Immunological and genetic determinants of pulmonary outcome in school aged children

Background: The prevalence of respiratory disorders in children has steadily increased over the past decades to such an extent that asthma is now the most common chronic disease of childhood. Childhood asthma resembles a complex syndrome rather than a single disease, and includes many wheeze phenotypes, making its diagnosis challenging. Most likely, it is not a single risk factor that determines whether a child develops asthma, but several risk factors (e.g. environmental, immunological, genetic, onset of respiratory symptoms) that each make small contributions to the development of the disease. Already infancy, lung function tests are available to assess airway disease. These tests are predominantly used in patients with Cystic Fibrosis (CF), for whom preservation of normal lung function is crucial. Despite recent advances in lung function testing, several methodological issues remain unanswered. Higher quality tests are required in order to effectively study the various risk factors involved in the development of complex airway diseases Aim: The first aim was to describe methodological issues during infant lung function testing in order to improve their quality. The second aim was to study different risk factors for asthma development, and to investigate their association with respiratory diseases during childhood. Methods: The study was conducted within the prospective Basel-Bern infant lung development (BILD) cohort, a population-based cohort of unselected infants of Central-European origin. The survey collects prenatal data via standardized interviews and cord blood samples for the assessment of immunological and genetic information. During the first year of life, research nurses call the parents weekly to assess the occurrence of respiratory symptoms. Pulmonary function tests, as well as measurement of fractional exhaled nitric oxide (FeNO) to assess airway inflammation, are completed at 5 weeks of age, and again at 6 years of age during follow-up. Results: We provided specific recommendations on how to improve outcomes from infant lung measurements. Furthermore, we measured airway obstruction using the interrupter technique (Rint) in unsedated infants shortly after birth, and were able to show that measurements were feasible but had a high variability. We compared Rint between term and preterm infants, and found that Rint was higher, and variability of Rint lower, in term-born infants. We assessed FeNO in healthy newborn infants, and in infants with CF. FeNO at birth had no predictive value for asthma development at school age. In CF patients, FeNO at birth was lower compared to matched healthy controls. We could also show that polymorphisms in the chitinase 3-like 1 (CHI3L1) gene encoding YKl-40 were associated with asthma at 6 years. There was some indication that increased YKL-40 levels at birth may also be involved in the development of airway disease. We also developed a novel method to characterize the time series of prospectively assessed respiratory symptom scores during infancy. This method assesses symptom dynamics in an observer-independent manner. Using this method, we were able to identify a high-risk phenotype, which was predominantly male, and contained more infants exposed to maternal asthma, and environmental tobacco smoke. This phenotype was also at increased risk for asthma and atopy at school age. Conclusions: Infant lung function is useful to study airway disease at an early age, and outcomes can be improved by applying minimal changes in analyses algorithms. Assessment of airway obstruction in infants is feasible, but measurements require careful interpretation due to the high variability. We found some indication that FeNO levels early in life are determined by environmental factors and the child's genetic profile. In CF patients, FeNO after birth was associated with the severity of the genetic mutation. In healthy infants, FeNO levels early in life seem to be influenced by environmental exposures. Our findings contribute additional, relevant knowledge on asthma risk factors and their association with respiratory symptoms from birth through school age. We found associations between genetics and the immunological status at birth with asthma at school age. The development of asthma may also depend on respiratory symptoms early in life. We could show that the pattern of symptom deterioration and recovery during the first year of life determines whether or not a child has persistent wheezing until school age.

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