PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1485473)

Clipboard (0)
None

Related Articles

1.  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
2.  Influenza and Pneumococcal Vaccinations for 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 analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Technology
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
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 Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
safety
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
safety
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431
3.  Impact of active and passive smoking as risk factors for asthma and COPD in women presenting to primary care in Syria: first report by the WHO-GARD survey group 
Background
The burden of chronic respiratory disease (CRD) is alarming. International studies suggest that women with CRD are undersurveyed and underdiagnosed by physicians worldwide. It is unclear what the prevalence of CRD is in the general population of Syria, particularly among women, since there has never been a survey on CRD in this nation. The purpose of this study was to investigate the impact of different patterns of smoking on CRD in women.
Materials and methods
We extracted data on smoking patterns and outcome in women from the Global Alliance Against Chronic Respiratory Diseases survey. Using spirometric measurements before and after the use of inhaled bronchodilators, we tracked the frequency of CRD in females active and passive narghile or cigarette smokers presenting to primary care. We administered the questionnaire to 788 randomly selected females seen during 1 week in the fiscal year 2009–2010 in 22 primary care centers in six different regions of Syria. Inclusion criteria were age >6 years, presenting for any medical complaint. In this cross-sectional study, three groups of female subjects were evaluated: active smokers of cigarettes, active smokers of narghiles, and passive smokers of either cigarettes or narghiles. These three groups were compared to a control group of female subjects not exposed to active or passive smoking.
Results
Exposure to active cigarette smoke but not narghile smoke was associated with doctor-diagnosed chronic obstructive pulmonary disease (COPD). However, neither cigarette nor narghile active smoking was associated with increased incidence of spirometrically diagnosed COPD. Paradoxically, exposure to passive smoking of either cigarettes or narghiles resulted in association with airway obstruction, defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 70% according to the Global initiative for chronic Obstructive Lung Disease criteria; association with FEV1 < 80% predicted, evidencing moderate to severe GOLD spirometric grade, and doctor-diagnosed COPD. Physicians tend to underdiagnose COPD in women who present to primary care clinics. Whereas around 15% of enrolled women had evidence of COPD with FEV1/FVC < 70% after bronchodilators, only 4.8% were physician-diagnosed. Asthma did not appear to be a significant spirometric finding in these female subjects, although around 11% had physician-diagnosed asthma. One limitation is FEV1/FVC < 70% could have also resulted from uncontrolled asthma. The same limitation has been reported by the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar (PLATINO) study.
Conclusion
Contrary to popular belief in developing countries, women exposed to tobacco smoke, whether active or passive, and whether by cigarettes or narghiles, like men are at increased risk for the development of COPD, although cultural habits and taboos may decrease the risk of active smoking in some women.
Recommendations
These findings will be considered for country and region strategy for noncommunicable diseases, to overcome underdiagnosis of CRD in women, fight widespread female cigarette and narghile smoking, and promote behavioral research in this field.
doi:10.2147/COPD.S50551
PMCID: PMC3794890  PMID: 24124359
passive smoking; women; COPD; asthma; narghile; water pipe; behavior
4.  Integrative Analysis of DNA Methylation and Gene Expression Data Identifies EPAS1 as a Key Regulator of COPD 
PLoS Genetics  2015;11(1):e1004898.
Chronic Obstructive Pulmonary Disease (COPD) is a complex disease. Genetic, epigenetic, and environmental factors are known to contribute to COPD risk and disease progression. Therefore we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified EPAS1 as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity. EPAS1 is distinct in comparison with other key regulators in terms of methylation profile and downstream target genes. Genes predicted to be regulated by EPAS1 were enriched for biological processes including signaling, cell communications, and system development. We confirmed that EPAS1 protein levels are lower in human COPD lung tissue compared to non-disease controls and that Epas1 gene expression is reduced in mice chronically exposed to cigarette smoke. As EPAS1 downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested EPAS1 function in human endothelial cells. EPAS1 knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with EPAS1 downstream genes in lung tissue including hypoxia responsive genes, and genes associated with emphysema severity. Our first integrative analysis of genome-wide DNA methylation and gene expression profiles illustrates that not only does DNA methylation play a ‘causal’ role in the molecular pathophysiology of COPD, but it can be leveraged to directly identify novel key mediators of this pathophysiology.
Author Summary
Chronic Obstructive Pulmonary Disease (COPD) is a common lung disease. It is the fourth leading cause of death in the world and is expected to be the third by 2020. COPD is a heterogeneous and complex disease consisting of obstruction in the small airways, emphysema, and chronic bronchitis. COPD is generally caused by exposure to noxious particles or gases, most commonly from cigarette smoking. However, only 20–25% of smokers develop clinically significant airflow obstruction. Smoking is known to cause epigenetic changes in lung tissues. Thus, genetics, epigenetic, and their interaction with environmental factors play an important role in COPD pathogenesis and progression. Currently, there are no therapeutics that can reverse COPD progression. In order to identify new targets that may lead to the development of therapeutics for curing COPD, we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified EPAS1 as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity.
doi:10.1371/journal.pgen.1004898
PMCID: PMC4287352  PMID: 25569234
5.  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
6.  Smoking Cessation for 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 determine the effectiveness and cost-effectiveness of smoking cessation interventions in the management of chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Tobacco smoking is the main risk factor for COPD. It is estimated that 50% of older smokers develop COPD and more than 80% of COPD-associated morbidity is attributed to tobacco smoking. According to the Canadian Community Health Survey, 38.5% of Ontarians who smoke have COPD. In patients with a significant history of smoking, COPD is usually present with symptoms of progressive dyspnea (shortness of breath), cough, and sputum production. Patients with COPD who smoke have a particularly high level of nicotine dependence, and about 30.4% to 43% of patients with moderate to severe COPD continue to smoke. Despite the severe symptoms that COPD patients suffer, the majority of patients with COPD are unable to quit smoking on their own; each year only about 1% of smokers succeed in quitting on their own initiative.
Technology
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. Smoking cessation can help to slow or halt the progression of COPD. Smoking cessation programs mainly target tobacco smoking, but may also encompass other substances that can be difficult to stop smoking due to the development of strong physical addictions or psychological dependencies resulting from their habitual use.
Smoking cessation strategies include both pharmacological and nonpharmacological (behavioural or psychosocial) approaches. The basic components of smoking cessation interventions include simple advice, written self-help materials, individual and group behavioural support, telephone quit lines, nicotine replacement therapy (NRT), and antidepressants. As nicotine addiction is a chronic, relapsing condition that usually requires several attempts to overcome, cessation support is often tailored to individual needs, while recognizing that in general, the more intensive the support, the greater the chance of success. Success at quitting smoking decreases in relation to:
a lack of motivation to quit,
a history of smoking more than a pack of cigarettes a day for more than 10 years,
a lack of social support, such as from family and friends, and
the presence of mental health disorders (such as depression).
Research Question
What are the effectiveness and cost-effectiveness of smoking cessation interventions compared with usual care for patients with COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on June 24, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations (1950 to June Week 3 2010), EMBASE (1980 to 2010 Week 24), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, and the Centre for Reviews and Dissemination for studies published between 1950 and June 2010. A single reviewer reviewed the abstracts and obtained full-text articles for those studies meeting the eligibility criteria. Reference lists were also examined for any additional relevant studies not identified through the search. Data were extracted using a standardized data abstraction form.
Inclusion Criteria
English-language, full reports from 1950 to week 3 of June, 2010;
either randomized controlled trials (RCTs), systematic reviews and meta-analyses, or non-RCTs with controls;
a proven diagnosis of COPD;
adult patients (≥ 18 years);
a smoking cessation intervention that comprised at least one of the treatment arms;
≥ 6 months’ abstinence as an outcome; and
patients followed for ≥ 6 months.
Exclusion Criteria
case reports
case series
Outcomes of Interest
≥ 6 months’ abstinence
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
Nine RCTs were identified from the literature search. The sample sizes ranged from 74 to 5,887 participants. A total of 8,291 participants were included in the nine studies. The mean age of the patients in the studies ranged from 54 to 64 years. The majority of studies used the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD staging criteria to stage the disease in study subjects. Studies included patients with mild COPD (2 studies), mild-moderate COPD (3 studies), moderate–severe COPD (1 study) and severe–very severe COPD (1 study). One study included persons at risk of COPD in addition to those with mild, moderate, or severe COPD, and 1 study did not define the stages of COPD. The individual quality of the studies was high. Smoking cessation interventions varied across studies and included counselling or pharmacotherapy or a combination of both. Two studies were delivered in a hospital setting, whereas the remaining 7 studies were delivered in an outpatient setting. All studies reported a usual care group or a placebo-controlled group (for the drug-only trials). The follow-up periods ranged from 6 months to 5 years. Due to excessive clinical heterogeneity in the interventions, studies were first grouped into categories of similar interventions; statistical pooling was subsequently performed, where appropriate. When possible, pooled estimates using relative risks for abstinence rates with 95% confidence intervals were calculated. The remaining studies were reported separately.
Abstinence Rates
Table ES1 provides a summary of the pooled estimates for abstinence, at longest follow-up, from the trials included in this review. It also shows the respective GRADE qualities of evidence.
Summary of Results*
Abbreviations: CI, confidence interval; NRT, nicotine replacement therapy.
Statistically significant (P < 0.05).
One trial used in this comparison had 2 treatment arms each examining a different antidepressant.
Conclusions
Based on a moderate quality of evidence, compared with usual care, abstinence rates are significantly higher in COPD patients receiving intensive counselling or a combination of intensive counselling and NRT.
Based on limited and moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving NRT compared with placebo.
Based on a moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving the antidepressant bupropion compared to placebo.
PMCID: PMC3384371  PMID: 23074432
7.  A Genome-Wide Association Study of Pulmonary Function Measures in the Framingham Heart Study 
PLoS Genetics  2009;5(3):e1000429.
The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV1/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV1/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV1/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV1 and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.
Author Summary
Cigarette smoking is the primary risk factor for impaired lung function, yet only 20% of smokers develop chronic obstructive pulmonary disease (COPD). This observation, along with family studies of lung function and COPD, suggests that genetic factors influence susceptibility to cigarette smoke. We examined the relationship between common genetic variants and measures of lung function in a sample of 7,691 participants from the Framingham Heart Study and confirmed our observations in 835 participants from the Family Heart Study selected to include cases of airflow obstruction. We identified a variant on chromosome 4 that was strongly associated with FEV1/FVC in the Framingham Study and confirmed the association in the Family Heart Study. The accompanying manuscript identified the same region to be associated with COPD. Several interesting genes are present in the region that we identified, including a gene (HHIP) interacting with a biological pathway involved in lung development, but it is not yet clear which gene in the region explains the association. Our results identified a region of chromosome 4 that warrants further study to understand the genetic effects influencing lung function.
doi:10.1371/journal.pgen.1000429
PMCID: PMC2652834  PMID: 19300500
8.  Community-Based Multidisciplinary Care for Patients With Stable 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 determine the effectiveness and cost-effectiveness of multidisciplinary care (MDC) compared with usual care (UC, single health care provider) for the treatment of stable chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Chronic obstructive pulmonary disease is a progressive disorder with episodes of acute exacerbations associated with significant morbidity and mortality. Cigarette smoking is linked causally to COPD in more than 80% of cases. Chronic obstructive pulmonary disease is among the most common chronic diseases worldwide and has an enormous impact on individuals, families, and societies through reduced quality of life and increased health resource utilization and mortality.
The estimated prevalence of COPD in Ontario in 2007 was 708,743 persons.
Technology
Multidisciplinary care involves professionals from a range of disciplines, working together to deliver comprehensive care that addresses as many of the patient’s health care and psychosocial needs as possible.
Two variables are inherent in the concept of a multidisciplinary team: i) the multidisciplinary components such as an enriched knowledge base and a range of clinical skills and experiences, and ii) the team components, which include but are not limited to, communication and support measures. However, the most effective number of team members and which disciplines should comprise the team for optimal effect is not yet known.
Research Question
What is the effectiveness and cost-effectiveness of MDC compared with UC (single health care provider) for the treatment of stable COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on July 19, 2010 using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 1, 1995 until July 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.
Inclusion Criteria
health technology assessments, systematic reviews, or randomized controlled trials
studies published between January 1995 and July 2010;
COPD study population
studies comparing MDC (2 or more health care disciplines participating in care) compared with UC (single health care provider)
Exclusion Criteria
grey literature
duplicate publications
non-English language publications
study population less than 18 years of age
Outcomes of Interest
hospital admissions
emergency department (ED) visits
mortality
health-related quality of life
lung function
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
Six randomized controlled trials were obtained from the literature search. Four of the 6 studies were completed in the United States. The sample size of the 6 studies ranged from 40 to 743 participants, with a mean study sample between 66 and 71 years of age. Only 2 studies characterized the study sample in terms of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD stage criteria, and in general the description of the study population in the other 4 studies was limited. The mean percent predicted forced expiratory volume in 1 second (% predicted FEV1) among study populations was between 32% and 59%. Using this criterion, 3 studies included persons with severe COPD and 2 with moderate COPD. Information was not available to classify the population in the sixth study.
Four studies had MDC treatment groups which included a physician. All studies except 1 reported a respiratory specialist (i.e., respiratory therapist, specialist nurse, or physician) as part of the multidisciplinary team. The UC group was comprised of a single health care practitioner who may or may not have been a respiratory specialist.
A meta-analysis was completed for 5 of the 7 outcome measures of interest including:
health-related quality of life,
lung function,
all-cause hospitalization,
COPD-specific hospitalization, and
mortality.
There was only 1 study contributing to the outcome of all-cause and COPD-specific ED visits which precluded pooling data for these outcomes. Subgroup analyses were not completed either because heterogeneity was not significant or there were a small number of studies that were meta-analysed for the outcome.
Quality of Life
Three studies reported results of quality of life assessment based on the St. George’s Respiratory Questionnaire (SGRQ). A mean decrease in the SGRQ indicates an improvement in quality of life while a mean increase indicates deterioration in quality of life. In all studies the mean change score from baseline to the end time point in the MDC treatment group showed either an improvement compared with the control group or less deterioration compared with the control group. The mean difference in change scores between MDC and UC groups was statistically significant in all 3 studies. The pooled weighted mean difference in total SGRQ score was −4.05 (95% confidence interval [CI], −6.47 to 1.63; P = 0.001). The GRADE quality of evidence was assessed as low for this outcome.
Lung Function
Two studies reported results of the FEV1 % predicted as a measure of lung function. A negative change from baseline infers deterioration in lung function and a positive change from baseline infers an improvement in lung function. The MDC group showed a statistically significant improvement in lung function up to 12 months compared with the UC group (P = 0.01). However this effect is not maintained at 2-year follow-up (P = 0.24). The pooled weighted mean difference in FEV1 percent predicted was 2.78 (95% CI, −1.82 to −7.37). The GRADE quality of evidence was assessed as very low for this outcome indicating that an estimate of effect is uncertain.
Hospital Admissions
All-Cause
Four studies reported results of all-cause hospital admissions in terms of number of persons with at least 1 admission during the follow-up period. Estimates from these 4 studies were pooled to determine a summary estimate. There is a statistically significant 25% relative risk (RR) reduction in all-cause hospitalizations in the MDC group compared with the UC group (P < 0.001). The index of heterogeneity (I2) value is 0%, indicating no statistical heterogeneity between studies. The GRADE quality of evidence was assessed as moderate for this outcome, indicating that further research may change the estimate of effect.
COPD-Specific Hospitalization
Three studies reported results of COPD-specific hospital admissions in terms of number of persons with at least 1 admission during the follow-up period. Estimates from these 3 studies were pooled to determine a summary estimate. There is a statistically significant 33% RR reduction in all-cause hospitalizations in the MDC group compared with the UC group (P = 0.002). The I2 value is 0%, indicating no statistical heterogeneity between studies. The GRADE quality of evidence was assessed as moderate for this outcome, indicating that further research may change the estimate of effect.
Emergency Department Visits
All-Cause
Two studies reported results of all-cause ED visits in terms of number of persons with at least 1 visit during the follow-up period. There is a statistically nonsignificant reduction in all-cause ED visits when data from these 2 studies are pooled (RR, 0.64; 95% CI, 0.31 to −1.33; P = 0.24). The GRADE quality of evidence was assessed as very low for this outcome indicating that an estimate of effect is uncertain.
COPD-Specific
One study reported results of COPD-specific ED visits in terms of number of persons with at least 1 visit during the follow-up period. There is a statistically significant 41% reduction in COPD-specific ED visits when the data from these 2 studies are pooled (RR, 0.59; 95% CI, 0.43−0.81; P < 0.001). The GRADE quality of evidence was assessed as moderate for this outcome.
Mortality
Three studies reported the mortality during the study follow-up period. Estimates from these 3 studies were pooled to determine a summary estimate. There is a statistically nonsignificant reduction in mortality between treatment groups (RR, 0.81; 95% CI, 0.52−1.27; P = 0.36). The I2 value is 19%, indicating low statistical heterogeneity between studies. All studies had a 12-month follow-up period. The GRADE quality of evidence was assessed as low for this outcome.
Conclusions
Significant effect estimates with moderate quality of evidence were found for all-cause hospitalization, COPD-specific hospitalization, and COPD-specific ED visits (Table ES1). A significant estimate with low quality evidence was found for the outcome of quality of life (Table ES2). All other outcome measures were nonsignificant and supported by low or very low quality of evidence.
Summary of Dichotomous Data
Abbreviations: CI, confidence intervals; COPD, chronic obstructive pulmonary disease; n, number.
Summary of Continuous Data
Abbreviations: CI, confidence intervals; FEV1, forced expiratory volume in 1 second; n, number; SGRQ, St. George’s Respiratory Questionnaire.
PMCID: PMC3384374  PMID: 23074433
9.  Comparison of clinical features between non-smokers with COPD and smokers with COPD: a retrospective observational study 
Background
Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD); however, the similarities and differences in clinical presentation between smokers and nonsmokers are not fully described in patients with COPD. This study was designed to address this issue in a general teaching hospital in the People’s Republic of China.
Methods
The medical records of patients hospitalized with a lung mass for further evaluation at Zhongshan Hospital, Fudan University, from January 2006 to December 2010 were reviewed and the data of interest were collected. The definition of COPD was according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric criteria. Participants who had a previous exacerbation within 4 weeks of admission, airflow limitation due to abnormalities in the large airways, or with other pulmonary diseases were excluded. Included subjects were divided into nonsmokers with COPD and smokers with COPD by a cutoff of a 5 pack-year smoking history.
Results
A total of 605 subjects were included in the final analysis. The average age was 64.8±8.5 years and 62.0% (375/605) were smokers. Eighty percent of the patients had mild to moderate disease (GOLD grade 1–2). Age and years with COPD were comparable between the two groups. Compared with smokers with COPD, nonsmokers with COPD were more likely to be female, reported less chronic cough and sputum, have less emphysema on radiologic examination, and higher measures of forced expiratory volume in the first second percent predicted (FEV1), forced expiratory volume in one second/forced vital capacity (FEV1/FVC%) percent predicted, maximal voluntary ventilation percent predicted, diffusing capacity of lung (DLCO) percent predicted, and DLCO/alveolar volume percent predicted, with lower levels of residual volume percent predicted and residual volume/total lung capacity percent predicted. There were no significant differences between the two groups with regard to distribution of disease severity, vital capacity percent predicted, total lung capacity percent predicted, PaO2, PaCO2, modified Medical Research Council dyspnea score, wheezing, airway reversibility, and comorbidities. Smoking amount (pack-years) was correlated negatively with FEV1 percent predicted, FEV1/FVC% percent predicted, inspiratory capacity percent predicted, inspiratory capacity/total lung capacity percent predicted, and DLCO percent predicted, and correlated positively with GOLD grade and symptoms.
Conclusion
Non-smokers with COPD had less impairment in airflow limitation and gas exchange, and a lower prevalence of emphysema, chronic cough, and sputum compared with their smoking counterparts. Tobacco cessation is warranted in smokers with COPD.
doi:10.2147/COPD.S52416
PMCID: PMC3890400  PMID: 24426780
chronic obstructive pulmonary disease; smokers; non-smokers; lung function; symptoms; emphysema
10.  Passive smoking and chronic obstructive pulmonary disease: cross-sectional analysis of data from the Health Survey for England 
BMJ Open  2011;1(2):e000153.
Objectives
There is increasing evidence that passive smoking is associated with chronic respiratory diseases, but its association with chronic obstructive pulmonary disease (COPD) requires more study. In this cross-sectional analysis of data from 3 years of the Health Survey for England, the association between passive smoking exposure and risk of COPD is evaluated.
Design
Cross-sectional analysis of the 1995, 1996 and 2001 Health Surveys for England including participants of white ethnicity, aged 40+ years with valid lung function data. COPD was defined using the lower limit of normal spirometric criteria for airflow obstruction. Standardised questions elicited self-reported information on demography, smoking history, ethnicity, occupation, asthma and respiratory symptoms (dyspnoea, chronic cough, chronic phlegm, wheeze). Passive smoking was measured by self-report of hours of exposure to cigarette smoke per week.
Results
Increasing passive smoke exposure was independently associated with increased risk of COPD, with adjusted OR 1.05 (95% CI 0.93 to 1.18) for 1–19 h and OR 1.18 (95% CI 1.01 to 1.39) for 20 or more hours of exposure per week. Similar patterns (although attenuated and non-significant) were observed among never smokers. More marked dose–response relationships were observed between passive smoking exposure and respiratory symptoms, but the most marked effects were on the development of clinically significant COPD (airflow obstruction plus symptoms), where the risk among never smokers was doubled (OR 1.98 (95% CI 1.03 to 3.79)) if exposure exceeded 20 h/week.
Conclusion
This analysis adds weight to the evidence suggesting an association between passive smoking exposure and COPD.
Article summary
Article focus
Passive exposure to cigarette smoke is established as an important independent risk factor for the development of chronic conditions such as heart disease and lung cancer.
Although there is growing evidence implicating passive smoking in asthma and other respiratory diseases, the evidence for its effect on chronic obstructive pulmonary disease (COPD) is inconsistent.
Using cross-sectional data from the annual Health Survey for England, we examined the association between self-reported exposure to passive smoking and COPD.
Key messages
We have demonstrated a significant dose–response relationship between hours of exposure to passive smoking and increasing risk of COPD.
The most marked effects were observed on the development of clinically significant COPD (airflow obstruction plus symptoms), where the risk among never smokers was doubled (OR 1.98 (95% CI 1.03 to 3.79)) if exposure exceeded 20 h/week.
Passive smoking is prevalent worldwide, and even after the 2007 public smoking ban in the UK, 20% of the adult English population are still exposed to up to 20 h of passive smoking per week, with 5% exposed to more than 20 h/week; further measures are needed to investigate and reduce exposures in the home and elsewhere.
Strengths and limitations of this study
Our study has the advantage of being a large sample representative of the English population (>21 000 participants), conducted over 3 separate years, with a standardised protocol and objective measure of lung function.
However, due to the cross-sectional nature of the design, temporal associations cannot necessarily be inferred.
The Health Survey for England was not designed for the specific analyses presented in this paper, and thus some of the measures are crude.
Self-reported passive smoke exposure is only a proxy for true exposure levels, but is accepted as the most practical method of assessment.
doi:10.1136/bmjopen-2011-000153
PMCID: PMC3191589  PMID: 22021874
11.  Determinants of airflow obstruction in severe alpha‐1‐antitrypsin deficiency 
Thorax  2007;62(9):806-813.
Background
Severe α1‐antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.
Methods
The AAT Genetic Modifier Study is a multicentre family‐based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted).
Results
In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non‐index cases (p<0.01). Men had lower pre‐ and post‐bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non‐index groups were examined separately, with men representing the majority of non‐index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non‐index men but not women.
Conclusion
In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
doi:10.1136/thx.2006.075846
PMCID: PMC2117297  PMID: 17389752
12.  The analyses of risk factors for COPD in the Li ethnic group in Hainan, People’s Republic of China 
Objective
To study the risk factors for chronic obstructive pulmonary disease (COPD) in Li population in Hainan province, People’s Republic of China.
Methods
Li people above 40 years of age from Hainan were chosen by stratified random cluster sampling between 2012 and 2014. All participants were interviewed with a home-visiting questionnaire, and spirometry was performed on all eligible participants. Patients with airflow limitation (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] <0.70) were further examined by postbronchodilator spirometry, and those with a postbronchodilator FEV1/FVC <0.70 was diagnosed with COPD. The information of physical condition and history, smoking intensity, smoking duration, second-hand smoking, education, job category, monthly household income, working years, residential environment, primary fuel for cooking and heating (biomass fuel including wood, crop residues, dung, and charcoal, or modern fuel such as natural gas, liquefied petroleum gas, electricity, and solar energy), ventilated kitchen, heating methods, air pollution, recurrent respiratory infections, family history of respiratory diseases, cough incentives, and allergies of COPD and non-COPD subjects was analyzed by univariate and multivariate logistic regression models to identify correlated risk factors for COPD.
Results
Out of the 5,463 Li participants, a total of 277 COPD cases were identified by spirometry, and 307 healthy subjects were randomly selected as controls. Univariate logistic regression analyses showed that older people (65 years and above), low body mass index (BMI), biomass smoke, 11–20 and >20 cigarettes/day, smoking for 40 years or more, second-hand smoking, recurrent respiratory infections, and induced cough were risk factors for COPD, whereas high BMI, high education level, and presence of ventilated kitchen were protective factors. Subsequent multivariate logistic regression model further demonstrated that aging, low BMI, biomass smoke, >20 cigarettes/day, and recurrent respiratory tract infections were high-risk factors for COPD in the Li population.
Conclusion
The incidence of COPD has a strong correlation with age, BMI, biomass smoke, >20 cigarettes/day, and recurrent respiratory infections, suggesting they were high-risk factors for COPD in Li population.
doi:10.2147/COPD.S86402
PMCID: PMC4670019  PMID: 26664107
chronic obstructive pulmonary disease; epidemiology; survey; Li population
13.  Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study 
Respiratory Research  2014;15(1):52.
Background
Chronic bronchitis (CB) has been related to poor outcomes in Chronic Obstructive Pulmonary Disease (COPD). From a clinical standpoint, we have shown that subjects with CB in a group with moderate to severe airflow obstruction were younger, more likely to be current smokers, male, Caucasian, had worse health related quality of life, more dyspnea, and increased exacerbation history compared to those without CB. We sought to further refine our clinical characterization of chronic bronchitics in a larger cohort and analyze the CT correlates of CB in COPD subjects. We hypothesized that COPD patients with CB would have thicker airways and a greater history of smoking, acute bronchitis, allergic rhinitis, and occupational exposures compared to those without CB.
Methods
We divided 2703 GOLD 1–4 subjects in the Genetic Epidemiology of COPD (COPDGene®) Study into two groups based on symptoms: chronic bronchitis (CB+, n = 663, 24.5%) and no chronic bronchitis (CB-, n = 2040, 75.5%). Subjects underwent extensive clinical characterization, and quantitative CT analysis to calculate mean wall area percent (WA%) of 6 segmental airways was performed using VIDA PW2 (http://www.vidadiagnostics.com). Square roots of the wall areas of bronchi with internal perimeters 10 mm and 15 mm (Pi10 and Pi15, respectively), % emphysema, %gas trapping, were calculated using 3D Slicer (http://www.slicer.org).
Results
There were no differences in % emphysema (11.4 ± 12.0 vs. 12.0 ± 12.6%, p = 0.347) or % gas trapping (35.3 ± 21.2 vs. 36.3 ± 20.6%, p = 0.272) between groups. Mean segmental WA% (63.0 ± 3.2 vs. 62.0 ± 3.1%, p < 0.0001), Pi10 (3.72 ± 0.15 vs. 3.69 ± 0.14 mm, p < 0.0001), and Pi15 (5.24 ± 0.22 vs. 5.17 ± 0.20, p < 0.0001) were greater in the CB + group. Greater percentages of gastroesophageal reflux, allergic rhinitis, histories of asthma and acute bronchitis, exposures to dusts and occupational exposures, and current smokers were seen in the CB + group. In multivariate binomial logistic regression, male gender, Caucasian race, a lower FEV1%, allergic rhinitis, history of acute bronchitis, current smoking, and increased airway wall thickness increased odds for having CB.
Conclusions
Histories of asthma, allergic rhinitis, acute bronchitis, current smoking, a lower FEV1%, Caucasian race, male gender, and increased airway wall thickness are associated with CB. These data provide clinical and radiologic correlations to the clinical phenotype of CB.
doi:10.1186/1465-9921-15-52
PMCID: PMC4067738  PMID: 24766722
Chronic bronchitis; Chronic obstructive pulmonary disease; Airway thickening; Asthma
14.  Effect of smoking on lung function, respiratory symptoms and respiratory diseases amongst HIV-positive subjects: a cross-sectional study 
Background
Smoking prevalence in human immunodeficiency virus (HIV) positive subjects is about three times of that in the general population. However, whether the extremely high smoking prevalence in HIV-positive subjects affects their lung function is unclear, particularly whether smoking decreases lung function more in HIV-positive subjects, compared to the general population. We conducted this study to determine the association between smoking and lung function, respiratory symptoms and diseases amongst HIV-positive subjects.
Results
Of 120 enrolled HIV-positive subjects, 119 had an acceptable spirogram. Ninety-four (79%) subjects were men, and 96 (81%) were white. Mean (standard deviation [SD]) age was 43.4 (8.4) years. Mean (SD) of forced expiratory volume in one second (FEV1) percent of age, gender, race and height predicted value (%FEV1) was 93.1% (15.7%). Seventy-five (63%) subjects had smoked 24.0 (18.0) pack-years. For every ten pack-years of smoking increment, %FEV1 decreased by 2.1% (95% confidence interval [CI]: -3.6%, -0.6%), after controlling for gender, race and restrictive lung function (R2 = 0.210). The loss of %FEV1 in our subjects was comparable to the general population. Compared to non-smokers, current smokers had higher odds of cough, sputum or breathlessness, after adjusting for highly active anti-retroviral therapy (HAART) use, odds ratio OR = 4.9 (95% CI: 2.0, 11.8). However respiratory symptom presence was similar between non-smokers and former smokers, OR = 1.0 (95% CI: 0.3, 2.8). All four cases of COPD (chronic obstructive pulmonary disease) had smoked. Four of ten cases of restrictive lung disease had smoked (p = 0.170), and three of five asthmatic subjects had smoked (p = 1.000).
Conclusions
Cumulative cigarette consumption was associated with worse lung function; however the loss of %FEV1 did not accelerate in HIV-positive population compared to the general population. Current smokers had higher odds of respiratory symptoms than non-smokers, while former smokers had the same odds of respiratory symptoms as non-smokers. Cigarette consumption was likely associated with more COPD cases in HIV-positive population; however more participants and longer follow up would be needed to estimate the effect of smoking on COPD development. Effective smoking cessation strategies are required for HIV-positive subjects.
doi:10.1186/1742-6405-7-6
PMCID: PMC2853483  PMID: 20298614
15.  Clinical and Radiologic Disease in Smokers With Normal Spirometry 
JAMA internal medicine  2015;175(9):1539-1549.
IMPORTANCE
Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free.
OBJECTIVE
To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0.
DESIGN, SETTING, AND PARTICIPANTS
Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 ≥80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011.
MAIN OUTCOMES AND MEASURES
Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life.
RESULTS
One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George’s Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P < .001) and a lower 6-minute walk distance, and 42.3% (127 of 300) of the GOLD 0 group had CT evidence of emphysema or airway thickening. The FEV1 percent predicted distribution and mean for the GOLD 0 group were lower but still within the normal range for the population. Current smoking was associated with more respiratory symptoms, but former smokers had greater emphysema and gas trapping. Advancing age was associated with smoking cessation and with more CT findings of disease. Individuals with respiratory impairments were more likely to use respiratory medications, and the use of these medications was associated with worse disease.
CONCLUSIONS AND RELEVANCE
Lung disease and impairments were common in smokers without spirometric COPD. Based on these results, we project that there are 35 million current and former smokers older than 55 years in the United States who may have unrecognized disease or impairment. The effect of chronic smoking on the lungs and the individual is substantially underestimated when using spirometry alone.
doi:10.1001/jamainternmed.2015.2735
PMCID: PMC4564354  PMID: 26098755
16.  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
17.  Lung Injury and Cancer 
Cigarette smoke has been connected to an array of chronic lung diseases and is a major source of morbidity and mortality. Active smoking is responsible for approximately 90% of lung cancer cases. In addition, cigarette smoke is associated with other chronic pulmonary diseases such as pulmonary edema, chronic bronchitis, and pulmonary emphysema, the last two also termed chronic obstructive pulmonary disease (COPD). Lung cancer and COPD are developed very frequently in chronic cigarette smokers. It has been known for some time that lung cancer incidence increases in patients with COPD. Even the existence of some low-grade emphysema without noticeable airflow obstruction is associated with significantly elevated risk of lung cancer. These recent clinical insights demand new thinking and exploration of novel mechanistic studies to fully understand these observations. Lung injury and repair involve cell death and hyperplasia of airway epithelial cells and infiltration of inflammatory cells. All of these occur simultaneously. The mechanisms of cell death and hyperplasia in the lung constitute two sides of the coin of lung injury and repair. However, most molecular studies in airway epithelial cells center on the mechanism(s) of either cell growth and proliferation or cell death and the ceramide-generating machinery that drives aberrant induction of apoptotic cell death. Very few address both sides of the coin as an outcome of cigarette smoke exposure, which is the focus of this review.
doi:10.1165/rcmb.2010-0220RT
PMCID: PMC2933544  PMID: 20525802
ceramide machinery; EGFR trafficking; cigarette smoke; lung injury; lung cancer
18.  Analysis of aberrant methylation on promoter sequences of tumor suppressor genes and total DNA in sputum samples: a promising tool for early detection of COPD and lung cancer in smokers 
Diagnostic Pathology  2012;7:87.
Background
Chronic obstructive pulmonary disease (COPD) is a disorder associated to cigarette smoke and lung cancer (LC). Since epigenetic changes in oncogenes and tumor suppressor genes (TSGs) are clearly important in the development of LC. In this study, we hypothesize that tobacco smokers are susceptible for methylation in the promoter region of TSGs in airway epithelial cells when compared with non-smoker subjects. The purpose of this study was to investigate the usefulness of detection of genes promoter methylation in sputum specimens, as a complementary tool to identify LC biomarkers among smokers with early COPD.
Methods
We determined the amount of DNA in induced sputum from patients with COPD (n = 23), LC (n = 26), as well as in healthy subjects (CTR) (n = 33), using a commercial kit for DNA purification, followed by absorbance measurement at 260 nm. The frequency of CDKN2A, CDH1 and MGMT promoter methylation in the same groups was determined by methylation-specific polymerase chain reaction (MSP). The Fisher’s exact test was employed to compare frequency of results between different groups.
Results
DNA concentration was 7.4 and 5.8 times higher in LC and COPD compared to the (CTR) (p < 0.0001), respectively. Methylation status of CDKN2A and MGMT was significantly higher in COPD and LC patients compared with CTR group (p < 0.0001). Frequency of CDH1 methylation only showed a statistically significant difference between LC patients and CTR group (p < 0.05).
Conclusions
We provide evidence that aberrant methylation of TSGs in samples of induced sputum is a useful tool for early diagnostic of lung diseases (LC and COPD) in smoker subjects.
Virtual slides
The abstract MUST finish with the following text: Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1127865005664160
doi:10.1186/1746-1596-7-87
PMCID: PMC3424112  PMID: 22818553
DNA methylation; Sputum; Lung cancer; COPD
19.  Whole Exome Re-Sequencing Implicates CCDC38 and Cilia Structure and Function in Resistance to Smoking Related Airflow Obstruction 
PLoS Genetics  2014;10(5):e1004314.
Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We hypothesised that these “resistant smokers” may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the “resistant smokers” and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34×10−4) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke.
Author Summary
Very large genome-wide association studies in general population cohorts have successfully identified at least 26 genes or gene regions associated with lung function and a number of these also show association with chronic obstructive pulmonary disease (COPD). However, these findings explain a small proportion of the heritability of lung function. Although the main risk factor for COPD is smoking, some individuals have normal or good lung function despite many years of heavy smoking. We hypothesised that studying these individuals might tell us more about the genetics of lung health. Re-sequencing of exomes, where all of the variation in the protein-coding portion of the genome can be measured, is a recent approach for the study of low frequency and rare variants. We undertook re-sequencing of the exomes of “resistant smokers” and used publicly available exome data for comparisons. Our findings implicate CCDC38, a gene which has previously shown association with lung function in the general population, and genes involved in cilia structure and lung function as having a role in resistance to smoking.
doi:10.1371/journal.pgen.1004314
PMCID: PMC4006731  PMID: 24786987
20.  Impact of heterozygote CFTR Mutations in COPD patients with Chronic Bronchitis 
Respiratory Research  2014;15(1):18.
Background
Cigarette smoking causes Chronic Obstructive Pulmonary Disease (COPD), the 3rd leading cause of death in the U.S. CFTR ion transport dysfunction has been implicated in COPD pathogenesis, and is associated with chronic bronchitis. However, susceptibility to smoke induced lung injury is variable and the underlying genetic contributors remain unclear. We hypothesized that presence of CFTR mutation heterozygosity may alter susceptibility to cigarette smoke induced CFTR dysfunction. Consequently, COPD patients with chronic bronchitis may have a higher rate of CFTR mutations compared to the general population.
Methods
Primary human bronchial epithelial cells derived from F508del CFTR heterozygotes and mice with (CFTR+/-) and without (CFTR+/+) CFTR heterozygosity were exposed to whole cigarette smoke (WCS); CFTR-dependent ion transport was assessed by Ussing chamber electrophysiology and nasal potential difference measurements, respectively. Caucasians with COPD and chronic bronchitis, age 40 to 80 with FEV1/FVC < 0.70 and FEV1 < 60% predicted, were selected for genetic analysis from participants in the NIH COPD Clinical Research Network’s Azithromycin for Prevention of Exacerbations of COPD in comparison to 32,900 Caucasian women who underwent prenatal genetic testing. Genetic analysis involved an allele-specific genotyping of 89 CFTR mutations.
Results
Exposure to WCS caused a pronounced reduction in CFTR activity in both CFTR (+/+) cells and F508del CFTR (+/-) cells; however, neither the degree of decrement (44.7% wild-type vs. 53.5% F508del heterozygous, P = NS) nor the residual CFTR activity were altered by CFTR heterozygosity. Similarly, WCS caused a marked reduction in CFTR activity measured by NPD in both wild type and CFTR heterozygous mice, but the severity of decrement (91.1% wild type vs. 47.7% CF heterozygous, P = NS) and the residual activity were not significantly affected by CFTR genetic status. Five of 127 (3.9%) COPD patients with chronic bronchitis were heterozygous for CFTR mutations which was not significantly different from controls (4.5%) (P = NS).
Conclusions
The magnitude of WCS induced reductions in CFTR activity was not affected by the presence of CFTR mutation heterozygosity. CFTR mutations do not increase the risk of COPD with chronic bronchitis. CFTR dysfunction due to smoking is primarily an acquired phenomenon and is not affected by the presence of congenital CFTR mutations.
doi:10.1186/1465-9921-15-18
PMCID: PMC3925354  PMID: 24517344
21.  Hospital-at-Home Programs for Patients With Acute Exacerbations of 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 analysis was to compare hospital-at-home care with inpatient hospital care for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) who present to the emergency department (ED).
Clinical Need: Condition and Target Population
Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease is a disease state characterized by airflow limitation that is not fully reversible. This airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. The natural history of COPD involves periods of acute-onset worsening of symptoms, particularly increased breathlessness, cough, and/or sputum, that go beyond normal day-to-day variations; these are known as acute exacerbations.
Two-thirds of COPD exacerbations are caused by an infection of the tracheobronchial tree or by air pollution; the cause in the remaining cases is unknown. On average, patients with moderate to severe COPD experience 2 or 3 exacerbations each year.
Exacerbations have an important impact on patients and on the health care system. For the patient, exacerbations result in decreased quality of life, potentially permanent losses of lung function, and an increased risk of mortality. For the health care system, exacerbations of COPD are a leading cause of ED visits and hospitalizations, particularly in winter.
Technology
Hospital-at-home programs offer an alternative for patients who present to the ED with an exacerbation of COPD and require hospital admission for their treatment. Hospital-at-home programs provide patients with visits in their home by medical professionals (typically specialist nurses) who monitor the patients, alter patients’ treatment plans if needed, and in some programs, provide additional care such as pulmonary rehabilitation, patient and caregiver education, and smoking cessation counselling.
There are 2 types of hospital-at-home programs: admission avoidance and early discharge hospital-at-home. In the former, admission avoidance hospital-at-home, after patients are assessed in the ED, they are prescribed the necessary medications and additional care needed (e.g., oxygen therapy) and then sent home where they receive regular visits from a medical professional. In early discharge hospital-at-home, after being assessed in the ED, patients are admitted to the hospital where they receive the initial phase of their treatment. These patients are discharged into a hospital-at-home program before the exacerbation has resolved. In both cases, once the exacerbation has resolved, the patient is discharged from the hospital-at-home program and no longer receives visits in his/her home.
In the models that exist to date, hospital-at-home programs differ from other home care programs because they deal with higher acuity patients who require higher acuity care, and because hospitals retain the medical and legal responsibility for patients. Furthermore, patients requiring home care services may require such services for long periods of time or indefinitely, whereas patients in hospital-at-home programs require and receive the services for a short period of time only.
Hospital-at-home care is not appropriate for all patients with acute exacerbations of COPD. Ineligible patients include: those with mild exacerbations that can be managed without admission to hospital; those who require admission to hospital; and those who cannot be safely treated in a hospital-at-home program either for medical reasons and/or because of a lack of, or poor, social support at home.
The proposed possible benefits of hospital-at-home for treatment of exacerbations of COPD include: decreased utilization of health care resources by avoiding hospital admission and/or reducing length of stay in hospital; decreased costs; increased health-related quality of life for patients and caregivers when treated at home; and reduced risk of hospital-acquired infections in this susceptible patient population.
Ontario Context
No hospital-at-home programs for the treatment of acute exacerbations of COPD were identified in Ontario. Patients requiring acute care for their exacerbations are treated in hospitals.
Research Question
What is the effectiveness, cost-effectiveness, and safety of hospital-at-home care compared with inpatient hospital care of acute exacerbations of COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on August 5, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 1990, to August 5, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists and health technology assessment websites were also examined for any additional relevant studies not identified through the systematic search.
Inclusion Criteria
English language full-text 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 including patients with COPD as well as patients with other conditions, if results are reported for COPD patients separately;
studies performed in patients with acute exacerbations of COPD who present to the ED;
studies published between January 1, 1990, and August 5, 2010;
studies comparing hospital-at-home and inpatient hospital care for patients with acute exacerbations of COPD;
studies that include at least 1 of the outcomes of interest (listed below).
Cochrane Collaboration reviews have defined hospital-at-home programs as those that provide patients with active treatment for their acute exacerbation in their home by medical professionals for a limited period of time (in this case, until the resolution of the exacerbation). If a hospital-at-home program had not been available, these patients would have been admitted to hospital for their treatment.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
Outcomes of Interest
Patient/clinical outcomes
mortality
lung function (forced expiratory volume in 1 second)
health-related quality of life
patient or caregiver preference
patient or caregiver satisfaction with care
complications
Health system outcomes
hospital readmissions
length of stay in hospital and hospital-at-home
ED visits
transfer to long-term care
days to readmission
eligibility for hospital-at-home
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1; otherwise, results were summarized descriptively. Data from RCTs were analyzed using intention-to-treat protocols. In addition, a sensitivity analysis was done assigning all missing data/withdrawals to the event. P values less than 0.05 were considered significant. A priori subgroup analyses were planned for the acuity of hospital-at-home program, type of hospital-at-home program (early discharge or admission avoidance), and severity of the patients’ COPD. Additional subgroup analyses were conducted as needed based on the identified 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
Fourteen studies met the inclusion criteria and were included in this review: 1 health technology assessment, 5 systematic reviews, and 7 RCTs.
The following conclusions are based on low to very low quality of evidence. The reviewed evidence was based on RCTs that were inadequately powered to observe differences between hospital-at-home and inpatient hospital care for most outcomes, so there is a strong possibility of type II error. Given the low to very low quality of evidence, these conclusions must be considered with caution.
Approximately 21% to 37% of patients with acute exacerbations of COPD who present to the ED may be eligible for hospital-at-home care.
Of the patients who are eligible for care, some may refuse to participate in hospital-at-home care.
Eligibility for hospital-at-home care may be increased depending on the design of the hospital-at-home program, such as the size of the geographical service area for hospital-at-home and the hours of operation for patient assessment and entry into hospital-at-home.
Hospital-at-home care for acute exacerbations of COPD was associated with a nonsignificant reduction in the risk of mortality and hospital readmissions compared with inpatient hospital care during 2- to 6-month follow-up.
Limited, very low quality evidence suggests that hospital readmissions are delayed in patients who received hospital-at-home care compared with those who received inpatient hospital care (mean additional days before readmission comparing hospital-at-home to inpatient hospital care ranged from 4 to 38 days).
There is insufficient evidence to determine whether hospital-at-home care, compared with inpatient hospital care, is associated with improved lung function.
The majority of studies did not find significant differences between hospital-at-home and inpatient hospital care for a variety of health-related quality of life measures at follow-up. However, follow-up may have been too late to observe an impact of hospital-at-home care on quality of life.
A conclusion about the impact of hospital-at-home care on length of stay for the initial exacerbation (defined as days in hospital or days in hospital plus hospital-at-home care for inpatient hospital and hospital-at-home, respectively) could not be determined because of limited and inconsistent evidence.
Patient and caregiver satisfaction with care is high for both hospital-at-home and inpatient hospital care.
PMCID: PMC3384361  PMID: 23074420
22.  Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease *  
OBJECTIVE:
Wood smoke exposure is a risk factor for COPD. For a given degree of airway obstruction, the reduction in DLCO is smaller in individuals with wood smoke-related COPD than in those with smoking-related COPD, suggesting that there is less emphysema in the former. The objective of this study was to compare HRCT findings between women with wood smoke-related COPD and women with smoking-related COPD.
METHODS:
Twenty-two women with severe COPD (FEV1/FVC ratio < 70% and FEV1 < 50%) were divided into two groups: those with wood smoke-related COPD (n = 12) and those with smoking-related COPD (n = 10). The two groups were compared regarding emphysema scores and airway involvement (as determined by HRCT); and functional abnormalities-spirometry results, DLCO, alveolar volume (VA), the DLCO/VA ratio, lung volumes, and specific airway resistance (sRaw).
RESULTS:
There were no significant differences between the two groups in terms of FEV1, sRaw, or lung hyperinflation. Decreases in DLCO and in the DLCO/VA ratio were greater in the smoking-related COPD group subjects, who also had higher emphysema scores, in comparison with the wood smoke-related COPD group subjects. In the wood smoke-related COPD group, HRCT scans showed no significant emphysema, the main findings being peribronchial thickening, bronchial dilation, and subsegmental atelectasis.
CONCLUSIONS:
Female patients with severe wood smoke-related COPD do not appear to develop emphysema, although they do show severe airway involvement. The reduction in DLCO and VA, with a normal DLCO/VA ratio, is probably due to severe bronchial obstruction and incomplete mixing of inspired gas during the determination of single-breath DLCO.
doi:10.1590/S1806-37132013000200005
PMCID: PMC4075823  PMID: 23670499
Pulmonary disease, chronic obstructive; Tomography; Air pollution; Biomass; Smoke; Respiratory function tests
23.  Smoking related COPD and facial wrinkling: is there a common susceptibility? 
Thorax  2006;61(7):568-571.
Background
Cigarette smoking causes accelerated facial wrinkling and predisposes to chronic obstructive pulmonary disease (COPD). However, it has long been recognised that there is a subgroup of susceptible smokers who are at increased risk of developing airflow obstruction. We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers.
Methods
One hundred and forty nine current and ex‐smokers were recruited from a family based study of COPD genetics, 68 (45.6%) of whom fulfilled the definition of COPD. 124 (83.2%) had no or minor facial wrinkling (Daniell
Results
Forced expiratory volume in 1 second (FEV1) was significantly lower in those with wrinkles than in those without (mean difference in FEV1 % predicted −13.7%, 95% CI −27.5 to 0.0, p = 0.05) and facial wrinkling was associated with a substantially increased risk of COPD (adjusted OR 5.0, 95% CI 1.3 to 18.5, p<0.02). The Daniell score correlated with the extent of emphysema on the CT scan (p<0.05) and facial wrinkling was also associated with a greater risk of more extensive emphysema (adjusted OR 3.0, 95% CI 1.0 to 9.3, p = 0.05).
Conclusion
Facial wrinkling is associated with COPD in smokers, and both disease processes may share a common susceptibility. Facial wrinkling in smokers may therefore be a biomarker of susceptibility to COPD.
doi:10.1136/thx.2005.053827
PMCID: PMC2104653  PMID: 16774949
chronic obstructive pulmonary disease; facial wrinkling; smoking
BMJ Open  2013;3(2):e002178.
Introduction
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with pulmonary and extra-pulmonary manifestations. Although COPD is a complex disease, diagnosis and staging are still based on simple spirometry measurements. Different COPD phenotypes exist based on clinical, physiological, immunological and radiological observations. Cigarette smoking is the most important risk factor for COPD, but only 15–20% of smokers develop the disease, suggesting a genetic predisposition. Unfortunately, little is known about the pathogenesis of COPD, and even less on the very first steps that are associated with an aberrant response to smoke exposure. This study aims to investigate the underlying local and systemic inflammation of different clinical COPD phenotypes, and acute effects of cigarette smoke exposure in individuals susceptible and non-susceptible for the development of COPD. Furthermore, we will investigate mechanisms associated with corticosteroid insensitivity. Our study will provide valuable information regarding the pathogenetic mechanisms underlying the natural course of COPD.
Methods and analysis
This cross-sectional study will include young and old individuals susceptible or non-susceptible to develop COPD. At a young age (18–40 years) 60 ‘party smokers’ will be included who are called susceptible or non-susceptible based on COPD prevalence in smoking family members. In addition, 30 healthy smokers (age 40–75 years) and 110 COPD patients will be included. Measurements will include questionnaires, pulmonary function, low-dose CT scanning of the lung, body composition, 6 min walking distance and biomarkers in peripheral blood, sputum, urine, exhaled breath condensate, epithelial lining fluid, bronchial brushes and biopsies. Non-biased approaches such as proteomics will be performed in blood and epithelial lining fluid.
Ethics and dissemination
This multicentre study was approved by the medical ethical committees of UMC Groningen and Utrecht, the Netherlands. The study findings will be presented at conferences and will be reported in peer-reviewed journals.
Trial registration
ClinicalTrials.gov, NCT00807469 (study 1) and NCT00850863 (study 2).
doi:10.1136/bmjopen-2012-002178
PMCID: PMC3586075  PMID: 23377993
COPD; Inflammation; Susceptibility; Corticosteroid insensitivity; Smoking
COPD  2008;5(5):274-281.
Rationale
Smoking-related respiratory diseases are a major cause of morbidity and mortality. However, the relationship between smoking and respiratory disease has not been well-studied among ethnic minorities in general and among women in particular.
Objective
The objective of this cross-sectional study was to evaluate the risk of airflow obstruction and to assess lung function among Hispanic and non-Hispanic white (NHW) female smokers in a New Mexico cohort.
Methods
Participants completed a questionnaire detailing smoking history and underwent spirometry testing. Outcomes studied included airflow obstruction, selected lung function parameters, and chronic mucus hyper-secretion. Chi square, logistic, and linear regression techniques were utilized.
Main findings
Of the 1,433 eligible women participants, 248 (17.3%) were Hispanic; and 319 had airflow obstruction (22.3%). Hispanic smokers were more likely to be current smokers, and report lower pack-years of smoking, compared to NHW smokers (p < 0.05 for all analyses). Further, Hispanic smokers were at a reduced risk of airflow obstruction compared to NHW smokers, with an O.R. of 0.51, 95% C.I. 0.34, 0.78 (p = 0.002) after adjustment for age, BMI, pack-years and duration of smoking, and current smoking status. Following adjustment for covariates, Hispanic smokers also had a higher mean absolute and percent predicted post-bronchodilator FEV1/FVC ratio, as well as higher mean percent predicted FEV1 (p < 0.05 for all analyses).
Principal conclusions
Hispanic female smokers in this New Mexico-based cohort had lower risk of airflow obstruction and better lung function than NHW female smokers. Further, smoking history did not completely explain these associations.
doi:10.1080/15412550802363345
PMCID: PMC3616889  PMID: 18972275
Hispanic ethnicity; Smokers; Airflow obstruction; Pulmonary function; Chronic mucus hyper-secretion; Women

Results 1-25 (1485473)