Γενετικοί πολυμορφισμοί προφλεγμονωδών και αντιφλεγμονωδών κυτταροκινών και ευπάθεια των νεογνών και βρεφών στην οξεία μέση ωτίτιδα

Abstract

Background: Acute otitis media (AOM) is the most common childhood infection, and despite the lower prevalence in neonates and early infancy, serious complications can occur. Pathogenesis is multi-factorial and little is known on the immature host responses to pathogens during otitis media. Extensive studies on the complex cytokine network and its genetically determined regulation have highlighted the significance as determinants of susceptibility and outcome of AOM.Objective: In the current study we investigated the genetic predisposition of the immune host’s response as related to susceptibility, severity and outcome of AOM in early infancy. For this purpose we have chosen 8 single nucleotide polymorphisms (SNPs) of pro-inflammatory and anti-inflammatory cytokines: IL6 (-174 G→C), IL10 (-1082 G→A, -819 C→T, -592 C→A), TNFα (-308 G→A), INFγ (+874 A→T), TGFβ1 (codon 10 C→T, codon 25 G→C).Methods: Neonates and infants with AOM hospitalized in pediatric units of University Hospital and Venizeleion General Hospital, both in Heraklion, Crete, during 2005-2006 were included and followed-up for three consecutive years. Demographics, history, clinical manifestations, and relapses were recorded. Cytokine single nucleotide polymorphisms were determined by the polymerase chain reaction method. We studied predisposing clinical factors affecting severity and chronicity of the disease, as well as cytokine genotypes as related to susceptibility, clinical course and outcome of AOM. Gender, patient’s atopy, exposure to smoke, siblings, breast feeding, and family history of AOM or atopy were considered as potential covariates in the epidemiological analysis. Results: 96 infants were analyzed, 58 (60.4%) were boys, mean age at enrolment was 2.4 months (range 0.6-7.92), and 52 (54%) were younger than 3 months. At the end of follow-up period, 81 (84.4%) infants presented with recurrent AOM episodes. Gastro-esophageal regurgitation, patient’s atopy and positive family history of AOM were related to increased recurrence rates (p=0.01, p=0.01, and p=0.02 respectively). IL10 (-1082) A and TGFβ1 (codon 10) T minor alleles were related to older age of AOM onset than the wild-type genotypes (p=0.007 and p=0.0039 respectively). As compared to wild genotypes, IL10 (-592 C→A, -819 C→T, -1082 G→A) θαη TGFβ1 (codon 10 C→T) genotypes carrying the alternative gene were related to more AOM episodes (p<0.0001, p<0.0001, p<0.0001, and p=0.002, respectively) and need for tympanostomy tubes (p=0.021, p=0.021, p=0.036, and p=0.049, respectively). The associations remained significant for AOM onset and recurrence after adjusting for confounding factors (multiple regression analysis).Conclusions: Our findings suggest that anti-inflammatory cytokine IL10 and TGFβ1 genotypes influence AOM onset, number of recurrent episodes and tympanostomy tube placement. This evidence expands our understanding toward pathogenesis and outlines the anti-inflammatory cytokine implication in the middle ear inflammation. Immunomodulation of host gene expression and modification of certain polymorphisms could possibly play a significant role in susceptibility and outcome of AOM. Identification of genetically susceptible infants will allow for individualized treatment and prevention strategies.