Genome-Wide Expression Profiles in Very Low Birth Weight Infants With Neonatal Sepsis

Abstract

BACKGROUND: Bacterial sepsis is associated with high morbidity and mortality in preterm infants. However, diagnosis of sepsis and identification of the causative agent remains challenging. Our aim was to determine genome-wide expression profiles of very low birth weight (VLBW) infants with and without bacterial sepsis and assess differences. METHODS: This was a prospective observational double-cohort study conducted in VLBW (<1500 g) infants with culture-positive bacterial sepsis and non-septic matched controls. Blood samples were collected as soon as clinical signs of sepsis were identified and before antibiotics were initiated. Total RNA was processed for genome-wide expression analysis using Affymetrix gene arrays. RESULTS: During a 19-month period, 17 septic VLBW infants and 19 matched controls were enrolled. First, a three-dimensional unsupervised principal component analysis based on the entire genome (28 000 transcripts) identified 3 clusters of patients based on gene expression patterns: Gram-positive sepsis, Gram-negative sepsis, and noninfected control infants. Furthermore, these groups were confirmed by using analysis of variance, which identified a transcriptional signature of 554 of genes. These genes had a significantly different expression among the groups. Of the 554 identified genes, 66 belonged to the tumor necrosis factor and 56 to cytokine signaling. The most significantly overexpressed pathways in septic neonates related with innate immune and inflammatory responses and were validated by real-time reverse transcription polymerase chain reaction. CONCLUSIONS: Our preliminary results suggest that genome-wide expression profiles discriminate septic from nonseptic VLBW infants early in the neonatal period. Further studies are needed to confirm these findings.

An Immunological Perspective on Neonatal Sepsis

“…This justifies direct observations in humans [106]. Most recently, two important genome-wide gene expression studies have provided insights into the molecular pathways activated in newborns with severe infections [88,107]. For instance, on the one hand marked transcriptional alterations in metabolic pathways associated with glucose transport, glycolysis, and cholesterol homeostasis, transport, and metabolism have been detected in newborns during active sepsis [88].…”

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

“…For example, the inclusion of preterm infants with a single blood culture positive for coagulase-negative Staphylococcus (CoNS) may be considered sepsis (33), which is outside of the accepted Centers for Disease Control and Prevention definition for CoNS infection (34). CoNS can be a causative organism of sepsis in neonates but is also considered a frequent contaminant, especially when not supported by documented sustained clinical or laboratory aberrations (33,35). To avoid this important potential limitation in our investigation, we used a mixed (clinical and laboratory) definition for sepsis that incorporated (a) timing of the sepsis event relative to birth, (b) persistence of significant clinical signs for at least 2 d, (c) objective evidence of a systemic inflammatory response and (d) exclusion of all CoNS infections.…”

Pathophysiology of Neonatal Sepsis

“…A study of VLBW infants with blood culture-proven late-onset sepsis (59% CoNS) identified a 554-gene signature associated with sepsis, with increased expression of the TNF-α network, including matrix metalloproteinase 8 and CD177 among the most commonly up-regulated genes. 465 Elevated matrix metalloproteinase 8 mRNA expression and activity in septic shock correlated with decreased survival and increased organ failure in pediatric patients. Matrix metalloproteinase 8 is a direct activator of NF-κB.…”