physical Examination

• Patients with abdominal pain associated with COVID-19 may appear in distress due to their general condition or the severity of abdominal pain. A person with pancreatitis will appear dehydrated, lethargic and in severe pain.
• Coffee ground gastric emesis indicates a possible upper GI bleed.

• Vital signs:
  • Heart rate/ Pulse: Tachycardia may be due to fever, pain or shock or anxiety.
  • Blood pressure: Depending upon the cause of abdominal pain a patient with mild disease may have a normal blood pressure with other presenting with shock due to gut perforation and resulting sepsis.
  • Respiratory rate: Tachypnea maybe due to high metabolic rate such as in fever and sepsis due to COVID-19 along with inefficient ventilation. Inefficient ventilation can be due to COVID-19 lung infection such as pneumonia or ARDS. Shallow breathing can be due to severe respiratory distress or abdominal pain.
  • Temperature: The patient can be febrile due to COVID-19 infection, hypothermic, or have a normal temperature.
• On Abdominal exam:
  • Inspection: Cullen's sign indicated acute pancreatitis but it has not been reported in COVID-19 associated acute pancreatitis cases.
  • Auscultation: Accompanying gastrointestinal infection may present as increased bowel sounds due to enteritis. Decreased bowel sounds or absent bowel sounds after a period of increased bowel sounds may indicate gut rupture.
  • Palpation:
    1. Based of a few case reports generalized abdominal or epigastric tenderness or right iliac fossa tenderness may accompany the symptom sometimes presenting exactly as acute pancreatitis, acute appendicitis, acute cholecystitis.
    2. Guarding (muscles contract as pressure is applied), rigidity (rigid abdominal wall- indicates peritoneal inflammation), and rebound tenderness (release of pressure causes pain) may point towards peritonitis a complication of acute appendicitis, gut perforation or rarely pancreatitis. The sign is important in leading decision making regarding the patient's need for surgery.
    3. Murphy's sign is important in the diagnosis of cholecystitis which has been reported with COVID-19.
  • Percussion: No significant findings associated with COVID-19 associated abdominal pain have been reported.
• The physical exam findings associated with COVID-19 can be viewed by clicking here.

Laboratory Findings

• There are no specific laboratory findings associated with abdominal pain in COVID-19 patients.
• Laboratory findings consistent with the presence of infectious virions in the GI or respiratory tract detected via reverse transcriptase-polymerase chain reaction (rRT-PCR) indicate a possible direct viral infectivity of the respective organ.
• Liver function tests: Biochemical markers of liver injury such as bilirubin, CRP, ALT, AST and Gamma GT may be increased in blood tests depicting liver injury.
• Serum electrolyes: such as sodium, potassium and magnesium may be normal in patients but an important test to exclude life-threatening conditions in patients presenting with abdominal pain. A case reports COVID-19 presenting with abdominal pain and hyponatremia probably due to SIADH. Electrolytes become vital in such cases of COVID-19 associated abdominal pain.
• Complete blood count: Provides information about the infectious status of the patient via leukocytosis such as in upper GI bleed and peritonitis, pancreatitis, or lymphocytes indicating viral infection.
• CRP and procalcitonin: The value provides information on the inflammation and superimposed bacterial source of infection. A case of COVID-19 presenting as acute pancreatitis reports elevated procalcitonin.
• D-Dimer: The level rise has been reported in a case of perforated acute abdomen in a patient with COVID-19.
• Serum amylase and lipase: Level rise demonstrate pancreatitis.
• Renal function tests: Deranged in a dehydrated person (increased urea) and patient with upper gastrointestinal bleeding or gut perforation as a complication of COVID-19 (increased BUN and creatinine).
• FOBT test: Reported to be found positive in patients with upper GI bleed.
• Endocscopy: In a patient with upper GI bleed upper GI endoscopy may reveal esophageal ulcers and sample for immunohistochemistry and immunofluorescent staining can help detect the virus.
• Some studies recommend evaluating the effectiveness of stool RT PCR for SARS-COV-2 virus that causes COVID-19 if initial nasopharyngeal RT PCR comes out negative in a case of high suspicion.

Electrocardiogram

• There are no ECG findings associated with COVID-19 associated abdominal pain.
• The electrocardiogram findings on COVID-19 can be viewed by clicking here.

X-ray

• A Chest X-ray may be normal or show consolidation, bilateral perihilar and interstitial opacities opacities with air bronchograms.
• Abdominal X-ray has been reported to be normal in a few studies available.
• The x-ray findings on COVID-19 can be viewed by clicking here.

Echocardiography or Ultrasound

• Ultrasound of the abdomen may or may not show any abnormal findings. A case of bowel inflammatory signs (peri-intestinal inflammatory reaction) has been reported in a patient with abdominal pain associated with COVID-19.
• The echocardiographic findings on COVID-19 can be viewed by clicking here.

CT scan

• CT scan abdomen maybe normal or confirm the peri-intestinal inflammatory reaction in a patient with pancreatitis associated with COVID.
• CT scan of abdomen reals extensive pneumoperitoneum and of chest shows pneumothorax in a patient with gut perforation associated with COVID-19.
• A retrospective observational study from Norway reported that COVID-19 patients presenting with abdominal pain as their chief complaint, the CT scan chest showed ground-glass opacities.
• The CT scan findings in COVID-19 can be viewed by clicking here.

Saggital lung view on a CT scan. Pneumonia in a COVID-19 patient presenting with just fever and right iliac fossa pain. Bilateral multifocal peripheral ill-defined ground-glass opacities with basal and posterior predominance, associated with few subpleural atelectatic bands - Case courtesy of Dr Ahmed Samir, Radiopaedia.org, rID: 76604

MRI

• There are no MRI findings associated with COVOD-19 associated abdominal pain.
• The MRI findings in COVID-19 can be viewed by clicking here.
  

Other Imaging Findings

In a case series, based on their experience, Poggiali et al. strongly recommend bedside lung ultrasound to detect the signs of respiratory COVID-19 infection even when there are no respiratory symptoms.

Treatment

Medical Therapy

• The mainstay of therapy for COVID-19 associated abdominal pain is treating the cause of the pain. Abdominal pain may be due to direct injury of an involved abdominal organ or merely one of the symptoms of COVID-19. Antiviral therapy for COVID-19 may be used along with supportive treatment.
• In nine patients with abdominal pain without abdominal organ involvement and just one of the symptoms of COVID-19, no antiviral therapy was required and patients and were discharged to self-isolation at home.
• The points below explain the treatments that have been mentioned in the literature for abdominal disease in different cases of abdominal pain associated with COVID-19. Few studies mention having used antiviral therapy as an adjunct for abdominal pain associated with COVID-19 infection. But, one case report details the dosage of antiviral treatment. The following recommended medical therapy is based on expert opinion rather than randomized control trials.
• Acute pancreatitis: A case of COVID-19 associated acute pancreatitis has been treated symptomatically with bowel rest, IV fluid therapy using crystalloid fluid, analgesia, and an empiric antibiotic use for the possibility of bacterial pneumonia. The response to medical therapy was monitored by the resolution of gastrointestinal symptoms including abdominal pain.
• Acute abdomen:
  • The predominant therapy for an acute abdomen due to peritonitis or peritonitis accompanied by GI perforation is a surgical approach. The initial stabilization tool for a patient with gastrointestinal perforation and hemodynamic instability was IV hydration, orotracheal intubation, broad-spectrum antibiotic therapy such as Tazocin 4.5 g 3×/day and Azithromycin 500 mg/day, and medications for COVID-19 (the name of medications used for COVID-19 infection treatment have not been mentioned in the respective literature). The generalizability of the dosage of the antibiotic mentioned is limited as the medication was used for an 80 year old female. The surgical approach has been described in the surgery section of the chapter.
  • An acute abdomen is treated with surgery but if required the generalized abdominal pain can be treated with opioids. Respiratory depression as a side effect of of opioid use should be kept in mind in COVID-19 infection which is predominantly a respiratory disease.
• Upper GI bleed: Among patient with upper GI bleed, gastrointestinal endoscopy was performed to determine the exact location of the bleeding and biopsy samples were taken. The bleeding stopped one day after the use of octreotide and esomeprazole. Low-dose vasopressors ensured hemodynamic stability. The response to medical therapy was monitored by monitoring vital signs and alleviation of hematemesis/coffee-ground emesis.
• Antiviral therapy: In patients presenting with abdominal pain as one of the symptoms of COVID-19 without any abdominal disease or due to abdominal organ injury, antiviral treatment has been used. The recommended regimen is based on the successful treatment of COVID-19 in a case of COVID-19 associated abdominal pain and SIADH. Antiviral treatment for COVID-19 virus infection may include:
  • chloroquine phosphate 250 mg twice a day
    
  • darunavir/cobicistat 950 mg daily and
    
  • Ribavirin 1200 mg twice a day for 14 days.
• Associated signs and symptoms: Associated vomiting is treated with antiemetic drugs and diarrhea is treated with antidiarrheal drugs such as loperamide if C.difficile infection has been ruled out. Supportive care such as IV fluid therapy may be required especially if severe vomiting accompanies abdominal pain.
• Treatment of pain: There are no formal recommendations for the treatment of abdominal pain that is COVID-19 related. But NSAIDS given in the infection, serve the purpose.
• IBDs: Although the COVID-19 infection and IBDs mimic in some parameters, glucocorticoids such as prednisone treatment should not be abruptly discontinued but tapered to a possible minimum dose.

Surgery

• An acute abdomen associated with COVID-19 having complications such as gut perforation requires surgery. The reported procedures performed include exploratory laparotomy, followed by GI repair or partial resection.

Primary Prevention

• There are no available vaccines for the prevention of COVID-19. There have been rigorous efforts in order to develop a vaccine for novel coronavirus and several vaccines are in the later phases of trials.
• The only prevention for COVID-19 associated abdominal pain is the prevention and early diagnosis of the coronavirus-19 infection itself. According to the CDC, the effective measure for primary prevention of COVID-19 include:
  • Frequent handwashing with soap and water for at least 20 seconds or using a alcohol based hand sanitizer with at least 60% alcohol. Alcohol means ethanol here not methanol/ wood alcohol, as FDA warns against the use of methanol containing handwash.
  • Staying at least 6 feet (about 2 arms’ length) from other people who do not live with you.
  • Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
  • Cleaning and disinfecting.

Secondary prevention

Effective measures for the secondary prevention of COVID-19 associated abdominal pain include the following:

• Contact tracing helps reduce the spread of the disease.
• In an unexplained abdominal pain, CXR, Chest CT scan or nasopharyngeal swab RT-PCR should be performed to diagnose the infection and treat it timely.
• For the prevention of transmission through gastrointestinal tract (presence of viral RNA in the stool raise suspicion for fecal-oral transmission)
  • Use of personal protective equipment (PPE) by the personnel handling the fecal matter or visiting the patient. Protective eyewear (such as goggles or a face shield) used by healthcare personnel should cover the front and sides of the face with no gaps between glasses and the face..
  • Screening of fecal microbiota transplant donors for COVID-19 is also recommended.
• If a patient with IBDs takes ⩾20 mg/day of prednisone, they should reduce the dose or taper the dse to discontinue to prevent COVID-19 infection. In case of positive test for COVID-19 infection, drug should be tapered to discontinue.