Abstract
Background:
Antimicrobial responses have been shown to be profoundly attenuated in very preterm neonates when examined on cord blood. However, we lack data on these responses at the time these neonates are most vulnerable to infections.
Methods:
Multiple cytokine responses to two prototypic Toll-like receptor (TLR) agonists: lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8) were prospectively measured in preterm neonates born ≤30 wk of gestation (n = 50) during the first 28 d of age using whole blood and single-cell multiparameter flow cytometry assays. Results were compared to term neonates (n = 30) and adult controls (n = 25).
Results:
In preterm neonates, LPS and R848 responses remained attenuated in both cord blood and in the first 28 d of age. These responses showed significant maturation over time after adjusting for gestational age and were confirmed in monocytes and dendritic cells on a per-cell basis. We detected no major contribution of chorioamnionitis, maternal antenatal corticosteroids or magnesium sulfate treatment, labor, or mode of delivery to the maturation of cytokine responses.
Conclusion:
Innate immune antimicrobial defenses are profoundly attenuated developmentally in very preterm neonates during the neonatal period, suggesting that exogenous factors drive the sustained systemic inflammation that has been linked to increased morbidities in these infants.
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References
Berrington JE, Hearn RI, Bythell M, Wright C, Embleton ND. Deaths in preterm infants: changing pathology over 2 decades. J Pediatr 2012;160:49–53.e1.
Sharma AA, Jen R, Butler A, Lavoie PM. The developing human preterm neonatal immune system: a case for more research in this area. Clin Immunol 2012;145:61–8.
Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Immune status in very preterm neonates. Pediatrics 2012;129:e967–74.
Palojärvi A, Andersson S, Turpeinen U, Janér C, Petäjä J. Antenatal betamethasone associates with transient immunodepression in very low birth weight infants. Neonatology 2013;104:275–82.
Prosser A, Hibbert J, Strunk T, et al. Phagocytosis of neonatal pathogens by peripheral blood neutrophils and monocytes from newborn preterm and term infants. Pediatr Res 2013;74:503–10.
Strunk T, Prosser A, Levy O, et al. Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation. Pediatr Res 2012;72:10–8.
Lavoie PM, Huang Q, Jolette E, et al. Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis. J Infect Dis 2010;202:1754–63.
Sharma AA, Jen R, Brant R, et al. Hierarchical maturation of innate immune defences in very preterm neonates. Neonatology 2014;106:1–9.
Förster-Waldl E, Sadeghi K, Tamandl D, et al. Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging. Pediatr Res 2005;58:121–4.
Sadeghi K, Berger A, Langgartner M, et al. Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. J Infect Dis 2007;195:296–302.
Chang BA, Huang Q, Quan J, et al. Early inflammation in the absence of overt infection in preterm neonates exposed to intensive care. Cytokine 2011;56:621–6.
Paananen R, Husa AK, Vuolteenaho R, Herva R, Kaukola T, Hallman M. Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia. J Pediatr 2009;154:39–43.e3.
Belderbos ME, Levy O, Stalpers F, Kimpen JL, Meyaard L, Bont L. Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors. PLoS One 2012;7:e33419.
Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR. Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 2004;173:4627–34.
Shen CM, Lin SC, Niu DM, Kou YR. Development of monocyte Toll-like receptor 2 and Toll-like receptor 4 in preterm newborns during the first few months of life. Pediatr Res 2013;73:685–91.
Strunk T, Inder T, Wang X, Burgner D, Mallard C, Levy O. Infection-induced inflammation and cerebral injury in preterm infants. Lancet Infect Dis 2014;14:751–62.
Wright CJ, Kirpalani H. Targeting inflammation to prevent bronchopulmonary dysplasia: can new insights be translated into therapies? Pediatrics 2011;128:111–26.
Picard C, von Bernuth H, Ghandil P, et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore) 2010;89:403–25.
Currie AJ, Davidson DJ, Reid GS, et al. Primary immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signaling. J Pediatr 2004;144:512–8.
Lavoie PM. Earlier initiation of enteral nutrition is associated with lower risk of late-onset bacteremia only in most mature very low birth weight infants. J Perinatol 2009;29:448–54.
Isaacs D ; Australasian Study Group For Neonatal Infections. A ten year, multicentre study of coagulase negative staphylococcal infections in Australasian neonatal units. Arch Dis Child Fetal Neonatal Ed 2003;88:F89–93.
Kramer BW, Ikegami M, Moss TJ, Nitsos I, Newnham JP, Jobe AH. Endotoxin-induced chorioamnionitis modulates innate immunity of monocytes in preterm sheep. Am J Respir Crit Care Med 2005;171:73–7.
Newnham JP, Kallapur SG, Kramer BW, et al. Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep. Am J Obstet Gynecol 2003;189:1458–66.
Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: Simplified newborn illness severity and mortality risk scores. J Pediatr 2001;138:92–100.
Jansen K, Blimkie D, Furlong J, et al. Polychromatic flow cytometric high-throughput assay to analyze the innate immune response to Toll-like receptor stimulation. J Immunol Methods 2008;336:183–92.
Acknowledgements
We thank Jennifer Claydon for coordination of the study, Kristi Finlay and the BC Women’s Hospital delivery room staff for help with recruitment of subjects, and Rosemary Delnavine for editorial revisions.
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Marchant, E., Kan, B., Sharma, A. et al. Attenuated innate immune defenses in very premature neonates during the neonatal period. Pediatr Res 78, 492–497 (2015). https://doi.org/10.1038/pr.2015.132
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DOI: https://doi.org/10.1038/pr.2015.132
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