Frequent respiratory tract infections in children. The role of environmental and genetic factors.

Abstract

Respiratory tract infections (RTI), presenting as common cold, pharyngitis, tonsillitis, acute otitis media, bronchitis or pneumonia are a major health problem in children. In this thesis common environmental and host factors, as well as plausible genetic factors were evaluated in a large birth cohort study in the Netherlands for their effect on frequent RTI in children. We explored the relationship between frequent RTI, atopy, exposure to environmental tobacco smoke (ETS), and the interaction between the later two in relation to susceptibility to RTI. We showed that children with intrauterine exposure to ETS who also exhibited early markers of atopy (high neonatal total IgE or symptoms of atopic dermatitis) had an increased risk for frequent RTI in preschool years. By contrast, intrauterine ETS exposure was unrelated to frequent RTI in children without these early markers of atopy. The potential association between atopy on its own and frequent RTI was also explored. We found that serum IgE and skin prick test were related to frequent RTI in school-aged children from allergic mothers. These findings suggest that atopy might affect susceptibility to RTI in some children, but the effect seems to be limited to high-risk children with a family predisposition for atopy. The second part of this thesis focused on the influence of genetic variation in innate immunity pathways on susceptibility to RTI during preschool years. We showed that polymorphisms or haplotypes of the MBL gene and the genes encoding Ficolin-2 and Ficolin-3, are not associated with frequent RTI. By contrast, minor alleles of polymorphisms in Toll-like receptor (TLR) genes TLR4 and TLR5 were shown to be associated, in a dose-responsive matter, with an increased risk of frequent RTI. Interestingly, maternal allergy, which is one of the features commonly used as risk factor for atopy in the child itself, seemed to modify the effect of variation in TLR genes on RTI frequency. Finally, we used previous findings combined with well-known environmental risk factors in order to develop a prediction rule for frequent RTI. We found that adequate prediction of frequent RTI in preschool years in our population is accomplished neither by using questionnaire-derived variables, genetic variables nor by a combination of both. Future epidemiological research into the background of RTI in children should focus on gene-gene interactions between innate immunity genes related to both infectious and atopic phenotypes. Interactions between genes and environmental factors such as exposure to ETS should also be taken into account. Therefore, large population-based cohort studies are required with a well defined RTI phenotype based on questionnaire-information on symptoms and doctor’s diagnosis of RTI, next to pathogen identification. Finally, we should make an effort to combine epidemiological and genetic data in upcoming prognostic studies, and to translate genetic data into preventive or therapeutic interventions, which at present is not realized in clinical practice.