What every physician needs to know:

Chronic obstructive pulmonary disease (COPD) refers to all lung diseases characterized by a decrease in expiratory airflow that is not completely reversible.

The term is usually employed in describing increased resistance to airflow in the small airways caused by excessive inflammation following chronic exposure to noxious inhaled substances. In contrast, asthma, although also a disease characterized by chronic obstruction to airflow, entails reversible airway inflammation that occurs in response to environmental antigens.

In COPD, the obstruction is expiratory in nature since airway resistance is greatest during the end of expiration, when the small airway lumen has the smallest diameter and offers the greatest resistance. This issue is important with regard to both symptoms and management outcomes.

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Although COPD exists in those who have never smoked and does occur in patients under age forty-five, the overwhelming majority of cases arise in the fifth and sixth decades of life and are related to chronic cigarette smoke exposure. Dust exposure results in a similar risk of developing COPD compared to that of exposure to biomass fuel smoke or cigarette smoke.

Although rare, genetic causes, specifically alpha-1 anti-trypsin (A1AT) deficiency should be ruled out in newly diagnosed COPD, as specific intervention may be offered for this disorder.


Chronic bronchitis

Chronic bronchitis is defined as cough or sputum production for at least three months per year for two or more years. Sputum production, which predominantly reflects inflammation of the medium and large airways, tends to be directly related to the irritating effects of ongoing smoke. Many studies suggest that smokers with chronic bronchitis and normal lung function are more likely to progress to COPD than those without chronic bronchitis. Smoking cessation may result in resolution of chronic bronchitis and reduction in the risk of progression to COPD. Compared to COPD patients without chronic bronchitis, patients with chronic bronchitis have a greater risk of exacerbations and disease progression and tend to be current smokers.


Emphysema is defined as permanent enlargement of alveolar spaces because of the destruction of alveolar walls. The pathologic changes are irreversible and are due to proteolytic destruction of the matrix framework of the alveoli. The loss of alveoli structure reduces lung elastic recoil, decreases the ability of the lung to tether open the small airways, and obliterates the pulmonary microcirculation involved in gas exchange. Patients with the emphysematous form of COPD generally have more dyspnea and weight loss and a greater risk for development of lung cancer than do COPD patients without emphysema.

Smoking-induced bronchiolitis

Smoking-induced bronchiolitis is defined as inflammation of the small airways associated with smoke exposure. It spans a spectrum from modest changes in small airway function to respiratory bronchiolitis-interstitial lung disease (RB-ILD). The small airways appear to be the first site of inflammation in young, otherwise healthy smokers; they also appear to be the initial area of airway remodeling in COPD. Functional loss of small airways probably occurs prior to development of emphysema.

Alpha-1 anti-trypsin (A1AT)-deficient emphysema

Alpha-1 anti-trypsin deficient emphysema is due to deficiency of the most abundant serum protease inhibitor (A1AT), resulting in significantly increased risk for both smoke- and occupation-induced COPD. A1AT deficiency commonly occurs at a younger age (the fourth or fifth decades) than typical COPD and results in a more homogeneous pattern of emphysema. A1AT deficiency may present with symptoms of asthma (in the absence of atopy) or bronchiectasis, even when emphysema is not severe. Severe A1AT deficiency is easily excluded by testing serum A1AT levels. Carriers of the more severe “Z” mutation appear to be at increased risk of smoking-related COPD than non-carriers.

Although each of these entities may be considered separate and distinct, they usually occur together, with one or more predominating in affected individuals.

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

The most common clinical manifestations of COPD, as discussed in detail elsewhere include:

  • Exertional dyspnea

  • Cough

  • Sputum production

  • Wheeze

  • Chest tightness/chest pain

  • Anorexia/weight loss

  • Spontaneous pneumothorax

  • Unexpected hypoxemia

Beware: there are other diseases that can mimic COPD:

The differential diagnosis of COPD is broad, and it includes many considerations, among them:

  • Asthma

  • Heart failure

  • Coronary artery disease

  • Bronchiectasis

  • Atypical pneumonia

  • Tuberculosis

  • Physical deconditioning

  • Restrictive lung diseases (including sarcoidosis and idiopathic pulmonary fibrosis)

  • Chronic fungal or atypical mycobacterial lung infections

  • Bronchiolitis

How and/or why did the patient develop COPD?

In developed countries, the predominant risk factor for development of COPD is cigarette smoking. According to the National Health and Nutrition Examination Survey (NHANES), dust and fumes may also cause COPD. After smoking and other confounders are accounted for, a slightly increased incidence of COPD is seen in certain occupations, including construction, plastics manufacturing, and utility work.

Only about 5 percent of physician-diagnosed COPD occurs in non-smokers. COPD in non-smokers is more common in those with asthma and in older individuals.

A key question in the pathogenesis of COPD is why so many people with significant exposure to known causes are spared the disease. Studies clearly show an increase in macrophage-predominant inflammation in the alveolar spaces and terminal bronchioles of current smokers. However, only 20 percent or fewer of chronic smokers develop symptomatic COPD. The current theory is that environmental, developmental, and genetic risk factors combine to create susceptibility to enhanced lung inflammation and failure of defenses against lung destruction (Figure 1).

Figure 1.

Molecular mechanisms of COPD Pathogenesis. Chronic exposure to noxious stimuli like cigarette smoke produces differential effects on multiple lung cell types. The complexity of this interaction produces lung remodeling that is both pro-fibrotic in airways and matrix-degrading in the alveolar space. Although we predominantly think of the role of protease production by inflammatory cells in response to cigarette smoke, some of the inter-individual variability in disease presentation likely relates to the effects on the intrinsic lung cells, such as the airway epithelium and fibroblasts. Activation of all cell types result in cytokine production, but airway epithelial cells produce cytokines and growth factors that can result in enhanced matrix synthesis while the alveolar wall fibroblasts undergo senescence and produce proteases. This contributes to the classic remodeling seen in COPD with thickened airway walls with loss of alveolar walls despite the presence of increased inflammatory cells in both locations.

Normal lung function is maximal at eighteen to twenty years of age. Maximal lung function may be significantly decreased by environmental or genetic factors in some asymptomatic individuals. The normal, age-related decline in lung function may be accelerated by environmental toxins like cigarette smoke. Although smoking cessation alters the rate of decline, some former smokers and many older individuals will eventually experience a decline in lung function below the threshold that defines obstructive lung disease. However, the risk of respiratory specific mortality remains low until significant loss of lung function occurs.

Variations in lung development, age-related decline in lung function, and exposure to noxious substances result in variable, age-dependent development of COPD. The nonmeasurability of genetic and environmental effects, along with an ability to estimate tobacco smoke exposure only roughly results in poor accuracy in predicting development of COPD in chronic smokers.

Individual differences in molecular pathogenic mechanisms of smoking-induced lung remodeling likely result in the variation of emphysematous versus airway predominant disease phenotype despite the same inciting cause.

Which individuals are at greatest risk of developing COPD?

Risk factors can be generally classified as environmental and genetic. The relative contribution of each in patients with COPD cannot be defined. Ideally, future studies will permit a directed therapeutic approach, based upon risk for disease progression.

Environmental risk factors for the development of COPD

Although cigarette smoke exposure is the predominant risk factor for development of COPD, occupational exposure to heavy dust or fumes or exposure to smoke from incomplete combustion of biomass fuels like wood smoke are likely to be equally as dangerous. Significant research interest focuses on the relationship between airway hyper-reactivity and development of COPD. Hyper-reactivity appears to occur after obstructive lung disease arises. Whether adolescent asthma and antigen exposure predispose to COPD in adults is unclear.

Chronic cough and sputum production may predict a subset of smokers with increased risk for developing COPD. Whether the quantity of environmental exposure relates to sputum production or cough is unknown; in patients with established COPD, cough and sputum production are more common in current smokers. The role of early-life lung infections as an environmental risk for the development of COPD has been debated. Although there are models of injury during lung development that lead to alveolar hypoplasia, a direct relationship between risk of COPD and common childhood lung infections has not been established.

Longitudinal studies suggest that early smoking by females may have a greater effect on maximal lung development than it does with males, and the effect may continue for a few years longer than it does in men, placing adolescent women at a much lower starting point for lung function before smoking-related declines occur. Whether females are at greater risk of early COPD because of a more rapid decline in function or because of the effects of smoking on lung development is unclear. Multiple studies have suggested a greater prevalence of severe COPD in women. Although women have historically had lower exposures to tobacco smoke and environmental fumes than men, this may change as more adolescent women decide to smoke.

Alpha-one antitrypsin deficiency as a genetic risk for COPD development

The most significant genetic risk factor for development of COPD is deficiency in A1AT (Serpin A1). Although the enzyme inhibits trypsin, its ability to inhibit neutrophil elastase is key to preventing development of lung disease. Neutrophils entering the lungs of patients with A1AT deficiency cause more lung destruction than they do in those without the deficiency because of unopposed enzyme activity in areas of the lung with low inhibitor levels (Figure 2).

Figure 2.

Classical protease/antiprotease imbalance model of COPD pathogenesis. As best defined by emphysema development in A1AT deficiency state, circulating and intrinsic lung cell production of anti-protease molecules results in a shield that protects the structural matrix of the alveolar wall. Increased presence and activation of inflammatory cells (e.g., macrophages and neutrophils) results in increased production of proteases. If this increased protease burden is not accounted for by an equal balance of circulating or local anti-protease, destruction of lung elastin and collagen (black and white lines) will occur. A1AT is one of the most abundant proteins in the circulation and an avid inhibitor of neutrophil elastase. In individuals with normal A1AT levels, there is adequate anti-protease diffusion into the area of the structural matrix to prevent degradation. However, when a genetic deficiency of A1AT reaches a threshold below which smoking-induced protease excess can not be inhibited, destruction of the lung matrix and emphysematous remodeling occurs.

Wide, unexplained variations in disease severity in individuals with comparable levels of A1AT deficiency, even after adjusting for smoking history, demonstrate the daunting task of establishing causality of other genetic polymorphisms of lesser pathogenic impact in the production of lung disease. Subjects suspected of having A1AT deficiency can be easily screened with a simple blood test available at most institutions. There is little reason for limiting screening of appropriate patients for this uncommon–but not rare–genetic disorder.

Differences in the levels of circulating A1AT protein (phenotype) are observed among individuals with the less severe S allele and those with the more severe Z allele. Individuals who have an SZ genotype and an SZ phenotype are at a lower risk for development of COPD than are those with the ZZ phenotype. Individuals heterozygous for A1AT deficiency (MZ genotype) may be at increased risk of accelerated emphysema if they smoke. Genetic testing of family members may assist in counseling regarding smoking cessation and/or avoidance.

Genetic predispositions other than A1AT deficiency for COPD development

Two basic approaches have been utilized to search for other genetic risk factors in subjects with COPD: the candidate gene approach and genome-wide association studies (GWAS):

The candidate gene approach, in which a gene suspected of a disease relationship (based on biologic plausibility) is investigated in a fair-sized cohort, is the more common approach. Important information may be uncovered using this technique, as significant positive findings may be observed even in fairly small cohorts. Unfortunately, failure to confirm positive findings often leads to more speculation regarding the roles of ethnicity, phenotypes, and other factors specific to the population studied. Given the data on phenotypic presentation in A1AT deficiency, this speculation is not surprising.

GWAS have been performed with widespread collections of biologic samples for genetic testing from large cohorts of patients with COPD. This approach, which is not hypothesis-driven, offers unique and often unexpected results. Like the candidate gene approach, GWAS may lead to erroneous conclusions, despite study of large populations. The technique is based on locations of gene polymorphisms, where there are large areas of linkage disequilibrium; therefore, while results may identify a region with a gene that can be potentially implicated in disease pathogenesis, the region may contain other genes related to lung development or smoking behavior.

For example, the leading candidate genes for development of both lung cancer and COPD are members of a gene family of nicotinic acetylcholine receptor alpha chains (CHRNA). However, given the potential for members of this gene family to interact with smoking behavior, causation and risk may be only indirectly related.

Other findings from GWAS suggest that we have overlooked the effect of abnormal lung development on subsequent risk for COPD (and asthma). Some genes discovered as genetic modifiers of COPD risk are also important in determining the heritability of lung function in individuals without disease. An example is the hedgehog interacting protein (HHIP), which is part of a pathway involved in limb patterning and embryonic development. An area near the HHIP gene is associated with both lung disease and a reduction in lung function in individuals with no overt disease. These findings reflect the complexity of the genetic risk for COPD, environmental influences, and our historical use of arbitrary measures (e.g., a fixed ratio of FEV1 to FVC) in defining the presence of disease (Figure 3).

Figure 3.

Lung development can impact the development of COPD and the risk of respiratory-related mortality. Yearly decline in forced expiratory volume at 1 second (FEV1) is generally estimated to be about 50ml per year in non-smokers and 200ml per year in current smokers. Normal individuals may cross a threshold defined as COPD if they survive long enough, but they are unlikely to develop increased respiratory-associated mortality. Retardation of lung growth by genetic and/or early-life environmental factors may accelerate the age at which smoking-dependent loss of lung function results in COPD and increased respiratory mortality. Individuals who have never smoked but who have retarded lung growth may cross the threshold that defines COPD, but given the different rate of decline, may never develop the increased risk of respiratory-related mortality seen in continued smokers. It is unusual for an individual to have knowledge of maximal lung function, so one reason the total exposure (number of pack-years smoked) correlates poorly with disease severity later in life, as defined by population-based surveys, may be developmental lung growth. However, what is most important is that smoking cessation returns the rate of decline to that of age-associated decline and may prevent or at least delay the development of COPD and increased risk of respiratory-associated mortality. This figure is based on cross-sectional survey data and age-related change is likely not as linear as depicted in the figure, and smoking cessation at age thirty may be more likely to revert to never-smoked rates of decline than smoking cessation at age fifty, based on more recent longitudinal studies. Although biomass fuel smoke exposure is less of an environmental hazard in the United States than in other countries, it likely has a consequence similar to that depicted above for tobacco smoke and to be equally as influenced by nutritional deficiency-related lung growth retardation.

With all of these caveats noted, genetic associations suggest that gene variations that influence antioxidants, protease/antiprotease balance, lung development, and cigarette smoking are important contributors to development of COPD. However, none of these suspected genetic modifiers has yet reached a level of clinical applicability to warrant patient screening or counseling to reduce the risk of COPD.

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

No blood test is diagnostic of COPD or useful in excluding it. Similarly, no blood or sputum test is helpful in tailoring or adjusting existing therapy. Studies that look for possible candidates as biomarkers of disease progression are listed in the bibliography. Currently, clinical judgment supersedes existing available laboratory studies in establishing the diagnosis.

If obstructive lung disease is present in the clinical setting of bronchiectasis, immunoglobulin levels, aspergillus serology, A1AT levels, and possibly sweat chloride or rheumatoid factor testing may be indicated for ruling out entities other than cigarette smoking as the predominant cause of obstruction and bronchiectasis. Sputum for non-tuberculous mycobacteria (NTM) may be useful in patients with bronchiectasis and a productive cough; if clinical suspicion of NTM is high, direct sampling with bronchoscopy may be necessary to make the diagnosis.

Symptoms of right heart failure in mild or moderate COPD might suggest concomitant obstructive sleep apnea (overlap syndrome). Right heart failure occurring in more severe COPD may represent pulmonary hypertension. A resting room air arterial blood gas can be performed, and if an elevated PaCO2 is present, symptom-guided additional studies are warranted. Given the high prevalence of cardiovascular disease in patients with COPD, symptoms of right heart failure may also be due to left heart failure. A normal PaCO2 in this setting may suggest need for further cardiac work-up. Resting hypoxemia and hypercarbia are independent prognostic factors predictive of shorter survival in COPD.

The presence of hypoxemia in the setting of severe obstructive lung disease is unpredictable, and the need for supplemental oxygen in severe obstructive lung disease should be considered at baseline as well as when any significant change in clinical status occurs.

Many of the treatments identified to specifically improve COPD are symptomatic but recent studies have demonstrated that reductions in exacerbation frequency can be obtained with several currently available therapeutics. In relation to laboratory testing an elevated eosinophil count has been associated with a higher likelihood of inhaled corticosteroid success in reduction of exacerbations. However, there has been no prospective confirmation of a specific threshold where eosinophil counts can be utilized to guide use of this therapy.

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

Many infectious causes of symptoms similar to those in COPD can be evaluated with a simple CXR (e.g., to rule-out active tuberculosis). However, so-called “classic” radiographic findings of COPD, including increased anterior-posterior diameter and flattened diaphragms, are not specific to the disorder. Many of these changes are seen with normal aging.

Although a CT scan may be useful in ruling out the presence of other lung diseases, the clinical relevance of a radiologic description of mild emphysema on CT is unclear since age-appropriate normals are not available. For example, a chest CT scan reading of emphysema should trigger pulmonary function testing rather than establishment of a diagnosis.

If interstitial lung disease or bronchiectasis is clinically suspected, a thin-section, high-resolution chest CT scan is indicated. Mild bronchiectasis may be seen in both A1AT deficiency and smoking-related COPD. However, moderate or severe bronchiectasis warrants additional evaluation for infectious and non-infectious causes of bronchiectasis other than COPD.

Since most subjects who undergo evaluation for COPD have an increased risk for lung cancer, based on current available data, a “low dose” cancer screening CT scan may be justified. The National Lung Screening Trial (NLST) demonstrated a survival benefit of annual lung CT scans in a population of subjects who were fifty-five years of age or older, had a thirty-pack-year or greater smoking history, and who were within fifteen years of quitting smoking or were still actively smoking.

Although small inflammatory nodules are commonly noted on CT scans performed in smokers and in those living in areas where histoplasmosis is endemic, the NLST included sufficient numbers of subjects in these categories to justify the additional, potentially invasive procedures that will be generated by false-positive scans.

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

The diagnosis of COPD is based on pulmonary function testing. All smokers with dyspnea or symptoms of chronic bronchitis should undergo pre- and post-bronchodilator pulmonary function testing. A reduction in expired airflow is the sina qua non for the diagnosis of COPD. Hence, pulmonary function testing is the cornerstone of establishing the diagnosis and is fundamental in assessing its severity and in predicting mortality. The spirometric standard for COPD is a persistent or permanent reduction of FEV1/FVC below a fixed ratio of 0.7. A growing consensus is that, since patients with severe airflow obstruction may be unable to achieve complete exhalation during a forced expiratory maneuver, measurement of FEV6 (forced expiratory volume at six seconds) may be an adequate surrogate for FEV1/FVC.

Severity of COPD is determined by the magnitude of the reduction in FEV1 compared with normative values based on height, gender, race, and age. Since aging results in a disproportionate decrease of FEV1 relative to FVC, spirometrically defined COPD becomes prevalent in healthy non-smokers who live long enough. Accordingly, some have suggested using the lower limit of normal (LLN) for FEV1/FVC, defining values that comprise the lowest 5 percent of the population as abnormal.

However, this approach does not appear to improve markedly the diagnosis of COPD in otherwise asymptomatic individuals. In fact, evaluation of a population-based cohort indicated that prediction of the rate of subsequent hospitalization for respiratory reasons was higher using the fixed-ratio method than it was using the LLN-based approach. (Presumably, the latter approach is more reflective of indolent disease in asymptomatic individuals.) In addition, post-bronchodilator measurements are preferred in defining obstruction in order to prevent misclassification of reversible disease. Many older, population-based studies did not assess post-bronchodilator measures.

Current guidelines from the Global Initiative on Obstructive Lung Disease (GOLD), which use the fixed-ratio method (FEV1/FVC <0.7) to define airway obstruction, stress the use of post-bronchodilator measurements. Although, in order to avoid overlap with asthma, studies of COPD commonly exclude patients with significant reversibility, those with significant airflow obstruction despite partial reversibility have COPD. In fact, patients with fixed expiratory airflow obstruction commonly demonstrate some reversibility that varies between physician visits. Furthermore, a significant response to methacholine following development of fixed airflow obstruction in COPD is common despite absence of a history of childhood asthma. However, a positive methacholine challenge test or documentation of reversible airflow obstruction does not reliably predict who among asymptomatic smokers will develop COPD with continued smoking.

Since pulmonary fibrosis is more prevalent in smokers, combined pulmonary fibrosis and emphysema (CPFE) may sometimes be present with attendant “pseudo-normalization” of spirometry and lung volumes. For this reason, further work-up of a low DLCO noted in the absence of clear obstructive lung disease may be an indication for a high-resolution chest CT scan.

Once the diagnosis of COPD has been established, patients with severe disease (GOLD Stage IV, FEV1< 30% predicted; see below) may benefit from a test for exercise-associated desaturation or a six-minute walk test. The BODE index, a tool that incorporates measurements of body mass index (B), airflow obstruction (O), dyspnea (D), and exercise capacity (E), utilizes the six-minute walk distance, in conjunction with other common measurements (FEV1, body mass index, and Medical Research Council Dyspnea Score), to predict survival in COPD.

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

Depending on symptoms, additional cardiac or cardiopulmonary exercise testing may be indicated, particularly if spirometry suggests an alternative diagnosis.

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

The diagnosis of COPD is not based on cytologic or genetic studies.

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

Medical Management

Severity in COPD is defined by the degree of expiratory airflow obstruction, expressed as FEV1 as a percent of predicted value. The GOLD stages are defined as Stage I (FEV1% > 80% predicted), Stage II (FEV1% < 80% but > 50% predicted), Stage III (FEV1,% < 50% but >30% predicted), and Stage IV (FEV1%, <30% predicted). Management is based on the stage of disease (Figure 4) (Figure 5) and presence of symptoms and/or exacerbations.

Figure 4.

Figure 5.

For Stage I disease, smoking cessation is the main goal. If smoking cessation is successful at this stage, progression to more severe disease may be prevented and cardiovascular and cancer risks are reduced.

For Stage II disease, smoking cessation and symptomatic therapies are both considered (Figure 5). Symptomatic therapies include both short- and long-acting beta-agonists (LABA) and long-acting anti-muscarinics (LAMA). Although most therapies approved for Stage II disease offer no survival benefit, recent data suggest that, in some patients, some therapies may decrease the frequency of exacerbations and may provide a survival benefit. The longest-acting agents may provide the greatest symptom relief and survival advantage. Therapeutic decisions in Stage II and Stage III disease can be considered with regard to those that improve symptoms alone, those that prevent exacerbations, and those that may be shown to improve survival. With these 3 goals in mind, therapeutic plans can be customized to individual patient needs. In the GOLD guidelines individual needs are based on an A, B, C, D categorization of symptoms and exacerbations that can be achieved with use of objective questionnaires.

Stage IV disease is commonly accompanied by hypoxemia. Treatment of significant hypoxemia (PaO2< 55 mm Hg) with supplemental oxygen provides a survival benefit that is greater for those treated continuously throughout the day than for those treated only nocturnally. Compelling evidence is lacking for use of supplemental oxygen for less severe hypoxemia, even in patients who have severe airflow obstruction and dyspnea. Only patients with significant hypoxemia have improvement in exercise capacity with use of supplemental oxygen.

Chronic nocturnal ventilation may be utilized for symptomatic hypercarbia and may result in clinical improvement; however, its use may not improve the patient’s ability to perform activities of daily living, nor may it confer a survival benefit. Pulmonary rehabilitation should be utilized for any disease stage to improve symptoms and functional capacity.

Surgical Management

For selected patients with severe disease, surgical options may be considered, including lung volume reduction surgery (LVRS) and lung transplantation. Many patients with COPD are not candidates for either procedure for a variety of reasons, including significant comorbidities. However, when utilized appropriately, these approaches may improve quality of life and chances of survival. Smoking cessation is an absolute requirement before consideration of any surgical options.

The mechanism for clinical improvement with LVRS is thought to be related to enhanced lung elastic recoil. Surgical removal of lung areas that have lost elastic recoil reduces hyperinflation in the remaining lung and restores ventilation to preserved parts of the lung that were previously compressed. Safe and successful application of LVRS requires appropriate patient selection: Those with heterogeneous, upper lobe-predominant disease, and a low exercise capacity after completing pulmonary rehabilitation (defined as <gender specific 40th percentile maximum workload – 25W in women, 40W in men) derive the greatest benefit, while individuals with an FEV1 less than 20 percent predicted with either DLCO less than 20 percent predicted or homogeneous emphysema have increased mortality and no benefit. Patients with A1AT deficiency-related emphysema do not benefit from surgery.

Since institution- and surgeon-specific volume are important determinants of outcomes, patients are likely to travel to referral institutions for surgery. Therefore, knowledge of these factors and evaluation of cardiac and other factors related to the ability to tolerate surgery can optimize referral practice. Although subjects with upper-lobe-predominant disease and a high exercise capacity do not gain a mortality benefit, there is sufficient improvement in measures of quality of life to warrant individualized discussions of risk and benefit, given the relatively long survival in otherwise healthy individuals with severe emphysema.

Lung transplantation provides a less clear survival advantage in COPD, when survival on the waiting list was compared with post-transplant survival. In the United States, organ allocation has been adjusted to reflect this fact. However, lung transplantation clearly enhances quality of life in patients with severe COPD who are good surgical candidates. (See Lung Transplantation)

Symptom-Based Therapy

One important factor to take into account is whether the patient experiences frequent acute exacerbations. Frequent exacerbations are generally considered to be three or more exacerbations over the preceding three years. In addition to the incremental morbidity and cost, data suggest that lung function decline is also steeper with frequent exacerbations.

Use of inhaled corticosteroids (ICS) may benefit patients with frequent exacerbations; otherwise, the incremental risk of pneumonia associated with use of ICS, although small, may outweigh their benefit. Elevated blood eosinophil counts may also assist in predicting which patients are more likely to derive exacerbation benefits of inhaled corticosteroids.

Phosphodiesterase-4 (PDE4) inhibitors also appear to benefit patients with chronic bronchitis who experience frequent exacerbations. However, unlike use of ICS, PDE4 inhibitors are suggested only for those with GOLD Stage III or Stage IV disease. Whether there is additional benefit from adding a PDE4 inhibitor to a regimen of ICS and a long-acting beta agonist is unknown. Occasionally use of these medications can be limited by gastrointestinal intolerability and insomnia, anxiety, and weight loss may occur as well. In GOLD Stages III and IV, depression and low body mass index may limit the pool of candidates appropriate for this therapy.

Both ICS and PDE4 inhibitors benefit current smokers and former smokers; hence, smoking does not preclude benefit from anti-inflammatory therapies.

Macrolides may be useful in reducing the frequency of acute exacerbations, but their long-term use may also increase development of drug-resistant mycobacteria and lead to hearing loss. In retrospective analyses macrolides may lack utility in current smokers so use in former smokers is preferred.

Use of Beta Adrenergic Blocking Agents

Because cardiovascular morbidity and mortality are common in COPD, a practical question regarding management concerns whether to tailor therapy for the lung disease to accommodate cardiac concerns, or vice versa. Beta-adrenergic blocking agents provide a survival benefit in coronary artery disease so their use should not be limited in COPD. Furthermore, although use of short-acting bronchodilators as rescue agents may be called into question in the setting of active coronary artery disease, large trials that incorporate the use of long-acting beta agonists and include patients with coronary atherosclerosis provide a clear safety profile and indicate a trend toward survival benefit.

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

Most patients with GOLD Stages I or II disease will not die of respiratory failure but are likely to die of non-respiratory causes before ever reaching GOLD Stage IV.

Generally, survival even in severe COPD is fairly long, so significant disability and morbidity may occur before palliative care decisions are entertained. Although survival predictions can be estimated using rules based on selected parameters, such as the BODE index (discussed previously), a realistic, patient-specific prediction regarding survival is not possible. Clearly, although the presence of hypoxemia or hypercarbia offers additional prognostic information, a formula that incorporates these parameters to predict survival does not exist.

The outcome in COPD may be best viewed with respect to symptomatic improvement in treated versus untreated disease. Most of the single-drug and combination therapies previously discussed provide a clinically significant improvement in quality of life. A discussion of the improvement achieved using pharmacologic agents constitutes an important aspect of patient care, as a patient’s lack of perceived benefit may not only limit the use of medications but also interfere with smoking abstinence. Studies that incorporate longer time frames for evaluating the effect of medications on survival suggest a survival benefit.

What other considerations exist for patients with COPD?

Future therapy for COPD may include adjuvants for lung regeneration.