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DIAGNOSTIC MARKERS IN NEONATAL SEPSIS

Published online by Cambridge University Press:  01 February 2007

HUGH S. LAM
Affiliation:
Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong
PAK C NG*
Affiliation:
Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong
*
Professor Pak C. Ng, Professor of Paediatrics, Department of Paediatrics, 6/F Clinical Sciences Building, Prince of Wales Hospital, Sha Tin, New Territories, Hong Kong

Extract

Breakthroughs in the management of sick newborns, including exogenous surfactant therapy, advance ventilation techniques, inhaled nitric oxide, and use of antenatal corticosteroids have led to substantial improvements in the survival of vulnerable preterm infants. Neonatal clinicians now have access to an ever increasing armament of antimicrobial agents to help combat infections. However, even with the support of such advanced therapeutic modalities, strict infection control measures and low thresholds for use of broad-spectrum antibiotics, the threat of bacterial infections especially in the most susceptible group of preterm, very low birth weight (VLBW) infants have persisted. A recent survey suggests that a significant proportion of VLBW infants (21%) have at least one episode of late-onset culture proven sepsis during their stay in the neonatal unit. Infected infants require longer hospital stay and have higher risk of developing complications, such as bronchopulmonary dysplasia and adverse long-term neurodevelopment. Neonates with infection often present with subtle and non-specific signs of sepsis. Some may be asymptomatic at the initial stages of infection. Even those infants with signs may not be clinically distinguishable from patients suffering from transient tachypnoea of the newborn, respiratory distress syndrome, apnoea of prematurity or acute exacerbation of bronchopulmonary dysplasia, during early phases of the disease. Such presentations can lead to both delayed treatment of genuinely infected infants and indiscriminate use of antibiotics in non-infected cases, resulting in acceleration of emergence of bacterial resistance, alteration of patterns of bacterial infection, and inefficient treatment of septicaemia. Both early and late-onset infections are important causes of neonatal morbidity and mortality. Methods to assist neonatal clinicians diagnose infants in the early stages of infection are, therefore, highly desirable.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2007

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References

REFERENCES

1Philip, AG. The evolution of neonatology. Pediatr Res 2005; 58: 799815.CrossRefGoogle ScholarPubMed
2Bland, RD. Neonatal chronic lung disease in the post-surfactant era. Biol Neonate 2005; 88: 181–91.Google Scholar
3Ng, PC, Wong, HL, Lyon, DJ, So, KW, Liu, F, Lam, RK et al. Combined use of alcohol hand rub and gloves reduces the incidence of late onset infection in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2004; 89: F33640.CrossRefGoogle ScholarPubMed
4Stoll, BJ, Hansen, N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network. Semin Perinatol 2003; 27: 293301.CrossRefGoogle ScholarPubMed
5Stoll, BJ, Hansen, N, Fanaroff, AA, Wright, LL, Carlo, WA, Ehrenkranz, RA et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002; 110: 285–91.CrossRefGoogle ScholarPubMed
6Stoll, BJ, Gordon, T, Korones, SB, Shankaran, S, Tysen, JE, Bauer, CR et al. Early-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996; 129: 7280.CrossRefGoogle ScholarPubMed
7Stoll, BJ, Gordon, T, Korones, SB, Shankaran, S, Tysen, JE, Bauer, CR et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996; 129: 6371.CrossRefGoogle ScholarPubMed
8Stoll, BJ, Hansen, NI, Adams-Chapman, I, Fanaroff, AA, Hintz, SR, Vohr, B et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292: 2357–65.CrossRefGoogle ScholarPubMed
9Ng, PC. Diagnostic markers of infection in neonates. Arch Dis Child Fetal Neonatal Ed 2004; 89: F22935.CrossRefGoogle ScholarPubMed
10Stoll, BJ, Hansen, N, Fanaroff, AA, Wright, LL, Carlo, WA, Ehrenkranz, RA et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 2002; 347: 240–47.CrossRefGoogle ScholarPubMed
11Polin, RA. The “ins and outs” of neonatal sepsis. J Pediatr 2003; 143: 34.CrossRefGoogle Scholar
12Ng, PC. Clinical trials for evaluating diagnostic markers of infection in neonates. Biol Neonate 2005; 87: 111–2.CrossRefGoogle ScholarPubMed
13Lekkou, A, Karakantza, M, Mouzaki, A, Kalfarentzos, F, Gogos, CA. Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections. Clin Diagn Lab Immunol 2004; 11: 161–67.Google ScholarPubMed
14Zakynthinos, SG, Papanikolaou, S, Theodoridis, T, Zakynthinos, EG, Christopoulou-Kokkinou, V, Katsaris, G et al. Sepsis severity is the major determinant of circulating thrombopoietin levels in septic patients. Crit Care Med 2004; 32: 1004–10.CrossRefGoogle ScholarPubMed
15Arnon, S, Litmanovitz, I, Regev, R, Lis, M, Shainkin-Kestenbaum, R, Dolfin, T. The prognostic virtue of inflammatory markers during late-onset sepsis in preterm infants. J Perinat Med 2004; 32: 176–80.Google Scholar
16Ng, PC, Cheng, SH, Chui, KM, Fok, TF, Wong, MY, 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 Child Fetal Neonatal Ed 1997; 77: F22127.Google Scholar
17Ng, PC, Li, K, Wong, RP, Chui, K, Wong, E, Li, G et al. Proinflammatory and anti-inflammatory cytokine responses in preterm infants with systemic infections. Arch Dis Child Fetal Neonatal Ed 2003; 88: F20913.CrossRefGoogle ScholarPubMed
18Schultz, C, Temming, P, Bucsky, P, Gopel, W, Strunk, T, Hartel, C. Immature anti-inflammatory response in neonates. Clin Exp Immunol 2004; 135: 130–36.Google Scholar
19Hodge, G, Hodge, S, Haslam, R, McPhee, A, Sepulveda, H, Morgan, E et al. Rapid simultaneous measurement of multiple cytokines using 100 microl sample volumes–association with neonatal sepsis. Clin Exp Immunol 2004; 137: 402407.CrossRefGoogle ScholarPubMed
20Procianoy, RS, Silveira, RC. The role of sample collection timing on interleukin-6 levels in early-onset neonatal sepsis. J Pediatr 2004; 80: 407–10.Google Scholar
21Verboon-Maciolek, MA, Thijsen, SF, Hemels, MA, Menses, M, van Loon, AM, Krediet, TG et al. Inflammatory mediators for the diagnosis and treatment of sepsis in early infancy. Pediatr Res 2006; 59: 457–61.CrossRefGoogle ScholarPubMed
22D'Alquen, D, Kramer, BW, Seidenspinner, S, Marx, A, Berg, D, Groneck, P et al. Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis. Pediatr Res 2005; 57: 263–69.CrossRefGoogle ScholarPubMed
23Franz, AR, Bauer, K, Schalk, A, Garland, SM, Bowman, ED, Rex, K 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: 18.Google Scholar
24Horisberger, T, Harbarth, S, Nadal, D, Baenziger, O, Fischer, JE. G-CSF and IL-8 for early diagnosis of sepsis in neonates and critically ill children – safety and cost effectiveness of a new laboratory prediction model: study protocol of a randomized controlled trial. Crit Care 2004; 8: R44350.CrossRefGoogle ScholarPubMed
25Orlikowsky, TW, Neunhoeffer, F, Goelz, R, Eichner, M, Henkel, C, Zwirner, M et al. Evaluation of IL-8-concentrations in plasma and lysed EDTA-blood in healthy neonates and those with suspected early onset bacterial infection. Pediatr Res 2004; 56: 804809.CrossRefGoogle ScholarPubMed
26van Dissel, JT, van Langevelde, P, Westendorp, RG, Kwappenberg, K, Frolich, M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351: 950–53.Google Scholar
27Ng, PC, Li, K, Leung, TF, Wong, RP, Li, G, Chui, KM et al. Early prediction of sepsis-induced disseminated intravascular coagulation with interleukin-10, interleukin-6, and RANTES in preterm infants. Clin Chem 2006; 52: 1181–189.CrossRefGoogle ScholarPubMed
28Ng, 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 (in press).CrossRefGoogle Scholar
29Ng, PC, Li, G, Chui, KM, Chu, WC, Li, K, Wong, RP et al. Neutrophil CD64 is a sensitive diagnostic marker for early-onset neonatal infection. Pediatr Res 2004; 56: 796803.Google Scholar
30Ng, PC, Li, K, Wong, RP, Chui, KM, Wong, E, Fok, TF. Neutrophil CD64 expression: a sensitive diagnostic marker for late-onset nosocomial infection in very low birthweight infants. Pediatr Res 2002; 51: 296303.CrossRefGoogle ScholarPubMed
31Hodge, G, Hodge, S, Han, P, Haslam, R. Multiple leucocyte activation markers to detect neonatal infection. Clin Exp Immunol 2004; 135: 125–29.CrossRefGoogle ScholarPubMed
32Turunen, 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: 270–75.CrossRefGoogle ScholarPubMed
33Nupponen, I, Andersson, S, Jarvenpaa, AL, Kautiainen, H, Repo, H. Neutrophil CD11b expression and circulating interleukin-8 as diagnostic markers for early-onset neonatal sepsis. Pediatrics 2001; 108: E12.CrossRefGoogle ScholarPubMed
34Weinschenk, NP, Farina, A, Bianchi, DW. Premature infants respond to early-onset and late-onset sepsis with leukocyte activation. J Pediatr 2000; 137: 345–50.CrossRefGoogle ScholarPubMed
35Nupponen, I, Pesonen, E, Andersson, S, Makela, A, Turunen, R, Kautiainen, H et al. Neutrophil activation in preterm infants who have respiratory distress syndrome. Pediatrics 2002; 110: 3641.CrossRefGoogle ScholarPubMed
36Hallwirth, U, Pomberger, G, Zaknun, D, Szepfalusi, Z, Horcher, E, Pollak, A et al. Monocyte phagocytosis as a reliable parameter for predicting early-onset sepsis in very low birthweight infants. Early Hum Dev 2002; 67: 19.Google Scholar
37Ng, PC, Li, G, Chui, KM, Chu, WC, Li, K, Wong, RP et al. Quantitative Measurement of Monocyte HLA-DR Expression in the Identification of Early-Onset Neonatal Infection. Biol Neonate 2005; 89: 7581.CrossRefGoogle ScholarPubMed
38Hodge, S, Hodge, G, Flower, R, Han, P. Surface activation markers of T lymphocytes: role in the detection of infection in neonates. Clin Exp Immunol 1998; 113: 3338.CrossRefGoogle ScholarPubMed
39Hodge, G, Hodge, S, Markus, C, Lawrence, A, Han, P. A marked decrease in L-selectin expression by leucocytes in infants with Bordetella pertussis infection: leucocytosis explained? Respirology 2003; 8: 157–62.CrossRefGoogle ScholarPubMed
40Resch, B, Gusenleitner, W, Muller, WD. Procalcitonin and interleukin-6 in the diagnosis of early-onset sepsis of the neonate. Acta Paediatr 2003; 92: 243–45.CrossRefGoogle ScholarPubMed
41Pavcnik-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. Intensive Care Med 2004; 30: 1454–460.CrossRefGoogle ScholarPubMed
42van Rossum, AM, Wulkan, RW, Oudesluys-Murphy, AM. Procalcitonin as an early marker of infection in neonates and children. Lancet Infect Dis 2004; 4: 620–30.Google Scholar
43Thayyil, S, Shenoy, M, Hamaluba, M, Gupta, A, Frater, J, Verber, IG. Is procalcitonin useful in early diagnosis of serious bacterial infections in children? Acta Paediatr 2005; 94: 155–58.Google Scholar
44Arnon, S, Litmanovitz, I, Regev, R, Bauer, S, Lis, M, Shainkin-Kestenbaum, R et al. Serum amyloid A protein is a useful inflammatory marker during late-onset sepsis in preterm infants. Biol Neonate 2005; 87: 105–10.CrossRefGoogle ScholarPubMed
45Lannergard, A, Friman, G, Ewald, U, Lind, L, Larsson, A. Serum amyloid A (SAA) protein and high-sensitivity C-reactive protein (hsCRP) in healthy newborn infants and healthy young through elderly adults. Acta Paediatr 2005; 94: 1198–202.CrossRefGoogle ScholarPubMed
46Behrendt, D, Dembinski, J, Heep, A, Bartmann, P. Lipopolysaccharide binding protein in preterm infants. Arch Dis Child Fetal Neonatal Ed 2004; 89: F55154.CrossRefGoogle ScholarPubMed
47Fries, E, Kaczmarczyk, A. Inter-alpha-inhibitor, hyaluronan and inflammation. Acta Biochim Pol 2003; 50: 735–42.Google Scholar
48Lim, YP, Bendelja, K, Opal, SM, Siryaporn, E, Hixson, DC, Palardy, JE. Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis. J Infect Dis 2003; 188: 919–26.Google Scholar
49Baek, YW, Brokat, S, Padbury, JF, Pinar, H, Hixson, DC, Lim, YP. Inter-alpha inhibitor proteins in infants and decreased levels in neonatal sepsis. J Pediatr 2003; 143: 11–5.CrossRefGoogle ScholarPubMed
50Turner, D, Hammerman, C, Rudensky, B, Schlesinger, Y, Goia, C, Schimmel, MS. Procalcitonin in preterm infants during the first few days of life: introducing an age related nomogram. Arch Dis Child Fetal Neonatal Ed 2006; 91: F28386.CrossRefGoogle ScholarPubMed
51Resch, B, Gusenleitner, W, Muller, W. Procalcitonin, interleukin-6, C-reactive protein and leukocyte counts in infants with bronchiolitis. Pediatr Infect Dis J 2003; 22: 475–76.CrossRefGoogle ScholarPubMed
52Joram, N, Boscher, C, Denizot, S, Loubersac, V, Winer, N, Roze, JC et al. Umbilical cord blood procalcitonin and C reactive protein concentrations as markers for early diagnosis of very early onset neonatal infection. Arch Dis Child Fetal Neonatal Ed 2006; 91: F6566.Google Scholar
53Peters, RP, Savelkoul, PH, Simoons-Smit, AM, Danner, SA, Vandenbroucke-Grauls, CM, van Agtmael, MA. Faster identification of pathogens in positive blood cultures by fluorescence in situ hybridization in routine practice. J Clin Microbiol 2006; 44: 119–23.Google Scholar
54Marlowe, EM, Hogan, JJ, Hindler, JF, Andruszkiewicz, I, Gordon, P, Bruckner, DA. Application of an rRNA probe matrix for rapid identification of bacteria and fungi from routine blood cultures. J Clin Microbiol 2003; 41: 5127–133.CrossRefGoogle ScholarPubMed
55Saglani, S, Harris, KA, Wallis, C, Hartley, JC. Empyema: the use of broad range 16S rDNA PCR for pathogen detection. Arch Dis Child 2005; 90: 7073.Google Scholar
56Breitkopf, C, Hammel, D, Scheld, HH, Peters, G, Becker, K. Impact of a molecular approach to improve the microbiological diagnosis of infective heart valve endocarditis. Circulation 2005; 111: 1415–421.CrossRefGoogle ScholarPubMed
57Call, DR, Bakko, MK, Krug, MJ, Roberts, MC. Identifying antimicrobial resistance genes with DNA microarrays. Antimicrob Agents Chemother 2003; 47: 3290–295.CrossRefGoogle ScholarPubMed
58Perreten, V, Vorlet-Fawer, L, Slickers, P, Ehricht, R, Kuhnert, P, Frey, J. Microarray-based detection of 90 antibiotic resistance genes of gram-positive bacteria. J Clin Microbiol 2005; 43: 2291–302.CrossRefGoogle ScholarPubMed
59Rantakokko-Jalava, K, Jalava, J. Optimal DNA isolation method for detection of bacteria in clinical specimens by broad-range PCR. J Clin Microbiol 2002; 40: 4211–217.Google Scholar
60Wittenhagen, P, Kronborg, G, Weis, N, Nielsen, H, Obel, N, Pedersen, SS et al. The plasma level of soluble urokinase receptor is elevated in patients with Streptococcus pneumoniae bacteraemia and predicts mortality. Clin Microbiol Infect 2004; 10: 409–15.Google Scholar
61Ward, PA. The dark side of C5a in sepsis. Nat Rev Immunol 2004; 4: 133–42.Google Scholar
62Huber-Lang, M, Sarma, JV, Rittirsch, D, Schreiber, H, Weiss, M, Flierl, M et al. Changes in the novel orphan, C5a receptor (C5L2), during experimental sepsis and sepsis in humans. J Immunol 2005; 174: 1104–10.Google Scholar