The novel coronavirus (now officially named severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), the causative agent of coronavirus disease 2019 (COVID-19), emerged at the end of 2019 in Wuhan, a city in Hubei Province of China. The virus jumped hosts from bats to humans and engulfed the whole world, causing more than three million deaths.¹ Originally thought to be a respiratory pathogen, SARS-CoV-2 has been shown to cause a dizzying array of symptoms including all major organ systems of the human body. As time elapsed, new strains have emerged, validating concerns about genetic mutation. No single treatment has proven beneficial in treating the consequences, and the world has been left at the mercy of this deadly pathogen. Initially, only symptomatic patients were tested and isolated. However, it quickly became evident that all contacts of the positive cases would also need to be tested, since many were found to have contracted the virus. Attempts at preparing a vaccine to bolster immunity started in mid-2020, and large-scale vaccination programs were implemented worldwide. However, the emergence of new strains in different countries and climates made SARS-CoV-2 an elusive target for prevention. The unpredictable range of symptoms in patients remains a cause of confusion and perplexity for clinicians.

Emerging data suggest that all patients presenting to a hospital with respiratory symptoms should be tested for COVID-19 with a high index of suspicion. Surgical societies have recommended testing all asymptomatic patients undergoing surgery with the fear of positive cases exposing all healthcare workers involved in their care. When hospitals were overwhelmed with COVID-19 cases, creating shortages of oxygen and hospital beds, elective cases were deferred, and all healthcare resources were diverted towards COVID-19 patients. In this context, patients with problems other than COVID-19 were subjected to long wait times, and some succumbed to their diseases due to a lack of prompt medical care. Those lucky enough to have found hospital beds were tested for COVID-19, and many were found to be infected. This prompted clinicians to search for other symptoms related to the virus. The coming months proved that SARS-CoV-2 could cause strokes, myocardial infarcts, mesenteric infarcts, acute limb ischemia, and a wide array of other symptomatology. This review aimed to establish whether COVID-19 is associated with pancreatitis.

A rapid review was performed to identify relevant cases.

Literature search strategy

The search engines used for the review were PubMed and Google Scholar, without any language restriction. The keywords used were “pancreatitis,” “necrotizing,” and “COVID-19.” Cases reported after January 2020 were included. A detailed review of the bibliography of the included cases was done.

Inclusion criteria

The search results were evaluated by abstracts and titles. The full texts of the relevant studies were evaluated. All case reports or case series presenting patients with a clinical, radiological, or biochemical diagnosis of COVID-19 along with a clinical, biochemical, or radiological diagnosis of acute pancreatitis were included. No other predisposing factors of pancreatitis such as gallstones or endoscopic retrograde cholangiopancreatography were present.

Data retrieval

Asad Ali Kerawala, Bhagwan Das, and Rabika Fatima performed the data retrieval. The country of the study, date of publication, age and sex of the patient, comorbidities, clinical course, any complications, treatment, and eventual outcome were recorded for all cases.

Findings

Tables 1^2–7 and 2^8–41 present the search results.

Table 1 . Reports of Patients with COVID-19 and Necrotizing Pancreatitis.

Author	Date of publication	Country	Sex	Age (yr)	Comorbidity	Mode of COVID-19 diagnosis	Mode of pancreatitis diagnosis	Treatment	Outcome
Kumaran et al2	Sep 2020	UK	Female	67	HTN, SMA stenosis-1 year previously	RT-PCR	Abdominal CT	Conservative management including antibiotics	Alive
Mohammadi Arbati and Molseghi3	13 Apr 2021	Iran	Male	28	None	RT-PCR	Abdominal CT	Conservative management including antibiotics	Alive
Maalouf et al4	28 Jan 2021	Lebanon	Male	62	HTN, DM, ESRD, renal transplant	RT-PCR	Abdominal CT	Conservative management including antibiotics	Alive
Alloway et al5	6 Jun 2020	USA	Female	7	None	RT-PCR	Abdominal CT	Conservative management including antibiotics	Alive
Madhurantakam et al6	18 Dec 2020	India	Female	48	HTN, DM, ESRD on dialysis	RT-PCR	Abdominal CT	Invasive ventilation plus steroids, antibiotics	N/A
Liaquat et al7	Jul 2020	USA	Male	53	None	RT-PCR	Abdominal CT	Antibiotics, percutaneous drainage of necrotic collection, Steroids	Alive

UK, United Kingdom; USA, United States of America; HTN, hypertension; SMA, superior mesenteric artery; DM, diabetes mellitus; ESRD, end-stage renal disease; RT-PCR, reverse transcriptase-polymerase chain reaction; CT, computed tomography; N/A, not available..

Table 2 . Patients with COVID-19 Presenting with Acute Pancreatitis (Non-Necrotizing).

Author	Date of publication	Country	Sex	Age (yr)	Comorbidity	Mode of COVID-19 diagnosis	Mode of pancreatitis diagnosis	Treatment	Outcome
Meireles et al8	May 2020	Portugal	Female	36	HTN, ESRD	RT-PCR	Biochemical markers	Conservative management	Alive
Aloysius et al9	20 Jul 2020	USA	Female	36	Obesity	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
Anand et al10	Jun 2020	UK	Female	59	Thrombophilia, history of cholecystectomy	RT-PCR	Abdominal CT	Conservative management	Alive
Hadi et al11	20 Jun 2020	Denmark	Female	47	None	RT-PCR	Biochemical markers and ultrasound	Invasive ventilation	N/A
		Denmark	Female	68	HTN, hyperthyroidism	RT-PCR	Biochemical markers	Invasive ventilation	N/A
Gadiparthi et al12	23 Jun 2020	USA	Male	40	None	RT-PCR	Abdominal CT	Intensive care admission and conservative management	Alive
Suchman et al13	2 Jan 2021	USA	N/A	N/A	None	RT-PCR	Biochemical markers, clinical	Conservative management	Alive
			Female	N/A	None	RT-PCR	Biochemical markers, clinical	Conservative management	Alive
Stevens et al14	Nov 2020	USA	Female	10	Obesity, asthma	RT-PCR	Abdominal CT	Intensive care admission and IV Immunoglobulins	Alive
Shinohara et al15	Nov 2020	Japan	Male	58	HTN	RT-PCR	Abdominal CT	Conservative management (antibiotics and steroids), ECMO	Alive
Kataria et al16	Jul 2020	Pakistan	Female	49	None	RT-PCR	Biochemical markers	Conservative management with antibiotics	Alive
Meyers et al17	Nov 2020	USA	Male	67	HTN, alcoholism	RT-PCR	Biochemical markers	Conservative management	Alive
Cheung et al18	Aug 2020	USA	Male	38	None	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
Kandasamy et al19	Nov 2020	India	Female	45	None	RT-PCR	Abdominal CT	Conservative management	Alive
Jespersen Nizamic et al20	Dec 2021	USA	Female	49	CKD, renal transplant—on immunosuppressants	RT-PCR	Abdominal CT	Conservative management including tacrolimus	Alive
Narang et al21	Mar 2021	USA	Female	20	Pregnant, obesity, history of cholecystectomy	RT-PCR	MRCP	Steroids, preterm induction of labor	Alive
Gonzalo-Voltas et al22	Aug 2020	Spain	Female	76	Smoker, hypercholesterolemia	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
Lakshmanan and Malik23	Aug 2020	USA	Male	68	ESRD, HTN, DM	RT-PCR	Abdominal CT	Conservative management	Alive
Simou et al24	Oct 2020	Morocco	N/A	67	DM, obesity, alcoholism, history of cholecystectomy	RT-PCR	Abdominal CT	Invasive ventilation	Expired
Wang et al25	Aug 2020	China	Male	42	None	RT-PCR	Biochemical markers and abdominal CT	Invasive ventilation	Expired
		China	Male	35	None	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
Brikman et al26	Jul 2020	Israel	Male	61	None	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
Tollard et al27	Mar 2021	France	Female	32	Obesity, DM, DKA	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Expired
Acherjya et al28	Oct 2020	Bangladesh	Female	57	HTN, DM, breast cancer, and laryngeal cancer—receiving radiation and chemotherapy	RT-PCR	Abdominal CT	Conservative management	Alive
Karimzadeh et al29	Jun 2020	Iran	Female	65	HTN, Asthma	RT-PCR	Clinical and biochemical diagnosis	Conservative management	Alive
Mazrouei et al30	Jun 2020	UAE	Male	24	None	RT-PCR	Abdominal CT	Conservative management	Alive
Samies et al31	Feb 2021	USA	Male	15	None	RT-PCR	Biochemical markers	Conservative management	Alive
		USA	Male	11	None	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
		USA	Female	16	History of pancreatitis	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
Alwaeli et al32	Nov 2020	USA	Male	30	None	RT-PCR	Biochemical markers and abdominal CT	Conservative management including TPN	Alive
Purayil et al33	Aug 2020	Qatar	Male	58	None	RT-PCR	Clinical and biochemical diagnosis	Conservative management	Alive
Rabice et al34	May 2020	USA	Female	36	Pregnant, obese, DM, pre-eclampsia	RT-PCR	Clinical and biochemical diagnosis	Conservative management	Alive
Patnaik et al35	Sep 2020	India	Male	29	None	RT-PCR	Biochemical markers and abdominal CT	Conservative management including antibiotics	Alive
Pinte and Baicus36	Jun 2020	Romania	Male	47	None	RT-PCR	Abdominal CT	Conservative management	Alive
Alves et al37	Sep 2020	Brazil	Female	56	HTN	RT-PCR	MRCP	Intensive care management	Alive
Ibrahim et al38	Oct 2020	Qatar	Male	36	None	RT-PCR	Abdominal CT	Intensive care management plus hemodialysis	N/A
Miao et al39	Jul 2020	France	Female	26	None	RT-PCR	Abdominal CT	Conservative management	Alive
Bokhari and Mahmood40	Sep 2020	Pakistan	Male	32	None	RT-PCR	Biochemical markers and abdominal CT	Conservative management	Alive
Hassani et al41	2020	Iran	Female	78	HTN, IHD	RT-PCR	Clinical and biochemical diagnosis	Invasive ventilation	Expired

UAE, United Arab Emirates; HTN, hypertension; ESRD, end-stage renal disease; CKD, chronic kidney disease; DM, diabetes mellitus; IHD, ischemic heart disease; DKA; diabetic ketoacidosis; RT-PCR, reverse transcription polymerase chain reaction; CT, computed tomography; MRCP, magnetic resonance cholangiopancreatography; ECMO, extracorporeal membrane oxygenation; TPN, total parenteral nutrition; N/A, not available..

Out of the 176 and 479 search results from Google Scholar and PubMed, respectively, 104 were relevant. After a detailed read, 35 publications fulfilled the inclusion criteria. The bibliography of these publications revealed 5 more articles pertinent to our study. Hence, a total of 38 publications (34 case reports and 4 case series) were analyzed.

Data synthesis

In total, 44 cases of acute pancreatitis (38 cases of acute edematous pancreatitis and 6 cases of necrotizing pancreatitis) in COVID-19 patients without any predisposing factors have been published since January 2020. Even though quite a few authors claimed to be the first to report the combination, after thorough research we came to the conclusion that the first case reported was in May 2020 from Portugal by Meireles et al⁸ Journals around the world have considered all COVID-19 related studies for fast track publication—and rightly so, as our understanding evolved from viewing SARS-CoV-2 as a respiratory virus to recognizing it as a pathogen capable of causing multiorgan disease. For this reason, there was an overlap of cases published in mid-2020.

Age and sex of patients

In the acute edematous cohort, 17 (44.7%) were males, 20 (52.6%) were females, and sex was not reported for 2 (5.3%) patients. The necrotizing group showed an even sex distribution, with three (50.0%) patients each. The median age of presentation was 45 years. The median ages of male and female patients were 38 and 47 years, respectively. The median age of patients with necrotizing pancreatitis was 50.5 years. The youngest case presented was necrotizing pancreatitis in a 7-year-old girl from the USA by Alloway et al⁵. Samies et al³¹ published a case series of three pediatric patients from the USA. The oldest patient reported was 78 years old from Iran.

Country of origin

The United States of America has been the country with the highest number of COVID-19 cases and deaths. The most cases reported were therefore from the USA itself (n = 16). Three cases were reported from Iran and India. Two cases each were published by authors from Pakistan, Denmark, France, China, Qatar, and the United Kingdom. Ten countries reported a single case each: Japan, the United Arab Emirates, Lebanon, Spain, Portugal, Bangladesh, Morocco, Israel, Brazil, and Romania.

Mode of diagnosis

Reverse-transcription polymerase chain reaction (RT-PCR) from a nasopharyngeal swab was used to confirm the diagnosis of COVID-19 in all patients. The diagnosis of acute pancreatitis was more varied. Computed tomography (CT) of the abdomen was the most frequently used modality for diagnosis, as it was performed in all (n = 6) patients with necrotizing pancreatitis and in 63.2% (n = 24) the non-necrotizing pancreatitis patients. Magnetic resonance cholangiopancreatography was used in only two patients. The remaining 12 were diagnosed with a combination of clinical findings and elevated biochemical markers for pancreatitis—namely, amylase and lipase.

Comorbidities

Twenty-two patients had no comorbidities and no significant past medical history. Hypertension was the most common comorbidity, present in 12 patients (27.3%), followed by diabetes mellitus (n = 7; 15.9%), end-stage renal disease (n = 5; 11.4%), and obesity (n = 6; 13.6%). Two cases were reported in pregnant women. The details are presented in Table 1.

Treatment modality

All six patients with necrotizing pancreatitis were treated with antibiotics and intensive care. Only one patient required invasive ventilation and one required percutaneous drainage of an infected collection.

In the acute edematous pancreatitis group, conservative management with bowel rest, intravenous fluids, analgesics, and anti-emetics in the ward was the most frequently used treatment modality (n = 26). Invasive ventilation was needed for eight patients. Extracorporeal membrane oxygenation was required for just one patient owing to respiratory failure from COVID-19. Total parenteral nutrition, a therapy used by some clinicians for pancreatitis, was only applied in one case. Preterm labor had to be induced in one pregnant patient; however, the other was treated successfully with conservative measures.

Outcomes

Fortunately, death was reported in only four (9.1%) patients. Historically, pancreatitis itself is a deadly disease with an unpredictable course, and in combination with the deleterious effects of COVID-19 on the immune system, the expectation would be to have a high mortality rate. The unexpectedly low mortality rate could be due to the incomplete information available at the time of publication. These cases were all reported rapidly, with a short follow-up. None of the patients in the necrotizing pancreatitis cohort succumbed to the disease, and both pregnant women gave birth to healthy babies and returned home healthy.

Since the beginning of the COVID-19 pandemic caused by a respiratory virus, SARS-CoV-2, the medical literature has reported several extra-respiratory manifestations caused by this virus, including acute pancreatitis.

Acute pancreatitis is among the most common health care emergencies encountered during routine clinical practice.⁴² Around 10%–20% of cases of acute pancreatitis have been reported to involve necrosis of the pancreatic gland itself and/or surrounding peripancreatic tissue, a condition known as acute necrotizing pancreatitis.⁴³

Infectious agents as an etiology of acute pancreatitis are not novel, as several infectious agents have been reported to infect the pancreas.⁴⁴ Several viruses have been described in the literature as etiologies of viral pancreatitis; the most common among them are mumps, cytomegalovirus, coxsackievirus, and hepatitis A-E virus.⁴⁵ The exact pathological mechanism by which these viruses induce pancreatic injury is still unknown. Some proposed mechanisms by which viruses can cause viral pancreatitis are the replication of viruses within acinar cells leading to the leakage and activation of pancreatic enzymes, cellular damage by ampullary edema, and cholangiopathy.⁴⁶

Studies done during the previous SARS-CoV pandemic, in the early 2000s, reported the presence of viral RNA and antigen within the pancreatic tissues.⁴⁷ Likewise, SARS-CoV-2 RNA was also detected in the fluid sampled from a pancreatic pseudocyst of a patient with pancreatitis and COVID-19 infection.⁴⁸ Because of the genomic similarity of SARS-CoV-2 and SARS-CoV and the expression of angiotensin-converting enzyme 2 (ACE2) receptors of SARS-CoV-2 in pancreatic tissues,^49,50 the pancreas can be assumed to be a potential target of SARS-CoV-2.

Though the exact mechanism by which SARS-CoV-2 causes pancreatitis is still unclear, but the extant studies have reported it to be a multifactorial phenomenon. COVID-19-associated pancreatic injury is thought to involve direct cellular damage via local replication of the virus within pancreatic cells, as they express ACE2 receptors at an even higher level than lung cells.⁵⁰ SARS-CoV-2 has a high binding affinity for ACE2 receptors, and after binding to these receptors, the virus utilizes a variety of host proteins including transmembrane protease serine 2 (TMPRSS2) for easy cellular entry.^51,52 In addition to direct injury, lipotoxicity has also recently been reported in COVID-19 patients, resulting in leakage of lipase from pancreatic cells and causing cellular damage.⁵³

Furthermore, cytokine storm secondary to a dysregulated inflammatory response also causes pancreatic injury, as described by Liu et al⁵⁰ in patients with severe COVID-19 disease. Thus, direct cellular injury, lipotoxicity, and severe inflammatory response syndrome in combination drive the disease progression, leading to not only pancreatitis, but also acute respiratory distress syndrome, multiorgan failure, and in some cases mortality.^54,55

From precise published data, it can be concluded that acute pancreatitis is less common than other gastrointestinal manifestations seen in COVID-19 patients. It was reported slightly more frequently in female patients and at a relatively younger age in male patients, with no age-related immunity, as it was reported in patients from 7 years to 78 years of age. Abdominal CT was the most common imaging modality used for the diagnosis of both necrotizing (in 100% of cases) and non-necrotizing pancreatitis (in 63% of cases). As in several other studies,^56–59 we found that hypertension was the most common comorbid condition in this review, followed by diabetes mellitus, obesity, and end-stage renal disease.

COVID-19 infection was confirmed by RT-PCR in all patients, and after confirmation of diagnosis, almost all patients diagnosed with pancreatitis received conventional conservative therapy with bowel rest, intravenous fluids, analgesics, and anti-emetics. Intensive care was required by all patients with necrotizing pancreatitis and in less than one-third of patients with edematous pancreatitis. Out of two pregnant patients, preterm labor was induced in one and the second one was managed conservatively.

The exact outcome data of acute pancreatitis in COVID-19 patients are quite difficult to report from this review, as the current status and complete follow-up of many patients were missing in the reported literature. This constitutes the most substantial limitation of our study. Mortality was reported in only 9% of the published cases in this review. The reason for this low mortality rate could be that viral pancreatitis is usually of mild severity, with most patients recovering on their own. The long-term effects of COVID-19 on the pancreas, as part of so-called “long COVID,” remain obscure. Only time will tell if any of these patients will develop chronic pancreatitis or pancreatic insufficiency in the long term. Although there are insufficient data to consider pancreatitis in all patients with COVID-19, the significant mortality associated with pancreatitis makes it imperative for the clinician to keep pancreatitis in the differential list in COVID-19 patients with any gastrointestinal symptoms.

Our review concludes that acute pancreatitis should be kept in the differential list of all COVID-19 patients with gastrointestinal manifestations, especially in patients with acute abdomen. Likewise, COVID-19 RT-PCR testing should be done in all patients diagnosed with acute pancreatitis for the timely isolation and observation of other COVID-19-associated complications.

None.

No potential conflict of interest relevant to this article was reported.