Pediatric Sepsis Markers: Interleukins and Others

Abstract

Cytokines are a very important part in the regulation of immune response in sepsis. They are cellular signaling proteins whose production is a result of activation of specific receptors. Variations in the genes encoding cytokines have a significant role in interindividual susceptibility to sepsis and its severity, and their function may be modulated by age, gender, and some environmental factors. Cytokines are classified into the subsets of proinflammatory, anti-inflammatory, and multiple function cytokines. Regulated balance between proinflammatory cytokines, anti-inflammatory cytokines, and soluble inhibitors of proinflammatory cytokines is important for eliminating pathogens and reducing inflammation. High levels of some cytokines, such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6, determine the course of disease and outcome in sepsis. Likewise, numerous other biomarkers may be potential indicators of sepsis, but none has been routinely used. The best approach to the diagnosis of sepsis is the combination of different biomarkers.

Keywords

sepsis - immune response - cytokines - other biomarkers

• References

• 1 Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8 (10) 776-787
• 2 Wen AQ, Gu W, Wang J. , et al. Clinical relevance of IL-1beta promoter polymorphisms (-1470, -511, and -31) in patients with major trauma. Shock 2010; 33 (06) 576-582
• 3 Zhang AQ, Pan W, Gao JW. , et al. Associations between interleukin-1 gene polymorphisms and sepsis risk: a meta-analysis. BMC Med Genet 2014; 15: 8
• 4 Watanabe E, Buchman TG, Hirasawa H, Zehnbauer BA. Association between lymphotoxin-alpha (tumor necrosis factor-beta) intron polymorphism and predisposition to severe sepsis is modified by gender and age. Crit Care Med 2010; 38 (01) 181-193
• 5 Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets--an updated view. Mediators Inflamm 2013; 2013: 165974
• 6 Blackwell TS, Christman JW. Sepsis and cytokines: current status. Br J Anaesth 1996; 77 (01) 110-117
• 7 de Jong HK, van der Poll T, Wiersinga WJ. The systemic pro-inflammatory response in sepsis. J Innate Immun 2010; 2 (05) 422-430
• 8 Balk R. Roger C. Bone, MD and the evolving paradigms of sepsis. Contrib Microbiol 2011; 17: 1-11
• 9 Cohen J. The immunopathogenesis of sepsis. Nature 2002; 420 (6917): 885-891
• 10 van der Poll T, van Deventer SJ. Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13 (02) 413-426 , ix
• 11 Berner R, Niemeyer CM, Leititis JU. , et al. Plasma levels and gene expression of granulocyte colony-stimulating factor, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis. Pediatr Res 1998; 44 (04) 469-477
• 12 Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 2010; 20 (02) 87-103
• 13 Lewis M, Tartaglia LA, Lee A. , et al. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci U S A 1991; 88 (07) 2830-2834
• 14 Shannon E, Noveck R, Sandoval F, Kamath B, Kearney M. Thalidomide suppressed interleukin-6 but not tumor necrosis factor-alpha in volunteers with experimental endotoxemia. Transl Res 2007; 150 (05) 275-280
• 15 Prashant A, Vishwanath P, Kulkarni P. , et al. Comparative assessment of cytokines and other inflammatory markers for the early diagnosis of neonatal sepsis-a case control study. PLoS One 2013; 8 (07) e68426
• 16 Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 2004; 202 (02) 145-156
• 17 van der Poll T, Büller HR, ten Cate H. , et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990; 322 (23) 1622-1627
• 18 Schouten M, Wiersinga WJ, Levi M, van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83 (03) 536-545
• 19 Silveira RC, Procianoy RS. Evaluation of interleukin-6, tumour necrosis factor-α and interleukin-1β for early diagnosis of neonatal sepsis. Acta Paediatr 1999; 88 (06) 647-650
• 20 Duncombe G, Veldhuizen RA, Gratton RJ, Han VK, Richardson BS. IL-6 and TNFalpha across the umbilical circulation in term pregnancies: relationship with labour events. Early Hum Dev 2010; 86 (02) 113-117
• 21 O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 2008; 226 (01) 10-18
• 22 Smith K, Bigham MT. Biomarkers in pediatric sepsis. Open Inflamm J 2011; 4: 24-30
• 23 Loisa P, Rinne T, Laine S, Hurme M, Kaukinen S. Anti-inflammatory cytokine response and the development of multiple organ failure in severe sepsis. Acta Anaesthesiol Scand 2003; 47 (03) 319-325
• 24 Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest 1988; 81 (04) 1162-1172
• 25 Dinarello CA. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res 2004; 10 (04) 201-222
• 26 Conte D, Holcik M, Lefebvre CA. , et al. Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol Cell Biol 2006; 26 (02) 699-708
• 27 Shimaoka M, Park EJ. Advances in understanding sepsis. Eur J Anaesthesiol Suppl 2008; 42 (42) 146-153
• 28 Gårdlund B, Sjölin J, Nilsson A, Roll M, Wickerts CJ, Wretlind B. Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. J Infect Dis 1995; 172 (01) 296-301
• 29 Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson RC. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 1990; 348 (6301): 550-552
• 30 Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 2012; 51 (05) (Suppl. 05) v3-v11
• 31 Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 2011; 7 (01) 33-42
• 32 Jawień J. New insights into immunological aspects of atherosclerosis. Pol Arch Med Wewn 2008; 118 (03) 127-131
• 33 Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65 (01) (Suppl. 01) S4-S10
• 34 Scheller J, Rose-John S. Interleukin-6 and its receptor: from bench to bedside. Med Microbiol Immunol (Berl) 2006; 195 (04) 173-183
• 35 Kishimoto T. The biology of interleukin-6. Blood 1989; 74 (01) 1-10
• 36 Tasci Y, Dilbaz B, Uzmez Onal B. , et al. The value of cord blood interleukin-6 levels for predicting chorioamnionitis, funisitis and neonatal infection in term premature rupture of membranes. Eur J Obstet Gynecol Reprod Biol 2006; 128 (1-2): 34-39
• 37 Remick DG, Bolgos G, Copeland S, Siddiqui J. Role of interleukin-6 in mortality from and physiologic response to sepsis. Infect Immun 2005; 73 (05) 2751-2757
• 38 Bloos F, Reinhart K. Rapid diagnosis of sepsis. Virulence 2014; 5 (01) 154-160
• 39 Takala A, Jousela I, Jansson SE. , et al. Markers of systemic inflammation predicting organ failure in community-acquired septic shock. Clin Sci (Lond) 1999; 97 (05) 529-538
• 40 Calfee CS, Thompson BT, Parsons PE, Ware LB, Matthay MA, Wong HR. Plasma interleukin-8 is not an effective risk stratification tool for adults with vasopressor-dependent septic shock. Crit Care Med 2010; 38 (06) 1436-1441
• 41 Wong HR, Cvijanovich N, Wheeler DS. , et al. Interleukin-8 as a stratification tool for interventional trials involving pediatric septic shock. Am J Respir Crit Care Med 2008; 178 (03) 276-282
• 42 Wong HR, Shanley TP, Sakthivel B. , et al. ; Genomics of Pediatric SIRS/Septic Shock Investigators. Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome. Physiol Genomics 2007; 30 (02) 146-155
• 43 Standage SW, Wong HR. Biomarkers for pediatric sepsis and septic shock. Expert Rev Anti Infect Ther 2011; 9 (01) 71-79
• 44 Fan Y, Yu JL. Umbilical blood biomarkers for predicting early-onset neonatal sepsis. World J Pediatr 2012; 8 (02) 101-108
• 45 Bhandari V. Effective biomarkers for diagnosis of neonatal sepsis. J Pediatric Infect Dis Soc 2014; 3 (03) 234-245
• 46 Silveira RC, Fortes Filho JB, Procianoy RS. Assessment of the contribution of cytokine plasma levels to detect retinopathy of prematurity in very low birth weight infants. Invest Ophthalmol Vis Sci 2011; 52 (03) 1297-1301
• 47 Jones LL, Vignali DA. Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily. Immunol Res 2011; 51 (01) 5-14
• 48 Howard M, Muchamuel T, Andrade S, Menon S. Interleukin 10 protects mice from lethal endotoxemia. J Exp Med 1993; 177 (04) 1205-1208
• 49 Ng PC, Lam HS. Biomarkers for late-onset neonatal sepsis: cytokines and beyond. Clin Perinatol 2010; 37 (03) 599-610
• 50 Zeng L, Gu W, Chen K. , et al. Clinical relevance of the interleukin 10 promoter polymorphisms in Chinese Han patients with major trauma: genetic association studies. Crit Care 2009; 13 (06) R188
• 51 Hazelzet JA, Kornelisse RF, van der Pouw Kraan TC. , et al. Interleukin 12 levels during the initial phase of septic shock with purpura in children: relation to severity of disease. Cytokine 1997; 9 (09) 711-716
• 52 Estaquier J, Idziorek T, Zou W. , et al. T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med 1995; 182 (06) 1759-1767
• 53 Weighardt H, Heidecke CD, Westerholt A. , et al. Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis. Ann Surg 2002; 235 (04) 560-567
• 54 Sherwin C, Broadbent R, Young S. , 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 Perinatol 2008; 25 (10) 629-636
• 55 Cui YL, Wang B, Gao HM. , et al. Interleukin-18 and miR-130a in severe sepsis patients with thrombocytopenia. Patient Prefer Adherence 2016; 10: 313-319
• 56 Kingsmore SF, Kennedy N, Halliday HL. , et al. Identification of diagnostic biomarkers for infection in premature neonates. Mol Cell Proteomics 2008; 7 (10) 1863-1875
• 57 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. Dan Med Bull 2008; 55 (04) 219-223
• 58 Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor β in human disease. N Engl J Med 2000; 342 (18) 1350-1358
• 59 Wan YY, Flavell RA. TGF-β and regulatory T cell in immunity and autoimmunity. J Clin Immunol 2008; 28 (06) 647-659
• 60 Kumar A, Kumar A, Paladugu B, Mensing J, Parrillo JE. Transforming growth factor-β1 blocks in vitro cardiac myocyte depression induced by tumor necrosis factor-α, interleukin-1β, and human septic shock serum. Crit Care Med 2007; 35 (02) 358-364
• 61 Perrella MA, Hsieh CM, Lee WS. , et al. Arrest of endotoxin-induced hypotension by transforming growth factor beta1. Proc Natl Acad Sci U S A 1996; 93 (05) 2054-2059
• 62 Knapp S, Thalhammer F, Locker GJ. , et al. Prognostic value of MIP-1 α, TGF-β 2, sELAM-1, and sVCAM-1 in patients with gram-positive sepsis. Clin Immunol Immunopathol 1998; 87 (02) 139-144
• 63 Seder RA, Paul WE, Davis MM, Fazekas de St Groth B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med 1992; 176 (04) 1091-1098
• 64 Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest 2000; 117 (04) 1162-1172
• 65 Wu HP, Wu CL, Chen CK. , et al. The interleukin-4 expression in patients with severe sepsis. J Crit Care 2008; 23 (04) 519-524
• 66 Weber GF, Chousterman BG, He S. , et al. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 2015; 347 (6227): 1260-1265
• 67 Lam HS, Wong SP, Cheung HM. , et al. Early diagnosis of intra-abdominal inflammation and sepsis by neutrophil CD64 expression in newborns. Neonatology 2011; 99 (02) 118-124
• 68 Rudensky B, Sirota G, Erlichman M, Yinnon AM, Schlesinger Y. Neutrophil CD64 expression as a diagnostic marker of bacterial infection in febrile children presenting to a hospital emergency department. Pediatr Emerg Care 2008; 24 (11) 745-748
• 69 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
• 70 Cid J, Aguinaco R, Sánchez R, García-Pardo G, Llorente A. Neutrophil CD64 expression as marker of bacterial infection: a systematic review and meta-analysis. J Infect 2010; 60 (05) 313-319
• 71 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
• 72 Muller Kobold AC, Tulleken JE, Zijlstra JG. , et al. Leukocyte activation in sepsis; correlations with disease state and mortality. Intensive Care Med 2000; 26 (07) 883-892
• 73 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. Pediatr Res 2005; 57 (02) 270-275
• 74 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 (01) 72-75
• 75 Mikkelsen ME, Miltiades AN, Gaieski DF. , et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 2009; 37 (05) 1670-1677
• 76 Jansen TC, van Bommel J, Bakker J. Blood lactate monitoring in critically ill patients: a systematic health technology assessment. Crit Care Med 2009; 37 (10) 2827-2839
• 77 Arnold RC, Shapiro NI, Jones AE. , et al; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009; 32 (01) 35-39
• 78 Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. ; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303 (08) 739-746
• 79 Scott HF, Donoghue AJ, Gaieski DF, Marchese RF, Mistry RD. The utility of early lactate testing in undifferentiated pediatric systemic inflammatory response syndrome. Acad Emerg Med 2012; 19 (11) 1276-1280
• 80 Alder MN, Lindsell CJ, Wong HR. The pediatric sepsis biomarker risk model: potential implications for sepsis therapy and biology. Expert Rev Anti Infect Ther 2014; 12 (07) 809-816
• 81 Pavcnik-Arnol M, Hojker S, Derganc M. Lipopolysaccharide-binding protein, lipopolysaccharide, and soluble CD14 in sepsis of critically ill neonates and children. Intensive Care Med 2007; 33 (06) 1025-1032
• 82 Arnon S, Litmanovitz I, Regev RH, Bauer S, Shainkin-Kestenbaum R, Dolfin T. Serum amyloid A: an early and accurate marker of neonatal early-onset sepsis. J Perinatol 2007; 27 (05) 297-302
• 83 Neville LF, Mathiak G, Bagasra O. The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev 1997; 8 (03) 207-219
• 84 Ng PC, Li K, Chui KM. , et al. IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants. Pediatr Res 2007; 61 (01) 93-98
• 85 Sama AE, D'Amore J, Ward MF, Chen G, Wang H. Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department. Acad Emerg Med 2004; 11 (08) 867-873
• 86 Yang H, Ochani M, Li J. , et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A 2004; 101 (01) 296-301
• 87 Hatada T, Wada H, Nobori T. , et al. Plasma concentrations and importance of High Mobility Group Box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost 2005; 94 (05) 975-979
• 88 Routsi C, Giamarellos-Bourboulis EJ, Antonopoulou A. , et al. Does soluble triggering receptor expressed on myeloid cells-1 play any role in the pathogenesis of septic shock?. Clin Exp Immunol 2005; 142 (01) 62-67
• 89 Gibot S, Cravoisy A, Kolopp-Sarda MN. , et al. Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis. Crit Care Med 2005; 33 (04) 792-796
• 90 Kaplan JM, Wong HR. Biomarker discovery and development in pediatric critical care medicine. Pediatr Crit Care Med 2011; 12 (02) 165-173
• 91 Nowak JE, Wheeler DS, Harmon KK, Wong HR. Admission chemokine (C-C motif) ligand 4 levels predict survival in pediatric septic shock. Pediatr Crit Care Med 2010; 11 (02) 213-216
• 92 Wong HR, Cvijanovich N, Lin R. , et al. Identification of pediatric septic shock subclasses based on genome-wide expression profiling. BMC Med 2009; 7: 34