COVID-19 Associated Pancreatitis: A Review of 66 Cases

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown itself with different clinical manifestations. Besides respiratory distress, cough, and fever, which were the most common symptoms, pancreatitis has been reported as a rare presentation of this disease, but the knowledge on this association and its pathogenesis is sparse. Methods: Four databases, including Pub Med, Scopus, Web of Science, and Google Scholar, were searched for the association of pancreatitis and SARS-CoV-2 infection, and 29 relevant articles were extracted and reviewed. Results: We reviewed 29 studies provided 66 cases developed acute pancreatitis while they were infected with SARS-CoV-2. The mean age of patients was 49.94 ± 16.96. The female to male ratio was 1.06 (33 to 31). In 44% of cases, acute pancreatitis developed as the primary presentation of Coronavirus Disease 2019 (COVID-19) and 9% of reported cases, expired. Conclusions: During this pandemic, SARS-CoV-2 should be considered in the differential diagnosis of the patients presenting with acute pancreatitis. Although pancreatitis will respond to standard care, these patients need isolation and observation for later development of respiratory symptoms. ratio 1.06 (33 to gender not in two cases 15). 16.96. records indicated that in 44% of patients, acute pancreatitis presented as the initial manifestation of COVID-19. No signicant past medical or surgical history was reported for 35% of cases. Among underlying disease reported in 65% of patients, hypertension was the most common. In a cohort study conducted by Inamdar et al., thirty-two COVID-19 positive patients with pancreatitis were reported. Idiopathic pancreatitis accounts for the majority of these cases. Gallstone, alcohol, and drugs were responsible for 16%, 6%, and 3% of pancreatitis in these patients, respectively (16). The mortality rate was 9% among all patients reported in the studies.


Background
Coronavirus disease 2019 (COVID-19) emerged in Wuhan city in December 2019, and rapidly involved almost all countries and territories in the world (1,2). The most common manifestations of this disease include fever, cough, dyspnea, sore throat, headache, and myalgia (3). Although it mainly involves the respiratory system, many studies have reported various extrapulmonary manifestations such as acute cardiac injury, heart failure, cardiac arrhythmia, acute ischemic stroke, cerebral venous thrombosis, encephalitis, and gastrointestinal symptoms (4)(5)(6)(7)(8). Digestive manifestations such as anorexia, nausea, vomiting, abdominal pain, diarrhea can range from mild to severe in their presentation. There are reports of more severe complications which may need urgent interventions including bowel ischemia and hepatic necrosis (9,10). Acute pancreatitis is a relatively rare presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (6). Pancreatitis has been reported with several different types of viruses through diverse mechanisms (11). It seems that the coronavirus can also affect the pancreas and cause pancreatic injury (12). The mechanism of pancreatitis in the course of COVID-19 is not entirely known. (13) In recent months, publications have reported acute pancreatitis as a COVID-19 manifestation. This study gives a detailed review of relevant articles and summarizes their ndings to clarify acute pancreatitis features induced by COVID-19.

Methods
This literature review was performed through a comprehensive search in three databases, including Pub Med, Scopus, and Web of Science. English articles about the association of SARS-CoV-2 and pancreatitis, published before 30 th of October 2020, were included in this review. We also searched Google Scholar or the grey literature and examined the rst 100 results. The search strategy employed for each database is shown in Table1.
All of the citations were imported to Endnote X9 software (Clarivate Analytics, USA), and all duplicates were excluded. Then we carried out the rst screening, and irrelevant articles were excluded according to their titles and abstracts. In the next step, full-text screening was performed to detect the eligible studies.
Finally, an Excel (Microsoft, Redmond, WA, USA) spreadsheet was used to extract the key ndings of the studies. All steps were done by two authors separately. In case of disagreements, a third person was consulted.

Results
We identi ed 73, 117, 51, 17 records in Pub Med, Scopus, Web of Science, and Google Scholar, respectively. After removing duplicates and screening, we found 29 publications (Figure 1), including 27 case reports and 2 cohort studies. Taken together, 66 patients with COVID-19 associated pancreatitis were reported. Table 2 represents the key characteristics of the cases. In terms of geographical location, nine studies (33.3 %) were from Asia, eight studies (29.6%) were from Europe, seven studies (25.9%) were from North America, two studies (7.4%) were from South America, and one study (3.7%) was from Africa. In total, the female to male ratio was 1.06 (33 to 31); gender was not mentioned in two cases (14,15). The mean age of patients (n=66) was 49.94 ± 16.96. Reviewed records indicated that in 44% of patients, acute pancreatitis presented as the initial manifestation of COVID-19. No signi cant past medical or surgical history was reported for 35% of cases. Among underlying disease reported in 65% of patients, hypertension was the most common. In a cohort study conducted by Inamdar et al., thirty-two COVID-19 positive patients with pancreatitis were reported. Idiopathic pancreatitis accounts for the majority of these cases. Gallstone, alcohol, and drugs were responsible for 16%, 6%, and 3% of pancreatitis in these patients, respectively (16). The mortality rate was 9% among all patients reported in the studies.
As mentioned earlier, SARS-CoV-2 pathogenicity for acute pancreatitis is not clear yet (13). Investigations have reported several mechanisms that explain pancreatic involvement during this disease. One of these mechanisms is based on Angiotensin-converting enzyme 2 (ACE2) receptor expression on the pancreatic cells (21). The pathogenicity of SARS-CoV-2 is through binding to the ACE2 receptor on alveolar cells in the lung (22). ACE2 receptor is also present on other organs such as the pancreas (23). According to this fact, the pancreatic tropism of the COVID-19 virus could be justi ed.
Timing ofpancreatitis presentation: The onset of pancreatitis presentations varied among studied cases. In some cases, acute pancreatitis was presented as the initial manifestation of COVID-19. In other ones, pancreatic injury developed from days to weeks after the emergence of respiratory symptoms. Evidently, the time of emerging pancreatitis presentations has not the same pattern in different patients.

Diagnosis:
COVID-19 can involve the gastrointestinal tract and may lead to pancreatic enzyme elevation (11,24). Although pancreatic enzyme elevation is one of the diagnostic criteria for acute pancreatitis, rising pancreatic enzymes is possible in infected patients in the absence of any pancreatitis presentations (25,26).
Therefore, in addition to the enzyme elevation, at least one of the following criteria should be considered in the diagnosis of acute pancreatitis in patients with COVID-19: characteristic acute pain in epigastric or right upper quadrant and abdominal imaging in favor of acute pancreatitis (26).
In the reviewed studies, pancreatic enzyme levels were detected from normal (27) to above 20 to 30 times more than the normal range (19,28). In addition to that, the C-Reactive Protein (CRP) level also was up to 20-times elevated (17). The most common pancreatitis presentation was sudden onset epigastric pain, which was reported mild to severe in different individuals. Other manifestations such as anorexia, nausea, vomiting, diarrhea, fever varied among patients. In one study, no abdominal symptoms were reported, and investigations to con rm acute Pancreatitis were done just due to persistent fever (14).
Acute pancreatitis was con rmed through abdominal imaging, especially Computed Tomography (CT) scans in the majority of the studies. The most common imaging ndings in publications were peripancreatic fat stranding and uid collection. Necrotizing pancreatitis, pancreatic uid collection, and pancreatic pseudocyst were also reported (29)(30)(31)(32). Although it is not a common procedure, in one study pseudocyst sample was tested positive for SARS-CoV-2 (33).
Ultrasonography was also a standard modality to exclude cholelithiasis as a common reason for pancreatitis.

Treatment and outcomes:
After con rming the diagnosis of the COVID-19, nearly all cases of COVID-19 associated pancreatitis were treated by two main strategies: (1) Treatment of COVID-19, which is supportive care in most cases or can include antiviral and anti-in ammatory drugs based on patients' conditions and each country guideline.
(2) Treating pancreatitis as routine ( uid resuscitation, analgesics, and antibiotics if indicated). Considering these treatments, the symptoms of most of the cases were resolved.

Limitations
Although we reviewed databases thoroughly, the infancy of the publications could impact our study.