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CC BY-NC-ND 4.0 · Journal of Child Science 2017; 07(01): e89-e95
DOI: 10.1055/s-0037-1603895
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Sepsis Biomarkers in Neonates and Children: C-Reactive Protein and Procalcitonin

J. Markic
1   University of Split School of Medicine, Split, Croatia
2   Department of Pediatrics, University Hospital of Split, Split, Croatia
,
M. Saraga
1   University of Split School of Medicine, Split, Croatia
2   Department of Pediatrics, University Hospital of Split, Split, Croatia
,
P. Dahlem
3   Department of Pediatrics, Medical Center Coburg, Academic Hospital of the University of Split, Coburg, Germany
› Author Affiliations
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Publication History

10 June 2016

07 March 2017

Publication Date:
26 July 2017 (online)

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Abstract

Bacteremia and sepsis are still significant causes of morbidity and mortality among children and neonates worldwide. Early recognition of bacterial sepsis and initiation of therapy is associated with better treatment outcomes but is challenging as many of the early clinical features can be similar to those in self-limiting viral illnesses. Diagnosis of bacteremia is also challenging because the use of blood culture, the gold standard for diagnosis of bacteremia, is fraught with difficulties. Therefore, various biomarkers are of great importance in the process of diagnosis of sepsis and evaluation of its severity. They can indicate the presence or absence or severity of sepsis and are helpful in differentiating bacterial from viral and fungal infection. Of the many proposed biomarkers for infection and/or sepsis, acute-phase proteins such as C-reactive protein (CRP) and procalcitonin (PCT) are widely used and have perhaps been most widely assessed. In this review, we will present the advantages and disadvantages of CRP and PCT determination in sepsis evaluation. It will be presented that it is still not always possible to predict accurately the presence of bacterial infection on the basis of clinical appearance and available laboratory tests. Therefore, the investigation of new and better biomarkers is challenging and ongoing.

Keywords

sepsis - biomarker - C-reactive protein - procalcitonin
 

  • References

  • 1 Brent AJ, Lakhanpaul M, Thompson M. , et al. Risk score to stratify children with suspected serious bacterial infection: observational cohort study. Arch Dis Child 2011; 96 (04) 361-367
    CrossrefPubMedGoogle Scholar
  • 2 Dellinger RP, Levy MM, Carlet JM. , et al; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36 (01) 296-327
    CrossrefPubMedGoogle Scholar
  • 3 Thompson MJ, Ninis N, Perera R. , et al. Clinical recognition of meningococcal disease in children and adolescents. Lancet 2006; 367 (9508): 397-403
    CrossrefPubMedGoogle Scholar
  • 4 Ng PC, Lam HS. Diagnostic markers for neonatal sepsis. Curr Opin Pediatr 2006; 18 (02) 125-131
    CrossrefPubMedGoogle Scholar
  • 5 Atkinson A, Colburn W, DeGruttola V. , et al; Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69 (03) 89-95
    CrossrefPubMedGoogle Scholar
  • 6 Marshall JC, Reinhart K. ; International Sepsis Forum. Biomarkers of sepsis. Crit Care Med 2009; 37 (07) 2290-2298
    CrossrefPubMedGoogle Scholar
  • 7 Kaplan JM, Wong HR. Biomarker discovery and development in pediatric critical care medicine. Pediatr Crit Care Med 2011; 12 (02) 165-173
    CrossrefPubMedGoogle Scholar
  • 8 Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J 1997; 16 (08) 735-746 , quiz 746–747
    CrossrefPubMedGoogle Scholar
  • 9 Du Clos TW. Function of C-reactive protein. Ann Med 2000; 32 (04) 274-278
    CrossrefPubMedGoogle Scholar
  • 10 Jardine L, Davies MW, Faoagali J. Incubation time required for neonatal blood cultures to become positive. J Paediatr Child Health 2006; 42 (12) 797-802
    CrossrefPubMedGoogle Scholar
  • 11 Hofer N, Zacharias E, Müller W, Resch B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012; 102 (01) 25-36
    CrossrefPubMedGoogle Scholar
  • 12 Couto RC, Barbosa JA, Pedrosa TM, Biscione FM. C-reactive protein-guided approach may shorten length of antimicrobial treatment of culture-proven late-onset sepsis: an intervention study. Braz J Infect Dis 2007; 11 (02) 240-245
    CrossrefPubMedGoogle Scholar
  • 13 Franz AR, Kron M, Pohlandt F, Steinbach G. Comparison of procalcitonin with interleukin 8, C-reactive protein and differential white blood cell count for the early diagnosis of bacterial infections in newborn infants. Pediatr Infect Dis J 1999; 18 (08) 666-671
    PubMedGoogle Scholar
  • 14 Haque KN. Defining common infections in children and neonates. J Hosp Infect 2007; 65 (Suppl. 02) 110-114
    CrossrefPubMedGoogle Scholar
  • 15 Philip AG, Mills PC. Use of C-reactive protein in minimizing antibiotic exposure: experience with infants initially admitted to a well-baby nursery. Pediatrics 2000; 106 (01) E4 . Doi:
    PubMedGoogle Scholar
  • 16 Franz AR, Steinbach G, Kron M, Pohlandt F. Reduction of unnecessary antibiotic therapy in newborn infants using interleukin-8 and C-reactive protein as markers of bacterial infections. Pediatrics 1999; 104 (3 Pt 1): 447-453
    PubMedGoogle Scholar
  • 17 Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998; 102 (04) E41
    CrossrefPubMedGoogle Scholar
  • 18 Pulliam PN, Attia MW, Cronan KM. C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics 2001; 108 (06) 1275-1279
    CrossrefPubMedGoogle Scholar
  • 19 Bilavsky E, Yarden-Bilavsky H, Ashkenazi S, Amir J. C-reactive protein as a marker of serious bacterial infections in hospitalized febrile infants. Acta Paediatr 2009; 98 (11) 1776-1780
    CrossrefPubMedGoogle Scholar
  • 20 Olaciregui I, Hernández U, Muñoz JA, Emparanza JI, Landa JJ. Markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin. Arch Dis Child 2009; 94 (07) 501-505
    CrossrefPubMedGoogle Scholar
  • 21 Gendrel D, Raymond J, Coste J. , et al. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections. Pediatr Infect Dis J 1999; 18 (10) 875-881
    CrossrefPubMedGoogle Scholar
  • 22 Póvoa P, Coelho L, Almeida E. , et al. C-reactive protein as a marker of infection in critically ill patients. Clin Microbiol Infect 2005; 11 (02) 101-108
    CrossrefPubMedGoogle Scholar
  • 23 Schmit X, Vincent JL. The time course of blood C-reactive protein concentrations in relation to the response to initial antimicrobial therapy in patients with sepsis. Infection 2008; 36 (03) 213-219
    CrossrefPubMedGoogle Scholar
  • 24 Sanders S, Barnett A, Correa-Velez I, Coulthard M, Doust J. Systematic review of the diagnostic accuracy of C-reactive protein to detect bacterial infection in nonhospitalized infants and children with fever. J Pediatr 2008; 153 (04) 570-574
    CrossrefPubMedGoogle Scholar
  • 25 Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 2008; 36 (03) 941-952
    CrossrefPubMedGoogle Scholar
  • 26 Christ-Crain M, Jaccard-Stolz D, Bingisser R. , et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004; 363 (9409): 600-607
    CrossrefPubMedGoogle Scholar
  • 27 Christ-Crain M, Stolz D, Bingisser R. , et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174 (01) 84-93
    CrossrefPubMedGoogle Scholar
  • 28 Stolz D, Christ-Crain M, Bingisser R. , et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007; 131 (01) 9-19
    CrossrefPubMedGoogle Scholar
  • 29 Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008; 177 (05) 498-505
    CrossrefPubMedGoogle Scholar
  • 30 Müller B, White JC, Nylén ES, Snider RH, Becker KL, Habener JF. Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab 2001; 86 (01) 396-404
    PubMedGoogle Scholar
  • 31 Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis 2007; 7 (03) 210-217
    CrossrefPubMedGoogle Scholar
  • 32 Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993; 341 (8844): 515-518
    CrossrefPubMedGoogle Scholar
  • 33 Müller B, Becker KL, Schächinger H. , et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 2000; 28 (04) 977-983
    CrossrefPubMedGoogle Scholar
  • 34 Nylen ES, O'Neill W, Jordan MH. , et al. Serum procalcitonin as an index of inhalation injury in burns. Horm Metab Res 1992; 24 (09) 439-443
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Whang KT, Steinwald PM, White JC. , et al. Serum calcitonin precursors in sepsis and systemic inflammation. J Clin Endocrinol Metab 1998; 83 (09) 3296-3301
    PubMedGoogle Scholar
  • 36 Nakamura A, Wada H, Ikejiri M. , et al. Efficacy of procalcitonin in the early diagnosis of bacterial infections in a critical care unit. Shock 2009; 31 (06) 586-591
    PubMedGoogle Scholar
  • 37 Luzzani A, Polati E, Dorizzi R, Rungatscher A, Pavan R, Merlini A. Comparison of procalcitonin and C-reactive protein as markers of sepsis. Crit Care Med 2003; 31 (06) 1737-1741
    CrossrefPubMedGoogle Scholar
  • 38 Stocker M, Fontana M, El Helou S, Wegscheider K, Berger TM. Use of procalcitonin-guided decision-making to shorten antibiotic therapy in suspected neonatal early-onset sepsis: prospective randomized intervention trial. Neonatology 2010; 97 (02) 165-174
    CrossrefPubMedGoogle Scholar
  • 39 Groselj-Grenc M, Ihan A, Pavcnik-Arnol M, Kopitar AN, Gmeiner-Stopar T, Derganc M. Neutrophil and monocyte CD64 indexes, lipopolysaccharide-binding protein, procalcitonin and C-reactive protein in sepsis of critically ill neonates and children. Intensive Care Med 2009; 35 (11) 1950-1958
    CrossrefPubMedGoogle Scholar
  • 40 Turner D, Hammerman C, Rudensky B, Schlesinger Y, Schimmel MS. The role of procalcitonin as a predictor of nosocomial sepsis in preterm infants. Acta Paediatr 2006; 95 (12) 1571-1576
    CrossrefPubMedGoogle Scholar
  • 41 Resch B, Gusenleitner W, Müller WD. Procalcitonin and interleukin-6 in the diagnosis of early-onset sepsis of the neonate. Acta Paediatr 2003; 92 (02) 243-245
    CrossrefPubMedGoogle Scholar
  • 42 Chiesa C, Panero A, Rossi N. , et al. Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. Clin Infect Dis 1998; 26 (03) 664-672
    CrossrefPubMedGoogle Scholar
  • 43 Chiesa C, Pellegrini G, Panero A. , et al. C-reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complications, and infection. Clin Chem 2003; 49 (01) 60-68
    CrossrefPubMedGoogle Scholar
  • 44 Bonac B, Derganc M, Wraber B, Hojker S. Interleukin-8 and procalcitonin in early diagnosis of early severe bacterial infection in critically ill neonates. Pflugers Arch 2000; 440 (5, Suppl): R72-R74
    PubMedGoogle Scholar
  • 45 Lapillonne A, Basson E, Monneret G, Bienvenu J, Salle BL. Lack of specificity of procalcitonin for sepsis diagnosis in premature infants. Lancet 1998; 351 (9110): 1211-1212
    CrossrefPubMedGoogle Scholar
  • 46 Maniaci V, Dauber A, Weiss S, Nylen E, Becker KL, Bachur R. Procalcitonin in young febrile infants for the detection of serious bacterial infections. Pediatrics 2008; 122 (04) 701-710
    CrossrefPubMedGoogle Scholar
  • 47 Kordek A, Torbé A, Tousty J. , et al. The determination of procalcitonin concentration in early-onset neonatal infection: a valuable test regardless of prenatal antibiotic therapy. Clin Pediatr (Phila) 2017; 56 (04) 333-340
    CrossrefPubMedGoogle Scholar
  • 48 Enguix A, Rey C, Concha A, Medina A, Coto D, Diéguez MA. Comparison of procalcitonin with C-reactive protein and serum amyloid for the early diagnosis of bacterial sepsis in critically ill neonates and children. Intensive Care Med 2001; 27 (01) 211-215
    CrossrefPubMedGoogle Scholar
  • 49 Fernández Lopez A, Luaces Cubells C, García García JJ, Fernández Pou J. ; Spanish Society of Pediatric Emergencies. Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and utility of a rapid qualitative test for this marker. Pediatr Infect Dis J 2003; 22 (10) 895-903
    CrossrefPubMedGoogle Scholar
  • 50 Prat C, Domínguez J, Rodrigo C. , et al. Use of quantitative and semiquantitative procalcitonin measurements to identify children with sepsis and meningitis. Eur J Clin Microbiol Infect Dis 2004; 23 (02) 136-138
    CrossrefPubMedGoogle Scholar
  • 51 Carrol ED, Newland P, Riordan FA, Thomson AP, Curtis N, Hart CA. Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash. Arch Dis Child 2002; 86 (04) 282-285
    CrossrefPubMedGoogle Scholar
  • 52 Hatherill M, Tibby SM, Sykes K, Turner C, Murdoch IA. Diagnostic markers of infection: comparison of procalcitonin with C reactive protein and leucocyte count. Arch Dis Child 1999; 81 (05) 417-421
    CrossrefPubMedGoogle Scholar
  • 53 Arkader R, Troster EJ, Lopes MR. , et al. Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome. Arch Dis Child 2006; 91 (02) 117-120
    CrossrefPubMedGoogle Scholar
  • 54 Casado-Flores J, Blanco-Quirós A, Asensio J, Arranz E, Garrote JA, Nieto M. Serum procalcitonin in children with suspected sepsis: a comparison with C-reactive protein and neutrophil count. Pediatr Crit Care Med 2003; 4 (02) 190-195
    CrossrefPubMedGoogle Scholar
  • 55 Fioretto JR, Martin JG, Kurokawa CS. , et al. Comparison between procalcitonin and C-reactive protein for early diagnosis of children with sepsis or septic shock. Inflamm Res 2010; 59 (08) 581-586
    CrossrefPubMedGoogle Scholar
  • 56 Rey C, Los Arcos M, Concha A. , et al. Procalcitonin and C-reactive protein as markers of systemic inflammatory response syndrome severity in critically ill children. Intensive Care Med 2007; 33 (03) 477-484
    CrossrefPubMedGoogle Scholar
  • 57 Simon L, Saint-Louis P, Amre DK, Lacroix J, Gauvin F. Procalcitonin and C-reactive protein as markers of bacterial infection in critically ill children at onset of systemic inflammatory response syndrome. Pediatr Crit Care Med 2008; 9 (04) 407-413
    CrossrefPubMedGoogle Scholar
  • 58 Carrol ED, Newland P, Thomson AP, Hart CA. Prognostic value of procalcitonin in children with meningococcal sepsis. Crit Care Med 2005; 33 (01) 224-225
    CrossrefPubMedGoogle Scholar
  • 59 Lacour AG, Gervaix A, Zamora SA. , et al. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr 2001; 160 (02) 95-100
    CrossrefPubMedGoogle Scholar
  • 60 Galetto-Lacour A, Zamora SA, Gervaix A. Bedside procalcitonin and C-reactive protein tests in children with fever without localizing signs of infection seen in a referral center. Pediatrics 2003; 112 (05) 1054-1060
    CrossrefPubMedGoogle Scholar
  • 61 Andreola B, Bressan S, Callegaro S, Liverani A, Plebani M, Da Dalt L. Procalcitonin and C-reactive protein as diagnostic markers of severe bacterial infections in febrile infants and children in the emergency department. Pediatr Infect Dis J 2007; 26 (08) 672-677
    CrossrefPubMedGoogle Scholar
  • 62 Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 2013; 13 (05) 426-435
    CrossrefPubMedGoogle Scholar
  • 63 Markic J, Jeroncic A, Polancec D. , et al. CD15s is a potential biomarker of serious bacterial infection in infants admitted to hospital. Eur J Pediatr 2013; 172 (10) 1363-1369
    CrossrefPubMedGoogle Scholar