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  • 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

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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
  1. Manu Nayar1,2,
  2. Chris Varghese3,
  3. Aditya Kanwar4,
  4. Ajith K Siriwardena5,
  5. Ali Raza Haque6,
  6. Altaf Awan7,
  7. Anita Balakrishnan8,
  8. Arab Rawashdeh9,
  9. Bogdan Ivanov10,
  10. Chetan Parmar11,
  11. Christopher M Halloran12,
  12. Clifford Caruana13,
  13. Cynthia-Michelle Borg14,
  14. Dhanny Gomez15,
  15. Dimitrios Damaskos16,
  16. Dimitrios Karavias17,
  17. Guy Finch18,
  18. Husam Ebied19,
  19. James K Pine20,
  20. James R A Skipworth21,
  21. James Milburn22,
  22. Javed Latif23,
  23. Jeyakumar Apollos24,
  24. Jihène El Kafsi25,
  25. John A Windsor26,
  26. Keith Roberts27,
  27. Kelvin Wang28,
  28. Krish Ravi29,
  29. Maria V Coats30,
  30. Marianne Hollyman31,
  31. Mary Phillips32,
  32. Michael Okocha33,
  33. Michael SJ Wilson34,
  34. Nadeem A Ameer35,
  35. Nagappan Kumar36,
  36. Nehal Shah37,
  37. Pierfrancesco Lapolla38,
  38. Connor Magee39,
  39. Bilal Al-Sarireh40,
  40. Raimundas Lunevicius41,
  41. Rami Benhmida11,
  42. Rishi Singhal42,
  43. Srinivasan Balachandra43,
  44. Semra Demirli Atıcı44,
  45. Shameen Jaunoo45,
  46. Simon Dwerryhouse46,
  47. Tamsin Boyce47,
  48. Vasileios Charalampakis48,
  49. Venkat Kanakala49,
  50. Zaigham Abbas50,
  51. Nilanjana Tewari51,
  52. Sanjay Pandanaboyana52,53
  53. COVIDPAN Collborative Group
    1. 1 HPB Unit, Freeman Hospital, Newcastle upon Tyne, UK
    2. 2 UK
    3. 3 Faculty of Medical and Health Sciences, Department of Surgery, The University of Auckland, Auckland, New Zealand
    4. 4 University Hospitals Plymouth NHS Trust, Plymouth, UK
    5. 5 Manchester Royal Infirmary, Manchester, UK
    6. 6 Frimley Park Hospital, Camberley, UK
    7. 7 Derby hospital, Derby, UK
    8. 8 Addenbrooke’s hospital, Cambridge, UK
    9. 9 Heartland hospital, Birmingham, Uk
    10. 10 Princess Alexandra Hospital, Harlow, Essex, UK
    11. 11 Whittington Hospital, London, UK
    12. 12 The Royal Liverpool Hospital, Liverpool, UK
    13. 13 Mater Dei Hospital, Malta
    14. 14 University Hospital Lewisham, Lewisham, UK
    15. 15 Nottingham City Hospital, Nottingham, UK
    16. 16 Royal Infirmary of Edinburgh, Edinburgh, UK
    17. 17 Southampton General hospital, Southampton, UK
    18. 18 Northampton General Hospital, Northampton, UK
    19. 19 St Thomas Hospital, London, UK
    20. 20 St James’s University Hospital, Leeds, UK
    21. 21 Bristol Royal Infirmary, Bristol, UK
    22. 22 Aberdeen Royal Infirmary, Aberdeen, UK
    23. 23 Derby Hospital, Derby, UK
    24. 24 Dumfries and Galloway Royal Infirmary, Dumfries, UK
    25. 25 Wexham Park Hospital, Camberley, UK
    26. 26 Auckland City Hospital, Auckland, New Zealand
    27. 27 Queen Elizabeth Hospital, Birmingham, UK
    28. 28 Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, UK
    29. 29 Chesterfield Royal Hospital NHS Trust, Chesterfield, UK
    30. 30 Glasgow Royal Infirmary, Glasgow, UK
    31. 31 Musgrove Park Hospital, Taunton, UK
    32. 32 Royal Surrey County Hospital, Surrey, UK
    33. 33 Southmead Hospital, North Bristol NHS Trust, UK
    34. 34 Forth Valley Royal Hospital, Larbert, UK
    35. 35 University Hospital of Coventry and Warwickshire, Coventry, UK
    36. 36 University Hospital of Wales, Cardiff, UK
    37. 37 Northern General Hospital, Sheffield, UK
    38. 38 Policlinico Umberto I, Sapienza University of Rome, Italy
    39. 39 Arrowe Park Hospital, Wirral, UK
    40. 40 Morriston Hospital, Swansea, UK
    41. 41 Aintree Hospital, Liverpool, UK
    42. 42 University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
    43. 43 Doncaster Royal Infirmary, Doncaster, UK
    44. 44 Department of General Surgery, University of Health Sciences Tepecik Training and Research Hospital, İzmir, Turkey
    45. 45 Brighton and Sussex University Hospitals NHS Trust, UK
    46. 46 Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK
    47. 47 The Royal Gwent Hospital, Newport, Wales, UK
    48. 48 South Warwickshire NHS Foundation Trust, Warwick, UK
    49. 49 James Cook University Hospital, Middlesborough, UK
    50. 50 Dr. Ziauddin University Hospital, Clifton Karachi, Pakistan
    51. 51 University Hospitals Coventry & Warwickshire, Coventry, UK
    52. 52 HPB and Transplant Unit, Freeman Hospital, Newcastle upon Tyne, UK
    53. 53 Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
    1. Correspondence to Sanjay Pandanaboyana, HPB and Transplant Unit, Freeman Hospital, Newcastle upon Tyne, UK; s.pandanaboyana{at}nhs.net

    https://doi.org/10.1136/gutjnl-2021-326218

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      We recently published in GUT the outcomes of acute pancreatitis (AP) and coexisting SARS-CoV-2 infection.1 A number of patients who were SARS-CoV-2 positive had AP of unknown aetiology (25%) speculating SARS-CoV-2 as a cause for AP similar to other viruses.2 However, most patients did not complete investigations to exclude other causes of AP. In addition, SARS-CoV-2 infection may cause aberrant glycometabolic control,3 however it is unknown if this increases the risk of long-term diabetes mellitus (DM). The follow-up data were collected 12 months from the date of recruitment for 1476 patients (118 patients who were SARS-CoV-2 positive and 1358 patients who were negative) to establish an aetiology for AP and development of DM. Among the 118 patients who were SARS-CoV-2 positive, 35 patients had idiopathic or unknown aetiology AP. Sixteen patients underwent either MRCP (n=13) or EUS (n=4) and the remaining patients underwent biochemical investigations to exclude other causes of AP. The final aetiology of AP was available for 83 (70.3%) patients and included gallstones (56, 47.4%), alcohol (19, 16.1%), post ERCP (2, 1.7%) and other (6, 5.1%). Overall, 23 patients had a change of aetiology, and in 35 (29.7%) patients AP was considered idiopathic. Patients who were SARS-CoV-2 positive were more likely to have idiopathic AP (34.7% vs 13.9%, p<0.001) with over five times increased risk after adjusting for age, smoking status, body mass index and ethnicity (OR: 5.34, p<0.001) (table 1 and online supplemental table S1).

      Supplemental material

      View this table:
      Table 1

      Comparison of baseline characteristics of all patients in the follow-up cohort by aetiology

      Thirteen (11.0%) patients in the SARS-CoV-2 positive group and 187 (13.8%) patients in the negative group were readmitted with AP (p=0.949). The aetiology and baseline characteristics are summarised in online supplemental table S2. The risk of readmission was higher in younger patients, and lower in those with gallstone and idiopathic aetiology (online supplemental table S3).

      Supplemental material

      Supplemental material

      Two patients developed DM and nine patients developed pancreatic exocrine insufficiency (PEI) in the SARS-CoV-2 positive group. SARS-CoV-2 did not increase the risk of DM (2.3% vs 2.5%, OR: 0.61, p=0.541) or PEI (OR: 1.11, p=0.828) (p>0.05; table 2).

      View this table:
      Table 2

      Impact of SARS-CoV-2 on mortality, PEI and DM

      Mortality after discharge was 12.7% in the SARS-CoV-2 positive group and 5.4% in the negative group (log-rank, p<0.0001; online supplemental figure S1). However, this was not statistically significant in a multivariable Cox-regression model (HR: 1.89, p=0.078).

      Supplemental material

      The higher number of patients with idiopathic AP in the present series raises speculation that SARS-Cov-2 may indeed cause AP. Recently autopsy evidence has identified SARS-CoV-2 virus in the pancreases of infected patients, with focal pancreatitis seen in autopsy specimens higher than that is diagnosed clinically.4 5 Laboratory evidence further suggests there is expression of ACE 2, TMPRSS and Neuropilin-1 receptors in exocrine and endocrine cells of pancreas which enables SARS-CoV-2 entry and replication, resulting in elevated cytokine levels causing ribosomal dysfunction and pancreatic injury.5–7 Recent series have further shown that AP during SARS-CoV-2 infection is frequent in intensive care unit8 with a third of critically ill patients developing AP.9

      Hyperglycaemia frequently noted SARS-CoV-2 infection is likely from viral replication in beta cells causing impaired glucose-stimulated insulin secretion,5 with glycaemic abnormalities detected for up to 2 months after recovery.3 In the present series, two patients in the positive group developed DM during follow-up and both had severe AP with necrosis which is likely the cause of DM rather than SARS-CoV-2-induced damage.

      We have shown that SARS-CoV-2 infection increases the risk of idiopathic AP, but not long-term diabetes. Further laboratory studies that can prove replication of SARS-CoV-2 virus in human pancreas cells with resultant cell injury are warranted to establish SARS-CoV-2 virus as an aetiology for AP. Epidemiological studies are needed that can show an increase in the incidence of AP during the current pandemic to further implicate SARS-CoV-2 infection as a cause for AP and will add indirect evidence. Similarly, larger cohort of patients with SARS-CoV-2 with temporal trends to support or refute the long-term risk of developing DM are warranted.

      Supplemental material

      Supplemental material

      Ethics statements

      Patient consent for publication

      References

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      Supplementary materials

      Footnotes

      • Twitter @drmanuknayar, @chrisvarghese98, @sanjay_HPB

      • Correction notice This article has been corrected since it published Online First. The collaborator group has been updated.

      • Collaborators COVIDPAN Collborative Group: Abeer Altaf (Department of Gastroenterology, Dr. Ziauddin University Hospital, Clifton Karachi, Pakistan); Alexandra Bell (Northern General Hospital, Sheffield, UK); Aleg Aliosin (Klaipeda University Hospital, Klaipeda, Lithuania.); Zahid Bahli (Altnagelvin Area Hospital, Londonderry, UK); Aman Ahmad (St. James University Hospital, Leeds, UK); Anantha Madhavan (James cook university hospital, Middlesbrough, UK); Andrea Mingoli (Policlinico Umberto I, Sapienza University of Rome, Italy); Angus White (The Royal Gwent Hospital, Newport, Wales); Arthur Cotton (Gloucestershire Hospitals NHS Foundation Trust, Gloucestershire, UK); Ashiv Patel (East surrey hospital, Surrey, UK); AyoBobola A Apampa (Royal Liverpool hospital, Liverpool, UK); Bakhat Yawar (Western Health and Social Care Trust, Altnagelvin, Northern Ireland, UK); Bamidele Famokunwa (Wexham Park Hospital, Slough, UK); Blazej Rybinski (University Hospitals Plymouth NHS Trust, Plymouth, UK); Bruno Cirillo (Policlinico Umberto I, Sapienza University of Rome, Italy); Bryony Ford (University Hospitals Plymouth NHS Trust, Plymouth, UK); Caitlin Jordan (Musgrove Park Hospital, Taunton, UK); Catrin Jones (Glasgow Royal Infirmary, Glasgow, UK); Chris Varghese (Auckland University, Auckland, New Zealand); Charalampos Konstantinou (Warwick Hospital, Warwick, UK); Charles Geoffrey, Dermot Stewart (Musgrove Park Hospital, Taunton, UK); Colin Wilson (Freeman hospital, Newcastle upon Tyne, UK); Daniel Marshall (St James’ University Hospital, Leeds, UK); David Bourne (Freeman hospital, Newcastle upon Tyne, UK); Danny Chandla (University Hospital Coventry and Warwickshire, Coventry, UK); Değercan Yeşilyurt (University of Health Sciences Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey); Dharmadev Trivedi (Southampton general hospital, Southampton, UK); Duncan Rutherford (Forth Valley Royal Hospital, Larbert, UK); Ebru Sezen Freed (Northampton General Hospital, Northampton, UK); Eleanor Massie (Forth Valley Royal Hospital, Larbert, UK); Elizabeth Ward (Royal Infirmary of Edinburgh, Edinburgh, UK); Ellen Murgitroyd (Royal Infirmary of Edinburgh, Edinburgh, UK); Emily Britton (Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK); Euan J Dickson (Glasgow Royal Infirmary, Glasgow, UK); Evripidis Tokidis (Chesterfield Royal Hospital NHS Trust, Chesterfield, UK); Faris Soliman (Morriston Hospital, Swansea, Wales, UK); Francesco Abbadessa (Freeman hospital, Newcastle UK); Gautam Singh (Frimley Park Hospital, Camberley, UK); Ghazaleh MOHAMMADI-ZANIANI (Freeman Hospital, Newcastle Upon Tyne, UK); Gordon Gregory (Nottingham city hospital, Nottingham, UK); George Ugwu (Doncaster Royal Infirmary, Doncaster, UK); George Brown (St James Hospital,Leeds, UK); Gioia Brachini (Policlinico Umberto I, Sapienza University of Rome, Italy); James Walmsley (Northampton General Hospital, Northampton, UK); Shabuddin Khan (Northampton General Hospital, Northampton, UK); Hadil Said (Wexham Park Hospital, Slough, UK); Heba Ali (Western Health and Social Care Trust, Altnagelvin. Northern Ireland); Harriet Whewell (The Royal Gwent Hospital, Newport,UK); Harry VM Spiers (Addenbrooke’s Hospital, Cambridge, UK); Henry D De’Ath (Frimley Park Hospital, Camberley, UK); Hu Ying Charmaine Chan (Southampton University Hospital, Southampton); Imran Bhatti (Royal Derby Hospital, Derby, UK); Islam Noaman (Royal Infirmary of Edinburgh, Edinburgh, UK); İsmail Sert (University of Health Sciences Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey); James A Gossage (Kings college hospital, London); Jack Martin (Addenbrooke’s hospital, Cambridge); James Blackwell (Nottingham city hospital, Nottingham, UK); James Williams (Bristol Royal Infirmary, Bristol, UK); Jasmine Grace Moore (Dumfries and Galloway Royal Infirmary, Dumfries, UK); Jenna Shepherd (Aberdeen Royal Infirmary, Aberdeen, UK); Jennifer Wheat (The University Hospital of Wales, Cardiff.); Jenny Cao (Addenbrooke’s Hospital, Cambridge); Jeremy Fenech (Mater Dei Hospital, Malta); John Leeds (Freeman Hospital, Newcastle Upon Tyne); Kofi Oppong (Freeman Hospital, Newcastle Upon Tyne); Anitha James (Wexham Park Hospital, Frimley, UK); Kai Hartshorn (University Hospital Coventry and Warwickshire, Coventry, UK); Kelsey Rowsell (Morriston Hospital, Swansea, UK); Ken Philip (Weston General Hospital, Bristol, UK); Khaled Abdelgalel (Warwick hospital, Warwick, UK); Kieran McGivern (Forth Valley Royal Hospital, Larbert, UK); Leo Richard Brown (Dumfries and Galloway Royal Infirmary, Dumfries, UK); Louise Howse (University Hospital Lewisham, Lewisham, UK); Louise M Finch (Manchester Royal Infirmary, Manchester, UK); Louise Silva (University Hospital of Wales, Cardiff, UK); Maitreyi Patel (Princess Alexandra Hospital, Harlow, UK); Mandeep Kaur (Royal Sussex County Hospital, Brighton, UK); Marcus Quinn (Southmead Hospital, Bristol, UK); Marwa Ahmed Jama (Northern General Hospital, Sheffield, UK); Rajiv Lahiri (Royal Surrey County Hospital, Essex, UK); James Hopkins (Southmead Hospital, Bristol, UK); Mohamed abousamra (Altnagelvin Area Hospital, Londonderry,UK); Mohamed Issa (Arrowe Park Hospital, Wirral, UK); Mohammed Hammoda (Morriston Hospital, Swansea,UK); Muhammad Ali Qadeer (Department of Gastroenterology, Dr. Ziauddin University Hospital, Clifton Karachi, Pakistan); Momin Eltayeb (St James Hospital, Leeds,UK); Muneeb Zafar (Dumfries and Galloway Royal Infirmary, Dumfries, UK); Mishal Shahid (Musgrove Park, Taunton, UK); Nanda Bandlamudi (Royal Derby Hospital, Derby, UK); Nnaemeka Chidumije (Heartlands hospital, Birmingham); Navneet Tiwari (Freeman Hospital, Newcastle Upon Tyne, UK); Obi Nwogwugwu (Bristol Royal Infirmary, Bristol, UK); Olivia Spence (Northern General hospital, Sheffield, UK); Paul Bassett (Stats consultancy LTD, UK); Paula Ghaneh (The Royal Liverpool Hospital, Liverpool, UK); Paula Strong (The University Hospital of Wales, Cardiff, UK); Peter Szatmary (The Royal Liverpool Hospital, Liverpool, UK); Riadh Salem (Wexham park, Frimley Health, UK); Rupaly Pande (Queen Elizabeth Hospital, Birmingham); Qazi R Muhammad (University Hospital Coventry and Warwickshire, Coventry, UK); Quentin M Nunes (Aintree Hospital, Liverpool, UK); Qurrat Al Ain Atif (Royal Sussex county hospital, Brighton, UK); Robert Sutton (The Royal Liverpool Hospital, Liverpool, UK); Robert Young (Arrowe Park Hospital, Wirral, UK); Roland Taylor (St James University Hospital, Leeds, UK); Sam Tingle (Freeman Hospital, Newcastle Upon Tyne, UK); Sarunas Dailidenas (Klaipeda University Hospital, Klaipeda, Lithuania); Sudin Daniel (Doncaster Royal Infirmary, Doncaster, UK); Sapna Gupta (Royal Gwent Hospital); Santhalingam Jegatheeswaran (Manchester Royal Infirmary, Manchester, UK); Sattam Halaseh (Weston General Hospital, Bristol, UK); Shehryar Noor (Aberdeen Royal Infirmary, Aberdeen, UK); Simon J McCluney (Whittington Hospital, London, UK); Sophie Allen (East surrey hospital, Surrey, UK); Stephanie Goh (Addenbrooke’s hospital, Cambridge, UK); Steven Brown (James cook university hospital, Middlesbrough, UK); Stuart Cowie (James cook university hospital, Middlesbrough, UK); Tayfun Kaya (University of Health Sciences Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey); Thomas Tolley (The Royal Gwent Hospital, Newport, Wales); Tamer Ghorab (Western Health and Social Care Trust; Altnagelvin. Northern Ireland. UK); Victoria Morrison-Jones (Southampton General hospital, Southampton, UK); John Moir (Freeman Hospital, Newcastle Upon Tyne).

      • Contributors MN and SP were responsible for manuscript preparation, study concept and critical review. CV helped in manuscript preparation and critical review. All COVIDPAN Collaborators recruited patients.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; internally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.