COPD phenotype description using principal components analysis

Background

Airway inflammation in COPD can be measured using biomarkers such as induced sputum and Fe_NO. This study set out to explore the heterogeneity of COPD using biomarkers of airway and systemic inflammation and pulmonary function by principal components analysis (PCA).

Subjects and Methods

In 127 COPD patients (mean FEV₁ 61%), pulmonary function, Fe_NO, plasma CRP and TNF-α, sputum differential cell counts and sputum IL8 (pg/ml) were measured. Principal components analysis as well as multivariate analysis was performed.

Results

PCA identified four main components (% variance): (1) sputum neutrophil cell count and supernatant IL8 and plasma TNF-α (20.2%), (2) Sputum eosinophils % and Fe_NO (18.2%), (3) Bronchodilator reversibility, FEV₁ and IC (15.1%) and (4) CRP (11.4%). These results were confirmed by linear regression multivariate analyses which showed strong associations between the variables within components 1 and 2.

Conclusion

COPD is a multi dimensional disease. Unrelated components of disease were identified, including neutrophilic airway inflammation which was associated with systemic inflammation, and sputum eosinophils which were related to increased Fe_NO. We confirm dissociation between airway inflammation and lung function in this cohort of patients.     

Investigation of Hydrogen Sulfide Exposure and Lung Function,Asthma and Chronic Obstructive Pulmonary Disease in a Geothermal Area of New Zealand

Background

Results have been conflicting whether long-term ambient hydrogen sulfide (H₂S) affects lung function or is a risk factor for asthma or chronic obstructive pulmonary disease (COPD). Rotorua city, New Zealand, has the world’s largest population exposed to ambient H₂S—from geothermal sources.

Objectives

We investigated associations of H₂S with lung function, COPD and asthma in this population.

Methods

1,204 of 1,639 study participants, aged 18–65 years during 2008–2010, provided satisfactory spirometry results. Residences, workplaces and schools over the last 30 years were geocoded. Exposures were estimated from data collected by summer and winter H₂S monitoring networks across Rotorua. Four metrics for H₂S exposure, representing both current and long-term (last 30 years) exposure, and also time-weighted average and peak exposures, were calculated. Departures from expected values for pre-bronchodilator lung function, calculated from prediction equations, were outcomes for linear regression models using quartiles of the H₂S exposure metrics. Separate models examined participants with and without evidence of asthma or COPD, and never- and ever-smokers. Logistic regression was used to investigate associations of COPD (a post-bronchodilator FEV₁/FVC < 70% of expected) and asthma (doctor-diagnosed or by FEV₁ response to bronchodilator) with H₂S exposure quartiles.

Results

None of the exposure metrics produced evidence of lung function decrement. The logistic regression analysis showed no evidence that long-term H₂S exposure at Rotorua levels was associated with either increased COPD or asthma risk. Some results suggested that recent ambient H₂S exposures were beneficially associated with lung function parameters.

Conclusions

The study found no evidence of reductions in lung function, or increased risk of COPD or asthma, from recent or long-term H₂S exposure at the relatively high ambient concentrations found in Rotorua. Suggestions of improved lung function associated with recent ambient H₂S exposures require confirmation in other studies.     

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Background

Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

Methods

We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV₁) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV₁ by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

Results

The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10^-7). In addition, meta-analysis using the five cohorts with ≥3 FEV₁ measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10^-8) at genome-wide significance. Neither locus was associated with FEV₁ decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV₁ decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

Conclusions

In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV₁ that harbor candidate genes with biologically plausible functional links to lung function.     

Association between Air Pollutants and Asthma Emergency Room Visits and Hospital Admissions in Time Series Studies: A Systematic Review and Meta-Analysis

Background

Air pollution constitutes a significant stimulus of asthma exacerbations; however, the impacts of exposure to major air pollutants on asthma-related hospital admissions and emergency room visits (ERVs) have not been fully determined.

Objective

We sought to quantify the associations between short-term exposure to air pollutants [ozone (O₃), carbon monoxide (CO), nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and particulate matter ≤10μm (PM₁₀) and PM_2.5] and the asthma-related emergency room visits (ERV) and hospitalizations.

Methods

Systematic computerized searches without language limitation were performed. Pooled relative risks (RRs) and 95% confidence intervals (95%CIs) were estimated using the random-effect models. Sensitivity analyses and subgroup analyses were also performed.

Results

After screening of 246 studies, 87 were included in our analyses. Air pollutants were associated with significantly increased risks of asthma ERVs and hospitalizations [O₃: RR(95%CI), 1.009 (1.006, 1.011); I² = 87.8%, population-attributable fraction (PAF) (95%CI): 0.8 (0.6, 1.1); CO: RR(95%CI), 1.045 (1.029, 1.061); I² = 85.7%, PAF (95%CI): 4.3 (2.8, 5.7); NO₂: RR(95%CI), 1.018 (1.014, 1.022); I² = 87.6%, PAF (95%CI): 1.8 (1.4, 2.2); SO₂: RR(95%CI), 1.011 (1.007, 1.015); I² = 77.1%, PAF (95%CI): 1.1 (0.7, 1.5); PM₁₀: RR(95%CI), 1.010 (1.008, 1.013); I² = 69.1%, PAF (95%CI): 1.1 (0.8, 1.3); PM_2.5: RR(95%CI), 1.023 (1.015, 1.031); I² = 82.8%, PAF (95%CI): 2.3 (1.5, 3.1)]. Sensitivity analyses yielded compatible findings as compared with the overall analyses without publication bias. Stronger associations were found in hospitalized males, children and elderly patients in warm seasons with lag of 2 days or greater.

Conclusion

Short-term exposures to air pollutants account for increased risks of asthma-related ERVs and hospitalizations that constitute a considerable healthcare utilization and socioeconomic burden.     

Socioeconomic Status and Longitudinal Lung Function of Healthy Mexican Children

Introduction

Our aim was to estimate the longitudinal effect of Socioeconomic status (SES) on lung function growth of Mexican children and adolescents.

Materials and Methods

A cohort of Mexican children in third grade of primary school was followed with spirometry twice a year for 6 years through secondary school. Multilevel mixed-effects lineal models were fitted for the spirometric variables of 2,641 respiratory-healthy Mexican children. Monthly family income (in 2002 U.S. dollars [USD]) and parents’ years completed at school were used as proxies of SES.

Results

Individuals with higher SES tended to have greater height for age, and smaller sitting height/standing height and crude lung function. For each 1-year increase of parents’ schooling, Forced expiratory volume in 1 sec (FEV₁) and Forced vital capacity (FVC) increased 8.5 (0.4%) and 10.6 mL (0.4%), respectively (p <0.05) when models were adjusted for gender. Impact of education on lung function was reduced drastically or abolished on adjusting by anthropometric variables and ozone.

Conclusions

Higher parental schooling and higher monthly family income were associated with higher lung function in healthy Mexican children, with the majority of the effect likely due to the increase in height-for-age.     

Pulmonary Impairment in Tuberculosis Survivors: The Korean National Health and Nutrition Examination Survey 2008-2012

Objectives

Pulmonary tuberculosis (TB) can affect lung function, but studies regarding long-term follow-up in patients with no sequelae on chest X-ray (CXR) have not been performed. We evaluated lung functional impairment and persistent respiratory symptoms in those with prior pulmonary TB and those with prior pulmonary TB with no residual sequelae on CXR, and determined risk factors for airflow obstruction.

Methods

We used data from adults aged ≥ 40 years from the annual Korean National Health and Nutrition Examination Surveys conducted between 2008 and 2012. P values for comparisons were adjusted for age, sex, and smoking status.

Results

In total of 14,967 adults, 822 subjects (5.5%) had diagnosed and treated pulmonary TB (mean 29.0 years ago). The FVC% (84.9 vs. 92.6), FEV₁% (83.4 vs. 92.4), and FEV₁/FVC% (73.4 vs. 77.9) were significantly decreased in subjects with prior pulmonary TB compared to those without (p < 0.001, each). In 12,885 subjects with no sequalae on CXR, those with prior pulmonary TB (296, 2.3%) had significantly lower FEV₁% (90.9 vs. 93.4, p = 0.001) and FEV₁/FVC% (76.6 vs. 78.4, p < 0.001) than those without. Subjects with prior pulmonary TB as well as subjects with no sequalae on CXR were more likely to experience cough and physical activity limitations due to pulmonary symptoms than those without prior pulmonary TB (p < 0.001, each). In total subjects, prior pulmonary TB (OR, 2.314; 95% CI, 1.922–2.785), along with age, male, asthma, and smoking mount was risk factor for airflow obstruction. In subjects with prior pulmonary tuberculosis, inactive TB lesion on chest x-ray (OR, 2.300; 95% CI, 1.606–3.294) were risk factors of airflow obstruction.

Conclusion

In addition to subjects with inactive TB lesion on CXR, subjects with no sequelae on CXR can show impaired pulmonary function and respiratory symptoms. Prior TB is a risk factor for airflow obstruction and that the risk is more important when they have inactive lesions on chest X-ray. Hence, the patients with treated TB should need to have regular follow-up of lung function and stop smoking for early detection and prevention of the chronic airway disease.     

Decreased Histone Deacetylase 2 (HDAC2) in Peripheral Blood Monocytes (PBMCs) of COPD Patients

Background

Histone deacetylase 2 (HDAC2) is a class I histone deacetylase family member that plays a critical role in suppressing inflammatory gene expression in the airways, lung parenchyma, and alveolar macrophages in patients with chronic obstructive pulmonary disease (COPD). However, the expression of HDAC2 in peripheral blood monocytes (PBMCs), nuclear factor kappa B (NF-κB) p65, and serum inflammatory cytokine levels in COPD patients, smokers, and non-smokers remains unclear.

Methods

PBMCs were obtained from COPD patients, healthy smokers, and healthy nonsmokers. The HDAC2 and NF-κB p65 expression were quantified by Western Blot. HDAC activity was assessed by an HDAC fluorometric immunoprecipitation activity assay kit. Serum tumor necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) levels were measured by ELISA.

Results

HDAC2 expression and HDAC activity were decreased in PBMCs in COPD patients compared with smokers and non-smokers. Increased NF-κB p65 expression, serum TNF-α and IL-8 levels were observed in COPD patients compared with nonsmokers. The FEV₁%pred was positively correlated with HDAC2 expression and HDAC activity in COPD patients. Smokers had decreased HDAC activity, increased NF-κB p65 expression and serum TNF-α compared with nonsmokers.

Conclusions

HDAC2 expression was decreased in PBMCs of COPD patients and was correlated with disease severity. The reduction of HDAC2 expression not only directly enhances the expression of inflammatory genes, but may account for the activation of NF-κB mediated inflammation. Decreased HDAC2 may serve as a potential biomarker of COPD and predict the decline of lung function.     

CT Air Trapping Is Independently Associated with Lung Function Reduction over Time

Purpose

We aimed to study the association between lung function decline and quantitative computed tomography (CT) air trapping.

Materials and Methods

Current and former heavy smokers in a lung cancer screening trial underwent volumetric low-dose CT in inspiration and expiration. Spirometry was obtained at baseline and after 3 years. The expiratory to inspiratory ratio of mean lung density (E/I-ratio_MLD) was used to quantify air trapping. CT emphysema was defined as voxels in inspiratory CT below −950 Hounsfield Unit. Linear mixed modeling was used to determine the association between CT air trapping and lung function.

Results

We included 985 subjects with a mean age of 61.3 years. Independent of CT emphysema, CT air trapping was significantly associated with a reduction in forced expiratory volume in one second (FEV₁) and the ratio of FEV₁ over the forced vital capacity (FEV₁/FVC); FEV₁ declines with 33 mL per percent increase in CT air trapping, while FEV₁/FVC declines 0.58% per percent increase (both p<0.001). CT air trapping further elicits accelerated loss of FEV₁/FVC (additional 0.24% reduction per percent increase; p = 0.014).

Conclusion

In a lung cancer screening cohort, quantitatively assessed air trapping on low-dose CT is independently associated with reduced lung function and accelerated decline of FEV₁/FVC.     

Long-term air pollution exposure and living close to busy roads are associated with COPD in women

Background

Lung function and exacerbations of chronic obstructive pulmonary disease (COPD) have been associated with short-term exposure to air pollution. However, the effect of long-term exposure to particulate matter from industry and traffic on COPD as defined by lung function has not been evaluated so far. Our study was designed to investigate the influence of long-term exposure to air pollution on respiratory symptoms and pulmonary function in 55-year-old women. We especially focused on COPD as defined by GOLD criteria and additionally compared the effects of air pollution on respiratory symptoms by questionnaire data and by lung function measurements.

Methods

In consecutive cross sectional studies conducted between 1985–1994, we investigated 4757 women living in the Rhine-Ruhr Basin of Germany. NO₂ and PM₁₀ exposure was assessed by measurements done in an 8 km grid, and traffic exposure by distance from the residential address to the nearest major road using Geographic Information System data. Lung function was determined and COPD was defined by using the GOLD criteria. Chronic respiratory symptoms and possible confounders were defined by questionnaire data. Linear and logistic regressions, including random effects were used to account for confounding and clustering on city level.

Results

The prevalence of COPD (GOLD stages 1–4) was 4.5%. COPD and pulmonary function were strongest affected by PM₁₀ and traffic related exposure. A 7 μg/m₃ increase in five year means of PM₁₀ (interquartile range) was associated with a 5.1% (95% CI 2.5%–7.7%) decrease in FEV₁, a 3.7% (95% CI 1.8%–5.5%) decrease in FVC and an odds ratio (OR) of 1.33 (95% CI 1.03–1.72) for COPD. Women living less than 100 m from a busy road also had a significantly decreased lung function and COPD was 1.79 times more likely (95% CI 1.06–3.02) than for those living farther away. Chronic symptoms as based on questionnaire information showed effects in the same direction, but less pronounced.

Conclusion

Chronic exposure to PM₁₀, NO₂ and living near a major road might increase the risk of developing COPD and can have a detrimental effect on lung function.     

Dietary intake,lung function and airway inflammation in Mexico City school children exposed to air pollutants

Introduction

Air pollutant exposure has been associated with an increase in inflammatory markers and a decline in lung function in asthmatic children. Several studies suggest that dietary intake of fruits and vegetables might modify the adverse effect of air pollutants.

Methods

A total of 158 asthmatic children recruited at the Children''s Hospital of Mexico and 50 non-asthmatic children were followed for 22 weeks. Pulmonary function was measured and nasal lavage collected and analyzed every 2 weeks. Dietary intake was evaluated using a 108-item food frequency questionnaire and a fruit and vegetable index (FVI) and a Mediterranean diet index (MDI) were constructed. The impact of these indices on lung function and interleukin-8 (IL-8) and their interaction with air pollutants were determined using mixed regression models with random intercept and random slope.

Results

FVI was inversely related to IL-8 levels in nasal lavage (p < 0.02) with a significant inverse trend (test for trend p < 0.001), MDI was positively related to lung function (p < 0.05), and children in the highest category of MDI had a higher FEV₁ (test for trend p < 0.12) and FVC (test for trend p < 0.06) than children in the lowest category. A significant interaction was observed between FVI and ozone for FEV₁ and FVC as was with MDI and ozone for FVC. No effect of diet was observed among healthy children.

Conclusion

Our results suggest that fruit and vegetable intake and close adherence to the Mediterranean diet have a beneficial effect on inflammatory response and lung function in asthmatic children living in Mexico City.     

Lacrimal Cytokines Assessment in Subjects Exposed to Different Levels of Ambient Air Pollution in a Large Metropolitan Area

Background

Air pollution is one of the most environmental health concerns in the world and has serious impact on human health, particularly in the mucous membranes of the respiratory tract and eyes. However, ocular hazardous effects to air pollutants are scarcely found in the literature.

Design

Panel study to evaluate the effect of different levels of ambient air pollution on lacrimal film cytokine levels of outdoor workers from a large metropolitan area.

Methods

Thirty healthy male workers, among them nineteen professionals who work on streets (taxi drivers and traffic controllers, high pollutants exposure, Group 1) and eleven workers of a Forest Institute (Group 2, lower pollutants exposure compared to group 1) were evaluated twice, 15 days apart. Exposure to ambient PM_2.5 (particulate matter equal or smaller than 2.5 μm) was 24 hour individually collected and the collection of tears was performed to measure interleukins (IL) 2, 4, 5 and 10 and interferon gamma (IFN-γ) levels. Data from both groups were compared using Student’s t test or Mann- Whitney test for cytokines. Individual PM_2.5 levels were categorized in tertiles (lower, middle and upper) and compared using one-way ANOVA. Relationship between PM_2.5 and cytokine levels was evaluated using generalized estimating equations (GEE).

Results

PM_2.5 levels in the three categories differed significantly (lower: ≤22 μg/m³; middle: 23–37.5 μg/m³; upper: >37.5 μg/m³; p<0.001). The subjects from the two groups were distributed unevenly in the lower category (Group 1 = 8%; Group 2 = 92%), the middle category (Group 1 = 89%; Group 2 = 11%) and the upper category (Group 1 = 100%). A significant relationship was found between IL-5 and IL-10 and PM_2.5 levels of the group 1, with an average decrease of 1.65 pg/mL of IL-5 level and of 0.78 pg/mL of IL-10 level in tear samples for each increment of 50 μg/m3 of PM_2.5 (p = 0.01 and p = 0.003, respectively).

Conclusion

High levels of PM_2.5 exposure is associated with decrease of IL-5 and IL-10 levels suggesting a possible modulatory action of ambient air pollution on ocular surface immune response.     

Instability in the COPD Diagnosis upon Repeat Testing Vary with the Definition of COPD

Background

A low FEV₁/FVC from post-bronchodilator spirometry is required to diagnose COPD. Both the FEV₁ and the FVC can vary over time; therefore, individuals can be given a diagnosis of mild COPD at one visit, but have normal spirometry during the next appointment, even without an intervention.

Methods

We analyzed two population-based surveys of adults with spirometry carried out for the same individuals 5-9 years after their baseline examination. We determined the factors associated with a change in the spirometry interpretation from one exam to the next utilizing different criteria commonly used to diagnose COPD.

Results

The rate of an inconsistent diagnosis of mild COPD was 11.7% using FEV₁/FVC <0.70, 5.9% using FEV₁/FEV₆ <the lower limit of the normal range, LLN and 4.1% using the GOLD stage 2-4 criterion. The most important factor associated with diagnostic inconsistency was the closeness of the ratio to the LLN during the first examination. Inconsistency decreased with a lower FEV₁.

Conclusions

Using FEV₁/FEV₆ <LLN or GOLD stage 2-4 as the criterion for airflow obstruction reduces inconsistencies in the diagnosis of mild COPD. Further improvement could be obtained by defining a borderline zone around the LLN (e.g. plus or minus 0.6 SD), or repeating the test in patients with borderline results.     

Impacts of Co-Existing Chronic Rhinosinusitis on Disease Severity and Risks of Exacerbations in Chinese Adults with Bronchiectasis

Background

Mounting evidence supports the notion of “one airway, one disease.”

Objective

To determine whether chronic rhinosinusitis (CRS) poses adverse impacts on Chinese adults with bronchiectasis.

Methods

We enrolled 148 consecutive adults with clinically stable bronchiectasis. CRS diagnosed based on the 2012 EP³OS criteria. We systematically evaluated the bronchiectasis etiology, radiology, lung function, sputum bacteriology, airway inflammatory biomarkers, Bronchiectasis Severity Index, cough sensitivity and healthcare resource utilization. All patients were prospectively followed-up for 1 year to examine the frequency of bronchiectasis exacerbations (BEs).

Results

Forty-seven patients (31.8%) were diagnosed as having CRS. Bronchiectasis etiologies did not vary statistically between CRS and no-CRS group. There was a trend towards non-statistically higher Bronchiectasis Severity Index [6.4±3.4 vs. 5.0(6.0), P = 0.19], a higher proportion of patients with BEs needing hospitalization before enrollment (48.9% vs. 29.7%, P = 0.13), poorer FVC [78.2±19.8% vs. 82.2(16.8)%, P = 0.54] and FEV₁ [68.2±24.8% vs. 74.8(21.2)%, P = 0.29], a higher prevalence of Pseudomonas aeruginosa isolated (36.2% vs. 26.7%, P = 0.27) or colonized in sputum (36.2% vs. 21.8%, P = 0.12) and greater capsaicin cough sensitivity [C2: 3.9(123.0) μmol/L vs. 11.7(123.0) μmol/L, P = 0.81; C5: 62.5(996.0) μmol/L vs. 250.0(973.0) μmol/L, P = 0.32]. Patients with CRS had significantly greater risks of experiencing BEs during follow-up (P = 0.02 for negative binominal regression test).

Conclusion

Chinese adults with bronchiectasis appear to have a lower prevalence of CRS than that in western countries. There was a trend towards greater adverse impacts on bronchiectasis in patients with CRS. Studies with greater sample sizes might help to resolve this issue. In future clinical practice, physicians should be vigilant to the screening of concomitant CRS in bronchiectasis so as to better improve patient’s healthcare. Our findings may be of clinical significance in that proper treatment of upper airway symptoms due to CRS will be the prevention of infection or re-infection of the tracheobronchial tree, which should be addressed for the future management of bronchiectasis.     

Long-Term Once-Daily Tiotropium Respimat? Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised,Placebo-Controlled Study

Background

This study assessed the long-term safety and efficacy of tiotropium Respimat, a long-acting inhaled anticholinergic bronchodilator, in asthma, added on to inhaled corticosteroids (ICS) with or without long-acting β₂-agonist (LABA).

Methods

285 patients with symptomatic asthma, despite treatment with ICS±LABA, were randomised 2:2:1 to once-daily tiotropium 5 μg, tiotropium 2.5 μg or placebo for 52 weeks (via the Respimat SoftMist inhaler) added on to ICS±LABA, in a double-blind, placebo-controlled, parallel-group study (NCT01340209). Primary objective: to describe the long-term safety profile of tiotropium. Secondary end points included: trough forced expiratory volume in 1 second (FEV₁) response; peak expiratory flow rate (PEFR) response; seven-question Asthma Control Questionnaire (ACQ-7) score.

Results

At Week 52, adverse-event (AE) rates with tiotropium 5 μg, 2.5 μg and placebo were 88.6%, 86.8% and 89.5%, respectively. Commonly reported AEs with tiotropium 5 μg, 2.5 μg and placebo were nasopharyngitis (48.2%, 44.7%, 42.1%), asthma (28.9%, 29.8%, 38.6%), decreased PEFR (15.8%, 7.9%, 21.1%), bronchitis (9.6%, 13.2%, 7.0%), pharyngitis (7.9%, 13.2%, 3.5%) and gastroenteritis (10.5%, 3.5%, 5.3%). In the tiotropium 5 μg, 2.5 μg and placebo groups, 8.8%, 5.3% and 5.3% of patients reported drug-related AEs; 3.5%, 3.5% and 15.8% reported serious AEs. Asthma worsening was the only serious AE reported in more than one patient. At Week 52, adjusted mean trough FEV₁ and trough PEFR responses were significantly higher with tiotropium 5 μg (but not 2.5 μg) versus placebo. ACQ-7 responder rates were higher with tiotropium 5 μg and 2.5 μg versus placebo at Week 24.

Conclusions

The long-term tiotropium Respimat safety profile was comparable with that of placebo Respimat, and associated with mild to moderate, non-serious AEs in patients with symptomatic asthma despite ICS±LABA therapy. Compared with placebo, tiotropium 5 μg, but not 2.5 μg, significantly improved lung function and symptoms, supporting the long-term efficacy of the 5 μg dose.

Trial Registration

ClinicalTrials.gov NCT01340209     

Epithelial Cell Mitochondrial Dysfunction and PINK1 Are Induced by Transforming Growth Factor- Beta1 in Pulmonary Fibrosis

Background

Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis.

Methods

We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis.

Results

Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1 ^-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis.

Conclusion

TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis.     

The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study

Background

Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the α-tocopherol isoform of vitamin E and have not included the isoform γ-tocopherol which we recently demonstrated in vitro opposes the function of α-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform α-tocopherol protects, but the isoform γ-tocopherol promotes lung inflammation and airway hyperresponsiveness.

Methods

To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA.

Results

In cross-sectional regression analysis at year 0, higher γ-tocopherol associated with lower FEV₁ (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher α-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of α-tocopherol, higher γ-tocopherol associated with a lower FEV₁ (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of γ-tocopherol, higher α-tocopherol associated with a higher FEV₁ (p = 0.03) in blacks. Serum γ-tocopherol >10 μM was associated with a 175–545 ml lower FEV₁ and FVC at ages 21–55 years.

Conclusion

Increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum γ-tocopherol >10 μM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV₁ and FVC at these concentrations of serum γ-tocopherol occur in up to 4.5 million adults in the population.     

Clinical Implications of Having Reduced Mid Forced Expiratory Flow Rates (FEF25-75), Independently of FEV1, in Adult Patients with Asthma

Introduction

FEF_25-75 is one of the standard results provided in spirometry reports; however, in adult asthmatics there is limited information on how this physiological measure relates to clinical or biological outcomes independently of the FEV₁ or the FEV₁/FVC ratio.

Purpose

To determine the association between Hankinson’s percent-predicted FEF_25-75 (FEF_25-75%) levels with changes in healthcare utilization, respiratory symptom frequency, and biomarkers of distal airway inflammation.

Methods

In participants enrolled in the Severe Asthma Research Program 1–2, we compared outcomes across FEF_25-75% quartiles. Multivariable analyses were done to avoid confounding by demographic characteristics, FEV₁, and the FEV₁/FVC ratio. In a sensitivity analysis, we also compared outcomes across participants with FEF_25-75% below the lower limit of normal (LLN) and FEV₁/FVC above LLN.

Results

Subjects in the lowest FEF_25-75% quartile had greater rates of healthcare utilization and higher exhaled nitric oxide and sputum eosinophils. In multivariable analysis, being in the lowest FEF_25-75% quartile remained significantly associated with nocturnal symptoms (OR 3.0 [95%CI 1.3–6.9]), persistent symptoms (OR 3.3 [95%CI 1–11], ICU admission for asthma (3.7 [1.3–10.8]) and blood eosinophil % (0.18 [0.07, 0.29]). In the sensitivity analysis, those with FEF_25-75% <LLN had significantly more nocturnal and persistent symptoms, emergency room visits, higher serum eosinophil levels and increased methacholine responsiveness.

Conclusions

After controlling for demographic variables, FEV₁ and FEV₁/FVC, a reduced FEF_25-75% is independently associated with previous ICU admission, persistent symptoms, nocturnal symptoms, blood eosinophilia and bronchial hyperreactivity. This suggests that in some asthmatics, a reduced FEF_25-75% is an independent biomarker for more severe asthma.     

Association of Lung Inflammatory Cells with Small Airways Function and Exhaled Breath Markers in Smokers – Is There a Specific Role for Mast Cells?

Background

Smoking is associated with a mixed inflammatory infiltrate in the airways. We evaluated whether airway inflammation in smokers is related to lung function parameters and inflammatory markers in exhaled breath.

Methods

Thirty-seven smokers undergoing lung resection for primary lung cancer were assessed pre-operatively by lung function testing including single-breath-nitrogen washout test (sb-N2-test), measurement of fractional exhaled nitric oxide (FeNO) and pH/8-isoprostane in exhaled breath condensate (EBC). Lung tissue sections containing cancer-free large (LA) and small airways (SA) were stained for inflammatory cells. Mucosal (MC_T) respectively connective tissue mast cells (MC_TC) and interleukin-17A (IL-17A) expression by mast cells was analysed using a double-staining protocol.

Results

The median number of neutrophils, macrophages and mast cells infiltrating the lamina propria and adventitia of SA was higher than in LA. Both MCTC and MC_T were higher in the lamina propria of SA compared to LA (MC_TC: 49 vs. 27.4 cells/mm²; MC_T: 162.5 vs. 35.4 cells/mm²; P<0.005 for both instances). IL-17A expression was predominantly detected in MC_TC of LA. Significant correlations were found for the slope of phase III % pred. of the sb-N2-test (r_s= -0.39), for the FEV₁% pred. (r_s= 0.37) and for FEV₁/FVC ratio (r_s=0.38) with MC_T in SA (P<0.05 for all instances). 8-isoprostane concentration correlated with the mast cells in the SA (r_s=0.44), there was no correlation for pH or FeNO with cellular distribution in SA.

Conclusions

Neutrophils, macrophages and mast cells are more prominent in the SA indicating that these cells are involved in the development of small airway dysfunction in smokers. Among these cell types, the best correlation was found for mast cells with lung function parameters and inflammatory markers in exhaled breath. Furthermore, the observed predominant expression of IL-17A in mast cells warrants further investigation to elucidate their role in smoking-induced lung injury, despite the lack of correlation with lung function and exhaled breath parameters.     

A randomized controlled trial of vitamin E and selenium on rate of decline in lung function

Background

The intake of nutrients with antioxidant properties is hypothesized to augment antioxidant defenses, decrease oxidant damage to tissues, and attenuate age-related rate of decline in lung function. The objective was to determine whether long-term intervention with selenium and/or vitamin E supplements attenuates the annual rate of decline in lung function, particularly in cigarette smokers.

Methods

The Respiratory Ancillary Study (RAS) tested the single and joint effects of selenium (200 μg/d L-selenomethionine) and vitamin E (400 IU/day all rac-α-tocopheryl acetate) in a randomized double-blind placebo-controlled trial. At the end of the intervention, 1,641 men had repeated pulmonary function tests separated by an average of 3 years. Linear mixed-effects regression models estimated the effect of intervention on annual rate of decline in lung function.

Results

Compared to placebo, intervention had no main effect on either forced expiratory volume in the first second (FEV₁) or forced expiratory flow (FEF_25–75). There was no evidence for a smoking by treatment interaction for FEV₁, but selenium attenuated rate of decline in FEF_25–75 in current smokers (P = 0.0219). For current smokers randomized to selenium, annual rate of decline in FEF_25–75 was similar to the annual decline experienced by never smokers randomized to placebo, with consistent effects for selenium alone and combined with vitamin E.

Conclusions

Among all men, there was no effect of selenium and/or vitamin E supplementation on rate of lung function decline. However, current smokers randomized to selenium had an attenuated rate of decline in FEF_25–75, a marker of airflow.

Trial registration

Clinicaltrials.gov identifier: NCT00241865.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0195-5) contains supplementary material, which is available to authorized users.     

Parathyroid Hormone as a Novel Biomarker for Chronic Obstructive Pulmonary Disease: Korean National Health and Nutrition Examination Survey

Objective

To understand and predict chronic obstructive pulmonary disease (COPD), a biomarker that reflects disease severity is needed.

Research Design and Methods

Data from 10269 adults aged over 40 years of age were retrieved from the Korea National Health and Nutrition Examination Survey (KNHANES), and 1302 patients met the criteria for COPD. The association between values of vitamin D and parathyroid hormone (PTH), and COPD severity including lung function and quality of life, were analyzed.

Results

In COPD patients, lung function was inversely related to PTH values (P = 0.02 for FVC [% predicted]; P < 0.001 for FEV₁ [% predicted]); however, the association of lung function with vitamin D levels was not statistically significant in a multivariable analysis. Value of PTH was independently associated with EQ5D-index (P = 0.04), but vitamin D level showed no significant relationship with EQ5D-index (P = 0.59) or EQ5D-VAS (P = 0.81).

Conclusions

Elevation of PTH, unlike vitamin D, is independently associated with COPD severity, and may be a better biomarker for COPD.