Pulmonary Medicine

COPD: Clinical Manifestations and Management (include pulmonary rehabilitation)

What every physician needs to know:

Chronic Obstructive Pulmonary Disease (COPD) is a clinically useful classification that includes several pathological processes. To varying degrees, these may all be present in individual patients, resulting in considerable clinical, physiologic, and pathologic heterogeneity. The defining feature of COPD is expiratory airflow limitation, detected and quantified using spirometry.

Because the clinical features are nonspecific, many individuals are incorrectly labeled as having COPD unless spirometry is obtained. Conversely, clinical symptoms may be subtle and discounted by the patient, resulting in substantial under-diagnosis. Historically, cigarette smoking is the most important risk factor for COPD, but not all smokers develop COPD, and there are other risk factors (Table 1) that have been identified as causes of COPD. In the absence of a smoking history, consideration of a diagnosis of COPD requires a high index of suspicion. Confirmation of a presumed diagnosis in smokers is necessary to avoid mis-diagnosis.

Table 1.

Risk factors for COPD

COPD is generally regarded as progressive, although recent studies have suggested that lung function may be stable over several years or may even improve slightly in some patients. In parallel with the natural decline in lung function that occurs with aging, COPD has been regarded as a disease of the elderly. However, mild disease, which may limit physical activity and which has prognostic implications, may be diagnosed in the fourth or fifth decades of life. Because of the aging of the population and exposures to risk factors, most notably cigarette smoking and air pollution, the prevalence of COPD in recent decades has risen in most countries. Currently, COPD is the third leading cause of death in the United States.

COPD is associated with extra-pulmonary diseases (Table 2), many of which have a higher incidence in smokers than in nonsmokers. However, the co-occurrence of COPD and these conditions is higher than would be expected based simply on their frequency. Whether this co-occurrence reflects shared risk factors or a pathogenetic process whereby lung disease leads to extra-pulmonary manifestations is not known. For the clinician, however, careful assessment and management of conditions associated with COPD is required in the management of COPD, and consideration of co-morbidities in COPD is important in patients with associated conditions.

Table 2.

Extrapulmonary Diseases Associated with COPD

Management of the patient with COPD requires an integrated approach that combines pharmacotherapy, non-pharmacologic approaches, and in selected cases, surgery.

Classification:

COPD has long been recognized as a clinically heterogeneous disorder. The classic descriptions of "pink puffer" and "blue bloater" have been useful constructs with regard to clinical findings. The term " pink puffer" is used to describe a patient with emphysema whose gas exchange and, hence, arterial oxygen saturation, are relatively well maintained. The term " blue bloater" refers to a patient with chronic bronchitis who has hypoxia that is due to ventilation-perfusion abnormalities, resultant pulmonary hypertension, and right heart failure. However, these classical terms do not capture the full heterogeneity of COPD; many patients have features of both emphysema and chronic bronchitis.

Pathophysiologic hallmarks of emphysema include destruction of alveolar walls and airflow limitation resulting from the loss of lung elastic recoil and lack of tethering of small airways. Both result in the collapse of small airways, particularly with forced exhalation, the mechanism that leads to expiratory airflow limitation in emphysema.

Anatomic forms of emphysema include centrilobular emphysema, which is the common form in cigarette smokers; in centrilobular disease, the central lobular region is destroyed, while peripheral lobular alveoli may be relatively intact. In pan-lobular emphysema, a disorder classically associated with emphysema in non-smoking, alpha-1 entitrypsin-deficient individuals, the entire lobule is affected uniformly. Often, centrilobular emphysema is most prominent in the upper lobes and superior segments of the lower lobes, while pan-lobular emphysema may be most prominent in the lower lobes.

Additional sub-types of emphysema have been described, although their clinical significance remains to be defined.

Pathophysiologic hallmarks of chronic bronchitis include the presence of cough and sputum; the most commonly used definition requires symptoms on most days for at least three months in two consecutive years, although this definition is highly arbitrary. Another pathophysiologic hallmark is mucus hyper-secretion that is due to enlargement of the mucus glands and goblet cell metaplasia. The increased airway secretions may contribute to airflow limitation, but they are not usually the major reason for expiratory airflow limitation.

In addition, disease of the small airways may lead to airway fibrosis and narrowing. This lesion is the major cause of expiratory airflow limitation in patients with COPD who have predominantly chronic bronchitis. Disease of the small airways may be present without prominent cough and sputum, resulting in airflow limitation without clear symptoms that meet the definition of chronic bronchitis. Conversely, subjects with marked cough and sputum may have relatively normal airflow.

COPD also affects the pulmonary vasculature, perhaps as a direct result of the inflammatory processes that are characteristic of the disorder; in addition, ventilation-perfusion abnormalities may be noted. Disease of the capillary bed may contribute to the development of emphysema. Primary or secondary vascular disease in the lung may contribute to pulmonary hypertension.

Are you sure your patient has COPD? What should you expect to find?

The most common symptoms of COPD include cough, sputum production, and dyspnea, particularly dyspnea on exertion. These symptoms may arise from a variety of diverse etiologies, and the clinical diagnosis of COPD is fraught with error. Confirmation of the diagnosis with spirometry is mandatory.

COPD develops slowly over many years, and perhaps for this reason, clinical features may be subtle. Since patients become dyspenic with exertion, many limit their level of activity and, as a result, are "symptom free"; many individuals adjust their expectations to a low level of functioning and have no complaints. This is neither denial nor poor reality testing, as the patient will give a highly accurate description of activity level and symptoms. Therefore, the astute clinician must inquire not only about the presence of dyspnea, but also about habitual levels of exertional activity in order to determine which levels precipitate dyspnea. The same is true for non-smokers with COPD. Therefore, COPD should be suspected in all individuals with reduced exertional activity, particularly if it is associated with dyspnea.

Cough and sputum production may be present as the defining features of chronic bronchitis, although airflow limitation can result from small airways in the absence of cough and sputum. Therefore, a clinical diagnosis cannot distinguish emphysema from airways disease with much reliability.

Physical signs that may be present later in the disease include prolongation of expiratory airflow, signs related to hyper-inflation of the chest, and if airways disease is present, adventitial lung sounds, including rhonchi and wheezes. However, these findings are neither terribly sensitive nor reliable, and a definitive diagnosis requires spirometry.

While COPD is defined by expiratory airflow limitation (of which there are several distinct causes), not all expiratory airflow limitation is due to COPD. Many of these conditions have symptoms that are similar to those of COPD.

Beware: there are other diseases that can mimic COPD:

A number of conditions may result in expiratory airflow limitation (Table 3). Most can be readily diagnosed by appropriate tests, which may include chest imaging or lung biopsy. Some diagnoses may be established on the basis of clinical features and lung function testing in the appropriate clinical setting, such as obliterative bronchiolitis following lung transplantation. However, in the absence of definitive testing, the differential diagnosis of obstructive lung diseases may be difficult. For example, lymphangioleiomyomatosis is often misdiagnosed as asthma.

Table 3.

Pulmonary Disorders Associated with Expiratory Airflow Limitation

Asthma is a particularly important differential diagnostic consideration in the evaluation of COPD; in fact, asthma and COPD may co-exist. While the two disorders may coexist, asthma may progress to fixed airflow limitation, which is clinically indistinguishable from "generic" COPD (except that a smoking history may be absent). Fixed airway obstruction may occur in as much as 15 percent of asthmatics. Asthma may well account for a large proportion of COPD in non-smokers; the airflow limitation is secondary to small airways fibrosis and narrowing. Whether these findings result from a process distinct from that that occurs in the small airways of smokers is currently debated.

A patient with asthma may have abnormal airflow most of the time; however, if airway function reverts to normal spontaneously or in response to treatment, COPD is excluded. If abnormal airflow is always present in a subject who meets the criteria for a diagnosis of asthma, according to current practice, both asthma and COPD should be diagnosed. Recognizing that asthma and COPD are present concurrently is important clinically, as treatment for both conditions is required.

Other conditions are usually much easier to distinguish from COPD. Many individuals with COPD are found to have mild bronchiectasis on a chest CT scan. Whether these individuals represent a specific subset of patients with COPD is unclear, although they typically have more severe cough and more frequent and severe exacerbations of lung disease than do those without bronchiectasis. At present, the approach to management is based on treatment for both COPD and bronchiectasis, as appropriate.

Which individuals are at greatest risk of developing COPD?

COPD is a classic, complex disease that results from gene-environment interactions. Cigarette smoking, the most common risk factor, accounts for about half of the attributable risk. Both active and passive smokers are at risk; although not all smokers get COPD, clinically meaningful disease may develop in about half of smokers who smoke long enough. Presumably, genetic factors contribute to the variable susceptibility to tobacco smoke.

A clear familial aggregation of COPD has been recognized, but while many genes have been related to COPD, only alpha-1 antitrypsin deficiency has been unequivocally established as a risk gene. The genes that are being identified as actively associated with COPD will likely account for the marked clinical heterogeneity of the condition. Environmental factors may well prove to be even more important. The degree to which genetic factors modify the risk of smoking or other exposures is undetermined.

A positive family history for COPD, a smoking history, exposure to passive smoke, living in an environment with indoor or outdoor air pollution, a history of asthma, or an occupational history associated with a significant exposure to dusts or fumes should prompt the clinician to obtain spirometry. If available, a history of childhood infections or low birth weight should prompt spirometry, as well.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Spirometry

The diagnosis of COPD requires spirometry, which also permits staging of the severity of airflow limitation. Spirometry is a simple, non-invasive test that can readily be performed in an office setting. Quality control algorithms are included in many modern spirometers, making spirometry feasible as a routine office test. Assessment of spirometry after bronchodilator testing helps establish the diagnosis of asthma.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for diagnosis are based on the ratio of the forced expiratory volume of air in one second (FEV1) to the total volume exhaled (the forced vital capacity, FVC). When FEV1/FVC is less than 0.7, the diagnosis of COPD is established by definition. However, both FEV1 and FVC decline with age, and since the FEV1 declines more, the ratio also declines. As a result, use of the "fixed ratio" of 0.7 results in over-diagnosis of COPD among the elderly and under-diagnosis among the more youthful. Consequently, some experts advocate use of an interpretation scheme based on the lower limit of normal (LLN) to define COPD. Tables that provide the LLN are not readily available in many clinical settings, so use of the fixed ratio is generally regarded as more practical, despite its statistical limitations.

Once the diagnosis of COPD is established, the FEV1, expressed as a percentage of predicted normal, is used to grade the severity of airflow limitation (Table 4). While treatment is based in part on the severity of airflow limitation, it is also driven by other clinical features that may not closely correlate with FEV 1. When clinical features, rather than the ratio of FEV1 to FVC, are used to dictate treatment, the clinical hazard of over-diagnosis of COPD using the fixed ratio method is thought not to be important.

Table 4.

Severity of Obstructive Lung Disease

Lung Volumes and Diffusion Capacity

More detailed pulmonary function testing, which includes assessment of lung volumes and diffusion capacity, may be helpful in supporting a diagnosis of emphysema. Increased lung volumes, together with air trapping, are a feature of emphysema, as is a loss of diffusion capacity. Other conditions may also increase lung volumes and/or reduce diffusion capacity, so these tests should be considered only in specific cases.

Measurement of Alpha-1 Antitrypsin (AAT) Level

The one genetic disorder that has been unequivocally associated with COPD is alpha-1 antitrypsin (AAT) deficiency. AAT levels may be quantified in a peripheral blood sample; in addition, the AAT protein may be phenotyped in peripheral blood specimens. Therefore, the diagnosis of AAT deficiency is usually made by first determining the level and then the phenotype.

AAT has many genetic variants. The most common is the M form; an individual with two copies of the M form has "normal" levels of AAT. The most common deficient form is the Z form. Individuals who are heterozygous (MZ) have intermediate levels of AAT and are not thought to be at increased risk for emphysema, while individuals who are homozygous for the Z form (ZZ) have severe deficiency of AAT and are at risk for emphysema. Those with rarer forms of deficiency, such as SZ or null, are also at risk.

AAT testing is generally recommended for individuals with COPD who are relatively young (under age 50 years), who have basilar-predominant disease, who have a family history of emphysema, or who have a limited smoking history. However, patients with COPD and AAT deficiency may present with none of these features. Since replacement therapy is available for AAT deficiency, routine testing of all newly diagnosed patients with COPD is advocated by some experts.

DNA testing may also establish the diagnosis of AAT deficiency, but it is not widely available.

Blood Gases and Percutaneous Oximetry

As COPD progresses, compromised gas exchange may lead to arterial hypoxemia and CO2 retention. For patients with an arterial oxygen tension less than 55 mm Hg, mortality is reduced by oxygen therapy. Blood gas testing is the most definitive method of assessment for hypoxemia, but percutaneous oximetry may provide similar information obtained non-invasively.

Sputum testing

Routine sputum analysis is not recommended for the evaluation of suspected COPD.

What imaging studies will be helpful in making or excluding the diagnosis of COPD?

Routine chest radiography is often used in the diagnosis of COPD; however, chest x-ray findings do not establish a diagnosis of COPD. Radiographic observations, which may be present with severe disease, include flattening of the diaphragm, increased substernal airspace, attenuation of vascular markings, and thickening of airways, but the findings are very insensitive. However, routine chest radiography may be helpful in excluding other conditions. Chest CT scanning may be more useful than routine chest radiography in the evaluation of COPD. While CT cannot establish a diagnosis of COPD (spirometry is required), it may be useful in determining the severity of emphysema and in documenting the presence of other pulmonary disease, including bronchiectasis, interstitial lung disease, and lung cancer.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of COPD?

Additional tests that may be useful in the evaluation of COPD include cardiopulmonary exercise testing and echocardiography.

A cardiopulmonary exercise test (CPET) measures oxygen uptake and carbon dioxide production during graded exercise. CPET may be used to establish work performed during exercise, to measure the anerobic threshold, and to determine maximum oxygen uptake, maximum ventilation, and maximum "oxygen pulse." If blood gases are obtained, CPET may be used to determine dead space ventilation. These parameters may be helpful in determining whether a respiratory or cardiac cause is responsible for dyspnea or exercise limitation. In addition, CPET can be used to establish parameters that are useful for optimizing a treatment prescription for pulmonary rehabilitation (see below).

Echocardiography is useful in assessing patients for pulmonary hypertension secondary to loss of pulmonary capillary bed or, more commonly, to hypoxemia in COPD.

What diagnostic procedures will be helpful in making or excluding the diagnosis of COPD?

Please see the section on non-invasive pulmonary diagnostic studies.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of COPD?

The histologic findings of COPD are readily recognizable. Lung tissue with alveolar wall destruction may be used to establish a diagnosis of emphysema. Similarly, hypertrophy of airway mucus glands, with or without metaplasia of airway epithelium, infiltration of the airway wall with inflammatory cells, and accumulation of myofibroblasts and extracellular matrix proteins may establish the presence of airway disease. However, the diagnosis is generally made without the benefit of biopsy. In addition, most biopsies sample a very limited portion of the lung. Establishing that a histologic diagnosis applies to the entire lung generally requires imaging or support from physiologic testing, so obtaining lung tissue for pathologic analysis is not the routine method for establishing a diagnosis of COPD.

If you decide the patient has COPD, how should the patient be managed?

Prevention of Disease Progression

The most important risk factor for COPD is cigarette smoking. Smoking cessation is a key goal for all individuals, particularly for patients with COPD. Smoking cessation slows the rate at which disease progresses, and the benefits are greater the earlier cessation is achieved. Mortality from associated diseases, particularly heart disease, is also improved following smoking cessation. The same smoking cessation strategies that are used in other smokers should be considered in COPD patients. Nicotine replacement, bupropiion, and varenicline have been tested in COPD patients and have been found effective in this population.

Modest reductions in the rate of loss of lung function have been reported with pharmacotherapy with fluticasone, salmeterol, and the combination of each compared to placebo in a large clinical trial. Another large clinical trial demonstrated a modest reduction in disease progression with tiotropium compared to placebo in patients with moderate disease. The reductions in decline with inhaled corticosteroids have been confirmed in meta-analyses, but the clinical importance of pharmacotherapy to slow disease progression remains to be determined.

Reduction of Symptoms and Improvement in Performance

Because patients with COPD experience dyspnea with exertion, many restrict physical activity. Treatment of COPD includes encouragement to increase physical activity and alleviation of symptoms.

Pharmacotherapy

The key to improving performance in COPD is bronchodilator therapy. By improving expiratory airflow, all bronchodilators reduce lung inflation, particularly the dynamic hyperinflation that occurs with exercise As a result, these agents may improve dyspnea with exercise performance. Therefore, bronchodilators are a first-line therapy for patients with COPD.

Three classes of bronchodilators are available: ß-adrenergic agonists, antimuscarinics, and theophylline. Inhaled medications are generally preferred over oral agents because their therapeutic ratio is better. Inhaled medications are available as metered-dose inhalers, dry powder inhalers, and nebulized solutions. All deliver medication effectively, but each requires education in proper use. Inhaler technique should be monitored regularly, as many patients stop using the devices correctly over time. Selection of an inhaler type and a specific device can be highly individualized; many find dry powder inhalers to be the most convenient, while nebulized solutions are often preferred by patients with severe disease.

Rapid-acting ß-agonists and anti-muscarinic agents that are of a relatively short duration may be appropriate for patients who are seldom symptomatic, and they may be useful for acute episodes of dyspnea. Long-acting ß-agonist bronchodilators and anti-muscarinics that can be taken once or twice daily are also available. Since patients with COPD are always physiologically limited, most with regular symptoms or significant activity limitation should be treated with regular doses of long-acting bronchodilators. Combined use of ß-agonist and anti-muscarinic agents may result in significantly improved airflow compared to use of a single agent.

Comparative effectiveness studies are not available to determine the best first agent. Some patients respond to one class of drugs and not to another, and the response may vary with time. As a result, empirical therapy with one or more bronchodilators in each patient is key. Since symptoms and function are related to level of activity, the assessment of clinical response requires careful observation by the clinician.

Theophylline has a modest bronchodilator effect and may improve symptoms further when added to bronchodilators. Inhaled corticosteroids and PDE4 inhibitors may also improve airflow modestly in COPD. These two agents are not bronchodilators, and the improvement in airflow is likely due to an anti-inflammatory effect. The clinical significance of the modest improvements in airflow is uncertain.

Pulmonary Rehabilitation

Pulmonary rehabilitation is the most effective intervention in COPD to improve symptoms, exercise performance, and health status. Pulmonary rehabilitation is a multidisciplinary intervention that includes education, psycho-social support, optimization of pharmacotherapy, and exercise training. Exercise training is key to improvement in dyspnea and performance; although it does not alter airflow, by making activity more efficient, less tachypnea, dynamic hyperinflation and dyspnea are noted. Synergies between rehabilitation and pharmacotherapy may be observed and optimal performance achieved by combining the two modalities.

Prevention of Exacerbations

Exacerbations of COPD are acute events in which symptoms of dyspnea, cough, and sputum production are increased substantially above a day-to-day baseline. These developments are often accompanied by marked fatigue. Sputum may become purulent, and systemic manifestation (e.g., fever) may be present. The episodes often require more aggressive treatment (see below). To some extent, acute exacerbations of COPD may be prevented by use of regular pharmacotherapy.

Routine influenza and pneumococcal immunizations are recommended. Guidelines also currently recommend several specific approaches for prevention of acute exacerbations of COPD. Long-acting bronchodilators, both ß-agonists and anti-cholinergics, may reduce exacerbation frequency, as do inhaled glucocorticoids (ICS). Only fluticasone and budesonide in combination with a long-acting ß-agonist bronchodilator are approved specifically for the treatment of COPD. However, many clinicians add an ICS approved for use in asthma to a bronchodilator to treat COPD. The PDE4 inhibitor, roflumilast, may also reduce exacerbations in patients with severe COPD, symptoms of chronic bronchitis, and a history of frequent exacerbations.

What is the prognosis for patients managed in the recommended ways?

COPD is generally regarded as a progressive disease, but recent data suggest that the progressive loss of lung function is most rapid among patients with moderate disease. Some patients remain stable, and a few may improve somewhat, at least over a three-year interval. Therefore, while a progressive course is most common, it is impossible to make specific predictions about progression in individual cases.

Except for smoking cessation, no specific therapy has been demonstrated to alter loss of lung function to a degree considered clinically important. However, many interventions may reduce the frequency of exacerbations and improve health status. Oxygen therapy and, in some cases, volume-reduction surgery, can improve survival.

What other considerations exist for patients with COPD?

None.

What’s the evidence?

"Global strategy for diagnosis, management and prevention of COPD". www.goldcopd.com.

The GOLD Guidelines are the most widely cited COPD guidelines. The guidelines, which are updated annually, review pathophysiology and treatment. The 2010 edition was widely referenced in preparation of this article. An update was released in November 2011.

Shapiro, SD, Robert, J, Mason, VCB. "Chronic bronchitis and emphysema". Textbook of Respiratory Medicine. Saunders. 2010. pp. 919-67.

This comprehensive review of COPD addresses historical changes in definitions, pathology, clinical features, pathophysiology, physiology, and treatment.

Mannino, DM. "Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994". Arch Intern Med. vol. 160. 2000. pp. 1683-9.

An analysis of a large CDC-sponsored study (> 20,000 individuals) that reports the prevalence of low lung function and the lack of accurate a priori diagnosis in the United States.

Fletcher, C. "The natural history of chronic bronchitis and emphysema". Oxford University Press. 1976.

The classic monograph that reports the comprehensive results of the "British Postal Workers Study." The analysis of this study has been the major influence on the concepts of the natural history of COPD since its publication.

Vestbo, J. "Changes in forced expiratory volume in 1 second over time in COPD". N Engl J Med. vol. 365. 2011. pp. 1184-92.

This observational study confirms that the majority of COPD patients progressively lose lung function, though more slowly than reported by Fletcher. Some individuals remained stable and some improved over three years.

Minino, A. "Deaths: Preliminary Data for 2008". National Vital Statistics Report. vol. 59. 2010. pp. 1-71.

This CDC report lists lower respiratory tract disease as the third leading cause of death in the United States.

Fabbri, LM. "Complex chronic comorbidities of COPD". Eur Respir J. vol. 31. 2008. pp. 204-12.

This review describes the relationship between COPD and many of the extra-pulmonary conditions that are associated with COPD more commonly than would be expected based on prevalence alone.

Niewohner, D, Stockley, R. "Structure-function relationships: the pathophysiology of airflow obstruction". Chronic obstructive pulmonary disease. Blackwell. 2007. pp. 3-19.

The chapter summarizes the anatomic basis for expiratory air flow limitation.

Matsuba, K. "The changes in airways structure associated with reduced forced expiratory volume in one second". Eur Respir J. vol. 2. 1989. pp. 834-9.

This reference relates small airway anatomic features to lung function in tissues removed from COPD patients during surgery.

Liebow, AA. "Pulmonary emphysema with special reference to vascular changes". Am Rev Respir Dis. vol. 80. 1959. pp. 67-93.

Introduces the concept that deficient maintenance of pulmonary vasculature could contribute to the development of emphysema. This concept can be contrasted with the British Hypothesis, which proposed the importance of airway secretions, and the Dutch Hypothesis, which proposed airways reactivity and the concept of protease-anti-protease balance. All of these concepts were suggested at about the same time.

O' Donnel, DE. "Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease". Proc Am Thorac Soc. vol. 3. 2006. pp. 180-4.

Review of the importance of dynamic hyperinflation, which is related to respiratory rate, for exertional dypsnea in COPD.

Rennard, S. "Impact of COPD in North America and Europe in 2000: subjects' perspective of Confronting COPD International Survey". Eur Respir J. vol. 20. 2002. pp. 799-805.

This manuscript describes the findings from a large random phone-based survey of COPD patients. Many of its findings differ from the concepts that derive from populations selected in health care settings. It confirms the high prevalence of limitations that do not engender interactions with the health care system.

Ulrik, CS. "Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma". Eur Respir J. vol. 14. 1999. pp. 892-6.

This prospective study describes the development of fixed airflow limitation in non-smoking asthmatics.

Lange, P. "A 15 year follow-up study of ventilatory function in adults with asthma". New Engl J Med. vol. 339. 1998. pp. 1194-200.

This paper describes the long follow-up of a large cohort of patients with asthma. The progressive loss of lung function, which exceeds that of the non-asthmatic population, is clearly described.

Patel, IS. "Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease". Am J Respir Crit Care Med. vol. 170. 2004. pp. 400-7.

This study utilized CT-scanning to demonstrate that bronchiectasis occurs in patients with COPD much more commonly than can be ascertained by conventional chest radiography.

Mannino, DM. "Global burden of COPD: risk factors, prevalence, and future trends". Lancet. vol. 370. 2007. pp. 765-73.

This paper assesses COPD from a global perspective. The importance of various risk factors is specifically addressed from an epidemiological perspective.

Rennard, SI. "COPD: The dangerous underestimate of 15%". Lancet. vol. 367. 2006. pp. 1216-9.

This brief review highlights the fact that the majority of smokers will develop COPD, a fraction that has not changed in many decades, although individuals do vary in their susceptibility to smoke. However, the often quoted statement that a minority of smokers develop COPD is a misquote from Fletcher et al., who stated that a minority are diagnosed, not that a minority develop the disease.

Silverman, EK, Spira, A, Pare, PD. "Genetics and geneomics of chronic obstructive pulmonary disease". Proc Am Thorac Soc. vol. 6. 2009. pp. 536-542.

This review provides an update on the genes that have been identified as candidate genes for COPD.

Silverman, EK, Sandhaus, RA. "Clinical Practice. Alpha1-antitrypson deficiency". N Engl J Med. vol. 360. 2009. pp. 2749-2757.

This review provides a brief but comprehensive update on the diagnosis and management of alpha 1-antitrypson deficiency.

Yawn, BP, Enright, PL, Lemanske, RJ. "Spirometry can be done in family physicians' offices and alters clinical decisions in management of asthma and COPD". Chest. vol. 132. 2007. pp. 1162-1168.

This study, co-authored by a family physician, a pulmonary physiologist, and colleagues, is one of many studies that have demonstrated the practicality of performing spirometry in the primary care setting.

Swanney, MP, Ruppel, G, Enright, PL. "Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction". Thorax. vol. 63. 2008. pp. 1046-1051.

This review describes the errors that result when a fixed ratio (0.7) for the FEV1/FVC ratio is used to define the threshold to diagnose COPD. Because the parameters change at different rates over a lifetime, the fixed ratio is too low for young individuals and too high for older ones.

Council, MR. "Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphesema. Report of the Medical Research Council Working Party". Lancet. vol. 1. 1981. pp. 681-686.

This was the first classic trial to demonstrate improved survival for hypoxic patients with COPD (who also had evidence of right heart failure) when supplemental oxygen therapy was used at night.

Group, NOTT. "Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial". Ann Intern Med. vol. 93. 1980. pp. 391-398.

This study demonstrated improved survival when individuals who were hypoxic at rest were treated with oxygen continuously, rather than only at night.

Coxson, HO. "Quantitative chest tomography in COPD research: chairman's summary". Proc Am Thorac Soc. vol. 5. 2008. pp. 874-877.

This review describes the use of CT-scanning to assess the lung in COPD. It provides an introduction to the issues related to emphysema quantification and the assessment of airways disease.

Sietsma, K, Mason, RJ, Martin, TR, King, TE, Schraufnagel, DE, Murray, JF, Nadel, JA. "Clinical Exercise Testing". Textbook of respiratory medicine. Saunders. 2010. pp. 554-577.

This chapter provides an overview of cardiopulmonary exercise testing.

Anthonisen, NR, Connett, JE, Kiley, JP. "Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1". JAMA. vol. 272. 1994. pp. 1497-1505.

This paper describes the results of the Lung Health Study, which assessed the effects of ipratropium and smoking cessation on the rate of lung function loss in patients with moderately severe (current GOLD classification) COPD. Ipratropium had no effect, but smoking cessation slowed the rate of lung function loss to that of a life-long non-smoker.

Kohansal, R, Martinez-Camblor, P, Agusti, A, Buist, AS, Mannino, DM, Soriano, JP. "The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort". Am J Respir Crit Care Med. vol. 180. 2009. pp. 3-10.

This paper describes the lung function changes in the Framingham cohort and confirms the general finding of Fletcher et al. that smoking is associated with a more rapid rate of lung function loss. Cessation slowed the rate of loss, but the effect was largest among younger (and more mildly affected) individuals.

"The health benefits of smoking cessation: a report of the Surgeon General". Department of Health and Human Services (US). 1990. pp. 90-8416.

Fiore, MC. "Treatment Tobacco Use and Dependence: 2008 Update". Department of Health and Human Services. 2008.

This is one of a series of Surgeon General's reports that deal with the subject of smoking. Although a bit out of date, it provides a comprehensive review of the benefits of smoking cessation. Subsequent studies have only confirmed the benefits, although additional benefits have been described.

Tashkin, D, Kanner, R, Bailey, W. "Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebo-controlled, randomised trial". Lancet. vol. 357. 2001. pp. 1571-1575.

This study specifically assesses the benefits of buprorion on smoking cessation in patients with COPD. While quit rates were lower than those in a general population, suggesting the COPD patients may have more difficulty quitting, buproprion was efficacious and the population was not "refractory."

Tashkin, DP, Rennard, S, Hays, JT, Ma, W, Lawrence, D, Lee, TC. "Effects of varenicline on smoking cessation in patients with mild to moderate COPD; a randomized controlled trial". Chest. vol. 139. 2011. pp. 591-599.

This study describes the benefits of varenicline in a population of COPD patients. As with other trails in COPD patients, the placebo quit rate was lower than that observed in other varenicline trials. The varenicline-treated group quit with a success rate similar to that observed in general population studies.

Celli, BR, Thomas, NE, Anderson, JA. "Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study". Am J Respir Crit Care Med. vol. 178. 2008. pp. 332-338.

This study provides a detailed analysis of the effect of treatment on the rate of FEV1 decline in the TORCH study, a 6000-subject, 3-year trial that compared salmeterol, fluticasone and the combination with placebo. Each component and the combination reduced FEV1 by 13, 13, and 16 ml/year ,respectively, all of which were statistically significant.

Decramer, M, Celli, B, Kesten, S, Lystig, T, Mehra, S, Tashkin, DP. "Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial". Lancet. vol. 374. 2009. pp. 1171-1178.

This paper describes the benefits of tiotropium compared to placebo in a sub-set of patients in the UPLIFT trial, a 6000-subject ,4-year trial. While there was no significant effect of tiotropium in the entire population, there was a 6 ml reduction (p<0.05) among those with moderate disease (FEV1>50% predicted).

Dahl, R, Backer, V, Ollgaard, B, Gerken, F, Kesten, S. "Assessment of patient performance of the HandiHaler compared with the metered dose inhaler four weeks after instruction". Respir Med. vol. 97. 2003. pp. 1126-1133.

This study describes the poor performance patients manifest for inhaler device use and highlights the need for continual education. A number of similar studies have found similar results.

Calverley, PM, Burge, PS, Spencer, S, Anderson, JA, Jones, PW. "Bronchodilator reversibility testing in chronic obstructive pulmonary disease". Thorax. vol. 58. 2003. pp. 659-664.

This study compared the bronchodilator response to inhaled albuterol administered on multiple occasions in a clinical trial. There was considerable variability in the response of an individual over time.

Taylor, DR, Buick, B, Kinney, C, Lowry, RC, McDevitt, DG. "The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction". Am Rev Respir Dis. vol. 131. 1985. pp. 747-751.

This study administered theophylline, albuterol, or a combination of the two and assessed airflow and patient preference. Airflow improvements were minimal with theophylline, but there was substantial patient preference for the theophylline-containing regimens. This result supports the concept that theophylline has benefits in addition to improving airflow.

Ries, AL, Bauldoff, GS, Carlin, BW. "Pulmonary medicine rehabilitation: Joint ACCP/AACVPR evidence-based clinical practice guidelines". Chest. vol. 131. 2007. pp. 4S-42S.

This is a comprehensive guideline and review on pulmonary rehabilitation.

Nici, L, Donner, C, Wouters, E. "American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation". Am J Respir Crit Care Med. vol. 173. 2006. pp. 1390-1413.

This is a second comprehensive guideline and review on pulmonary rehabilitation.

Ries, AL, Kaplan, RM, Limberg, TM, Prewitt, LM. "Effects of pulmonary rehabilitation of physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease". Ann Intern Med. vol. 122. 1995. pp. 823-832.

This study compared a rehabilitation program that contained exercise with an education program alone. The exercise program improved performance, while the education program did not.

Casaburi, R, Kukafka, D, Cooper, CB, Witek, TJ, Kesten, S. "Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD". Chest. vol. 127. 2005. pp. 809-817.

This study randomized subjects to receive either tiopropium or placebo. After four weeks, there was a modest improvement in exercise performance in tiotropium-treated subjects. All subjects then underwent comprehensive rehabilitation. The placebo group improved much more with rehab than the tiotropium-treated group improved with medicaioin. However, the tiotropium-treated group further improved with rehab by an amount that was greater than that achieved in the placebo group. This result supports a beneficial interaction between tiotropium treatment and rehabilitation.

Qaseem, A, Wilt, TJ, Weinberger, SE. "Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and the European Respiratory Society". Ann Intern Med. vol. 155. 2007. pp. 179-191.

This brief update on diagnosis and treatment of COPD, which specifically addresses the issue of who should be assessed by spirometry, provides an overview for therapeutic approaches.

Calverley, PM, Rabe, KF, Goehring, UM, Kristiansen, S, Fabbri, LM, Martinez, FJ. "Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials". Lancet. vol. 374. 2009. pp. 685-694.

This paper describes the results of the two pivotal clinical trials that supported the approval of roflumilast for the treatment of COPD in the United States and Europe.

Fishman, A, Martinez, F, Naunheim, K. "A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema". N Engl J Med. vol. 348. 2003. pp. 2059-2073.

This paper describes the results of the NETT study, which compared volume reduction surgery with medical treatment. Surgery was superior for those with localized upper lobe disease and a poor response to rehabilitation, while medical treatment was better for those with diffuse disease.

Calverley, PM, Anderson, JA, Celli, B. "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease". N Engl J Med. vol. 356. 2007. pp. 775-789.

This paper describes the primary outcome date for TORCH, which assessed the effect of fluticasone, salmeterol, and the combination of the two on survival in COPD. A 17 percent reduction in mortality was observed in the combination compared to placebo that did not achieve statistical significance (p=0.052).

Tashkin, DP, Celli, B, Senn, S. "A 4-year trial of tiotropium in chronic obstructive pulmonary disease". N Engl J Med. vol. 359. 2008. pp. 1543-1554.

This paper describes the primary results from the TORCH study. An effect of tiotropium on the rate of lung function decline was not observed. Although not the primary outcome, a statistically significant reduction in mortality was observed at the end of the treatment, although this significance was lost with evaluation one month later.

Spencer, S, Jones, PW. "Time course of recovery of health status following an infective exacerbation of chronic bronchitis". Thorax. vol. 58. 2003. pp. 589-593.

This paper describes the changes in health status (SGRQ) following COPD exacerbation. Health status improved substantially, approximately three-fold more than the four units that define clinical importance in the first month after the exacerbation. Between three and six months after the exacerbation, health status continues to improve by a difference that approaches four units, which is consistent with a long convalescence following an exacerbation.

Hurst, JR, Vestbo, J, Anzueto, A. "Susceptibility to exacerbation in chronic obstructive pulmonary disease". N Engl J Med. vol. 363. pp. 1128-1138.

This paper describes observations made in the ECLIPSE study, in which individuals who manifest two or more exacerbations in a year appear to be a stable phenotype. This result supports the concept that some COPD patients are frequent exacerbators.

Mannino, DM, Buist, AS, Petty, TL, Enright, PL, Redd, SC. "Lung function and mortality in the United States: data from the first National Health and Nutrition Examination Survey follow up study". Thorax. vol. 58. 2003. pp. 388-393.

This study evaluates the causes of death in patients with COPD using data from an epidemiologic database. Cardiac disease is the most important cause.

Celli, BR, Cote, CG, Marin, JM. "The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease". N Engl J Med. vol. 350. 2004. pp. 1005-1012.

This paper describes the development of a multi-component index that is better than individual measures at predicting survival in COPD.
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