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Review Article| Volume 52, ISSUE 1, P37-48, March 2023

The Pancreas in Coronavirus Disease 2019 Infection

Published:December 12, 2022DOI:https://doi.org/10.1016/j.gtc.2022.12.002
The Pancreas in Coronavirus Disease 2019 Infection
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      Keywords

      Key points

      • •
        Many similarities between severe acute respiratory syndrome coronavirus-2 infection and acute pancreatitis (AP) are described but there is still a paucity of evidence to establish coronavirus disease 2019 (COVID-19) as a cause of AP.
      • •
        Patients with both COVID-19 and AP should be carefully managed because evidence indicates they may have a worse outcome.
      • •
        Careful attention to etiologic workup, patients comorbidities and chronic medications, disease management and diagnosis, and publishing guidelines should guide future case reports.
      • •
        COVID-19 vaccination has indisputable advantages but a few cases of AP have been reported after vaccination, which should alert and turn physicians to abdominal pain development after inoculation.
      • •
        Pancreas cancer diagnosis and management have been deeply influenced by the pandemic. Expert consensus and international and local guidelines should be implemented to allow safe management pathways to be resumed and improved.

      Introduction

      Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the pandemic of coronavirus disease 2019 (COVID-19) that has caused more than 600 million infections and 6.5 million deaths worldwide, involving more than 200 countries.

      WHO. WHO Coronavirus Disease (COVID-19) Dashboard 2022, Available at: https://covid19.who.int/?adgroupsurvey=%7Badgroupsurvey%7D&gclid=EAIaIQobChMInp-Px8Le-QIVRpNmAh3-Xww9EAAYASABEgLA7PD_BwE. Accessed September 7, 2022.

      Initially considered a respiratory disease, the gastrointestinal tract has been described as playing a key role in the route of infection, clinical manifestations, and disease outcomes.
      • Kariyawasam J.C.
      • Jayarajah U.
      • Riza R.
      • et al.
      Gastrointestinal manifestations in COVID-19.
      Trans R Soc Trop Med Hyg. 2021; 115: 1362-1388
      Pancreatic involvement was also found and several cases of pancreatic enzyme elevation and acute pancreatitis (AP) have been reported. However, the available data are difficult to interpret, and COVID-19 has not been definitively associated with AP, leaving several questions open.
      • de-Madaria E.
      • Capurso G.
      COVID-19 and acute pancreatitis: examining the causality.
      Nat Rev Gastroenterol Hepatol. 2021; 18: 3-4
      In this review, we aim to examine mechanisms of pancreatic involvement by SARS-CoV-2, the link between COVID-19 and AP, the influence of COVID-19 on chronic pancreatitis (CP), and the impact of COVID-19 on pancreatic cancer treatment, prognosis, and pancreatic surgery.

      Materials and methods

      A review of the literature was conducted using PubMed and EMBASE databases on September 26, 2022, for publications on COVID-19 and acute and CP and pancreatic cancer. A grey literature search using the same keywords was performed using Google Scholar to increase the search sensitivity. Articles on pediatric patients and pregnant women were excluded. References of eligible articles were also screened for additional articles. The literature search was restricted to articles published in English.

      Mechanisms of pancreatic injury

      Several studies have examined possible mechanisms of pancreatic injury by SARS-CoV-2.
      SARS-CoV-2 enters human cells through angiotensin converting enzyme (ACE2) receptors, with transmembrane serine protease 2 (TMPRSS2) priming, which are highly expressed in human gastrointestinal cells.
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      • Tang M.
      • Zheng X.
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      Evidence for Gastrointestinal infection of SARS-CoV-2.
      Gastroenterology. 2020; 158: 1831-1833.e3
      After viral entry, virus-specific RNA and proteins are synthesized in the cytoplasm of host cells to assemble new virions, which are then released to the gastrointestinal tract and detected in stool, confirming fecal–oral transmission.
      • Xiao F.
      • Tang M.
      • Zheng X.
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      Evidence for Gastrointestinal infection of SARS-CoV-2.
      Gastroenterology. 2020; 158: 1831-1833.e3
      ACE2 is also highly expressed in pancreatic ductal, acinar, and islet cells,
      • Liu F.
      • Long X.
      • Zhang B.
      • et al.
      ACE2 Expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection.
      Clin Gastroenterol Hepatol. 2020; 18: 2128-2130.e2
      and the virus could thereby spread from the duodenal epithelium to the pancreatic cells. Furthermore, SARS-CoV-2 has been associated with endotheliitis and microischemic disease, which could occur in the pancreas.
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      • Azoulay E.
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      The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection.
      Crit Care. 2020; 24: 353
      Histopathological studies in patients who died from severe COVID-19 infection report findings of pancreatitis and of SARS-CoV-2 identified in pancreatic pseudocyst fluid samples in patients who did not develop AP, showing SARS-CoV-2 tropism for pancreatic cells.
      • Schepis T.
      • Larghi A.
      • Papa A.
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      SARS-CoV2 RNA detection in a pancreatic pseudocyst sample.
      Pancreatology. 2020; 20: 1011-1012
      , 
      • Hinojosa V.
      • Gamboa E.
      • Varon J.
      Pancreatic pseudocysts as a late manifestation of COVID-19.
      Cureus. 2022; 14: e22181
      , 
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      • Naresh K.N.
      • Roufosse C.
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      Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study.
      Lancet Microbe. 2020; 1: e245-e253
      SARS-CoV-2 has been reported to result in insulin deficiency and the development of type 1 diabetes mellitus.
      • Boddu S.K.
      • Aurangabadkar G.
      • Kuchay M.S.
      New onset diabetes, type 1 diabetes and COVID-19.
      Diabetes Metab Syndr. 2020; 14: 2211-2217
      Although an increase of type 1 diabetes mellitus was observed in children, it is still unknown whether β cell injury is permanent or transient.
      • Boddu S.K.
      • Aurangabadkar G.
      • Kuchay M.S.
      New onset diabetes, type 1 diabetes and COVID-19.
      Diabetes Metab Syndr. 2020; 14: 2211-2217
      ,
      • Unsworth R.
      • Wallace S.
      • Oliver N.S.
      • et al.
      New-onset Type 1 diabetes in children during COVID-19: Multicenter Regional Findings in the U.K.
      Diabetes Care. 2020; 43: e170-e171
      Long-term results of the COVIDPAN study did not show an increased frequency of long-term diabetes.
      • Nayar M.
      • Varghese C.
      • Kanwar A.
      • et al.
      SARS-CoV-2 infection is associated with an increased risk of idiopathic acute pancreatitis but not pancreatic exocrine insufficiency or diabetes: long-term results of the COVIDPAN study.
      Gut. 2022; 71: 1444-1447
      In patients already diagnosed with diabetes, SARS-CoV-2 induced β cell dysfunction may cause an uncontrolled hyperglycemic state, which in turn may contribute to COVID-19 increased severity and mortality.
      • Boddu S.K.
      • Aurangabadkar G.
      • Kuchay M.S.
      New onset diabetes, type 1 diabetes and COVID-19.
      Diabetes Metab Syndr. 2020; 14: 2211-2217
      ,
      • Abramczyk U.
      • Nowaczyński M.
      • Słomczyński A.
      • et al.
      Consequences of COVID-19 for the pancreas.
      Int J Mol Sci. 2022; 23
      Derangements of Na+/H+ exchange and lactate pathway are other potential mechanisms of glucose metabolism dysregulation from SARS-CoV-2 infection.
      • Cure E.
      • Cumhur Cure M.
      COVID-19 may affect the endocrine pancreas by activating Na+/H+ exchanger 2 and increasing lactate levels.
      J Endocrinol Invest. 2020; 43: 1167-1168
      A broad-spectrum of proinflammatory cytokines, including interleukin-2 (IL-2), IL-6, IL-8, IL-10, CXCL12, interferon (IFN)-γ, and tumor-necrosis factor-α, are released during COVID-19 infection, which may result from SARS-CoV-2 binding to ACE2 receptors in pancreatic cells
      • Mehta P.
      • McAuley D.F.
      • Brown M.
      • et al.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      The Lancet. 2020; 395: 1033-1034
      ,
      • Shaharuddin S.H.
      • Wang V.
      • Santos R.S.
      • et al.
      Deleterious effects of SARS-CoV-2 infection on human pancreatic cells.
      Front Cell Infect Microbiol. 2021; 11: 678482
      but can also cause direct damage to surrounding dendritic cells and naïve T-cell activation in genetically predisposed individuals.
      • Caruso P.
      • Longo M.
      • Esposito K.
      • et al.
      Type 1 diabetes triggered by covid-19 pandemic: A potential outbreak?.
      Diabetes Res Clin Pract. 2020; 164: 108219
      It is also hypothesized that pancreatic lipase increases lipolysis and plasma levels of unsaturated fatty acids, which can in turn damage mitochondria and contribute to proinflammatory cytokine release.
      • Hegyi P.
      • Szakács Z.
      • Sahin-Tóth M.
      Lipotoxicity and cytokine storm in severe acute pancreatitis and COVID-19.
      Gastroenterology. 2020; 159: 824-827
      ,
      • Tang Q.
      • Gao L.
      • Tong Z.
      • et al.
      Hyperlipidemia, COVID-19 and acute pancreatitis: a tale of three entities.
      Am J Med Sci. 2022; 364: 257-263
      In both COVID-19 and AP, the cytokine storm is responsible for the disease severity, specifically elevated IL-6 levels, which are related to the development of the acute respiratory distress syndrome and cause increased mortality in AP.
      • Liu B.
      • Li M.
      • Zhou Z.
      • et al.
      Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?.
      J Autoimmun. 2020; 111: 102452
      ,
      • Rao S.A.
      • Kunte A.R.
      Interleukin-6: An early predictive marker for severity of acute pancreatitis.
      Indian J Crit Care Med. 2017; 21: 424-428
      Moreover, immune-response pathways are severely impacted by antibody production during SARS-CoV-2 infection, which may potentially cause increased IL-6 production.
      • Iwasaki A.
      • Yang Y.
      The potential danger of suboptimal antibody responses in COVID-19.
      Nat Rev Immunol. 2020; 20: 339-341
      The cytokine storm is also directly involved in the coagulation cascade deregulation, which may in turn increase AP severity.
      • Wang D.
      • Hu B.
      • Hu C.
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      JAMA. 2020; 323: 1061-1069
      Several drugs used in the treatment of COVID-19, including corticosteroids, azithromycin, remdesivir, lopinavir/ritonavir, and IFN-β, have been implicated in the development of AP and hyperglycemia.
      • Abramczyk U.
      • Nowaczyński M.
      • Słomczyński A.
      • et al.
      Consequences of COVID-19 for the pancreas.
      Int J Mol Sci. 2022; 23
      ,
      • Yamamoto K.
      • Oka K.
      • Sakae H.
      • et al.
      Acute pancreatitis related to COVID-19 infection.
      Intern Med. 2021; 60: 2159-2160
      , 
      • Khadka S.
      • Williams K.
      • Solanki S.
      Remdesivir-associated pancreatitis.
      Am J Ther. 2022; 29: e444-e446
      , 
      • Miyazaki K.
      • Yoshimura Y.
      • Miyata N.
      • et al.
      Acute pancreatitis or severe increase in pancreatic enzyme levels following remdesivir administration in COVID-19 patients: an observational study.
      Sci Rep. 2022; 12: 5323
      , 
      • Kuraoka N.
      • Hashimoto S.
      • Matsui S.
      Remdesivir-induced pancreatitis in a patient with coronavirus disease 2019.
      Pancreas. 2022; 51: e88-e89
      Nevertheless, prednisolone is recommended for the treatment of specific preexisting conditions in patients with COVID-19, including cases of autoimmune AP.
      • Liaquat H.
      • Shupp B.
      • Kapoor S.
      • et al.
      High-dose prednisone for treatment of autoimmune pancreatitis in a patient with coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
      Am J Case Rep. 2020; 21: e926475

      Acute Pancreatitis and Coronavirus Disease 2019

      AP seems an infrequent complication of COVID-19 and large retrospective studies found no increased incidence of AP during the pandemic.
      • Inamdar S.
      • Benias P.C.
      • Liu Y.
      • et al.
      Prevalence, risk factors, and outcomes of hospitalized patients with coronavirus disease 2019 presenting as acute pancreatitis.
      Gastroenterology. 2020; 159: 2226-2228.e2
      , 
      • Ò Miró
      • Llorens P.
      • Jiménez S.
      • et al.
      Frequency of five unusual presentations in patients with COVID-19: results of the UMC-19-S(1).
      Epidemiol Infect. 2020; 148: e189
      , 
      • Ò Miró
      • Llorens P.
      • Jiménez S.
      • et al.
      A case-control emergency department-based analysis of acute pancreatitis in Covid-19: Results of the UMC-19-S(6).
      J Hepatobiliary Pancreat Sci. 2021; 28: 953-966
      In fact, some centers have reported a decreased number of admissions for AP, probably due to patient reluctance to present to the emergency department during the pandemic but also because of reluctance of emergency room physicians to admit patients with mild AP.

      Çolak E. and Çiftci A.B., Acute biliary pancreatitis management during the coronavirus disease 2019 pandemic, Healthcare (Basel), 10 (7), 2022, 1284.

      ,
      • Ramsey M.L.
      • Patel A.
      • Sobotka L.A.
      • et al.
      Hospital trends of acute pancreatitis during the coronavirus disease 2019 pandemic.
      Pancreas. 2022; 51: 422-426
      However, idiopathic AP was diagnosed in a greater proportion of patients with COVID-19, implicating SARS-CoV-2 in a causative role.
      • Inamdar S.
      • Benias P.C.
      • Liu Y.
      • et al.
      Prevalence, risk factors, and outcomes of hospitalized patients with coronavirus disease 2019 presenting as acute pancreatitis.
      Gastroenterology. 2020; 159: 2226-2228.e2
      ,
      • Ebib B.
      • Bacaksiz F.
      • Ekin N.
      Does COVID-19 cause pancreatitis?.
      Arq Gastroenterol. 2022; 59: 71-74
      The diagnosis of AP should rely on the Atlanta criteria, and isolated elevations of amylase and lipase should not be misdiagnosed as AP.
      • Pezzilli R.
      • Centanni S.
      • Mondoni M.
      • et al.
      Patients with coronavirus disease 2019 interstitial pneumonia exhibit pancreatic hyperenzymemia and not acute pancreatitis.
      Pancreas. 2021; 50: 732-735
      In fact, SARS-CoV-2 can directly cause increased amylase and/or lipase levels and can also cause several complications that can increase the levels of these enzymes, including renal failure, acidosis, and diabetes. Up to 23% of patients may exhibit increased amylase levels but only a minority has AP according to the Atlanta Criteria.
      • Bacaksız F.
      • Ebik B.
      • Ekin N.
      • et al.
      Pancreatic damage in COVID-19: Why? How?.
      Int J Clin Pract. 2021; 75: e14692
      , 
      • Troncone E.
      • Salvatori S.
      • Sena G.
      • et al.
      Low frequency of acute pancreatitis in hospitalized COVID-19 patients.
      Pancreas. 2021; 50: 393-398
      , 
      • Ding P.
      • Song B.
      • Liu X.
      • et al.
      Elevated pancreatic enzymes in ICU patients with COVID-19 in Wuhan, China: A retrospective study.
      Front Med (Lausanne). 2021; 8: 663646
      High lipasemia without AP can be detected in up to one-third of patients with COVID-19.
      • Rasch S.
      • Herner A.
      • Schmid R.M.
      • et al.
      High lipasemia is frequent in Covid-19 associated acute respiratory distress syndrome.
      Pancreatology. 2021; 21: 306-311
      , 
      • McNabb-Baltar J.
      • Jin D.X.
      • Grover A.S.
      • et al.
      Lipase elevation in patients with COVID-19.
      Am J Gastroenterol. 2020; 115: 1286-1288
      , 
      • Caruso S.
      • Aloisio E.
      • Dolci A.
      • et al.
      Lipase elevation in serum of COVID-19 patients: frequency, extent of increase and clinical value.
      Clin Chem Lab Med. 2022; 60: 135-142
      Many case reports and case series have been published linking COVID-19 to AP development. However, most reports have a paucity of clinical information and a lack of adherence to CARE guidelines on publishing. Moreover, the temporal gap between COVID-19 diagnosis and AP is very heterogeneous making it difficult to establish a causal link between these entities in some cases. Complete etiological workup according to current evidence, including MRI and endoscopic ultrasonography, was pursued in a minority of patients, rendering the attribution of SARS-CoV-2 as the causative agent of AP doubtful in some cases.
      • Juhász M.F.
      • Ocskay K.
      • Kiss S.
      • et al.
      Insufficient etiological workup of COVID-19-associated acute pancreatitis: A systematic review.
      World J Gastroenterol. 2020; 26: 6270-6278
      COVID-19 also causes immune dysregulation that may favor other infections, including cytomegalovirus (CMV), which in turn could cause AP.
      • Marchi G.
      • Vianello A.
      • Crisafulli E.
      • et al.
      Cytomegalovirus-induced gastrointestinal bleeding and pancreatitis complicating severe Covid-19 pneumonia: A paradigmatic Case.
      Mediterr J Hematol Infect Dis. 2020; 12: e2020060
      Multivariate regression analysis revealed that elevated amylase and lipase levels were significantly associated with the severity of COVID-19, ICU admission, and mortality in hospitalized patients with COVID-19.
      • Bacaksız F.
      • Ebik B.
      • Ekin N.
      • et al.
      Pancreatic damage in COVID-19: Why? How?.
      Int J Clin Pract. 2021; 75: e14692
      , 
      • Troncone E.
      • Salvatori S.
      • Sena G.
      • et al.
      Low frequency of acute pancreatitis in hospitalized COVID-19 patients.
      Pancreas. 2021; 50: 393-398
      , 
      • Ding P.
      • Song B.
      • Liu X.
      • et al.
      Elevated pancreatic enzymes in ICU patients with COVID-19 in Wuhan, China: A retrospective study.
      Front Med (Lausanne). 2021; 8: 663646
      ,
      • Mitrovic M.
      • Tadic B.
      • Jankovic A.
      • et al.
      Fatal gastrointestinal bleeding associated with acute pancreatitis as a complication of Covid-19: a case report.
      J Int Med Res. 2022; 50 (3000605221098179)
      ,
      • Goyal H.
      • Sachdeva S.
      • Perisetti A.
      • et al.
      Hyperlipasemia and potential pancreatic injury patterns in COVID-19: A marker of severity or innocent bystander?.
      Gastroenterology. 2021; 160: 946-948.e2
      Moreover, in patients without AP, elevations of pancreatic enzymes may be indicators of overall disease severity and poor prognostic indicators.
      • Benias P.C.
      • Inamdar S.
      • Wee D.
      • et al.
      Analysis of outcomes in COVID-19 patients with varying degrees of hyperlipasemia.
      Pancreas. 2021; 50: 1310-1313
      , 
      • Li G.
      • Liu T.
      • Jin G.
      • et al.
      Serum amylase elevation is associated with adverse clinical outcomes in patients with coronavirus disease 2019.
      Aging (Albany NY). 2021; 13: 23442-23458
      , 
      • Ramsey M.L.
      • Elmunzer B.J.
      • Krishna S.G.
      Serum lipase elevations in COVID-19 patients reflect critical illness and not acute pancreatitis.
      Clin Gastroenterol Hepatol. 2021; 19: 1982-1987
      , 
      • Kiyak M.
      • Düzenli T.
      Lipase elevation on admission predicts worse clinical outcomes in patients with COVID-19.
      Pancreatology. 2022; 22: 665-670
      , 
      • Singh R.R.
      • Chhabra P.
      • Kumta N.A.
      Does hyperlipasemia predict worse clinical outcomes in COVID-19? A multicenter retrospective cohort study.
      J Clin Gastroenterol. 2022; 56: e227-e231
      Lipase/lymphocyte ratio was also found to be a predictor of mortality in AP patients with COVID-19.
      • Haydar F.G.
      • Otal Y.
      • Avcioglu G.
      Evaluation of patients with acute pancreatitis associated with SARS-CoV-2 (COVID-19); The importance of lipase/lymphocyte ratio in predicting mortality.
      Bratisl Lek Listy. 2022; 123: 428-434
      Single-cell sequencing data have identified a subgroup of neutrophils with high expression of IFN and a proinflammatory phenotype in COVID-19, which may be involved in AP severity.
      • Zhang D.
      • Wang M.
      • Zhang Y.
      • et al.
      Novel insight on marker genes and pathogenic peripheral neutrophil subtypes in acute pancreatitis.
      Front Immunol. 2022; 13: 964622
      A low T-cell count has also been suggested as a surrogate for poor clinical outcomes.
      • Wang K.
      • Luo J.
      • Tan F.
      • et al.
      Acute pancreatitis as the initial manifestation in 2 cases of COVID-19 in Wuhan, China.
      Open Forum Infect Dis. 2020; 7: ofaa324
      Imaging findings suggestive of AP, including peripancreatic stranding and fluid collections, were more frequent in patients with COVID-19 and considering with elevations of pancreatic enzymes may aid in the diagnosis of AP, specifically in severe cases, when patients are frequently intubated.
      • Grusova G.
      • Bruha R.
      • Bircakova B.
      • et al.
      Pancreatic injury in patients with SARS-Cov-2 (COVID-19) infection: a retrospective analysis of CT findings.
      Gastroenterol Res Pract. 2021; 2021: 5390337
      However, computerized tomography of the abdomen is not strictly indicated in patients with elevated pancreatic enzymes levels because most frequently elevated amylase levels may be a nonspecific manifestation of shock/critical illness.
      • Stephens J.R.
      • Wong J.L.C.
      • Broomhead R.
      • et al.
      Raised serum amylase in patients with COVID-19 may not be associated with pancreatitis.
      Br J Surg. 2021; 108: e152-e153
      The temporal relation between AP and COVID-19 infection is very variable. AP may be more severe in patients with COVID-19 but not necessarily linked to the SARS-CoV-2 viral load, as suggested by the COVIDPAN study.
      • de-Madaria E.
      • Capurso G.
      COVID-19 and acute pancreatitis: examining the causality.
      Nat Rev Gastroenterol Hepatol. 2021; 18: 3-4
      Several studies found that patients with COVID-19 infection had significantly AP mortality

      Çolak E. and Çiftci A.B., Acute biliary pancreatitis management during the coronavirus disease 2019 pandemic, Healthcare (Basel), 10 (7), 2022, 1284.

      ,
      • Mutneja H.R.
      • Bhurwal A.
      • Arora S.
      • et al.
      Acute pancreatitis in patients with COVID-19 is more severe and lethal: a systematic review and meta-analysis.
      Scand J Gastroenterol. 2021; 56: 1467-1472
      , 
      • Annie F.H.
      • Chumbe J.
      • Searls L.
      • et al.
      Acute pancreatitis due to COVID-19 active infection.
      Cureus. 2021; 13: e20410
      , 
      • Pandanaboyana S.
      • Moir J.
      • Leeds J.S.
      • et al.
      SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study.
      Gut. 2021; 70: 1061-1069
      , 
      • Samanta J.
      • Mahapatra S.J.
      • Kumar N.
      • et al.
      Virus related acute pancreatitis and virus superinfection in the 'Dual disease' model of acute pancreatitis and SARS-Co-V2 infection: a multicentre prospective study.
      Pancreatology. 2022; 22: 339-347
      , 
      • Ahmed A.
      • Fisher J.C.
      • Pochapin M.B.
      • et al.
      Hyperlipasemia in absence of acute pancreatitis is associated with elevated D-dimer and adverse outcomes in COVID 19 disease.
      Pancreatology. 2021; 21: 698-703
      and significantly increased the risk of severe AP,
      • Mutneja H.R.
      • Bhurwal A.
      • Arora S.
      • et al.
      Acute pancreatitis in patients with COVID-19 is more severe and lethal: a systematic review and meta-analysis.
      Scand J Gastroenterol. 2021; 56: 1467-1472
      ,
      • Pandanaboyana S.
      • Moir J.
      • Leeds J.S.
      • et al.
      SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study.
      Gut. 2021; 70: 1061-1069
      ,
      • Karaali R.
      • Topal F.
      Evaluating the effect of SARS-Cov-2 infection on prognosis and mortality in patients with acute pancreatitis.
      Am J Emerg Med. 2021; 49: 378-384
      necrotizing AP,
      • Mutneja H.R.
      • Bhurwal A.
      • Arora S.
      • et al.
      Acute pancreatitis in patients with COVID-19 is more severe and lethal: a systematic review and meta-analysis.
      Scand J Gastroenterol. 2021; 56: 1467-1472
      ICU admission,

      Çolak E. and Çiftci A.B., Acute biliary pancreatitis management during the coronavirus disease 2019 pandemic, Healthcare (Basel), 10 (7), 2022, 1284.

      ,
      • Annie F.H.
      • Chumbe J.
      • Searls L.
      • et al.
      Acute pancreatitis due to COVID-19 active infection.
      Cureus. 2021; 13: e20410
      ,
      • Ahmed A.
      • Fisher J.C.
      • Pochapin M.B.
      • et al.
      Hyperlipasemia in absence of acute pancreatitis is associated with elevated D-dimer and adverse outcomes in COVID 19 disease.
      Pancreatology. 2021; 21: 698-703
      ,
      • Karaali R.
      • Topal F.
      Evaluating the effect of SARS-Cov-2 infection on prognosis and mortality in patients with acute pancreatitis.
      Am J Emerg Med. 2021; 49: 378-384
      need for mechanical ventilation
      • Inamdar S.
      • Benias P.C.
      • Liu Y.
      • et al.
      Prevalence, risk factors, and outcomes of hospitalized patients with coronavirus disease 2019 presenting as acute pancreatitis.
      Gastroenterology. 2020; 159: 2226-2228.e2
      and longer length of hospital stay,
      • Inamdar S.
      • Benias P.C.
      • Liu Y.
      • et al.
      Prevalence, risk factors, and outcomes of hospitalized patients with coronavirus disease 2019 presenting as acute pancreatitis.
      Gastroenterology. 2020; 159: 2226-2228.e2
      ,
      • Mutneja H.R.
      • Bhurwal A.
      • Arora S.
      • et al.
      Acute pancreatitis in patients with COVID-19 is more severe and lethal: a systematic review and meta-analysis.
      Scand J Gastroenterol. 2021; 56: 1467-1472
      , 
      • Annie F.H.
      • Chumbe J.
      • Searls L.
      • et al.
      Acute pancreatitis due to COVID-19 active infection.
      Cureus. 2021; 13: e20410
      , 
      • Pandanaboyana S.
      • Moir J.
      • Leeds J.S.
      • et al.
      SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study.
      Gut. 2021; 70: 1061-1069
      ,
      • Meric S.
      • Aktokmakyan T.V.
      • Tokocin M.
      • et al.
      COVID-19 and acute biliary pancreatitis: comparative analysis between the normal period and COVID-19 pandemic.
      Ann Ital Chir. 2021; 92: 728-731
      compared with COVID-negative patients. Thus, AP may have a poor prognosis in patients with COVID-19. However, patients with previous inflammatory insults to the pancreas were found at greater risk of severe COVID-19 infection and mortality.
      • Huang B.Z.
      • Sidell M.A.
      • Wu B.U.
      • et al.
      Pre-Existing pancreatitis and elevated risks of COVID-19 severity and mortality.
      Gastroenterology. 2022; 162: 1758-1760.e3

      Pancreatitis after coronavirus disease 2019 vaccination

      The benefits of COVID-19 vaccination are indisputable. Only 2 cases of AP were reported in almost 38,000 patients during a phase 2/3 clinical trial of COVID-19 mRNA vaccine.

      Document VB. Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document. In: Administration UFaD, editor. 2020. Available at: https://www.fda.gov/media/144246/download. Accessed December 10, 2020.

      However, physicians should be aware of emerging side-effects, including severe abdominal pain after vaccination, which could indicate AP. The exact mechanisms of vaccine-induced AP are unclear but may be related to molecular mimicry. To our knowledge, only 6 cases of AP attributed to COVID-19 vaccination have been published.
      • Parkash O.
      • Sharko A.
      • Farooqi A.
      • et al.
      Acute pancreatitis: A possible side effect of COVID-19 vaccine.
      Cureus. 2021; 13: e14741
      , 

      Cieślewicz A., Dudek M., Krela-Kaźmierczak I., et al., Pancreatic injury after COVID-19 vaccine-A case report, Vaccines (Basel), 9 (6), 2021, 576.

      , 
      • Ozaka S.
      • Kodera T.
      • Ariki S.
      • et al.
      Acute pancreatitis soon after COVID-19 vaccination: a case report.
      Medicine (Baltimore). 2022; 101: e28471
      , 
      • Cacdac R.
      • Jamali A.
      • Jamali R.
      • et al.
      Acute pancreatitis as an adverse effect of COVID-19 vaccination.
      SAGE Open Med Case Rep. 2022; 10 (2050313x221131169)
      , 
      • Patel A.H.
      • Amin R.
      • Lalos A.T.
      Acute liver injury and IgG4-related autoimmune pancreatitis following mRNA-based COVID-19 vaccination.
      Hepatol Forum. 2022; 3: 97-99
      , 
      • Walter T.
      • Connor S.
      • Stedman C.
      • et al.
      A case of acute necrotising pancreatitis following the second dose of Pfizer-BioNTech COVID-19 mRNA vaccine.
      Br J Clin Pharmacol. 2022; 88: 1385-1386

      Alcohol-Induced Acute Pancreatitis During Coronavirus Disease 2019 Outbreak

      COVID-19 lockdowns dramatically influenced the population’s social behavior. Several studies have shown an increase in alcohol consumption in the general population during COVID-19 lockdowns. An increase in hospital admissions for alcohol-induced AP has been observed in some hospitals during these periods, which have decreased after the restrictions were eased.
      • Mak W.K.
      • Di Mauro D.
      • Pearce E.
      • et al.
      Hospital admissions from alcohol-related acute pancreatitis during the COVID-19 pandemic: A single-centre study.
      World J Clin Cases. 2022; 10: 8837-8843
      ,
      • Itoshima H.
      • Shin J.H.
      • Takada D.
      • et al.
      The impact of the COVID-19 epidemic on hospital admissions for alcohol-related liver disease and pancreatitis in Japan.
      Sci Rep. 2021; 11: 14054
      However, this “shadow pandemic” of alcohol-related illnesses was not observed at all centers and all locations.
      • Ramsey M.L.
      • Patel A.
      • Sobotka L.A.
      • et al.
      Hospital trends of acute pancreatitis during the coronavirus disease 2019 pandemic.
      Pancreas. 2022; 51: 422-426

      Chronic Pancreatitis and Coronavirus Disease 2019

      There is a paucity of data about CP during the pandemic. Most cases have an attributable cause, thus making it difficult to link SARS-CoV-2 to either an aggravation of an existing CP or a new diagnosis of CP.
      Recommendations on CP surgery have been made. A large international survey on pancreatic surgery agreed that CP surgery should be postponed, unless the patient is experiencing lifethreatening complications.
      • Oba A.
      • Stoop T.F.
      • Löhr M.
      • et al.
      Global survey on pancreatic surgery during the COVID-19 pandemic.
      Ann Surg. 2020; 272: e87-e93

      Pancreas Cancer and Pancreatic Surgery During the Pandemic

      The pandemic has deeply affected the diagnostic, management, and referral pathways of pancreatic cancer worldwide, with significant geographic variability,
      • Kajiwara Saito M.
      • Morishima T.
      • Ma C.
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      Diagnosis and treatment of digestive cancers during COVID-19 in Japan: a cancer Registry-based Study on the Impact of COVID-19 on Cancer Care in Osaka (CanReCO).
      PLoS One. 2022; 17: e0274918
      including suspension of patient visits, imaging and endoscopic examinations, and delays and changes of elective cancer therapies and surgeries. These changes inevitably affect short-term and long-term patient care and prognosis and possibly decrease overall survival, although the specific influence on patients’ outcomes is still unknown.
      • Kuzuu K.
      • Misawa N.
      • Ashikari K.
      • et al.
      Gastrointestinal cancer stage at diagnosis before and during the COVID-19 pandemic in Japan.
      JAMA Netw Open. 2021; 4: e2126334
      , 
      • McKay S.C.
      • Pathak S.
      • Wilkin R.J.W.
      • et al.
      Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience.
      HPB (Oxford). 2021; 23: 1656-1665
      , 
      • Katona B.W.
      • Mahmud N.
      • Dbouk M.
      • et al.
      COVID-19 related pancreatic cancer surveillance disruptions amongst high-risk individuals.
      Pancreatology. 2021; 21: 1048-1051
      , 
      • Tejedor-Tejada J.
      • Gómez-Díez C.
      • Robles Gaitero S.
      • et al.
      Impact of the SARS-CoV-2 pandemic on pancreatic cancer: diagnosis and short-term survival.
      Rev Esp Enferm Dig. 2022; 114: 509-510
      , 
      • Peacock H.M.
      • Tambuyzer T.
      • Verdoodt F.
      • et al.
      Decline and incomplete recovery in cancer diagnoses during the COVID-19 pandemic in Belgium: a year-long, population-level analysis.
      ESMO Open. 2021; 6: 100197
      , 
      • Paluri R.
      • Laursen A.
      • Gaeta J.
      • et al.
      Impact of the COVID-19 pandemic on management of patients with metastatic pancreatic ductal adenocarcinoma in the United States.
      Oncologist. 2022; 27: e518-e523
      , 
      • Brugel M.
      • Letrillart L.
      • Evrard C.
      • et al.
      Impact of the COVID-19 pandemic on disease stage and treatment for patients with pancreatic adenocarcinoma: A French comprehensive multicentre ambispective observational cohort study (CAPANCOVID).
      Eur J Cancer. 2022; 166: 8-20
      , 

      Madge O., Brodey A., Bowen J., et al., The COVID-19 pandemic is associated with reduced survival after pancreatic ductal adenocarcinoma diagnosis: A single-centre retrospective analysis, J Clin Med, 11 (9), 2022, 2574.

      , 
      • Balakrishnan A.
      • Lesurtel M.
      • Siriwardena A.K.
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      Delivery of hepato-pancreato-biliary surgery during the COVID-19 pandemic: an European-African Hepato-Pancreato-Biliary Association (E-AHPBA) cross-sectional survey.
      HPB (Oxford). 2020; 22: 1128-1134
      In Italy, a reduction of 9.9% in new diagnosis of pancreatic cancer in 2020 compared with 2019 was reported.
      • Buscarini E.
      • Benedetti A.
      • Monica F.
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      Changes in digestive cancer diagnosis during the SARS-CoV-2 pandemic in Italy: A nationwide survey.
      Dig Liver Dis. 2021; 53: 682-688
      More patients presented with more advanced pancreatic cancers in 2020 compared with 2019,
      • Paluri R.
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      Oncologist. 2022; 27: e518-e523
      ,
      • Brugel M.
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      Impact of the COVID-19 pandemic on disease stage and treatment for patients with pancreatic adenocarcinoma: A French comprehensive multicentre ambispective observational cohort study (CAPANCOVID).
      Eur J Cancer. 2022; 166: 8-20
      and the pandemic caused considerable emotional and social distress among these patients, suggesting the need for a psychological support network.
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      ,

      Alexander A., Fung S., Eichler M., et al., Quality of life in patients with pancreatic cancer before and during the COVID-19 pandemic, Int J Environ Res Public Health, 19 (6), 2022, 3731.

      A third-level referral center in Italy recorded a 20% reduction in pancreatic resections during 2020 and a global survey from 267 centers in 37 countries reported a reduction in weekly pancreatic resections from 3 to 1.
      • Oba A.
      • Stoop T.F.
      • Löhr M.
      • et al.
      Global survey on pancreatic surgery during the COVID-19 pandemic.
      Ann Surg. 2020; 272: e87-e93
      ,
      • Marchegiani G.
      • Perri G.
      • Bianchi B.
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      Pancreatic surgery during COVID-19 pandemic: major activity disruption of a third-level referral center during 2020.
      Updates Surg. 2022; 74: 953-961
      Efforts should be made to reschedule pancreatic cancer surveillance programs and improve the staging and workup pathways to improve oncological outcomes.
      • Moslim M.A.
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      • Stöss C.
      • et al.
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      Dig Surg. 2021; 38: 158-165
      In a large multicenter prospective cohort study on pancreas and liver surgery outcomes during the pandemic, patients without SARS-CoV-2 infection had acceptable morbidity and mortality, highlighting the need to protect patients and continue to evaluate them for pancreatic cancer surgery.
      • McKay S.C.
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      Moreover, patients diagnosed with cancer require frequent hospital visits. They were found to have a 2-fold increase of COVID-19 infection, as compared with the general population.
      • Yu J.
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      Immunosuppression as a cancer treatment effect, elevated cytokine levels, altered expression of receptors for SARS-CoV-2, and a prothrombotic state in patients with various cancers may exacerbate the effects of COVID-19. SARS-CoV-2 infection was associated with a significant increase in perioperative morbidity and mortality.
      • McKay S.C.
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      HPB (Oxford). 2022; 24: 1668-1678
      The optimal timing for surgery for pancreatic cancer is controversial, and no published guidelines exist on the timing for surgery for patients undergoing primary resection. The National Comprehensive Cancer Network (NCCN) guidelines recommend surgery at 4 to 8 weeks after completing neoadjuvant therapy.
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      Based on the finding that no differences in mortality were found among stage I patients with pancreatic adenocarcinoma who received neoadjuvant and adjuvant therapy, the Society of Surgical Oncology recommended the administration of neoadjuvant therapy to all patients with resectable pancreatic cancer. Other recommendations included the extension of neoadjuvant therapy or radiation therapy.
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      The American College of Surgeons proposed an Elective Case Triage Guidelines for Surgical Care and categorized the growing severity of the COVID-19 pandemic in hospitals into 3 phases based on the availability of medical resources. Subsequently, a specific tier system for pancreatic surgery was proposed to guide pancreatic surgery for different pancreatic cancers according to patients’ comorbidities, tumor malignant potential, and COVID-19 phase.
      • Kato H.
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      The European Society for Medical Oncology also developed specific guidelines for pancreatic cancer, defining priority grades for outpatient visits, imaging examinations, image-guided surgical procedures, and medical therapies to ensure the continuity of the oncological treatments during the pandemic.
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      An international survey on pancreatic surgery during COVID-19 also reached consensus on 13 statements and moderate agreement on 5 statements to guide pancreatic surgery.
      • Oba A.
      • Stoop T.F.
      • Löhr M.
      • et al.
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      Ann Surg. 2020; 272: e87-e93
      National societies and expert centers developed consensus statements and analyzed the impact of COVID-19 on pancreas surgery to ensure optimal resource utilization and define treatment prioritization.
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      Adv Clin Exp Med. 2022; 31: 389-398
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      Practical recommendations for the management of patients with gastroenteropancreatic and thoracic (carcinoid) neuroendocrine neoplasms in the COVID-19 era.
      Eur J Cancer. 2021; 144: 200-214
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      • Marchegiani G.
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      Love (Pancreatic Surgery) in the time of cholera (COVID-19).
      Dig Surg. 2020; 37: 524-526
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      • Doyle J.P.
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      The cancer hub approach for upper gastrointestinal surgery during COVID-19 pandemic: Outcomes from a UK cancer centre.
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      • Pietrantonio F.
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      Systemic treatment of patients with gastrointestinal cancers during the COVID-19 outbreak: COVID-19-adapted Recommendations of the National Cancer Institute of Milan.
      Clin Colorectal Cancer. 2020; 19: 156-164
      Recommendations for the prophylaxis of venous thromboembolism (VTE) and for the treatment of established VTE for patients with cancer are similar, regardless of whether they have COVID-19. As such, patients with cancer and COVID-19 should be assessed for VTE risk similar to any other patient. Pharmacological prophylaxis should be given in the same dose and with the same anticoagulant but primary prophylaxis of VTE is not recommended in ambulatory patients with COVID-19 with cancer.
      • Farge D.
      • Frere C.
      • Connors J.M.
      • et al.
      2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19.
      Lancet Oncol. 2022; 23: e334-e347
      New technologies, including telemedicine, have a role in the management of pancreatic cancer during the COVID-19 pandemic, and may gain increasing relevance in the future.
      • Tripepi M.
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      Telemedicine and pancreatic cancer: a systematic review.
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      Summary

      SARS-CoV-2 infection and AP share several pathophysiologic similarities but there is still a paucity of evidence to establish COVID-19 as a cause of AP. Complete etiological workup and attention to patients’ comorbidities, chronic medications, and social habits, along with rigorous publishing guidelines, should guide future case reports.
      COVID-19 also caused major challenges to pancreas cancer diagnosis and management, interrupting established management pathways. Several international and national concensus should be implemented as soon as possible to resume cancer treatments, including surgery, and minimize the negative pandemic effect on patient outcomes.

      Clinics care points

      • •
        SARS-CoV-2 can cause pancreatic injury by several mechanisms, but it is yet to established as a cause of AP.
      • •
        Etiologic workup is of major importance in establishing AP cause, especially in CIOVID-19 positive patients.
      • •
        International and national guidelines and norms shloud be put in practice to minimize the effects of the pandemic in pancreatic cancer diagnosis and management.

      Disclosure

      The authors have nothing to disclose.

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      Publication history

      Published online: December 12, 2022

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      DOI: https://doi.org/10.1016/j.gtc.2022.12.002

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      © 2022 Elsevier Inc. All rights reserved.

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