Chronic Obstructive Pulmonary Disease (COPD)

Practice Essentials

Chronic obstructive pulmonary disease (COPD) is estimated to affect 32 million persons in the United States and is the third leading cause of death in this country.^[1]Patients typically have symptoms of chronic bronchitis and emphysema, but the classic triad also includes asthma or a combination of the above (see the image below).

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Venn diagram of chronic obstructive pulmonary disease (COPD). Chronic obstructive lung disease is a disorder in which subsets of patients may have dom....

Chronic bronchitis is defined clinically as the presence of a chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded).

Emphysema is defined pathologically as an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.

Signs and symptoms

Patients typically present with a combination of signs and symptoms of chronic bronchitis, emphysema, and reactive airway disease. Symptoms include the following:

Cough, usually worse in the mornings and productive of a small amount of colorless sputum
Breathlessness: The most significant symptom, but usually does not occur until the sixth decade of life
Wheezing: May occur in some patients, particularly during exertion and exacerbations

While the sensitivity of physical examination in detecting mild-to-moderate COPD is relatively poor, the physical signs are quite specific and sensitive for severe disease. Findings in severe disease include the following:

Tachypnea and respiratory distress with simple activities
Use of accessory respiratory muscles and paradoxical indrawing of lower intercostal spaces (Hoover sign)
Cyanosis
Elevated jugular venous pulse (JVP)
Peripheral edema

Thoracic examination reveals the following:

Hyperinflation (barrel chest)
Wheezing – Frequently heard on forced and unforced expiration
Diffusely decreased breath sounds
Hyperresonance on percussion
Prolonged expiration
Coarse crackles beginning with inspiration in some cases

Certain characteristics allow differentiation between disease that is predominantly chronic bronchitis and that which is predominantly emphysema. Chronic bronchitis characteristics include the following:

Patients may be obese
Frequent cough and expectoration are typical
Use of accessory muscles of respiration is common
Coarse rhonchi and wheezing may be heard on auscultation
Patients may have signs of right heart failure (ie, cor pulmonale), such as edema and cyanosis

Emphysema characteristics include the following:

Patients may be very thin with a barrel chest
Patients typically have little or no cough or expectoration
Breathing may be assisted by pursed lips and use of accessory respiratory muscles; patients may adopt the tripod sitting position
The chest may be hyperresonant, and wheezing may be heard
Heart sounds are very distant

See Clinical Presentation for more detail.

Diagnosis

The formal diagnosis of COPD is made with spirometry; when the ratio of forced expiratory volume in 1 second over forced vital capacity (FEV₁/FVC) is less than 70% of that predicted for a matched control, it is diagnostic for a significant obstructive defect. Criteria for assessing the severity of airflow obstruction (based on the percent predicted postbronchodilator FEV₁) are as follows:

Stage I (mild): FEV₁ 80% or greater of predicted
Stage II (moderate): FEV₁ 50-79% of predicted
Stage III (severe): FEV₁ 30-49% of predicted
Stage IV (very severe): FEV₁ less than 30% of predicted or FEV₁ less than 50% and chronic respiratory failure

Arterial blood gas (ABG) findings are as follows:

ABGs provide the best clues as to acuteness and severity of disease exacerbation
Patients with mild COPD have mild to moderate hypoxemia without hypercapnia
As the disease progresses, hypoxemia worsens and hypercapnia may develop, with the latter commonly being observed as the FEV₁ falls below 1 L/s or 30% of the predicted value
pH usually is near normal; a pH below 7.3 generally indicates acute respiratory compromise
Chronic respiratory acidosis leads to compensatory metabolic alkalosis

In patients with emphysema, frontal and lateral chest radiographs reveal the following:

Flattening of the diaphragm
Increased retrosternal air space
A long, narrow heart shadow
Rapidly tapering vascular shadows accompanied by hyperlucency of the lungs
Radiographs in patients with chronic bronchitis show increased bronchovascular markings and cardiomegaly

Advantages of high-resolution CT include the following:

Greater sensitivity than standard chest radiography
High specificity for diagnosing emphysema (outlined bullae are not always visible on a radiograph)
May provide an adjunctive means of diagnosing various forms of COPD (eg, lower lobe disease may suggest alpha1-antitrypsin (AAT) deficiency
May help the clinician determine whether surgical intervention would benefit the patient

Other tests are as follows:

Hematocrit – Patients with polycythemia (hematocrit greater than 52% in men or 47% in women) should be evaluated for hypoxemia at rest, with exertion, or during sleep
Serum potassium – Diuretics, beta-adrenergic agonists, and theophylline act to lower potassium levels
Measure AAT in all patients younger than 40 years, in those with a family history of emphysema at an early age, or with emphysematous changes in a nonsmoker (also see Alpha1-Antitrypsin Deficiency).
Sputum evaluation will show a transformation from mucoid in stable chronic bronchitis to purulent in acute exacerbations
Pulse oximetry, combined with clinical observation, provides instant feedback on a patient's status
Electrocardiography can help establish that hypoxia is not resulting in cardiac ischemia and that the underlying cause of respiratory difficulty is not cardiac in nature
The distance walked in 6 minutes (6MWD) is a good predictor of all-cause and respiratory mortality in patients with moderate COPD^{[2, 3]}; patients with COPD who desaturate during the 6MWD have a higher mortality rate than do those who do not desaturate
Two-dimensional echocardiography can screen for pulmonary hypertension
Right-sided heart catheterization can confirm pulmonary artery hypertension and gauge the response to vasodilators

See Workup for more detail.

Management

Smoking cessation continues to be the most important therapeutic intervention for COPD. Risk factor reduction (eg, influenza vaccine) is appropriate for all stages of COPD. Approaches to management by stage include the following:

Stage I (mild obstruction): Short-acting bronchodilator as needed
Stage II (moderate obstruction): Short-acting bronchodilator as needed; long-acting bronchodilator(s); cardiopulmonary rehabilitation
Stage III (severe obstruction): Short-acting bronchodilator as needed; long-acting bronchodilator(s); cardiopulmonary rehabilitation; inhaled glucocorticoids if repeated exacerbations
Stage IV (very severe obstruction or moderate obstruction with evidence of chronic respiratory failure): Short-acting bronchodilator as needed; long-acting bronchodilator(s); cardiopulmonary rehabilitation; inhaled glucocorticoids if repeated exacerbation; long-term oxygen therapy (if criteria met); consider surgical options such as lung volume reduction surgery (LVRS) and lung transplantation

Agents used include the following:

Short-acting beta₂ -agonist bronchodilators (eg, albuterol, metaproterenol, levalbuterol, pirbuterol)
Long-acting beta₂ -agonist bronchodilators (eg, salmeterol, formoterol, arformoterol, indacaterol, vilanterol)
Respiratory anticholinergics (eg, ipratropium, tiotropium, aclidinium, revefenacin)
Xanthine derivatives (ie, theophylline)
Phosphodiesterase-4 Inhibitors (ie, roflumilast)
Inhaled corticosteroids (eg, fluticasone, budesonide): Peripheral blood eosinophil counts may help stratify the likelihood of efficacy.
Oral corticosteroids (eg, prednisone)
Beta₂ -agonist and anticholinergic combinations (eg, ipratropium and albuterol, umeclidinium bromide/vilanterol inhaled)
Beta₂ -agonist and corticosteroid combinations (eg, budesonide/formoterol, fluticasone and salmeterol, vilanterol/fluticasone inhaled)

Pulmonary rehabilitation programs are typically multidisciplinary approaches that emphasize the following:

Patient and family education
Smoking cessation
Medical management (including oxygen and immunization)
Respiratory and chest physiotherapy
Physical therapy with bronchopulmonary hygiene, exercise, and vocational rehabilitation
Psychosocial support

Indications for admission for acute exacerbations include the following:

Failure of outpatient treatment
Marked increase in dyspnea
Altered mental status
Increase in hypoxemia or hypercapnia
Inability to tolerate oral medications such as antibiotics or steroids

See Treatment and Medication for more detail.

References

Pathophysiology

Pathologic changes in chronic obstructive pulmonary disease (COPD) occur in the large (central) airways, the small (peripheral) bronchioles, and the lung parenchyma. Most cases of COPD are the result of exposure to noxious stimuli, most often cigarette smoke. The normal inflammatory response is amplified in persons prone to COPD development. The pathogenic mechanisms are not clear but are most likely diverse. Increased numbers of activated polymorphonuclear leukocytes and macrophages release elastases in a manner that cannot be counteracted effectively by antiproteases, resulting in lung destruction.

The primary offender has been found to be human leukocyte elastase, with synergistic roles suggested for proteinase-3 and macrophage-derived matrix metalloproteinases (MMPs), cysteine proteinases, and a plasminogen activator. Additionally, increased oxidative stress caused by free radicals in cigarette smoke, the oxidants released by phagocytes, and polymorphonuclear leukocytes all may lead to apoptosis or necrosis of exposed cells. Accelerated aging and autoimmune mechanisms have also been proposed as having roles in the pathogenesis of COPD.^{[5, 6]}

Cigarette smoke causes neutrophil influx, which is required for the secretion of MMPs; this suggests, therefore, that neutrophils and macrophages are required for the development of emphysema.

Studies have also shown that in addition to macrophages, T lymphocytes, particularly CD8⁺, play an important role in the pathogenesis of smoking-induced airflow limitation.

To support the inflammation hypothesis further, a stepwise increase in alveolar inflammation has been found in surgical specimens from patients without COPD versus patients with mild or severe emphysema. Indeed, mounting evidence supports the concept that dysregulation of apoptosis and defective clearance of apoptotic cells by macrophages play a prominent role in airway inflammation, particularly in emphysema.^[7]Azithromycin (Zithromax) has been shown to improve this macrophage clearance function, providing a possible future treatment modality.^[8]

In patients with stable COPD without known cardiovascular disease, there is a high prevalence of microalbuminuria, which is associated with hypoxemia independent of other risk factors.^[9]

Chronic bronchitis

Mucous gland hyperplasia (as seen in the images below) is the histologic hallmark of chronic bronchitis. Airway structural changes include atrophy, focal squamous metaplasia, ciliary abnormalities, variable amounts of airway smooth muscle hyperplasia, inflammation, and bronchial wall thickening.

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Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.

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Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells (high-powered vi....

Damage to the endothelium impairs the mucociliary response that clears bacteria and mucus. Inflammation and secretions provide the obstructive component of chronic bronchitis. Neutrophilia develops in the airway lumen, and neutrophilic infiltrates accumulate in the submucosa. The respiratory bronchioles display a mononuclear inflammatory process, lumen occlusion by mucus plugging, goblet cell metaplasia, smooth muscle hyperplasia, and distortion due to fibrosis. These changes, combined with loss of supporting alveolar attachments, cause airflow limitation by allowing airway walls to deform and narrow the airway lumen.

In contrast to emphysema, chronic bronchitis is associated with a relatively undamaged pulmonary capillary bed. The body responds by decreasing ventilation and increasing cardiac output. This V/Q mismatch results in rapid circulation in a poorly ventilated lung, leading to hypoxemia and polycythemia. Eventually, hypercapnia and respiratory acidosis develop, leading to pulmonary artery vasoconstriction and cor pulmonale. With the ensuing hypoxemia, polycythemia, and increased CO₂ retention, these patients have signs of right heart failure and are known as "blue bloaters."

Emphysema

Emphysema is a pathologic diagnosis defined by permanent enlargement of airspaces distal to the terminal bronchioles. This leads to a dramatic decline in the alveolar surface area available for gas exchange. Furthermore, loss of alveoli leads to airflow limitation by 2 mechanisms. First, loss of the alveolar walls results in a decrease in elastic recoil, which leads to airflow limitation. Second, loss of the alveolar supporting structure leads to airway narrowing, which further limits airflow.

Emphysema has 3 morphologic patterns:

Centriacinar
Panacinar
Distal acinar, or paraseptal

Centriacinar emphysema is characterized by focal destruction limited to the respiratory bronchioles and the central portions of the acini. This form of emphysema is associated with cigarette smoking and is typically most severe in the upper lobes.

Panacinar emphysema involves the entire alveolus distal to the terminal bronchiole. The panacinar type is typically most severe in the lower lung zones and generally develops in patients with homozygous alpha1-antitrypsin (AAT) deficiency.

Distal acinar emphysema, or paraseptal emphysema, is the least common form and involves distal airway structures, alveolar ducts, and sacs. This form of emphysema is localized to fibrous septa or to the pleura and leads to formation of bullae (as seen in the images below). The apical bullae may cause pneumothorax. Paraseptal emphysema is not associated with airflow obstruction.

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Gross pathology of advanced emphysema. Large bullae are present on the surface of the lung.

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Gross pathology of a patient with emphysema showing bullae on the surface.

The gradual destruction of alveolar septae (shown in the image below) and of the pulmonary capillary bed in emphysema leads to a decreased ability to oxygenate blood. The body compensates with lowered cardiac output and hyperventilation. This V/Q mismatch results in relatively limited blood flow through a fairly well oxygenated lung with normal blood gases and pressures in the lung, in contrast to the situation in chronic bronchitis. Because of low cardiac output, the rest of the body also suffers from tissue hypoxia and pulmonary cachexia. Eventually, these patients develop muscle wasting and weight loss and are identified as "pink puffers."

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At high magnification, loss of alveolar walls and dilatation of airspaces in emphysema can be seen.

Emphysematous destruction and small airway inflammation

Emphysematous destruction and small airway inflammation often are found in combination in individual patients, leading to the spectrum that is known as COPD. When emphysema is moderate or severe, loss of elastic recoil, rather than bronchiolar disease, is the dominant mechanism of airflow limitation. By contrast, when emphysema is mild, bronchiolar abnormalities are most responsible for the majority of the deficit in lung function. Although airflow obstruction in emphysema is often irreversible, bronchoconstriction due to inflammation accounts for some reversibility. Airflow limitation is not the only pathophysiologic mechanism by which symptoms occur.

Dynamic hyperinflation

Lung volumes, particularly dynamic hyperinflation, have also been shown to play a crucial role in the development of dyspnea perceived during exercise. In fact, the improvement in exercise capacity brought about by several treatment modalities, including bronchodilators, oxygen therapy, lung volume reduction surgery (LVRS), and maneuvers learned in pulmonary rehabilitation, is more likely due to delaying dynamic hyperinflation rather than improving the degree of airflow obstruction.^{[10, 11, 12, 13, 14, 15, 16, 17]}Additionally, hyperinflation (defined as the ratio of inspiratory capacity to total lung capacity [IC/TLC]) has been shown to predict survival better than forced expiratory volume in 1 second (FEV₁).^[7]

References

Etiology

Cigarette smoking

The primary cause of COPD is exposure to tobacco smoke. Overall, tobacco smoking accounts for as much as 90% of COPD risk.

Cigarette smoking induces macrophages to release neutrophil chemotactic factors and elastases, which lead to tissue destruction. Clinically significant COPD develops in 15% of cigarette smokers, although this number is believed to be an underestimate. Age of initiation of smoking, total pack-years, and current smoking status predict COPD mortality.

People who smoke have an increased annual decline in FEV₁: the physiologic normal decline in FEV₁ is estimated to be 20-30 ml/y, but the rate of decline in COPD patients is generally 60 ml/y or greater.

Secondhand smoke, or environmental tobacco smoke, increases the risk of respiratory infections, augments asthma symptoms, and causes a measurable reduction in pulmonary function.

A study by Nagelmann et al concluded that lung function deviation and lung structural changes are present in people who smoke cigarettes before the clinical signs of airway obstruction reveal them.^[18]These changes can be detected by body plethysmography and diffusing capacity measurement with routine spirometry.

Environmental factors

COPD does occur in individuals who have never smoked.^[19]Although the role of air pollution in the etiology of COPD is unclear, the effect is small when compared with that of cigarette smoking. In developing countries, the use of biomass fuels with indoor cooking and heating is likely to be a major contributor to the worldwide prevalence of COPD. Long-term exposure to traffic-related air pollution may be a factor in COPD in patients with diabetes and asthma.^[20]

Airway hyperresponsiveness

Airway hyperresponsiveness (ie, Dutch hypothesis) stipulates that patients who have nonspecific airway hyperreactivity and who smoke are at increased risk of developing COPD with an accelerated decline in lung function. Nonspecific airway hyperreactivity is inversely related to FEV₁ and may predict a decline in lung function.

The data regarding the possible role of airway hyperresponsiveness as a risk factor for the development of COPD in people who smoke are unclear. It is important to note, however, that 60% demonstrate bronchial hyperresponsiveness.^[21]Moreover, bronchial hyperreactivity may result from airway inflammation observed with the development of smoking-related chronic bronchitis. This may contribute to airway remodeling, leading to a more fixed obstruction, as is seen in persons with COPD.

Alpha1-antitrypsin deficiency

Alpha1-antitrypsin (AAT) is a glycoprotein member of the serine protease inhibitor family that is synthesized in the liver and is secreted into the bloodstream. The main purpose of this 394-amino-acid, single-chain protein is to neutralize neutrophil elastase in the lung interstitium and to protect the lung parenchyma from elastolytic breakdown. Severe AAT deficiency predisposes to unopposed elastolysis with the clinical sequela of an early onset of panacinar emphysema. To see complete information on Alpha1-Antitrypsin Deficiency, please go to the main article by clicking here.

AAT deficiency is the only known genetic risk factor for developing COPD and accounts for less than 1% of all cases in the United States. Severe AAT deficiency leads to premature emphysema at an average age of 53 years for nonsmokers and 40 years for smokers.

Nearly 24 variants of the AAT molecule have been identified, and all are inherited as codominant alleles. The most common M allele (PiM) may be found in 90% of people, and homozygous (PiMM) phenotypes produce serum levels within the reference range. The homozygous PiZZ state is the most common deficiency state and accounts for 95% of people in the severely deficient category.

Intravenous drug use

Emphysema occurs in approximately 2% of persons who use intravenous (IV) drugs. This is attributed to pulmonary vascular damage that results from the insoluble filler (eg, cornstarch, cotton fibers, cellulose, talc) contained in methadone or methylphenidate.

The bullous cysts found in association with IV use of cocaine or heroin occur predominantly in the upper lobes. In contrast, methadone and methylphenidate injections are associated with basilar and panacinar emphysema.

Immunodeficiency syndromes

Human immunodeficiency virus (HIV) infection has been found to be an independent risk factor for COPD, even after controlling for confounding variables such as smoking, IV drug use, race, and age.^[22]

Apical and cortical bullous lung damage occurs in patients who have autoimmune deficiency syndrome and Pneumocystis carinii infection. Reversible pneumatoceles are observed in 10-20% of patients with this infection.

Vasculitis syndrome

Hypocomplementemic vasculitis urticaria syndrome (HVUS) may be associated with obstructive lung disease. Other manifestations include angioedema, nondeforming arthritis, sinusitis, conjunctivitis, and pericarditis.

Connective tissue disorders

Cutis laxa is a disorder of elastin that is characterized most prominently by the appearance of premature aging. The disease usually is congenital, with various forms of inheritance (ie, dominant, recessive). Precocious emphysema has been described in association with cutis laxa as early as the neonatal period or infancy. The pathogenesis of this disorder includes a defect in the synthesis of elastin or tropoelastin.

Marfan syndrome is an autosomal dominant inherited disease of type I collagen characterized by abnormal length of the extremities, subluxation of the lenses, and cardiovascular abnormality. Pulmonary abnormalities, including emphysema, have been described in approximately 10% of patients.

Ehlers-Danlos syndrome refers to a group of inherited connective tissue disorders with manifestations that include hyperextensibility of the skin and joints, easy bruisability, and pseudotumors; it has also been associated with a higher prevalence of COPD.

Salla disease

Salla disease is an autosomal recessive storage disorder described in Scandinavia; the disease is characterized by intralysosomal accumulation of sialic acid in various tissues. The most important clinical manifestations are severe mental retardation, ataxia, and nystagmus. Precocious emphysema has been described and likely is secondary to impaired inhibitory activity of serum trypsin.

References

Prognosis

COPD is the third leading cause of death in the United States.^[1]In terms of COPD as the underlying cause of death, absolute mortality rates for US patients aged 25 years or older (2005) were 77.3 deaths per 100,000 males and 56.0 deaths per 100,000 females, or 64.3 persons per 100,000 overall. Internationally, overall mortality rates from COPD vary markedly, from more than 400 deaths per 100,000 males aged 65-74 years in Romania to fewer than 100 deaths per 100,000 population in Japan.

The FEV₁ was used to predict outcome in COPD until other factors were identified to play a role in determining the outcome of COPD patients. These discoveries resulted in the creation of the multidimensional BODE index (body mass index, obstruction [FEV₁], dyspnea [modified Medical Research Council dyspnea scale], and exercise capacity [6MWD]).^[28]This index was developed to assess an individual’s risk of death or hospitalization.

Prognosis is based on a point system, with all 4 factors used to determine the score, as follows:

Body mass index: greater than 21 = 0 points; less than 21 = 1 point
FEV₁ (postbronchodilator percent predicted): greater than 65% = 0 points; 50-64% = 1 point; 36-49% = 2 points; less than 35% = 3 points
Modified Medical Research Council (MMRC) dyspnea scale: MMRC 0 = dyspneic on strenuous exercise (0 points); MMRC 1 = dyspneic on walking a slight hill (0 points); MMRC 2 = dyspneic on walking level ground, must stop occasionally due to breathlessness (1 point); MMRC 3 = dyspneic after walking 100 yards or a few minutes (2 points); MMRC 4 = cannot leave house; dyspneic doing activities of daily living (3 points)
Six-minute walking distance: greater than 350 meters = 0 points; 250-349 meters = 1 point; 150-249 meters = 2 points; less than 149 meters = 3 points

The approximate 4-year survival based on the point system above is as follows:

0-2 points = 80%
3-4 points = 67%
5-6 points = 57%
7-10 points = 18%

The use of a clinical scoring system reinforces that determinants of prognosis in COPD remain multifactorial. Waschki et al argued that objective assessments of physical activity, including 6-minute walk test results, are best able to predict mortality.^[29]However, additional socioeconomic factors also likely play a role in COPD prognosis; for example, a retrospective cohort study highlighted the increased risk of COPD-related mortality in patients who reside in isolated rural areas.^[30]

A study by Sundh et al determined that the Clinical COPD Questionnaire (CCQ), which estimates quality of life in patients with COPD, is effective.^[31]The CCQ identified that heart disease, depression, and underweight status are independently associated with lower health-related quality of life in patients with COPD.

In a multicenter, prospective, observational study of 201 consecutive patients with moderate-to-severe COPD, Martinez-Garcia et al reported that in addition to smoking, pulmonary hypertension, and declining lung function (known risk factors for mortality in patients with COPD),^[32]bronchiectasis (which is common in patients with moderate-to-severe COPD) is independently associated with increased risk of all-cause mortality.^{[32, 33]}

In this study, those who had bronchiectasis were found to be 2.5 times more likely to die than those who did not.^[33]Bronchiectasis remained an independent factor after adjustment for dyspnea, partial pressure of oxygen, body mass index, presence of potentially pathogenic microorganisms in sputum, presence of daily sputum production, number of severe exacerbations and peripheral albumin, and ultrasensitive C-reactive protein concentrations.

References

History

Most patients with chronic obstructive pulmonary disease (COPD) seek medical attention late in the course of their disease. Patients often ignore the symptoms because they start gradually and progress over the course of years. Patients often modify their lifestyle to minimize dyspnea and ignore cough and sputum production. With retroactive questioning, a multiyear history can be elicited.

Patients typically present with a combination of signs and symptoms of chronic bronchitis, emphysema, and reactive airway disease. These include cough, worsening dyspnea, progressive exercise intolerance, sputum production, and alteration in mental status. Symptoms include the following:

Productive cough or acute chest illness
Breathlessness
Wheezing

Systemic manifestations (decreased fat-free mass, impaired systemic muscle function, osteoporosis, anemia, depression, pulmonary hypertension, cor pulmonale, left-sided heart failure

A productive cough or an acute chest illness is common. The cough usually is worse in the mornings and produces a small amount of colorless sputum.

Breathlessness is the most significant symptom, but it usually does not occur until the sixth decade of life (although it may occur much earlier). By the time the FEV₁ has fallen to 50% of predicted, the patient is usually breathless upon minimal exertion. Despite the fact that FEV₁ is the most common variable used to grade the severity of COPD, although it is not the best predictor of mortality.

Wheezing may occur in some patients, particularly during exertion and exacerbations.

The value of patient history and physical examination was addressed in the 2011 update to the American College of Physicians/American College of Chest Physicians/American Thoracic Society/European Respiratory Society (ACP/ACCP/ATS/ERS) guideline for diagnosis and management of stable COPD. According to the 2011 guideline, a history of more than 40 pack-years of smoking was the best single predictor of airflow obstruction; however, the most helpful information was provided by a combination of the following 3 signs^[34]:

Self-reported smoking history of more than 55 pack-years
Wheezing on auscultation
Self-reported wheezing

If all 3 signs are absent, airflow obstruction can be nearly ruled out.^[34]

With disease progression, intervals between acute exacerbations become shorter, and each exacerbation may be more severe. The rate of COPD exacerbations appears to reflect an independent susceptibility phenotype.^[35]

COPD is now known to be a disease with systemic manifestations, and the quantification of these manifestations has proved to be a better predictor of mortality than lung function alone. Many patients with COPD may have decreased fat-free mass, impaired systemic muscle function, osteoporosis, anemia, depression, pulmonary hypertension, cor pulmonale, and even left-sided heart failure. Depression is not uncommon in subjects with COPD.^[36]

In a study by Spitzer et al in Germany, airflow limitation as measured by spirometry was significantly more common in adults with posttraumatic stress disorder than in controls. Results were adjusted for lifestyle, clinical, and sociodemographic factors.^[37]

In addition, COPD appears to increase the risk for mild cognitive impairment (MCI). Investigators from the Mayo Clinic Study of Aging—a population-based, cross-sectional study of 1,927 participants—reported an association between COPD and an increased risk of having MCI, MCI subtypes, and memory loss in elderly patients.^{[38, 39]}They also observed a dose-response relationship between COPD duration and an increased risk for cognitive problems.

The prevalence of MCI was significantly higher in patients with COPD (n = 288) (27%) than in those without COPD (15%), and there was a nearly twofold higher odds ratio (1.87) for MCI in patients with COPD. Moreover, the odds ratio increased from 1.6 in patients with COPD for 5 years or less to 2.1 in those who had COPD for longer than 5 years.^{[38, 39]}

Some important clinical and historical differences may help distinguish between the types of COPD. Classic findings for patients with chronic bronchitis include productive cough with gradual progression to intermittent dyspnea; frequent and recurrent pulmonary infections; and progressive cardiac/respiratory failure with edema and weight gain. Classic findings for patients with emphysema include a long history of progressive dyspnea with late onset of nonproductive cough; occasional mucopurulent relapses; and eventual cachexia and respiratory failure.

References

Approach Considerations

The goal of COPD management is to improve a patient’s functional status and quality of life by preserving optimal lung function, improving symptoms, and preventing the recurrence of exacerbations. Currently, no treatments aside from lung transplantation have been shown to significantly improve lung function or decrease mortality; however, oxygen therapy (when appropriate) and smoking cessation may reduce mortality. Once the diagnosis of COPD is established, it is important to educate the patient about the disease and to encourage his or her active participation in therapy.

Results of a randomized controlled trial showed that a comprehensive disease management strategy, which included a patient education session, a self-treatment plan for exacerbations, and a monthly follow-up call from a case manager, is associated with a lower hospitalization rate and fewer emergency department visits.^[45]A study by Dewan et al determined that a multicomponent disease management program in patients with COPD was cost-effective, saving $593 per patient.^[46]

Indications for intensive care admission are confusion, lethargy, respiratory muscle fatigue, worsening hypoxemia, and respiratory acidosis (pH < 7.30), as well as clinical concern for impending or active respiratory failure. (BiPAP can be done on the floor in some hospitals, including widely in the United Kingdom).

Oral and inhaled medications are used for patients with stable disease to reduce dyspnea and improve exercise tolerance. Most of the medications used are directed at the following 4 potentially reversible causes of airflow limitation in a disease state that has largely fixed obstruction:

Bronchial smooth muscle contraction
Bronchial mucosal congestion and edema
Airway inflammation
Increased airway secretions

Diet

Inadequate nutritional status associated with low body weight in patients with COPD is associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rates. Nutritional support is an important part of comprehensive care in patients with COPD.

Bronchodilation

Bronchodilators are the backbone of any COPD treatment regimen. They work by dilating airways, thereby decreasing airflow resistance. This increases airflow and decreases dynamic hyperinflation. Lack of response in pulmonary function testing should not preclude their use. These drugs provide symptomatic relief but do not alter disease progression or decrease mortality.

Beta2 agonists and cholinergic/muscarinic antagonists

The initial choice of agent remains in debate. Historically, beta2 agonists were considered first line and anticholinergics were added as adjuncts. Not surprisingly, studies have shown combination therapy results in greater bronchodilator response and provides greater relief. Monotherapy with either agent and combination therapy with both are acceptable options. The adverse effect profile may help guide therapy. Generally, long-acting bronchodilators are more beneficial than short-acting ones.^{[2, 11, 16]}

Beta2-agonist bronchodilators activate specific B2-adrenergic receptors on the surface of smooth muscle cells, which increases intracellular cyclic adenosine monophosphate (cAMP) and smooth muscle relaxation. Even patients who have no measurable increase in post-bronchodilator expiratory airflow may benefit from treatment with beta2 agonists. The inhaled route is preferred because it minimizes adverse systemic effects. The adverse effects are predictable and include tachycardia and tremors. Although rare, beta2 agonists may also precipitate a cardiac arrhythmia.

Anticholinergic drugs compete with acetylcholine for postganglionic muscarinic receptors, thereby inhibiting cholinergically mediated bronchomotor tone, resulting in bronchodilation. They block vagally mediated reflex arcs that cause bronchoconstriction. Clinical benefit is gained through a decrease in exercise-induced dynamic hyperinflation. These agents are poorly absorbed systemically and are relatively safe. Reported adverse effects include dry mouth, dry eyes, metallic taste, and prostatic symptoms.

In a study of men with COPD aged 66 years or older from Ontario, Canada, acute urinary retention (AUR) was found to be significantly more prevalent in users of inhaled anticholinergic medications (IACs) than in nonusers. The risk of AUR was higher in patients receiving both short-acting and long-acting IACs than in patients using a single IAC, and evidence of benign prostatic hyperplasia also increased the AUR risk.^[47]

Inhaled delivery of medications is preferred over the oral route to help minimize potential adverse effects. Some patients may have difficulty achieving effective delivery of the medication using a metered-dose inhaler; use of a spacer or nebulizer may be beneficial in these patients.

The use of newly prescribed inhaled long-acting beta-agonist and long-acting anticholinergic drugs for COPD was associated with a 31% increased risk of experiencing a cardiovascular event in a recent nested case-control analysis of a retrospective cohort study. Both agents showed an increased risk of acute coronary syndrome and heart failure, but not arrhythmias or stroke. With both agents, the risk of events was highest within the first 2 or 3 weeks of initiating treatment. There was no significant difference in events between the 2 treatments.^{[48, 49]}

In 2013, the results from the SPARK trial showed that in patients with severe COPD, a once-daily fixed-dose combination of indacaterol (a beta2 agonist) and glycopyrronium (a muscarinic antagonist) can improve lung functioning and reduce exacerbations, as compared with monotherapy with either glycopyrronium or tiotropium (both of which are muscarinic antagonists).^[50]

Also in 2013, indacaterol and tiotropium were shown to be equally effective in a 52-week, randomized, blinded, parallel-group study consisting of more than 3400 patients with severe COPD who had had at least one exacerbation in the past year.^{[51, 52]}Results from use of the 2 agents demonstrated similar improvements in baseline dyspnea and health status, with similar safety profiles.

Patients treated with indacaterol had a 29% higher exacerbation rate, but needed rescue medication less frequently than patients treated with tiotropium.^{[51, 52]}In both groups, improvements were observed from baseline in trough FEV₁ at week 12 (0.114 L with indacaterol and 0.126 L with tiotropium) and at week 52 (0.073 L with indacaterol and 0.092 L with tiotropium).^{[51, 52]}

In 2015, glycopyrrolate was approved as a new respiratory inhalant dosage form. Glycopyrrolate is a long-acting muscarinic antagonist (LAMA) that produces bronchodilation by inhibiting acetylcholine’s effect on muscarinic receptors in the airway smooth muscle. It is available alone (Seebri Neohaler, encapsulated powder for inhalation; Lonhala Magnair, solution for nebulization) and in combination with indacaterol, a long-acting beta2-agonist (Utibron Neohaler).

Approval of indacaterol/glycopyrrolate inhaler was based the FLIGHT1 and FLIGHT2 12-week trials (n=2038) that measured lung function compared with its individual bronchodilator components, as well as placebo. Indacaterol/glycopyrrolate was statistically superior in terms of FEV₁ area under the curve from 0-12 hours compared with its individual components (P< .001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P< .001).^[53]

Glycopyrrolate inhaled/formoterol (Bevespi Aerosphere) is a long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) combination that was approved in April 2016. It is indicated for the long-term, maintenance treatment of airflow obstruction with COPD, including chronic bronchitis and/or emphysema. Approval is based on the PINNACLE trial program, which demonstrated that the glycopyrrolate/formoterol combination inhalant achieved statistically significant improvement in morning predose FEV₁ at 24 weeks (P< .001) compared with the individual components of the combination and placebo.^[54]

Umeclidinium bromide and vilanterol (Anoro Ellipta) is a LAMA and LABA inhalation powder approved by the FDA for long-term maintenance of COPD.^{[55, 56]}Approval was based on a series of dose-ranging studies in more than 2400 patients—two 6-month, placebo-controlled efficacy and safety studies; two 6-month, active-controlled efficacy and safety studies; and a 12-month safety study.^{[56, 57]} This agent carries a boxed warning regarding use of LABAs and an increased risk of asthma-related death.^{[55, 56]}Umeclidinium and vilanterol inhalation powder is not approved for asthma therapy, and it is not meant to be used as rescue therapy for sudden breathing problems (eg, acute bronchospasm). Serious adverse effects include paradoxical bronchospasm, cardiovascular effects, acute narrow-angle glaucoma, and worsening of urinary retention.^{[55, 56]}

Olodaterol inhaled (Stirverdi Respimat) was approved by the FDA in July, 2014, for maintenance bronchodilator treatment in patients with COPD. Olodaterol is a long-acting beta2 agonist (LABA) that activates specific β2-adrenergic receptors on the surface of smooth muscle cells, which increases intracellular cAMP and smooth muscle relaxation. Approval was based on data from more than 3,000 patients with COPD studied over a 48-week period. Results demonstrated the long-term efficacy (eg, improved FEV1 at 0-3 hr and trough FEV1) and safety of once-daily olodaterol 5 mcg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy.^{[58, 59]}

Tiotropium

Although the results of the Understanding Potential Long Term Impacts on Function With Tiotropium (UPLIFT) trial did not show a change in the rate of decline of FEV₁ or mortality when compared with placebo, it did show a significant reduction in the frequency of COPD exacerbations and hospitalizations and an improvement in quality of life.^{[60, 61, 62, 63]}

Evidence is mounting of the efficacy of tiotropium over long-acting beta agonists. Two large, randomized trials have compared tiotropium, salmeterol (Serevent), and placebo.^{[61, 64]}Both studies showed greater improvement in lung function, dyspnea, and quality of life in the tiotropium group versus the salmeterol group. A study by Brusasco et al also showed a delay in first exacerbations and fewer exacerbations per year in the tiotropium group.^[64]

A 1-year, randomized, double-blind, double-dummy, parallel group study by Vogelmeier et al determined that tiotropium is more effective than salmeterol in preventing exacerbations in patients with moderate-to-very-severe COPD.^[65]

Tiotropium is available in a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. For adults, the contents of 1 capsule (18 mcg) are inhaled every day via the HandiHaler device. Contraindications, drug interactions, and adverse effects are similar to those of ipratropium.

A systematic review and meta-analysis by Singh et al of 5 randomized controlled trials of the Respimat tiotropium mist inhaler in patients with COPD found a 52% increased risk of mortality (all cause) versus placebo.^[66]A randomized study comparing the Respimat mist inhaler to the HandiHaler inhalation device is ongoing as of August 2011.

Aclidinium

Aclidinium (Tudorza Pressair), a long-acting, antimuscarinic (M3) metered-dose inhaler was approved by the FDA in July 2012. Approval was based on randomized, placebo-controlled, clinical trials involving 1276 patients aged >40 years with COPD. The mean 12-week predose FEV1 improvements vs placebo were 0.12 L, 0.07 L, and 0.11 L (P< 0.001) in the trials, with a 24-week improvement of 0.13 L in the 6-month trial. Mean peak improvements in lung function (FEV1) assessed after the first dose were similar to those observed at week 12 in each study.^[67]

Umeclidinium bromide

Umeclidinium bromide blocks the action of acetylcholine at muscarinic receptors in the bronchial airways (M3) by preventing increase in intracellular calcium concentration, leading to relaxation of airway smooth muscle. It is available in the United States as a combination inhaled powder with vilanterol (Anoro Ellipta), and is the first once-daily dual bronchodilator approved. It is also available as a single entity inhaler (Incruse Ellipta). Approval for the combination was based on 7 phase III trials including nearly 6,000 patients with COPD. Four 24-week primary efficacy studies (measuring improvement of trough FEV1) and a 52-week long-term safety study were the key studies. Two 12-week exercise/lung function studies provided supportive lung function data and contributed to safety data.^{[68, 69]}

Revefenacin

Revefenacin is a once-daily, long-acting muscarinic antagonist that inhibits smooth-muscle M3 receptors in the airway, leading to bronchodilation. It is indicated for maintenance treatment of COPD. Revefenacin is administered by nebulizer using a mouthpiece. Approval was based on two 12-week, phase III trials including more than 1200 patients with COPD. Revefenacin demonstrated a significant improvement in baseline trough FEV1 compared with placebo in both trials.^[70]

Phosphodiesterase inhibitors

Phosphodiesterase inhibitors increase intracellular cyclic adenosine monophosphate (cAMP) and result in bronchodilation. Additionally, they may improve diaphragm muscle contractility and stimulate the respiratory center.

Theophylline is a nonspecific phosphodiesterase inhibitor and is now limited to use as an adjunctive agent. Theophylline has a narrow therapeutic window with significant adverse effects, including anxiety, tremors, insomnia, nausea, cardiac arrhythmia (particularly multifocal atrial tachycardia), and seizures. It is reserved for patients with hard-to-control COPD or for individuals who are not able to use inhaled agents effectively.

Theophylline is metabolized primarily via the hepatic cytochrome P450 system, a process affected by age, cardiac status, and liver abnormalities. Serum levels of theophylline need to be monitored because of the potential for toxicity. The previously recommended target range of 15-20 mg/dL has now been reduced to 8-13 mg/dL.

Roflumilast (Daliresp) and cilomilast (Ariflo) are second-generation, selective phosphodiesterase-4 inhibitors. They cause a reduction of the inflammatory process (macrophages and CD8⁺ lymphocytes) in patients with COPD. Cilomilast is completely absorbed following oral administration and has a half-life of approximately 6.5 hours. A dose of 15 mg twice daily has been found to be clinically effective. Nausea, presumably of central origin, is the principal adverse reaction. The FDA advisory panel rejected approval of cilomilast in 2002.

Roflumilast was approved by the FDA in 2011 as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. In 2 randomized, double-blind, placebo-controlled, multicenter trials, increased FEV₁ levels were found in patients who received roflumilast, and the rate of COPD exacerbations was reduced by 17% in these patients.^[71]

Endogenous opioids

A study by Gifford et al found that the administration of endogenous opioids modulated the intensity and unpleasantness of breathlessness in patients with COPD.^[72]

Beta-adrenergic antagonists (beta-blockers)

Cardiovascular disease is common in patients with COPD and is a leading cause of mortality; however, use of beta-blockers has been discouraged in these patients due to a perceived risk of bronchospasm and concern about inhibition of beta-agonist medication. However, a study by Short et al of 5977 patients in Scotland found that the addition of a cardioselective beta-blocker to established inhaled treatment did not appear to harm pulmonary function and did reduce COPD exacerbations, hospital admissions, and all cause mortality versus controls over a mean follow-up of 4.35 years.^[73]

References

Smoking Cessation

Smoking cessation continues to be the most important therapeutic intervention for COPD. Most patients with COPD have a history of smoking or are currently smoking tobacco products. A smoking cessation plan is an essential part of a comprehensive management plan.

However, the success rates for cessation programs are low because of the addictive power of nicotine. These rates can also be negatively impacted by such factors as conditioned responses to smoking-associated stimuli, poor education, forceful promotional campaigns by the tobacco industry, and psychological problems, including depression. The process of smoking cessation typically requires multiple interventional approaches, including both pharmacologic and non-pharmacologic modalities, and will likely require multiple attempts to maintain success.

The transition from smoking to not smoking occurs in the following 5 stages:

Precontemplation
Contemplation
Preparation
Action
Maintenance

Smoking intervention programs include self-help, group, health care provider delivered, workplace, and community programs.

Setting a quit date may be helpful. Physicians and other health care providers should participate in setting the target date and follow-up with respect to maintenance.

Successful cessation programs usually use the following resources and tools:

Patient education
A target date to quit
Follow-up support
Relapse prevention
Advice for healthy lifestyle changes
Social support systems
Adjuncts to treatment (ie, pharmacologic agents)

Mottillo et al reported meta-analysis results indicating that intensive behavioral interventions, including (but not limited to) individual counseling and telephone counseling, offer considerable benefit for increasing smoking abstinence.^[74]

Supervised use of pharmacologic agents is an important adjunct to self-help and group smoking cessation programs.

Nicotine is the ingredient in cigarettes primarily responsible for tobacco addiction. Withdrawal from nicotine may cause unpleasant adverse effects, including anxiety, irritability, difficulty concentrating, anger, fatigue, drowsiness, depression, and sleep disruption. These effects usually occur during the first several weeks.

Nicotine replacement therapies after smoking cessation reduce withdrawal symptoms. If a smoker requires his or her first cigarette within 30 minutes of waking, the individual most likely is highly addicted and would benefit from nicotine replacement therapy.

Several nicotine replacement therapies are available.

Nicotine polacrilex (Nicorette, Nicorette Plus) is a chewing gum and has better quit rates than does counseling alone. Nicotine replacement therapy chewing pieces are marketed in 2 strengths (2 mg, 4 mg). An individual who smokes 1 pack per day should use 4-mg pieces. The 2-mg pieces are to be used by individuals who smoke less than 1 pack per day. Instruct patients to chew hourly and also to chew when needed for their initial cravings for 2 weeks. Gradually reduce the amount chewed over the next 3 months.

Transdermal nicotine patches are readily available for replacement therapy. Long-term success rates are 22-42%, compared with 2-25% for placebo. These agents are well tolerated, and the adverse effects are limited to local skin reactions. Nicotine replacement therapy patches are sold under the trade names NicoDerm, Nicotrol, and Habitrol. Each of these products is dosed with a scheduled graduated decrease in nicotine over 6-10 weeks.

The use of the antidepressant bupropion (Zyban) is also effective for smoking cessation. This nonnicotine aid to smoking cessation enhances central nervous system nonadrenergic function. One study demonstrated that 23% of patients sustained cessation at 1 year, compared with 12% who sustained cessation with the placebo. Bupropion may also be effective in patients who have not been able to quit smoking with nicotine replacement therapy.

Another drug used in smoking cessation is varenicline (Chantix). Varenicline is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Its action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Agonistic activity is significantly lower than nicotine.

References

Management of Inflammation

Inflammation plays a significant role in the pathogenesis of COPD. Systemic and inhaled corticosteroids attempt to temper this inflammation and positively alter the course of disease.

The use of systemic steroids in the treatment of acute exacerbations is widely accepted and recommended, given their high efficacy. A meta-analysis concluded that oral and parenteral corticosteroids significantly reduced treatment failure and the need for additional medical treatment and that they increased the rate of improvement in lung function and dyspnea over the first 72 hours.^[75]Note that systemic steroids are not as effective in treating COPD exacerbations as they are in treating bronchial asthma exacerbations.

On the other hand, the use of oral steroids in persons with chronic stable COPD is widely discouraged, given their adverse effects, which include hypertension, glucose intolerance, osteoporosis, fractures, and cataracts. A Cochrane review showed no benefit at low-dose therapy and short-lived benefit with higher doses (>30 mg of prednisolone).^[76]

Inhaled corticosteroids provide a more direct route of administration to the airways and, similar to other inhaled agents, are only minimally absorbed. Consequently, aside from the development of thrush, the systemic adverse effects of these medications at standard doses are negligible. Despite the theoretical benefit, the current consensus is that inhaled corticosteroids do not decrease the decline in FEV₁, although they have been shown to decrease the frequency of exacerbations and improve quality of life for symptomatic patients with an FEV₁ of less than 50%.^[77]

Inhaled corticosteroids are not recommended as monotherapy and should be added to a regimen that already includes a long-acting bronchodilator. The Towards a Revolution in COPD Health (TORCH) trial showed that a combination of an inhaled corticosteroid and a long-acting beta agonist was more beneficial than inhaled corticosteroids alone.^[78]These data suggest that in patients with COPD, inhaled corticosteroids should be used only in conjunction with a long-acting beta agonist.

However, patients treated with inhaled corticosteroids were noted to have an increased rate of pneumonia. The debate continues on the use of inhaled corticosteroids and the risk for pneumonia in patients with COPD. For example, no significant difference in pneumonia risk was found between patients who used inhaled budesonide and those who did not in a study by Sin et al. The authors analyzed data from 7 large clinical trials (n = 7042) of patients with stable COPD who used inhaled budesonide (n = 3801), with or without formoterol (Symbicort or Pulmicort, respectively) or a control regimen (placebo or formoterol alone [Oxis]). Increasing age and decreasing percent of predicted FEV₁ were the only variables that were significantly associated with occurrence of pneumonia.^[79]

Research has demonstrated that blood eosinophil count appears to be a promising biomarker of response to inhaled corticosteroids in patients with COPD. In one study, those patients with elevated eosinophil count reductions in exacerbations with combination inhaled corticosteroids and LABAs, compared with LABAs alone, were 24% in patients with baseline eosinophil counts of greater than or equal to 2% to less than 4%, 32% for those with counts of 4% to less than 6%, and 42% for those with eosinophil counts of greater than or equal to 6%.^[80]Similar results were found in two other studies.^{[81, 82]}

Despite the possible increased risk of pneumonia associated with inhaled corticosteroids, a retrospective cohort study showed that in patients with COPD hospitalized with pneumonia, prior use of inhaled corticosteroids was actually associated with decreased mortality and less mechanical ventilation.^[83]Therefore the benefit of inhaled corticosteroids in selected patients will likely continue to outweigh the risks.

Intravenous steroids are often used in high doses for acute exacerbations in the inpatient setting; recent research suggests that there is likely no benefit of IV over oral steroid formulations in acute exacerbations, and thus IV steroids should be reserved only for those patients unable to tolerate oral intake.

Nonsteroidal anti-inflammatory medications have not been shown conclusively to have any benefit in COPD. No response has been shown to medications targeting interleukin-8 and tumor necrosis factor-alpha. Leukotriene inhibitors commonly used in asthma have also not proven to be beneficial in COPD.

However, macrolide antibiotics have been shown to have anti-inflammatory effects in the airways of COPD patients. More specifically, azithromycin has been shown to improve the phagocytic function of pulmonary macrophages and to be a potent anti-inflammatory.^[8]

Azithromycin is used clinically for its anti-inflammatory effects in patients with cystic fibrosis and in lung transplantation patients with chronic rejection. Furthermore, one study showed that erythromycin reduced the frequency of exacerbations in 109 patients with COPD treated over 12 months.^[84]A subsequent larger randomized controlled trial of 1142 patients showed a slight decrease in COPD exacerbations for patients given azithromycin over 1 year compared with placebo.^[85]However, this study also noted an increase in hearing decrements in the patients receiving azithromycin (25% in the treatment group compared with 20% in the placebo group; P =0.04). The noted side effect combined with the concern for breeding antimicrobial resistance continues to prevent widespread use of azithromycin for prevention of COPD exacerbations.

References

Oxygen Therapy and Hypoxemia

COPD is commonly associated with progressive hypoxemia. Oxygen administration reduces mortality rates in patients with advanced COPD because of the favorable effects on pulmonary hemodynamics.

Long-term oxygen therapy improves survival 2-fold or more in hypoxemic patients with COPD, according to 2 landmark trials, the British Medical Research Council (MRC) study and the US National Heart, Lung and Blood Institute’s Nocturnal Oxygen Therapy Trial (NOTT). Hypoxemia is defined as PaO₂ (partial pressure of oxygen in arterial blood) of less than 55 mm Hg or oxygen saturation of less than 90%. Oxygen was used for 15-19 hours per day.^{[88, 89, 90]}

Therefore, specialists recommend long-term oxygen therapy for patients with a PaO₂ of less than 55 mm Hg, a PaO₂ of less than 59 mm Hg with evidence of polycythemia, or cor pulmonale. Reevaluate these patients 1-3 months after initiating therapy, because some patients may not require long-term oxygen.

Many patients with COPD who are not hypoxemic at rest worsen during exertion. Home supplemental oxygen commonly is prescribed for these patients. Oxygen supplementation during exercise can prevent increases in pulmonary artery pressure, reduce dyspnea, and improve exercise tolerance.

In a 2008 study, however, patients with COPD-related hypoxemia and exertional desaturation who completed a program of pulmonary rehabilitation failed to show any benefit in domestic activity, health-related quality of life, or time spent outside of the home when compared with those who received placebo.^[91]Hence, the benefits of home ambulatory oxygen for this subset of patients remain controversial.

Oxygen therapy generally is safe. Oxygen toxicity from high inspired concentrations (>60%) is well recognized. Little is known about the long-term effects of low-flow oxygen. However, the increased survival and quality-of-life benefits of long-term oxygen therapy outweigh the possible risks of oxygen toxicity.

Carbon dioxide retention from depression of hypoxic drive has been overemphasized. Despite the widely held belief that too much oxygen causes significant respiratory depression, multiple studies in the literature dispute this view. With administration of oxygen, PaCO₂ rises, but not in proportion to the very minor changes in respiratory drive. Carbon dioxide retention is more likely a consequence of ventilation-perfusion mismatching rather than respiratory center depression. While this complication is not common, it is best avoided by titrating oxygen delivery to maintain the PaO₂ at 60-65 mm Hg.

The major physical hazards of oxygen therapy are fires or explosions. Patients, family, and other caregivers must be warned not to smoke. Overall, major accidents are rare and can be avoided by good patient and family training.

The continuous-flow nasal cannula is the standard means of oxygen delivery for the stable hypoxemic patient. It is simple, reliable, and generally well tolerated. Each liter of oxygen flow adds 3-4% to the fraction of inspired oxygen (FiO₂). Nasal oxygen delivery also is beneficial for most mouth-breathing patients. Humidification generally is not necessary when the patient receives oxygen by nasal cannula at flows of less than 5 L/min. (See the images below.)

View Image

Oxygen therapy via nasal cannula.

View Image

Home supplemental oxygen.

Oxygen-conserving devices function by delivering all of the supplemental oxygen during early inhalation. These devices improve the portability of oxygen therapy and may reduce overall costs. Three distinct oxygen-conserving devices are available: reservoir cannulas, demand-pulse delivery devices, and transtracheal oxygen delivery. Transtracheal oxygen delivery involves the insertion of a catheter percutaneously between the second and third tracheal interspace. Transtracheal oxygen delivery is invasive and requires special training for the physician, the patient, and the caregiver. The procedure has risks as well as medical benefits but has limited application.

NIPPV for hypercapneic respiratory failure

Noninvasive positive-pressure ventilation (NIPPV), as the name suggests, allows the delivery of positive-pressure ventilation without the use of an endotracheal tube. In place of the tube is a tight-fitting nasal or facial mask that is attached to a continuous positive airway pressure (CPAP) or a bilevel positive airway pressure (BiPAP) machine (as seen below). The positive pressure is beneficial in hypercapneic respiratory failure by decreasing the work of breathing, allowing a larger tidal volume for a given respiratory effort, and hence improving alveolar ventilation.^[92]

View Image

Bilevel positive airway pressure (BiPAP).

NIPPV has been shown to provide significant benefits in selected patients with acute hypercapneic respiratory failure due to COPD, including a reduction in the need for endotracheal intubation, reduced hospital stay, and a mortality benefit.^{[93, 94]}This modality should not be used in patients who are unable to protect their airway, are hemodynamically unstable, have significant secretions, are uncooperative, or have an Acute Physiology and Chronic Health Evaluation (APACHE) score of greater than 29.^[95]

Another study suggests that in patients with chronic hypercapneic respiratory failure who are undergoing pulmonary rehabilitation, nocturnal NIPPV may improve quality of life, daytime PaCO₂, and exercise tolerance.^[88]

References

Long-term Monitoring

Follow-up

Disposition after an AECOPD depends on the clinical picture for each patient more than on any single laboratory value or test. In general, the longer the exacerbation, the more airway edema and debris are present. Nearly all discharged patients should receive a short steroid burst and an increase in the frequency of inhaler therapy. Close follow-up should be arranged with the patient's regular care provider. Other therapies should be considered on a case-by-case basis.

Additional follow-up recommendations are as follows:

Patients with severe or unstable disease should be seen monthly
When their condition is stable, patients may be seen biannually
Check theophylline level with each dose adjustment, when interacting medications are added, and routinely every 6-12 months
For patients on home oxygen, check arterial blood gases (ABGs) yearly or with any change in condition
Monitor oxygen saturation more frequently than ABGs

Pulmonary rehabilitation

Many patients with COPD are unable to enjoy life to the fullest because of shortness of breath, physical limitations, and inactivity. Pulmonary rehabilitation encompasses an array of therapeutic modalities designed to improve the patient's quality of life by decreasing airflow limitation, preventing secondary medical complications, and alleviating respiratory symptoms. The 3 major goals of the comprehensive management of COPD are the following:

Lessen airflow limitation
Prevent and treat secondary medical complications (eg, hypoxemia, infection)
Decrease respiratory symptoms and improve quality of life

Successful implementation of a pulmonary rehabilitation program usually requires a team approach, with individual components provided by healthcare professionals who have experience in managing COPD (eg, physician, dietitian, nurse, respiratory therapist, exercise physiologist, physical therapist, occupational therapist, recreational therapist, cardiorespiratory technician, pharmacist, psychosocial professionals). This multidisciplinary approach emphasizes the following:

Patient and family education
Smoking cessation
Medical management (including oxygen and immunization)
Respiratory and chest physiotherapy
Physical therapy with bronchopulmonary hygiene, exercise, and vocational rehabilitation
Psychosocial support

As a result of rehabilitation, improvements have been shown in objective measures of patients’ quality of life, well-being, and health status, including reduction in respiratory symptoms, increases in exercise tolerance and functional activities (eg, walking), reduction in anxiety and depression, and increases in feelings of control and self-esteem.

An observational study has shown that pulmonary rehabilitation also improves the BODE index score in patients with COPD and is associated with better outcomes.^[101]Quality of life improvements after pulmonary rehabilitation can also be measured using the COPD Assessment Test (CAT), an 8-question patient-completed instrument.^[102]In addition, pulmonary rehabilitation results in substantial savings in health care costs by reducing hospitalizations and the use of medical resources.

Pulmonary rehabilitation programs usually are conducted in an outpatient setting. A rehabilitation program may include a number of components and should be tailored to the needs of the individual patient. Provide all patients who complete the program with guidelines for continuing at home.

Education is key to comprehensive pulmonary rehabilitation. The educational component prepares the patient and family to be actively involved in providing care. This reliance on patients to assume charge of their care is known as collaborative self-management.

Exercise training is a mandatory component of pulmonary rehabilitation. Patients with COPD should perform aerobic lower extremity endurance exercises regularly to enhance performance of daily activities and reduce dyspnea. Upper extremity exercise training improves dyspnea and allows increased activities of daily living requiring the use of upper extremities.

Breathing retraining techniques (eg, diaphragmatic, pursed lip breathing) may improve the ventilatory pattern and prevent dynamic airway compression.

View Image

Pulmonary rehabilitation.

Special concerns

Many commercial airplanes fly at altitudes of 30,000-40,000 feet. However, the cabin is pressurized to an altitude of 5000-8000 feet. At these altitudes, atmospheric partial pressure of oxygen (PO₂) is 132-109 mm Hg, compared with 159 mm Hg at sea level.

Acute reduction in PO₂ stimulates peripheral chemoreceptors, which results in hyperventilation. When determining whether or not a COPD patient can safely fly, the clinician should first use a prediction equation to determine whether the patient will become hypoxemic at high altitudes. A prediction equation used to estimate PaO₂ at 8000 feet (2440 m) is as follows:

PaO₂ = 22.8 - 2.74X + 0.68Y

(X = altitude; Y = arterial PO₂ at sea level)

A predicted PaO₂ of 50 mm Hg or less at an altitude of 8000 feet is an indication for supplemental oxygen. Arrange supplemental oxygen prior to the flight directly through the airline or through the airline agent (at an extra expense). If there is any question regarding the calculation, many pulmonary physiology labs can also perform altitude simulation tests to confirm or refute the need for in-flight oxygen.

Patients with COPD may develop substantial decreases in nocturnal PaO₂ during all phases of sleep, but particularly during the rapid eye movement phase. These episodes are associated initially with a rise in pulmonary arterial pressures and a disturbance in sleep architecture, but they may develop into pulmonary arterial hypertension and cor pulmonale if hypoxemia remains untreated.

Prescribe oxygen for patients who have daytime PaO₂ greater than 60 mm Hg but who demonstrate substantial nocturnal hypoxemia.

References

Management Guidelines

GOLD guidelines

The 2018 clinical practice guidelines from the GOLD report on COPD are summarized.^{[105, 109]}

Diagnosis and initial assessment recommendations are as follows:

COPD should be considered in any patient with dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors.
Spirometry is required to make the diagnosis; a postbronchodilator FEV₁/FVC ratio of less than 0.70 confirms the presence of persistent airflow limitation.
COPD assessment goals are to determine the level of airflow limitation, the impact of disease on the patient’s health status, and the risk of future events (eg, exacerbations, hospital admissions, death) to guide therapy.
Concomitant chronic diseases occur frequently in COPD patients and should be treated because they can independently affect mortality and hospitalizations.

Prevention and maintenance therapy recommendations are as follows:

Smoking cessation is key. Pharmacotherapy and nicotine replacement increase long-term smoking abstinence rates, as do legislative bans on smoking. The effectiveness and safety of e-cigarettes as a smoking cessation aid is uncertain.
Pharmacologic therapy can reduce the symptoms of COPD, can reduce the severity and frequency of exacerbations, and can improve exercise tolerance and health status.
Pharmacologic treatment regimens should be individualized. They should be guided by symptom severity; exacerbation risk; adverse effects; comorbidities; drug availability and cost; and patient response, preference, and ability to utilize the various drug delivery devices.
Inhaler technique should be assessed regularly.
Pneumococcal and influenza vaccinations decrease the incidence of lower respiratory tract infections.
Pulmonary rehabilitation improves symptoms, physical and emotional participation in everyday activities, and quality of life.
Patients with severe resting chronic hypoxemia have improved survival with long-term oxygen therapy.
In patients with stable COPD and resting or exercise-induced moderate desaturation, routine long-term oxygen treatment is not recommended; however, consider individual patient factors regarding the need for supplemental oxygen.
With severe chronic hypercapnia and a history of hospitalization for acute respiratory failure, long-term noninvasive ventilation may prevent rehospitalization and decrease mortality.
Select patients with advanced emphysema refractory to optimized medical care may benefit from surgical or bronchoscopic interventional treatments.
In advanced COPD, palliative approaches are effective in controlling symptoms.

Stable COPD recommendations are as follows:

In stable COPD, base the management strategy on an individualized assessment of the symptoms and risk of exacerbations.
Strongly urge smoking cessation in patients who smoke.
Treatment goals are symptom reduction and reduction in future exacerbations. Pharmacologic treatments should be complemented by nonpharmacologic interventions.

Exacerbation recommendations are as follows:

A COPD exacerbation is defined as acute respiratory symptom worsening with the need for additional therapy. Several factors can lead to an exacerbation, the most common being respiratory tract infections.
The recommended initial bronchodilators to treat an exacerbation are short-acting beta2-agonists, with or without short-acting anticholinergics.
As soon as possible before hospital discharge, initiate maintenance therapy with a long-acting bronchodilator.
Systemic corticosteroids can improve lung function and oxygenation. They also shorten recovery time and hospital duration. The duration of systemic corticosteroid therapy should not exceed 5-7 days.
If indicated, antibiotic therapy can shorten recovery time, reduce the risk of early relapse and treatment failure, and reduce hospitalization duration. The duration of antibiotic therapy should not exceed 5-7 days.
Owing to increased adverse effect profiles, methylxanthines are not recommended.
The first mode of ventilation used in COPD with acute respiratory failure and without contraindications is noninvasive mechanical ventilation. It improves gas exchange, reduces the work of breathing, decreases the need for intubation, decreases hospitalization duration, and improves survival.

COPD and comorbidity recommendations are as follows:

Treat COPD comorbidities with the usual standard of care, regardless of the presence of COPD. COPD treatment should not be altered by the presence of comorbidities.
Lung cancer is a common comorbidity with COPD and is a main cause of mortality.
Cardiovascular disease is an important frequent COPD comorbidity, as are osteoporosis and anxiety/depression. The latter two are underdiagnosed and associated with poor health status and prognosis.
Gastroesophageal reflux disease can increase the risk of exacerbations and poor health status.
Simplicity of treatment and minimization of polypharmacy are emphasized in a multimorbidity and COPD treatment plan.

In the 2016 update of the GOLD guidelines, a rubric is used that assesses symptoms, breathlessness, spirometric classification, and risk of exacerbations to classify patients according to the following groups^[4]:

Group A (low risk/less symptoms): Stage I or II, 1 or fewer exacerbation per year no hospitalization, modified Medical Research Council (mMRC) 0-1 or COPD Assessment Test (CAT) less than 10
Group B (low risk/more symptoms): Stage I or II, 1 or fewer exacerbation per year no hospitalization, mMRC 2 or higher or CAT 10 or higher
Group C (high risk/less symptoms): Stage III or IV, 2 or more per year 1 or more exacerbation with hospitalization, mMRC 0-1 or CAT less than 10
Group D (high risk/more symptoms): Stage III or IV, 2 or more per year 1 or more exacerbation with hospitalization, mMRC 2 or higher or CAT 10 or higher

The GOLD patient group-based management recommendations include the following^[4]:

Group A-D: Reduction of risk factors (influenza and pneumococcal vaccine); smoking cessation; physical activity; short-acting anticholinergic or short-acting beta-adrenergic agonists as needed
Group B: Long-acting anticholinergics or long-acting beta-adrenergic agonists; cardiopulmonary rehabilitation
Group C: Inhaled corticosteroid and long-acting beta-adrenergic agonists or long-acting anticholinergics; cardiopulmonary rehabilitation
Group D: Inhaled corticosteroid and long-acting beta-adrenergic agonists and/or long-acting anticholinergics; cardiopulmonary rehabilitation; long-term oxygen therapy (if criteria met); consider surgical options such as lung volume reduction surgery (LVRS)

VA/DoD guidelines

In 2014, the VA/DoD released updated guidelines for the management of COPD.^[106]These guidelines were endorsed with qualifications by the Institute of Clinical Systems Improvement (ICSI) in 2016.^[110]The VA/DoD guidelines classify patients with COPD into the following two groups:

Patients who experience frequent exacerbations (two or more/year, defined as prescription of corticosteroids, prescription of antibiotics, hospitalization, or emergency department visit)
Patients without frequent exacerbations

Major management recommendations include the following:

Prevention and risk reduction efforts include smoking cessation and vaccination
Short-acting beta-adrenergic agonists as needed for rescue therapy
Long-acting bronchodilators to patients with stable COPD who continue to have respiratory symptoms (eg, dyspnea, cough)
Inhaled long-acting antimuscarinic agent (LAMA) tiotropium as first-line maintenance therapy in patients with stable COPD respiratory symptoms (eg, dyspnea, cough) and as first-line therapy for patients with severe airflow obstruction (ie, post bronchodilator FEV₁< 50%) or a history of COPD exacerbations
For clinically stable patients who have not had exacerbations on short-acting antimuscarinic agents (SAMA), continue treatment rather than switch to long-acting bronchodilators (Note: ICSI qualifies this guidance and recommends offering first-line therapy of LAMA but allows for continuance of SAMA if patient preference or cost considerations make it preferred.)
Inhaled corticosteroid should not be used as a first-line monotherapy in symptomatic patients with stable COPD
Combination therapy with long-acting antimuscarinic agent and long-acting beta-adrenergic agonists for patients who have persistent dyspnea on monotherapy; inhaled corticosteroid may be added as a third medication if dyspnea persists or patient experiences exacerbations
Offer pulmonary rehabilitation to stable patients with exercise limitation despite pharmacologic treatment and to patients who have recently been hospitalized for an acute exacerbation

ACP, ACCP, ATS, and ERS joint guidelines

In 2011, the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society issued joint guidelines for the diagnosis and management of stable COPD. The major recommendations include the following^[34]:

In symptomatic patients, use of spirometry to diagnose airflow obstruction; spirometry should not be used to routinely screen for airflow obstruction in asymptomatic individuals (strong recommendation)
Inhaled bronchodilators may be used to treat symptomatic patients with FEV₁ between 60% and 80% predicted (weak recommendation) and for symptomatic patients with FEV₁ less than 60% predicted (strong recommendation)
Monotherapy using either long-acting inhaled anticholinergics or long-acting inhaled beta-adrenergic agonists for symptomatic patients with FEV₁ less than 60% predicted (strong recommendation); choice of specific monotherapy should be based on patient preference, cost, and adverse effect profile
Combination inhaled therapies (long-acting inhaled anticholinergics, long-acting inhaled beta-adrenergic agonists, or inhaled corticosteroids) may be considered for symptomatic patients with FEV₁ less than 60% predicted (weak recommendation)
Pulmonary rehabilitation for symptomatic patients with an FEV₁ less than 50% predicted (strong recommendation); pulmonary rehabilitation may be considered for symptomatic or exercise-limited patients with an FEV₁ greater than 50% predicted (weak recommendation)
Continuous oxygen therapy in patients who have severe resting hypoxemia (PaO₂ ≤55 mm Hg or SpO₂ ≤88%) (strong recommendation)

References

Acute Exacerbation Guidelines

In 2015, the American College of Chest Physicians and Canadian Thoracic Society released guidelines on the prevention of acute exacerbations of COPD.^[108]

Major recommendations include the following:

The 23-valent pneumococcal vaccine is recommended; however, evidence is insufficient that pneumococcal vaccination prevents COPD acute exacerbations
Administer the influenza vaccine annually
Provide smoking cessation counseling and treatment
Provide pulmonary rehabilitation for those with moderate, severe, or very severe COPD who have had a recent exacerbation
Provide education with a written action plan and case management
For patients with a history of COPD acute exacerbations, education and case management should include direct access to a healthcare specialist at least monthly
Telemonitoring is not beneficial compared with usual care

In patients with moderate-to-severe COPD, recommendations are as follows:

Long-acting beta-2 agonists are beneficial, but LAMAs are superior to prevent moderate-to-severe acute exacerbations
Use a SAMA rather than a short-acting beta2-agonist as monotherapy to prevent acute mild-to-moderate exacerbations
Use a SAMA plus a short-acting beta2-agonist to prevent acute moderate exacerbations of COPD
Use long-acting beta2-agonist monotherapy rather than SAMA monotherapy to prevent acute exacerbations of COPD
Use a LAMA instead of a SAMA to prevent acute moderate-to-severe exacerbations
A combination of a SAMA plus a long-acting beta2-agonist is better than long-acting beta2-agonist monotherapy to prevent acute mild-to-moderate exacerbations

In patients with stable, moderate, severe, and very severe COPD, recommendations are as follows:

A maintenance combination of inhaled corticosteroid and long-acting beta2-agonist therapy is better than corticosteroid monotherapy or beta2-agonist monotherapy to prevent acute exacerbations of COPD

In patients with stable COPD, recommendations are as follows:

Use a maintenance combination of inhaled corticosteroid and long-acting-beta2 agonist therapy or inhaled long-acting anticholinergic monotherapy for acute exacerbations
A maintenance combination of inhaled long-acting anticholinergic, corticosteroid, and long-acting beta2-agonist therapy or inhaled long-acting anticholinergic monotherapy are both effective to prevent acute exacerbations

In patients aged 40 years who are smokers or have a history of smoking, recommendations are as follows:

Use a long-term macrolide to prevent acute exacerbations in patients with moderate-to-severe COPD with a history of one or more moderate or severe exacerbations in the prior year despite optimal maintenance inhaler therapy
In patients with an acute exacerbation, systemic corticosteroids should be given orally or intravenously to prevent hospitalization for subsequent acute exacerbations of COPD in the first 30 days (only) after the initial exacerbation
For patients with moderate-to-severe COPD and chronic bronchitis and a history of at least one exacerbation in the last year, use roflumilast to prevent acute exacerbations
For stable patients, use an oral slow-release theophylline twice daily to prevent acute exacerbations
For patients with moderate-to-severe COPD and two or more exacerbations in the last 2 years, use oral N-acetylcysteine to prevent acute exacerbations
For stable patients who continue to have acute exacerbations in spite of maximal therapy to reduce them, oral carbocysteine should be used to prevent acute exacerbations if available
For those with moderate-to-severe COPD at risk for exacerbations, statins are not recommended to prevent exacerbations

References

What is chronic obstructive pulmonary disease (COPD), and how common is it in the US?What are the signs and symptoms of chronic obstructive pulmonary disease (COPD)?What signs of chronic obstructive pulmonary disease (COPD) are observed in a thoracic exam?Which characteristics differentiate chronic bronchitis and emphysema in patients presenting with chronic obstructive pulmonary disease (COPD)?Which office test is used to diagnose chronic obstructive pulmonary disease (COPD), and what are the stages?How are arterial blood gas (ABG) findings used to determine acuteness and severity of chronic obstructive pulmonary disease (COPD)?Which type of chest radiographs are used in patients with emphysema associated with chronic obstructive pulmonary disease (COPD), and what are the findings?What are the advantages of high-resolution CT scanning in the diagnosis of chronic obstructive pulmonary disease (COPD)?In addition to spirometry and imaging, what additional tests that can be used in the diagnosis of chronic obstructive pulmonary disease (COPD)?What are the management strategies for each stage of chronic obstructive pulmonary disease (COPD)?Which drugs are used to treat chronic obstructive pulmonary disease (COPD)?What are the elements of a pulmonary rehabilitation program in chronic obstructive pulmonary disease (COPD) management?When is hospitalization indicated in patients with chronic obstructive pulmonary disease (COPD)?How common is chronic obstructive pulmonary disease (COPD) in the US, and which conditions are included in the classic triad of COPD?How has our understanding of chronic bronchitis and emphysema in chronic obstructive pulmonary disease (COPD) evolved?How do the GOLD guidelines define chronic obstructive pulmonary disease (COPD)?Which types of medications are used in the treatment of chronic obstructive pulmonary disease (COPD)?What is the pathophysiology of emphysema in chronic obstructive pulmonary disease (COPD)?What is the pathogenesis of chronic obstructive pulmonary disease (COPD)?What is the pathophysiology of chronic bronchitis in chronic obstructive pulmonary disease (COPD)?What are the roles of emphysematous destruction and small airway inflammation in chronic obstructive pulmonary disease (COPD) pathophysiology?What is the role of dynamic hyperinflation in chronic obstructive pulmonary disease (COPD) pathophysiology?What is the role of cigarette smoking in chronic obstructive pulmonary disease (COPD)?Which environmental factors contribute to the development of chronic obstructive pulmonary disease (COPD)?What is the role of airway hyperresponsiveness (Dutch hypothesis) in the development of chronic obstructive pulmonary disease (COPD)?What is alpha1-antitrypsin (AAT), and what is its role in the development of chronic obstructive pulmonary disease (COPD)?How does IV drug use contribute to the development of chronic obstructive pulmonary disease (COPD)?What is the role of immunodeficiency syndromes in the development of chronic obstructive pulmonary disease (COPD)?Which inflammatory processes are associated with chronic obstructive pulmonary disease (COPD)?Which connective tissue disorders are associated with the development of chronic obstructive pulmonary disease (COPD)?What is Salla disease, and how is it associated with the development of chronic obstructive pulmonary disease (COPD)?How prevalent are emphysema and chronic bronchitis in the US, and why is the prevalence of chronic obstructive pulmonary disease (COPD) likely underestimated?What is the worldwide prevalence of chronic obstructive pulmonary disease (COPD)?Is chronic obstructive pulmonary disease (COPD) more common in men or women?What is the prevalence of chronic obstructive pulmonary disease (COPD) in patients with a history of smoking?What is the mortality rate associated with chronic obstructive pulmonary disease (COPD)?What is the BODE index, and how is used to estimate the prognosis of chronic obstructive pulmonary disease (COPD)?Are questionnaires effective in assessing quality of life in patients with chronic obstructive pulmonary disease (COPD)?What are the risk factors for mortality in patients with chronic obstructive pulmonary disease (COPD)?What can patients do to actively manage their chronic obstructive pulmonary disease (COPD)?When do patients with chronic obstructive pulmonary disease (COPD) typically seek treatment, and which signs and symptoms are observed at presentation?According to the COPD guidelines, what 3 signs indicate airflow obstruction in patients presenting with chronic obstructive pulmonary disease (COPD)?How does chronic obstructive pulmonary disease (COPD) progress, and which comorbidities contribute to mortality?What is the role of chronic obstructive pulmonary disease (COPD) in mild cognitive impairment (MCI)?How can the clinical and historical findings be used to differentiate the types of chronic obstructive pulmonary disease (COPD)?Which respiratory findings in a patient with chronic obstructive pulmonary disease (COPD) are associated with severe disease?How do the characteristics of chronic bronchitis and emphysema differ in chronic obstructive pulmonary disease (COPD)?What is the GOLD criteria for staging chronic obstructive pulmonary disease (COPD), and what other staging systems are used in COPD?How is congestive heart failure (CHF) differentiated from chronic obstructive pulmonary disease (COPD)?How is bronchiectasis differentiated from chronic obstructive pulmonary disease (COPD)?How is bronchiolitis obliterans distinguished from chronic obstructive pulmonary disease (COPD)?How is adult-onset asthma distinguished from chronic obstructive pulmonary disease (COPD)?What are the differential diagnoses for Chronic Obstructive Pulmonary Disease (COPD)?What is the defining feature of chronic obstructive pulmonary disease (COPD)?How is the formal diagnosis of chronic obstructive pulmonary disease (COPD) made?Are blood-based biomarkers used in the diagnosis of chronic obstructive pulmonary disease (COPD)?Why is chronic obstructive pulmonary disease (COPD) underdiagnosed in its early stages?How is arterial blood gas (ABG) analysis used to determine the acuteness and severity of chronic obstructive pulmonary disease (COPD)?How is pH level used to assess respiratory compromise in chronic obstructive pulmonary disease (COPD)?Which electrolyte levels should be monitored in patients with chronic obstructive pulmonary disease (COPD)?What is the role of alpha1-antitrypsin (AAT) testing in the workup of chronic obstructive pulmonary disease (COPD)?What are the characteristics of sputum in chronic obstructive pulmonary disease (COPD)?How does B-type natriuretic peptide (BNP) bind?What is the role of B-type natriuretic peptide (BNP) levels in evaluating chronic obstructive pulmonary disease (COPD) exacerbations?What do chest radiographs demonstrate in patients with severe chronic obstructive pulmonary disease (COPD)?How is high-resolution CT (HRCT) scanning used in patients with chronic obstructive pulmonary disease (COPD)?What are the causes and effects of pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD)?What is the role of echocardiography in the diagnosis of chronic obstructive pulmonary disease (COPD)?What is the role of pulmonary function tests in the workup of chronic obstructive pulmonary disease (COPD)?How is the 6-minute walking distance (6MWD) test used in the evaluation of patients with chronic obstructive pulmonary disease (COPD)?What is the role of pulse oximetry in the workup of chronic obstructive pulmonary disease (COPD)?What is the role of ECG in the workup of chronic obstructive pulmonary disease (COPD)?When is right-sided heart catheterization indicated in patients with chronic obstructive pulmonary disease (COPD)?What hematocrit level in chronic hypoxemia indicates polycythemia?How effective is aclidinium in the treatment of chronic obstructive pulmonary disease (COPD)?How does umeclidinium bromide work in the treatment of chronic obstructive pulmonary disease (COPD), and is it safe and effective?What is the goal of treatment in chronic obstructive pulmonary disease (COPD), and what options are available?What is the most effective disease management strategy for chronic obstructive pulmonary disease (COPD)?When should a patient with chronic obstructive pulmonary disease (COPD) be admitted to an ICU?What types of medications are used in the treatment of chronic obstructive pulmonary disease (COPD)?What is the role of nutrition in chronic obstructive pulmonary disease (COPD)?What is the role of bronchodilators in chronic obstructive pulmonary disease (COPD)?Which medications are most effective as first-line therapy in the treatment of chronic obstructive pulmonary disease (COPD)?How do beta2-agonist bronchodilators work to treat chronic obstructive pulmonary disease (COPD), and what are the potential adverse effects?How do anticholinergic drugs work to treat chronic obstructive pulmonary disease (COPD), and what are the potential adverse effects?What adverse effects of anticholinergic drugs have been demonstrated in men with chronic obstructive pulmonary disease (COPD)?What is the preferred method of delivery of medications in the treatment of chronic obstructive pulmonary disease (COPD)?What are the risks associated with using newly prescribed long-acting beta-agonist and anticholinergic treatments for chronic obstructive pulmonary disease (COPD)?Is combination or monotherapy more effective in the treatment of chronic obstructive pulmonary disease (COPD)?How does glycopyrrolate work to treat chronic obstructive pulmonary disease (COPD)?How does combination glycopyrrolate/formoterol therapy work to treat chronic obstructive pulmonary disease (COPD)?What long-term maintenance options are available for chronic obstructive pulmonary disease (COPD)?What is the efficacy of tiotropium in the treatment of chronic obstructive pulmonary disease (COPD)?What is the efficacy of aclidinium in the treatment of chronic obstructive pulmonary disease (COPD)?What is the efficacy of umeclidinium bromide in the treatment of chronic obstructive pulmonary disease (COPD)?What is the efficacy of revefenacin in the treatment of chronic obstructive pulmonary disease (COPD)?How do phosphodiesterase inhibitors work in the treatment of chronic obstructive pulmonary disease (COPD)?How is theophylline used in the treatment of chronic obstructive pulmonary disease (COPD)?How is roflumilast used in the treatment of chronic obstructive pulmonary disease (COPD)?How do endogenous opioids help patients with chronic obstructive pulmonary disease (COPD)?What is the role of beta-blockers in the treatment of patients with cardiovascular disease and chronic obstructive pulmonary disease (COPD)?What is the role of a smoking cessation plan in the treatment of chronic obstructive pulmonary disease (COPD)?What are the stages of smoking cessation?What resources are available to help patients with chronic obstructive pulmonary disease (COPD) stop smoking?What are the symptoms of nicotine withdrawal, and how can they be prevented?What nicotine replacement therapies are available that can help patients with chronic obstructive pulmonary disease (COPD) stop smoking?How is inflammation in chronic obstructive pulmonary disease (COPD) treated?What is the role of inhaled corticosteroids in the treatment of inflammation in chronic obstructive pulmonary disease (COPD)?How is the efficacy of inhaled corticosteroids on inflammation in chronic obstructive pulmonary disease (COPD) measured?What is the role of IV steroids in the treatment of inflammation associated with chronic obstructive pulmonary disease (COPD)?What is the role of NSAIDs in the treatment of inflammation in chronic obstructive pulmonary disease (COPD)?What is the role of azithromycin in the treatment of chronic obstructive pulmonary disease (COPD)?How is infection treated in chronic obstructive pulmonary disease (COPD)?How are sputum viscosity and secretion clearance managed in chronic obstructive pulmonary disease (COPD)?How are proton pump inhibitors (PPIs) used to treat exacerbations and the common cold in patients with chronic obstructive pulmonary disease (COPD)?How is hypoxemia treated in chronic obstructive pulmonary disease (COPD)?What causes carbon dioxide retention, and how can it be avoided in patients with chronic obstructive pulmonary disease (COPD)?What are the physical hazards of oxygen therapy in chronic obstructive pulmonary disease (COPD), and how can they be avoided?How is oxygen delivered in stable hypoxemic patients?What is noninvasive positive-pressure ventilation (NIPPV), and how is it used in the treatment of chronic obstructive pulmonary disease (COPD)?Which vaccinations are indicated to reduce infection in patients with chronic obstructive pulmonary disease (COPD)?What are the treatment options for alpha1-antitrypsin (AAT) deficiency in chronic obstructive pulmonary disease (COPD)?When is hospitalization indicated for patients with chronic obstructive pulmonary disease (COPD)?How common are acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and how are they treated?When is assisted ventilation indicated in the treatment of chronic obstructive pulmonary disease (COPD)?When is bullectomy indicated in the treatment of chronic obstructive pulmonary disease (COPD)?What is the role of lung volume reduction surgery in the treatment of chronic obstructive pulmonary disease (COPD)?What is the role of lung transplantation in the treatment of chronic obstructive pulmonary disease (COPD)?What follow-up is indicated after an acute exacerbation of chronic obstructive pulmonary disease (AECOPD)?What are the main goals of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD)?How is a successful pulmonary rehabilitation program implemented in chronic obstructive pulmonary disease (COPD)?What are the benefits of a pulmonary rehabilitation program for patients with chronic obstructive pulmonary disease (COPD)?What is the typical approach to a pulmonary rehabilitation program for patients with chronic obstructive pulmonary disease (COPD)?What is the role of patient education in a pulmonary rehabilitation program for chronic obstructive pulmonary disease (COPD)?What is the role of exercise in a pulmonary rehabilitation program for chronic obstructive pulmonary disease (COPD)?What is the role of breathing exercises in patients with chronic obstructive pulmonary disease (COPD)?When is it safe for patients with chronic obstructive pulmonary disease (COPD) to fly, and what accommodations can be made when necessary?What is the role PaO2 measurement in determining if oxygen therapy is indicated for sleep in patients with chronic obstructive pulmonary disease (COPD)?What is the role of an end-of-life care discussion in patients with chronic obstructive pulmonary disease (COPD)?What guidelines exist regarding chronic obstructive pulmonary disease (COPD)?What are the screening guidelines for chronic obstructive pulmonary disease (COPD)?What are the guidelines for preventing tobacco use in patients who smoke or who have chronic obstructive pulmonary disease (COPD)?What are the GOLD guidelines for the general management of chronic obstructive pulmonary disease (COPD)?What are the GOLD guidelines for the classification of chronic obstructive pulmonary disease (COPD)?What are the GOLD patient group-based management recommendations for the treatment of patients with chronic obstructive pulmonary disease (COPD)?What are the VA/DoD guidelines for the management of chronic obstructive pulmonary disease (COPD)?What are the ACP, ACCP, ATS, and ERS joint guidelines for the diagnosis and management of stable chronic obstructive pulmonary disease (COPD)?What are the guidelines for the use of noninvasive ventilation in patients with chronic obstructive pulmonary disease (COPD)?What are the guidelines for the prevention of acute exacerbations in chronic obstructive pulmonary disease (COPD)?What are the guidelines for the prevention of acute exacerbations in moderate-to-severe chronic obstructive pulmonary disease (COPD)?What are the guidelines for the prevention of acute exacerbations in patients with any stage of chronic obstructive pulmonary disease (COPD)?What are the guidelines for the prevention of acute exacerbations in stable chronic obstructive pulmonary disease (COPD)?What are the guidelines for the prevention of acute exacerbations of chronic obstructive pulmonary disease (COPD) in patients aged 40 years or older who smoke or have a history of smoking?Which types of medications are used for the treatment of chronic obstructive pulmonary disease (COPD)?Which medications in the drug class Beta2-Adrenergic Agonists, Short-Acting are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Beta2-Adrenergic Agonists, Long-Acting are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Anticholinergics, Respiratory are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Xanthine Derivative are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Phosphodiesterase-4 Inhibitors are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Corticosteroids, Inhalant are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Corticosteroids, Oral are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Beta-Adrenergic Agonist and Anticholinergic Agent Combinations are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Beta2-Adrenergic Agonist and Corticosteroid Combinations are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Antibiotics are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Smoking Cessation Therapies are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?Which medications in the drug class Other Combinations are used in the treatment of Chronic Obstructive Pulmonary Disease (COPD)?

References

Author

Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Annie Harrington, MD, Fellow in Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.

Nader Kamangar, MD, FACP, FCCP, FCCM, Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Chief, Division of Pulmonary and Critical Care Medicine, Vice-Chair, Department of Medicine, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Nidhi S Nikhanj, MD, Fellow, Department of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

John J Oppenheimer, MD, Clinical Professor, Department of Medicine, Rutgers New Jersey Medical School; Director of Clinical Research, Pulmonary and Allergy Associates, PA

Disclosure: Received research grant from: quintiles, PRA, ICON, Novartis: Adjudication<br/>Received consulting fee from AZ for consulting; Received consulting fee from Glaxo, Myelin, Meda for consulting; Received grant/research funds from Glaxo for independent contractor; Received consulting fee from Merck for consulting; Received honoraria from Annals of Allergy Asthma Immunology for none; Partner received honoraria from ABAI for none. for: Atlantic Health System.

Acknowledgements

Ryland P Byrd Jr, MD Professor, Department of Internal Medicine, Division of Pulmonary Medicine and Critical Care Medicine, Program Director of Pulmonary Diseases and Critical Care Medicine Fellowship, East Tennessee State University, James H Quillen College of Medicine; Medical Director of Respiratory Therapy, James H Quillen Veterans Affairs Medical Center

Ryland P Byrd Jr, MD is a member of the following medical societies: American College of Chest Physicians and American Thoracic Society

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Chronic Obstructive Pulmonary Disease (COPD)

Practice Essentials

Venn diagram of chronic obstructive pulmonary disease (COPD). Chronic obstructive lung disease is a disorder in which subsets of patients may have dom....

Signs and symptoms

Diagnosis

Management

Background

Venn diagram of chronic obstructive pulmonary disease (COPD). Chronic obstructive lung disease is a disorder in which subsets of patients may have dom....

Pathophysiology

Chronic bronchitis

Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.

Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells (high-powered vi....

Emphysema

Gross pathology of advanced emphysema. Large bullae are present on the surface of the lung.

Gross pathology of a patient with emphysema showing bullae on the surface.

At high magnification, loss of alveolar walls and dilatation of airspaces in emphysema can be seen.

Emphysematous destruction and small airway inflammation

Dynamic hyperinflation

Etiology

Cigarette smoking

Environmental factors

Airway hyperresponsiveness

Alpha1-antitrypsin deficiency

Intravenous drug use

Immunodeficiency syndromes

Vasculitis syndrome

Connective tissue disorders

Salla disease

Epidemiology

Prognosis

Patient Education

History

Physical Examination

Staging

Approach Considerations

Arterial Blood Gas Analysis

Serum Chemistries

Alpha1-Antitrypsin

Sputum Evaluation

B-Type Natriuretic Peptide

Chest Radiography

Posteroanterior (PA) and lateral chest radiograph in a patient with severe chronic obstructive pulmonary disease (COPD). Hyperinflation, depressed dia....

A lung with emphysema shows increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragm on lateral chest radiogr....

A lung with emphysema shows increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragm on posteroanterior chest....

Computed Tomography

Severe bullous disease as seen on a computed tomography (CT) scan in a patient with chronic obstructive pulmonary disease (COPD).

Two-Dimensional Echocardiography

Pulmonary Function Tests

Pressure volume curve comparing lungs with emphysema, lungs with restrictive disease, and normal lungs.

Flow volume curve of a patient with emphysema shows marked decrease in expiratory flow, hyperinflation, and air trapping (patient B) compared with a p....

Forced expiratory volume in 1 second (FEV1) can be used to evaluate the prognosis in patients with emphysema. The benefit of smoking cessation is show....

Six-Minute Walking Distance

Other Studies

Electrocardiography

Right-Sided Heart catheterization

Hematocrit

Approach Considerations

Diet

Bronchodilation

Beta2 agonists and cholinergic/muscarinic antagonists

Tiotropium

Aclidinium

Umeclidinium bromide

Revefenacin

Phosphodiesterase inhibitors

Endogenous opioids

Beta-adrenergic antagonists (beta-blockers)

Smoking Cessation

Management of Inflammation

Management of Infection

Management of Sputum Viscosity and Secretion Clearance

PPIs for Exacerbations and the Common Cold

Oxygen Therapy and Hypoxemia

Oxygen therapy via nasal cannula.

Home supplemental oxygen.

NIPPV for hypercapneic respiratory failure

Bilevel positive airway pressure (BiPAP).

Vaccination to Reduce Infections

Alpha1-Antitrypsin Deficiency Treatment

Inpatient Care