Trajectory of lung function in diabetic adults: A 16-year follow-up study of community-based prospective cohorts.

BACKGROUND AND OBJECTIVE: To investigate the difference in lung function according to diabetes status in a community-based prospective study. METHODS: Individuals aged 40-69 years from two community-based cohorts were followed prospectively for 16 years. A spirometer was used to evaluate lung function at baseline, and lung function tests were carried out biennially thereafter. Multivariable linear regression analysis was performed for the cross-sectional and longitudinal analyses based on diabetes status. RESULTS: Among the 6483 subjects, 2114 (32.6%) had prediabetes and 671 (10.4%) had diabetes. The prediabetes and diabetes groups had lower baseline % predicted values of forced expiratory volume in 1 s (FEV1) (mean, -1.853; 95% confidence interval [CI] -2.715 to -0.990 for prediabetes and mean, -4.088; 95% CI -5.424 to -2.752 for diabetes) and forced vital capacity (FVC) (mean, -2.087; 95% CI -2.837 to -1.337 for prediabetes and mean, -4.622; 95% CI -5.784 to -3.460 for diabetes) compared to the normoglycemia group after adjusting for relevant covariates. The rate of decline in FEV1% predicted (mean, -0.227; 95% CI -0.366 to -0.089) and FVC % predicted (mean, -0.232; 95% CI -0.347 to -0.117) during follow-up were faster in the diabetes group than in the normoglycemia group. The diabetes group had a lower proportion of normal ventilation (ptrend = 0.048) and higher proportions of restrictive (ptrend = 0.001) and mixed (ptrend = 0.035) ventilatory disorders at the last follow-up. CONCLUSION: Diabetes is associated with a lower baseline lung function and a faster rate of deterioration.

Lung function trajectory of rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: To explore the course of lung function and RA disease activity and predictive factors for deteriorating lung function in patients with RA-interstitial lung disease (ILD). METHODS: The Korean Rheumatoid Arthritis-Interstitial Lung Disease cohort is a multicentre, prospective observational cohort. Patients with RA-ILD were enrolled and followed up annually for 3 years for RA disease activity and ILD status assessment. Group-based modelling was used to cluster a similar predicted percentage of forced vital capacity (FVC%) patterns into trajectories. RESULTS: This study included 140 patients who underwent at least two pulmonary function tests. Four distinctive trajectories for predicted FVC% were 'improving' [n = 11 (7.9%)], 'stable' [n = 68 (38.4%)], 'slowly declining' [n = 54 (48.6%)] and 'rapidly declining' [n = 7 (5.0%)]. Most (77.7%) patients maintained or improved to low RA disease activity. The lung function trajectory was not comparable to the RA disease activity trajectory. Age ≥70 years [relative risk (RR) 10.8 (95% CI 1.30, 89.71)] and early RA diagnosed within the preceding 2 years [RR 10.1 (95% CI 1.22, 84.2)] were associated with increased risk for rapidly declining predicted FVC%. The risk for deterioration or mortality increased in patients with a simultaneous diagnosis of RA and ILD within 24 weeks [RR 9.18 (95% CI 2.05, 41.0)] and the extent of lung involvement [RR 3.28 (95% CI 1.12, 9.60)]. CONCLUSION: Most patients with RA-ILD experienced stable or slowly declining lung function. In 5% of patients, predicted FVC% deteriorated rapidly, especially in older adults with early RA. The lung function trajectory was not comparable to the RA disease activity trajectory.

Novel Lung Growth Strategy with Biological Therapy Targeting Airway Remodeling in Childhood Bronchial Asthma.

Anti-inflammatory therapy, centered on inhaled steroids, suppresses airway inflammation in asthma, reduces asthma mortality and hospitalization rates, and achieves clinical remission in many pediatric patients. However, the spontaneous remission rate of childhood asthma in adulthood is not high, and airway inflammation and airway remodeling persist after remission of asthma symptoms. Childhood asthma impairs normal lung maturation, interferes with peak lung function in adolescence, reduces lung function in adulthood, and increases the risk of developing chronic obstructive pulmonary disease (COPD). Early suppression of airway inflammation in childhood and prevention of asthma exacerbations may improve lung maturation, leading to good lung function and prevention of adult COPD. Biological drugs that target T-helper 2 (Th2) cytokines are used in patients with severe pediatric asthma to reduce exacerbations and airway inflammation and improve respiratory function. They may also suppress airway remodeling in childhood and prevent respiratory deterioration in adulthood, reducing the risk of COPD and improving long-term prognosis. No studies have demonstrated a suppressive effect on airway remodeling in childhood severe asthma, and further clinical trials using airway imaging analysis are needed to ascertain the inhibitory effect of biological drugs on airway remodeling in severe childhood asthma. In this review, we describe the natural prognosis of lung function in childhood asthma and the risk of developing adult COPD, the pathophysiology of allergic airway inflammation and airway remodeling via Th2 cytokines, and the inhibitory effect of biological drugs on airway remodeling in childhood asthma.

Impact of early life exposures on respiratory disease.

The antecedents of asthma and chronic obstructive pulmonary disease (COPD) lie before school age. Adverse effects are transgenerational, antenatal and in the preschool years. Antenatal adverse effects impair spirometry by causing low birth weight, altered lung structure and immune function, and sensitizing the foetus to later insults. The key stages of normal lung health are lung function at birth, lung growth to a plateau age 20-25 years, and the phase of decline thereafter; contrary to perceived wisdom, accelerated decline is not related to smoking. There are different trajectories of lung function. Lung function usually tracks from preschool to late middle age. Asthma is driven by antenatal and early life influences. The airflow obstruction, emphysema and multi-morbidity of COPD all start early. Failure to reach a normal plateau and accelerated decline in lung function are risk factors for COPD. Airway disease cannot be prevented in adult life; prevention must start early.

Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood.

BACKGROUND: The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood. METHODS: DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex. RESULTS: High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases. CONCLUSION: The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.

Predicting Lung Health Trajectories for Survivors of Preterm Birth.

Rates of preterm birth (<37 weeks of gestation) are increasing worldwide. Improved perinatal care has markedly increased survival of very (<32 weeks gestation) and extremely (<28 weeks gestation) preterm infants, however, long term respiratory sequalae are common among survivors. Importantly, individual's lung function trajectories are determined early in life and tend to track over the life course. Preterm infants are impacted by antenatal, postnatal and early life perturbations to normal lung growth and development, potentially resulting in significant shifts from the "normal" lung function trajectory. This review summarizes what is currently known about the long-term lung function trajectories in survivors of preterm birth. Further, this review highlights how antenatal, perinatal and early life factors are likely to contribute to individual lung health trajectories across the life course.

Childhood Origins of Adult Lung Disease as Opportunities for Prevention.

Prenatal and childhood exposures have been shown to impact lung development, lung function trajectory, and incidence and prevalence of respiratory disease. Early life may serve as a window of susceptibility to such exposures, with the potential to influence lifelong respiratory health. Risk factors encountered in early life with potentially durable impact on lung health include prematurity, respiratory viral illness, allergen sensitization and exposure, tobacco use and exposure, indoor and outdoor pollution, diet, and obesity. These exposures vary in the extent to which they are modifiable, and interventions aimed at reducing harmful exposures range from individual-level behavior modification to policy initiatives implemented to promote population health. For many exposures, including tobacco-related exposures, multilevel interventions are needed. Future research is needed to provide insight as to early-life interventions to promote optimal lung growth and prevent development of chronic respiratory disease. Clinicians should play an active role, assisting individual patients in avoiding known detrimental exposures including maternal smoking during pregnancy and initiation of active smoking. Clinicians can be empowered by evidence to support policies promoting reduction of population-level risk factors, such as restriction on electronic cigarette sales and legislation to uphold air quality standards, to encourage attainment of maximal lung function and reduce risk of chronic lung disease.

Adult Life-Course Trajectories of Lung Function and the Development of Emphysema: The CARDIA Lung Study.

BACKGROUND: Peak lung function and rate of decline predict future airflow obstruction and nonrespiratory comorbid conditions. Associations between lung function trajectories and emphysema have not been explored. METHODS: Using data from the population-based CARDIA Study, we sought to describe the prevalence of visually ascertained emphysema at multiple time points and contextualize its development based upon participant's adult life course measures of lung function. There were 3171 men and women enrolled at a mean age of 25 years, who underwent serial spirometric examinations through a mean age of 55 years. Trajectories for the change in percent-predicted forced expiratory volume in one second (FEV1) were determined by fitting a mixture model via maximum likelihood. Emphysema was visually identified on computed tomographic scans and its prevalence reported at mean ages of 40, 45, and 50 years. RESULTS: We identified 5 trajectories describing peak and change in FEV1: "Preserved Ideal," "Preserved Good," "Preserved Impaired," "Worsening," and "Persistently Poor." Ever smokers comprised part of all 5 trajectories. The prevalence of emphysema was 1.7% (n = 46; mean age of 40 years), 2.5% (n = 67; mean age of 45 years), and 7.1% (n = 189; mean age of 50 years). Of those with emphysema at a mean age of 50 years, 18.0% were never smokers. Worsening and poor lung health trajectories were associated with increased odds of future emphysema independent of chronic tobacco smoke exposure (odds ratio 5.06; confidence interval, 1.84-13.96; odds ratio 4.85; confidence interval, 1.43-16.44). CONCLUSIONS: Lower peak and accelerated decline in FEV1 are risk factors for future emphysema independent of smoking status.

Reduction in mouse allergen exposure is associated with greater lung function growth.

BACKGROUND: Current childhood asthma therapies have little effect on lung function trajectory. OBJECTIVE: We sought to determine whether mouse allergen exposure reduction is associated with lung function growth in mouse-sensitized/exposed asthmatic children. METHODS: Three hundred fifty mouse-sensitized/exposed asthmatic children (5-17 years old) were enrolled in a 1-year randomized trial of integrated pest management plus education versus education alone. Prebronchodilator/postbronchodilator spirometry was performed at baseline and 6 and 12 months, and bedroom floor mouse allergen levels were measured every 3 months. Mouse allergen reduction was defined as a 75% or greater decrease in mouse allergen levels from baseline. Treatment groups were combined for analyses because there were no differences in outcomes between groups. Changes in lung function over time were modeled, adjusting for age, sex, race, atopy, group, and bronchodilator reversibility and including an interaction term (allergen reduction*time). RESULTS: The study population was predominantly black (79.4%) and low income (66.3% [<$30,000]). At baseline, the median mouse allergen level was 5.7 µg/g (interquartile range, 1.5-22.8 µg/g), and the mean (SD) prebronchodilator FEV1/forced vital capacity ratio was 80.2% (9.0%). Ninety-two (26.3%) participants had 75% or greater reduction in mouse allergen levels. For a 10-year-old black boy, 75% or greater allergen reduction was associated with an increase in prebronchodilator FEV1 of 238 mL/y (95% CI, 177-299 mL/y), whereas less than 75% allergen reduction was associated with an increase in prebronchodilator FEV1 of 131 mL/y (95% CI, 97-166 mL/y). Estimated differences in prebronchodilator and postbronchodilator FEV1 growth were as follows: 107 mL/y (95% CI, 37-177 mL/y; Pint = .003) and 48 mL/y (95% CI, -17 to 113 mL/y; Pint = .15), respectively. Estimated differences in prebronchodilator and postbronchodilator forced expiratory flow at 25% to 75% of vital capacity growth were as follows: 182 mL/y (95% CI, 61-304 mL/y; Pint = .003) and 181 mL/y (95% CI, 48-314 mL/y; Pint = .008), respectively. CONCLUSION: Mouse allergen reduction is associated with greater increases in prebronchodilator FEV1 and prebronchodilator/postbronchodilator forced expiratory flow at 25% to 75% of vital capacity over 1 year among sensitized/exposed asthmatic children.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Lung function trajectories from birth through puberty reflect asthma phenotypes with allergic comorbidity.

BACKGROUND: Childhood asthma phenotypes reflecting underlying developmental mechanisms are sought, with little information on asthma phenotypes based on allergic comorbidities. OBJECTIVE: We asked whether lung function trajectories from birth to 16 years were associated with asthma phenotypes with comorbid allergic rhinitis and atopic dermatitis. METHODS: Lung function (given as z scores) was measured at birth in 329 subjects in the "Environment and Childhood Asthma" birth cohort study in Oslo by using tidal flow volume loops, and at 10 and 16 years by using spirometry. Asthma phenotypes were classified on the basis of recurrent bronchial obstruction at 0 to 2 years, and asthma from the 2- to 10-year and 10- to 16-year intervals, and by combining asthma, atopic dermatitis, and/or allergic rhinitis from 10 to 16 years, stratifying for allergic sensitization. The reference group included 231 subjects without recurrent bronchial obstruction or asthma. RESULTS: Lung function trajectories differed significantly for asthma comorbidity phenotypes for FEV1, forced expiratory flow at 25% to 75% of forced vital capacity, and FEV1/forced vital capacity (all P < .0001). Significant lung function impairment was observed from birth through 16 years among subjects with asthma, atopic dermatitis, and allergic rhinitis. Lung function trajectories in subjects with asthma at 10 to 16 years or asthma in remission differed significantly for all 3 spirometric values compared with the trajectories in those who never had asthma (P < .0001), but not between asthma groups. Allergic sensitization was not significantly associated with asthma phenotype lung function trajectories. CONCLUSIONS: The trajectory consisting of impaired lung function from birth throughout childhood in children with asthma, atopic dermatitis, and allergic rhinitis appears less likely to be driven by allergic sensitization, and may imply disease onset in utero, with clinical presentation later in childhood.