Early inflammation in the absence of overt infection in preterm neonates exposed to intensive care

Chang, Brent A.; Huang, Qing; Quan, Joanne; Chau, Vann; Ladd, Mihoko; Kwan, Eddie; McFadden, Deborah E.; Lacaze‐Masmonteil, Thierry; Miller, Steven P.; Lavoie, Pascal M.

doi:10.1016/j.cyto.2011.08.028

Cited by 33 publications

(30 citation statements)

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“…High circulating levels of inflammatory cytokines have been observed in very preterm infants exposed to intensive care (11) and have been repeatedly linked to worse outcomes such as bronchopulmonary dysplasia (12), white matter injury, and neurodevelopmental impairments (16). These results have led to speculations that the innate immune system of these infants is hyper-rather than hypo-responsive during the neonatal period (17).…”

Section: Discussionmentioning

confidence: 94%

“…We and others have shown that TLR-induced cytokine immune reactivity are profoundly attenuated in cord blood of very preterm neonates and develops asynchronously over the last trimester of gestation (6)(7)(8)(9)(10). These infants also display sustainably high levels of systemic inflammation, indicating a potential immune dysregulation that has also been associated with worsened clinical outcomes (11). On the other hand, cord blood responses may not adequately reflect important developmental adaptation occurring during the first few weeks after birth.…”

mentioning

confidence: 99%

“…To avoid an experimental historical bias during recruitment, a proportional number of preterm, term, and adult subjects were tested over the course of the study. Chorioamnionitis was defined histologically as previously described (11). Antenatal corticosteroid and magnesium sulfate exposure were defined as occurring within 72 and 24 h prior to delivery, respectively.…”

Section: Study Populationmentioning

confidence: 99%

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Attenuated innate immune defenses in very premature neonates during the neonatal period

et al. 2015

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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.d espite improvements in neonatal health care, mortality from infections has continued to increase in very preterm neonates over the last two decades, owing to the improved survival of smaller and more vulnerable infants (1). However, the underlying immunological basis of their high morbidities and high vulnerability to sepsis remains poorly understood (2). To defend themselves against infection, neonates rely on first-line, innate immune defense mechanisms. These mechanisms include the detection of specific microbial molecular structures called pathogenassociated molecular patterns through specialized receptors termed pattern recognition receptors (PRR), but also other defense mechanisms such as phagocytosis and antigen presentation to the adaptive immune system.It is widely stated that the high risk of neonatal sepsis observed in these infants is due to immature immune defense mechanisms. However, data are lacking on the development of immune functions beyond measures performed on umbilical cord blood. Recent studies have reported reduced antigen-presenting receptor expression during the first week of age in infants born below 33 wk of gestation (3,4). In contrast, phagocytic functions in these infants are more comparable to term infants (5). Toll-like receptors (TLRs) play a predominant role as a major family of PRR that act as essential "detectors" in the recognition of microbial pathogens by the innate immune system. We and others have shown that TLR-induced cytokine immune reactivity are profoundly attenuated in cord blood of very preterm neonates and develops asynchronously over the last trimester of gestation (6-10). These infants als...

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

Section: Study Populationmentioning

confidence: 99%

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Attenuated innate immune defenses in very premature neonates during the neonatal period

et al. 2015

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“…The findings have important clinical implications, since earlier studies have indicated that transient bacteremia commonly occurs in infants with sepsis [100,101]. Another study has demonstrated persistent sub-clinical inflammation in the absence of overt clinical signs of infection in these infants throughout the neonatal period, possibly due to an ongoing exposure to intensive care therapies [102]. In light of these findings, better strategies will be necessary to both limit the sustained exposure of premature infants to any potential triggers of inflammation or sources of transient bacteremia, and to prevent infections [103].…”

Section: Lessons From Neonatal Mouse Modelsmentioning

confidence: 89%

An Immunological Perspective on Neonatal Sepsis

Kan

Razzaghian

Lavoie

2016

Trends in Molecular Medicine

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Despite concerted international efforts, mortality from neonatal infections remains unacceptably high in some areas of the world, particularly for premature infants. Recent developments in flow cytometry and next-generation sequencing technologies have led to major discoveries over the past few years, providing a more integrated understanding of the developing human immune system in the context of its microbial environment. We review these recent findings, focusing on how in human newborns incomplete maturation of the immune system before a full term of gestation impacts on their vulnerability to infection. We also discuss some of the clinical implications of this research in guiding the design of more-accurate age-adapted diagnostic and preventive strategies for neonatal sepsis.

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“…38,[41][42][43][44] In extreme preterm infants, high systemic inflammatory biomarkers are measured in the earliest hours after birth and for extended periods of time during the neonatal period, particularly in infants exposed to mechanical ventilation and supplemental O 2 . [45][46][47][48][49] Preterm infants also have a limited ability to counteract inflammatory and oxidative stress during the neonatal period. 50 Sustained oxidative stress and inflammation are key factors contributing to the development of BPD as well as other neonatal complications.…”

Section: Figurementioning

confidence: 99%

Omega-3 Long-Chain Polyunsaturated Fatty Acids for Extremely Preterm Infants: A Systematic Review

et al. 2014

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BACKGROUND AND OBJECTIVE: Omega-3 long chain polyunsaturated fatty acid (LCPUFA) exposure can be associated with reduced neonatal morbidities. We systematically review the evidence for the benefits of omega-3 LCPUFAs for reducing neonatal morbidities in extremely preterm infants.METHODS: Data sources were PubMed, Embase, Center for Reviews and Dissemination, and the Cochrane Register of Controlled Trials. Original studies were selected that included infants born at ,29 weeks' gestation, those published until May 2013, and those that evaluated the relationship between omega-3 LCPUFA supplementation and major adverse neonatal outcomes. Data were extracted on study design and outcome. Effect estimates were pooled. RESULTS:Of the 1876 studies identified, 18 randomized controlled trials (RCTs) and 6 observational studies met the defined criteria. No RCT specifically targeted a population of extremely preterm infants. Based on RCTs, omega-3 LCPUFA was not associated with a decreased risk of bronchopulmonary dysplasia in infants overall (pooled risk ratio [RR] 0.97, 95% confidence interval [CI] 0.82-1.13], 12 studies, n = 2809 infants); however, when considering RCTs that include only infants born at #32 weeks' gestation, a trend toward a reduction in the risk of bronchopulmonary dysplasia (pooled RR 0.88, 95% CI 0.74-1.05, 7 studies, n = 1156 infants) and a reduction in the risk of necrotizing enterocolitis (pooled RR 0.50, 95% CI 0.23-1.10, 5 studies, n = 900 infants) was observed with LCPUFA.CONCLUSIONS: Large-scale interventional studies are required to determine the clinical benefits of omega-3 LCPUFA, specifically in extremely preterm infants, during the neonatal period. Dr Marc conceptualized and designed the protocol, screened the titles and abstracts, and retrieved articles for inclusion and quality, performed the analyses, drafted the initial manuscript, and approved the final manuscript as submitted; Ms Zhang critically reviewed the protocol, screened the titles and abstracts and retrieved articles for inclusion and quality, drafted the tables and figures, and reviewed the final manuscript as submitted; Dr Lavoie screened the articles for quality, revised the manuscript, participated in the redaction of the final manuscript, and reviewed the final manuscript as submitted; Dr Rhainds designed and conducted the systematic database search, reviewed the manuscript, and approved the final manuscript as submitted; and Dr Lacaze-Masmonteil reviewed the manuscript and approved the final manuscript as submitted.www.pediatrics.org/cgi

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Early inflammation in the absence of overt infection in preterm neonates exposed to intensive care

Abstract: Background-Systemic inflammation, typically attributed to sepsis, has been repeatedly linked to adverse long-term outcomes in infants born prematurely. However, it is unclear whether other factors can contribute to potentially harmful systemic inflammatory responses.

Cited by 33 publications

References 30 publications

Attenuated innate immune defenses in very premature neonates during the neonatal period

Attenuated innate immune defenses in very premature neonates during the neonatal period

An Immunological Perspective on Neonatal Sepsis

Omega-3 Long-Chain Polyunsaturated Fatty Acids for Extremely Preterm Infants: A Systematic Review

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