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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.  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
3.  Chronic obstructive pulmonary disease 
The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD) in adults aged >40 yr is approximately 9-10 per cent. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults had shown that the overall prevalence of chronic bronchitis in adults >35 yr is 3.49 per cent. The development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. Pathological changes in COPD are observed in central airways, small airways and alveolar space. The proposed pathogenesis of COPD includes proteinase-antiproteinase hypothesis, immunological mechanisms, oxidant-antioxidant balance, systemic inflammation, apoptosis and ineffective repair. Airflow limitation in COPD is defined as a postbronchodilator FEV1 (forced expiratory volume in 1 sec) to FVC (forced vital capacity) ratio <0.70. COPD is characterized by an accelerated decline in FEV1. Co morbidities associated with COPD are cardiovascular disorders (coronary artery disease and chronic heart failure), hypertension, metabolic diseases (diabetes mellitus, metabolic syndrome and obesity), bone disease (osteoporosis and osteopenia), stroke, lung cancer, cachexia, skeletal muscle weakness, anaemia, depression and cognitive decline. The assessment of COPD is required to determine the severity of the disease, its impact on the health status and the risk of future events (e.g., exacerbations, hospital admissions or death) and this is essential to guide therapy. COPD is treated with inhaled bronchodilators, inhaled corticosteroids, oral theophylline and oral phosphodiesterase-4 inhibitor. Non pharmacological treatment of COPD includes smoking cessation, pulmonary rehabilitation and nutritional support. Lung volume reduction surgery and lung transplantation are advised in selected severe patients. Global strategy for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease guidelines recommend influenza and pneumococcal vaccinations.
PMCID: PMC3657849  PMID: 23563369
Airflow limitation; air pollution; bronchodilators; chronic obstructive pulmonary disease; exacerbations; lung; pulmonary rehabilitation; smoking
4.  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
5.  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
6.  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
7.  Virus-induced exacerbations in asthma and COPD 
Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and/or airflow limitation due to pulmonary emphysema. Chronic bronchitis, pulmonary emphysema, and bronchial asthma may all be associated with airflow limitation; therefore, exacerbation of asthma may be associated with the pathophysiology of COPD. Furthermore, recent studies have suggested that the exacerbation of asthma, namely virus-induced asthma, may be associated with a wide variety of respiratory viruses. COPD and asthma have different underlying pathophysiological processes and thus require individual therapies. Exacerbation of both COPD and asthma, which are basically defined and diagnosed by clinical symptoms, is associated with a rapid decline in lung function and increased mortality. Similar pathogens, including human rhinovirus, respiratory syncytial virus, influenza virus, parainfluenza virus, and coronavirus, are also frequently detected during exacerbation of asthma and/or COPD. Immune response to respiratory viral infections, which may be related to the severity of exacerbation in each disease, varies in patients with both COPD and asthma. In this regard, it is crucial to recognize and understand both the similarities and differences of clinical features in patients with COPD and/or asthma associated with respiratory viral infections, especially in the exacerbative stage. In relation to definition, epidemiology, and pathophysiology, this review aims to summarize current knowledge concerning exacerbation of both COPD and asthma by focusing on the clinical significance of associated respiratory virus infections.
doi:10.3389/fmicb.2013.00293
PMCID: PMC3787546  PMID: 24098299
asthma; COPD; respiratory virus; exacerbation; overlap syndrome; human rhinovirus; respiratory syncytial virus
8.  Association between Chronic Obstructive Pulmonary Disease and Lung Cancer: A Case-Control Study in Southern Chinese and a Meta-Analysis 
PLoS ONE  2012;7(9):e46144.
Background
Lung cancer and chronic obstructive pulmonary disease (COPD) share a common risk factor in cigarette smoking and a large portion of patients with lung cancer suffer from COPD synchronously. We therefore hypothesized that COPD is an independent risk factor for lung cancer. Our aim was to investigate the intrinsic linkage of COPD (or emphysema, chronic bronchitis and asthma) and lung cancer.
Methods
The present hospital-based case-control study included 1,069 patients with newly diagnosed lung cancer and 1,132 age frequency matched cancer-free controls. The odds ratios (ORs) for the associations between each previous pulmonary disease and lung cancer were estimated with logistic regression models, adjusting for age, sex, family history of cancer, BMI and pack year smoking. In meta-analysis, the pooled effects of previous pulmonary diseases were analyzed with random effects models; and stratification analyses were conducted on smoking status and ethnicity.
Results
In the case-control study, previous COPD was associated with the odds for increased risk of lung cancer (OR = 1.29, 95% confidence interval [CI] = 1.00∼1.68); so were emphysema (OR = 1.55, 95%CI = 1.03∼2.32) and chronic bronchitis (OR = 1.22, 95%CI = 0.99∼1.67); while asthma was associated with odds for decreased risk of lung cancer (OR = 0.29, 95%CI = 0.16∼0.53). These associations were more pronounced in smokers (P<.05 for all strata), but not in non-smokers. In meta-analysis, 35 studies (22,010 cases and 44,438 controls) were identified. COPD was significantly associated with the odds for increased risk of lung cancer (pooled OR = 2.76; 95% CI = 1.85–4.11), so were emphysema (OR = 3.02; 95% CI = 2.41–3.79) and chronic bronchitis (OR = 1.88; 95% CI = 1.49–2.36); and these associations were more pronounced in smokers than in non-smokers (P<.001 respectively). No significant association was observed for asthma.
Conclusion
Previous COPD could increase the risk of lung cancer, especially in smokers.
doi:10.1371/journal.pone.0046144
PMCID: PMC3460937  PMID: 23029414
9.  Experiences of Living and Dying With 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 of Analysis
The objective of this analysis was to review empirical qualitative research on the experiences of patients with chronic obstructive pulmonary disease (COPD), informal caregivers (“carers”), and health care providers—from the point of diagnosis, through daily living and exacerbation episodes, to the end of life.
Clinical Need and Target Population
Qualitative empirical studies (from social sciences, clinical, and related fields) can offer important information about how patients experience their condition. This exploration of the qualitative literature offers insights into patients’ perspectives on COPD, their needs, and how interventions might affect their experiences. The experiences of caregivers are also explored.
Research Question
What do patients with COPD, their informal caregivers (“carers”), and health care providers experience over the course of COPD?
Research Methods
Literature Search
Search Strategy
Literature searches for studies published from January 1, 2000, to November 2010 were performed on November 29, 2010, using OVID MEDLINE; on November 26, 2010, using ISI Web of Science; and on November 28, 2010, using EBSCO Cumulative Index to Nursing and Allied Health Literature (CINAHL). Titles and abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. One additional report, highly relevant to the synthesis, appeared in early 2011 during the drafting of this analysis and was included post hoc.
Inclusion Criteria
English-language full reports
studies published between January 1, 2000, and November 2010
primary qualitative empirical research (using any descriptive or interpretive qualitative methodology, including the qualitative component of mixed-methods studies) and secondary syntheses of primary qualitative empirical research
studies addressing any aspect of the experiences of living or dying with COPD from the perspective of persons at risk, patients, health care providers, or informal carers; studies addressing multiple conditions were included if COPD was addressed explicitly
Exclusion Criteria
studies addressing topics other than the experiences of living or dying with COPD from the perspective of persons at risk, patients, health care providers, or informal carers
studies labelled “qualitative” but not using a qualitative descriptive or interpretive methodology (e.g., case studies, experiments, or observational analysis using qualitative categorical variables)
quantitative research (i.e., using statistical hypothesis testing, using primarily quantitative data or analyses, or expressing results in quantitative or statistical terms)
studies that did not pose an empirical research objective or question, or involve the primary or secondary analysis of empirical data
Outcomes of Interest
qualitative descriptions and interpretations (narrative or theoretical) of personal and social experiences of COPD
Summary of Findings
Experiences at Diagnosis
Patients typically seek initial treatment for an acute episode rather than for chronic early symptoms of COPD.
Many patients initially misunderstand terms such as COPD, chronic obstructive pulmonary disease, or exacerbation.
Patients may not realize that COPD is incurable and fatal; some physicians themselves do not consider early COPD to be a fatal disease.
Smokers may not readily understand or agree with the idea that smoking caused or worsens their COPD. Those who believe there is a causal link may feel regret or shame.
Experiences of Living Day to Day
COPD patients experience alternating good days and bad days. A roller-coaster pattern of ups and downs becomes apparent, and COPD becomes a way of life.
Patients use many means (social, psychological, medical, organizational) to control what they can, and to cope with what they cannot. Economic hardship, comorbidities, language barriers, and low health literacy can make coping more difficult.
Increasing vulnerability and unpredictable setbacks make patients dependent on others for practical assistance, but functional limitations, institutional living or self-consciousness can isolate patients from the people they need.
For smokers, medical advice to quit can conflict with increased desire to smoke as a coping strategy.
Many of the factors that isolate COPD patients from social contact also isolate them from health care.
Experiences of Exacerbations
Patients may not always attribute repeated exacerbations to advancing disease, instead seeing them as temporary setbacks caused by activities, environmental factors, faltering self-management, or infection.
Lack of confidence in community-based services leads some patients to seek hospital admission, but patients also feel vulnerable when hospitalized. They may feel dependent on others for care or traumatized by hospital care routines.
Upon hospital discharge following an exacerbation, patients may face new levels of uncertainty about their illness, prognosis, care providers, and supports.
Experiences of the End of Life
Patients tend to be poorly informed about the long-term prognosis of COPD and what to expect toward the end of life; this lack of understanding impairs quality of life as the disease progresses.
As the end of life approaches, COPD patients face the usual challenges of daily living, but in a context of increasing exacerbations and deepening dependency. Activities and mobility decrease, and life may become confined.
Some clinicians have difficulty identifying the beginning of “the end of life,” given the unpredictable course of COPD. Long-term physician-patient relationships, familiarity and understanding, trust, good communication skills, sensitivity, and secure discussion settings can help facilitate end-of-life discussions.
Divergent meanings and goals of palliative care in COPD lead to confusion about whether such services are the responsibility of home care, primary care, specialty care, or even critical care. Palliative end-of-life care may not be anticipated prior to referral for such care. A palliative care referral can convey the demoralizing message that providers have “given up.”
Experiences of Carers
Carers’ challenges often echo patients’ challenges, and include anxiety, uncertainty about the future, helplessness, powerlessness, depression, difficulties maintaining employment, loss of mobility and freedoms, strained relationships, and growing social isolation.
Carers feel pressured by their many roles, struggling to maintain patience when they feel overwhelmed, and often feeling guilty about not doing enough.
Carers often face their own health problems and may have difficulty sustaining employment.
Synthesis: A Disease Trajectory Reflecting Patient Experiences
The flux of needs in COPD calls for service continuity and flexibility to allow both health care providers and patients to respond to the unpredictable yet increasing demands of the disease over time.
PMCID: PMC3384365  PMID: 23074423
10.  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
11.  Cigarette smoke affects dendritic cell maturation in the small airways of patients with chronic obstructive pulmonary disease 
Molecular Medicine Reports  2014;11(1):219-225.
The aim of the present study was to characterize and quantify the numbers and expression levels of cells markers associated with dendritic cell (DC) maturation in small airways in current smokers and non-smokers with or without chronic obstructive pulmonary disease (COPD). Lung tissues from the following 32 patients were obtained during resection for lung cancer: Eight smokers with COPD, eight non-smokers with COPD, eight current smokers without COPD and eight non-smokers without COPD, serving as a control. The tissue sections were immunostained for cluster of differentiation (CD)83+ and CD1a+ to delineate mature and immature DCs, and chemokine receptor type 7 (CCR7+) to detect DC migratory ability. Myeloid DCs were collected from the lung tissues, and subsequently the CD83+ and CCR7+ expression levels in the lung myeloid DCs were detected using flow cytometry. The expression levels of CD83+, CD1a+ and CCR7+ mRNA in total lung RNA were evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Evident chronic bronchitis and emphysema pathological changes were observed in the lung tissues of patients with COPD. The results revealed that the numbers of CD83+ and CCR7+ DCs were reduced but the numbers of CD1a+ DCs were significantly increased in the COPD group as compared with the control group (P<0.05, respectively). Using RT-qPCR, the expression levels of CCR7+ and CD83+ mRNA were found to be reduced in the smokers with COPD as compared with the non-smokers without COPD group (P<0.05, respectively). Excessive local adaptive immune responses are key elements in the pathogenesis of COPD. Cigarette smoke may stimulate immune responses by impairing the homing of airway DCs to the lymph nodes and reduce the migratory potential of DCs. The present study revealed that COPD is associated with reduced numbers of mature CD83+ DCs and lower CCR7+ expression levels in small airways.
doi:10.3892/mmr.2014.2759
PMCID: PMC4237095  PMID: 25338516
chronic obstructive pulmonary disease; reverse transcription polymerase chain reaction; chemokine receptor type 7; dendritic cells; cluster of differentiation 83; cluster of differentiation 1a
12.  Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease (COPD) Using an Ontario Policy Model 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-Term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Background
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. The inflammation causes repeated cycles of injury and repair in the airway wall— inflammatory cells release a variety of chemicals and lead to cellular damage. The inflammation process also contributes to the loss of elastic recoil pressure in the lung, thereby reducing the driving pressure for expiratory flow through narrowed and poorly supported airways, in which airflow resistance is significantly increased. Expiratory flow limitation is the pathophysiological hallmark of COPD.
Exacerbations of COPD contribute considerably to morbidity and mortality, and impose a burden on the health care system. They are a leading cause of emergency room visits and hospitalizations, particularly in the winter. In Canada, the reported average cost for treating a moderate exacerbation is $641; for a major exacerbation, the cost is $10,086.
Objective
The objective of this study was to evaluate the cost-effectiveness and budget impact of the following interventions in moderate to very severe COPD, investigated in the Medical Advisory Secretariat Chronic Obstructive Pulmonary Disease Mega-Analysis Series:
smoking cessation programs in moderate COPD in an outpatient setting:
– intensive counselling (IC) versus usual care (UC)
– nicotine replacement therapy (NRT) versus UC
– IC + NRT versus placebo
– bupropion versus placebo
multidisciplinary care (MDC) teams versus UC in moderate to severe COPD in an outpatient setting
pulmonary rehabilitation (PR) versus UC following acute exacerbations in moderate to severe COPD
long-term oxygen therapy (LTOT) versus UC in severe hypoxemia in COPD in an outpatient setting
ventilation:
– noninvasive positive pressure ventilation (NPPV) + usual medical care versus usual medical care in acute respiratory failure due to an acute exacerbation in severe COPD in an inpatient setting
– weaning with NPPV versus weaning with invasive mechanical ventilation in acute respiratory failure due to an acute exacerbation in very severe COPD in an inpatient setting
Methods
A cost-utility analysis was conducted using a Markov probabilistic model. The model consists of different health states based on the Global Initiative for Chronic Obstructive Lung Disease COPD severity classification. Patients were assigned different costs and utilities depending on their severity health state during each model cycle. In addition to moving between health states, patients were at risk of acute exacerbations of COPD in each model cycle. During each cycle, patients could have no acute exacerbation, a minor acute exacerbation, or a major exacerbation. For the purposes of the model, a major exacerbation was defined as one that required hospitalization. Patients were assigned different costs and utilities in each model cycle, depending on whether they experienced an exacerbation, and its severity.
Starting cohorts reflected the various patient populations from the trials analyzed. Incremental cost-effectiveness ratios (ICERs)—that is, costs per quality-adjusted life-year (QALY)—were estimated for each intervention using clinical parameters and summary estimates of relative risks of (re)hospitalization, as well as mortality and abstinence rates, from the COPD mega-analysis evidence-based analyses.
A budget impact analysis was also conducted to project incremental costs already being incurred or resources already in use in Ontario. Using provincial data, medical literature, and expert opinion, health system impacts were calculated for the strategies investigated.
All costs are reported in Canadian dollars.
Results
All smoking cessation programs were dominant (i.e., less expensive and more effective overall). Assuming a base case cost of $1,041 and $1,527 per patient for MDC and PR, the ICER was calculated to be $14,123 per QALY and $17,938 per QALY, respectively. When the costs of MDC and PR were varied in a 1-way sensitivity analysis to reflect variation in resource utilization reported in the literature, the ICER increased to $55,322 per QALY and $56,270 per QALY, respectively. Assuming a base case cost of $2,261 per year per patient for LTOT as reported by data from the Ontario provincial program, the ICER was calculated to be $38,993 per QALY. Ventilation strategies were dominant (i.e., cheaper and more effective), as reflected by the clinical evidence of significant in-hospital days avoided in the study group.
Ontario currently pays for IC through physician billing (translating to a current burden of $8 million) and bupropion through the Ontario Drug Benefit program (translating to a current burden of almost $2 million). The burden of NRT was projected to be $10 million, with future expenditures of up to $1 million in Years 1 to 3 for incident cases.
Ontario currently pays for some chronic disease management programs. Based on the most recent Family Health Team data, the costs of MDC programs to manage COPD were estimated at $85 million in fiscal year 2010, with projected future expenditures of up to $51 million for incident cases, assuming the base case cost of the program. However, this estimate does not accurately reflect the current costs to the province because of lack of report by Family Health Teams, lack of capture of programs outside this model of care by any data set in the province, and because the resource utilization and frequency of visits/follow-up phone calls were based on the findings in the literature rather than the actual Family Health Team COPD management programs in place in Ontario. Therefore, MDC resources being utilized in the province are unknown and difficult to measure.
Data on COPD-related hospitalizations were pulled from Ontario administrative data sets and based on consultation with experts. Half of hospitalized patients will access PR resources at least once, and half of these will repeat the therapy, translating to a potential burden of $17 million to $32 million, depending on the cost of the program. These resources are currently being absorbed, but since utilization is not being captured by any data set in the province, it is difficult to quantify and estimate. Provincial programs may be under-resourced, and patients may not be accessing these services effectively.
Data from the LTOT provincial program (based on fiscal year 2006 information) suggested that the burden was $65 million, with potential expenditures of up to $0.2 million in Years 1 to 3 for incident cases.
From the clinical evidence on ventilation (i.e., reduction in length of stay in hospital), there were potential cost savings to the hospitals of $42 million and $12 million for NPPV and weaning with NPPV, respectively, if the study intervention were adopted. Future cost savings were projected to be up to $4 million and $1 million, respectively, for incident cases.
Conclusions
Currently, costs for most of these interventions are being absorbed by provider services, the Ontario Drug Benefit Program, the Assistive Devices Program, and the hospital global budget. The most cost-effective intervention for COPD will depend on decision-makers’ willingness to pay. Lack of provincial data sets capturing resource utilization for the various interventions poses a challenge for estimating current burden and future expenditures.
PMCID: PMC3384363  PMID: 23074422
13.  Distinguishing adult-onset asthma from COPD: a review and a new approach 
Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are major public health burdens. This review presents a comprehensive synopsis of their epidemiology, pathophysiology, and clinical presentations; describes how they can be distinguished; and considers both established and proposed new approaches to their management. Both adult-onset asthma and COPD are complex diseases arising from gene–environment interactions. Early life exposures such as childhood infections, smoke, obesity, and allergy influence adult-onset asthma. While the established environmental risk factors for COPD are adult tobacco and biomass smoke, there is emerging evidence that some childhood exposures such as maternal smoking and infections may cause COPD. Asthma has been characterized predominantly by Type 2 helper T cell (Th2) cytokine-mediated eosinophilic airway inflammation associated with airway hyperresponsiveness. In established COPD, the inflammatory cell infiltrate in small airways comprises predominantly neutrophils and cytotoxic T cells (CD8 positive lymphocytes). Parenchymal destruction (emphysema) in COPD is associated with loss of lung tissue elasticity, and small airways collapse during exhalation. The precise definition of chronic airflow limitation is affected by age; a fixed cut-off of forced expiratory volume in 1 second/forced vital capacity leads to overdiagnosis of COPD in the elderly. Traditional approaches to distinguishing between asthma and COPD have highlighted age of onset, variability of symptoms, reversibility of airflow limitation, and atopy. Each of these is associated with error due to overlap and convergence of clinical characteristics. The management of chronic stable asthma and COPD is similarly convergent. New approaches to the management of obstructive airway diseases in adults have been proposed based on inflammometry and also multidimensional assessment, which focuses on the four domains of the airways, comorbidity, self-management, and risk factors. Short-acting beta-agonists provide effective symptom relief in airway diseases. Inhalers combining a long-acting beta-agonist and corticosteroid are now widely used for both asthma and COPD. Written action plans are a cornerstone of asthma management although evidence for self-management in COPD is less compelling. The current management of chronic asthma in adults is based on achieving and maintaining control through step-up and step-down approaches, but further trials of back-titration in COPD are required before a similar approach can be endorsed. Long-acting inhaled anticholinergic medications are particularly useful in COPD. Other distinctive features of management include pulmonary rehabilitation, home oxygen, and end of life care.
doi:10.2147/COPD.S46761
PMCID: PMC4166213  PMID: 25246782
chronic obstructive pulmonary disease; diagnosis; management; adults; inflammometry
14.  Respiratory symptoms in adults are related to impaired quality of life, regardless of asthma and COPD: results from the European community respiratory health survey 
Background
Respiratory symptoms are common in the general population, and their presence is related to Health-related quality of life (HRQoL). The objective was to describe the association of respiratory symptoms with HRQoL in subjects with and without asthma or COPD and to investigate the role of atopy, bronchial hyperresponsiveness (BHR), and lung function in HRQoL.
Methods
The European Community Respiratory Health Survey (ECRHS) I and II provided data on HRQoL, lung function, respiratory symptoms, asthma, atopy, and BHR from 6009 subjects. Generic HRQoL was assessed through the physical component summary (PCS) score and the mental component summary (MCS) score of the SF-36.
Factor analyses and linear regressions adjusted for age, gender, smoking, occupation, BMI, comorbidity, and study centre were conducted.
Results
Having breathlessness at rest in ECRHS II was associated with mean score (95% CI) impairment in PCS of -8.05 (-11.18, -4.93). Impairment in MCS score in subjects waking up with chest tightness was -4.02 (-5.51, -2.52). The magnitude of HRQoL impairment associated with respiratory symptoms was similar for subjects with and without asthma/COPD. Adjustments for atopy, BHR, and lung function did not explain the association of respiratory symptoms and HRQoL in subjects without asthma and/or COPD.
Conclusion
Subjects with respiratory symptoms had poorer HRQoL; including subjects without a diagnosis of asthma or COPD. These findings suggest that respiratory symptoms in the absence of a medical diagnosis of asthma or COPD are by no means trivial, and that clarifying the nature and natural history of respiratory symptoms is a relevant challenge.
Several community studies have estimated the prevalence of common respiratory symptoms like cough, dyspnoea, and wheeze in adults [1-3]. Although the prevalence varies to a large degree between studies and geographical areas, respiratory symptoms are quite common. The prevalences of respiratory symptoms in the European Community Respiratory Health Study (ECRHS) varied from one percent to 35% [1]. In fact, two studies have reported that more than half of the adult population suffers from one or more respiratory symptoms [4,5].
Respiratory symptoms are important markers of the risk of having or developing disease. Respiratory symptoms have been shown to be predictors for lung function decline [6-8], asthma [9,10], and even all-cause mortality in a general population study [11]. In patients with a known diagnosis of asthma or chronic obstructive pulmonary disease (COPD), respiratory symptoms are important determinants of reduced health related quality of life (HRQoL) [12-15]. The prevalence of respiratory symptoms exceeds the combined prevalences of asthma and COPD, and both asthma and COPD are frequently undiagnosed diseases [16-18]. Thus, the high prevalence of respipratory symptoms may mirror undiagnosed and untreated disease.
The common occurrence of respiratory symptoms calls for attention to how these symptoms affect health also in subjects with no diagnosis of obstructive airways disease. Impaired HRQoL in the presence of respiratory symptoms have been found in two population-based studies [6,19], but no study of respiratory sypmtoms and HRQoL have separate analyses for subjects with and without asthma and COPD, and no study provide information about extensive objective measurements of respiratory health.
The ECRHS is a randomly sampled, multi-cultural, population based cohort study. The ECRHS included measurements of atopy, bronchial hyperresponsiveness (BHR), and lung function, and offers a unique opportunity to investigate how respiratory symptoms affect HRQoL among subjects both with and without obstructive lung disease.
In the present paper we aimed to: 1) Describe the relationship between respiratory symptoms and HRQoL in an international adult general population and: 2) To assess whether this relationship varied with presence of asthma and/or COPD, or presence of objective functional markers like atopy and BHR.
doi:10.1186/1477-7525-8-107
PMCID: PMC2954977  PMID: 20875099
15.  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
16.  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
17.  Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema 
Background
Smoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists. We summarize evidence for various smoking indices.
Methods
Based on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking. Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded. Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment. For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics.
Results
Of 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema. RR estimates are markedly heterogeneous. Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11-2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94). For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition. Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated. For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function. For all outcomes, risk increases with amount smoked and pack-years. Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD. No clear relationship is seen with duration of smoking.
Conclusions
The results confirm and quantify the causal relationships with smoking.
doi:10.1186/1471-2466-11-36
PMCID: PMC3128042  PMID: 21672193
18.  Chronic Bronchitis and Current Smoking Are Associated with More Goblet Cells in Moderate to Severe COPD and Smokers without Airflow Obstruction 
PLoS ONE  2015;10(2):e0116108.
Background
Goblet cell hyperplasia is a classic but variable pathologic finding in COPD. Current literature shows that smoking is a risk factor for chronic bronchitis but the relationship of these clinical features to the presence and magnitude of large airway goblet cell hyperplasia has not been well described. We hypothesized that current smokers and chronic bronchitics would have more goblet cells than nonsmokers or those without chronic bronchitis (CB), independent of airflow obstruction.
Methods
We recruited 15 subjects with moderate to severe COPD, 12 healthy smokers, and 11 healthy nonsmokers. Six endobronchial mucosal biopsies per subject were obtained by bronchoscopy and stained with periodic acid Schiff-Alcian Blue. Goblet cell density (GCD) was quantified as goblet cell number per millimeter of basement membrane. Mucin volume density (MVD) was quantified as volume of mucin per unit area of basement membrane.
Results
Healthy smokers had a greater GCD and MVD than nonsmokers and COPD subjects. COPD subjects had a greater GCD than nonsmokers. When current smokers (healthy smokers and COPD current smokers, n = 19) were compared with all nonsmokers (nonsmoking controls and COPD ex-smokers, n = 19), current smokers had a greater GCD and MVD. When those with CB (n = 12) were compared to those without CB (n = 26), the CB group had greater GCD. This finding was also seen in those with CB in the COPD group alone. In multivariate analysis, current smoking and CB were significant predictors of GCD using demographics, lung function, and smoking pack years as covariates. All other covariates were not significant predictors of GCD or MVD.
Conclusions
Current smoking is associated with a more goblet cell hyperplasia and number, and CB is associated with more goblet cells, independent of the presence of airflow obstruction. This provides clinical and pathologic correlation for smokers with and without COPD.
doi:10.1371/journal.pone.0116108
PMCID: PMC4315442  PMID: 25646735
19.  The clinical and integrated management of COPD. An official document of AIMAR (Interdisciplinary Association for Research in Lung Disease), AIPO (Italian Association of Hospital Pulmonologists), SIMER (Italian Society of Respiratory Medicine), SIMG (Italian Society of General Medicine) 
COPD is a chronic pathological condition of the respiratory system characterized by persistent and partially reversible airflow obstruction, to which variably contribute remodeling of bronchi (chronic bronchitis), bronchioles (small airway disease) and lung parenchyma (pulmonary emphysema). COPD can cause important systemic effects and be associated with complications and comorbidities. The diagnosis of COPD is based on the presence of respiratory symptoms and/or a history of exposure to risk factors, and the demonstration of airflow obstruction by spirometry. GARD of WHO has defined COPD "a preventable and treatable disease". The integration among general practitioner, chest physician as well as other specialists, whenever required, assures the best management of the COPD person, when specific targets to be achieved are well defined in a diagnostic and therapeutic route, previously designed and shared with appropriateness. The first-line pharmacologic treatment of COPD is represented by inhaled long-acting bronchodilators. In symptomatic patients, with pre-bronchodilator FEV1 < 60% predicted and ≥ 2 exacerbations/year, ICS may be added to LABA. The use of fixed-dose, single-inhaler combination may improve the adherence to treatment. Long term oxygen therapy (LTOT) is indicated in stable patients, at rest while receiving the best possible treatment, and exhibiting a PaO2 ≤ 55 mmHg (SO2 < 88%) or PaO2 values between 56 and 59 mmHg (SO2 < 89%) associated with pulmonary arterial hypertension, cor pulmonale, or edema of the lower limbs or hematocrit > 55%. Respiratory rehabilitation is addressed to patients with chronic respiratory disease in all stages of severity who report symptoms and limitation of their daily activity. It must be integrated in an individual patient tailored treatment as it improves dyspnea, exercise performance, and quality of life. Acute exacerbation of COPD is a sudden worsening of usual symptoms in a person with COPD, over and beyond normal daily variability that requires treatment modification. The pharmacologic therapy can be applied at home and includes the administration of drugs used during the stable phase by increasing the dose or modifying the route, and adding, whenever required, drugs as antibiotics or systemic corticosteroids. In case of patients who because of COPD severity and/or of exacerbations do not respond promptly to treatment at home hospital admission should be considered. Patients with "severe" or "very severe" COPD who experience exacerbations should be carried out in respiratory unit, based on the severity of acute respiratory failure. An integrated system is required in the community in order to ensure adequate treatments also outside acute care hospital settings and rehabilitation centers. This article is being simultaneously published in Sarcoidosis Vasc Diffuse Lung Dis 2014, 31(Suppl. 1);3-21.
doi:10.1186/2049-6958-9-25
PMCID: PMC4107539  PMID: 25057359
COPD; Integrated care; Management
20.  Prevalence of chronic obstructive pulmonary disease among adult male cigarettes smokers: a community-based study in Jordan 
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. The prevalence of COPD among cigarette smokers in the Middle East is not well studied. A prospective descriptive study was performed in the north of Jordan. Male cigarette smokers (≥10 pack-year) aged 35 years and older were recruited from the community. They completed a questionnaire and a postbronchodilator spirometry. Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (postbronchodilator forced expiratory volume in 1 second <70%) was used to define COPD. A total of 512 subjects completed the study protocol. According to the GOLD criteria, 42 subjects (8.2%) had COPD. Of those, 27 subjects (64.3%) had symptomatic COPD. Using the GOLD criteria, eight subjects (19%) with COPD had mild disease, 24 (57.1%) had moderate disease, eight (19%) had severe disease, and two (4.8%) had very severe disease. Only 10.6% were aware of COPD as a smoking-related respiratory illness, and 6.4% had received counseling about risk for COPD by a physician. Chronic bronchitis (cough for 3 months in 2 consecutive years) was reported by 15% of the subjects, wheezes by 44.1%, and dyspnea by 65.2%. Subjects with COPD reported having more chronic bronchitis 18/42 (42.9%) and wheezing 28/42 (66.7%) than subjects without COPD. The prevalence of COPD increased with increased number of pack-years smoked. In conclusion, COPD prevalence among cigarette-smoking men in Jordan is lower than in the developed world. COPD was largely underdiagnosed, despite the majority of participants being symptomatic and having moderate to severe disease.
doi:10.2147/COPD.S62898
PMCID: PMC4113569  PMID: 25092972
COPD; spirometry; GOLD; smoking; chronic bronchitis; Jordan
21.  Chronic Obstructive Pulmonary Disease and Altered Risk of Lung Cancer in a Population-Based Case-Control Study 
PLoS ONE  2009;4(10):e7380.
Background
Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking.
Methodology/Principal Findings
The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5–2.5), emphysema (OR = 1.9, 95% CI = 1.4–2.8), or COPD (OR = 2.5, 95% CI = 2.0–3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30–0.78).
Conclusions/Significance
These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.
doi:10.1371/journal.pone.0007380
PMCID: PMC2753644  PMID: 19812684
22.  COPD 
Clinical Evidence  2011;2011:1502.
Introduction
Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. The main risk factor for the development and deterioration of COPD is smoking.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of maintenance drug treatment in stable COPD? What are the effects of smoking cessation interventions in people with stable COPD? What are the effects of non-drug interventions in people with stable COPD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 119 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha1 antitrypsin, antibiotics (prophylactic), anticholinergics (inhaled), beta2 agonists (inhaled), corticosteroids (oral and inhaled), general physical activity enhancement, inspiratory muscle training, nutritional supplementation, mucolytics, oxygen treatment (long-term domiciliary treatment), peripheral muscle strength training, psychosocial and pharmacological interventions for smoking cessation, pulmonary rehabilitation, and theophylline.
Key Points
The main risk factor for the development and deterioration of chronic obstructive pulmonary disease (COPD) is smoking.
Inhaled anticholinergics and beta2 agonists improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo. It is unclear whether inhaled anticholinergics or inhaled beta2 agonists are the more consistently effective drug class in the treatment of COPD.Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta2 agonists. Long-acting inhaled anticholinergics may improve lung function compared with long-acting beta2 agonists.Combined treatment with inhaled anticholinergics plus beta2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long-term effects are unknown.
Inhaled corticosteroids reduce exacerbations in COPD and reduce decline in FEV1, but the beneficial effects are small. Oral corticosteroids may improve short-term lung function, but have serious adverse effects. Combined inhaled corticosteroids plus long-acting beta2 agonists improve lung function, symptoms, and health-related quality of life, and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.
Long-term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia.
Theophylline may improve lung function compared with placebo, but adverse effects limit its usefulness in stable COPD.
We don't know whether mucolytic drugs, prophylactic antibiotics, or alpha1 antitrypsin improve outcomes in people with COPD compared with placebo.
Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.
Multi-modality pulmonary rehabilitation can improve exercise capacity, dyspnoea, and health-related quality of life in people with stable COPD; general physical exercises and peripheral muscle training can improve exercise capacity; inspiratory muscle training may improve lung function and exercise capacity; but nutritional supplementation has not been shown to be beneficial.
PMCID: PMC3275305  PMID: 21639960
23.  COPD 
Clinical Evidence  2008;2008:1502.
Introduction
Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. The main risk factor for the development and deterioration of COPD is smoking.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of maintenance drug treatment in stable COPD? What are the effects of maintenance drug treatment in stable COPD? What are the effects of non-drug interventions in people with stable COPD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha1 antitrypsin, antibiotics (prophylactic), anticholinergics (inhaled), beta2 agonists (inhaled), corticosteroids (oral and inhaled), general physical activity enhancement, inspiratory muscle training, maintaining healthy weight, mucolytics, oxygen treatment (long-term domiciliary treatment), peripheral muscle strength training, psychosocial and pharmacological interventions for smoking cessation, pulmonary rehabilitation, and theophylline.
Key Points
The main risk factor for the development and deterioration of chronic obstructive pulmonary disease (COPD) is smoking.
Inhaled anticholinergics and beta2 agonists improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo. It is unclear whether inhaled anticholinergics or inhaled beta2 agonists are the more consistently effective drug class in the treatment of COPD.Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta2 agonists. Long-acting inhaled anticholinergic drugs may improve lung function compared with long-acting beta2 agonists.Combined treatment with inhaled anticholinergics and beta2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long-term effects are unknown.
Inhaled corticosteroids reduce exacerbations in COPD and reduce decline in FEV1, but the beneficial effects are small. Oral corticosteroids may improve short-term lung function, but have serious adverse effects. Combined inhaled corticosteroids plus long-acting beta2 agonists improve lung function and symptoms and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.
Long-term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia.
Theophylline may improve lung function compared with placebo, but adverse effects limit their usefulness in stable COPD.
We don't know whether mucolytic drugs, prophylactic antibiotics, or alpha1 antitrypsin improve outcomes in people with COPD compared with placebo.
Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.
Multi-modality pulmonary rehabilitation and exercises can improve exercise capacity in people with stable COPD, but nutritional supplementation has not been shown to be beneficial.
PMCID: PMC2907933  PMID: 19445783
24.  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
25.  Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure 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 health technology assessment was to determine the effectiveness and cost-effectiveness of noninvasive ventilation for stable chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Noninvasive ventilation is used for COPD patients with chronic respiratory failure. Chronic respiratory failure in COPD patients may be due to the inability of the pulmonary system to coordinate ventilation, leading to adverse arterial levels of oxygen and carbon dioxide. Noninvasive ventilation in stable COPD patients has the potential to improve quality of life, prolong survival, and improve gas exchange and sleep quality in patients who are symptomatic after optimal therapy, have hypercapnia or nocturnal hypoventilation and mild hypercapnia, and are frequently hospitalized.
Technology
Noninvasive positive pressure ventilation (NPPV) is any form of positive ventilatory support without the use of an endotracheal tube. For stable COPD, the standard of care when using noninvasive ventilation is bilevel positive airway pressure (BiPAP). Bilevel positive airway pressure involves both inspiratory and expiratory pressure, high during inspiration and lower during expiration. It acts as a pressure support to accentuate a patient’s inspiratory efforts. The gradient between pressures maintains alveolar ventilation and helps to reduce carbon dioxide levels. Outpatients typically use BiPAP at night. Additional advantages of using BiPAP include resting of respiratory muscles, decreased work of breathing, and control of obstructive hypopnea.
Research Question
What is the effectiveness and cost-effectiveness of noninvasive ventilation, compared with no ventilation while receiving usual care, for stable COPD patients?
Research Methods
Literature Search
Search Strategy
A literature search was performed on December 3, 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, 2004 to 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. When the reviewer was unsure of the eligibility of articles, a second clinical epidemiologist and then a group of epidemiologists reviewed these until consensus was reached.
Inclusion Criteria
full-text English language articles,
studies published between January 1, 2004 and December 3, 2010,
journal articles that report on the effectiveness or cost-effectiveness of noninvasive ventilation,
clearly described study design and methods, and
health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs).
Exclusion Criteria
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
cross-over RCTs
studies on noninvasive negative pressure ventilation (e.g., iron lung)
studies that combine ventilation therapy with other regimens (e.g., daytime NPPV plus exercise or pulmonary rehabilitation)
studies on heliox with NPPV
studies on pulmonary rehabilitation with NPPV
Outcomes of Interest
mortality/survival
hospitalizations/readmissions
length of stay in hospital
forced expiratory volume
arterial partial pressure of oxygen
arterial partial pressure of carbon dioxide
dyspnea
exercise tolerance
health-related quality of life
Note: arterial pressure of oxygen and carbon dioxide are surrogate outcomes.
Statistical Methods
A meta-analysis and an analysis of individual studies were performed using Review Manager Version 5. For continuous data, a mean difference was calculated, and for dichotomous data, a relative risk ratio was calculated for RCTs. For continuous variables with mean baseline and mean follow-up data, a change value was calculated as the difference between the 2 mean values.
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
Conclusions
The following conclusions refer to stable, severe COPD patients receiving usual care.
Short-Term Studies
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation on oxygen gas exchange, carbon dioxide gas exchange, and exercise tolerance measured using the 6 Minute Walking Test.
Based on very low quality of evidence, there is no effect of NPPV therapy on lung function measured as forced expiratory volume in 1 second (Type II error not excluded).
Long-Term Studies
Based on moderate quality of evidence, there is no effect of NPPV therapy for the outcomes of mortality, lung function measured as forced expiratory volume in 1 second, and exercise tolerance measured using the 6 Minute Walking Test.
Based on low quality of evidence, there is no effect of NPPV therapy for the outcomes of oxygen gas exchange and carbon dioxide gas exchange (Type II error not excluded).
Qualitative Assessment
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation for dyspnea based on reduced Borg score or Medical Research Council dyspnea score.
Based on moderate quality of evidence, there is no effect of NPPV therapy for hospitalizations.
Health-related quality of life could not be evaluated.
PMCID: PMC3384378  PMID: 23074437

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