Sepsis is a life-threatening condition due to untreated or severe infections, leading to an uncontrollable inflammatory response throughout the body and eventually organ failure. Sepsis often occurs in patients with an impaired immune system, including post-operative cases and in the presence of pre-existing diseases. Early detection of infection and development of sepsis is important to initiate adequate life-supporting therapy. Unfortunately, early markers of sepsis are not available or not reliable. Thus, there is an ongoing need for better diagnostic tests.
In animal experiments, we observed that pancreatic stone protein (PSP), a protein produced by the pancreas during pancreatitis, is also markedly increased in the serum during inflammatory events affecting other organs. Therefore, we hypothesize that serum levels of PSP act as a biomarker for infection and sepsis. To test this hypothesis, we developed an assay able to accurately measure PSP levels in human serum and quantified PSP values in a study of accident patients that required emergency treatment. In this study, we showed that patients developing sepsis had highly increased PSP values, even before the clinical diagnosis of the disease. We concluded that PSP is a useful diagnostic test with a better diagnostic efficacy than currently established serum markers such as C-reactive protein (CRP), Interleukin 6 (IL-6) and procalcitonin (PCT). To further confirm the validity of this marker, we planned and initiated several clinical trials under different clinical situations.
The prevalence of a disease in the population has an important influence on the positive predictive value of a diagnostic test. Thus, we aim to compare the accuracy of the PSP test with the current serum markers in two stages of trials that include cohorts with high (stage 1) and low (stage 2) incidence of sepsis. In addition, we plan a prospective randomized trial that uses PSP values as a basis for a clinical decision (stage 3).
With these clinical studies we will be able to validate PSP as a marker of infection and sepsis. We perceive a number of potential clinical applications: earlier and patient tailored administration of antibiotics, interventions during intensive care including ventilation and hemofiltration, and the indication for operation or re-operation. In conjunction with currently established serum markers, clinical decisions based on PSP may lead to a reduction of morbidity, mortality and costs.
What is special about the project?
This project evaluates a new biomarker which has not been recognized by physicians and surgeons dealing with infection and sepsis. Validation under various clinical situations will provide recommendations for its use in clinical practice. The assay should reach commercial applicability in a few years. Establishing an alternative biomarker available for clinical diagnosis and therapy monitoring will increase the chances for better care of severely ill patients.
We have concluded and published clinical evaluation of PSP under different conditions, particularly in the setting of postoperative intensive care. Studies still under way are focusing on postoperative outcome after abdominal surgery, evaluation of PSP as a diagnostic tool for appendectomy, the evaluation of PSP in septic complications during pregnancy and in patients with severe burns.
Several of our studies evaluated the potential of PSP in combination with other serum markers (e.g. PCT) to increase the diagnostic power. This would be an interesting approach in a ‘point-of-care’ situation in the intensive care unit, where results should be quickly available for decision making.
Proper timing for the application of antibiotics is an important issue in several diseases, e.g. severe burns. Here, PSP might be a good diagnostic tool to help initiate antibiotic therapy.
Keel M, Harter L, Reding T, Sun LK, Hersberger M, Seifert B, et al. Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Crit Care Med 2009;37:1642-8;
Boeck L, Graf R, Eggimann P, Pargger H, Raptis DA, Smyrnios N, et al. Pancreatic stone protein: a marker of organ failure and outcome in ventilator-associated pneumonia. Chest 2011;140:925-32;
Bacon S, Kyithar MP, Schmid J, Rizvi SR, Bonner C, Graf R, et al. Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward. BMC Endocr Disord 2012;12:13;
Que YA, Delodder F, Guessous I, Graf R, Bain M, Calandra T, et al. Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management. Crit Care 2012;16:R114;
Tschuor C, Raptis DA, Limani P, Bachler T, Oberkofler CE, Breitenstein S, et al. The value of pancreatic stone protein in predicting acute appendicitis in patients presenting at the emergency department with abdominal pain. BMC Gastroenterol 2012;12:154;
Gukasjan R, Raptis DA, Schulz HU, Halangk W, Graf R. Pancreatic Stone Protein Predicts Outcome in Patients With Peritonitis in the ICU*. Crit Care Med 2013;41:1027-36;
Llewelyn MJ, Berger M, Gregory M, Ramaiah R, Taylor AL, Curdt I, et al. Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care. Crit Care 2013;17:R60;
Scherr A, Graf R, Bain M, Christ-Crain M, Muller B, Tamm M, et al. Pancreatic stone protein predicts positive sputum bacteriology in exacerbations of COPD. Chest 2013;143:379-87;
Schlapbach LJ, Graf R, Woerner A, Fontana M, Zimmermann-Baer U, Glauser D, et al. Pancreatic stone protein as a novel marker for neonatal sepsis. Intensive Care Med 2013;39:754-63;
Fisher OM, Oberkofler CE, Raptis DA, Soll C, Bechir M, Schiesser M, 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:e004914;
Klein HJ, Csordas A, Falk V, Slankamenac K, Rudiger A, Schonrath F, et al. Pancreatic stone protein predicts postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique. PloS one 2015;10:e0120276;
Que YA, Guessous I, Dupuis Lozeron E, Alves de Oliveira CR, Ferreira Oliveira C, Graf R, et al. Prognostication of mortality in critically ill patients with severe infections. Chest 2015;
Schlapbach LJ, Giannoni E, Wellmann S, Stocker M, Ammann RA, and Graf R. Normal values for pancreatic stone protein in different age groups. BMC Anesthesiol 15: 168, 2015.
Persons involved in the project
Prof. Dr. Rolf Graf, project leader rolf.
Dr. Sabrina Sonda, University Hospital Zurich sabrina.
Dr. Dimitri Raptis, University Hospital Zurich dimitri.
Theresia Reding Graf MSc (University Hospital Zurich)
Dr. Perparim Limani (University Hospital Zurich)
Anja Zabel (Technician)
Last update to this project presentation 17.10.2018