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

Feasibility of nasal NO screening in healthy newborns

BACKGROUND Nasal nitric oxide (nNO) measurement is recommended as a first line screening test for primary ciliary dyskinesia (PCD). While reliable velum- and non-velum-closure techniques exist for preschool children and older individuals, no data are available for neonates. AIMS To determine feasibility of nNO screening and nNO concentration in healthy newborns in the first week of life. METHODS Nasal NO was analyzed in tidal breathing during natural sleep using a CLD-88 sp NO analyzer (chemoluminescence sensor) and a NIOX MINO (electrochemical sensor). Test success and nNO concentration were determined and compared between the two devices. RESULTS Nasal NO was measured in 62 healthy neonates within the first week of life. Feasibility of nNO measurement was 100% for at least one nostril and 85.5% for both nostrils using the chemoluminescence device, but significantly lower with the electrochemical device (85.5% and 53.2%; p < .001). Median nNO concentration was 38 ppb (interquartile range, 27-55; range, 9-100) with the ECOMEDICS device and 23 (15-33, 8-59) with the NIOX MINO (p < .001), with a trend towards higher values for older subjects. None of the subjects exceeded nNO levels of 100 ppb. CONCLUSION Measurement of nNO using a chemoluminescence device is highly feasible in newborns during natural sleep. However, nNO levels are considerably lower compared to the published data for older individuals and in the range of a PCD reference group of infants between 4 and 8 weeks of age, potentially resulting in a great overlap with subjects with PCD in this age group. Therefore, screening for PCD using nasal NO might not be useful in the first week of life. Upon clinical suspicion, other diagnostic tests such as high-speed video analysis of the cilia should be applied

Validation of computerized wheeze detection in young infants during the first months of life

Background Several respiratory diseases are associated with specific respiratory sounds. In contrast to auscultation, computerized lung sound analysis is objective and can be performed continuously over an extended period. Moreover, audio recordings can be stored. Computerized lung sounds have rarely been assessed in neonates during the first year of life. This study was designed to determine and validate optimal cut-off values for computerized wheeze detection, based on the assessment by trained clinicians of stored records of lung sounds, in infants aged <1 year. Methods Lung sounds in 120 sleeping infants, of median (interquartile range) postmenstrual age of 51 (44.5–67.5) weeks, were recorded on 144 test occasions by an automatic wheeze detection device (PulmoTrack®). The records were retrospectively evaluated by three trained clinicians blinded to the results. Optimal cut-off values for the automatically determined relative durations of inspiratory and expiratory wheezing were determined by receiver operating curve analysis, and sensitivity and specificity were calculated. Results The optimal cut-off values for the automatically detected durations of inspiratory and expiratory wheezing were 2% and 3%, respectively. These cutoffs had a sensitivity and specificity of 85.7% and 80.7%, respectively, for inspiratory wheezing and 84.6% and 82.5%, respectively, for expiratory wheezing. Inter-observer reliability among the experts was moderate, with a Fleiss’ Kappa (95% confidence interval) of 0.59 (0.57-0.62) for inspiratory and 0.54 (0.52 - 0.57) for expiratory wheezing. Conclusion Computerized wheeze detection is feasible during the first year of life. This method is more objective and can be more readily standardized than subjective auscultation, providing quantitative and noninvasive information about the extent of wheezing

Association of transportation noise with sleep during the first year of life: a longitudinal study

STUDY OBJECTIVES: During infancy, adequate sleep is crucial for physical and neurocognitive development. In adults and children, night-time noise exposure is associated with sleep disturbances. However, whether and to what extent infants' sleep is affected, is unknown. Thus, this study investigated the relationship between nocturnal transportation noise and actimetry-derived habitual sleep behavior across the first year of life. METHODS: In 144 healthy infants (63 girls), nocturnal (23:00-7:00) transportation noise (i.e., road, railway, and aircraft) was modelled at the infants' individual places of residence. Using actimetry, we recorded movement patterns for 11 days in a longitudinal design at 3, 6, and 12 months of age and derived the recently proposed core sleep composites of night-time sleep duration, activity, and variability. Using linear mixed-effects models, we determined associations between noise exposure and sleep composites. Sex, gestational age, parents' highest educational level, infants' age, and the existence of siblings served as control variables. RESULTS: In models without interactions, night-time transportation noise was unrelated to sleep composites across the first year of life (p > .16). Exploratory analyses of an interaction between noise and the existence of siblings yielded an association between night-time transportation noise and sleep duration in infants without siblings only (p = .004). CONCLUSION: In our study, sleep in infants during the first year of life was relatively robust against external perturbation by night-time transportation noise. However, particularly in children without siblings increasing night-time transportation noise reduced sleep duration. This suggests that the habitual noise environment may modulate individual susceptibility to adverse effects of noise on sleep

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

Possible effects of left pulmonary artery stenting in single ventricle patients on bronchial area, lung volume and lung function

BACKGROUND Left pulmonary artery (LPA) stenting is often required in single ventricle (SV) patients. Due to their close anatomical relationship an LPA stent could potentially compress the left main bronchus (LMB). We assessed the impact of LPA stenting on bronchial size, pulmonary volumes, and lung function in a cohort of SV patients. METHODS Forty-nine patients underwent cardiovascular magnetic resonance (CMR) and 36 spirometry 11 (8-15) years after Fontan. All patients were free of respiratory symptoms. LPA stents were inserted in 17 (35%) patients at 8.8 (3.4-12.6) years. Area/shape of the main bronchi (n = 46) and lung volumes (n = 47) were calculated from CMR-ZTE images for each lung and transformed in right-to-left (r/l) ratio and indexed for BSA. The effect of early stent insertion (prior to stage III) was analyzed. RESULTS Patients with LPA stent had larger r/l ratio for main bronchus area (p < 0.001) and r/l ratio difference for lung volumes was slightly larger in patients with early stenting. A trend toward a deformation of LMB shape in patients with LPA stent and toward a higher prevalence of abnormal spirometry in patients with early stent implantation was observed. CONCLUSIONS In this cohort of patients, early insertion of LPA stents seems to relate with smaller LMB sizes and a trend toward smaller left lung volume and higher prevalence of impaired lung function. Whether these findings are caused by the stent or, at least to a certain degree, present prior to the implantation needs to be verified

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

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