Relationships among the concentrations of 25 inflammation-associated proteins during the first postnatal weeks in the blood of infants born before the 28th week of gestation

Leviton, Alan; Allred, Elizabeth N.; Yamamoto, Hidemi S.; Fichorova, Raina N.

doi:10.1016/j.cyto.2011.11.004

Cited by 33 publications

(35 citation statements)

References 47 publications

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“…14,15 In addition, a strong initial inflammatory insult initiates a cascade of events in which some mediators, such as IL-8, E-SEL and ICAM-1, occur downstream from others, including IL-1β and TNF-α, and consequently peak later 16 . This induction of multiple components of the inflammatory systems, is an example of a non-linear system in which changes in components of the inflammatory system alter relationships with other components.…”

Section: Discussionmentioning

confidence: 99%

“…That is what we found in this sample of very preterm newborns. 15 Elevated concentrations of 17 of the 25 proteins (including cytokines, chemokines, adhesion molecules, matrix metalloproteinases, a growth factor, its receptors, and a growth factor’s binding protein) were each associated with elevated concentrations of 15 or more other proteins.…”

Section: Discussionmentioning

confidence: 99%

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The Breadth and Type of Systemic Inflammation and the Risk of Adverse Neurological Outcomes in Extremely Low Gestation Newborns

Kuban

O’Shea

Allred

et al. 2015

Pediatric Neurology

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We hypothesized that the risk of brain damage in extremely preterm neonates increases with the breadth and type of systemic inflammation, indexed by the number of elevated inflammation-related proteins and the number of functional categories of inflammation-related proteins exhibiting an elevated concentration. Methods In blood from 881 infants born before 28 weeks gestation, we measured the concentrations of 25 inflammation-related proteins, representing 6 functional categories (cytokines, chemokines, growth factors, adhesion molecules, metalloproteinases, and liver-produced acute phase reactant proteins) on postnatal days 1, 7, and 14 and evaluated associations between the number and type of proteins whose concentrations were elevated on two separate occasions a week apart and the diagnoses of ventriculomegaly as a neonate, and, at 2 years, microcephaly, impaired early cognitive functioning, cerebral palsy, and autism risk as assessed with the Modified Checklist for Autism in Toddlers (M-CHAT) screen, and, in a subset of these children from 12 of 14 sites (n= 826), an attention problem identified with the Child Behavior Checklist (CBCL). Results The risk of abnormal brain structure and function overall was increased among children who had recurrent/persistent elevations of the 25 protein. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were elevated. When we focused our analysis on 10 proteins previously found to be associated consistently with neurological outcomes, we found the risk of low Mental Development Index (MDI) on the Bayley Scales of Infant Development-II, microcephaly, and a CBCL-defined attention problem increased with higher numbers of these recurrently/persistently elevated proteins. Interpretation Increasing breadth of early neonatal inflammation, indexed by the number of protein elevations or the number of protein functional classes elevated, is associated with increasing risk of disorders of brain structure and function among infants born extremely premature.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Breadth and Type of Systemic Inflammation and the Risk of Adverse Neurological Outcomes in Extremely Low Gestation Newborns

Kuban

O’Shea

Allred

et al. 2015

Pediatric Neurology

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“…Nonetheless, the 25 proteins selected represent broadly the mediators of inflammation including cytokines, chemokines, adhesion molecules, metalloproteinases, and growth factors that reflect all different steps of the inflammatory process [20] and not necessarily contributing unique information about a distinct or separate exposure, and in these sample their top quartile concentrations tend to vary together. [21]…”

Section: Methodsmentioning

confidence: 99%

The relationship between TSH and systemic inflammation in extremely preterm newborns

et al. 2014

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Purpose Elevated thyrotropin (TSH) levels in critically ill extremely premature infants have been attributed to transient hypothyroidism of prematurity or non-thyroidal illness syndrome. We evaluated the hypothesis that relatively high TSH levels in the first two postnatal weeks follow recovery from systemic inflammation, similar to non-thyroidal illness syndrome. Design/Methods The study was conducted in 14 Neonatal Intensive Care Units and approved by each individual Institutional Review Board. We measured the concentrations of TSH and 25 inflammation-related proteins in blood spots obtained on postnatal days 1, 7, and 14. We then evaluated the temporal relationships between hyperthyrotropinemia (HTT), defined as a TSH concentration in the highest quartile for gestational age and postnatal day, and elevated levels of inflammation-related proteins. Results 880 newborns less than 28 weeks of gestation were included. Elevated concentrations of inflammation-related proteins during the first or second week did not precede day-14 HTT. Systemic inflammation on day 7 was associated with day-14 HTT only if inflammation persisted through the end of the two week period. HTT frequently accompanied elevated concentrations of inflammation-related proteins on the same day. Conclusions The hypothesis that HTT follows recovery from severe illness, defined as preceding systemic inflammation, is weakly supported by our study. Our findings more prominently support the hypothesis that TSH conveys information about concomitant inflammation in the extremely premature newborn.

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“…With more than 600 children and our classifying exposure as the top quartile, and such outcomes as MDI < 55 identified in 96 children, we have a power of 0.95 to appreciate an odds ratio of 1.75. Other strengths are the selection of infants based on gestational age, not birth weight,[63] prospective collection of all data, examiners who were not aware of the medical histories of the children they examined, thereby minimizing “diagnostic suspicion bias,”[64] efforts to minimize observer variability in the assessment of neurodevelopmental functions,[65] modest attrition, and finally, protein data of high quality 19,20 , and high content validity. [14, 15, 19, 66]…”

Section: Discussionmentioning

confidence: 99%

“…[19, 20] In addition, one set of measurements was made in 2009–2010 and the second in 2015, and, while the distributions of each were similar, they were not identical. Consequently, we divided our sample into 30 groups defined by gestational age category (23–24, 25–26, 27 weeks), postnatal day of blood collection (1, 7, 14, 21 and 28), and measurement set (2009–2010, 2015).…”

Section: Methodsmentioning

confidence: 99%

Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation

Leviton

Allred

Fichorova

et al. 2016

Early Human Development

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Background Systemic inflammation during the first two postnatal weeks in extremely preterm newborns (< 28 weeks gestation) has been associated with an increased risk of neurodevelopmental dysfunctions. Little is known, however, about the relationship between systemic inflammation during the third and fourth postnatal weeks and subsequent development. Methods We measured the concentrations of 16 inflammation-related proteins in blood spots collected on postnatal days 21 (N = 749) and 28 (N = 697) from infants born before the 28th week of gestation and assessed at age 2 years. We then sought the developmental correlates of top quartile concentrations for gestational age and day the specimen was collected. Odds ratios and 95% confidence intervals were calculated from regular or multinomial logistic regression models (as appropriate). Results Top quartile concentrations of CRP, IL-1β, IL-6, IL-6R, TNF-R2, IL-8, ICAM-1, and TSH on both days 21 and 28 were associated with ventriculomegaly (when in the NICU) and microcephaly at age 2 years. Top quartile concentrations of CRP, SAA, IL-6, TNF-R2, IL-8, and ICAM-1 were associated with Mental Development Index (MDI) of the Bayley-II < 55, while top quartile concentrations of CRP, TNF-α (inversely), IL-8, and ICAM-1 were associated with Psychomotor Development Index (PDI) < 55 Conclusion Extremely preterm newborns who had systemic inflammation during the third and fourth postnatal weeks were at increased risk of ventriculomegaly during the months after birth, and of microcephaly, and low Bayley Scale scores at 2 years of age.

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Relationships among the concentrations of 25 inflammation-associated proteins during the first postnatal weeks in the blood of infants born before the 28th week of gestation

Cited by 33 publications

References 47 publications

The Breadth and Type of Systemic Inflammation and the Risk of Adverse Neurological Outcomes in Extremely Low Gestation Newborns

The Breadth and Type of Systemic Inflammation and the Risk of Adverse Neurological Outcomes in Extremely Low Gestation Newborns

The relationship between TSH and systemic inflammation in extremely preterm newborns

Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation

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