Biomarkers of sepsis in neonates and children

Sepsis, and related complications, is still a common cause of death in hospitalized patients worldwide, especially in critically ill neonates and children. Sepsis is also responsible for significant morbidity, and financial burden. It is very important to recognize sepsis early, since delayed diagnosis is associated with worse outcome. The early detection of sepsis remains a great challenge for clinicians because the use of blood cultures, the gold standard for diagnosis of bacteremia, is fraught with difficulties. The role of different immune and metabolic biomarkers is to improve the diagnosis, treatment and prognosis of sepsis. White blood cell count, C-reactive protein and procalcitonin are currently the most widely used biomarkers, but they have limited abilities to

distinguish sepsis from other inflammatory conditions or to predict outcome. In this review, these biomarkers will be discussed along with novel diagnostic, prognostic and treatment response biomarkers, including interleukins -6, -8, -18, tumor necrosis factor – alpha, CD11b, CD64 and CD15s. The future of sepsis biomarkers lies in extensive validation studies of all novel biomarkers and their combinations as early predictors of sepsis. Also, research to identify novel sepsis biomarkers and develop specific therapeutic strategies based on biomarker information has to be continued.

infant, child, biomarkers, CD15s antigen, C-reactive protein, procalcitonin

1. Levine D, Platt S, Dayan P, Macias C, Zorc J, Krief W, et al. Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. Pediatrics 2004;113(6):1728-34.

2. Ashkenazi-Hoffnung L, Livni G, Amir J, Bilavsky E. Serious bacterial infections in hospitalized febrile infants aged 90 days or younger: The traditional combination of ampicillin and gentamicin is still appropriate.Scandin J Infect Dis 2011;43(6-7):489-94.

3. Bilavsky E, Yarden-Bilavsky H, Ashkenazi S, Amir J. C-reactive protein as a marker of serious bacterial infections in hospitalized febrile infants. Acta Paediatrica 2009;98(11):1776-80.

4. Levy M, Fink M, Marshall J, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31(4):1250-6.

5. Angus D, Linde-Zwirble W, Lidicker J, Clermont G, Carcillo J, Pinsky M. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29(7):1303-10.

6. Olaciregui I, Hernandez U, Munoz J, Emparanza J, Landa J. Markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin. Arch Dis Childhood

2009;94(7):501-5.

7. Dellinger R, Levy M, Carlet J, Bion J, Parker M, Jaeschke R, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36(1):296-327.

8. Ng P, Lam H. Diagnostic markers for neonatal sepsis. Curr Opin Ped 2006;18(2):125-31.

9. Marshall J, Reinhart K, Forum IS. Biomarkers of sepsis. Crit Care Med 2009;37(7):2290-8.

10. Atkinson A, Colburn W, DeGruttola V, DeMets D, Downing G, Hoth D, et al. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharm Therap 2001;69(3):89-95.

11. Kaplan J, Wong H. Biomarker discovery and development in pediatric critical care medicine. Ped Crit Care Med 2011;12(2):165-73.

12. Davis B. Improved diagnostic approaches to infection/sepsis detection. Exp Rev Mol Diag 2005;5(2):193-207.

13. Zeitoun A, Gad S, Attia F, Abu Maziad A, Bell E. Evaluation of neutrophilic CD64, interleukin 10 and procalcitonin as diagnostic markers of early- and late-onset neonatal sepsis. Scandin J Infect Dis 2010;42(4):299-305.

14. Lacour A, Gervaix A, Zamora S, Vadas L, Lombard P, Dayer J, 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. Europ J Ped 2001;160(2):95-100.

15. Bonsu B, Harper M. Identifying febrile young infants with bacteremia: Is the peripheral white blood cell count an accurate screen? Ann Emerg Med 2003;42(2):216-25.

16. Galetto-Lacour A, Zamora S, 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(5):1054-60.

17. Rudinsky S, Carstairs K, Reardon J, Simon L, Riffenburgh R, Tanen D. Serious Bacterial Infections in Febrile Infants in the Post-Pneumococcal Conjugate Vaccine Era. Acad Emerg Med 2009;16(7):585-90.

18. Du Clos T. Function of C-reactive protein. Ann Med 2000;32(4):274-8.

19. Couto R, Barbosa J, Pedrosa T, Biscione F. C-reactive protein-guided approach may shorten length of antimicrobial treatment of culture-proven late-onset sepsis. An intervention study. Brazil J Infect Dis 2007;11(2):240-5.

20. Franz A, 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):447-53.

21. 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(6):1275-9.

22. Tang B, Eslick G, Craig J, McLean A. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis 2007;7(3):210-7.

23. Lopez A, Cubells C, Garcia J, Pou J, Emergencies SSP. 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. Ped Infect Dis J

2003;22(10):895-903.

24. Prat C, Dominguez J, Rodrigo C, Gimenez M, Azuara M, Blanco S, et al. Use of quantitative and semiquantitative procalcitonin measurements to identify children with sepsis and meningitis. Europ J Clin Microb Infect Dis 2004;23(2):136-8.

25. Carrol E, Newland P, Riordan F, Thomson A, Curtis N, Hart C. Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash. Arch Dis Childhood 2002;86(4):282-5.

26. Gendrel D, Raymond J, Coste J, Moulin F, Lorrot M, Guerin S, et al. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections. Ped Infect Dis J 1999;18(10):875-81.

27. Berner R, Niemeyer C, Leititis J, Funke A, Schwab C, Rau U, et al. Plasma levels and gene expression of granulocyte colony-stimulating factor, tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis. Ped Research 1998;44(4):469-77.

28. Sullivan J, kilpatrick L, Costarino A, Lee S, Harris M. Correlation of plasma cytokine elevations with mortality-rate in children with sepsis. J Ped 1992;120(4):510-5.

29. Strait R, Kelly K, Kurup V. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 levels in febrile, young children with and without occult bacteremia. Pediatrics 1999;104(6):1321-6.

30. Layseca-Espinosa E, Perez-Gonzalez L, Torres-Montes A, Baranda L, de la Fuente H, Rosenstein Y, et al. Expression of CD64 as a potential marker of neonatal sepsis. Ped Allerg Immunol 2002;13(5):319-27.

31. 31. Takala A, Jousela I, Jansson S, Olkkola K, Takkunen O, Orpana A, et al. Markers of systemic inflammation predicting organ failure in community-acquired septic shock. Clin Sci 1999;97(5):529-38.

32. 32. Franz A, 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. Ped Infect Dis J 1999;18(8):666-71.

33. 33. Nupponen I, Andersson S, Järvenpää AL, Kautiainen H, Repo H. Neutrophil CD11b expression and circulating interleukin-8 as diagnostic markers for early-onset neonatal sepsis. Pediatrics 2001;108(1):E12.

34. 34. Cusumano V, Midiri A, Cusumano V, Bellantoni A, De Sossi G, Teti G, et al. Interleukin-18 is an essential element in host resistance to experimental group B streptococcal disease in neonates. Infect Immunol 2004;72(1):295-300.

35. 35. Kingsmore S, Kennedy N, Halliday H, Van Velkinburgh J, Zhong S, Gabriel V, et al. Identification of Diagnostic Biomarkers for Infection in Premature Neonates. Molec Cell Proteom 2008;7(10):1863-75.

36. 36. Bender L, Thaarup J, Varming K, Krarup H, Ellermann-Eriksen S, Ebbesen F. Early and late markers for the detection of early-onset neonatal sepsis. Danish Med Bull 2008;55(4):219-23.

37. 37. Ng P, Cheng S, Chui K, Fok T, Wong M, Wong W, et al. Diagnosis of late onset neonatal sepsis with cytokines, adhesion molecule, and C-reactive protein in preterm very low birthweight infants. Arch Dis Childhood 1997;77(3):F221-F7.

38. 38. Gonzalez-Amaro R, Sanchez-Madrid F. Cell adhesion molecules: Selectins and integrins. Crit Rev Immunol 1999;19(5-6):389-429.

39. 39. Sengelov H, Kjeldsen L, Diamond M, Springer T, Borregaard N. Subcellular-localization and dynamics of mac-1 (alpha(m)beta(2)) in human neutrophils. J Clin Invest 1993;92(3):1467-76.

40. 40. Kobold A, Tulleken J, Zijlstra J, Sluiter W, Hermans J, Kallenberg C, et al. Leukocyte activation in sepsis; correlations with disease state and mortality. Int Care Med 2000;26(7):883-92.

41. 41. Turunen R, Andersson S, Nupponen I, Kautiainen H, Siitonen S, Repo

H. Increased CD11b-density on circulating phagocytes as an early sign of late-onset sepsis in extremely low-birth-weight infants. Ped Research 2005;57(2):270-5.

42. 42. Weirich E, Rabin R, Maldonado Y, Benitz W, Modler S, Herzenberg L. Neutrophil CD11b expression as a diagnostic marker for early-onset neonatal infection. J Ped 1998;132(3):445-51.

43. 43. Genel F, Atlihan F, Gulez N, Kazanci E, Vergin C, Terek D, 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 Ped 2012;8(1):72-5.

44. 44. Nakae H, Endo S, Inada K, Takakuwa T, Kasai T. Changes in adhesion molecule levels in sepsis. Research Communications in Molecular Pathol Pharm 1996;91(3):329-38.

45. 45. Chen S, Alon R, Fuhlbrigge R, Springer T. Rolling and transient tethering of leukocytes on antibodies reveal specializations of selectins. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(7):3172-7.

46. 46. Zen K, Cui L, Zhang C, Liu Y. Critical role of Mac-1 sialyl Lewis x moieties in regulating neutrophil degranulation and transmigration. J Mol Biol 2007;374(1):54-63.

47. 47. Markic J, Jeroncic A, Polancec D, Bosnjak N, Markotic A, Mestrovic J, et al. CD15s is a potential biomarker of serious bacterial infection in infants admitted to hospital. Eur J Pediatr 2013;172(10):1363-9.

48. 48. Hoffmann J. Neutrophil CD64: a diagnostic marker for infection and sepsis. Clin Chem Lab Med 2009;47(8):903-16.

49. 49. Ng P, Li G, Chui K, Chu W, Li K, Wong R, et al. Neutrophil CD64 is a sensitive diagnostic marker for early-onset neonatal infection. Ped Research 2004;56(5):796-803.

50. 50. Bhandari V, Wang C, Rinder C, Rinder H. Hematologic profile of sepsis in neonates: Neutrophil CD64 as a diagnostic marker. Pediatrics 2008;121(1):129-34.

51. 51. Groselj-Grenc M, Ihan A, Pavcnik-Arnol M, Kopitar A, 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. Int Care Med

2009;35(11):1950-8.

52. 52. Fjaertoft G, Hakansson L, Pauksens K, Sisask G, Venge P. Neutrophil CD64 (Fc gamma RI) expression is a specific marker of bacterial infection: A study on the kinetics and the impact of major surgery. Scand J Infect Dis 2007;39(6-7):525-35.

53. 53. Davis B, Olsen S, Ahmad E, Bigelow N. Neutrophil CD64 is an improved indicator of infection or sepsis in emergency department patients. Arch Pathol Lab Med 2006;130(5):654-61.

54. 54. Cid J, Aguinaco R, Sanchez R, Garcia-Pardo G, Llorente A. Neutrophil CD64 expression as marker of bacterial infection: A systematic review and meta-analysis. J Infect 2010;60(5):313-9.

55. 55. Arnon S, Litmanovitz I, Regev R, Bauer S, Shainkin-Kestenbaum R, Dolfin T. Serum amyloid A: an early and accurate marker of neonatal early-onset sepsis. J Perinat 2007;27(5):297-302.

56. 56. Sherwin C, Broadbent R, Young S, Worth J, McCaffrey F, Medlicott N, et al. Utility of Interleukin-12 and Interleukin-10 in Comparison with Other Cytokines and Acute-Phase Reactants in the Diagnosis of Neonatal Sepsis. Am J Perin 2008;25(10):629-36.

57. 57. Ng P, Li K, Chui K, Leung T, Wong R, Chu W, et al. IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants. Ped Research 2007;61(1):93-8.

58. 58. Pavcnik-Arnol M, Hojker S, Derganc M. Lipopolysaccharide-binding protein, lipopolysaccharide, and soluble CD14 in sepsis of critically ill neonates and children. Int Care Med 2007;33(6):1025-32.