Pulmonary fissure integrity and collateral ventilation in COPD patients

Purpose: To investigate whether the integrity (completeness) of pulmonary fissures affects pulmonary function in patients with chronic obstructive pulmonary disease (COPD). Materials and Methods: A dataset consisting of 573 CT exams acquired on different subjects was collected from a COPD study. According to the global initiative for chronic obstructive lung disease (GOLD) criteria, these subjects (examinations) were classified into five different subgroups, namely non-COPD (222 subjects), GOLD-I (83 subjects), GOLD-II (141 subjects), GOLD-III (63 subjects), and GOLD-IV (64 subjects), in terms of disease severity. An available computer tool was used to aid in an objective and efficient quantification of fissure integrity. The correlations between fissure integrity, and pulmonary functions (e.g., FEV1, and FEV1/FVC) and COPD severity were assessed using Pearson and Spearman's correlation coefficients, respectively. Results: For the five sub-groups ranging from non-COPD to GOLD-IV, the average integrities of the right oblique fissure (ROF) were 81.8%, 82.4%, 81.8%, 82.8%, and 80.2%, respectively; the average integrities of the right horizontal fissure (RHF) were 62.6%, 61.8%, 62.1%, 62.2%, and 62.3%, respectively; the average integrities of the left oblique fissure (LOF) were 82.0%, 83.2%, 81.7%, 82.0%, and 78.4%, respectively; and the average integrities of all fissures in the entire lung were 78.0%, 78.6%, 78.1%, 78.5%, and 76.4%, respectively. Their Pearson correlation coefficients with FEV1 and FE1/FVC range from 0.027 to 0.248 with p values larger than 0.05. Their Spearman correlation coefficients with COPD severity except GOLD-IV range from -0.013 to -0.073 with p values larger than 0.08. Conclusion: There is no significant difference in fissure integrity for patients with different levels of disease severity, suggesting that the development of COPD does not change the completeness of pulmonary fissures and incomplete fissures alone may not contribute to the collateral ventilation. © 2014 Pu et al

Design for a multicenter, randomized, sham-controlled study to evaluate safety and efficacy after treatment with the Nuvaira (R) lung denervation system in subjects with chronic obstructive pulmonary disease (AIRFLOW-3)

Background Targeted lung denervation (TLD) is a bronchoscopically delivered ablation therapy that selectively interrupts pulmonary parasympathetic nerve signaling. The procedure has the potential to alter airway smooth muscle tone and reactivity, decrease mucous secretion, and reduce airway inflammation and reflex airway hyperresponsiveness. Secondary outcome analysis of a previous randomized, sham-controlled trial showed a reduction in moderate-to-severe exacerbations in patients with COPD after TLD treatment. A pivotal trial, AIRFLOW-3 has been designed to evaluate the safety and efficacy of TLD combined with optimal medical therapy to reduce moderate or severe exacerbations throughout 1 year, compared with optimal medical therapy alone. Methods The study design is a multicenter, randomized, full sham bronchoscopy controlled, double-blind trial that will enroll 400 patients (1:1 randomization). Key inclusion criteria are FEV1/FVC < 0.7, FEV1 30 to 60% of predicted, post-bronchodilator, ≥ 2 moderate or 1 severe COPD exacerbations in the prior year, and COPD assessment test (CAT) ≥ 10. Primary objective will be the comparison of moderate or severe COPD exacerbations through 12 months of TLD therapy with optimal medical therapy versus optimal medical therapy alone. The sham group will be allowed to cross over at 1 year. Patients will be followed for up to 5 years. Discussion The multicenter, randomized, full sham bronchoscopy controlled, double-blind AIRFLOW-3 trial will evaluate the efficacy of TLD to reduce moderate or severe COPD exacerbations beyond optimal medical therapy alone. The target population are patients with COPD, who suffer persistent symptoms and exacerbations despite optimal treatment, defining an unmet medical need requiring novel therapeutic solutions. This trial is registered at clinicaltrials.gov: NCT03639051

Missing value imputation in high-dimensional phenomic data: Imputable or not, and how?

Background: In modern biomedical research of complex diseases, a large number of demographic and clinical variables, herein called phenomic data, are often collected and missing values (MVs) are inevitable in the data collection process. Since many downstream statistical and bioinformatics methods require complete data matrix, imputation is a common and practical solution. In high-throughput experiments such as microarray experiments, continuous intensities are measured and many mature missing value imputation methods have been developed and widely applied. Numerous methods for missing data imputation of microarray data have been developed. Large phenomic data, however, contain continuous, nominal, binary and ordinal data types, which void application of most methods. Though several methods have been developed in the past few years, not a single complete guideline is proposed with respect to phenomic missing data imputation. Results: In this paper, we investigated existing imputation methods for phenomic data, proposed a self-training selection (STS) scheme to select the best imputation method and provide a practical guideline for general applications. We introduced a novel concept of "imputability measure" (IM) to identify missing values that are fundamentally inadequate to impute. In addition, we also developed four variations of K-nearest-neighbor (KNN) methods and compared with two existing methods, multivariate imputation by chained equations (MICE) and missForest. The four variations are imputation by variables (KNN-V), by subjects (KNN-S), their weighted hybrid (KNN-H) and an adaptively weighted hybrid (KNN-A). We performed simulations and applied different imputation methods and the STS scheme to three lung disease phenomic datasets to evaluate the methods. An R package "phenomeImpute" is made publicly available. Conclusions: Simulations and applications to real datasets showed that MICE often did not perform well, KNN-A, KNN-H and random forest were among the top performers although no method universally performed the best. Imputation of missing values with low imputability measures increased imputation errors greatly and could potentially deteriorate downstream analyses. The STS scheme was accurate in selecting the optimal method by evaluating methods in a second layer of missingness simulation. All source files for the simulation and the real data analyses are available on the author's publication website

Airway resistance at maximum inhalation as a marker of asthma and airway hyperresponsiveness

<p>Abstract</p> <p>Background</p> <p>Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (R_min) is abnormally elevated in subjects with airway hyperresponsiveness.</p> <p>Methods</p> <p>The R_minwas measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. R_minand spirometric indices were measured before and after bronchodilation (albuterol) and bronchoconstriction (methacholine). A preliminary study of 84 healthy subjects first established height dependence of baseline R_minvalues.</p> <p>Results</p> <p>Asthmatics had a higher baseline R_min% predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004). Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline R_minwas able to identify subjects with airway hyperresponsiveness (PC₂₀< 16 mg/mL) better than most spirometric indices (Area under curve = 0.85, 0.78, and 0.87 for R_min% predicted, FEV₁% predicted, and FEF_25-75% predicted, respectively). Also, 80% of the subjects with baseline R_min< 100% predicted did not have airway hyperresponsiveness while 100% of subjects with R_min> 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic.</p> <p>Conclusions</p> <p>These findings suggest that baseline R_min, a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline R_minto asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, R_mincould provide a clinically useful tool for assessing asthma and monitoring response to treatment.</p

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease

Prescribing cycle training intensity from the six-minute walk test for patients with COPD

Background: Cycle training intensity for patients with chronic obstructive pulmonary disease (COPD) is normally based on an incremental cycle test. Such tests are expensive and not readily available to clinicians. The six-minute walk test (6MWT) has been proposed as an alternative to an incremental cycle test for this purpose, based on the findings of previous research that the peak oxygen consumption (VO2peak) for the incremental cycle test and the 6MWT was equivalent in participants with COPD. A regression equation relating distance walked on the 6MWT and peak work rate (Wpeak) on the incremental cycle test has been described. The aim of this study is to measure the physiological responses to constant load cycle exercise performed at an intensity of 60% Wpeak determined from the 6MWT in participants with stable COPD. Methods/Design: This study is a prospective, repeated measures design. Thirty-five participants with stable COPD and mild to severe lung disease will be recruited from referrals to pulmonary rehabilitation. Subjects with co-morbidities limiting exercise performance will be excluded. Two 6MWTs will be performed. The better 6MWT will be used to calculate Wpeak for cycle exercise from a regression equation. After 30 minutes rest, subjects will perform ten minutes of constantload cycle exercise at 60% of the calculated Wpeak. During all exercise, cardiorespiratory and metabolic data (Cosmed K4b2), dyspnoea and rate of perceived exertion (RPE) will be recorded. The VO2 measured at the end of cycle exercise will be compared to VO2peak of the 6MWT (VO2bike/ VO2walk). Pearson's correlation coefficient will be calculated for the relationship between VO2bike and VO2walk. A one-way analysis of variance (ANOVA), with Bonferroni correction, will be performed to determine whether the ratio of VO2bike/VO2walk is affected by disease severity. Discussion: This novel study will measure the physiological responses to cycle exercise, in terms of VO2peak, performed at an intensity determined from the 6MWT in participants with COPD. Positive findings will enable clinicians to more precisely prescribe cycle training intensity by utilising a simple, reliable and inexpensive 6MWT, thus providing a better standard of care for patients with COPD referred to pulmonary rehabilitation

A Combined Pulmonary Function and Emphysema Score Prognostic Index for Staging in Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is characterized by high morbidity and mortality. Lung computed tomography parameters, individually or as part of a composite index, may provide more prognostic information than pulmonary function tests alone.To investigate the prognostic value of emphysema score and pulmonary artery measurements compared with lung function parameters in COPD and construct a prognostic index using a contingent staging approach.Predictors of mortality were assessed in COPD outpatients whose lung computed tomography, spirometry, lung volumes and gas transfer data were collected prospectively in a clinical database. Univariate and multivariate Cox proportional hazard analysis models with bootstrap techniques were used.169 patients were included (59.8% male, 61.1 years old; Forced Expiratory Volume in 1 second % predicted: 40.5±19.2). 20.1% died; mean survival was 115.4 months. Age (HR = 1.098, 95% Cl = 1.04-1.252) and emphysema score (HR = 1.034, 95% CI = 1.007-1.07) were the only independent predictors of mortality. Pulmonary artery dimensions were not associated with survival. An emphysema score of 55% was chosen as the optimal threshold and 30% and 65% as suboptimals. Where emphysema score was between 30% and 65% (intermediate risk) the optimal lung volume threshold, a functional residual capacity of 210% predicted, was applied. This contingent staging approach separated patients with an intermediate risk based on emphysema score alone into high risk (Functional Residual Capacity ≥210% predicted) or low risk (Functional Residual Capacity <210% predicted). This approach was more discriminatory for survival (HR = 3.123; 95% CI = 1.094-10.412) than either individual component alone.Although to an extent limited by the small sample size, this preliminary study indicates that the composite Emphysema score-Functional Residual Capacity index might provide a better separation of high and low risk patients with COPD, than other individual predictors alone

The Role of Circulating Serotonin in the Development of Chronic Obstructive Pulmonary Disease

BACKGROUND: Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD). The serotonin transporter (SERT) gene polymorphism has been reported to be associated with COPD, and the degree of cigarette smoking has been shown to be a significant mediator in this relationship. The interrelation between circulating serotonin (5-hydroxytyptamine, 5-HT), cigarette smoking and COPD is however largely unknown. The current study aimed at investigating the mediation effects of plasma 5-HT on cigarette smoking-induced COPD and the relation between plasma 5-HT levels and age. METHODS: The association between plasma 5-HT, age and COPD was analyzed in a total of 62 COPD patients (ever-smokers) and 117 control subjects (healthy non-smokers and ever-smokers). Plasma 5-HT levels were measured by enzyme-linked immuno assay (EIA). RESULTS: The elevated plasma 5-HT levels were significantly associated with increased odds for COPD (OR = 1.221, 95% CI = 1.123 to 1.319, p<0.0001). The effect remained significant after being adjusted for age and pack-years smoked (OR = 1.271, 95% CI = 1.134 to 1.408, p = 0.0003). Furthermore, plasma 5-HT was found to mediate the relation between pack-years smoked and COPD. A positive correlation (r = 0.303, p = 0.017) was found between plasma 5-HT levels and age in COPD, but not in the control subjects (r = -0.149, p = 0.108). CONCLUSION: Our results suggest that cigarette smoke-induced COPD is partially mediated by the plasma levels of 5-HT, and that these become elevated with increased age in COPD. The elevated plasma 5-HT levels in COPD might contribute to the pathogenesis of this disease.published_or_final_versio

MyD88 in lung resident cells governs airway inflammatory and pulmonary function responses to organic dust treatment

Inhalation of organic dusts within agriculture environments contributes to the development and/or severity of airway diseases, including asthma and chronic bronchitis. MyD88 KO (knockout) mice are nearly completely protected against the inflammatory and bronchoconstriction effects induced by acute organic dust extract (ODE) treatments. However, the contribution of MyD88 in lung epithelial cell responses remains unclear. In the present study, we first addressed whether ODE-induced changes in epithelial cell responses were MyD88-dependent by quantitating ciliary beat frequency and cell migration following wounding by electric cell-substrate impedance sensing. We demonstrate that the normative ciliary beat slowing response to ODE is delayed in MyD88 KO tracheal epithelial cells as compared to wild type (WT) control. Similarly, the normative ODE-induced slowing of cell migration in response to wound repair was aberrant in MyD88 KO cells. Next, we created MyD88 bone marrow chimera mice to investigate the relative contribution of MyD88-dependent signaling in lung resident (predominately epithelial cells) versus hematopoietic cells. Importantly, we demonstrate that ODE-induced airway hyperresponsiveness is MyD88-dependent in lung resident cells, whereas MyD88 action in hematopoietic cells is mainly responsible for ODE-induced TNF-α release. MyD88 signaling in lung resident and hematopoietic cells are necessary for ODE-induced IL-6 and neutrophil chemoattractant (CXCL1 and CXCL2) release and neutrophil influx. Collectively, these findings underscore an important role for MyD88 in lung resident cells for regulating ciliary motility, wound repair and inflammatory responses to ODE, and moreover, show that airway hyperresponsiveness appears uncoupled from airway inflammatory consequences to organic dust challenge in terms of MyD88 involvement. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-015-0272-9) contains supplementary material, which is available to authorized users