The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway ...obstruction and emphysematous destruction in COPD.
We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles.
On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001).
These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).
Based on surface brushings and bronchoalveolar lavage fluid, Hilty and coworkers demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), ...which have now been confirmed by others.
To extend these findings to human lung tissue samples.
DNA from lung tissue samples was obtained from nonsmokers (n = 8); smokers without COPD (n = 8); patients with very severe COPD (Global Initiative for COPD GOLD 4) (n = 8); and patients with cystic fibrosis (CF) (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying 16S rRNA gene fragments. Total bacterial populations were measured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing.
Total bacterial populations within lung tissue were small (20-1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P < 0.001). Terminal restriction fragment length polymorphism analysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, a second to the GOLD 4 group, and the third to the CF-positive control group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007).
There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD.
Noninvasive mechanical ventilation (NIV) is widely used in the acute care setting for acute respiratory failure (ARF) across a variety of aetiologies. This document provides European Respiratory ...Society/American Thoracic Society recommendations for the clinical application of NIV based on the most current literature.The guideline committee was composed of clinicians, methodologists and experts in the field of NIV. The committee developed recommendations based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology for each actionable question. The GRADE Evidence to Decision framework in the guideline development tool was used to generate recommendations. A number of topics were addressed using technical summaries without recommendations and these are discussed in the supplementary material.This guideline committee developed recommendations for 11 actionable questions in a PICO (population-intervention-comparison-outcome) format, all addressing the use of NIV for various aetiologies of ARF. The specific conditions where recommendations were made include exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary oedema,
hypoxaemic respiratory failure, immunocompromised patients, chest trauma, palliation, post-operative care, weaning and post-extubation.This document summarises the current state of knowledge regarding the role of NIV in ARF. Evidence-based recommendations provide guidance to relevant stakeholders.
Genetics and Genomics of Pulmonary Arterial Hypertension Machado, Rajiv D., PhD; Eickelberg, Oliver, MD; Elliott, C. Gregory, MD ...
Journal of the American College of Cardiology,
06/2009, Letnik:
54, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditable (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases ...have long been recognized and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene ( BMPR2 ), or, much less commonly, 2 other members of the transforming growth factor-β superfamily, activin-like kinase-type 1 ( ALK1 ) and endoglin ( ENG ), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2 . We provide a summary of BMPR2 mutations associated with HPAH, most of which are unique to each family and are presumed to result in loss of function. We review the finding of missense variants and variants of unknown significance in BMPR2 in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counseling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.
This paper considers nonstandard hypothesis testing problems that involve a nuisance parameter. We establish an upper bound on the weighted average power of all valid tests, and develop a numerical ...algorithm that determines a feasible test with power close to the bound. The approach is illustrated in six applications: inference about a linear regression coefficient when the sign of a control coefficient is known; small sample inference about the difference in means from two independent Gaussian samples from populations with potentially different variances; inference about the break date in structural break models with moderate break magnitude; predictability tests when the regressor is highly persistent; inference about an interval identified parameter; and inference about a linear regression coefficient when the necessity of a control is in doubt.
ABSTRACT
Audits and case reviews of the acute delivery of non‐invasive ventilation (NIV) have shown that the results achieved in real life often fall short of those achieved in research trials. ...Factors include inappropriate selection of patients for NIV and failure to apply NIV correctly. This highlights the need for proper training of all involved individuals. This article addresses the different skills needed in a team to provide an effective NIV service. Some detail is given in each of the key areas but it is not comprehensive and should stimulate further learning (reading, attendance on courses, e‐learning, etc.), determined by the needs of the individual.
Outcomes after exacerbations of chronic obstructive pulmonary disease (COPD) requiring acute noninvasive ventilation (NIV) are poor and there are few treatments to prevent hospital readmission and ...death.
To investigate the effect of home NIV plus oxygen on time to readmission or death in patients with persistent hypercapnia after an acute COPD exacerbation.
A randomized clinical trial of patients with persistent hypercapnia (Paco2 >53 mm Hg) 2 weeks to 4 weeks after resolution of respiratory acidemia, who were recruited from 13 UK centers between 2010 and 2015. Exclusion criteria included obesity (body mass index BMI >35), obstructive sleep apnea syndrome, or other causes of respiratory failure. Of 2021 patients screened, 124 were eligible.
There were 59 patients randomized to home oxygen alone (median oxygen flow rate, 1.0 L/min interquartile range {IQR}, 0.5-2.0 L/min) and 57 patients to home oxygen plus home NIV (median oxygen flow rate, 1.0 L/min IQR, 0.5-1.5 L/min). The median home ventilator settings were an inspiratory positive airway pressure of 24 (IQR, 22-26) cm H2O, an expiratory positive airway pressure of 4 (IQR, 4-5) cm H2O, and a backup rate of 14 (IQR, 14-16) breaths/minute.
Time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and BMI.
A total of 116 patients (mean SD age of 67 10 years, 53% female, mean BMI of 21.6 IQR, 18.2-26.1, mean SD forced expiratory volume in the first second of expiration of 0.6 L 0.2 L, and mean SD Paco2 while breathing room air of 59 7 mm Hg) were randomized. Sixty-four patients (28 in home oxygen alone and 36 in home oxygen plus home NIV) completed the 12-month study period. The median time to readmission or death was 4.3 months (IQR, 1.3-13.8 months) in the home oxygen plus home NIV group vs 1.4 months (IQR, 0.5-3.9 months) in the home oxygen alone group, adjusted hazard ratio of 0.49 (95% CI, 0.31-0.77; P = .002). The 12-month risk of readmission or death was 63.4% in the home oxygen plus home NIV group vs 80.4% in the home oxygen alone group, absolute risk reduction of 17.0% (95% CI, 0.1%-34.0%). At 12 months, 16 patients had died in the home oxygen plus home NIV group vs 19 in the home oxygen alone group.
Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months.
clinicaltrials.gov Identifier: NCT00990132.
The relatively sparse but diverse microbiome in human lungs may become less diverse in chronic obstructive pulmonary disease (COPD). This article examines the relationship of this microbiome to ...emphysematous tissue destruction, number of terminal bronchioles, infiltrating inflammatory cells, and host gene expression.
Culture-independent pyrosequencing microbiome analysis was used to examine the V3-V5 regions of bacterial 16S ribosomal DNA in 40 samples of lung from 5 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease GOLD stage 4) and 28 samples from 4 donors (controls). A second protocol based on the V1-V3 regions was used to verify the bacterial microbiome results. Within lung tissue samples the microbiome was compared with results of micro-computed tomography, infiltrating inflammatory cells measured by quantitative histology, and host gene expression.
Ten operational taxonomic units (OTUs) was found sufficient to discriminate between control and GOLD stage 4 lung tissue, which included known pathogens such as Haemophilus influenzae. We also observed a decline in microbial diversity that was associated with emphysematous destruction, remodeling of the bronchiolar and alveolar tissue, and the infiltration of the tissue by CD4(+) T cells. Specific OTUs were also associated with neutrophils, eosinophils, and B-cell infiltration (P < 0.05). The expression profiles of 859 genes and 235 genes were associated with either enrichment or reductions of Firmicutes and Proteobacteria, respectively, at a false discovery rate cutoff of less than 0.1.
These results support the hypothesis that there is a host immune response to microorganisms within the lung microbiome that appears to contribute to the pathogenesis of COPD.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder, which is accompanied by a variety of comorbidities including metabolic, reproductive, and psychiatric disorders. Genome-wide ...association studies have identified several genetic variants that are associated with PCOS. However, these variants often occur outside of coding regions and require further investigation to understand their contribution to PCOS. A transcriptome-wide association study (TWAS) was performed to uncover heritable gene expression profiles that are associated with PCOS in two independent cohorts. Causal gene prioritization was subsequently performed and expression of genes prioritized through these analyses was examined in 49 PCOS patients and 30 controls. TWAS analyses revealed that increased expression of ARL14EP was significantly associated with PCOS risk in the discovery (P = 1.6 × 10
) and replication cohorts (P = 2.0 × 10
). Gene prioritization pipelines provided further evidence that ARL14EP is the most likely causal gene at this locus. ARL14EP gene expression was shown to be significantly different between PCOS cases and controls, after adjusting for body mass index, age and testosterone levels (P = 1.2 × 10
). This study has provided evidence for the role of ARL14EP in PCOS. Given that ARL14EP has been reported to play an important role in chromatin remodeling, variants affecting the expression of ARL14EP may also affect the expression of other genes that contribute to PCOS pathogenesis.
The concept that small conducting airways less than 2 mm in diameter become the major site of airflow obstruction in chronic obstructive pulmonary disease (COPD) is well established in the scientific ...literature, and the last generation of small conducting airways, terminal bronchioles, are known to be destroyed in patients with very severe COPD. We aimed to determine whether destruction of the terminal and transitional bronchioles (the first generation of respiratory airways) occurs before, or in parallel with, emphysematous tissue destruction.
In this cross-sectional analysis, we applied a novel multiresolution CT imaging protocol to tissue samples obtained using a systematic uniform sampling method to obtain representative unbiased samples of the whole lung or lobe of smokers with normal lung function (controls) and patients with mild COPD (Global Initiative for Chronic Obstructive Lung Disease GOLD stage 1), moderate COPD (GOLD 2), or very severe COPD (GOLD 4). Patients with GOLD 1 or GOLD 2 COPD and smokers with normal lung function had undergone lobectomy and pneumonectomy, and patients with GOLD 4 COPD had undergone lung transplantation. Lung tissue samples were used for stereological assessment of the number and morphology of terminal and transitional bronchioles, airspace size (mean linear intercept), and alveolar surface area.
Of the 34 patients included in this study, ten were controls (smokers with normal lung function), ten patients had GOLD 1 COPD, eight had GOLD 2 COPD, and six had GOLD 4 COPD with centrilobular emphysema. The 34 lung specimens provided 262 lung samples. Compared with control smokers, the number of terminal bronchioles decreased by 40% in patients with GOLD 1 COPD (p=0·014) and 43% in patients with GOLD 2 COPD (p=0·036), the number of transitional bronchioles decreased by 56% in patients with GOLD 1 COPD (p=0·0001) and 59% in patients with GOLD 2 COPD (p=0·0001), and alveolar surface area decreased by 33% in patients with GOLD 1 COPD (p=0·019) and 45% in patients with GOLD 2 COPD (p=0·0021). These pathological changes were found to correlate with lung function decline. We also showed significant loss of terminal and transitional bronchioles in lung samples from patients with GOLD 1 or GOLD 2 COPD that had a normal alveolar surface area. Remaining small airways were found to have thickened walls and narrowed lumens, which become more obstructed with increasing COPD GOLD stage.
These data show that small airways disease is a pathological feature in mild and moderate COPD. Importantly, this study emphasises that early intervention for disease modification might be required by patients with mild or moderate COPD.
Canadian Institutes of Health Research.
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