Preserved ratio impaired spirometry (PRISm) is defined as a FEV
of less than 80% predicted and a FEV
/forced vital capacity (FVC) ratio of 0·70 or higher. Previous research has indicated that PRISm ...is associated with respiratory symptoms and is a precursor of chronic obstructive pulmonary disease (COPD). However, these findings are based on relatively small selective cohorts with short follow-up. We aimed to determine the prevalence, risk factors, clinical implications, and mortality of PRISm in a large adult general population.
For this cohort analysis, we used data from the UKBiobank to assess PRISm prevalence, risk factors and associated symptoms, and associated comorbidities in a large adult population. Participants with spirometry deemed acceptable by an investigator (best measure FEV
and FVC values) at baseline were included. Participants were excluded if they did not have acceptable spirometry or were missing data on body-mass index or smoking status. Control spirometry was defined as a FEV
of 80% or more predicted and a FEV
/FVC ratio of 0·70 or higher. Airflow obstruction was defined as a FEV
/FVC ratio of less than 0·70. We used multivariable regression to determine risk factors for PRISm and associated comorbidities. Individuals who lived within close proximity to an assessment centre were invited for follow-up, with repeat spirometry. Only participants who had been included at baseline were examined in follow-up. This allowed for a longitudinal analysis of PRISm over time and risk factors for transition to airflow obstruction. We also did the survival analysis for a 12-year period.
Participants were recruited by UK Biobank between Dec 19, 2006, and Oct 10, 2010. We included 351 874 UK Biobank participants (189 247 women and 162 627 men) in our study, with a median follow-up of 9·0 years (IQR 8·0-10·0). 38 639 (11·0%) of 351 874 participants had PRISm at baseline. After adjustment, PRISm was strongly associated with obesity (odds ratio OR 2·40 2·26-2·55, p<0·0001), current smoking (1·48 1·36-1·62, p<0·0001), and patient reported doctor-diagnosed asthma (1·76 1·66-1·88, p<0·0001). Other risk factors identified included female sex, being overweight, trunk fat mass, and trunk fat percentage. PRISm was strongly associated with symptoms and comorbidity including increased risk of breathlessness (adjusted OR 2·0 95% CI 1·91-2·14, p<0·0001) and cardiovascular disease (adjusted OR 1·71 1·64-1·83, p<0·0001 for heart attack). Longitudinal analysis showed that 241 (12·2%) of 1973 participants who had PRISm at baseline had transitioned to airflow obstruction consistent with COPD. PRISm was associated with increased all-cause mortality (adjusted hazard ratio 1·61 95% CI 1·53-1·69, p<0·0001) versus control participants.
PRISm was associated with breathlessness, multimorbidity, and increased risk of death, which does not seem to be explained by smoking, obesity, or existing lung disease. Although for many patients PRISm is transient, it is important to understand which individuals are at risk of progressive lung function abnormalities. Further research into the genetic, structural and functional pathophysiology of PRISm is warranted.
UK Medical Research Council and University of Bristol.
The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we ...found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.
Background Asthma has its origins in early childhood, but different patterns of childhood wheezing vary in their associations with subsequent asthma, atopy, and bronchial hyperresponsiveness (BHR). ...Novel wheezing phenotypes have been identified on the basis of analyses of longitudinal data from the Avon Longitudinal Study of Parents And Children (ALSPAC). It is unclear whether these phenotypes can be replicated in other birth cohorts. Objective To compare wheezing phenotypes identified in the first 8 years of life in the ALSPAC study and the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Methods We used longitudinal latent class analysis to identify phenotypes on the basis of repeated reports of wheezing from 0 to 8 years in 5760 children from the ALSPAC study and 2810 children from the PIAMA study. Phenotypes were compared between cohorts. Associations with asthma, atopy, BHR, and lung function were analyzed by using weighted regression analyses. Results The model with the best fit to PIAMA data in the first 8 years of life was a 5-class model. Phenotypes identified in the PIAMA study had wheezing patterns that were similar to those previously reported in ALSPAC, adding further evidence to the existence of an intermediate-onset phenotype with onset of wheeze after 2 years of age. Associations with asthma, atopy, BHR, and lung function were remarkably similar in the 2 cohorts. Conclusion Wheezing phenotypes identified by using longitudinal latent class analysis were comparable in 2 large birth cohorts. Study of genetic and environmental factors associated with different phenotypes may help elucidate the origins of asthma.
The term "atopic march" has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not ...adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level.
Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time. Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts.
The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (∼ 7% of those with symptoms) follow trajectory profiles resembling the atopic march. Please see later in the article for the Editors' Summary.
Background Variable patterns of childhood wheezing might indicate differences in the cause and prognosis of respiratory illnesses. Better understanding of these patterns could facilitate ...identification of modifiable factors related to development of asthma. Objectives We characterized childhood wheezing phenotypes from infancy to adolescence and their associations with asthma outcomes. Methods Latent class analysis was used to derive phenotypes based on patterns of wheezing recorded at up to 14 time points from birth to 16½ years among 12,303 participants from the Avon Longitudinal Study of Parents and Children. Measures of lung function (FEV1 , forced vital capacity FVC, and forced expiratory flow between 25% and 75% FEF25-75 ) and fraction of exhaled nitric oxide (F eno ) were made at 14 to 15 years of age. Results Six wheezing phenotypes were identified: never/infrequent, preschool-onset remitting, midchildhood-onset remitting, school age–onset persisting, late childhood–onset persisting, and continuous wheeze. The 3 persistent phenotypes were associated with bronchodilator reversibility of 12% or greater (BDR) from baseline (odds ratio OR range, 2.14-3.34), a F eno value of 35 ppb or greater (OR range, 3.82-6.24), and lung function decrements (mean range of differences: −0.22 to −0.27 SD units (SDU) for FEV1 /FVC ratio and −0.21 to −0.33 SDU for FEF25-75 ) compared with never/infrequent wheeze. Midchildhood-onset (4½ years) remitting wheeze was associated with BDR (OR, 1.77; 95% CI, 1.11-2.82), a F eno value of 35 ppb or greater (OR, 1.72; 95% CI, 1.14-2.59), FEV1 /FVC ratio decrements (OR, −0.22 SDU; 95% CI, −0.36 to −0.08 SDU), and FEF25-75 decrements (OR, −0.16 SDU; 95% CI, −0.30 to −0.01 SDU). Preschool-onset (18 months) remitting wheeze was only associated with FEV1 /FVC ratio decrements (OR, −0.15 SDU; 95% CI, −0.25 to −0.05 SDU) and FEF25-75 decrements (OR, −0.14 SDU; 95% CI, −0.24 to −0.04 SDU). The persisting phenotypes showed evidence of sex stratification during adolescence. Conclusions Early childhood–onset wheezing that persists into adolescence represents the clearest target group for interventions to maximize lung function outcomes.
•Very little is known about the effect of greenspaces on respiratory health.•Repeated data on greenspaces and lung function up to 24 years of age were analysed.•Children living in more vegetated ...places may have better lung function.•Children living near urban green spaces may have better lung function.•Air pollution and urbanicity could play a role, but further studies are warranted.
Residing in greener areas is increasingly linked to beneficial health outcomes, but little is known about its effect on respiratory health.
We examined associations between residential greenness and nearby green spaces with lung function up to 24 years in the UK Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.
Lung function was measured by spirometry at eight, 15 and 24 years of age. Greenness levels within circular buffers (100–1000 m) around the birth, eight-, 15- and 24-year home addresses were calculated using the satellite-derived Normalized Difference Vegetation Index and averaged (lifetime greenness). The presence and proportion of green spaces (urban green spaces, forests and agricultural land) within a 300 m buffer was determined. First, associations between repeated greenness and green space variables and repeated lung function parameters were assessed using generalized estimation equations (N = 7094, 47.9% male). Second, associations between lifetime average greenness and lifetime average proportion of green spaces with lung function at 24-years were assessed using linear regression models (N = 1763, 39.6% male). All models were adjusted for individual and environmental covariates.
Using repeated greenspace and lung function data at eight, 15 and 24 years, greenness in a 100 m buffer was associated with higher FEV1 and FVC (11.4 ml 2.6, 20.3 and 12.2 ml 1.8, 22.7, respectively, per interquartile range increase), as was the presence of urban green spaces in a 300 m buffer (20.3 ml −0.1, 40.7 and 23.1 ml -0.3, 46.5 for FEV1 and FVC, respectively). These associations were independent of air pollution, urbanicity and socio-economic status. Lifetime average greenness within a 100 m buffer and proportion of agricultural land within a 300 m buffer were associated with better lung function at 24 years but adjusting for asthma attenuated these associations.
This study provides suggestive evidence that children whose homes are in more vegetated places or are in close proximity of green spaces have better lung function up to 24 years of age.
Body composition changes throughout life may explain the inconsistent associations reported between body mass index and lung function in children.
To assess the associations of body weight and ...composition trajectories from 7 to 15 years with lung function at 15 years and lung function growth between 8 and 15 years.
Sex-specific body mass index, lean body mass index, and fat mass index trajectories were developed using Group-Based Trajectory Modeling on data collected at least twice between 7 and 15 years from 6,964 children (49% boys) in the UK Avon Longitudinal Study of Parents and Children birth cohort. Associations of these trajectories with post-bronchodilation lung function parameters at 15 years and with lung function growth rates from 8 to 15 years were assessed using multivariable linear regression models, stratified by sex, in a subgroup with lung function data (
= 3,575).
For all body mass measures we identified parallel trajectories that increased with age. There was no consistent evidence of an association between the body mass index trajectories and lung function measures. Higher lean body mass index trajectories were associated with higher levels and growth rates of FVC, FEV
, and forced expiratory flow, midexpiratory phase in both sexes (e.g., boys in the highest lean body mass index trajectory had on average a 0.62 L 95% confidence interval, 0.44-0.79;
trend < 0.0001 higher FVC at 15 yr than boys in the lowest trajectory). Increasing fat mass index trajectories were associated with lower levels and growth rates of FEV
and forced expiratory flow, midexpiratory phase only in boys and lower levels of FEV
/FVC in both sexes.
Higher lean body mass during childhood and adolescence is consistently associated with higher lung function at 15 years in both sexes, whereas higher fat mass is associated with lower levels of only some lung function parameters.
The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear.
To investigate within-individual patterns of morbidity ...of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood.
We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (
mutations and 17q21 variants), increase the risk of multimorbidity.
Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern.
mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (
by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity.
Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.
Background Maternal stress in early life has been associated with the development of asthma in children, although it is unclear whether there are any critical periods of exposure. The association of ...asthma with prenatal exposure to maternal stress has not been reported. Objective We tested whether prenatal and postnatal anxiety and/or depression in pregnant women predicted the risk of their offspring developing asthma in childhood. Methods The Avon Longitudinal Study of Parents and Children is a population-based birth cohort recruited during pregnancy. Data were available on maternal anxiety scores and asthma at age 7½ years in 5810 children. Anxiety was assessed at 18 and 32 weeks of gestation by using the validated Crown-Crisp Experiential Index. Asthma was defined at age 7½ years as doctor-diagnosed asthma with current symptoms or treatment in the previous 12 months. Multivariable logistic regression was used to determine the association of prenatal anxiety with asthma (odds ratio; 95% CI). Results Independent of postnatal anxiety and adjusted for a number of likely confounders, there was a higher likelihood of asthma at age 7½ years (odds ratio, 1.64; 95% CI, 1.25-2.17) in children of mothers in the highest compared with lowest quartile of anxiety scores at 32 weeks of gestation, with evidence for a dose-response ( P value for trend <0.001). Conclusions Maternal anxiety symptoms as an indicator of stress during fetal life may program the development of asthma during childhood.
The objective of this study was to examine the associations of childhood wheezing phenotypes with asthma, lung function and exhaled nitric oxide fraction (FeNO) in adolescence.In a population-based, ...prospective cohort study of 6841 children, we used latent class analysis to identify wheezing phenotypes during the first 7 years of life. Physician-diagnosed asthma, spirometry and FeNO were assessed at 14-15 years.Compared with never/infrequent wheeze, intermediate-onset and persistent wheeze were consistently strongest associated with higher risk of asthma (risk ratio (95% CI) 10.9 (8.97-13.16) and 9.13 (7.74-10.77), respectively), lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (mean difference in standard deviation units (SDU) (95% CI) -0.34 (-0.54- -0.14) and -0.50 (-0.62- -0.38), respectively), lower forced expiratory flow at 25-75% of FVC (FEF25-75%) (mean difference in SDU (95% CI) -0.30 (-0.49- -0.10) and -0.42 (-0.54- -0.30), respectively) and increased FEV1 bronchodilator reversibility (mean difference in SDU (95% CI) 0.12 (0.02-0.22) and 0.13 (0.06-0.19), respectively). Prolonged early and persistent wheeze were associated with a decline in FEV1/FVC ratio and FEF25-75% between 8-9 and 14-15 years. Intermediate-onset, late-onset and persistent wheeze were associated with higher FeNO ratios (ratio of geometric means (95% CI) 1.90 (1.59-2.29), 1.57 (1.39-1.77) and 1.37 (1.22-1.53), respectively, compared with never/infrequent wheeze).Early-onset wheezing phenotypes persisting after 18 months of age show the strongest associations with asthma, lower lung function, even worsening from mid-childhood, and higher FeNO levels in adolescence.
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