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

CFTR genotype and maximal exercise capacity in cystic fibrosis: a cross-sectional study

RATIONALE: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with CF may present an important determinant of aerobic exercise capacity in CF. Previous studies on the relationship between CFTR genotype and aerobic exercise capacity are scarce and contradictory. OBJECTIVES: This study was designed to explore factors influencing aerobic exercise capacity, expressed as peak oxygen consumption (VO2peak) with a specific focus on CFTR genotype in children and adults with CF. METHODS: In an international, multicenter cross-sectional study we collected data on CFTR genotype and cardiopulmonary exercise tests (CPET) in patients with CF eight years and older. CFTR mutations were classified into functional classes I-V. RESULTS: The final analysis included 726 patients (45% females, age 8 to 61 years, FEV1 16 to 123 % predicted) from 17 CF centers in North America, Europe, Australia and Asia whom all had both valid maximal CPET and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (VO2peak, 77.3±19.1 % predicted), but values were comparable among different CFTR classes. Using linear regression analysis adjusted for relevant confounders, lung function and body mass index, but not CFTR genotype were the main predictors of VO2peak. CONCLUSIONS: We conclude that lung disease severity and reduced nutritional status rather than CFTR genotypes are the major determinants of aerobic exercise capacity in patients with CF

Age and body mass index affect fit of spirometry Global Lung Function Initiative references in schoolchildren

BACKGROUND: References from the Global Lung Function Initiative (GLI) are widely used to interpret children's spirometry results. We assessed fit for healthy schoolchildren. METHODS: LuftiBus in the School was a population-based cross-sectional study undertaken in 2013-2016 in the canton of Zurich, Switzerland. Parents and their children aged 6-17 years answered questionnaires about respiratory symptoms and lifestyle. Children underwent spirometry in a mobile lung function lab. We calculated GLI-based z-scores for forced expiratory volume in 1 s (FEV$_{1}$), forced vital capacity (FVC), FEV$_{1}$/FVC and forced expiratory flow for 25-75% of FVC (FEF$_{25-75}$) for healthy White participants. We defined appropriate fit to GLI references by mean values between +0.5 and -0.5 z-scores. We assessed whether fit varied by age, body mass index, height and sex using linear regression models. RESULTS: We analysed data from 2036 children with valid FEV$_{1}$ measurements, of whom 1762 also had valid FVC measurements. The median age was 12.2 years. Fit was appropriate for children aged 6-11 years for all indices. In adolescents aged 12-17 years, fit was appropriate for FEV$_{1}$/FVC z-scores (mean±sd -0.09±1.02), but not for FEV$_{1}$ (-0.62±0.98), FVC (-0.60±0.98) and FEF$_{25-75}$ (-0.54±1.02). Mean FEV$_{1}$, FVC and FEF$_{25-75}$ z-scores fitted better in children considered overweight (-0.25, -0.13 and -0.38, respectively) than normal weight (-0.55, -0.50 and -0.55, respectively; p-trend <0.001, 0.014 and <0.001, respectively). FEV$_{1}$, FVC and FEF$_{25-75}$ z-scores depended on both age and height (p-interaction 0.033, 0.019 and <0.001, respectively). CONCLUSION: GLI-based FEV$_{1}$, FVC, and FEF$_{25-75}$ z-scores do not fit White Swiss adolescents well. This should be considered when using reference equations for clinical decision-making, research and international comparison

Age and body mass index affect fit of spirometry Global Lung Function Initiative references in schoolchildren.

Background References from the Global Lung Function Initiative (GLI) are widely used to interpret children's spirometry results. We assessed fit for healthy schoolchildren. Methods LuftiBus in the School was a population-based cross-sectional study undertaken in 2013-2016 in the canton of Zurich, Switzerland. Parents and their children aged 6-17 years answered questionnaires about respiratory symptoms and lifestyle. Children underwent spirometry in a mobile lung function lab. We calculated GLI-based z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and forced expiratory flow for 25-75% of FVC (FEF25-75) for healthy White participants. We defined appropriate fit to GLI references by mean values between +0.5 and -0.5 z-scores. We assessed whether fit varied by age, body mass index, height and sex using linear regression models. Results We analysed data from 2036 children with valid FEV1 measurements, of whom 1762 also had valid FVC measurements. The median age was 12.2 years. Fit was appropriate for children aged 6-11 years for all indices. In adolescents aged 12-17 years, fit was appropriate for FEV1/FVC z-scores (mean±sd -0.09±1.02), but not for FEV1 (-0.62±0.98), FVC (-0.60±0.98) and FEF25-75 (-0.54±1.02). Mean FEV1, FVC and FEF25-75 z-scores fitted better in children considered overweight (-0.25, -0.13 and -0.38, respectively) than normal weight (-0.55, -0.50 and -0.55, respectively; p-trend <0.001, 0.014 and <0.001, respectively). FEV1, FVC and FEF25-75 z-scores depended on both age and height (p-interaction 0.033, 0.019 and <0.001, respectively). Conclusion GLI-based FEV1, FVC, and FEF25-75 z-scores do not fit White Swiss adolescents well. This should be considered when using reference equations for clinical decision-making, research and international comparison

Agreement of parent- and child-reported wheeze and its association with measurable asthma traits

Objectives In epidemiological studies, childhood asthma is usually assessed with questionnaires directed at parents or children, and these may give different answers. We studied how well parents and children agreed when asked to report symptoms of wheeze and investigated whose answers were closer to measurable traits of asthma. Methods LuftiBus in the school is a cross-sectional survey of respiratory health among Swiss schoolchildren aged 6–17 years. We applied questionnaires to parents and children asking about wheeze and exertional wheeze in the past year. We assessed agreement between parent–child answers with Cohen's kappa (k), and associations of answers from children and parents with fractional exhaled nitric oxide (FeNO) and forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC), using quantile regression. Results We received questionnaires from 3079 children and their parents. Agreement was poor for reported wheeze (k = 0.37) and exertional wheeze (k = 0.36). Median FeNO varied when wheeze was reported by children (19 ppb, interquartile range [IQR]: 9–44), parents (22 ppb, IQR: 12–46), both (31 ppb, IQR: 16–55), or neither (11 ppb, IQR: 7–19). Median absolute FEV1/FVC was the same when wheeze was reported by children (84%, IQR: 78–89) and by parents (84%, IQR: 78–89), lower when reported by both (82%, IQR: 78–87), and higher when reported by neither (87%, IQR: 82–91). For exertional wheeze findings were similar. Results did not differ by age or sex. Conclusion Our findings suggest that surveying both parents and children and combining their responses can help us to better identify children with measurable asthma traits

Evaluation of the Double-Tracer Gas Single-Breath Washout Test in a Pediatric Field Study

BACKGROUND: The early life origins of chronic pulmonary diseases are thought to arise in peripheral small airways. Predictors of ventilation inhomogeneity, a proxy of peripheral airway function, are understudied in schoolchildren. RESEARCH QUESTION: Is the double-tracer gas single-breath washout (DTG-SBW) measurement feasible in a pediatric field study setting? What are the predictors of the DTG-SBWderived ventilation inhomogeneity estimate in unselected schoolchildren? STUDY DESIGN AND METHODS: In this prospective cross-sectional field study, a mobile lung function testing unit visited participating schools in Switzerland. We applied DTG-SBW, fraction of exhaled nitric oxide (FENO), and spirometry measurements. The DTG-SBW is based on tidal inhalation of helium and sulfur-hexafluoride, and the phase III slope (SIIIHeSF6) is derived. We assessed feasibility, repeatability, and associations of SIIIHe-SF6 with the potential predictors of anthropometrics, presence of wheeze (ie, parental report of one or more episode of wheeze in the prior year), FENO, FEV1, and FEV1/FVC. RESULTS: In 1,782 children, 5,223 DTG-SBW trials were obtained. The DTG-SBW was acceptable in 1,449 children (81.3%); the coefficient of variation was 39.8%. SIIIHe-SF6 was independently but weakly positively associated with age and BMI. In 276 children (21.2%), wheeze was reported. SIIIHe-SF6 was higher by 0.049 g.mol.L-1 in children with wheeze compared with those without and remained associated with wheeze after adjusting for age and BMI in a multivariable linear regression model. SIIIHe-SF6 was not associated with FENO, FEV1, and FEV1/FVC. INTERPRETATION: The DTG-SBW is feasible in a pediatric field study setting. On the population level, age, body composition, and wheeze are independent predictors of peripheral airway function in unselected schoolchildren. The variation of the DTG-SBW possibly constrains its current applicability on the individual level

Pollen exposure is associated with risk of respiratory symptoms during the first year of life

BACKGROUND: Pollen exposure is associated with respiratory symptoms in children and adults. However, the association of pollen exposure with respiratory symptoms during infancy, a particularly vulnerable period, remains unclear. We examined whether pollen exposure is associated with respiratory symptoms in infants and whether maternal atopy, infant's sex or air pollution modifies this association. METHODS: We investigated 14,874 observations from 401 healthy infants of a prospective birth cohort. The association between pollen exposure and respiratory symptoms, assessed in weekly telephone interviews, was evaluated using generalized additive mixed models (GAMMs). Effect modification by maternal atopy, infant's sex, and air pollution (NO$_{2}$ , PM$_{2.5}$ ) was assessed with interaction terms. RESULTS: Per infant, 37 ± 2 (mean ± SD) respiratory symptom scores were assessed during the analysis period (January through September). Pollen exposure was associated with increased respiratory symptoms during the daytime (RR [95% CI] per 10% pollen/m$^{3}$ : combined 1.006 [1.002, 1.009]; tree 1.005 [1.002, 1.008]; grass 1.009 [1.000, 1.23]) and nighttime (combined 1.003 [0.999, 1.007]; tree 1.003 [0.999, 1.007]; grass 1.014 [1.004, 1.024]). While there was no effect modification by maternal atopy and infant's sex, a complex crossover interaction between combined pollen and PM$_{2.5}$ was found (p-value 0.003). CONCLUSION: Even as early as during the first year of life, pollen exposure was associated with an increased risk of respiratory symptoms, independent of maternal atopy and infant's sex. Because infancy is a particularly vulnerable period for lung development, the identified adverse effect of pollen exposure may be relevant for the evolvement of chronic childhood asthma