Date Published: July 7, 2014
Publisher: Public Library of Science
Author(s): Susanna Esposito, Alberto Zampiero, Lorenza Pugni, Silvia Tabano, Claudio Pelucchi, Beatrice Ghirardi, Leonardo Terranova, Monica Miozzo, Fabio Mosca, Nicola Principi, Stefan Bereswill.
Identifying single nucleotide polymorphisms (SNPs) in the genes involved in sepsis may help to clarify the pathophysiology of neonatal sepsis. The aim of this study was to evaluate the relationships between sepsis in pre-term neonates and genes potentially involved in the response to invasion by infectious agents. The study involved 101 pre-term neonates born between June 2008 and May 2012 with a diagnosis of microbiologically confirmed sepsis, 98 pre-term neonates with clinical sepsis and 100 randomly selected, otherwise healthy pre-term neonates born during the study period. During the study, 47 SNPs in 18 candidate genes were genotyped on Guthrie cards using an ABI PRISM 7900 HT Fast real-time and MAssARRAY for nucleic acids instruments. Genotypes CT and TT of rs1143643 (the IL1β gene) and genotype GG of rs2664349GG (the MMP-16 gene) were associated with a significantly increased overall risk of developing sepsis (p = 0.03, p = 0.05 and p = 0.03), whereas genotypes AG of rs4358188 (the BPI gene) and CT of rs1799946 (the DEFβ1 gene) were associated with a significantly reduced risk of developing sepsis (p = 0.05 for both). Among the patients with bacteriologically confirmed sepsis, only genotype GG of rs2664349 (the MMP-16 gene) showed a significant association with an increased risk (p = 0.02). Genotypes GG of rs2569190 (the CD14 gene) and AT of rs4073 (the IL8 gene) were associated with a significantly increased risk of developing severe sepsis (p = 0.05 and p = 0.01). Genotype AG of rs1800629 (the LTA gene) and genotypes CC and CT of rs1341023 (the BPI gene) were associated with a significantly increased risk of developing Gram-negative sepsis (p = 0.04, p = 0.04 and p = 0.03). These results show that genetic variability seems to play a role in sepsis in pre-term neonates by influencing susceptibility to and the severity of the disease, as well as the risk of having disease due to specific pathogens.
Despite significant advances in supportive care, neonatal sepsis continues to be a major cause of morbidity and mortality, particularly among premature infants. It occurs in 1/1,000 full-term and 4/1,000 premature live births, and mortality rates can reach values up to 20% in some settings and among very low-birth-weight (VLBW) infants –.
During the study period, the parents of two premature neonates in the group with clinical sepsis and a negative blood culture withdrew their authorisation to use their children’s blood and clinical data. Consequently, the results refer to 101 children with microbiologically confirmed sepsis, 98 patients with clinical sepsis and no positive blood culture, and 100 controls. Table 2 shows the demographic and clinical characteristics of the three groups, which were perfectly comparable in terms of gestational age, birth weight, gender, ethnicity and cesarean delivery. The neonates with microbiologically confirmed or clinical sepsis required mechanical ventilation significantly more frequently (p<0.05) and had a significantly worse outcome (p<0.05) than the controls, thus confirming the importance of sepsis in conditioning the final outcome. However, there was no difference in these variable between the two sepsis groups. The children with microbiological or clinical sepsis had late-onset sepsis (>72 hours) occurring at an average age of respectively 24 and 26 days.
Identifying genetic variants that can predict human susceptibility to, and outcomes of sepsis may help to identify patients at higher risk of death or serious complications who require prompt and aggressive therapy. This is extremely important in premature neonates, who are at highest risk of developing poorly controllable severe bacterial infections for a number of reasons. Susceptibility to sepsis in our study population was related to SNPs in the IL1β, MMP-16, BPI, and DEFβ1 genes. However, whereas SNPs in the IL1β and in MMP-16 genes were associated with an increased risk of sepsis, variations of BPI and DEFβ1 seemed to play a protective role.