Intensive Care Medicine

, Volume 39, Issue 4, pp 754–763 | Cite as

Pancreatic stone protein as a novel marker for neonatal sepsis

  • Luregn J. Schlapbach
  • Rolf Graf
  • Andreas Woerner
  • Matteo Fontana
  • Urs Zimmermann-Baer
  • David Glauser
  • Eric Giannoni
  • Thierry Roger
  • Christoph Müller
  • Mathias Nelle
  • Martin Stocker
Pediatric Original



Early-onset sepsis (EOS) is one of the main causes for the admission of newborns to the neonatal intensive care unit. However, traditional infection markers are poor diagnostic markers of EOS. Pancreatic stone protein (PSP) is a promising sepsis marker in adults. The aim of this study was to investigate whether determining PSP improves the diagnosis of EOS in comparison with other infection markers.


This was a prospective multicentre study involving 137 infants with a gestational age of >34 weeks who were admitted with suspected EOS. PSP, procalcitonin (PCT), soluble human triggering receptor expressed on myeloid cells-1 (sTREM-1), macrophage migration inhibitory factor (MIF) and C-reactive protein (CRP) were measured at admission. Receiver-operating characteristic (ROC) curve analysis was performed.


The level of PSP in infected infants was significantly higher than that in uninfected ones (median 11.3 vs. 7.5 ng/ml, respectively; p = 0.001). The ROC area under the curve was 0.69 [95 % confidence interval (CI) 0.59–0.80; p < 0.001] for PSP, 0.77 (95 % CI 0.66–0.87; p < 0.001) for PCT, 0.66 (95 % CI 0.55–0.77; p = 0.006) for CRP, 0.62 (0.51–0.73; p = 0.055) for sTREM-1 and 0.54 (0.41–0.67; p = 0.54) for MIF. PSP independently of PCT predicted EOS (p < 0.001), and the use of both markers concomitantly significantly increased the ability to diagnose EOS. A bioscore combining PSP (>9 ng/ml) and PCT (>2 ng/ml) was the best predictor of EOS (0.83; 95 % CI 0.74–0.93; p < 0.001) and resulted in a negative predictive value of 100 % and a positive predictive value of 71 %.


In this prospective study, the diagnostic performance of PSP and PCT was superior to that of traditional markers and a combination bioscore improved the diagnosis of sepsis. Our findings suggest that PSP is a valuable biomarker in combination with PCT in EOS.


C-reactive protein Infant Macrophage migration inhibitory factor Pancreatic stone protein Procalcitonin Sepsis sTREM-1 



Area under the curve


C-reactive protein


Early-onset sepsis


Immature by total ratio


Macrophage migration inhibiting factor




Pancreatic stone protein


Receiver-operating characteristic


Soluble human triggering receptor expressed on myeloid cells-1


White blood cell count



The authors thank Claudia Schad (Division of Neonatology, University of Bern, Switzerland) for help in data acquisition; Martha Bain (University Hospital Zurich, Switzerland) for excellent technical support with PSP measurements; Silvia Rihs and Leslie Saurer (Department of Pathology, University of Bern, Switzerland) for help in performing sTREM-1 ELISA; Fred C. G. J. Sweep (Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands) for kindly providing antibodies used in the MIF ELISA; Marlies Knaup Reymond (Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland) for performing the MIF ELISA. This study was funded by a grant from the Vinetum Foundation, Biel, Switzerland (LJS) and supported by grants from the Swiss National Science Foundation (TR, Grant 310030_138488) and the Amelie Waring Foundation, Zurich, Switzerland (RG).


  1. 1.
    Phares CR, Lynfield R, Farley MM, Mohle-Boetani J, Harrison LH, Petit S, Craig AS, Schaffner W, Zansky SM, Gershman K, Stefonek KR, Albanese BA, Zell ER, Schuchat A, Schrag SJ (2008) Epidemiology of invasive group B streptococcal disease in the United States, 1999–2005. JAMA 299:2056–2065CrossRefPubMedGoogle Scholar
  2. 2.
    Stafford IA, Stewart RD, Sheffield JS, Wendel GD Jr, Sanchez PJ, McIntire DD, Roberts SW (2012) Efficacy of maternal and neonatal chemoprophylaxis for early-onset group B streptococcal disease. Obstet Gynecol 120:123–129CrossRefPubMedGoogle Scholar
  3. 3.
    Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP, Bizzarro MJ, Goldberg RN, Frantz ID 3rd, Hale EC, Shankaran S, Kennedy K, Carlo WA, Watterberg KL, Bell EF, Walsh MC, Schibler K, Laptook AR, Shane AL, Schrag SJ, Das A, Higgins RD (2011) Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics 127:817–826CrossRefPubMedGoogle Scholar
  4. 4.
    Al-Taiar A, Hammoud MS, Cuiqing L, Lee JK, Lui KM, Nakwan N, Isaacs D (2012) Neonatal infections in China, Malaysia, Hong Kong and Thailand. Arch Dis Child Fetal Neonatal Ed [Epub ahead of print]Google Scholar
  5. 5.
    Kuhn P, Dheu C, Bolender C, Chognot D, Keller L, Demil H, Donato L, Langer B, Messer J, Astruc D (2010) Incidence and distribution of pathogens in early-onset neonatal sepsis in the era of antenatal antibiotics. Paediatr Perinat Epidemiol 24:479–487CrossRefPubMedGoogle Scholar
  6. 6.
    Polin RA (2012) Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics 129:1006–1015CrossRefPubMedGoogle Scholar
  7. 7.
    Bassler D, Stoll BJ, Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS (2009) Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics 123:313–318CrossRefPubMedGoogle Scholar
  8. 8.
    Kermorvant-Duchemin E, Laborie S, Rabilloud M, Lapillonne A, Claris O (2008) Outcome and prognostic factors in neonates with septic shock. Pediatr Crit Care Med 9:186–191CrossRefPubMedGoogle Scholar
  9. 9.
    Stocker M, Fontana M, El Helou S, Wegscheider K, Berger TM (2010) Use of procalcitonin-guided decision-making to shorten antibiotic therapy in suspected neonatal early-onset sepsis: prospective randomized intervention trial. Neonatology 97:165–174CrossRefPubMedGoogle Scholar
  10. 10.
    Gibot S, Bene MC, Noel R, Massin F, Guy J, Cravoisy A, Barraud D, De Carvalho Bittencourt M, Quenot JP, Bollaert PE, Faure G, Charles PE (2012) Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med 186:65–71CrossRefPubMedGoogle Scholar
  11. 11.
    van Rossum AM, Wulkan RW, Oudesluys-Murphy AM (2004) Procalcitonin as an early marker of infection in neonates and children. Lancet Infect Dis 4:620–630CrossRefPubMedGoogle Scholar
  12. 12.
    Sarafidis K, Soubasi-Griva V, Piretzi K, Thomaidou A, Agakidou E, Taparkou A, Diamanti E, Drossou-Agakidou V (2010) Diagnostic utility of elevated serum soluble triggering receptor expressed on myeloid cells (sTREM)-1 in infected neonates. Intensive Care Med 36:864–868CrossRefPubMedGoogle Scholar
  13. 13.
    Jiyong J, Tiancha H, Wei C, Huahao S (2008) Diagnostic value of the soluble triggering receptor expressed on myeloid cells-1 in bacterial infection: a meta-analysis. Intensive Care Med 35(4):587–595Google Scholar
  14. 14.
    Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3:791–800CrossRefPubMedGoogle Scholar
  15. 15.
    Emonts M, Sweep FC, Grebenchtchikov N, Geurts-Moespot A, Knaup M, Chanson AL, Erard V, Renner P, Hermans PW, Hazelzet JA, Calandra T (2007) Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis. Clin Infect Dis 44:1321–1328CrossRefPubMedGoogle Scholar
  16. 16.
    Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hultner L, Heumann D, Mannel D, Bucala R, Glauser MP (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6:164–170CrossRefPubMedGoogle Scholar
  17. 17.
    Boeck L, Graf R, Eggimann P, Pargger H, Raptis DA, Smyrnios N, Thakkar N, Siegemund M, Rakic J, Tamm M, Stolz D (2011) Pancreatic stone protein: a marker of organ failure and outcome in ventilator-associated pneumonia. Chest 140:925–932CrossRefPubMedGoogle Scholar
  18. 18.
    Keel M, Harter L, Reding T, Sun LK, Hersberger M, Seifert B, Bimmler D, Graf R (2009) Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Crit Care Med 37:1642–1648CrossRefPubMedGoogle Scholar
  19. 19.
    Stocker M, Hop WC, van Rossum AM (2010) Neonatal Procalcitonin Intervention Study (NeoPInS): effect of Procalcitonin-guided decision making on duration of antibiotic therapy in suspected neonatal early-onset sepsis: a multi-centre randomized superiority and non-inferiority Intervention Study. BMC Pediatr 10:89CrossRefPubMedGoogle Scholar
  20. 20.
    Radstake TR, Sweep FC, Welsing P, Franke B, Vermeulen SH, Geurts-Moespot A, Calandra T, Donn R, van Riel PL (2005) Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor. Arthritis Rheum 52:3020–3029CrossRefPubMedGoogle Scholar
  21. 21.
    Radsak MP, Taube C, Haselmayer P, Tenzer S, Salih HR, Wiewrodt R, Buhl R, Schild H (2007) Soluble triggering receptor expressed on myeloid cells 1 is released in patients with stable chronic obstructive pulmonary disease. Clin Dev Immunol 2007:52040CrossRefPubMedGoogle Scholar
  22. 22.
    Weston EJ, Pondo T, Lewis MM, Martell-Cleary P, Morin C, Jewell B, Daily P, Apostol M, Petit S, Farley M, Lynfield R, Reingold A, Hansen NI, Stoll BJ, Shane AJ, Zell E, Schrag SJ (2011) The burden of invasive early-onset neonatal sepsis in the United States, 2005–2008. Pediatr Infect Dis J 30:937–941CrossRefPubMedGoogle Scholar
  23. 23.
    Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI, Sanchez PJ, Ambalavanan N, Benjamin DK Jr (2009) Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 123:58–66CrossRefPubMedGoogle Scholar
  24. 24.
    Kopterides P, Siempos II, Tsangaris I, Tsantes A, Armaganidis A (2010) Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med 38:2229–2241CrossRefPubMedGoogle Scholar
  25. 25.
    Jacquot A, Labaune JM, Baum TP, Putet G, Picaud JC (2009) Rapid quantitative procalcitonin measurement to diagnose nosocomial infections in newborn infants. Arch Dis Child Fetal Neonatal Ed 94:F345–F348CrossRefPubMedGoogle Scholar
  26. 26.
    Chiesa C, Panero A, Rossi N, Stegagno M, De Giusti M, Osborn JF, Pacifico L (1998) Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. Clin Infect Dis 26:664–672CrossRefPubMedGoogle Scholar
  27. 27.
    Auriti C, Fiscarelli E, Ronchetti MP, Argentieri M, Marrocco G, Quondamcarlo A, Seganti G, Bagnoli F, Buonocore G, Serra G, Bacolla G, Mastropasqua S, Mari A, Corchia C, Prencipe G, Piersigilli F, Rava L, Di Ciommo V (2011) Procalcitonin in detecting neonatal nosocomial sepsis. Arch Dis Child Fetal Neonatal Ed [Epub ahead of print]Google Scholar
  28. 28.
    Vouloumanou EK, Plessa E, Karageorgopoulos DE, Mantadakis E, Falagas ME (2011) Serum procalcitonin as a diagnostic marker for neonatal sepsis: a systematic review and meta-analysis. Intensive Care Med 37:747–762CrossRefPubMedGoogle Scholar
  29. 29.
    Roger T, David J, Glauser MP, Calandra T (2001) MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414:920–924CrossRefPubMedGoogle Scholar
  30. 30.
    Prencipe G, Auriti C, Inglese R, Devito R, Ronchetti MP, Seganti G, Rava L, Orzalesi M, De Benedetti F (2011) A polymorphism in the macrophage migration inhibitory factor promoter is associated with bronchopulmonary dysplasia. Pediatr Res 69:142–147CrossRefPubMedGoogle Scholar
  31. 31.
    Murphy K, Weiner J (2012) Use of leukocyte counts in evaluation of early-onset neonatal sepsis. Pediatr Infect Dis J 31:16–19CrossRefPubMedGoogle Scholar
  32. 32.
    Gomez B, Mintegi S, Benito J, Egireun A, Garcia D, Astobiza E (2010) Blood culture and bacteremia predictors in infants less than three months of age with fever without source. Pediatr Infect Dis J 29:43–47CrossRefPubMedGoogle Scholar
  33. 33.
    Connell TG, Rele M, Cowley D, Buttery JP, Curtis N (2007) How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children’s hospital. Pediatrics 119:891–896CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2013

Authors and Affiliations

  • Luregn J. Schlapbach
    • 1
    • 2
  • Rolf Graf
    • 3
  • Andreas Woerner
    • 1
  • Matteo Fontana
    • 4
  • Urs Zimmermann-Baer
    • 5
  • David Glauser
    • 5
  • Eric Giannoni
    • 6
    • 7
  • Thierry Roger
    • 7
  • Christoph Müller
    • 8
  • Mathias Nelle
    • 1
  • Martin Stocker
    • 4
  1. 1.Neonatal and Pediatric Intensive Care Unit, Department of PaediatricsUniversity of BerneBernSwitzerland
  2. 2.Paediatric Critical Care Research Group, Paediatric Intensive Care UnitMater Children’s HospitalSouth BrisbaneAustralia
  3. 3.Swiss HPB Center, Department of SurgeryUniversity Hospital ZurichZurichSwitzerland
  4. 4.Neonatal Intensive Care UnitChildren’s Hospital LucerneLucerneSwitzerland
  5. 5.Clinic of Neonatology, Department of PaediatricsCantonal Hospital WinterthurWinterthurSwitzerland
  6. 6.Service of NeonatologyCentre Hospitalier Universitaire Vaudois and University of LausanneLausanneSwitzerland
  7. 7.Infectious Diseases ServiceCentre Hospitalier Universitaire Vaudois and University of LausanneLausanneSwitzerland
  8. 8.Institute for PathologyUniversity of BerneBernSwitzerland

Personalised recommendations