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1.  Multidrug resistance-associated protein-1 (MRP1) genetic variants, MRP1 protein levels and severity of COPD 
Respiratory Research  2010;11(1):60.
Background
Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in MRP1 significantly associate with level of FEV1 in two independent population based cohorts. The aim of our study was to assess the associations of MRP1 SNPs with FEV1 level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients.
Methods
Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in MRP1 were genotyped in 110 COPD patients. The effects of MRP1 SNPs were analyzed using linear regression models.
Results
One SNP, rs212093 was significantly associated with a higher FEV1 level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV1 level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies.
Conclusions
This is the first study linking MRP1 SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of MRP1 SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies.
doi:10.1186/1465-9921-11-60
PMCID: PMC2882908  PMID: 20487524
2.  Airway inflammation contributes to health status in COPD: a cross-sectional study 
Respiratory Research  2006;7(1):140.
Background
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and airway inflammation, accompanied by decreased health status. It is still unknown which factors are responsible for the impaired health status in COPD. We postulated that airway inflammation negatively contributes to health status in COPD.
Methods
In 114 COPD patients (99 male, age: 62 ± 8 yr, 41 [31–55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV1: 63 ± 9% pred, FEV1/IVC: 48 ± 9%) we obtained induced sputum and measured health status (St. George's respiratory questionnaire (SGRQ)), postbronchodilator FEV1, hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC20). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients.
Results
Univariate analysis showed that SGRQ total and symptom score were positively associated with % sputum macrophages (r = 0.20, p = 0.05; and r = 0.20, p = 0.04, respectively). Multiple regression analysis confirmed these relationships, providing significant contributions of % sputum macrophages (B = 0.25, p = 0.021) and RV/TLC (B = 0.60, p = 0.002) to SGRQ total score. Furthermore, SGRQ symptom score was associated with % sputum macrophages (B = 0.30, p = 0.03) and RV/TLC (B = 0.48, p = 0.044), whilst SGRQ activity score was associated with % sputum macrophages (B = 0.46, p = 0.002), RV/TLC (B = 0.61, p = 0.015), and PC20 (B = -9.3, p = 0.024). Current smoking and FEV1 were not significantly associated with health status in the multiple regression analysis.
Conclusion
We conclude that worse health status in COPD patients is associated with higher inflammatory cell counts in induced sputum. Our findings suggest that airway inflammation and hyperinflation independently contribute to impaired health status in COPD. This may provide a rationale for anti-inflammatory therapy in this disease.
doi:10.1186/1465-9921-7-140
PMCID: PMC1697818  PMID: 17137518
3.  Genetic variants in ADAM33 are associated with airway inflammation and lung function in COPD 
BMC Pulmonary Medicine  2014;14(1):173.
Background
Genetic factors play a role in the development and severity of chronic obstructive pulmonary disease (COPD). The pathogenesis of COPD is a multifactorial process including an inflammatory cell profile. Recent studies revealed that single nucleotide polymorphisms (SNPs) within ADAM33 increased the susceptibility to COPD through changing the airway inflammatory process and lung function.
Methods
In this paper, we investigated associations of four polymorphisms (T1, T2, S2 and Q-1) of ADAM33 as well as their haplotypes with pulmonary function and airway inflammatory process in an East Asian population of patients with COPD.
Results
We found that T1, T2 and Q-1 were significantly associated with the changes of pulmonary function and components of cells in sputum of COPD, and T1 and Q-1 were significantly associated with cytokines and mediators of inflammation in airway of COPD in recessive models. 10 haplotypes were significantly associated with transfer factor of the lung for carbon monoxide in the disease state, 4 haplotypes were significantly associated with forced expiratory volume in one second, and other haplotypes were associated with airway inflammation.
Conclusions
We confirmed for the first time that ADAM33 was involved in the pathogenesis of COPD by affecting airway inflammation and immune response in an East Asian population. Our results made the genetic background of COPD, a common and disabling disease, more apparent, which would supply genetic support for the study of the mechanism, classification and treatment for this disease.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-173) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2466-14-173
PMCID: PMC4228268  PMID: 25369941
Chronic obstructive pulmonary disease; SNP; ADAM33; Haplotype; Pulmonary function; Airway inflammatory process
4.  Expression of ADAMs and Their Inhibitors in Sputum from Patients with Asthma 
Molecular Medicine  2006;12(7-8):171-179.
ADAMs (a disintegrin and metalloprotease) constitute a family of cell surface proteins containing disintegrin and metalloprotease domains which associate features of adhesion molecules and proteases. ADAMTSs (a disintegrin and metalloprotease with thrombospondin motifs) bear thrombospondin type I motifs in C-terminal extremity, and most of them are secreted proteins. Because genetic studies have shown that ADAM-33 gene polymorphisms are associated with asthma, we designed this study to assess mRNA expression profile of several ADAM and ADAMTS proteases in sputum from patients with asthma and to investigate the relationship between expression of these proteases and asthma-associated inflammation and airway obstruction. mRNA expression profile of selected ADAM and ADAMTS proteinases (ADAM-8, -9, -10, -12, -15, -17, and -33; ADAMTS-1, -2, -15, -16, -17, -18, and -19), their physiological inhibitors TIMP-1 and TIMP-3, and RECK, a membrane-anchored MMP activity regulator, was obtained by RT-PCR analysis performed on cells collected by sputum induction from 21 patients with mild to moderate asthma and 17 healthy individuals. mRNA levels of ADAM-8, ADAM-9, ADAM-12, TIMP-1, and TIMP-3 were significantly increased, whereas mRNA levels coding for ADAMTS-1, ADAMTS-15, and RECK were significantly decreased in patients with asthma compared with control patients. ADAM-8 expression was negatively correlated with the forced expiratory volume at the first second (FEV1) (r = −0.57, P < 0.01), whereas ADAMTS-1 and RECK expressions were positively correlated to FEV1 (r = 0.45, P < 0.05, and r = 0.55, P = 0.01, respectively). We conclude that expression of ADAMs and ADAMTSs and their inhibitors is modulated in airways from patients with asthma and that these molecules may play a role in the pathogenesis of asthma.
doi:10.2119/2006-00028.Paulissen
PMCID: PMC1626598  PMID: 17088949
5.  Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease (COPD) Using an Ontario Policy Model 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-Term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Background
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. The inflammation causes repeated cycles of injury and repair in the airway wall— inflammatory cells release a variety of chemicals and lead to cellular damage. The inflammation process also contributes to the loss of elastic recoil pressure in the lung, thereby reducing the driving pressure for expiratory flow through narrowed and poorly supported airways, in which airflow resistance is significantly increased. Expiratory flow limitation is the pathophysiological hallmark of COPD.
Exacerbations of COPD contribute considerably to morbidity and mortality, and impose a burden on the health care system. They are a leading cause of emergency room visits and hospitalizations, particularly in the winter. In Canada, the reported average cost for treating a moderate exacerbation is $641; for a major exacerbation, the cost is $10,086.
Objective
The objective of this study was to evaluate the cost-effectiveness and budget impact of the following interventions in moderate to very severe COPD, investigated in the Medical Advisory Secretariat Chronic Obstructive Pulmonary Disease Mega-Analysis Series:
smoking cessation programs in moderate COPD in an outpatient setting:
– intensive counselling (IC) versus usual care (UC)
– nicotine replacement therapy (NRT) versus UC
– IC + NRT versus placebo
– bupropion versus placebo
multidisciplinary care (MDC) teams versus UC in moderate to severe COPD in an outpatient setting
pulmonary rehabilitation (PR) versus UC following acute exacerbations in moderate to severe COPD
long-term oxygen therapy (LTOT) versus UC in severe hypoxemia in COPD in an outpatient setting
ventilation:
– noninvasive positive pressure ventilation (NPPV) + usual medical care versus usual medical care in acute respiratory failure due to an acute exacerbation in severe COPD in an inpatient setting
– weaning with NPPV versus weaning with invasive mechanical ventilation in acute respiratory failure due to an acute exacerbation in very severe COPD in an inpatient setting
Methods
A cost-utility analysis was conducted using a Markov probabilistic model. The model consists of different health states based on the Global Initiative for Chronic Obstructive Lung Disease COPD severity classification. Patients were assigned different costs and utilities depending on their severity health state during each model cycle. In addition to moving between health states, patients were at risk of acute exacerbations of COPD in each model cycle. During each cycle, patients could have no acute exacerbation, a minor acute exacerbation, or a major exacerbation. For the purposes of the model, a major exacerbation was defined as one that required hospitalization. Patients were assigned different costs and utilities in each model cycle, depending on whether they experienced an exacerbation, and its severity.
Starting cohorts reflected the various patient populations from the trials analyzed. Incremental cost-effectiveness ratios (ICERs)—that is, costs per quality-adjusted life-year (QALY)—were estimated for each intervention using clinical parameters and summary estimates of relative risks of (re)hospitalization, as well as mortality and abstinence rates, from the COPD mega-analysis evidence-based analyses.
A budget impact analysis was also conducted to project incremental costs already being incurred or resources already in use in Ontario. Using provincial data, medical literature, and expert opinion, health system impacts were calculated for the strategies investigated.
All costs are reported in Canadian dollars.
Results
All smoking cessation programs were dominant (i.e., less expensive and more effective overall). Assuming a base case cost of $1,041 and $1,527 per patient for MDC and PR, the ICER was calculated to be $14,123 per QALY and $17,938 per QALY, respectively. When the costs of MDC and PR were varied in a 1-way sensitivity analysis to reflect variation in resource utilization reported in the literature, the ICER increased to $55,322 per QALY and $56,270 per QALY, respectively. Assuming a base case cost of $2,261 per year per patient for LTOT as reported by data from the Ontario provincial program, the ICER was calculated to be $38,993 per QALY. Ventilation strategies were dominant (i.e., cheaper and more effective), as reflected by the clinical evidence of significant in-hospital days avoided in the study group.
Ontario currently pays for IC through physician billing (translating to a current burden of $8 million) and bupropion through the Ontario Drug Benefit program (translating to a current burden of almost $2 million). The burden of NRT was projected to be $10 million, with future expenditures of up to $1 million in Years 1 to 3 for incident cases.
Ontario currently pays for some chronic disease management programs. Based on the most recent Family Health Team data, the costs of MDC programs to manage COPD were estimated at $85 million in fiscal year 2010, with projected future expenditures of up to $51 million for incident cases, assuming the base case cost of the program. However, this estimate does not accurately reflect the current costs to the province because of lack of report by Family Health Teams, lack of capture of programs outside this model of care by any data set in the province, and because the resource utilization and frequency of visits/follow-up phone calls were based on the findings in the literature rather than the actual Family Health Team COPD management programs in place in Ontario. Therefore, MDC resources being utilized in the province are unknown and difficult to measure.
Data on COPD-related hospitalizations were pulled from Ontario administrative data sets and based on consultation with experts. Half of hospitalized patients will access PR resources at least once, and half of these will repeat the therapy, translating to a potential burden of $17 million to $32 million, depending on the cost of the program. These resources are currently being absorbed, but since utilization is not being captured by any data set in the province, it is difficult to quantify and estimate. Provincial programs may be under-resourced, and patients may not be accessing these services effectively.
Data from the LTOT provincial program (based on fiscal year 2006 information) suggested that the burden was $65 million, with potential expenditures of up to $0.2 million in Years 1 to 3 for incident cases.
From the clinical evidence on ventilation (i.e., reduction in length of stay in hospital), there were potential cost savings to the hospitals of $42 million and $12 million for NPPV and weaning with NPPV, respectively, if the study intervention were adopted. Future cost savings were projected to be up to $4 million and $1 million, respectively, for incident cases.
Conclusions
Currently, costs for most of these interventions are being absorbed by provider services, the Ontario Drug Benefit Program, the Assistive Devices Program, and the hospital global budget. The most cost-effective intervention for COPD will depend on decision-makers’ willingness to pay. Lack of provincial data sets capturing resource utilization for the various interventions poses a challenge for estimating current burden and future expenditures.
PMCID: PMC3384363  PMID: 23074422
6.  ADAM33 Gene Polymorphisms and Mortality. A Prospective Cohort Study 
PLoS ONE  2013;8(7):e67768.
The ADAM33 gene is associated with the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) and atherosclerosis. In this study we investigated all-cause, COPD and cardiovascular mortality, in relation to single nucleotide polymorphisms (SNPs) in ADAM33 (Q_1, S_1, S_2, T_1 and T_2) that were genotyped in 1,390 subjects from the Vlagtwedde/Vlaardingen cohort. Participants were examined at entry in 1989/1990 and followed up till evaluation of the vital status on December 31st, 2008. Using Cox proportional hazards regression we estimated the risk of the SNPs in relation to mortality, adjusting for gender, age, FEV1, height, place of residence and packyears of smoking. Additionally, we performed stratified analyses according to gender and smoking habits. After 18 years, 284 (20.4%) subjects had died (107 due to cardiovascular disease and 20 due to COPD). Individuals homozygous for the minor allele of SNP T_2 had an increased risk of all-cause and cardiovascular mortality compared to wild types: hazard ratio 3.6 (95% confidence interval 2.0 to 6.7) and 3.4 (1.2 to 9.5) respectively. Individuals homozygous for the minor allele of S_1, S_2, T_2 or Q_1 had a significantly increased risk of COPD mortality. In stratified analyses the risk of all-cause mortality associated with SNP T_2 did not change: females 3.5 (1.5 to 8.3), males 3.1 (1.2 to 7.6), never smokers 3.8 (0.9 to 16.3), ever smokers 3.6 (1.8 to 7.2). This study shows for the first time that ADAM33 is a pleiotropic gene that is associated with all-cause, COPD and cardiovascular mortality, independent of potential confounders.
doi:10.1371/journal.pone.0067768
PMCID: PMC3701578  PMID: 23861802
7.  Airway inflammation and mannitol challenge test in COPD 
Respiratory Research  2011;12(1):11.
Background
Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD.
Methods
Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum.
Results
There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum.
Conclusions
In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD.
Trial registration
Netherlands Trial Register (NTR): NTR1283
doi:10.1186/1465-9921-12-11
PMCID: PMC3036630  PMID: 21241520
8.  Polymorphisms in Surfactant Protein–D Are Associated with Chronic Obstructive Pulmonary Disease 
Chronic obstructive pulmonary disease (COPD) is characterized by alveolar destruction and abnormal inflammatory responses to noxious stimuli. Surfactant protein–D (SFTPD) is immunomodulatory and essential to host defense. We hypothesized that polymorphisms in SFTPD could influence the susceptibility to COPD. We genotyped six single-nucleotide polymorphisms (SNPs) in surfactant protein D in 389 patients with COPD in the National Emphysema Treatment Trial (NETT) and 472 smoking control subjects from the Normative Aging Study (NAS). Case-control association analysis was performed using Cochran–Armitage trend tests and multivariate logistic regression. The replication of significant associations was attempted in the Boston Early-Onset COPD Study, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and the Bergen Cohort. We also correlated SFTPD genotypes with serum concentrations of surfactant protein–D (SP-D) in the ECLIPSE Study. In the NETT–NAS case-control analysis, four SFTPD SNPs were associated with susceptibility to COPD: rs2245121 (P = 0.01), rs911887 (P = 0.006), rs6413520 (P = 0.004), and rs721917 (P = 0.006). In the family-based analysis of the Boston Early-Onset COPD Study, rs911887 was associated with prebronchodilator and postbronchodilator FEV1 (P = 0.003 and P = 0.02, respectively). An intronic SNP in SFTPD, rs7078012, was associated with COPD in the ECLIPSE Study and the Bergen Cohort. Multiple SFTPD SNPs were associated with serum SP-D concentrations in the ECLIPSE Study. We demonstrated an association of polymorphisms in SFTPD with COPD in multiple populations. We demonstrated a correlation between SFTPD SNPs and SP-D protein concentrations. The SNPs associated with COPD and SP-D concentrations differed, suggesting distinct genetic influences on susceptibility to COPD and SP-D concentrations.
doi:10.1165/rcmb.2009-0360OC
PMCID: PMC3095932  PMID: 20448057
COPD; surfactant protein–D; single-nucleotide polymorphisms; genetics
9.  Bronchial responsiveness and acute bronchodilator response in chronic obstructive pulmonary disease and diffuse panbronchiolitis. 
Thorax  1994;49(6):540-544.
BACKGROUND--Diffuse panbronchiolitis (DPB) is characterised clinically by chronic airflow limitation and respiratory tract infection, and pathologically by chronic bronchiolar inflammation. To elucidate the functional differences between chronic obstructive pulmonary disease (COPD) and DPB the bronchial responsiveness to methacholine was compared in 64 patients with COPD and 32 patients with DPB, and the bronchodilator response was compared in 72 patients with COPD and 49 with DPB. METHODS--Bronchial responsiveness to methacholine was determined by the dosimeter method and expressed as PD20FEV1, and bronchodilator response was measured as the change in percentage predicted response with 5 mg nebulised salbutamol. RESULTS--Baseline FEV1 was similar in the two groups of patients. Patients with COPD were more responsive to methacholine than were those with DPB (geometric mean PD20FEV1 8.87 v 48.0 cumulative units). Reversibility of air flow obstruction, expressed as the difference between the percentage predicted postbronchodilator FEV1 and prebronchodilator FEV1, was significantly larger in patients with COPD than in those with DPB (7.87 (6.52)% v 4.16 (4.43)%). CONCLUSIONS--The observation that patients with DPB differ substantially in bronchial responsiveness from those with COPD is thought to reflect the difference in the mechanisms of these two diseases--that is, airway disease in DPB and more parenchymal disease in the group of patients with COPD. The nature of bronchiolar inflammation in COPD and DPB is also different, possibly explaining the difference in bronchial responsiveness. More fixed airflow limitation as a result of structural bronchiolar lesions in DPB will explain the smaller reversibility of airflow obstruction.
PMCID: PMC474939  PMID: 8016789
10.  Pulmonary function tests, sputum induction, and bronchial provocation tests: diagnostic tools in the challenge of distinguishing asthma and COPD phenotypes in clinical practice 
Background:
Despite a number of important differences in the pathogenesis, course, and prognosis, asthma and chronic obstructive pulmonary disease (COPD) have many features in common. Furthermore, smoking induces considerable overlap in pathogenesis and clinical features between these conditions. This study aimed to reveal what inflammatory patterns prevail in clinically established diagnosis groups, including overlap phenotypes of asthma and COPD, and to evaluate the correlation with airway reversibility and hyperreactivity in these overlapping conditions.
Methods:
A total of 110 patients (17 healthy subjects; 16 “healthy” smokers; 46 asthma patients: 24 smokers and 22 non-smokers; and 31 COPD patients: 10 COPD patients with reversibility and 21 without) participated in the study. Induced sputum, reversibility testing, methacholine and adenosine 5’monophosphate (AMP) provocation challenges, and skin prick testing were performed. Airways inflammation was assessed by differential cell counts, and cytokines (interleukin-8 [IL-8] and tumor necrosis factor-alpha [TNF-α]) were measured in induced sputum by enzyme-linked immunosorbent assay (ELISA).
Results:
COPD patients with reversibility had increased sputum neutrophils, IL-8, and TNF-α levels compared to smoking asthmatics. No difference was found in inflammatory cells and cytokines between COPD subgroups. Sputum neutrophilia was inversely correlated with the change in forced expiratory volume in one second (ΔFEV1) in smoking asthmatic patients (r = −0.563, P = 0.036). No correlation was found between airway hyperresponsiveness (AHR), either with methacholine or AMP, and inflammation in asthmatic patients, regardless of smoking. Reversibility was not correlated with inflammation in COPD patients. However, the response to AMP challenge was correlated with sputum neutrophils (r = 0.844, P = 0.001).
Conclusion:
Although overlaps exist in the disease characteristics of asthma and COPD, the combination of lung function testing, sputum induction, and AHR reveals information that facilitates the distinction between these diseases, allowing clinicians to better tailor their therapy.
PMCID: PMC2939684  PMID: 20856828
asthma; COPD; smoking; lung function; airway hyperresponsiveness
11.  Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers 
Respiratory Research  2009;10(1):21.
Background
Variation in ADAM33 has been shown to be important in the development of asthma and altered lung function. This relationship however, has not been investigated in the population susceptible to COPD; long term tobacco smokers. We evaluated the association between polymorphisms in ADAM33 gene with COPD and lung function in long term tobacco smokers.
Methods
Caucasian subjects, at least 50 year old, who smoked ≥ 20 pack-years (n = 880) were genotyped for 25 single nucleotide polymorphisms (SNPs) in ADAM33. COPD was defined as an FEV1/FVC ratio < 70% and percent-predicted (pp)FEV1 < 75% (n = 287). The control group had an FEV1/FVC ratio ≥ 70% and ppFEV1 ≥ 80% (n = 311) despite ≥ 20 pack years of smoking. Logistic and linear regressions were used for the analysis. Age, sex, and smoking status were considered as potential confounders.
Results
Five SNPs in ADAM33 were associated with COPD (Q-1, intronic: p < 0.003; S1, Ile → Val: p < 0.003; S2, Gly → Gly: p < 0.04; V-1 intronic: p < 0.002; V4, in 3' untranslated region: p < 0.007). Q-1, S1 and V-1 were also associated with ppFEV1, FEV1/FVC ratio and ppFEF25–75 (p values 0.001 – 0.02). S2 was associated with FEV1/FVC ratio (p < 0.05). The association between S1 and residual volume revealed a trend toward significance (p value < 0.07). Linkage disequilibrium and haplotype analyses suggested that S1 had the strongest degree of association with COPD and pulmonary function abnormalities.
Conclusion
Five SNPs in ADAM33 were associated with COPD and lung function in long-term smokers. Functional studies will be needed to evaluate the biologic significance of these polymorphisms in the pathogenesis of COPD.
doi:10.1186/1465-9921-10-21
PMCID: PMC2664793  PMID: 19284602
12.  ADAM33 gene polymorphisms in chronic obstructive pulmonary disease 
European Journal of Medical Research  2009;14(Suppl 4):182-186.
Study objective
The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by an interaction of environmental influences, particularly cigarette smoking, and genetic determinants. Given the global increase in COPD, research on the genomic variants that affect susceptibility to this complex disorder is reviving. In the present study, we investigated whether single nucleotide polymorphisms in 'a disinter-grin and metalloprotease' 33 (ADAM33) are associated with the development and course of COPD.
Patients and design
We genotyped 150 German COPD patients and 152 healthy controls for the presence of the F+1 and S_2 SNPs in ADAM 33 that lead to the base pair exchange G to A and C to G, respectively. To assess whether these genetic variants are influential in the course of COPD, we subdivided the cohort into two subgroups comprising 60 patients with a stable and 90 patients with an unstable course of disease.
Results
In ADAM33, the frequency of the F+1 A allele was 35.0% among stable and 43.9% among unstable COPD subjects, which was not significantly different from the 35.5% found in the controls (P = 0.92 and P = 0.07, respectively). The frequency of the S_2 mutant allele in subjects with a stable COPD was 23.3% (P = 0.32), in subjects with an unstable course 30.6% (P = 0.47).
Conclusion
The study shows that there is no significant difference in the distribution of the tested SNPs between subjects with and without COPD. Furthermore, these polymorphisms appear to have no consequences for the stability of the disease course.
doi:10.1186/2047-783X-14-S4-182
PMCID: PMC3521362  PMID: 20156753
COPD; ADAM33; genetics
13.  Delay of airway epithelial wound repair in COPD is associated with airflow obstruction severity 
Respiratory Research  2014;15(1):151.
Background
Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD.
Methods
Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze.
Results
13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [−0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 105 AU in COPD GOLD D vs 12.8 ± 0.13 105 AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]).
Conclusion
Our results showed an abnormal bronchial epithelial wound closure process in severe COPD. Further studies are needed to elucidate the contribution and the regulation of this mechanism in the complex pathophysiology of COPD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0151-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12931-014-0151-9
PMCID: PMC4251925  PMID: 25427655
COPD; Airway epithelium; Bronchial cells; Bronchiolar cells; Wound repair; Cell proliferation
14.  Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based analysis was to examine the effectiveness, safety, and cost-effectiveness of noninvasive positive pressure ventilation (NPPV) in the following patient populations: patients with acute respiratory failure (ARF) due to acute exacerbations of chronic obstructive pulmonary disease (COPD); weaning of COPD patients from invasive mechanical ventilation (IMV); and prevention of or treatment of recurrent respiratory failure in COPD patients after extubation from IMV.
Clinical Need and Target Population
Acute Hypercapnic Respiratory Failure
Respiratory failure occurs when the respiratory system cannot oxygenate the blood and/or remove carbon dioxide from the blood. It can be either acute or chronic and is classified as either hypoxemic (type I) or hypercapnic (type II) respiratory failure. Acute hypercapnic respiratory failure frequently occurs in COPD patients experiencing acute exacerbations of COPD, so this is the focus of this evidence-based analysis. Hypercapnic respiratory failure occurs due to a decrease in the drive to breathe, typically due to increased work to breathe in COPD patients.
Technology
There are several treatment options for ARF. Usual medical care (UMC) attempts to facilitate adequate oxygenation and treat the cause of the exacerbation, and typically consists of supplemental oxygen, and a variety of medications such as bronchodilators, corticosteroids, and antibiotics. The failure rate of UMC is high and has been estimated to occur in 10% to 50% of cases.
The alternative is mechanical ventilation, either invasive or noninvasive. Invasive mechanical ventilation involves sedating the patient, creating an artificial airway through endotracheal intubation, and attaching the patient to a ventilator. While this provides airway protection and direct access to drain sputum, it can lead to substantial morbidity, including tracheal injuries and ventilator-associated pneumonia (VAP).
While both positive and negative pressure noninvasive ventilation exists, noninvasive negative pressure ventilation such as the iron lung is no longer in use in Ontario. Noninvasive positive pressure ventilation provides ventilatory support through a facial or nasal mask and reduces inspiratory work. Noninvasive positive pressure ventilation can often be used intermittently for short periods of time to treat respiratory failure, which allows patients to continue to eat, drink, talk, and participate in their own treatment decisions. In addition, patients do not require sedation, airway defence mechanisms and swallowing functions are maintained, trauma to the trachea and larynx are avoided, and the risk for VAP is reduced. Common complications are damage to facial and nasal skin, higher incidence of gastric distension with aspiration risk, sleeping disorders, and conjunctivitis. In addition, NPPV does not allow direct access to the airway to drain secretions and requires patients to cooperate, and due to potential discomfort, compliance and tolerance may be low.
In addition to treating ARF, NPPV can be used to wean patients from IMV through the gradual removal of ventilation support until the patient can breathe spontaneously. Five to 30% of patients have difficultly weaning. Tapering levels of ventilatory support to wean patients from IMV can be achieved using IMV or NPPV. The use of NPPV helps to reduce the risk of VAP by shortening the time the patient is intubated.
Following extubation from IMV, ARF may recur, leading to extubation failure and the need for reintubation, which has been associated with increased risk of nosocomial pneumonia and mortality. To avoid these complications, NPPV has been proposed to help prevent ARF recurrence and/or to treat respiratory failure when it recurs, thereby preventing the need for reintubation.
Research Questions
What is the effectiveness, cost-effectiveness, and safety of NPPV for the treatment of acute hypercapnic respiratory failure due to acute exacerbations of COPD compared with
usual medical care, and
invasive mechanical ventilation?
What is the effectiveness, cost-effectiveness, and safety of NPPV compared with IMV in COPD patients after IMV for the following purposes:
weaning COPD patients from IMV,
preventing ARF in COPD patients after extubation from IMV, and
treating ARF in COPD patients after extubation from IMV?
Research Methods
Literature Search
A literature search was performed on December 3, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), Wiley Cochrane, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Since there were numerous studies that examined the effectiveness of NPPV for the treatment of ARF due to exacerbations of COPD published before 2004, pre-2004 trials which met the inclusion/exclusion criteria for this evidence-based review were identified by hand-searching reference lists of included studies and systematic reviews.
Inclusion Criteria
English language full-reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies performed with patients with a mix of conditions if results are reported for COPD patients separately;
patient population: (Question 1) patients with acute hypercapnic respiratory failure due to an exacerbation of COPD; (Question 2a) COPD patients being weaned from IMV; (Questions 2b and 2c) COPD patients who have been extubated from IMV.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
studies examining noninvasive negative pressure ventilation
studies comparing modes of ventilation
studies comparing patient-ventilation interfaces
studies examining outcomes not listed below, such as physiologic effects including heart rate, arterial blood gases, and blood pressure
Outcomes of Interest
mortality
intubation rates
length of stay (intensive care unit [ICU] and hospital)
health-related quality of life
breathlessness
duration of mechanical ventilation
weaning failure
complications
NPPV tolerance and compliance
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1, otherwise, the results were summarized descriptively. Dichotomous data were pooled into relative risks using random effects models and continuous data were pooled using weighted mean differences with a random effects model. Analyses using data from RCTs were done using intention-to-treat protocols; P values < 0.05 were considered significant. A priori subgroup analyses were planned for severity of respiratory failure, location of treatment (ICU or hospital ward), and mode of ventilation with additional subgroups as needed based on the literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
NPPV for the Treatment of ARF due to Acute Exacerbations of COPD
NPPV Plus Usual Medical Care Versus Usual Medical Care Alone for First Line Treatment
A total of 1,000 participants were included in 11 RCTs1; the sample size ranged from 23 to 342. The mean age of the participants ranged from approximately 60 to 72 years of age. Based on either the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD stage criteria or the mean percent predicted forced expiratory volume in 1 second (FEV1), 4 of the studies included people with severe COPD, and there was inadequate information to classify the remaining 7 studies by COPD severity. The severity of the respiratory failure was classified into 4 categories using the study population mean pH level as follows: mild (pH ≥ 7.35), moderate (7.30 ≤ pH < 7.35), severe (7.25 ≤ pH < 7.30), and very severe (pH < 7.25). Based on these categories, 3 studies included patients with a mild respiratory failure, 3 with moderate respiratory failure, 4 with severe respiratory failure, and 1 with very severe respiratory failure.
The studies were conducted either in the ICU (3 of 11 studies) or general or respiratory wards (8 of 11 studies) in hospitals, with patients in the NPPV group receiving bilevel positive airway pressure (BiPAP) ventilatory support, except in 2 studies, which used pressure support ventilation and volume cycled ventilation, respectively. Patients received ventilation through nasal, facial, or oronasal masks. All studies specified a protocol or schedule for NPPV delivery, but this varied substantially across the studies. For example, some studies restricted the amount of ventilation per day (e.g., 6 hours per day) and the number of days it was offered (e.g., maximum of 3 days); whereas, other studies provided patients with ventilation for as long as they could tolerate it and recommended it for much longer periods of time (e.g., 7 to 10 days). These differences are an important source of clinical heterogeneity between the studies. In addition to NPPV, all patients in the NPPV group also received UMC. Usual medical care varied between the studies, but common medications included supplemental oxygen, bronchodilators, corticosteroids, antibiotics, diuretics, and respiratory stimulators.
The individual quality of the studies ranged. Common methodological issues included lack of blinding and allocation concealment, and small sample sizes.
Need for Endotracheal Intubation
Eleven studies reported the need for endotracheal intubation as an outcome. The pooled results showed a significant reduction in the need for endotracheal intubation in the NPPV plus UMC group compared with the UMC alone group (relative risk [RR], 0.38; 95% confidence interval [CI], 0.28−0.50). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Inhospital Mortality
Nine studies reported inhospital mortality as an outcome. The pooled results showed a significant reduction in inhospital mortality in the NPPV plus UMC group compared with the UMC group (RR, 0.53; 95% CI, 0.35−0.81). When subgrouped by severity of respiratory failure, the results remained significant for the moderate and severe respiratory failure groups.
GRADE: moderate
Hospital Length of Stay
Eleven studies reported hospital length of stay (LOS) as an outcome. The pooled results showed a significant decrease in the mean length of stay for the NPPV plus UMC group compared with the UMC alone group (weighted mean difference [WMD], −2.68 days; 95% CI, −4.41 to −0.94 days). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Complications
Five studies reported complications. Common complications in the NPPV plus UMC group included pneumonia, gastrointestinal disorders or bleeds, skin abrasions, eye irritation, gastric insufflation, and sepsis. Similar complications were observed in the UMC group including pneumonia, sepsis, gastrointestinal disorders or bleeds, pneumothorax, and complicated endotracheal intubations. Many of the more serious complications in both groups occurred in those patients who required endotracheal intubation. Three of the studies compared complications in the NPPV plus UMC and UMC groups. While the data could not be pooled, overall, the NPPV plus UMC group experienced fewer complications than the UMC group.
GRADE: low
Tolerance/Compliance
Eight studies reported patient tolerance or compliance with NPPV as an outcome. NPPV intolerance ranged from 5% to 29%. NPPV tolerance was generally higher for patients with more severe respiratory failure. Compliance with the NPPV protocol was reported by 2 studies, which showed compliance decreases over time, even over short periods such as 3 days.
NPPV Versus IMV for the Treatment of Patients Who Failed Usual Medical Care
A total of 205 participants were included in 2 studies; the sample sizes of these studies were 49 and 156. The mean age of the patients was 71 to 73 years of age in 1 study, and the median age was 54 to 58 years of age in the second study. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, patients in 1 study had very severe COPD. The COPD severity could not be classified in the second study. Both studies had study populations with a mean pH less than 7.23, which was classified as very severe respiratory failure in this analysis. One study enrolled patients with ARF due to acute exacerbations of COPD who had failed medical therapy. The patient population was not clearly defined in the second study, and it was not clear whether they had to have failed medical therapy before entry into the study.
Both studies were conducted in the ICU. Patients in the NPPV group received BiPAP ventilatory support through nasal or full facial masks. Patients in the IMV group received pressure support ventilation.
Common methodological issues included small sample size, lack of blinding, and unclear methods of randomization and allocation concealment. Due to the uncertainty about whether both studies included the same patient population and substantial differences in the direction and significance of the results, the results of the studies were not pooled.
Mortality
Both studies reported ICU mortality. Neither study showed a significant difference in ICU mortality between the NPPV and IMV groups, but 1 study showed a higher mortality rate in the NPPV group (21.7% vs. 11.5%) while the other study showed a lower mortality rate in the NPPV group (5.1% vs. 6.4%). One study reported 1-year mortality and showed a nonsignificant reduction in mortality in the NPPV group compared with the IMV group (26.1% vs. 46.1%).
GRADE: low to very low
Intensive Care Unit Length of Stay
Both studies reported LOS in the ICU. The results were inconsistent. One study showed a statistically significant shorter LOS in the NPPV group compared with the IMV group (5 ± 1.35 days vs. 9.29 ± 3 days; P < 0.001); whereas, the other study showed a nonsignificantly longer LOS in the NPPV group compared with the IMV group (22 ± 19 days vs. 21 ± 20 days; P = 0.86).
GRADE: very low
Duration of Mechanical Ventilation
Both studies reported the duration of mechanical ventilation (including both invasive and noninvasive ventilation). The results were inconsistent. One study showed a statistically significant shorter duration of mechanical ventilation in the NPPV group compared with the IMV group (3.92 ± 1.08 days vs. 7.17 ± 2.22 days; P < 0.001); whereas, the other study showed a nonsignificantly longer duration of mechanical ventilation in the NPPV group compared with the IMV group (16 ± 19 days vs. 15 ± 21 days; P = 0.86). GRADE: very low
Complications
Both studies reported ventilator-associated pneumonia and tracheotomies. Both showed a reduction in ventilator-associated pneumonia in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 34.6%, P = 0.07; and 6.4% vs. 37.2%, P < 0.001, respectively). Similarly, both studies showed a reduction in tracheotomies in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 23.1%, P = 0.29; and 6.4% vs. 34.6%; P < 0.001).
GRADE: very low
Other Outcomes
One of the studies followed patients for 12 months. At the end of follow-up, patients in the NPPV group had a significantly lower rate of needing de novo oxygen supplementation at home. In addition, the IMV group experienced significant increases in functional limitations due to COPD, while no increase was seen in the NPPV group. Finally, no significant differences were observed for hospital readmissions, ICU readmissions, and patients with an open tracheotomy, between the NPPV and IMV groups.
NPPV for Weaning COPD Patients From IMV
A total of 80 participants were included in the 2 RCTs; the sample sizes of the studies were 30 and 50 patients. The mean age of the participants ranged from 58 to 69 years of age. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, both studies included patients with very severe COPD. Both studies also included patients with very severe respiratory failure (mean pH of the study populations was less than 7.23). Chronic obstructive pulmonary disease patients receiving IMV were enrolled in the study if they failed a T-piece weaning trial (spontaneous breathing test), so they could not be directly extubated from IMV.
Both studies were conducted in the ICU. Patients in the NPPV group received weaning using either BiPAP or pressure support ventilation NPPV through a face mask, and patients in the IMV weaning group received pressure support ventilation. In both cases, weaning was achieved by tapering the ventilation level.
The individual quality of the studies ranged. Common methodological problems included unclear randomization methods and allocation concealment, lack of blinding, and small sample size.
Mortality
Both studies reported mortality as an outcome. The pooled results showed a significant reduction in ICU mortality in the NPPV group compared with the IMV group (RR, 0.47; 95% CI, 0.23−0.97; P = 0.04).
GRADE: moderate
Intensive Care Unit Length of Stay
Both studies reported ICU LOS as an outcome. The pooled results showed a nonsignificant reduction in ICU LOS in the NPPV group compared with the IMV group (WMD, −5.21 days; 95% CI, −11.60 to 1.18 days).
GRADE: low
Duration of Mechanical Ventilation
Both studies reported duration of mechanical ventilation (including both invasive and noninvasive ventilation) as an outcome. The pooled results showed a nonsignificant reduction in duration of mechanical ventilation (WMD, −3.55 days; 95% CI, −8.55 to 1.44 days).
GRADE: low
Nosocomial Pneumonia
Both studies reported nosocominal pneumonia as an outcome. The pooled results showed a significant reduction in nosocomial pneumonia in the NPPV group compared with the IMV group (RR, 0.14; 95% CI, 0.03−0.71; P = 0.02).
GRADE: moderate
Weaning Failure
One study reported a significant reduction in weaning failure in the NPPV group compared with the IMV group, but the results were not reported in the publication. In this study, 1 of 25 patients in the NPPV group and 2 of 25 patients in the IMV group could not be weaned after 60 days in the ICU.
NPPV After Extubation of COPD Patients From IMV
The literature was reviewed to identify studies examining the effectiveness of NPPV compared with UMC in preventing recurrence of ARF after extubation from IMV or treating acute ARF which has recurred after extubation from IMV. No studies that included only COPD patients or reported results for COPD patients separately were identified for the prevention of ARF postextubation.
One study was identified for the treatment of ARF in COPD patients that recurred within 48 hours of extubation from IMV. This study included 221 patients, of whom 23 had COPD. A post hoc subgroup analysis was conducted examining the rate of reintubation in the COPD patients only. A nonsignificant reduction in the rate of reintubation was observed in the NPPV group compared with the UMC group (7 of 14 patients vs. 6 of 9 patients, P = 0.67). GRADE: low
Conclusions
NPPV Plus UMC Versus UMC Alone for First Line Treatment of ARF due to Acute Exacerbations of COPD
Moderate quality of evidence showed that compared with UMC, NPPV plus UMC significantly reduced the need for endotracheal intubation, inhospital mortality, and the mean length of hospital stay.
Low quality of evidence showed a lower rate of complications in the NPPV plus UMC group compared with the UMC group.
NPPV Versus IMV for the Treatment of ARF in Patients Who Have Failed UMC
Due to inconsistent and low to very low quality of evidence, there was insufficient evidence to draw conclusions on the comparison of NPPV versus IMV for patients who failed UMC.
NPPV for Weaning COPD Patients From IMV
Moderate quality of evidence showed that weaning COPD patients from IMV using NPPV results in significant reductions in mortality, nosocomial pneumonia, and weaning failure compared with weaning with IMV.
Low quality of evidence showed a nonsignificant reduction in the mean LOS and mean duration of mechanical ventilation in the NPPV group compared with the IMV group.
NPPV for the Treatment of ARF in COPD Patients After Extubation From IMV
Low quality of evidence showed a nonsignificant reduction in the rate of reintubation in the NPPV group compared with the UMC group; however, there was inadequate evidence to draw conclusions on the effectiveness of NPPV for the treatment of ARF in COPD patients after extubation from IMV
PMCID: PMC3384377  PMID: 23074436
15.  Inhaled Steroids Modulate Extracellular Matrix Composition in Bronchial Biopsies of COPD Patients: A Randomized, Controlled Trial 
PLoS ONE  2013;8(5):e63430.
Rationale
Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD), which involves changes in extracellular matrix. This is thought to contribute to airway remodeling and airflow obstruction. We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation, but can also attenuate lung function decline in moderate-severe COPD. We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD.
Objective
To compare major extracellular matrix components (elastic fibers; proteoglycans [versican, decorin]; collagens type I and III) in bronchial biopsies 1) after 30-months inhaled steroids treatment or placebo; and 2) between current and ex-smokers with COPD.
Methods
We included 64 moderate-severe, steroid-naive COPD patients (24/40 (ex)-smokers, 62±7 years, 46 (31–54) packyears, post-bronchodilator forced expiratory volume in one second (FEV1) 62±9% predicted) at baseline in this randomized, controlled trial. 19 and 13 patients received 30-months treatment with fluticasone or placebo, respectively. Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content. Percentage and density of stained area were calculated by digital image analysis.
Results
30-Months inhaled steroids increased the percentage stained area of versican (9.6% [CI 0.9 to 18.3%]; p = 0.03) and collagen III (20.6% [CI 3.8 to 37.4%]; p = 0.02) compared to placebo. Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment (Rs = 0.45, p = 0.04). There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins.
Conclusions
These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD. This is associated with increased lung function, suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD. Smoking status is not associated with bronchial extracellular matrix proteins.
Trial Registration
ClinicalTrials.gov NCT00158847
doi:10.1371/journal.pone.0063430
PMCID: PMC3646783  PMID: 23667615
16.  Association of ADAM33 gene polymorphisms with COPD in a northeastern Chinese population 
BMC Medical Genetics  2009;10:132.
Background
Chronic obstructive pulmonary disease (COPD) is influenced by both environmental and genetic factors. ADAM33 (a disintegrin and metalloproteinase 33) has been one of the most exciting candidate genes for asthma since its first association with the disease in Caucasian populations. Recently, ADAM33 was shown to be associated with excessive decline of lung function and COPD. The aim of this study was to evaluate the potential relationship between polymorphisms of ADAM33 and COPD in a Han population in northeastern China.
Methods
A total of 312 COPD patients and a control group of 319 healthy volunteers were recruited for this study. Eight polymorphic loci (V4, T+1, T2, T1, S2, S1, Q-1, and F+1) of ADAM33 were selected for genotyping. Genotypes were determined by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
Results
Statistically significant differences in the distributions of the T2G, T1G, S2C, and Q-1G alleles between patients and controls were observed (P < 0.001, odds ratio (OR) = 2.81, 95% confidence interval (CI) = 2.19-3.61; P < 0.001, OR = 2.60, 95% CI = 2.06-3.30; P = 0.03, OR = 1.31, 95% CI = 1.02-1.69; and P < 0.001, OR = 1.93, 95% CI = 1.50-2.50, respectively). Haplotype analysis showed that the frequencies of the CGGGGAGC, CGGGGAGT, CGGGCAGC, and CGGGGGGC haplotypes were significantly higher in the case group than in the control group (P = 0.0002, 0.0001, 0.0005, and 0.0074, respectively). In contrast, the haplotype CGAAGAGC was more common in the control group than in the case group (P < 0.0001).
Conclusion
These preliminary results suggest an association between ADAM33 polymorphisms and COPD in a Chinese Han population.
doi:10.1186/1471-2350-10-132
PMCID: PMC2797784  PMID: 20003279
17.  Lung Function and Incidence of Chronic Obstructive Pulmonary Disease after Improved Cooking Fuels and Kitchen Ventilation: A 9-Year Prospective Cohort Study 
PLoS Medicine  2014;11(3):e1001621.
Pixin Ran, Nanshan Zhong, and colleagues report that cleaner cooking fuels and improved ventilation were associated with better lung function and reduced COPD among a cohort of villagers in Southern China.
Please see later in the article for the Editors' Summary
Background
Biomass smoke is associated with the risk of chronic obstructive pulmonary disease (COPD), but few studies have elaborated approaches to reduce the risk of COPD from biomass burning. The purpose of this study was to determine whether improved cooking fuels and ventilation have effects on pulmonary function and the incidence of COPD.
Methods and Findings
A 9-y prospective cohort study was conducted among 996 eligible participants aged at least 40 y from November 1, 2002, through November 30, 2011, in 12 villages in southern China. Interventions were implemented starting in 2002 to improve kitchen ventilation (by providing support and instruction for improving biomass stoves or installing exhaust fans) and to promote the use of clean fuels (i.e., biogas) instead of biomass for cooking (by providing support and instruction for installing household biogas digesters); questionnaire interviews and spirometry tests were performed in 2005, 2008, and 2011. That the interventions improved air quality was confirmed via measurements of indoor air pollutants (i.e., SO2, CO, CO2, NO2, and particulate matter with an aerodynamic diameter of 10 µm or less) in a randomly selected subset of the participants' homes. Annual declines in lung function and COPD incidence were compared between those who took up one, both, or neither of the interventions.
Use of clean fuels and improved ventilation were associated with a reduced decline in forced expiratory volume in 1 s (FEV1): decline in FEV1 was reduced by 12 ml/y (95% CI, 4 to 20 ml/y) and 13 ml/y (95% CI, 4 to 23 ml/y) in those who used clean fuels and improved ventilation, respectively, compared to those who took up neither intervention, after adjustment for confounders. The combined improvements of use of clean fuels and improved ventilation had the greatest favorable effects on the decline in FEV1, with a slowing of 16 ml/y (95% CI, 9 to 23 ml/y). The longer the duration of improved fuel use and ventilation, the greater the benefits in slowing the decline of FEV1 (p<0.05). The reduction in the risk of COPD was unequivocal after the fuel and ventilation improvements, with an odds ratio of 0.28 (95% CI, 0.11 to 0.73) for both improvements.
Conclusions
Replacing biomass with biogas for cooking and improving kitchen ventilation are associated with a reduced decline in FEV1 and risk of COPD.
Trial Registration
Chinese Clinical Trial Register ChiCTR-OCH-12002398
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Nearly 3 billion people in developing countries heat their homes and cook by burning biomass—wood, crop waste, and animal dung—in open fires and leaky stoves. Burning biomass this way releases pollutants into the home that impair lung function and that are responsible for more than a million deaths from chronic obstructive pulmonary disease (COPD) every year. COPD is a group of diseases that interfere with breathing. Normally, air is breathed in through the nose or mouth and travels down the windpipe into two bronchial tubes (airways) in the lungs. These tubes branch into smaller tubes (bronchioles) that end in bunches of tiny air sacs (alveoli). Oxygen in the air passes through the thin walls of these sacs into small blood vessels and is taken to the heart for circulation round the body. The two main types of COPD—chronic bronchitis (long-term irritation and swelling of the bronchial tubes) and emphysema (damage to the walls of the alveoli)—make it hard for people to breathe. Most people with COPD have both chronic bronchitis and emphysema, both of which are caused by long-term exposure to cigarette smoke, indoor air pollution, and other lung irritants. Symptoms of COPD include breathlessness during exercise and a persistent cough that produces large amounts of phlegm (mucus). There is no cure for COPD, but drugs and oxygen therapy can relieve its symptoms, and avoiding lung irritants can slow disease progression.
Why Was This Study Done?
Exposure to indoor air pollution has been associated with impaired lung function and COPD in several studies. However, few studies have assessed the long-term effects on lung function and on the incidence of COPD (the proportion of a population that develops COPD each year) of replacing biomass with biogas (a clean fuel produced by bacterial digestion of biodegradable materials) for cooking and heating, or of improving kitchen ventilation during cooking. Here, the researchers undertook a nine-year prospective cohort study in rural southern China to investigate whether these interventions are associated with any effects on lung function and on the incidence of COPD. A prospective cohort study enrolls a group of people, determines their characteristics at baseline, and follows them over time to see whether specific characteristic are associated with specific outcomes.
What Did the Researchers Do and Find?
The researchers offered nearly 1,000 people living in 12 villages in southern China access to biogas and to improved kitchen ventilation. All the participants, who adopted these interventions according to personal preferences, completed a questionnaire about their smoking habits and occupational exposure to pollutants and had their lung function measured using a spirometry test at the start and end of the study. Some participants also completed a questionnaire and had their lung function measured three and six years into the study. Finally, the researchers measured levels of indoor air pollution in a randomly selected subset of homes at the end of the study to confirm that the interventions had reduced indoor air pollution. Compared with non-use, the use of clean fuels and of improved ventilation were both associated with a reduction in the decline in lung function over time after adjusting for known characteristics that affect lung function, such as smoking. The use of both interventions reduced the decline in lung function more markedly than either intervention alone, and the benefits of using the interventions increased with length of use. Notably, the combined use of both interventions reduced the risk of COPD occurrence among the study participants.
What Do These Findings Mean?
These findings suggest that, among people living in rural southern China, the combined interventions of use of biogas instead of biomass and improved kitchen ventilation were associated with a reduced decline in lung function over time and with a reduced risk of COPD. Because participants were not randomly allocated to intervention groups, the people who adopted the interventions may have shared other unknown characteristics (confounders) that affected their lung function (for example, having a healthier lifestyle). Thus, it is not possible to conclude that either intervention actually caused a reduction in the decline in lung function. Nevertheless, these findings suggest that the use of biogas as a substitute for biomass for cooking and heating and improvements in kitchen ventilation might lead to a reduction in the global burden of COPD associated with biomass smoke.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001621.
The US National Heart, Lung, and Blood Institute provides detailed information for the public about COPD
The US Centers for Disease Control and Prevention provides information about COPD and links to other resources (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about COPD, personal stories, and links to other resources
The British Lung Foundation, a not-for-profit organization, provides information about COPD in several languages
The Global Initiative for Chronic Obstructive Lung Disease works to improve prevention and treatment of COPD around the world
The World Health Organization provides information about all aspects of indoor air pollution and health (in English, French, and Spanish)
MedlinePlus provides links to other information about COPD (in English and Spanish)
doi:10.1371/journal.pmed.1001621
PMCID: PMC3965383  PMID: 24667834
18.  POLYMORPHISMS IN THE SUPEROXIDE DISMUTASE-3 GENE ARE ASSOCIATED WITH EMPHYSEMA IN COPD 
COPD  2010;7(4):262-268.
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes.
We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1) and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n=389) and smoking controls from the Normative Aging Study (NAS, n=472). We examined whether the SNPs were associated with COPD status, lung function variables, and quantitative CT measurements of emphysema and airway wall thickness. Further, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n=3061) and the Boston Early-Onset COPD Study (EOCOPD, n=949).
In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p=0.029 and p=0.0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p=0.048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations.
In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
doi:10.3109/15412555.2010.496821
PMCID: PMC2923920  PMID: 20673035
19.  S100A7/psoriasin expression in the human lung: unchanged in patients with COPD, but upregulated upon positive S. aureus detection 
Background
Progressive airway inflammation and susceptibility to the airway colonisation and infection are characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). Antimicrobial peptides (AMPs) are central to the function of the innate host immune response against microbial pathogens and are regulators of inflammation and immunity. S100A7/psoriasin, a recently described AMP, is an essential component of the human epithelia against invading pathogens and acts as an effector molecule of the host innate defence in the skin. We hypothesized that S100A7/psoriasin is involved in the airway mucosal immunity and differently regulated and expressed in the lung during progression of COPD.
Methods
S100A7/psoriasin gene expression was assessed in bronchial biopsies and bronchoalveolar lavage (BAL) fluid cells of healthy controls and COPD patients. Using confocal microscopy and immunohistochemistry, the protein expression of S100A7/psoriasin was investigated.
Results
Here, we report that S100A7/psoriasin, the major antimicrobial peptide of the human skin, is constitutively expressed in perinuclear granules of human bronchial epithelial cells and alveolar macrophages. Whereas typical activators of the innate immune response like TLR ligands and cytokines induced the upregulation of CXCL-8 mRNA and release of CXCL-8 by epithelial cells, S100A7/psoriasin mRNA expression was not modulated. To investigate a potential association of S100A7/psoriasin with COPD, S100A7/psoriasin mRNA expression was assessed in bronchial biopsies and BAL fluid cells of patients at different stages of COPD and controls. Overall, 10 healthy individuals and 34 COPD patients were enrolled in this study. We found an association of S100A7/psoriasin mRNA expression with bacterial detection in the tracheobronchial system (p = 0.0304), which was the strongest in individuals positive for with S. aureus (p = 0.0005). However, S100A7/psoriasin mRNA expression was not altered during the progression of COPD.
Conclusions
S100A7/psoriasin gene expression is unchanged in the airways during COPD. The newly identified association of S100A7/psoriasin with S. aureus may provide new insights into the antimicrobial defence response of the human airways, leading to the induction of S100A7/psoriasin upon microbial challenge.
doi:10.1186/1471-2466-11-10
PMCID: PMC3050873  PMID: 21324122
20.  Bronchial hyperresponsiveness in women with chronic obstructive pulmonary disease related to wood smoke 
Purpose
Chronic obstructive pulmonary disease (COPD) related to wood smoke exposure is characterized by important inflammation of the central and peripheral airways without significant emphysema. The objective of this study is to describe the bronchial hyperresponsiveness (BHR) level in women with COPD related to wood smoke exposure and to compare it with the BHR in women with COPD related to tobacco smoking.
Materials and methods
Two groups of women with stable COPD were studied: (1) wood smoke exposed (WS-COPD); and (2) tobacco smoke exposed (TS-COPD). A methacholine challenge test (MCT) was performed in all patients according to American Thoracic Society criteria. BHR levels were compared using the methacholine concentration, which caused a 20% fall in the FEV1 (PC20).
Results
Thirty-one patients, 19 with WS-COPD and 12 with TS-COPD, were included. There were no significant differences between the groups in baseline FVC, FEV1, IC, FEF25–75, and FEF25–75/FVC. All 31 patients had a positive MCT (PC20 < 16 mg/mL) and the fall in the FEV1 and IC was similar in both groups. The severity of BHR was significantly higher in the WS-COPD patients (PC20: 0.39 mg/mL) than in the TS-COPD patients (PC20: 1.24 mg/mL) (P = 0.028). The presence of cough, phlegm, and dyspnea during the test were similar in both groups.
Conclusion
We found moderate to severe BHR in women with WS-COPD, which was more severe than in the TS-COPD women with similar age and airflow obstruction. This paper suggests that the structural and inflammatory changes induced by the chronic exposure to wood smoke, described in other studies, can explain the differences with TS-COPD patients. Future studies may clarify our understanding of the impact of BHR on COPD physiopathology, phenotypes, and treatment strategies.
doi:10.2147/COPD.S30410
PMCID: PMC3393338  PMID: 22791990
biomass fuels; indoor air pollution; wood smoke; COPD; methacholine challenge test
21.  T-Bet Polymorphisms Are Associated with Asthma and Airway Hyperresponsiveness 
Rationale: T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-γ production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR.
Objectives: To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association.
Methods: Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels.
Main Results: We identified 24 variants. Evidence of association was observed between c.−7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.−7947 and three other variants were also associated with AHR (log-methacholine PC20, p = 0.02–0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3′UTR. Evidence of association of AHR with c.−7947, but not with other 3′UTR SNPs, was replicated in an independent cohort of adult males with AHR.
Conclusions: These data suggest that T-bet variation contributes to airway responsiveness in asthma.
doi:10.1164/rccm.200503-505OC
PMCID: PMC2662983  PMID: 16179640
immunoglobulin E; single nucleotide polymorphism; T-box; TBX21
22.  Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2011;6(9):e24395.
Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.
doi:10.1371/journal.pone.0024395
PMCID: PMC3174957  PMID: 21949713
23.  Predictors of cardiovascular disease in asthma and chronic obstructive pulmonary disease 
Background
Cardiovascular disease (CVD) is a common comorbidity in patients with chronic airway obstruction, and is associated with systemic inflammation and airway obstruction. The aim of this study was to evaluate the predictors of CVD in two different conditions causing chronic airway obstruction, asthma and COPD.
Methods
Lung function tests, clinical and echocardiographic data were assessed in 229 consecutive patients, 100 with asthma and 129 with COPD. CVD was classified into: pressure overload (PO) and volume overload (VO). Sub-analysis of patients with ischemic heart disease (IHD) and pulmonary hypertension (PH) was also performed.
Results
CVD was found in 185 patients (81%: 51% COPD and 30% asthmatics) and consisted of PO in 42% and of VO in 38% patients. COPD patients, as compared to asthmatics, had older age, more severe airway obstruction, higher prevalence of males, of smokers, and of CVD (91% vs 68%), either PO (46% vs 38%) or VO (45% vs 30%). CVD was associated with older age and more severe airway obstruction both in asthma and COPD. In the overall patients the predictive factors of CVD were age, COPD, and male sex; those of PO were COPD, BMI, VC, FEV1 and MEF50 and those of VO were age, VC and MEF50. In asthma, the predictors of CVD were VC, FEV1, FEV1 /VC%, and PaO2, those of PO were VC, FEV1 and FEV1 /VC%, while for VO there was no predictor. In COPD the predictors of CVD were age, GOLD class and sex, those of VO age, VC and MEF50, and that of PO was BMI. Sub-analysis showed that IHD was predicted by COPD, age, BMI and FEV1, while PH (found only in 25 COPD patients), was predicted by VO (present in 80% of the patients) and FEV1. In subjects aged 65 years or more the prevalence of CVD, PO and VO was similar in asthmatic and COPD patients, but COPD patients had higher prevalence of males, smokers, IHD, PH, lower FEV1 and higher CRP.
Conclusions
The results of this study indicate that cardiovascular diseases are frequent in patients with chronic obstructive disorders, particularly in COPD patients. The strongest predictors of CVD are age and airway obstruction. COPD patients have higher prevalence of ischemic heart disease and pulmonary hypertension. In the elderly the prevalence of PO and VO in asthma and COPD patients is similar.
doi:10.1186/2049-6958-8-58
PMCID: PMC3844573  PMID: 24004921
Airway obstruction; Asthma; Cardiovascular disease; COPD; Pressure overload; Volume overload
24.  Impact of a functional polymorphism in the PAR-1 gene promoter in COPD and COPD exacerbations 
Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (P < 0.001). The rs2227744G>A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted.
doi:10.1152/ajplung.00128.2014
PMCID: PMC4137163  PMID: 24973402
PAR-1; F2R; SNP; COPD; COPD exacerbation
25.  Basement membrane and vascular remodelling in smokers and chronic obstructive pulmonary disease: a cross-sectional study 
Respiratory Research  2010;11(1):105.
Background
Little is known about airway remodelling in bronchial biopsies (BB) in smokers and chronic obstructive pulmonary disease (COPD). We conducted an initial pilot study comparing BB from COPD patients with nonsmoking controls. This pilot study suggested the presence of reticular basement membrane (Rbm) fragmentation and altered vessel distribution in COPD.
Methods
To determine whether Rbm fragmentation and altered vessel distribution in BB were specific for COPD we designed a cross-sectional study and stained BB from 19 current smokers and 14 ex-smokers with mild to moderate COPD and compared these to 15 current smokers with normal lung function and 17 healthy and nonsmoking subjects.
Results
Thickness of the Rbm was not significantly different between groups; although in COPD this parameter was quite variable. The Rbm showed fragmentation and splitting in both current smoking groups and ex-smoker COPD compared with healthy nonsmokers (p < 0.02); smoking and COPD seemed to have additive effects. Rbm fragmentation correlated with smoking history in COPD but not with age. There were more vessels in the Rbm and fewer vessels in the lamina propria in current smokers compared to healthy nonsmokers (p < 0.05). The number of vessels staining for vascular endothelial growth factor (VEGF) in the Rbm was higher in both current smoker groups and ex-smoker COPD compared to healthy nonsmokers (p < 0.004). In current smoker COPD VEGF vessel staining correlated with FEV1% predicted (r = 0.61, p < 0.02).
Conclusions
Airway remodelling in smokers and mild to moderate COPD is associated with fragmentation of the Rbm and altered distribution of vessels in the airway wall. Rbm fragmentation was also present to as great an extent in ex-smokers with COPD. These characteristics may have potential physiological consequences.
doi:10.1186/1465-9921-11-105
PMCID: PMC2918561  PMID: 20670454

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