Biomarkers in the diagnosis of neonatal sepsis


Authors: Z. Straňák 1,2;  K. Boráková 1
Authors‘ workplace: Ústav pro péči o matku a dítě, Praha 1;  3. lékařská fakulta, Univerzita Karlova, Praha 2
Published in: Čes-slov Pediat 2021; 76 (1): 55-62.
Category: Review

Overview

Neonatal sepsis (NS) is defined as a presence of microorganisms in primarily sterile body fluids and a presence of clinical and/or laboratory signs of a systemic inflammatory response. Given that clinical signs of sepsis are non-specific and the sensitivity of blood culture is low, biological indicators (biomarkers) of infection are essential for the diagnosis and rational therapy of NS.

In this comprehensive paper authors present the current possibilities of determining biomarkers in the diagnosis of NS. Commonly used biomarkers are changes in leukocyte and neutrophil counts, C-reactive protein, procalcitonin and interleukin-6. However, sensitivity and specificity of these standard markers are relatively low in the first hours after birth. Biomarkers of NS that are under intensive reasearch are acute-phase proteins, cytokines, leukocyte surface antigens and their soluble forms. Recent studies present the possibility of diagnosing infection by detecting extracellular vesicles (apoptotic bodies, microparticles, exosomes), which are released by cells after exposure to various stress signals, including infection.

The aim of the comprehensive paper is to evaluate the standard biomarkers of NS and presentation of new biomarkers that have the potential to refine the diagnosis and therapy of NS.

Keywords:

Neonatal sepsis – diagnostics – biomarker


Sources

  1.    Shane AL, Stoll BJ. Neonatal sepsis: progress towards improved outcomes. J Infect. 2014; 68 (Suppl 1): S24–S32.

  2.    Simonsen K, Anderson-Berry A, Delair S, et al. Early-onset neonatal sepsis. Clin Microbiol Rev 2014; 27 (1): 21–47.

  3.    Hendricks-Munoz K, Xu J, Mally P. Biomarkers for neonatal sepsis: recent developments. Res Rep Neonatol 2014; 2014: 157–168.

  4.    Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clin Perinatol 1991; 18: 361–381.

  5.    Hornik CP, Benjamin DK, Becker KC, et al. Use of the complete blood cell count in early-onset neonatal sepsis. Pediatr Infect Dis J 2012; 31: 799–802.

  6.    Schmutz N, Henry E, Jopling J, et al. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. J Perinatol 2008; 28 (4): 275–281.

  7.    Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease. I. Reference values for neutrophilic cells. J Pediatr 1979; 95: 89–98.

  8.    Del Vecchio A. Evaluation and management of thrombocytopenic neonates in the intensive care unit. Early Hum Dev 2014; 90 (Suppl 2): S51–55.

  9.    Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001; 38: 189–197.

10.    Pepys MB. Hirschfield GM: C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805–1812.

11.    Kääpä P, Koistinen E. Maternal and neonatal C-reactive protein after interventions during delivery. Acta Obstet Gynecol Scand 1993; 72 (7): 543–546.

12.    Oliveira CPL, Flôr-de-Lima F, Rocha GMD, et al. Meconium aspiration syndrome: risk factors and predictors of severity. J Matern Fetal Neonatal Med 2019; 32 (9): 1492–1498.

13.    el Hanache A, Gourrier E, Karoubi P, et al. Modification of C-reactive protein after instillation of natural exogenous surfactants. Arch Pediatr 1997; 4 (1): 27–31.

14.    Hofer N, Zacharias E, Müller W, et al. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012; 102 (1): 25–36.

15.    Benitz WE, Han MY, Madan A, et al. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998; 102: E41.

16.    Ruan L, Chen GY, Liu Z, et al. The combination of procalcitonin and C-reactive protein or presepsin alone improves the accuracy of diagnosis of neonatal sepsis: a meta-analysis and systematic review. Crit Care 2018; 22 (1): 316.

17.    Franz AR, Bauer K, Schalk A, et al. Measurement of interleukin 8 in combination with C-reactive protein reduced unnecessary antibiotic therapy in newborn infants: a multicenter, randomized, controlled trial. Pediatrics 2004; 114 (1): 1–8.

18.    Laborada G, Rego M, Jain A, et al. Diagnostic value of cytokines and C-reactive protein in the first 24 hours of neonatal sepsis. Am J Perinatol 2003; 20 (8): 491–501.

19.    Pacifico L, Osborn JF, Natale F, et al. Procalcitonin in pediatrics. Adv Clin Chem 2013; 59: 203–263.

20.    Chiesa C, Pacifico L, Osborn JF, et al. Early-onset neonatal sepsis: still room for improvement in procalcitonin diagnostic accuracy studies. Medicine 2015; 94: e1230.

21.    Arnon S, Litmanovitz I, Regev RH, et al. Serum amyloid A: an early and accurate marker of neonatal early-onset sepsis. J Perinatol 2007; 27 (5): 297–302.

22.    Malle E, De Beer FC. Human serum amyloid A (SAA) protein: a prominent acute-phase reactant for clinical practice. Eur J Clin Invest 1996; 26: 427–435.

23.    Nakayama T, Sonoda S, Urano T, et al. Monitoring both serum amyloid A protein and C-reactive protein as inflammatory markers in infectious diseases. Clin Chem 1993; 39: 293–297.

24.    Wahab Mohamed WA, Saeed MA. Mannose-binding lectin serum levels in neonatal sepsis and septic shock. J Matern Fetal Neonatal Med 2012; 25 (4): 411–414.

25.    Behrendt D, Dembinski J, Heep A, et al. Lipopolysaccharide binding protein in preterm infants. Arch Dis Child Fetal Neonatal Ed 2004; 89: F551–F554.

26.    Pavcnik-Arnol M, Hojker S, Derganc M. Lipopolysaccharide-binding protein in critically ill neonates and children with suspected infection: comparison with procalcitonin, interleukin-6, and C- reactive protein. Intens Care Med 2004; 30: 1454–1460.

27.    Berner R, Furll B, Stelter F, et al. Elevated levels of lipopolysaccharide-binding protein and soluble CD14 in plasma in neonatal early-onset sepsis. Clin Diagn Lab Immunol 2002; 9: 440–445.

28.    Pavcnik-Arnol M, Hojker S, Derganc M. Lipopolysaccharide-binding protein, lipopolysaccharide, and soluble CD14 in sepsis of critically ill neonates and children. Intens Care Med 2007; 33 (6): 1025–1032.

29.    Baek YW, Brokat S, Padbury JF, et al. Inter-a inhibitor proteins in infants and decreased levels in neonatal sepsis. J Pediatr 2003; 143 (1): 11–15.

30.    Balduyck M, Albani D, Jourdain M, et al. Inflammation-induced systemic proteolysis of inter-alpha-inhibitor in plasma from patients with sepsis. J Lab Clin Med 2000; 135: 188–198.

31.    Chaaban H, Singh K, Huang J, et al. The role of interalpha inhibitor proteins in the diagnosis of neonatal sepsis. J Pediatr 2009; 154: 620–622.e1.

32.     Hořejší V, Bartůňková J, Brdička T, Špíšek R. Základy imunologie. 6. vyd. Kapitola Cytokiny. Praha: Triton, 2017: 100–101.

33.    Chiesa C, Pacifico L, Natale F, et al. Fetal and early neonatal interleukin-6 response. Cytokine 2015; 76 (1): 1–12.

34.    Hou T, Huang D, Zeng R, et al. Accuracy of serum interleukin (IL)-6 in sepsis diagnosis: a systematic review and meta-analysis. Int J Clin Exp Med 2015; 8 (9): 15238–15245.

35.    Baggiolini M, Walz A, Kunkel SL. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 1989; 84 (4): 1045–1049.

36.    Martin H, Olander B, Norman M. Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-alpha in the diagnosis of early-onset neonatal sepsis. Pediatrics 2001; 108 (4): E61.

37.    Schultz C, Temming P, Bucsky P, et al. Immature anti‐inflammatory response in neonates. Clin Exp Immunol 2004; 135 (1): 130–136.

38.    Zeitoun AA, Gad SS, Attia FM, et al. Evaluation of neutrophilic CD64, interleukin 10 and procalcitonin as diagnostic markers of early-and late-onset neonatal sepsis. Scand J Infect Dis 2010; 42 (4): 299–305.

39.    Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007; 450 (7169): 566–569.

40.    Du WX, He Y, Jiang HY, et al. Interleukin 35: A novel candidate biomarker to diagnose early onset sepsis in neonates. Clin Chim Acta 2016; 462: 90–95.

41.   Santana Reyes C, García-Muñoz F, Reyes D, et al. Role of cytokines (interleukin-1beta, 6, 8, tumour necrosis factor-alpha, and soluble receptor of interleukin-2) and C-reactive protein in the diagnosis of neonatal sepsis. Acta Paediatr 2003; 92 (2): 221–227.

42.    Gokmen Z, Ozkiraz S, Kulaksizoglu S, et al. Resistin – a novel feature in the diagnosis of sepsis in premature neonates. Am J Perinatol 2013; 30 (06): 513–518.

43.    Genel F, Atlihan F, Gulez N, et al. Evaluation of adhesion molecules CD64, CD11b and CD62L in neutrophils and monocytes of peripheral blood for early diagnosis of neonatal infection. World J Pediatr 2012; 8 (1):72–75.

44.    van Maldeghem I, Nusman CM, Visser DH. Soluble CD14 subtype (sCD14-ST) as biomarker in neonatal early-onset sepsis and late-onset sepsis: a systematic review and meta-analysis. BMC Immunol 2019; 20 (1): 17.

45.   Mussap M, Noto A, Fravega M, et al. Soluble CD14 subtype presepsin (sCD14-ST) and lipopolysaccharide binding protein (LBP) in neonatal sepsis: new clinical and analytical perspectives for two old biomarkers. J Matern Fetal Neonatal Med 2011; 24 (2): 12–14.

46.    Piccin A, Murphy W, Smith OP. Circulating microparticles: pathophysiology and clinical implications. Blood Rev 2007; 21 (3): 157–171.

47.    Reid VL, Webster NR. Role of microparticles in sepsis. Br J Anaesth 2012; 109 (4): 503–513.

48.    Memar MY, Alizadeh N, Varshochi M, et al. Immunologic biomarkers for diagnostic of early-onset neonatal sepsis. J Matern Fetal Neonatal Med 2019; 32 (1): 143–153.

49.   Meisner M. Procalcitonin, Biochemistry and Clinical Diagnosis. 1st ed. Bremen: UNI-MED, 2010: 1–128. ISBN 978-3-8374-1241-3.

50.    Ting Xiao, Li-Ping Chen, Ding-Chang Wu. The clinical significance of sCD14-ST for blood biomarker in neonatal hematosepsis. Medicine (Baltimore) 2017; 96 (18): e6823.

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Neonatology Paediatrics General practitioner for children and adolescents
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