Reduced Lung Function Growth Research Articles

Blood eosinophils associate with reduced lung function growth in adolescent asthmatics.

Background and ObjectiveSome children with asthma have low lung growth, putting them at increased risk for COPD later in life. However, it is currently not clear who will experience this adverse growth pattern. We therefore investigated the predictive role of blood eosinophils as a type 2 inflammation marker in lung growth, focusing on the presence and severity of asthma.MethodsWe investigated blood eosinophils and lung function growth (percentage of predicted values) using linear mixed models in children and adolescents from two longitudinal cohorts. One cohort was hospital‐based and consisted of asthmatic children at their first outpatient clinic visit after referral by the general practitioner (n = 133, mean age 9.8), while the second was a general population‐based birth cohort (PIAMA, asthma n = 52 and non‐asthma n = 433, mean age 8.1). The hospital‐based cohort had not been treated with inhaled corticosteroids (ICS) before referral.ResultsSubjects in the hospital‐based asthma cohort had more severe asthma compared with the asthmatic subjects in the population‐based cohort, defined by lower lung function levels and a higher prevalence of bronchial hyper‐responsiveness. In the asthma cohort, higher blood eosinophil numbers were associated with less growth in FEV1 (estimated change in lung function per 1 unit increase in ln blood eosinophils (B): −0.66%/year (95% confidence interval (CI): −1.11 to −0.20, p < .01)) and FVC (B: −0.40%/year (95% CI: −0.75 to −0.05), p = .025)) during follow‐up in adolescence (min 7, max 17 years). These associations were not observed in the general population‐based birth cohort, regardless of asthma status during follow‐up (age 8–16).Conclusions and Clinical RelevanceBlood eosinophil counts in children with asthma not treated with ICS at referral were predictive of lower growth in FEV1 and FVC during follow‐up in adolescence. Our findings indicate that this association is dependent on the degree of asthma severity. Future studies should address whether anti‐eosinophilic treatments preserve lung function growth in children with asthma.

COPD-associated miR-145-5p is downregulated in early-decline FEV1 trajectories in childhood asthma

Background:Many microRNAs (miRNAs) have been associated with asthma and chronic obstructive pulmonary disease (COPD). Longitudinal lung function growth trajectories of children with asthma—normal growth, reduced growth (RG), early decline (ED), and RG with an ED (RGED)—have been observed, with RG and RGED associated with adverse outcomes, including COPD.Objective:Our aim was to determine whether circulating miRNAs from an early age in children with asthma would be prognostic of reduced lung function growth patterns over the next 16 years.Methods:We performed small RNA sequencing on sera from 492 children aged 5 to 12 years with mild-to-moderate asthma from the CAMP clinical trial, who were subsequently followed for 12 to 16 years. miRNAs were assessed for differential expression between previously assigned lung function growth patterns.Results:We had 448 samples and 259 miRNAs for differential analysis. In a comparison of the normal and the most severe group (ie, normal growth compared with RGED), we found 1 strongly dysregulated miRNA, hsa-miR-145-5p (P < 8.01E–05). This miR was downregulated in both ED groups (ie, ED and RGED). We verified that miR-145-5p was strongly associated with airway smooth muscle cell growth in vitro.Conclusion:Our results showed that miR-145-5p is associated with the ED patterns of lung function growth leading to COPD in children with asthma and additionally increases airway smooth muscle cell proliferation. This represents a significant extension of our understanding of the role of miR-145-5p in COPD and suggests that reduced expression of miR-145-5p is a risk factor for ED of long-term lung function.

Air Pollution Exposure and Lung Function Until Age 16 Years: The PIAMA Birth Cohort Study

Evidence for the effects of air pollution exposure on lung function growth into adolescence is scarce. Therefore, the purpose of this study was to investigate the associations of air pollution exposure from birth with lung function growth from ages 8 to 16 and lung function at age 16. Potential confounders (sex and asthma diagnosis) were also explored.The study was performed within the Dutch population-based Prevention and Incidence of Asthma and Mite Allergy birth cohort. From the 3963 pregnant women initially enrolled, 915 children (mean age: 16.3 years) had sufficient longitudinal data for this study.Both longitudinal (n = 915) and cross-sectional (n = 721) analyses were conducted. Researchers estimated residential concentrations of nitrogen dioxide, “soot,” and particulate matter (PMx, where x is the 50% cutoff aerodynamic diameter in μm) with diameters of <2.5 μm (PM2.5), <10 μm (PM10), and 2.5 to 10 μm (PMcoarse) during the preschool, primary school, and secondary school time windows by land use regression models. Associations with (growth in) forced expiratory volume in 1 second (FEV1) and forced vital capacity were analyzed by linear (mixed effects) regression.Greater air pollution exposure was associated with reduced FEV1 growth (eg, adjusted difference: −0.26% [95% confidence interval: −0.49 to −0.03%] per interquartile range increase in secondary school PM2.5) and lower FEV1 (adjusted difference: −2.36% [95% confidence interval: −3.76 to −0.94%]) but was not adversely associated with forced vital capacity. Associations with FEV1 were stronger in boys than girls and were not modified by asthma status.Greater air pollution exposure may lead to increased airway obstruction but not reduced lung volume in adolescence.This study supports previous longitudinal studies that have reported an association between air pollution exposure and reduced lung function growth. The association between lower FEV1 and PM2.5 exposure during the secondary school time window suggests that exposure during this time frame is critical. This study was limited by a lack of racial diversity, which could create differing results because of epigenetic changes. Future longitudinal studies should address this issue.

Timing of secondhand smoke, pet, dampness or mould exposure and lung function in adolescence

BackgroundThe relevance of timing of exposure in the associations of secondhand tobacco smoke (SHS), pets, and dampness or mould exposure with lung function is unclear. We investigated the relevance of...

Precision medicine in childhood asthma.

Childhood asthma is a heterogeneous disease and many children have uncontrolled disease. Therefore an individualized approach is needed to improve asthma outcomes in children. Precision medicine using clinical characteristics, biomarkers, and the rapidly involving field of genomics and pharmacogenomics aims to achieve asthma control and reduce future risks with less side-effects in individual children with asthma. It is not yet possible to select treatment options on clinical characteristics. Novel monoclonal antibodies are efficacious in patients with severe, eosinophilic asthma. Reduced lung function growth and early decline is a prevalent finding in children with persistent asthma. Pharmacogenetic studies have identified children at risk for cortisol suppression when using inhaled corticosteroids. Clinical characteristics and simple biomarkers like eosinophils, IgE, and the fraction of exhaled nitric oxide may be used in clinical practice for a basic precision medicine approach, deciding which children will have the best chance to respond to inhaled corticosteroids and to the biologicals omalizumab and mepolizumab.Further application of pharmacogenomics and breathomics needs additional studies before they can be applied as tools for precision medicine in individual children with asthma.

Trajectory of spirometric and exhaled nitric oxide measurements in Chinese schoolchildren with asthma.

Lung function growth occurs in most asthmatic children. A subgroup has subnormal lung function trajectory, but such data are limited in children. This prospective study characterized longitudinal changes of spirometric indices and fractional exhaled nitric oxide level (FeNO) among asthmatic children and identified their genetic and environmental determinants. Chinese asthmatic children recruited from pediatric clinics underwent 5-year follow-up for pre-bronchodilator spirometric indices and FeNO. Fourteen asthma-associated single nucleotide polymorphisms (SNPs) were genotyped. Generalized estimating equation was used to analyze longitudinal changes of spirometric indices and FeNO. One hundred and ninety-three asthmatic children, aged 9.7 (1.9)years, had significant annual decline of 1.3% for forced vital capacity (FVC) and annual increase of 1.2% and 3.6% for FEV1 /FVC and FEF25-75 , respectively. Patients who received inhaled corticosteroid (ICS) had 2.4% lower baseline FEV1 /FVC but 0.81% higher annual increase in FEV1 . Body mass index (BMI) was associated inversely with FEV1 /FVC but positively with FEV1 % and FVC% changes. Asthma exacerbation was associated with lower FEV1 % and FVC% but not their longitudinal changes. When classified by FEV1 curve, one-quarter of patients had reduced lung function growth which was associated with female gender and lower spirometric and higher FeNO values at baseline. IL33_rs1342326 was associated with spirometric indices and FeNO, whereas GSDMB_rs2305480 was significantly associated with FEV1 /FVC change. Asthmatic children have annual decline in FVC and increase in FEV1 /FVC and FEF25-75 . Their lung function trajectory is influenced by gender, ICS treatment, BMI, and asthma exacerbations. IL33 and GSDMB may be candidate genes for their lung function growth.

Whole genome prediction and heritability of childhood asthma phenotypes.

IntroductionWhile whole genome prediction (WGP) methods have recently demonstrated successes in the prediction of complex genetic diseases, they have not yet been applied to asthma and related phenotypes. Longitudinal patterns of lung function differ between asthmatics, but these phenotypes have not been assessed for heritability or predictive ability. Herein, we assess the heritability and genetic predictability of asthma‐related phenotypes.MethodsWe applied several WGP methods to a well‐phenotyped cohort of 832 children with mild‐to‐moderate asthma from CAMP. We assessed narrow‐sense heritability and predictability for airway hyperresponsiveness, serum immunoglobulin E, blood eosinophil count, pre‐ and post‐bronchodilator forced expiratory volume in 1 sec (FEV1), bronchodilator response, steroid responsiveness, and longitudinal patterns of lung function (normal growth, reduced growth, early decline, and their combinations). Prediction accuracy was evaluated using a training/testing set split of the cohort.ResultsWe found that longitudinal lung function phenotypes demonstrated significant narrow‐sense heritability (reduced growth, 95%; normal growth with early decline, 55%). These same phenotypes also showed significant polygenic prediction (areas under the curve [AUCs] 56% to 62%). Including additional demographic covariates in the models increased prediction 4–8%, with reduced growth increasing from 62% to 66% AUC. We found that prediction with a genomic relatedness matrix was improved by filtering available SNPs based on chromatin evidence, and this result extended across cohorts.ConclusionsLongitudinal reduced lung function growth displayed extremely high heritability. All phenotypes with significant heritability showed significant polygenic prediction. Using SNP‐prioritization increased prediction across cohorts. WGP methods show promise in predicting asthma‐related heritable traits.

Early life Exposure to Environmental Tobacco Exposure and Atherogenesis

Background: Early exposure to environmental tobacco smoke (ETS) is associated with adverse health outcomes in children and adolescents: reduced lung function growth, asthma and adverse birth outcomes. Less is known on the impact of early life ETS exposure on cardiovascular health and atherosclerosis, although ETS is considered to be highly atherogenic in adults and remains a prevalent exposure in utero and childhood. Aim: 1. Present the state of knowledge on early life/childhood risk factors for atherogenesis, focusing on early life ETS exposure. 2. Present complexity and challenges in investigating early life origins of health and disease 3. and the SAPALDIA Youth Study designed to study early life factors of atherosclerosis. Results: Atherosclerosis is a multi-factorial disease with origins in childhood and in utero. Metabolic and morphologic alterations may result from ETS with toxic compounds crossing the placenta barrier and vaso-constrictive agents reducing the blood flow to the fetus. Childhood ETS exposure has been associated with cardiovascular risk factors: obesity,metabolic syndrome,leptin, adinopectin, CRP, oxidative stress. Studies on ETS and functional or structural changes of the vasculature in children are few. The challenge in research on early life origins of disease lies in the disparity of timing of exposure and disease manifestation. Developmental plasticity and adaptive responses of the human organism add to the complexity. The SAPALDIA Youth Study, the first Swiss offspring study, is designed to study early life factors and cardiovascular health, with a focus on atherosclerosis, addressing vulnerable time windows. Conclusion: ETS exposure in childhood is a risk factor for atherogenesis in adults and children. Considerable evidence supports the early life impact of ETS exposure on children’s cardiovascular risk profile. First findings pointing to functional and structural changes to the vasculature in children need affirmation. The SAPALDIA Youth Study can bridge the time windows of early exposure and later disease manifestation.

Paediatric asthma: where to go?

Asthma is the leading chronic disease in children in the Western world, affecting 5–20% of school-aged children in Europe [1]. Childhood asthma is a serious public health problem. First, it causes considerable morbidity with high frequencies of sleep disturbances, emergency visits, school absence, and limitations of physical activity, and healthcare utilisation [2]. As quoted by Hedlin et al . [3] in this issue of European Respiratory Review , asthma is the fourth most common cause of disability-adjusted life years for children aged 10–14 yrs. Secondly, as asthma is associated with reduced lung function growth, and lung function at a young age is a determinant of lung function in adult life, optimal treatment is of major concern for long-term prognosis [4, 5]. Several efforts have been made to improve knowledge on childhood asthma in order to unravel pathogenesis, and improve treatment modalities and monitoring strategies, as reflected by almost 2,000 papers published on asthma and children in 2011 and 2012. In this issue, Hedlin et al. [3], in an extensive overview, bring together all novel findings on paediatric asthma and delineate future directions. The GA2LEN initiative is an inspiring example of how international collaboration may take a clinical problem, such as problematic severe asthma, further. The proposed work-up of asthmatic children who are uncontrolled on high doses of medication and the classification into “difficult to treat” or “therapy resistant” provides the clinician with practical tools on how to treat these patients. However, several questions remain to be answered. As pointed out by Hedlin et al. [3], heterogeneity of asthma in general and problematic asthma …

Residential proximity to main roads and lung function in healthy young children: Table 1–

To the Editors: In preschool children, exposure to traffic-related emissions is associated with increased prevalence of respiratory symptoms [1–3] and, in school-aged children, with reduced lung function growth [4]. However, to date, the association between air pollution and preschool lung function remains unclear. In a cross-sectional study, we investigated the effects of residential proximity to main roads and air pollutants on lung function in healthy preschool children. Spirometric forced vital capacity, forced expiratory volume in 1 s and 0.5 s, lung clearance index (LCI) by multiple breath washout, plethysmographic specific airway resistance (s R aw) and exhaled nitric oxide fraction ( F eNO) were measured in healthy preschool children as part of another study protocol [5 …

CHILDREN’S HEALTH: Gene Variants May Predict Lung Health

Genetic research is beginning to provide potential insights on why some people are more vulnerable than others to various pollutants. Now a few more pieces can be added to the extraordinarily complex puzzle. In the April 2009 American Journal of Respiratory and Critical Care Medicine, researchers from the University of Southern California report that several inherited glutathione S−transferase (GST) gene variants were associated with lung function growth during adolescence, and one variant helped predict poor lung function in children whose mothers had smoked during pregnancy. GST genes are expressed in the lungs, among other organs, and may influence the development of normal lung function. This study focused on a class of GST genes called GSTMs. The best studied of these is GSTM1, which has been implicated in lung cancer, asthma, and other respiratory diseases in children and adults. To find out more about other variants, the authors looked at GSTM2, GSTM3, GSTM4, and GSTM5. They analyzed the genotypes in conjuction with eight years’ worth of lung function and genotyping data from 2,108 Southern California schoolchildren, starting around age 10 years. For GSTM2, two common haplotypes (patterns of genetic variation) were observed. One haplotype found in 28% of non−Hispanic whites and 44% of Hispanic whites was associated with better lung development than other haplotypes, whereas a second haplotype found in 35% of non−Hispanic whites and 30% of Hispanic whites was associated with significantly less lung function growth over time. Deficits in measures of lung function growth were twice as big in children with two copies of the haplotype versus those with one copy, and the deficits associated with this haplotype were greater among children of mothers who smoked during pregnancy. The presence of a GSTM4 haplotype found in 22% of non−Hispanic whites and 16% of Hispanic whites was associated with significantly reduced lung function growth relative to children with other haplotypes. As with the GSTM2 variant above, deficits in lung function growth were doubled among children with 2 copies of the haplotype. A GSTM3 haplotype found in about 7% of the children was associated with a deficit in one of three measures of lung function growth. The authors believe this to be the first study to report evidence of an interaction between GSTM2 variants and prenatal tobacco smoke exposure on lung function growth. They noted that GSTM genes are expressed in fetal tissue at relatively low levels, and GSTs and other phase II (detoxification) enzymes are relatively inactive in fetal tissue compared with phase I enzymes (which activate toxic metabolites and carcinogens). “This suggests that fetuses are much more susceptible to environmental exposures than adults,” they wrote. “Genetic polymorphisms in phase II enzymes that further inhibit enzyme activity may exacerbate this susceptibility.” In addition, respiratory health and development in childhood is known to play an important role in adult respiratory health. This study “points out again that the genetic makeup of a population may be very important when considering health risks from environmental exposures,” says principal investigator Frank Gilliland, who directs the NIEHS−supported Southern California Environmental Health Sciences Center at the University of Southern California. His team speculates that GSTM−influenced failure to detoxify reactive oxygen species reduces lung protection and triggers an inflammatory cascade, bronchial constriction, and airway hyperresponsiveness, producing asthma−like symptoms and impaired lung development. However, more information would be needed before public health officials could set or adjust regulatory standards based on variation in vulnerability among subpopulations. And even with such additional data, Medea Imboden, a molecular epidemiologist at the University of Zurich, cautions against overemphasizing the GST gene family. “You always have doubts about the functional relevance of the variants,” says Imboden. “If you think of all the genes not yet known to contribute to respiratory health and bodily defense systems against air pollutants, GSTs might turn out to play a minor role.” But for now, she adds, “they are good candidates.”

Parental Smoking and Lung Function in Children

Both prenatal and postnatal passive smoking have been linked with respiratory symptoms and asthma in childhood. Their differential contributions to lung function growth in the general children's population are less clear. To study the relative impact of pre- and postnatal exposure on respiratory functions of primary school children in a wide range of geographic settings, we analyzed flow and volume data of more than 20,000 children (aged 6-12 yr) from nine countries in Europe and North America. Exposure information had been obtained by comparable questionnaires, and spirometry followed a protocol of the American Thoracic Society/European Respiratory Society. Linear and logistic regressions were used, controlling for individual risk factors and study area. Heterogeneity between study-specific results and mean effects were estimated using meta-analytic tools. Smoking during pregnancy was associated with decreases in lung function parameters between -1% (FEV1) and -6% maximal expiratory flow at 25% of vital capacity left (MEF25). A 4% lower maximal midexpiratory flow (MMEF) corresponded to a 40% increase in the risk of poor lung function (MMEF < 75% of expected). Associations with current passive smoking were weaker though still measurable, with effects ranging from -0.5% (FEV1) to -2% maximal expiratory flow (MEF50). Considering the high number of children exposed to maternal smoking in utero and the even higher number exposed to passive smoking after birth, this risk factor for reduced lung function growth remains a serious pediatric and public health issue.

METHODS TO DETERMINE WHETHER AIR POLLUTION ASSOCIATED DEFICITS IN LUNG FUNCTION GROWTH ARE CORRELATED WITH SMALL AIRWAYS STRUCTURE AND FUNCTION ASSESSED BY HRCT: RESULTS FROM A PILOT STUDY

ISEE-386 Introduction: Lung function growth is frequently quantified using spirometry in environmental epidemiologic studies of air pollution; however, most studies have focused on the effects of acute exposures on short-term changes in airway function. Findings from the Children's Health Study (CHS), a 10-year study of the chronic effects of air pollution among 6000 children residing in 12 Southern California communities, indicate that current levels of air pollutants are associated with reduced lung function growth and lower maximum attained measures of airway flows. It is critically important to establish whether the deficits in flows occur as a result of irreversible anatomic changes in the airway structure, size or wall thickness that indicate elevated long-term risk for adverse health outcomes, or whether the deficits arise from potentially reversible physiologic changes that may not influence long-term risk. Recent developments in lung imaging using High-Resolution Computed Tomography (HRCT) now make it feasible to non-invasively study the structure of small airways and the entire airway using volumetric reconstructions. These developments make it possible to investigate the anatomic relationship between air pollution-associated deficits in spirometric measures of airway flow and permanent changes in the structure and function of the small airways. Aim: In this pilot study, we aimed to develop methods and test the feasibility for a larger scale study of the effects of air pollution on lung structure using HRCT to assess small airway diameter, wall thickness and luminal area, air trapping and parenchymal changes among CHS participants with contrasting exposure histories. Methods: We contacted previous participants from the CHS during a routine follow-up visit who were old enough to have achieved maximum lung function, had lung function measured by the CHS on at least 2 occasions, and were current residents of communities within 200 miles of Los Angeles. Participants were selected based on the community of residence at the time of participation the Children's Health Study, of which approximately half were from communities with poor air quality. Results: We were able to successfully obtain HRCT scans from 40 previous CHS participants (mean age at scan, 24.9 years; females=“22”), using a low dose of radiation (80 mAs), which minimized the risk to patients, while maintaining an acceptable image quality. While a relatively low number of CHS participants declined participation in the HRCT pilot study, the primary reason participants gave for declining participation was due to distance to USC rather than the CT scan. Preliminary results from the HRCT scans are provided. Conclusion: Developments in lung imaging using HRCT have made it possible to study structural changes in lung development at a radiation dose acceptable to healthy volunteers and an image quality useful in determining structural deficits in airway size and diameter.

Breathless in Los Angeles: The Exhausting Search for Clean Air

Population growth and the proliferation of roadways in Southern California have facilitated a glut of mobile air pollution sources (cars and trucks), resulting in substantial atmospheric pollution. Despite successful efforts over the past 40 years to reduce pollution, an alarming set of health effects attributable to air pollution have been described in Southern California. The Children's Health Study indicates that reduced lung function growth, increased school absences, asthma exacerbation, and new-onset asthma are occurring at current levels of air pollution, with sizable economic consequences. We describe these findings and urge a more aggressive effort to reduce air pollution exposures to protect our children's health. Lessons from this "case study" have national implications.