Pancreatic Stone Protein Measurement to Screen and Diagnose Sepsis in the Context of the Surviving Sepsis Campaign Recommendations.

Main Article Content

François Ventura Philippe Eggimann Thomas Daix Bruno François Jérôme Pugin

Abstract

Sepsis occurs yearly in 48.9 million people worldwide of whom 11 million will die. Sepsis is defined as a life-threatening dysregulated reaction of the body in response to a bacterial infection, leading to organ dysfunction. The Surviving Sepsis Campaign made numerous recommendations for sepsis diagnosis and treatment using an evidence-based medicine approach. Frequently, levels of evidence of these recommendations are poor and lack clear clinical guidance.  Interestingly, these guidelines strongly recommend, with a moderate quality of evidence, screening of nosocomial sepsis in acutely ill hospitalized high-risk patients. The definition of acutely ill and high-risk patients is not specified, nor it is indicated which tools should be used. The diagnosis of infection and the subsequent administration of antibiotics relies solely on rapid clinical assessment, as recommended by the Best Practice Statement. Again, the elements used for clinical assessment are poorly defined, encompassing patient history, clinical examination, and unspecified tests for both infectious and non-infectious causes of acute illness. In the real world and based on these recommendations, only 30 to 40% of empiric broad-spectrum antibiotic administrations are appropriate, contributing to the emergence of antimicrobial resistant bacteria, toxicity related to antibiotic administration, and costs. The aim of this review article is to show that the use of biomarkers, such as the Pancreatic Stone Protein, could be the specific tests and tools to help the clinician to diagnose and manage sepsis. Over 600 peer-reviewed publications have studied the physiology of Pancreatic Stone Protein and more than 50 evaluated its usefulness to screen for the development of nosocomial sepsis and diagnose sepsis.

Keywords: Sepsis, Septic shock, infection, bacterial infection, biomarker, pancreatic stone protein, organ failure, antibiotics, antimicrobial resistance

Article Details

How to Cite
VENTURA, François et al. Pancreatic Stone Protein Measurement to Screen and Diagnose Sepsis in the Context of the Surviving Sepsis Campaign Recommendations.. Medical Research Archives, [S.l.], v. 11, n. 12, jan. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4893>. Date accessed: 06 dec. 2024. doi: https://doi.org/10.18103/mra.v11i12.4893.
Section
Review Articles

References

1. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. 2016;315(8):801-810.
2. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet. 2020;395(10219):200-211.
3. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical care medicine. 2006;34(6):1589-1596.
4. Torio CM, Moore BJ. National inpatient hospital costs: the most expensive conditions by payer, 2013: statistical brief# 204. Healthcare cost and utilization project (HCUP) statistical briefs. 2006:2006-2016.
5. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Critical care medicine. 2021;49(11):e1063-e1143.
6. Ventura F. Diagnosis of Sepsis. Paper presented at: Presented at Area Critica2021; Bologna.
7. Klein Klouwenberg PM, Cremer OL, van Vught LA, et al. Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Critical care. 2015;19:1-8.
8. Murray CJ, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet. 2022;399(10325):629-655.
9. Sartelli M, Barie PS, Coccolini F, et al. Ten golden rules for optimal antibiotic use in hospital settings: the WARNING call to action. World Journal of Emergency Surgery. 2023;18(1):50.
10. Dyar O, Moran-Gilad J, Greub G, Pulcini C, Committee EE, Committee EE. Diagnostic stewardship: are we using the right term? Clinical Microbiology and Infection. 2019;25(3):272-273.
11. Swissnoso. Infections associées aux soins. Infections associées aux soins. https://swissnoso.ch/fr/de-quoi-sagit-il/infections-associees-aux-soins/. Accessed 23/11/2023.
12. Vincent J-L, Sakr Y, Singer M, et al. Prevalence and outcomes of infection among patients in intensive care units in 2017. Jama. 2020;323(15):1478-1487.
13. Dadgostar P. Antimicrobial resistance: implications and costs. Infection and drug resistance. 2019:3903-3910.
14. Markwart R, Saito H, Harder T, et al. Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis. Intensive care medicine. 2020;46:1536-1551.
15. Farinas-Alvarez C, Farinas M, Fernandez-Mazarrasa C, Llorca J, Casanova D, Delgado-Rodríguez M. Analysis of risk factors for nosocomial sepsis in surgical patients. Journal of British Surgery. 2000;87(8):1076-1081.
16. Appelgren P, Hellström I, Weitzberg E, Söderlund V, Bindslev L, Ransjö U. Risk factors for nosocomial intensive care infection: a long‐term prospective analysis. Acta anaesthesiologica scandinavica. 2001;45(6):710-719.
17. Pierrakos C, Velissaris D, Bisdorff M, Marshall JC, Vincent J-L. Biomarkers of sepsis: time for a reappraisal. Critical Care. 2020;24(1):1-15.
18. Marshall JC, Reinhart K. Biomarkers of sepsis. Critical care medicine. 2009;37(7):2290-2298.
19. Graf R. Pancreatic stone protein–sepsis and the riddles of the exocrine pancreas. Pancreatology. 2020;20(3):301-304.
20. De Caro A, Lohse J, Sarles H. Characterization of a protein isolated from pancreatic calculi of men suffering from chronic calcifying pancreatitis. Biochemical and biophysical research communications. 1979;87(4):1176-1182.
21. Multigner L, De Caro A, Lombardo D, Campese D, Sarles H. Pancreatic stone protein, a phosphoprotein which inhibits calcium carbonate precipitation from human pancreatic juice. Biochemical and biophysical research communications. 1983;110(1):69-74.
22. De Reggi M, Gharib B, Patard L, Stoven V. Lithostathine, the presumed pancreatic stone inhibitor, does not interact specifically with calcium carbonate crystals. Journal of Biological Chemistry. 1998;273(9):4967-4971.
23. Terazono K, Yamamoto H, Takasawa S, et al. A novel gene activated in regenerating islets. Journal of Biological Chemistry. 1988;263(5):2111-2114.
24. Watanabe T, Yonekura H, Terazono K, Yamamoto H, Okamoto H. Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues. The reg protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene. Journal of Biological Chemistry. 1990;265(13):7432-7439.
25. Jin CX, Hayakawa T, Ko SB, Ishiguro H, Kitagawa M. Pancreatic stone protein/regenerating protein family in pancreatic and gastrointestinal diseases. Internal Medicine. 2011;50(15):1507-1516.
26. Schiesser M, Bimmler D, Frick T, Graf R. Conformational changes of pancreatitis-associated protein (PAP) activated by trypsin lead to insoluble protein aggregates. Pancreas. 2001;22(2):186-192.
27. Iovanna J, Frigerio JM, Dusetti N, Ramare F, Raibaud P, Dagorn JC. Lithostathine, an inhibitor of CaCO3, crystal growth in pancreatic juice, induces bacterial aggregation. Pancreas. 1993;8(5):597-601.
28. Keel M, Härter L, Reding T, et al. Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Critical care medicine. 2009;37(5):1642-1648.
29. Pugin J, Daix T, Pagani J-L, et al. Serial measurement of pancreatic stone protein for the early detection of sepsis in intensive care unit patients: a prospective multicentric study. Critical care. 2021;25(1):1-9.
30. Prazak J, Irincheeva I, Llewelyn MJ, et al. Accuracy of pancreatic stone protein for the diagnosis of infection in hospitalized adults: a systematic review and individual patient level meta-analysis. Critical care. 2021;25(1):1-10.
31. Zuercher P, Moser A, Garcia de Guadiana-Romualdo L, et al. Discriminative performance of pancreatic stone protein in predicting ICU mortality and infection severity in adult patients with infection: a systematic review and individual patient level meta-analysis. Infection. 2023:1-11.
32. Eggimann P, Que Y-A, Rebeaud F. Measurement of pancreatic stone protein in the identification and management of sepsis. Biomarkers in medicine. 2019;13(02):135-145.
33. Fidalgo P, Nora D, Coelho L, Povoa P. Pancreatic stone protein: review of a new biomarker in sepsis. Journal of Clinical Medicine. 2022;11(4):1085.
34. Schneider JE, Dick K, Cooper JT, Chami N. Pancreatic stone protein point-of-care testing can reduce healthcare expenditure in sepsis. Health Economics Review. 2022;12(1):1-11.
35. Putallaz L, van den Bogaard P, Laub P, Rebeaud F. Nanofluidics drives point-of-care technology for on the spot protein marker analysis with rapid actionable results. J Nanomed Nanotechnol. 2019;10:536.
36. Xiang Z, Chen X, Zhou X, et al. Development and application of a novel aldehyde nanoparticle-based amplified luminescent proximity homogeneous assay for rapid quantitation of pancreatic stone protein. Clinica Chimica Acta. 2022;535:120-130.
37. Ventura F, Gasche Y, Rached AKB, et al. Pancreatic stone protein as a biomarker for the early diagnosis of post-operative peritonitis, intra-abdominal infection and sepsis. Journal of Surgical Case Reports. 2022;2022(11):rjac497.
38. Van Singer M, Brahier T, Brochu Vez M-J, Gerhard Donnet H, Hugli O, Boillat-Blanco N. Pancreatic stone protein for early mortality prediction in COVID-19 patients. Critical Care. 2021;25:1-4.
39. Lagadinou M, Paraskevas T, Velissaris D, et al. The role of pancreatic stone protein as a prognostic factor for COVID-19 patients. Eur Rev Med Pharmacol Sci. 2022;26(17):6391-6395.
40. Melegari G, Giuliani E, Di Pietro G, et al. Point-of-care pancreatic stone protein measurement in critically ill COVID-19 patients. BMC anesthesiology. 2023;23(1):226.
41. Eggimann P, Que Y-A, Ventura F. Repetitive Assessment of Biomarker Combinations as a New Paradigm to Detect Sepsis Early. In: Annual Update in Intensive Care and Emergency Medicine 2023. Springer; 2023:83-92.
42. Ventura F, Vora S. ICU Management & Practice: Focus on Antimicrobial Resistance and Sepsis. ICU Management & Practice. 2022;22(4):163-164.
43. Ventura F. Sepsis Diagnosis: Pancreatic Stone Protein in Adults, Children, and Neonates. ICU Management & Practice. 2023;23(1):12-13.
44. Cui C, Fu M, Gao B. Procalcitonin and pancreatic stone protein function as biomarkers in early diagnosis of pediatric acute osteomyelitis. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2017;23:5211.
45. Jiří Ž, Kýr M, Vavřina M, Fedora M. Pancreatic stone protein–a possible biomarker of multiorgan failure and mortality in children sepsis. Cytokine. 2014;66(2):106-111.
46. Wu Q, Nie J, Wu F-x, Zou X-l, Chen F-y. Prognostic value of high-sensitivity C-reactive protein, procalcitonin and pancreatic stone protein in pediatric sepsis. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2017;23:1533.
47. Peng H-Y, Zhu Y-M, Zhang X-P, Kang X-Y. Value of pancreatic stone protein/regenerating protein in severity evaluation and prognosis prediction for children with sepsis. Zhongguo Dang dai er ke za zhi= Chinese Journal of Contemporary Pediatrics. 2015;17(11):1183-1188.
48. Saleh NY, Aboelghar HM, Garib MI, Rizk MS, Mahmoud AA. Pediatric sepsis diagnostic and prognostic biomarkers: pancreatic stone protein, copeptin, and apolipoprotein AV. Pediatric Research. 2023:1-8.
49. Bottari G, Caruso M, Paionni E, et al. Accuracy of Pancreatic Stone Protein for diagnosis of sepsis in children admitted to pediatric intensive care or high-dependency care: a pilot study. Italian Journal of Pediatrics. 2023;49(1):134.
50. Huo J-M, Huo R, Hu L, Lu S-W, Zu J. Value of procalcitonin, high sensitivity C-reactive protein and pancreatic stone protein in predicting prognosis of children with sepsis. Sichuan da xue xue bao Yi xue ban= Journal of Sichuan University Medical Science Edition. 2017;48(3):422-426.
51. Antari V, Skoura L, Hatzipantelis E, et al. Kinetics and role of pancreatic stone protein and midregional proadrenomedullin as predictors of sepsis and bacteremia in children with hematological malignancies. Mediterranean Journal of Hematology and Infectious Diseases. 2023;15(1).
52. Schlapbach LJ, Graf R, Woerner A, et al. Pancreatic stone protein as a novel marker for neonatal sepsis. Intensive care medicine. 2013;39:754-763.
53. Rass AA, Talat MA, Arafa MA, et al. The role of pancreatic stone protein in diagnosis of early onset neonatal sepsis. BioMed Research International. 2016;2016.
54. Wu R, Zha L, Hu JH, Wu JM, Tian ZF. The value of pancreatic stone protein in the prediction of infected neonates. Minerva Pediatr. 2017;69(6):489-494.
55. Palmiere C, Augsburger M. Pancreatic stone protein as a postmortem biochemical marker for the diagnosis of sepsis. Legal Medicine. 2015;17(1):9-13.
56. Brun R, Vonzun L, Cliffe B, et al. The Role of Pancreatic Stone Protein (PSP) as a Biomarker of Pregnancy-Related Diseases. Journal of clinical medicine. 2023;12(13):4428.
57. Li L, Jia D, Graf R, Yang J. Elevated serum level of pancreatic stone protein/regenerating protein (PSP/reg) is observed in diabetic kidney disease. Oncotarget. 2017;8(24):38145.
58. Tschuor C, Raptis DA, Limani P, et al. The value of pancreatic stone protein in predicting acute appendicitis in patients presenting at the emergency department with abdominal pain. BMC gastroenterology. 2012;12(1):1-5.
59. Fisher OM, Oberkofler CE, Raptis DA, et al. Pancreatic stone protein (PSP) and pancreatitis-associated protein (PAP): a protocol of a cohort study on the diagnostic efficacy and prognostic value of PSP and PAP as postoperative markers of septic complications in patients undergoing abdominal surgery (PSP study). BMJ open. 2014;4(3):e004914.
60. Gouel-Chéron A, Dupin M, Chanteperdix M, et al. Concomitant assessment of PSP and NT-proCNP as predictive markers of sepsis in severe trauma patients under mechanical ventilation. Critical Care. 2013;17:1-2.
61. De Waele JJ. Pancreatic stone protein for predicting outcome in peritonitis: limitations and challenges. Critical care medicine. 2013;41(4):1150-1151.
62. Lajaunias F. PSP and NT-proCNP assessed for predisposition to infection. Critical Care. 2013;17(5):450.
63. Lopes D, Chumbinho B, Bandovas JP, et al. Pancreatic stone protein as a biomarker of sepsis. Critical Care. 2022;26(1):100.
64. Busani S, Girardis M. PSP/reg: a new stone in sepsis biomarkers? Critical care. 2012;16(4):1-2.
65. Honore PM, Redant S, Djimafo P, et al. PSP is a promising biomarker of sepsis; however, potential elimination by RRT must be considered. Critical Care. 2022;26(1):342.
66. Correction to: Pancreatic stone protein as a biomarker for the early diagnosis of post-operative peritonitis, intra-abdominal infection and sepsis. J Surg Case Rep. 2022;2022(12):rjac633.
67. García de Guadiana‐Romualdo L, Berger M, Jiménez‐Santos E, et al. Pancreatic stone protein and soluble CD25 for infection and sepsis in an emergency department. European Journal of Clinical Investigation. 2017;47(4):297-304.
68. García de Guadiana-Romualdo L, Jiménez-Santos E, Cerezuela-Fuentes P, et al. Analyzing the capability of PSP, PCT and sCD25 to support the diagnosis of infection in cancer patients with febrile neutropenia. Clinical Chemistry and Laboratory Medicine (CCLM). 2019;57(4):540-548.
69. Klein HJ, Csordas A, Falk V, et al. Pancreatic stone protein predicts postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique. PloS one. 2015;10(3):e0120276.
70. Scherr A, Graf R, Bain M, et al. Pancreatic stone protein predicts positive sputum bacteriology in exacerbations of COPD. Chest. 2013;143(2):379-387.
71. Llewelyn MJ, Berger M, Gregory M, et al. Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care. Critical care. 2013;17:1-11.
72. Gukasjan R, Raptis DA, Schulz H-U, Halangk W, Graf R. Pancreatic stone protein predicts outcome in patients with peritonitis in the ICU. Critical care medicine. 2013;41(4):1027-1036.
73. Loots FJ, Smits M, Jenniskens K, et al. Added Diagnostic Value of Biomarkers in Patients with Suspected Sepsis: A Prospective Cohort Study in Out-Of-Hours Primary Care. The journal of applied laboratory medicine. 2022;7(5):1088-1097.
74. de Hond TA, Oosterheert JJ, van Hemert-Glaubitz SJ, Musson RE, Kaasjager KA. Pancreatic Stone Protein as a Biomarker for Sepsis at the Emergency Department of a Large Tertiary Hospital. Pathogens. 2022;11(5):559.
75. Michailides C, Lagadinou M, Paraskevas T, et al. The Role of the Pancreatic Stone Protein in Predicting Intra-Abdominal Infection-Related Complications: A Prospective Observational Single-Center Cohort Study. Microorganisms. 2023;11(10):2579.
76. Benninga R, Haquette C, Cateau C. Nanofluidic Technology Enables Rapid Quantification of Pancreatic Stone Protein as an Early Biomarker of Sepsis Method Comparison of the abioSCOPE® In-Vitro Diagnostic Device. Paper presented at: 28th AACC International CPOCT Symposium: Meeting Evolving Patient Needs Using Point-of-Care Testing 2022; Montreal.
77. Klein HJ, Niggemann P, Buehler PK, et al. Pancreatic stone protein predicts sepsis in severely burned patients irrespective of trauma severity: a monocentric observational study. Annals of Surgery. 2021;274(6):e1179-e1186.
78. Niggemann P, Rittirsch D, Buehler PK, et al. Incidence and time point of sepsis detection as related to different sepsis definitions in severely burned patients and their accompanying time course of pro-inflammatory biomarkers. Journal of Personalized Medicine. 2021;11(8):701.
79. Abionic. Evaluation of Immunoassay Measurements of Pancreatic Stone Protein Performed on abioSCOPE® Device With the PSP Assay on ICU Patients at Risk of Sepsis as an Aid in Identifying Sepsis. ClinicalTrials.gov NCT04105699 Web site. https://clinicaltrials.gov/ct2/show/NCT04105699. Accessed 23/11/2023.
80. Que Y-A, Guessous I, Dupuis-Lozeron E, et al. Prognostication of mortality in critically 111 patients with severe infections. Chest. 2015;148(3):674-682.
81. Garcia de Guadiana-Romualdo L, Albaladejo-Otón MD, Berger M, et al. Prognostic performance of pancreatic stone protein in critically ill patients with sepsis. Biomarkers in Medicine. 2019;13(17):1469-1480.
82. Que Y-A, Delodder F, Guessous I, et al. Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management. Critical care. 2012;16:1-9.
83. Hu P, Deng W, Li Q, et al. The critical role of pancreatic stone protein/regenerating protein in sepsis-related multiorgan failure. Frontiers in Medicine. 2023;10:1172529.
84. Boeck L, Graf R, Eggimann P, et al. Pancreatic stone protein: a marker of organ failure and outcome in ventilator-associated pneumonia. Chest. 2011;140(4):925-932.
85. Hayakawa T, Kondo T, Shibata T, et al. Serum pancreatic stone protein in pancreatic diseases. International journal of pancreatology. 1993;13:97-103.
86. Reding T, Palmiere C, Pazhepurackel C, et al. The pancreas responds to remote damage and systemic stress by secretion of the pancreatic secretory proteins PSP/regI and PAP/regIII. Oncotarget. 2017;8(18):30162.
87. Satomura Y, Sawabu N, Mouri I, et al. Measurement of serum PSP/reg-protein concentration in various diseases with a newly developed enzyme-linked immunosorbent assay. Journal of gastroenterology. 1995;30:643-650.
88. Tatemichi N, Takahashi C, Hayakawa S, et al. Enzyme immunoassay and characterization of pancreatic stone proteins in human urine. Journal of clinical laboratory analysis. 1993;7(6):365-370.
89. Rojas CR, de Guadiana-Romualdo LG, Sánchez SM, et al. Role of Pancreatic Stone Protein as an Early Biomarker for Risk Stratification of Acute Pancreatitis. Digestive Diseases and Sciences. 2022;67(7):3275-3283.
90. Costantini E, Carlin M, Porta M, Brizzi MF. Type 2 diabetes mellitus and sepsis: state of the art, certainties and missing evidence. Acta Diabetologica. 2021;58(9):1139-1151.
91. Rivas AM, Nugent K. Hyperglycemia, insulin, and insulin resistance in sepsis. The American Journal of the Medical Sciences. 2021;361(3):297-302.
92. Stone S, Abreu D, Mahadevan J, et al. Pancreatic stone protein/regenerating protein is a potential biomarker for endoplasmic reticulum stress in beta cells. Scientific reports. 2019;9(1):5199.
93. Gulhar R, Ashraf MA, Jialal I. Physiology, Acute Phase Reactants. In: StatPearls. StatPearls Publishing; 2023.
94. Klein HJ, Buehler PK, Niggemann P, et al. Expression of pancreatic stone protein is unaffected by trauma and subsequent surgery in burn patients. World Journal of Surgery. 2020;44:3000-3009.
95. Klein H, Rittirsch D, Bühler P, et al. Response of routine inflammatory biomarkers and novel Pancreatic Stone Protein to inhalation injury and its interference with sepsis detection in severely burned patients. Burns. 2020;47.
96. Paudel R, Dogra P, Montgomery-Yates AA, Yataco AC. Procalcitonin: A promising tool or just another overhyped test? International Journal of Medical Sciences. 2020;17(3):332.
97. Du Clos TW. Function of C-reactive protein. Annals of medicine. 2000;32(4):274-278.
98. Ventura F, Greub G, Jacob S, Liles C. Sepsis biomarkers to screen, diagnose, monitor, and stratify risk. In. Diagnostics 2023.
99. Ventura F, Tissieres P, Pugin J. Sepsis Diagnosis: Clinical Signs, Scores, and Biomarkers. A checklist of criteria to assess the usefulness of a biomarker to be integrated into sepsis guidelines. ICU Management & Practice. 2023;23(11):10-11.
100. Saeed K, Wilson DC, Bloos F, et al. The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study. Critical Care. 2019;23:1-15.
101. Elke G, Bloos F, Wilson DC, et al. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis-a secondary analysis of a large randomised controlled trial. Critical Care. 2018;22:1-12.
102. Schlapbach LJ, Giannoni E, Wellmann S, Stocker M, Ammann RA, Graf R. Normal values for pancreatic stone protein in different age groups. BMC anesthesiology. 2015;15:1-6.
103. Vonzun L, Brun R, Gadient-Limani N, et al. Serum Pancreatic Stone Protein Reference Values in Healthy Pregnant Women: A Prospective Cohort Study. Journal of Clinical Medicine. 2023;12(9):3200.