Acute pancreatitis associated with severe acute respiratory syndrome coronavirus-2 infection: a case report and review of the literature

Introduction We report a case of Severe acute respiratory syndrome coronavirus-2 infection with acute pancreatitis as the only presenting symptom. To the best of our knowledge, there are few case reports of the same presentation. Case presentation An otherwise healthy 44-year-old white male from Egypt presented to the hospital with severe epigastric pain and over ten attacks of nonprojectile vomiting (first, gastric content, then bilious). Acute pancreatitis was suspected and confirmed by serum amylase, serum lipase, and computed tomography scan that showed mild diffuse enlargement of the pancreas. The patient did not have any risk factor for acute pancreatitis, and extensive investigations did not reveal a clear etiology. Given a potential occupational exposure, a nasopharyngeal swab for polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 was done, which was positive despite the absence of the typical symptoms of severe acute respiratory syndrome coronavirus 2 such as fever and respiratory symptoms. The patient was managed conservatively. For pancreatitis, he was kept nil per os for 2 days and received intravenous lactated Ringer’s (10 ml per kg per hour), nalbuphine, alpha chymotrypsin, omeprazole, and cyclizine lactate. For severe acute respiratory syndrome coronavirus 2, he received a 5-day course of intravenous azithromycin (500 mg per day). He improved quickly and was discharged by the fifth day. We know that abdominal pain is not a rare symptom of severe acute respiratory syndrome coronavirus 2, and we also know that elevated levels of serum amylase and lipase were reported in severe acute respiratory syndrome coronavirus-2 patients, especially those with severe symptoms. However, the association between severe acute respiratory syndrome coronavirus-2 infection and idiopathic acute pancreatitis is rare and has been reported only a few times. Conclusion We believe further studies should be conducted to determine the extent of pancreatic involvement in severe acute respiratory syndrome coronavirus-2 patients and the possible causality between severe acute respiratory syndrome coronavirus 2 and acute pancreatitis. We reviewed the literature regarding the association between severe acute respiratory syndrome coronavirus 2 and acute pancreatitis patients. Published data suggest that severe acute respiratory syndrome coronavirus 2 possibly could be a risk factor for acute pancreatitis.


Introduction
With over 149 million confirmed cases and 3.14 million deaths worldwide as of 29 April 2021, coronavirus disease 2019 (COVID-19) has declared itself the most significant global health emergency humanity had to face in decades Open Access *Correspondence: muhammed.elhadi.uot@gmail.com 4 Faculty of Medicine, University of Tripoli, University Road, Furnaj, 13275 Tripoli, Libya Full list of author information is available at the end of the article [1]. After more than 10 months of the pandemic, we still lack a comprehensive understanding of the virus pathophysiology and how it manifests in different patients. Gastrointestinal (GI) manifestations were reported in about 18% of patients, with diarrhea being the most commonly reported GI symptom [2] that is most likely due to alteration of enterocyte permeability [3]. Mild-to-moderate liver injury was reported as well, and the exact mechanism is still not fully understood [3]. Acute abdominal pain has also been reported, and its exact pathophysiology is still elusive. Acute pancreatitis was reported a few times as a cause of abdominal pain in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and it is not clear if the virus could involve the pancreas specifically. We are reporting a case of COVID-19 presenting with acute pancreatitis without other risk factors for pancreatitis.

Case presentation
A previously healthy 44-year-old white male presented to the emergency department with severe epigastric pain radiating to the back and frequent vomiting (over ten attacks, first gastric content, then bilious with no blood) for 3 days on 22 June 2020. Four days before the beginning of his abdominal symptoms, the patient received a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after undergoing a nasopharyngeal swab for reverse-transcription polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 infection as part of surveillance screening after contacting several COVID-19 patients during his work in a hotel in Sharm El-Sheikh, Egypt, and the patient was asked to self-isolate. However, he presented to our care after 5 days of SARS-COV-2 diagnosis with acute pancreatitis. The patient did not have any respiratory symptoms at that time.
During history taking, the patient denied any respiratory symptoms such as cough or dyspnea. The patient denied smoking, alcohol, or drug intake (illicit or therapeutic except for occasional use of paracetamol for right knee pain). The patient was a middle-class worker who denied exposure to any hazardous substances at his work place. He also denied any previous similar attacks of abdominal pain. There was no family history of similar attacks. His vital signs were as follows: blood pressure of 94/50 mmHg, pulse rate of 112 beats per minute, respiratory rate of 27 breaths per minute, temperature of 37.5 °C, and oxygen saturation of 98% on room air. Abdominal examination revealed marked tenderness in the epigastric region without distension. Neurological examination did not reveal any abnormalities. Intravenous fluid resuscitation was started immediately with a bolus of 1.5 L of lactated Ringer's.
A repeat nasopharyngeal Reverse transcription polymerase chain reaction (RT-PCR) was performed on the day of admission to the hospital as a part of the local protocols for suspected cases. The results came back positive on 24 June 2020. The patient was then transferred from the medical ward to an isolation center in the same hospital, explicitly dedicated to COVID-19 patients.
An abdominal X-ray was done and was unremarkable. However, abdominal-pelvic ultrasonography revealed mild diffuse enlargement of the pancreatic head with normal gall bladder and biliary tract. Serum amylase was 773, and serum lipase was 286 ( Table 1). The diagnosis of mild acute pancreatitis was confirmed with an abdominal CT scan that revealed mild diffuse enlargement of the pancreas (Figure 1). The patient was managed conservatively for 4 days. For pancreatitis, he was kept NPO for 2 days during which he received 10 ml/ kg/hour of lactated Ringer's; he also received nalbuphine (10-20 mg per day, intramuscular) for analgesia, omeprazole (40 mg once daily, intravenous) for ulcer prophylaxis and cyclizine lactate (50 mg twice daily, intravenous) for vomiting. On the third day, anorexia and vomiting subsided, and the patient was started on oral feeding, which he tolerated well. On the fifth day, the patient was vitally stable and symptom-free and was advised to continue his

Discussion
Although rare, acute pancreatitis can be caused by viral, bacterial, fungal, and parasitic infections. Viral pancreatitis is known to be caused by mumps, cytomegalovirus, hepatitis B virus, herpes simplex virus, varicella-zoster virus, and human immunodeficiency virus (HIV) [4][5][6].
Although coronaviruses are not known to cause pancreatitis in humans, the 2003 SARS was associated with damage to the endocrine pancreas and acute diabetes [7]. This effect was explained by damage to acinar cells through the virus binding to angiotensin-converting enzyme 2 (ACE2) receptors [7]. Liu et al. reported elevated amylase and lipase in 16.41% and 1.85% of patients with severe and mild SARS-CoV-2 infections, respectively, suggesting some degree of pancreatic injury [8]. This injury's exact pathophysiology is not well understood, but SARS-CoV-2 may involve the exocrine pancreas in the same manner SARS involves the endocrine pancreas: through ACE2 receptor binding, especially now that we know that SARS-CoV-2 binds ACE2 receptors ten times stronger than the 2003 SARS [9]. A recent study published by Müller et al. found that SARS-CoV-2 has the ability to infect and replicates in β-cell of pancreatic        islets of Langerhans as they detected SARS-CoV-2 nucleocapsid protein in the pancreatic cells of postmortem patients [10]. Their findings may explain the reason behind the metabolic dysregulations of COVID-19 patients, such as impaired glucose homeostasis and abnormal amylase or lipase levels [8].
We report the first African case report of acute pancreatitis presenting as SARS-CoV-2 infection. Our patient had acute acalculous pancreatitis in association with SARS-CoV-2 infection. We managed to exclude alcoholism, drugs, hypertriglyceridemia, hypercalcemia (by laboratory testing), and trauma (by history) as potential etiologies. The patient denied any previous attacks or family history of similar symptoms. We did not test our patient for autoimmune pancreatitis since this was not feasible at our institution. Also, we did not test for viral causes of pancreatitis other than hepatitis B virus and human immunodeficiency virus, which both were negative.
We searched the literature in PubMed/Medline up to 3 January 2021 to identify published case reports of COVID-19 associated with pancreatitis. We identified only 29 cases published in 25 articles (Table 2). SARS-CoV-2 infections were diagnosed with RT-PCR in all cases except one case with antibody testing. Three cases were in the pediatric age group < 18 years. Including our case, patients have a mean age of 43.5 years, and 14 were males (46.6%). The majority of the cases had abdominal pain and/or vomiting, 82% of patients had elevated serum lipase, and almost all patients had elevated serum lipase and/or amylase. Moreover, 72% of patients had abdominal CT findings suggestive of pancreatitis. All patients were discharged alive, except two patients were still in the intensive care unit (ICU), and only one patient died (Table 3).
Acute pancreatitis appears to be an infrequent complication/association of COVID-19. One retrospective study from the USA analyzing 11,883 patients with COVID-19 found that the point prevalence of pancreatitis was 0.27% (32 patients) [11]. However, another prospective international study of acute pancreatitis during the COVID-19 pandemic concluded that acute pancreatitis with SARS-CoV-2 infection has a higher risk of severity and poor clinical outcomes, including the risk of organ dysfunction higher 30-day inpatient mortality compared with acute pancreatitis patients who are SARS-CoV-2-negative [12].

Conclusion
Until solid evidence on the relation between pancreatitis and SARS-CoV-2 is provided, we believe acute pancreatitis should be considered a potential explanation for acute abdominal pain in SARS-CoV-2 patients. Such evidence should rise from well-designed epidemiological studies as well as autopsy studies.