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Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the Ϫ159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannosebinding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture-proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n ϭ15) and the IL6-174G allele (n ϭ121) had a significantly higher rate of blood culture-proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p ϭ 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; p Ͻ 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0 -3.9; p ϭ 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0 -10.4; p ϭ 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5% versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p ϭ 0.033). Although advances in neonatal intensive care have led to improved survival, sepsis continues to be an important cause of death among VLBW infants (1, 2). Recent advances in our understanding of the innate immune system triggered the identification of specific point mutations that are associated with an altered response of the innate immune system. CD14 is the main receptor for bacterial LPS and is expressed on the surface of phagocytes. In adults, the homozygotic Ϫ159T mutation of the CD14 gene (CD14-159T) is associated with a high mortality rate in sepsis (3). The TLR4 is a coreceptor for LPS, harboring a transmembrane domain, which is important for intracellular signaling. The 896G mutation of the TLR4 (TLR4-896G) leads in vitro to a reduced NF-B activation after LPS stimulation, and in vivo to a reduced systemic inflammatory response after LPS inhalation (4). This mutation was found frequently in adults who developed septic shock (5), suggesting an association of this mutation with sepsis. NOD2 is a gene that also confers responsiveness to bacterial LPS. The NOD2-3020insC mutation is associated in vitro with reduced NF-B response after stimulation with several Gram-negative bacteria (6) and is associated with Crohns' disease (6 -8). IL-6 is an important proinf...

There is growing evidence that sepsis-related complications in neonates are crucially mediated by the action of proinflammatory cytokines. It has previously been demonstrated that elevated IL-6 and IL-8 levels can predict brain damage and chronic lung disease in preterm infants. However, it is the current view that neonates have a reduced capability to produce proinflammatory cytokines. To clarify this issue, we analyzed the inflammatory response in term and preterm infants directly at the single cell level by flow cytometry. Endotoxin challenge was performed under defined conditions on monocytes obtained from 50 healthy adults and 119 neonates, which consist of 45 term infants, 63 preterm infants (26.1-36.7 wk of gestational age), and 11 preterm infants with proven infection (24.6 -29.9 wk). Our results challenge the existing view of an immature inflammatory response by demonstrating that term infants and preterm infants display a higher percentage of IL-6 -and IL-8 -positive cells than adults. After preincubation with dexamethasone the number of cytokine-positive cells decreased in all groups, but the number of IL-8 -positive cells remained higher in term and preterm infants Ͼ32 wk compared with adults. These observations demonstrate not only a well-developed but also an enhanced inflammatory response in term and preterm infants. Under consideration of several detrimental effects of IL-6 and IL-8, our data may have major implications on the pathophysiology of inflammatorytriggered neonatal diseases. Neonatal bacterial sepsis remains a critical determinant of outcome in infants of very low birth weight despite the availability of antibiotics (1-3). The immaturity of the neonatal immune system, especially a reduced cytokine-producing capacity, was assumed to be responsible for the high susceptibility to infections (4 -11). Particularly, the high prevalence of complications secondary to infections represents a major determinant of neonatal mortality and morbidity (3). Although older children and adults are usually able to restrict bacterial infections, neonates often develop a severe systemic inflammatory response with detrimental effects. There is growing evidence that this process is crucially mediated by the action of distinct inflammatory cytokines (12, 13). It has previously been demonstrated that elevated IL-6 and IL-8 levels in cord blood and lung lavage can predict neonatal brain damage and chronic lung disease in preterm infants (14 -16). Furthermore, proinflammatory cytokines could be demonstrated in high amounts in brain white matter lesions of preterm infants (17). These observations strongly suggest a key role of proinflammatory cytokines in the pathogenesis of several neonatal diseases. Although a variety of studies have been performed on inflammatory mediators in neonates during infection, these data can be misleading because of the evolving immunoparalysis occurring in progressing sepsis (18,19). To better characterize the inflammatory response in neonates we performed an ex vivo model of sepsis, ...

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