Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis

Wynn, James L.; Neu, Josef; Moldawer, Lyle L.; Levy, Ofer

doi:10.1038/jp.2008.132

Cited by 79 publications

(66 citation statements)

References 114 publications

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“…Many attempts have been made to improve immune function in neonates and reduce the incidence and burden of infection (31). The failure of these interventions in large randomized trials likely reflects underappreciated differences in the functional capacity of the neonatal host response (32).…”

Section: Discussionmentioning

confidence: 99%

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Wynn

Cvijanovich²,

Allen

et al. 2011

Mol Med

127

109

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Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock developmental-age groups defined as neonates (≤28 d, n = 17), infants (1 month to 1 year, n = 62), toddlers (2-5 years, n = 54) and schoolage (≥6 years, n = 47) and age-matched controls. Direct intergroup comparisons demonstrated profound changes in neonates, relative to older children. Neonates with septic shock demonstrated reduced expression of genes representing key pathways of innate and adaptive immunity. In contrast to the largely upregulated transcriptome in all other groups, neonates exhibited a predominantly downregulated transcriptome when compared with controls. Neonates and school-age subjects had the most uniquely regulated genes relative to controls. Age-specific studies of the host response are necessary to identify developmentally relevant translational opportunities that may lead to improved sepsis outcomes.

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Section: Discussionmentioning

confidence: 99%

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Wynn

Cvijanovich²,

Allen

et al. 2011

Mol Med

127

109

View full text Add to dashboard Cite

show abstract

“…In a large (n = 8,515) multicenter study of preterm infants born after <29 wks completed gestation, 36% developed sepsis during their birth hospitalization (3). Neither the treatment of neonatal sepsis nor the neurodevelopmental outcomes in surviving infants have changed significantly over the last 30 years despite multiple failed attempts to reduce the burden of infection (4,5). Accurate diagnostic tests for sepsis and prognostic tests to determine risk of poor outcome when infected are lacking.…”

Section: Introductionmentioning

confidence: 99%

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

Wynn

Guthrie

Wong

et al. 2015

Mol Med

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Neonates manifest a unique host response to sepsis even among other children. Preterm neonates may experience sepsis soon after birth or during often-protracted birth hospitalizations as they attain physiologic maturity. We examined the transcriptome using genome-wide expression profiling on prospectively collected peripheral blood samples from infants evaluated for sepsis within 24 h after clinical presentation. Simultaneous plasma samples were examined for alterations in inflammatory mediators. Group designation (sepsis or uninfected) was determined retrospectively on the basis of clinical exam and laboratory results over the next 72 h from the time of evaluation. Unsupervised analysis showed the major node of separation between groups was timing of sepsis episode relative to birth (early, <3 d, or late, ≥3 d). Principal component analyses revealed significant differences between patients with early or late sepsis despite the presence of similar key immunologic pathway aberrations in both groups. Unique to neonates, the uninfected state and host response to sepsis is significantly affected by timing relative to birth. Future therapeutic approaches may need to be tailored to the timing of the infectious event based on postnatal age.

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“…Death associated with neonatal sepsis has remained largely unchanged over the last 2 decades, and neonatal sepsis is responsible for more than 1 million deaths per year worldwide (13,25). Mortality rates are particularly elevated in very lowbirth-weight infants (Ͻ1,500 g at birth) and have been reported to be as high as 50% (12,24).…”

mentioning

confidence: 99%

Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis

et al. 2011

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Previous studies have suggested that neonates rely heavily on innate immunity for their antimicrobial response to bacterial infections. However, the innate immune response by neonates to bacterial infection remains poorly characterized. Here, we show that in a murine model of neonatal polymicrobial sepsis, CXC ligand 10 (CXCL10) concentrations increase in the blood and peritoneum concordant with the peritoneal recruitment of granulocytes and macrophages. Additionally, CXC receptor 3 (CXCR3) expression on elicited peritoneal macrophages and granulocytes increases following sepsis. Blockade of CXCL10 worsens not only recruitment and phagocytic function of peritoneal granulocytes and macrophages but also survival. Deletion of CXCR3 also significantly increases mortality to a septic challenge. Finally, we demonstrate that the protective adjuvant effect of pretreatment with a Toll-like receptor 4 agonist to neonatal sepsis is dependent on an endogenous CXCL10 response and that pretreatment of neonates with CXCL10 can also significantly improve macrophage and granulocyte function and modestly improve outcome to polymicrobial sepsis. Together, these data suggest a critical role for CXCL10 signaling during neonatal sepsis.

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Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis

Cited by 79 publications

References 114 publications

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis

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