Updated: Dec 30, 2019
Author: Kamran Boka, MD, MS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 



Emphysema and chronic bronchitis are airflow-limited states contained within the disease state known as chronic obstructive pulmonary disease (COPD).[1] Just as asthma is no longer grouped with COPD, the current definition of COPD put forth by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) also no longer distinguishes between emphysema and chronic bronchitis.[2]

Emphysema is pathologically defined as an abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis.[1] This process leads to reduced gas exchange, changes in airway dynamics that impair expiratory airflow, and progressive air trapping.[3]  Clinically, the term emphysema is used interchangeably with chronic obstructive pulmonary disease, or COPD.

The theory surrounding this definition has been around since the 1950s, with a key concept of irreversibility and/or permanent acinar damage. However, new data posit that increased collagen deposition leads to active fibrosis, which inevitably is associated with breakdown of the lung’s elastic framework. An entity known as combined pulmonary fibrosis and emphysema (CPFE) has been shown to exist in a subset of emphysematous patients.[4]  This implies an association between fibrosis and the permanence of alveolar damage. The complex mechanism thought to be responsible is the interplay between Notch and Wnt, two signaling pathways playing critical roles in epithelial and mesenchymal precursor cell maintenance and differentiation.[5]

Discussions on how obstructive diseases share similar phenotypes have been emerging and evolving within the literature. Asthma and chronic obstructive pulmonary disease overlap syndrome (ACOS) is a term that has been used to describe patients who have severe COPD and/or severe asthma who find themselves with frequent exacerbations/hospitalizations and difficult-to-control or refractory symptoms. In its 2017 guidelines update the Global Initiative for Asthma (GINA)-Global Initiative for Chronic Obstructive Lung Diseases (GOLD) explained that it no longer used the term asthma-COPD overlap syndrome (ASCO) because asthma-COPD overlap does not describe a single disease entity. Presentations with combined features of both disorders more likely have several different phenotypes of airway disease caused by a variety of mechanisms. [6]

Chronic lower respiratory disease, primarily COPD, is the third leading cause of death in the United States and the fourth leading cause of death worldwide, although it may become the fourth global cause of death in 2020.[1] Almost 15.7 million Americans (6.4%) in 2014 reported that they were diagnosed with COPD, however the actual number is likely much higer. More than 50% of adults with low pulmonary function were not aware that they had COPD. The following groups were more likely to report COPD in 2013[7] :

  • People aged 65–74 years and ≥ 75 years.
  • American Indian/Alaska Natives and multiracial non-Hispanics.
  • Women.
  • Individuals who were unemployed, retired, or unable to work.
  • Individuals with less than a high school education.
  • Individuals who were divorced, widowed, or separated.
  • Current or former smokers.
  • People with a history of asthma.

The risk factors thought to be responsible for the development of COPD are all associated with an accelerated decline in FEV1 over time. Tobacco smoke is a key factor in the development and progression of COPD, although exposure to air pollutants in the home and workplace, genetic factors, and respiratory infections also play a role. Women in developing countries who are exposed to biomass cooking of liquids and fuels, including wood, crops, animal dung, and coal, are at increased risk of developing COPD. Add to that poor ventilation of the home and dependent family members’ (children and elderly persons) risk also increases. Globally, COPD is a disease of occupation and environmental pollutants too, including but not limited to organic and inorganic dusts, isocyanates, and phosgenes.[8]

The latest systematic review looked at the impact of air pollution on COPD sufferers (inclusive of articles prior to 1990); the investigators concluded that the need to continue to improve air quality guidelines is more important than ever as biomass cooking in low-income nations was clearly associated with COPD mortality in adult female nonsmokers [9] .

However, the evolution of disease based on smoke exposure differs widely among people, suggesting genetic factors to be involved. It is not truly known why certain people with a positive smoke exposure develop injury patterns, symptoms, and disease. For instance, the Lung Health Study from 2002 showed that a third of smokers never developed impaired lung function after 11 years despite a baseline study of airway obstruction.[10]

Genetic risk factors for the development of COPD include alpha-1-antitrypsin (AAT) deficiency (also known as alpha-1 antiprotease deficiency). AAT is a glycoprotein member of the serine protease inhibitor family that is synthesized in the liver and is secreted into the blood stream. 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. If not inactivated by AAT, neutrophil elastase destroys lung connective tissue leading to emphysema. Therefore, severe AAT deficiency predisposes to unopposed elastolysis with the clinical sequela of an early onset of panacinar emphysema.

Deficiency of AAT is inherited as an autosomal codominant condition. The gene, located on the long arm of chromosome 14, expresses different phenotypes (serum protease inhibitor phenotype notated Pi type). The most common type of severe AAT phenotype (more than 90%) occurs in individuals who are homozygous for the Z allele. Homozygous individuals (Pi ZZ), usually of northern European descent, have serum levels well below the reference range levels at about 20% of the normal level (2.5 to 7 mmol/L). The normal M allele phenotype is Pi MM, with levels of 20-48 mmol/L.[11]  Lifetime nonsmokers who are homozygous for the Z allele rarely develop emphysema. Hence, cigarette smoking is the most important risk factor for emphysema development in individuals with AATD. 

The hallmark physical examination finding of emphysema is the limitation of expiratory flow with relative preservation of inspiratory flow.  A forced expiratory time more than 6 seconds indicates severe expiratory airflow obstruction. The forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC) are used in determining flows. The ratio of the two (FEV1/FVC) results as a percentage on spirometry and is used to confirm the diagnosis of obstructive airway disease and assess responses to treatment and disease progression.

The goal of therapy is to relieve symptoms, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations, and reduce mortality.  [12]    Treatments should be added in a stepwise fashion to reach these goals.

Once the diagnosis of chronic obstructive pulmonary disease (COPD) is established, the patient should be educated about the disease and should be encouraged to participate actively in therapy. For patient education resources, visit the Lung Disease and Respiratory Health Center. 


Once innate respiratory defenses of the lung’s epithelial cell barrier and mucociliary transport system are infiltrated by foreign/invading antigens (noxious cigarette ingredients, for instance), the responding inflammatory immune cells (including polymorphonuclear cells, eosinophils, macrophages, CD4 positive and CD8 positive lymphocytes) transport the antigens to the bronchial associated lymphatic tissue layer (BALT). It is here where the majority of the release of neutrophilic chemotactic factors is thought to occur. Proteolytic enzymes like matrix-metalloproteinases (MMPs) are mainly released by macrophages, which lead to destruction of the lung’s epithelial barrier.

Macrophages are found to be 5- to 10-fold higher in the bronchoalveolar lavage fluid of emphysematous patients.[13] Also, along with macrophages, the release of proteases and free radical hydrogen peroxide from neutrophils adds to the epithelial ruination, specifically with emphasis on the basement membrane. This is why neutrophils are thought to be highly important in the pathogenesis of emphysema at the tissue level, a differentiator to the mainly eosinophilic inflammatory response in airways affected by asthma.

After all, the T lymphocytes in the sputum of emphysematous smokers are mainly CD8 positive cells.[14] These cells release chemotactic factors to recruit more cells (pro-inflammatory cytokines that amplify the inflammation) and growth factors that promote structural change. The inflammation is further amplified by oxidative stress and protease production. Oxidants are produced from cigarette smoke and released from inflammatory cells. Proteases are produced by inflammatory, macrophage, and epithelial cells, which fuel bronchiolar edema from an elastin-destroying protease-antiprotease imbalance. This protease-menace is elastase, released by macrophages, and responsible for breakdown of the lung’s fragile elastic lamina (of which elastin is a structural protein component).[13] This is believed to be central in the development of emphysema. Peptides from elastin can be detected in increased quantities in patients with emphysema and AAT.[15]

The repair process of airway remodeling further exacerbates emphysema’s anatomical derangements with key characters such as vascular endothelial growth factor (VEGF), which is expressed in airway smooth muscle cells and is responsible for neovascularization and expression of increased and possibly abnormal patterns of fibroblastic development. It is these structural changes of mucus hyperplasia, bronchiolar edema, and smooth muscle hypertrophy and fibrosis in smokers’ airways that result in the small airways narrowing of less than two millimeters.

AATD lung disease is due to the relative deficiency in the blood and lungs of the alpha-1 antitrypsin (AAT) protein. Although evidence suggests a more complicated cascade of proteolytic and inflammatory factors as the cause of emphysema in AATD, unopposed neutrophil elastase activity within the pulmonary interstitium with resultant connective tissue destruction remains an important contributor to the pathogenesis of emphysema.[16]


Pathologically defined as permanent enlargement of airspaces distal to the terminal bronchioles, emphysema creates an environment leading to a dramatic decline in the alveolar surface area available for gas exchange. Loss of individual alveoli with septal wall destruction leads to airflow limitation via two mechanisms. First, loss of alveolar wall results in a decrease in elastic recoil, which subsequently limits airflow. Second, loss of alveolar supporting structures is indirectly responsible for airway narrowing, again limiting airflow.[17]

Though the paradigm for classification continues to evolve, the described morphological pathology of region-specific emphysema remains in three types:[18]

  • Centriacinar (centrilobular)

  • Panacinar (panlobular)

  • Paraseptal

Centriacinar emphysema is the most common type of pulmonary emphysema mainly localized to the proximal respiratory bronchioles with focal destruction and predominantly found in the upper lung zones. The surrounding lung parenchyma is usually normal with untouched distal alveolar ducts and sacs. Also known as centrilobular emphysema, this entity is associated with and closely-related to long-standing cigarette smoking and dust inhalation.[19, 20]

Emphysema. Centrilobular emphysema. Courtesy of Dr Emphysema. Centrilobular emphysema. Courtesy of Dr Frank Gaillard, Radiopaedia.org (http://radiopaedia.org/cases/emphysema-diagrams).

Panacinar emphysema destroys the entire alveolus uniformly and is predominant in the lower half of the lungs. Panacinar emphysema generally is observed in patients with homozygous (Pi ZZ) alpha1-antitrypsin (AAT) deficiency. In people who smoke, focal panacinar emphysema at the lung bases may accompany centriacinar emphysema.[19, 20]

Emphysema. Panlobular emphysema. Courtesy of Dr Fr Emphysema. Panlobular emphysema. Courtesy of Dr Frank Gaillard, Radiopaedia.org (http://radiopaedia.org/cases/emphysema-diagrams).

Paraseptal emphysema, also known as distal acinar emphysema, preferentially involves the distal airway structures, alveolar ducts, and alveolar sacs. The process is localized around the septae of the lungs or pleura. Although airflow is frequently preserved, the apical bullae may lead to spontaneous pneumothorax. Giant bullae occasionally cause severe compression of adjacent lung tissue.[19, 20]

Emphysema. Paraseptal emphysema. Courtesy of Dr Fr Emphysema. Paraseptal emphysema. Courtesy of Dr Frank Gaillard, Radiopaedia.org (http://radiopaedia.org/cases/emphysema-diagrams).
Emphysema. Gross pathology of bullous emphysema sh Emphysema. Gross pathology of bullous emphysema shows bullae on the surface of the lungs.
Emphysema. Gross pathology of emphysema shows bull Emphysema. Gross pathology of emphysema shows bullae on the lung surface.


Smoking is by far the single most clearly established environmental risk factor for emphysema/chronic bronchitis. Eight out of 10 cases of COPD are caused by smoking.[21]  Chronic occupational exposure to inhaled mineral dusts, metal fumes, organic dusts (e.g. wood, grains), diesel exhaust fumes, and/or chemical gases or vapors is estimated to be the cause of 19.2% of COPD in smokers and 31.1% of COPD in individuals with no history of smoking.[2]

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by the production of an abnormal AAT protein.  Although the mechanisms are not completely known, it is believed that in the lungs, low-levels of AAT allow for the destructive effects of neutrophil elastase to go unchecked, which results in damage to the delicate gas exchange region of the lungs (alveoli), eventually leading to emphysema in individuals as young as 30 years of age.  Among patients with COPD, up to 3% are estimated to have AATD. It can also cause life threatening liver damage in adults and children and liver cancer in adults.[16]

Emphysema occurs in approximately 2% of persons who use intravenous drugs. This is attributed to pulmonary vascular damage resulting from the insoluble filler (eg, cornstarch, cotton fibers, cellulose, talc) contained in methadone or methylphenidate.The bullous cysts found in association with intravenous use of cocaine or heroin occur predominantly in the upper lobes. In contrast, methadone and methylphenidate injections are associated with basilar and panacinar emphysema.

Human immunodeficiency virus (HIV) infection was found to be an independent risk factor for emphysema, even after controlling for confounding variables such as smoking, intravenous 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.

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

Cutis laxa, a disorder of elastin that is characterized most prominently by the appearance of premature aging. The disease is usually 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.

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.



COPD was the fourth leading cause of death globally and accounted for more than 3 million deaths in 2012. In the United States, it is the third leading cause of death.[2] In 2014, almost 15.7 million Americans (6.4%) reported that they were diagnosed with COPD. The prevalence of COPD varies considerably by state, from less than 4% in Hawaii, Colorado, and Utah to over 9% in Alabama, Tennessee, Kentucky, and West Virginia. The states with the highest COPD prevalence are clustered along the Ohio and lower Mississippi Rivers.[7] Because the prevalence is based on the number of adults who have ever been told by any health care provider that they have emphysema or chronic bronchitis, the actual number is thought to be much higher. Most patients do not seek medical care until the disease is in its later stages and more than 50% of adults with low pulmonary function were not aware that they had COPD. 

The Burden of Obstructive Lung Disease (BOLD) study showed that the global prevalence of COPD (stage II or higher) was 10.1%.[23] This figure varied by geographic location and by sex with a pooled prevalence among men of 11.8% (8.6-22.2%) and among women of 8.5% (5.1-16.7%). The differences can, in part, be explained by site and sex differences in the prevalence of smoking. These rates are similar to rates observed in the Proyecto Latino Americano de Investigacion en Obstruccion Pulmonar (PLATINO study), which studied 5 countries in Latin America.[24]  

The 2014 Surgeon General's report found the risks for COPD were increasing, especially in women. Their risk for COPD is now similar to the risk among men. Women smokers in certain age groups are more than 38 times as likely to develop COPD, compared with women who have never smoked. Moreover, women are dying from COPD more frequently than men, and  are more likely to develop severe COPD at younger ages.[21]  

Alpha-1 antitrypsin deficiency (AATD) is among the most prevalent potentially fatal genetic disorders in the U.S., and occurs approximately equally in men and women. The incidence of AADT among whites is estimated between 1/2500 and 1/3000. Among patients with COPD, up to 3% have AATD. The overwhelming majority of individuals with AATD have not been diagnosed; approximately 10% of the individuals in the United States estimated to have AATD have received a diagnosis. Alpha-1 antitrypsin deficiency (AATD) has been identified in virtually all populations but is most common in individuals of Scandinavian, British, Spanish and Portuguese descent.[16]  


Various measures have been shown to correlate with prognosis in COPD, including forced expiratory volume in 1 second (FEV1), diffusion capacity for carbon monoxide (DLCO), blood gas measurements, body mass index (BMI), exercise capacity, and clinical status. A correlation has also been established between radiographic severity of emphysema and mortality.[25]

Patients with features of both asthma and COPD experience more frequent exacerbations, have a poorer quality of life, decline in lung function more rapidly and have a higher mortality rate than patients with COPD alone.[6]  Those with COPD and higher serum alpha-1 antitrypsin levels also have a worse systemic inflammation status and higher 10-year mortality.[26]

Comorbidities are common with COPD and have a significant impact on prognosis. Lung cancer is a common cause of death in COPD. Gastroesophageal reflux (GERD) increases the risk of exacerbations. Osteoporosis, anxiety and depression are frequent but under-diagnosed comorbidities that are associated with poor health status and worse prognosis.  Other frequent comorbidities include metabolic syndromes, cardiovascular disease, hypertension and bronchiectasis.[2]

A widely used simple prognostication tool is the BODE index, which is based on the BMI, obstruction (FEV1), dyspnea (using Medical Research Council Dyspnea Scale), and exercise capacity (ie, 6-minute walk distance).

BODE index

Body mass index is scored as follows:

  • Greater than 21 = 0 points

  • Less than 21 = 1 point

FEV1 (postbronchodilator percent predicted) is scored as follows:

  • Greater than 65% = 0 points

  • 50-64% = 1 point

  • 36-49% = 2 points

  • Less than 35% = 3 points

The Modified Medical Research Council (MMRC) dyspnea scale is scored as follows:

  • 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)

The 6-minute walking distance is scored as follows:

  • Greater than 350 meters = 0 points

  • 250-349 meters = 1 point

  • 150-249 meters = 2 points

  • Less than 149 meters = 3 points

The BODE scoring for approximate 4-year survival is as follows:

  • 0-2 points = 80%

  • 3-4 points = 67%

  • 5-6 points = 57%

  • 7-10 points = 18%

Although age-adjusted death rates for COPD have declined among US men between 1999 (57.0 per 100,000) and 2014 (44.3 per 100,000) in the United States, there has been no significant change among death rates in women (35.3 per 100,000 in 1999 and 35.6 per 100,000 in 2014). Age-adjusted death rates in 2014 varied between states and ranged from 15.3 per 100,000 in Hawaii to 62.8 per 100,000 in Kentucky. The states with the highest COPD death rates are clustered along the Ohio and Mississippi Rivers.[7]




COPD should be considered in any patient with dyspnea, chronic cough or sputum production or a history of exposure to risk factors. Most patients seek medical attention late in the course of their disease, usually ignoring smoldering symptoms that start gradually and progress over the course of years. Patients will adapt and modify their lifestyles in order to minimize dyspnea and ignore cough and mucus production. With questioning, a multiyear history can be elicited.

Generally, patients present in their fifth decade of life with a productive cough or acute chest illness. This cough, commonly referred to as a "smoker's cough," typically is worse in the morning with finite production of clear-to-white sputum. The cause of this is usually undiagnosed concomitant chronic bronchitis.

Dyspnea, emphysema's most significant symptom, does not generally occur until the sixth decade of life. By the time the forced expiratory volume in 1 second (FEV1) has fallen to 50% of predicted, the patient is breathless upon minimal exertion.

Wheezing may occur in some patients, particularly during exertion and exacerbations. Listen to typical wheezing with the link below.

Emphysema Wheezing (MP3)

Auscultation of patient during exacerbation of COPD/emphysema. Courtesy of James Heilman, MD, published by Wikipedia.

AAT-deficient patients present earlier than other COPD patients, usually in their fourth or fifth decade of life, with severe AAT deficiency mainly affecting the lungs and the liver. Liver dysfunction dominates the clinical picture in the first decade of life. Patients who are homozygous (Pi ZZ) develop emphysema with the following distinctive features: early presentation (< 45 y), predilection of emphysematous changes in the lung bases, and the panacinar morphological pattern.

Physical Examination

Emphysema’s physiologic hallmark physical examination finding is the limitation of expiratory flow with relative preservation of inspiratory flow. It takes longer to exhale than it does to inhale. Measurement of the forced expiratory time maneuver is a simple bedside test; a forced expiratory time more than 6 seconds indicates severe expiratory airflow obstruction. The forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC) are important in determining flows. The ratio of the two (FEV1/FVC) results as a percentage during the spirometry portion of pulmonary function testing and is the objective diagnostic means of labeling a patient with COPD.

Although the sensitivity of the physical evaluation in mild-to-moderate disease is relatively poor, the physical signs are quite sensitive and specific in severe disease. Patients with severe disease may experience tachypnea and dyspnea with mild exertion.

The respiratory rate increases in proportion to disease severity with the use of accessory respiratory muscles and paradoxical contraction of lower intercostal spaces becoming evident during exacerbations.

In end-stage emphysema, cyanosis, elevated jugular venous pressure, atrophy of limb musculature, and peripheral edema due to the development of pulmonary hypertension, right-to-left shunting, and/or right heart failure can easily be observed.

Thoracic examination reveals a 2:1 increase in anterior to posterior diameter (“barrel chest”), diffuse or focal wheezing, diffusely diminished breath sounds, hyperresonance upon percussion, prolonged expiration, and/or hyperinflation on chest radiographs.



Diagnostic Considerations

Common alternative diagnoses and suggestive diagnostic features are as follows:

  • Congestive heart failure: This condition may produce wheezing and is often difficult to differentiate from emphysema. However, a history of orthopnea and paroxysmal nocturnal dyspnea, the presence of fine basal crackles, and typical findings on chest radiographs can lead to the diagnosis of congestive heart failure.
  • Bronchiectasis: Patients with bronchiectasis have chronic production of copious purulent sputum, coarse crackles and clubbing upon physical examination, and abnormal findings on chest radiographs and CT scans.
  • Bronchiolitis obliterans: Obliterative bronchiolitis is observed in younger persons who do not smoke and in persons with collagen-vascular diseases. A CT scan characteristically shows areas of mosaic attenuation without evidence of generalized emphysema.
  • Chronic asthma: The delayed onset of severe asthma may be difficult to distinguish in older patients, but the important distinction is a significant bronchodilator response and normal diffusion (ie, diffusing capacity of lung for carbon monoxide [DLCO]) on pulmonary function tests.

Differential Diagnoses



Approach Considerations

COPD is diagnosed based on clinical symptom and history of exposure to risk factors.[1] Spirometry is required to confirm diagnosis. Further assessments are made to determine the level of airflow limitation, the impact of disease on health status, and the risk of exacerbations, in order to guide therapy.


The workup of an individual with AATD-related emphysema should include testing for early detection and follow-up of a variety of associated conditions including liver disease, granulomatosis with polyangiitis, and panniculitis. . For example, the Alpha-1 Foundgation recommends patients be regularly monitored for liver disease with liver ultrasound and laboratory testing of AST, ALT, GGT, albumin, bilirubin, INR, and platelets,[16]  

Asthma-COPD overlap

Asthma, COPD and asthma-COPD overlap are differentiated based on a comparison of the number of features characteristic of each possible diagnosis. Spirometry and peak expiratory flow measurement is performed to confirm of exclude diagnoses. Referral to a pulmonologist for diagnosis may be necessary under the following circumstances:

  • Diagnosis is uncertain or alternative diagnoses such as bronchiectasis, post-tuberculous scarring, bronchiolitis, pulmonary fibrosis, pulmonary hypertension need to be excluded
  • Atypical or additional signs and symptoms (e.g., hemoptysis, weight loss, night sweats, signs of bronchielctasis or other structural lung disease) are present
  • Chronic airway disease is suspected but few features of asthma and COPD are present
  • Comorbidities are present that may interfere with assessment of airway disease

Laboratory Studies

The following laboratory studies are useful:

  • Arterial blood gas analysis: Patients with mild chronic obstructive pulmonary disease (COPD) have mild-to-moderate hypoxemia without hypercapnia. As the disease progresses, hypoxemia worsens and hypercapnia develops.

  • Hematocrit: Chronic hypoxemia may lead to polycythemia. A hematocrit value higher than 52% in men and higher than 47% in women is indicative of the condition. Patients should be evaluated for hypoxemia at four times: at rest, with ambulation, with exertion, and during sleep. Correction of hypoxemia should reduce secondary polycythemia in patients who have quit smoking.

  • Serum bicarbonate: Chronic respiratory acidosis leads to compensatory metabolic alkalosis. In the absence of blood gas measurements, serum bicarbonate levels are useful for following disease progression.

  • Sputum evaluation: In patients with stable chronic bronchitis and in emphysema, the sputum is mucoid and the predominant cells are macrophages. With an exacerbation, the sputum becomes purulent, with excessive neutrophils and a mixture of organisms visualized through Gram staining. Streptococcus pneumoniae and Haemophilus influenzae are pathogens frequently cultured during exacerbations.

AATD Testing

All individuals with COPD regardless of age or ethnicity should be tested for AATD.[2, 16, 27] Of the approximately 75 different alleles for alpha1-antitrypsin (AAT) deficiency variants, 10-15 are associated with serum levels below the protective threshold of 11 mmol/L. The diagnosis of severe AAT deficiency is confirmed when the serum level falls below the protective threshold value (ie, 3-7 mmol/L). More than 95% of all severely AAT deficient individuals have either the ZZ or SZ genotype. In addition MZ individuals who smoke are also at increased risk for airflow obstruction.[16]  

AAT levels cannot be used alone to identify at risk individuals because the AAT level vary with inflammation, pregnancy, and in children. Confirmatory testing using a second method such as proteinase inhibitor (Pi) typing and/or AAT genotyping is required. More advanced testing, such as expanded genotyping for rare AAT alleles and gene sequencing, may also be considered confirmatory testing.[16]

Imaging Studies

Chest radiograph

Frontal and lateral chest radiographs reveal signs of hyperinflation: flattening ("coving") of diaphragms, increased retrosternal air space (see on lateral chest films), and a long narrow heart shadow. Rapid tapering vascular shadows accompanied by hyperlucency of the lungs are signs of emphysema. With complicating pulmonary hypertension, the hilar vascular shadows become prominent; right ventricular enlargement and an opacity in the lower retrosternal air space may also occur.

Note the images below.

Emphysema. This chest radiograph shows hyperinflat Emphysema. This chest radiograph shows hyperinflation, flattened diaphragms, increased retrosternal space, and hyperlucency of the lung parenchyma in emphysema.
Emphysema. An emphysematous lung shows an increase Emphysema. An emphysematous lung shows an increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragms on posteroanterior (PA) film.
Emphysema. An emphysematous lung shows an increase Emphysema. An emphysematous lung shows an increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragms on a lateral chest radiograph.
Emphysema. The differential diagnosis of a unilate Emphysema. The differential diagnosis of a unilateral hyperlucent lung includes pulmonary arterial hypoplasia and Swyer-James syndrome. The expiratory chest radiograph exhibits evidence of air trapping and is helpful in making the diagnosis. Swyer-James syndrome is unilateral bronchiolitis obliterans, which develops during early childhood.
Emphysema. A lateral chest radiograph of Swyer-Jam Emphysema. A lateral chest radiograph of Swyer-James syndrome may demonstrate some of the features of emphysema.

CT scan

High-resolution CT (HRCT) scanning is more sensitive than standard chest radiography. HRCT scanning is highly specific for diagnosing emphysema and outlines bullae that are not always observed on radiographs. A CT scan is indicated when the patient is being considered for a surgical intervention such as bullectomy or lung-volume reduction surgery. A CT scan is not indicated in the routine care of patients with COPD.

Note the images below.

Emphysema. A computed tomography scan shows emphys Emphysema. A computed tomography scan shows emphysematous bullae in the upper lobes.
Emphysema. Diffuse emphysema secondary to cigarett Emphysema. Diffuse emphysema secondary to cigarette smoking.
Emphysema. A computed tomograph scan showing sever Emphysema. A computed tomograph scan showing severe emphysema and bullous disease.

Other Tests

Pulmonary function tests

These measurements are necessary for the diagnosis of obstructive airway disease and for assessments of its severity. In addition, spirometry is helpful for assessing responses to treatment and disease progression.

Forced expiratory volume in 1 second (FEV1) is a reproducible test and is the most common index of airflow obstruction. Lung volume measurements show an increase in total lung capacity, functional residual capacity, and residual volume. The vital capacity is decreased.

DLCO is decreased in proportion to the severity of emphysema.

Lung mechanics and gas exchange worsen during acute exacerbations.

As many as 30% of patients have an increase in FEV1 of 15% or more after inhalation of a bronchodilator. The absence of bronchodilator response does not justify withholding bronchodilator therapy. Studies have shown that most patients with emphysema and COPD will have a small but significant degree of reversibility of airflow obstruction (defined as 12% and at least 200 mL improvement in the FEV1).

Note the images below.

Emphysema. A pressure-volume curve is drawn for a Emphysema. A pressure-volume curve is drawn for a patient with restrictive lung disease and obstructive disease and is compared to healthy lungs.
Emphysema. A flow-volume curve of lungs with emphy Emphysema. A flow-volume curve of lungs with emphysema shows a marked decrease in expiratory flows, hyperinflation, and air trapping (patient B) compared to a patient with restrictive lung disease, who has reduced lung volumes and preserved flows (patient A).
Emphysema. Forced expiratory volume in 1 second (F Emphysema. Forced expiratory volume in 1 second (FEV1) can be used to evaluate the prognosis in patients with emphysema. The benefit of smoking cessation is shown here because the deterioration in lung function parallels that of a nonsmoker, even in late stages of the disease.


The FEV1 is used to stage the severity of COPD. It is normalized as a percentage of predicted for healthy controls. The following Global Initiative for Chronic Obstructive Lung Disease staging system is widely used (note that the postbronchodilator FEV1 is used)[2] :

  • Stage I (mild) - FEV1 of 80% or more of predicted

  • Stage II (moderate) - FEV1 of less than 80% and 50% or more of predicted

  • Stage III (severe) - FEV1 less than 50% and 30% or more of predicted

  • Stage IV (very severe) - FEV1 less than 30% of predicted or FEV1 less than 50% and chronic respiratory failure

Respiratory failure is defined as a PaO2 less than 60 mm Hg (kPa 8.0) or a PaCO2 higher than 50 mm Hg (kPa 6.7).

The COPD Foundation Pocket Consultant Guide (PCG) uses 5 grades as follows[28] :

  • Stage 0 (normal) - Normal spirometry does not rule out emphysema, chronic bronchitis, asthma or risk of developing either exacerbations or COPD
  • Stage I (mild) - FEV1 of more than 60% of predicted

  • Stage II (moderate) - FEV1 of less than 60% and 30% or more of predicted

  • Stage III (severe) - FEV1 less than 30% of predicted

  • Stage U (undefined) - FEV1/ FVC ratio more than 0,7,  FEV1 less than 80% of predicted. This is consistent with restriction muscle weakness and other pathologies

The PCG 5 grades allow for a normal category as well as an undefined category of reduced lung function without criteria for chronic obstruction. The other 3 categories fit with the 2011 American College of Physicians, American College of Chest Physicians, American Thoracic Society, European Respiratory Society Consensus Statement that identified high levels of evidence to support using an FEV1 < 60% of predicted (moderate COPD) as the cut off for increased risk of exacerbation and an FEV1 < 30% of predicted (severe COPD) as the cut off where hypoxemia is more likely to require continuous oxygen therapy.[29]



Approach Considerations

The goal of therapy is to relieve symptoms, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations, and reduce mortality.[12] Treatments should be added in a stepwise fashion to reach these goals.

Smoking cessation is the single most effective therapy for most COPD patients.[12] Studies have shown that a less than 10-minute discussion by a physician can motivate a patient to quit smoking. A smoking cessation plan is an essential part of a comprehensive treatment plan. Although many believe that the success rates for smoking cessation are low because of the addictive potential of nicotine, it is the conditioned response to smoking-associated stimuli, including oral fixation, habit, psychosocial stressors, and forceful promotional campaigns by the tobacco industry, which are more dominant players. The process of smoking cessation must involve multiple interventions. Quitting "cold turkey" has been shown to have the greatest success rate over all other quitting aids.

Smoking Cessation Interventions

The transition from smoking to nonsmoking status involves 5 stages. These stages are (1) precontemplation, (2) contemplation, (3) preparation, (4) action, and (5) maintenance. Smoking intervention programs include self-help, group, physician-delivered, workplace, and community programs. Setting a target date to quit may be helpful. Physicians and other health care providers should participate in setting the target date and should 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, pharmacological agents)

According to the US Preventive Services Task Force guidelines, clinicians should ask all adults about the use of tobacco products and provide cessation interventions to current users. The guideline engages a “5-A” approach to counseling that includes the following[12] :

  • Ask about tobacco use.

  • Advise to quit through personalized messages.

  • Assess willingness to quit.

  • Assist with quitting.

  • Arrange follow-up care and support.

The task force also advises clinicians to ask all pregnant women, regardless of age, about tobacco use. Those who currently smoke should receive pregnancy-tailored counseling supplemented with self-help materials. Brief behavioral counseling and pharmacotherapy are each effective alone, although they are most beneficial when used together.

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 the addiction of smoking. Withdrawal from nicotine may cause unpleasant adverse effects (ie, anxiety, irritability, difficulty concentrating, anger, fatigue, drowsiness, depression, and sleep disruption). These effects usually occur during the first weeks after quitting smoking. Nicotine replacement therapies after smoking cessation reduce withdrawal symptoms. A person who smokes and who requires the first cigarette within 30 minutes of waking is likely to be highly addicted and would benefit from nicotine replacement therapy. Several nicotine replacement therapies are available.

Nicotine polacrilex is a chewing gum and produces improved quit rates compared to counseling alone. Transdermal nicotine patches are readily available for replacement therapy. Long-term success rates have been 22-42%, compared with 2-25% with placebos. These agents are well tolerated, and the adverse effects are limited to localized skin reactions. The use of an antidepressant medication, bupropion at 150 mg bid has been shown to be effective for smoking cessation and may be used in combination with nicotine replacement therapy.

Varenicline is approved for smoking cessation. This agent is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Its mechanism of action is believed to be binding the nicotinic subtype receptor, producing agonist activity while simultaneously preventing nicotine binding. Varenicline's agonistic activity is significantly lower than nicotine's.

Medical Care

Medical management generally includes the use of bronchodilators alone or in combination with anti-inflammatory drugs (eg, corticosteroids, phosphodiesterase-4 inhibitors) and supportive care (eg, oxygen therapy, ventilatory support, pulmonary rehabilitation, palliative care).[1]


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

Short-acting bronchodilators

The two classes of short-acting bronchodilators are beta2-agonists and anticholinergic agents. Beta2-agonists stimulate beta2-adrenergic receptors, increasing cyclic adenosine monophosphate (cAMP) and resulting in bronchodilation. The inhaled route is preferred because it minimizes adverse systemic effects. The adverse effects are predictable and include tachycardia and tremors. Although rare, they may also precipitate a cardiac arrhythmia. Anticholinergic agents block M2 and M3 cholinergic receptors and result in bronchodilation. These agents are poorly absorbed systemically and are relatively safe. Reported adverse effects include dry mouth, metallic taste, and prostatic symptoms.

The initial choice of agent remains in debate. Historically, beta2 agonists were considered first line and anticholinergics added as adjuncts. Not surprisingly, studies have shown combination therapy results in greater bronchodilator response and provides greater relief.[30] Monotherapy with either agent and combination therapy with both are acceptable options. The adverse effect profile may help guide therapy.

Long-acting bronchodilators

If short-acting agents do not provide sufficient relief, patients should be placed on a long-acting bronchodilator. Like the short-acting agents, the choices include long-acting beta agonists or long-acting muscarinic agents. In general, neither agent is preferred over the other. Oral phosphodiesterase inhibitors such as theophylline also provide long-acting bronchodilation, although their use is currently limited.


Long-acting beta-agonists (LABA) include salmeterol, formoterol, arformoterol, and indacaterol. They all require twice-daily dosing, except for indacaterol, which is administered once daily.[31] Multiple studies have demonstrated the benefit and safety of long-acting beta-agonists. The 2007 Toward a Revolution in COPD Health (TORCH) trial studied salmeterol with and without fluticasone versus placebo over a three-year period.[32] It demonstrated decreased exacerbation rates, improved lung function, and improved quality of life. The TORCH trial showed a trend towards mortality benefit of combination therapy with salmeterol plus fluticasone.

Tiotropium was introduced in 2004 and is the only available long-acting muscarinic agonist (LAMA) at this time. Tiotropium has been shown to provide 24-hour bronchodilation and is hence dosed once daily.[33] The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial studied the effects of use over a 4-year period.[34] The UPLIFT trial showed improvements in lung function, quality of life, and exacerbations, but it did not show a decrease in the rate of decline of lung function.

Evidence is mounting on the efficacy of tiotropium over long-acting beta-agonists. Two large randomized trials have compared tiotropium, salmeterol, and placebo.[35, 36] Both studies showed greater improvement in lung function, dyspnea, and quality of life in the tiotropium group versus the salmeterol group. The study by Brusasco et al also showed a delay in first exacerbations and fewer exacerbations per year in the tiotropium group.[35]

In 2012, aclidinium was approved for the long-term maintenance treatment of bronchospasm in emphysema and chronic bronchitis. The FDA-approved dosage is 400 µg inhaled twice daily. Aclidinium works as a long-acting, antimuscarinic (M3 receptor profile) (LAMA).[37]

Umeclidinium bromide is an M3 LAMA that has been approved for COPD, yet it is contraindicated in patients with severe hypersensitivity to milk proteins. Dosing is 62.5 µg inhaled once daily.

LAMA-LABA combinations have been shown to reduce COPD flares. In the 1-year EFfect of Indacaterol Glycopyrronium Vs Fluticasone Salmeterol on COPD Exacerbations (FLAME) trial, over 3000 patients with moderate-to-severe COPD (and with at least one exacerbation during the previous year) were randomized to either combination of once-daily glycopyrronium/indacaterol (LAMA/LABA) at 50/110 µg versus twice daily fluticasone/salmeterol (ICS/LABA) at 500/50 µg. The international investigation found an 11% reduction in exacerbations in the LAMA/LABA group. Glycopyrronium/indacaterol showed noninferiority. The incidence of pneumonia was less in the LAMA/LABA group as well.[38]

Phosphodiesterase inhibitors

Phosphodiesterase (PDE) inhibitors increase intracellular cAMP and result in bronchodilation. 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 cardiac effects. It is reserved for patients with hard-to-control COPD or for individuals who are not able to use inhaled agents effectively. Roflumilast and cilomilast are second-generation, selective PDE-4 inhibitors. They cause a reduction of the inflammatory process (macrophages and CD8+ lymphocytes) in patients with COPD. Twice-daily dosing has been found to be clinically effective. An 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. To analyze the impact of roflumilast on the incidence of COPD exacerbations requiring corticosteroids, Calverley et al performed 2 randomized, double-blind, placebo-controlled multicenter trials. Patients with COPD were randomly assigned to receive roflumilast once daily or placebo for 52 weeks. Both studies revealed increased FEV1 levels in patients who received roflumilast, as compared with patients who received placebo (P< 0.0001). In addition, the rate of COPD exacerbations was reduced by 17% in patients who received roflumilast (P< 0.0003).[39]

Anti-inflammatory therapy

Inflammation plays a significant role in the pathogenesis of COPD. Oral and inhaled corticosteroids (ICS) attempt to temper this inflammation and positively alter the course of disease. The use of oral steroids in the treatment of acute exacerbations is widely accepted and recommended, given their high efficacy. On the other hand, use of oral steroids in the management of stable chronic COPD is not recommended, given their adverse effects. ICS, similar to other inhaled agents, are only minimally absorbed and therefore systemic adverse effects are limited. Nonsteroidal antiinflammatory drugs such as cromolyn and nedocromil have not been shown to be efficacious in the treatment of COPD.

ICS are widely used in COPD patients despite limited evidence of benefit. Despite the theoretical benefit, the current consensus is that ICS do not decrease the decline in FEV1.[40] They have, however, been shown to decrease the frequency of exacerbations and improve quality of life for symptomatic patients with an forced expiratory volume in 1 second (FEV1) of less than 50%.[41] ICS are not recommended as monotherapy and should be added to a regimen that already includes a long-acting bronchodilator.

Oral steroids have been widely used in the treatment of acute exacerbation of COPD. A meta-analysis concluded that oral or parenteral corticosteroids (1) significantly reduced treatment failure and need for additional medical treatment and (2) increased the rate of improvement in lung function and dyspnea over the first 72 hours.[42] The use of oral steroids in persons with chronic stable COPD is widely discouraged given the adverse effect profile, which includes hypertension, glucose intolerance, osteoporosis, fractures, and cataracts, among others. A Cochrane review showed no benefit at low-dose therapy and short-lived benefit with higher doses (>30 mg of prednisolone).[42]

Debate continues regarding use of ICS and the risk for pneumonia in patients with COPD. Sin et al analyzed data from 7 large clinical trials (n = 7042) of patients with stable COPD who used inhaled budesonide (n = 3801) or a control regimen (placebo or formoterol alone). No significant difference was recorded for pneumonia occurrence between the budesonide group (3%; n = 122) and the control group (3%; n = 103). Increasing age and decreasing percent of predicted FEV1 were the only variables that were significantly associated with pneumonia occurrence.[43]

A concern over many years has been if cardiovascular risk is heightened in patients with COPD on combination ICS/LABA; however, it has been shown that the presence of cardiovascular disease should not affect the role of the combination ICS/LABA in COPD. The Study to Understand Mortality and MorbITy (SUMMIT) was an international, multicenter randomization of over 16,000 subjects with moderate COPD (postbronchodilator FEV1 between 50% and 70% of the predicted value) and at increased risk, or documented risk, of cardiovascular disease. The investigators enrolled patients in permuted blocks to receive once-daily inhaled placebo, fluticasone furoate (100 µg), vilanterol (25 µg), or the combination of fluticasone furoate/vilanterol (100/25 µg). The primary outcome was all-cause mortality, with secondary outcomes on composite of cardiovascular events and the on-treatment rate of decline in FEV1. Over 3 years, treatment with fluticasone furoate and vilanterol (when compared with placebo) did not affect the mortality or cardiovascular outcomes.[44]


In patients with COPD, chronic infection or colonization of the lower airways with S pneumoniae, H influenzae, and/or Moraxella catarrhalis is common. Patients with severe disease have a higher prevalence of Gram-negative organisms such as Pseudomonas. The use of antibiotics for the treatment of acute exacerbations is well supported.[45] The patients who benefited most from antibiotic therapy were those with exacerbations that were characterized by at least two of the following: increases in dyspnea, sputum production, and sputum purulence (The Winnipeg criteria). 

Inpatient management of acute exacerbations of COPD includes empiric antibiotic coverage with a macrolide, a beta-lactam, or doxycycline.

The prophylactic use of antibiotics, in particular azithromycin, to prevent COPD exacerbations has been explored over the past 20 years. In 2011, Albert et al reported on the use of azithromycin to prevent exacerbations of COPD[44] ; they showed that among 1,142 patients with severe COPD (defined as an FEV1 of less than 40% predicted), those randomized to take 250 mg of daily azithromycin for 1 year had fewer clinical exacerbations, longer time to first exacerbation, and higher quality of life scores when compared with placebo. Adverse effects include hearing loss and prolongation of the QT interval.

In 2013, the FDA released an announcement of sudden death associated with azithromycin, stating that patients at particular risk for developing torsades de pointes were known to have preexisting prolonged QT interval, low levels of potassium or magnesium, bradycardia, history of antiarrhythmics, or known arrhythmias.

Mucolytic agents

Viscous lung secretions in patients with COPD consist of mucus-derived glycoproteins and leukocyte-derived DNA. Mucolytic agents reduce sputum viscosity and improve secretion clearance. Although mucolytic agents have been shown to decrease cough and chest discomfort, they have not been shown to improve dyspnea or lung function.[46]

However, in 2009-2010, Chinese investigators designed and implemented a prospective, randomized, double-blind placebo-controlled trial, studying the effects of long-term oral N-acetylcysteine at 600 mg twice daily in subjects with GOLD stage I COPD. They found long-term use (over a year and a half) can actually prevent exacerbations in moderate disease. Interesting enough, exacerbations of COPD were the most significant adverse effect of the trial.[47] The study was published in The Lancet in March of 2014.

Proton pump inhibitors

Sasaki et al conducted a randomized, observer-blind, controlled trial to determine if proton pump inhibitors (PPIs) reduce the incidence of common colds in patients with COPD. Patients (n = 100) were assigned to conventional therapy (control group) or conventional therapy plus PPI (lansoprazole 15 mg/d). The frequency of common colds and COPD exacerbations was measured, and the number of exacerbations per person over 12 months was significantly lower in the PPI group compared with the control group (P< .001). No significant difference in the numbers of common colds was observed between the PPI group and the control group. The authors concluded that although lansoprazole showed a significant decrease in COPD exacerbations, more definitive clinical trials are required.[48]

Oxygen therapy

Chronic hypoxemia may develop in patients with severe stable COPD (GOLD stage IV). Two landmark trials, the British Medical Research Council (MRC) study and the National Heart, Lung, Blood Institute's Nocturnal Oxygen Therapy Trial (NOTT) showed that long-term oxygen therapy improves survival by 2-fold or more in hypoxemic patients with COPD. Hypoxemia was defined as a PaO2 of less than 55 mm Hg or oxygen saturation of less than 90%. Exercise-induced hypoxemia is also an accepted indication for supplemental oxygen because it improves exercise performance.[49]

Oxygen toxicity from high oxygen concentrations (FiO2 >60%) is well recognized. Little is known about the long-term effects of low-flow oxygen. The increased survival rate and quality-of-life benefits of long-term oxygen therapy outweigh the possible risks. PaCO2 retention from depression of the hypoxic drive has been overemphasized. PaCO2 retention more likely is a consequence of ventilation/perfusion mismatching than of respiratory center depression. While this complication is not common, it can be avoided by titrating oxygen delivery to maintain the PaO2 at 60-65 mm Hg.

The continuous-flow nasal cannula is the standard means of oxygen delivery for stable hypoxemic patients. The cannula is simple, reliable, and generally well tolerated. Each liter of oxygen flow adds 3-4% to the fraction of inspired oxygen (FIO2). Oxygen-conserving devices function by delivering all of the oxygen during early inhalation. These devices improve the portability of oxygen therapy and reduce the overall costs. Three distinct oxygen-conserving devices are available, and they include reservoir cannulas, demand-pulse delivery devices, and transtracheal oxygen delivery. Although no longer regularly performed I he United States, transtracheal oxygen delivery involves insertion of a catheter percutaneously between the second and third tracheal interspace. Transtracheal oxygen delivery is invasive and requires special training for the physician, patient, and caregiver. The procedure has risks and medical benefits but is of limited applicability.

Sleep and COPD

Patients with COPD may develop substantial decreases in nocturnal PaO2 during all phases of sleep but particularly during rapid eye movement sleep. These episodes are associated with rises in pulmonary arterial pressures and disturbance in sleep architecture initially, but patients may develop pulmonary arterial hypertension and cor pulmonale if the hypoxemia remains untreated. Therefore, patients who have a daytime PaO2 greater than 60 mm Hg but demonstrate substantial nocturnal hypoxemia should be prescribed oxygen supplementation for use during sleep.


Infections can lead to COPD exacerbations. Vaccinations are a safe and effective modality to reduced infections in susceptible COPD patients. The pneumococcal vaccine should be offered to all patients older than 65 years or patients of any age who have an FEV1 of less than 40% of predicted. The influenza vaccine should be given annually to all COPD patients.

There is emerging evidence that the current 23-valent pneumococcal vaccine administered to patients with COPD may not be as effective as previously thought; a 2013 Cochrane review suggests the evidence is less clear for routine support of vaccination against all-cause pneumonia.[50, 51] Efficacy was shown in subgroups of patients younger than 65 years with severe airflow obstruction, but not otherwise. The 23-valent vaccine includes serotypes studied to be effective against nearly 72-95% of invasive pneumococcal diseases. A 13-valent vaccine is being studied in Europe with enhanced immunogenicity, and is already approved for children and adults with chronic illnesses older than 50 years. Despite the data discussed here, it should be noted that current guidelines recommend pneumococcal vaccination in patients with emphysema and COPD aged 65 years and older.[52]

Alpha1-antitrypsin deficiency

The treatment strategies for alpha1-antitrypsin (AAT) deficiency involve reducing the neutrophil elastase burden, primarily by smoking cessation, and augmenting the levels of AAT. Available augmentation strategies include pharmacologic attempts to increase endogenous production of AAT by the liver (ie, danazol, tamoxifen) or administration of purified AAT by periodic intravenous infusion or by inhalation. Tamoxifen can increase endogenous production of AAT to a limited extent, so this may be beneficial in persons with the PIZZ phenotype.

Intravenous augmentation therapy is the only available approach that can increase serum levels to greater than 11 mmol/L, the protective threshold. Studies show that the infusions can maintain levels of more than 11 mmol/L, and replacement is administered weekly (60 mg/kg), biweekly (120 mg/kg), or monthly (250 mg/kg). The ability of intravenous AAT augmentation to alter the clinical course of patients with AAT deficiency has not been demonstrated. Uncontrolled observations of patients suggest that the FEV1 may fall at a slower rate in patients who receive AAT replacement.[53]


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.

Acute Exacerbation of COPD

Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) is defined as worsening of cough, increase in phlegm production, change in phlegm quality, and increase in dyspnea. AECOPDs are common in the course of the disease. Previously thought to occur at random, careful analysis by Hurst et al has shown AECOPDs occur in clusters.[54]  The study showed patients with an AECOPD were at an increased risk of another attack in the 8 weeks following their initial episode. Close follow up during this “brittle” period may lead to earlier treatment and better clinical outcomes.

AECOPDs are a major reason for hospital admission in the United States, although mild episodes may be treated in an outpatient setting. Indications for admission include failure of outpatient treatment, marked increase in dyspnea, altered mental status, and increase in hypoxemia or hypercapnia. Care must be taken to evaluate for other conditions that may mimic AECOPD.[55]

AECOPD can result in hypoxemia and hypercapnia. Mild episodes may be managed with supplemental oxygen to keep PaO2 of 60 mm Hg. If the episode is severe, the patient may require ventilatory support in the form of either noninvasive positive-pressure ventilation (NIPPV) or invasive positive-pressure ventilation. The use of NIPPV is now well studied and supported in patients who have no contraindication to its use. A Cochrane review showed NIPPV reduces mortality, avoids endotracheal intubation, and decreased treatment failure.[56]

Pharmacological treatment of COPD includes bronchodilators, antibiotics, and steroids. Short-acting bronchodilators are the mainstay of therapy. Combinations of a beta2-agonist and anticholinergic agent are commonly used together, although the benefit of both over either is marginal. Oral or parenteral steroids are indicated in the treatment of AECOPD and have been shown to shorten recovery time and improve outcome. Importantly, taper the steroid course over 7-14 days because prolonged courses offer no additional benefit and increase adverse effects. Antibiotics have been shown to provide benefit in patients who present with dyspnea, increased purulence, and increased volume of sputum. The choice of antibiotics should be based on suspected etiology, patient history, and prevalent resistance patterns.

The role of antibiotics for prophylaxis against an exacerbation remains unclear. A study by Albert et al did show a decrease in the frequency of exacerbation in patients treated with daily azithromycin.[45]  However, this came at the cost of hearing impairment and increased macrolide resistance. Further long-term studies are needed before this can be recommended as standard of care.

Surgical Care

Various surgical approaches to improve symptoms and restore function in patients with emphysema have been described. These should be offered to carefully selected patients as they may provide great benefit. However, the benefits of surgery may be tempered by significant morbidity.[3]


Removal of giant bullae has been a standard approach in selected patients for many years. Bullae can range from a few centimeters to occupying a third of the hemithorax. Giant bullae may compress adjacent lung tissue, reducing the blood flow and ventilation to the relatively healthy lung. Removal of these bullae may result in expansion of compressed lungs and improvement of lung function. Giant bullectomy can produce subjective and objective improvement in selected patients, ie, those who have bullae that occupy at least 30%—and preferably 50%—of the hemithorax that compress adjacent lung, with an FEV1 of less than 50% of predicted and relatively preserved lung function otherwise.

Lung volume reduction surgery

Lung volume reduction surgery (LVRS) attempts to decrease hyperinflation by surgically resecting the most diseased parts of the lung. This improves airflow by increasing the elastic recoil of the remaining lung and the mechanical efficiency of the respiratory muscles to generate expiratory pressures. The National Emphysema Treatment Trial (NETT) compared LVRS with medical management over a 4-year period. Subgroup analysis revealed the greatest benefit was achieved for patients with upper lobe–predominant emphysema and low exercise tolerance. These patients had improvement in mortality, work capacity, and quality of life. LVRS was shown to increase mortality in subjects considered to be high-risk patients (eg, FEV1< 20% predicted and either DLCO < 20% predicted or homogeneous changes on chest CT scan).[57]

Lung volume reduction surgery is not recommended for patients with AATD-related emphysema.[16]

Endobronchial valve placement

Endobronchial valve placement through bronchoscopy is under investigation as an alternative to LVRS. These valves are unidirectional and allow exhalation but do not allow inhalation. This results in a deflated lung distal to the valve. Bronchi are chosen to isolate segments of the lung that show the greatest emphysema and hyperinflation. The benefit, similar to LVRS, is obtained by decreasing the volume of most diseased portions of the lung.

The Endobronchial Valve for Emphysema Palliation Trial (VENT) studied the safety and efficacy of this approach in a nonblinded, prospective, randomized multicenter study. Results showed a modest but significant improvement in both the FEV 1 (relative increase, 6.8%) and 6-minute walk test (relative increase, 19.1 m) in the study group. Analysis revealed that the greatest benefit was obtained by those patients with greater heterogeneity of emphysema and intact interlobar fissures. The study group unfortunately also showed significantly higher rates of COPD exacerbations and hemoptysis.[58]

Lung transplantation

COPD makes up the largest single category of patients who undergo lung transplantation. Lung transplantation provides improved quality of life and functional capacity but does not result in survival benefit. The lack of survival benefit makes the timing of transplant difficult. The patients selected to receive transplants should have a life expectancy of 2 years or less. Current guidelines by the International Society of Heart and Lung Transplantation recommends referring for transplantation when the BODE index (body mass index, obstruction [FEV1], dyspnea [ie, Medical Research Council Dyspnea Scale], and exercise capacity [ie, 6-min walking distance]) is greater than 5.[59]

Pulmonary Rehabilitation

Pulmonary rehabilitation (PR) is beneficial for symptomatic medically stable patients with COPD and supervised, center-based PR is also effective during or soon after acute exacerbations. Comprehensive PR has similar benefits when delivered in inpatient, outpatient, and community-based settings. As such, it should be a standard of care alongside other well-established treatments (such as pharmacotherapy, supplemental oxygen, or noninvasive ventilation).[60]

Generally, a minimum of 8 weeks (two to three sessions per week) of outpatient or community-based treatment is needed to achieve an effect on exercise performance and quality of life. Longer programs may produce greater gains, and repeat courses have been shown benefits equivalent to those of first-time participation. Patients completing a PR program benefit from a maintenance exercise program to support the continuation of positive exercise behavior.[61]

Exercise training is the cornerstone component of PR. Concurrent behavioral interventions, such as promoting self-efficacy and teaching collaborative self-management skills, are also integral to optimizing patient outcomes.[60]  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. These individuals include physicians, nurses, dietitians, respiratory therapists, exercise physiologists, physical therapists, occupational therapists, recreational therapists, cardiorespiratory technicians, pharmacists, and psychosocial professionals. 

A rehabilitation program may include a number of components and should be tailored to the needs of the individual patient. Breathing retraining techniques (eg, diaphragmatic and pursed-lip breathing) may improve the ventilatory pattern and may prevent dynamic airway compression.

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 the upper extremities. Breathing retraining techniques (eg, diaphragmatic and pursed-lip breathing) may improve the ventilatory pattern and may prevent dynamic airway compression. However, many patients with advanced emphysema may be have serious deconditioning and not have the baseline muscular strength to proceed with vigorous activity. Patients with “pulmonary cachexia” may have upper extremity wasting and atrophy of many of their accessory breathing musculature. Thought to be caused by advanced disease and malnutrition, this systemic condition has had limited therapy until evidence suggested benefit in the addition of anabolic steroidsduring pulmonary rehabilitation.[62]

Following pulmonary rehabilitation, improvements have been demonstrated in objective measures of quality of life, well-being, and health status, including reduction in respiratory symptoms, increases in exercise tolerance and functional activities, less anxiety and depression, and increased feelings of control and self-esteem. Pulmonary rehabilitation also results in substantial savings in healthcare costs by reducing hospital and medical resource use.

Also see Pulmonary Rehabilitation 


Referral to a pulmonary specialist is indicated for the following:

  • Symptoms persist and/or exacerbations occur despite treatment
  • If diagnosis is uncertain or alternative diagnoses such as bronchiectasis, post-tuberculous scarring, bronchiolitis, pulmonary fibrosis, pulmonary hypertension need to be excluded
  • ATTD is diagnosed
  • Atypical or additional signs and symptoms (e.g., hemoptysis, weight loss, night sweats, signs of bronchielctasis or other structural lung disease) are present
  • Chronic airway disease is suspected but few features of asthma and COPD are present
  • Comorbidities are present that may interfere with assessment and management of airway disease

Air travel

Many commercial airplanes fly at altitudes of 30,000-40,000 feet, but passenger cabins are pressurized to an altitude of 5,000-8,000 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. Usually, this increase in tidal volume (caused by increase in minute ventilation) is subtle and not recognized by the healthy population. In patients with COPD and emphysema, it may be noticeable. The following is a prediction equation used to estimate PaO2 at 8000 feet (2440 m):

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 8,000 feet is an indication for supplemental oxygen. This can be arranged prior to the flight through the airline directly or through the airline agent but requires extra expense.[62]



Guidelines Summary

The COPD Foundation Pocket consultant Guide (PCG) defines COPD as post bronchodilator FEV1/FVC ratio less than 0.7 on spirometry and provides an algorithm for pharmacologic treatment selection based on symptoms and exacerbations. All patients should receivie smoking cessation support, vaccines and participate in a regular excercise program.[28]  

For patients with MMRC 0,1 and less than 2 exacerbations per year, short-acting beta2 agonist as needed is recommended. If symptoms persist, LAMA therapy is indicated.  MMRC 0, 1 and 2 for more exacerbations per year, the recommended treatment options include[28] :

  • LAMA monotherapy
  • Combination LAMA and LABA therapy
  • Combination LABA and ICS

For persistent symptoms or exacerbations, combination LAMA, LABA and ICS therapy is recommended.

For MMRC 2 or greater, pulmonary rehabilitation with either LAMA monotherapy or combination LAMA and LABA therapy. Combination LAMA, LABA and ICS therapy is recommended to treat persistent symptoms or exacerbations.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) offers the following guidelines for pharmacologic treatment of COPD[2] :

  • Inhaled bronchodilators are central to symptom management and should be given to prevent or reduce symptoms
  • Regular and as needed use of short acting beta2 agonist or short-acting antimuscarinics improve FEV 1 and decrease symptoms
  • Both LABA and LAMA monotherapy significantly improve lung function, dyspnea, health status and reduce exacerbations
  • LAMAs are more effective than LABAs for reducing exacerbations and decreasing hospitalizations
  • Combination LABA and LAMA therapy is superior to either LABA and LAMA monotherapy and ICS/LABA combination therapy for increasing FEV 1 and decreasing symptoms as well as reducing exacerbations
  • Tiotropium improves effectiveness of pulmonary rehabiliation

Management of acute exacerbations of COPD

GOLD guidelines include the following recommendations for the treatment of acute exacerbations of COPD (AECOPD)[2] :

  • Short-acting inhaled beta2-antagonists, with or without short-acting anticholinergics for initial treatment
  • Maintenance therapy with long-acting bronchodialators should begin prior to hospital discharge
  • Antibiotics, when indicated, and corticosteroids for no more than 5-7 days
  • Noninvasive mechanical ventilation should be the first mode of ventilation in acute respiratory failure
  • Methylxanthines are not recommended
  • Appropriate measures for exacerbation prevention should be initiated following an AECOPD 

VA/DoD guidelines recommend antibiotic use for patients with acute exacerbations who have increased dyspnea and increased sputum purulence (change in sputum color) or volume. Choice of antibiotic should be based on local resistance patterns and patient characteristics. First-line antibiotic choice include[27] :

  • Doxycycline
  • Trimethoprim/sulfamethoxazole (TMP-SMX)
  • Second generation cephalosporin
  • Amoxicillin
  • Amoxicillin/clavulanate
  • Azithromycin.

Broader spectrum antibiotics (e.g., quinolones) are reserved for patients with specific indications including[27] :

  • Critically ill patients in the intensive care unit (ICU)
  • Patients with recent history of resistance, treatment failure, or antibiotic use
  • Patients with risk factors for health care associated infections.

For outpatients with AECOPD who are treated with antibiotics, a five-day course of the chosen antibiotic is recommended. In agreement with the GOLD guidelines, a course of oral corticosteroids for 5-7 days is also recommeded.[27]

In addition to GOLD and the VA/DoD, the European Respiratory Society/American Thoracic Society (ERS/ATS) released joint guidelines for the management of AECOPD. The recommendations are summarized below[63]

  • For ambulatory patients, treatment with a short course (≤14 days) of oral corticosteroids and administration of antibiotics; Antibiotic selection should be based upon local sensitivity patterns.
  • For hospitalized patients, oral administration of corticosteroids is preferred over IV if gastrointestinal access and function are intact 
  • For exacerbation associated with acute or acute-on-chronic hypercapnic respiratory failure, provide noninvasive mechanical ventilation 
  • A home-based management program involving nurses and potentially other healthcare professionals ( e.g. physicians, social workers and physical therapists), also known as “hospital-at-home”, may be considered as an alternative to hospitalization in patients presenting to the emergency department with a COPD exacerbation
  • Pulmonary rehabilitation should not be initated during hospitalization but should begin within 3 weeks after hospital discharge

Guidelines for the prevention of AECOPDs have been issued by the following organizations:

  • European Respiratory Society/American Thoracic Society (ERS/ATS)
  • American College of Chest Physicians/Canadian Thoracic Society (ACCP/CTS)

The ACCP/CTS guidelines address three areas of prevention: nonpharmacologic treatments, maintenance inhaled therapies and oral therapy in patients with a history of smoking. The recommendations for nonpharmacologic treatments include[64]

  • Although the 23-valent pneumococcal vaccine should be administered as part of overall medical management, there is not sufficient evidence that vaccination prevents acute exacerbations;  however, the influenza vaccine should be given annually to prevent AECOPDs 
  • Smoking cessation counseling and treatment is an important component of a comprehensive prevention strategy 
  • Pulmonary rehabilitation should be initiated following a recent exacerbation (ie, ≤ 4 weeks) 
  • Education or case management alone should not be used for prevention of AECOPD; education and case management for prevention of exacerbations should include direct access to a health-care specialist at least monthly. 
  • Telemonitoring compared with usual care has not shown to prevent AECOPD 

Key recommendations for maintenance inhaled therapies in patients with moderate to severe airflow obstruction include[64] :

  • Long-acting muscarinic antagonist (LAMA) for prevention of moderate to severe AECOPD 
  • Short-acting muscarinic antagonist to prevent mild-moderate AECOPD 
  • Short-acting muscarinic antagonist plus short-acting beta2-agonists to prevent moderate AECOPD 

ERS/ATS guidelines recommend an oral mucolytic agent and a macrolide antibiotic to prevent future AECOPDs in patients with moderate or severe airflow obstruction and AECOPDs despite optimal inhaled therapy.[65]  

For patients with stable COPD, the guidelines include the following recommendations for inhaled maintenance therapies[64] :

  • Maintenance combination inhaled corticosteroid/long-acting beta2-agonist (LABA) therapy to prevent AECOPD 
  • Both inhaled long-acting anticholinergic/LABA therapy and inhaled long-acting anticholinergic monotherapy are effective to prevent AECOPD 

ERS/ATS guidelines recommend a LAMA be prescribed in preference to LABA monotherapy to prevent future AECOPD in patients who have moderate or severe airflow obstruction and a history of one or more exacerbations during the previous year.[65]

For oral therapy in patients with a history of smoking, recommendations included[64] :

  • Use of a long-term macrolide to prevent acute exacerbations in patients who have a history of moderate or severe AECOPD in the previous year despite optimal maintenance inhaler therapy
  • Within 30 days following an acute exacerbation, systemic corticosteroids administed orally or by IV to prevent hospitalization for subsequent AECOPDs 
  • Slow-release theophylline twice daily to prevent AECOPD in patients with stable COPD
  • N-acetylcysteine to prevent AECOPDs in patients with a history of two or more exacerbations in the previous 2 years

ERS/ATS guidelines recommend roflumilast to prevent future exacerbations in patients with severe or very severe airflow obstruction, symptoms of chronic bronchitis and exacerbations despite optimal inhaled therapy. In addition, ERS/ATS guidelines recommend against the use of fluoroquinolone therapy for the prevention of AECOPD .[65]  

Pulmonary Rehabilitation

The British Thoracic Society has released guidelines for the use of pulmonary rehabilitation in the management of COPD which include both evidence-based recommendations and good practice points for which there is no research evidence.  The guidelines recommend that pulmonary rehabilitation be offered to patients with COPD with a goal of improving exercise capacity, dyspnea, psychological health and health status by a clinically important improvements. The key recommendations include[66] :

  • Pulmonary rehabilitation programs should be a minimum of twice-weekly supervised sessions for a duration of 6-12 weeks
  • Efficacy of pulmonary rehabilitation needs to be regularly assessed by demonstrating clinically important improvements in exercise capacity, dyspnoea and health status
  • To ensure strength and endurance benefits, a combination of progressive muscle resistance and aerobic training should be delivered; interval and continuous training can be applied safely and effectively
  • Pulmonary rehabilitation should be provided within a supervised program. If a structured home-based program is considered, mechanisms to offer remote support and/or supervision, provision of home exercise equipment and patient selection are important considerations
  • Patients should be taking bronchodilator therapy prior to referral to pulmonary rehabilitation
  • Pulmonary rehabilitation at hospital discharge should be offered to patients following acute exacerbation of COPD to commence within 1 month of discharge.
  • Inspiratory muscle training (IMT) is not recommended as a routine adjunct to pulmonary rehabilitation
  • Patients with low BMI and evidence of quadriceps weakness who are unable or unwilling to participate in pulmonary rehabilitation could be considered for neuromuscular electrical stimulation (NMES)
  • Repeat pulmonary rehabilitation should be considered in patients who have completed a course of pulmonary rehabilitation more than 1 year previously
  • All patients completing pulmonary rehabilitation should be encouraged to continue to exercise beyond the program

Alpha-1 antitrypsin deficiency (AATD)

Clinical practice guidelines have been released by the Alpha-1 Foundation for the diagnosis and management of Alpha-1-antitrypsin deficiency (AATD).[16]  The guidelines are intended to update the joint guidelines published the American Thoracic Society (ATS) and the European Respiratory Society in 2003.[11]

Genetic Testing

The Alpha-1 Foundation recommends the following high-risk groups receive genetic testing for AATD[16] :

  • All individuals with COPD regardless of age or ethnicity 
  • All individuals with unexplained chronic liver disease
  • All individuals with necrotizing panniculitis, granulomatosis with polyangiitis, or unexplained bronchiectasis 
  • Parents, siblings, and children, as well as extended family of individuals identified with an abnormal gene for AAT, should be provided genetic counseling and offered testing for AATD 

In addition, for diagnostic testing of symptomatic individuals, genotyping for at least the S and Z alleles is recommended. The guidelines recommend against AAT level testing alone for family testing after a proband is identified because it does not fully characterize disease risk from AATD. Advanced or confirmatory testing should include Pi-typing, AAT level testing, and/or expanded genotyping.

The World Health Organization (WHO) recommends that all patients with COPD should be screened once for AATD.[2]  VA/DoD recommends testing for AATD in patients presenting with early onset COPD or a family history of early onset COPD and patients with confirmed AATD should be referred to a pulmonologist for management of treatment.[27]


The Alpha-1 Foundation guidelines include the following recommendations for evaluation and monitoring[16] :

  • Complete lung function testing should be performed for initial evaluation
  • Spirometry test should be performed at least annually
  • In newly diagnosed patients who are symptomatic and/or have abnormal pulmonary function testing, a baseline CT scan of the chest; serial chest CT scanning to monitor disease progression is not recommended
  • Monitoring for liver disease at annual intervals (or more frequently as indicated by clinical circumstances) should include focused physical exam for signs of liver disease, liver ultrasound, and laboratory testing of AST, ALT, GGT, albumin, bilirubin, INR, and platelets 


The Alpha-1 Foundation guidelines recommend intravenous (IV) augmentation therapy for patients with confirmed AATD and an FEV1 less than or equal to 65% predicted and/or necrotizing panniculitis. Recommendation against IV augementation therapy include[16] :

  • Individuals with the MZ genotype of AATD
  • Individuals with lung disease due to AATD who continue to smoke
  • Individuals with AATD and emphysema or bronchiectasis who do not have airflow obstruction
  • The treatment of liver disease due to AATD
  • Individuals who have undergone liver transplantation

In addition, doses higher than the FDA approved dose and montioring AAT blood levels to assess dosing are not recommended.

Asthma-COPD Overlap

In 2017, the Global Initiative for Asthma (GINA) and the Global Initiative for Obstructive Lung Disease (GOLD) released updated guidelines for the diagnosis and treatment of asthma, COPD and asthma-COPD overlap. The main goal of the consensus-based guidelines is to assist non-pulmonary specialists in the identification of chronic airflow obstructive disease, distinguish between asthma, COPD and ASCO, and determine initial treatment approach.[6]

GINA-GOLD no longer use the term asthma-COPD overlap syndrome (ASCO) as asthma-COPD overlap does not describe a single disease entity. Patients with combined features of both disorders more likely have several different phenotypes of airway disease caused by a variety of mechanisms. 

The guidelines suggest a stepwise approach to diagnosis that includes the following steps[6] :

  • Step 1: Identifying patients at risk for chronic airway disease through clinical history, physical examination, radiology and screening questionnaires
  • Step 2: Differentiate asthma, COPD and asthma-COPD overlap based on a comparison of the number of features in favor of each possible diagnosis
  • Step 3: Perform spirometry and peak expiratory flow measurement to confirm or exclude diagnoses

Initial treatment recommendations include[6] :

  • For patients with characteristic features of asthma: adequate controller therapy with inhaled corticosteroids (ICS), but not long-acting bronchodilators as monotherapy
  • For patients with characteristic features of COPD: symptomatic treatment with brochodialators or combination ICS-bronchodilator therapy, but not ICS monotherapy
  • For patients with characteristics of both asthma and COPD: ICS in a low or moderate dose depending on severity of symptoms; add on treatment with long-acting beta-antagonist (LABA) and/or long-acting muscarinic antagonist (LAMA). Do not treat with LABA monotherapy

For all three diagnoses of chronic airflow limitation, treat comorbidities, reduce modifiable risk factors (i.e., smoking cessation, vaccinations), increase physical activity, encourage appropriate self-management strategies and perform regular follow-up. For COPD and asthma-COPD overlap, pulmonary rehabilitation is appropriate.

Referral to a pulmonary specialist is indicated for the following[6] :

  • Symptoms persist and/or exacerbations occur despite treatment
  • If diagnosis is uncertain or alternative diagnoses such as bronchiectasis, post-tuberculous scarring, bronchiolitis, pulmonary fibrosis, pulmonary hypertension need to be excluded
  • Atypical or additional signs and symptoms (e.g., hemoptysis, weight loss, night sweats, signs of bronchielctasis or other structural lung disease)
  • Chronic airway disease is suspected but few features of asthma and COPD are present
  • Comorbidities are present that may interfere with assessment and management of airway disease


Medication Summary

Oral and inhaled medications are used for patients with stable emphysema to reduce dyspnea and improve exercise tolerance. Most of the medications used in emphysema treatment are directed at the 4 potentially reversible mechanisms of airflow limitation: (1) bronchial smooth muscle contraction, (2) bronchial mucosal congestion and edema, (3) airway inflammation, and (4) increased airway secretions.


Class Summary

These agents decrease muscle tone in both the small and large airways of the lungs, thereby increasing ventilation. This category includes beta-adrenergic agents, methylxanthines, and anticholinergics.

Albuterol (Proventil, Ventolin)

Albuterol is a beta2 agonist that relaxes bronchial smooth muscle by action on beta2 receptors, with little effect on cardiac muscle contractility. Most patients (even those who have no measurable increase in expiratory flow) benefit from treatment. Inhaled beta-agonists initially are prescribed as needed. Frequency may be increased. Institute a regular schedule in patients on anticholinergic drugs who remain symptomatic. Albuterol is available as liquid for nebulizer, MDIs, and dry-powder inhalers.

Metaproterenol (Alupent)

Metaproterenol relaxes bronchial smooth muscle by action on beta2 receptors, with little effect on cardiac muscle contractility. Most patients (even those who have no measurable increase in expiratory flow) benefit from treatment. Inhaled beta-agonists initially are prescribed as needed. Frequency may be increased. Institute a regular schedule in patients on anticholinergic drugs who remain symptomatic. Metaproterenol is available as liquid for nebulizer, MDIs, and dry-powder inhalers.

Levalbuterol (Xopenex)

Levalbuterol is used for the treatment or prevention of bronchospasm. It is a selective beta2-agonist agent. Albuterol is a racemic mixture, while levalbuterol contains only the active R-enantiomer of albuterol. The S-enantiomer does not bind to beta2-receptors, but it may be responsible for some adverse effects of racemic albuterol, including bronchial hyperreactivity and reduced pulmonary function during prolonged use.

Ipratropium (Atrovent)

Ipratropium is chemically related to atropine. It has antisecretory properties, and, when applied locally, it inhibits secretions from serous and seromucous glands lining the nasal mucosa. Ipratropium is used on a fixed schedule with a beta-agonist.

Salmeterol (Serevent)

By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, salmeterol can relieve bronchospasm. The effect also may facilitate expectoration. Salmeterol may be useful when bronchodilators are used frequently. More studies are needed to establish the role for these agents. When administered at high or more frequent doses than recommended, the incidence of adverse effects is higher. The bronchodilating effect lasts longer than12 hours. It is used on a fixed schedule in addition to regular use of anticholinergic agents.

Formoterol (Oxis, Foradil)

Formoterol is currently not available in the United States (investigational beta-agonist with rapid onset and long duration of action). By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, it can relieve bronchospasms. The effect also may facilitate expectoration. Formoterol has been shown to improve symptoms and morning peak flows in asthma. It may be useful when bronchodilators are used frequently. More studies are needed to establish the role for these agents. When administered at high or more frequent doses than recommended, the incidence of adverse effects is higher. The bronchodilating effect lasts longer than 12 hours. Formoterol is used on a fixed schedule in addition to regular use of anticholinergic agents.

Indacaterol, inhaled (Arcapta Neohaler)

Indacaterol is a long-acting beta2-agonist (LABA) indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. LABAs act locally in the lungs as bronchodilators. Indacaterol stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP; increased cyclic AMP levels cause relaxation of bronchial smooth muscle. It is not for use as initial therapy in patients with acute deteriorating COPD.

Tiotropium (Spiriva)

Tiotropium is a quaternary ammonium compound. It elicits anticholinergic/antimuscarinic effects with inhibitory effects on M3 receptors on airway smooth muscles, leading to bronchodilation. It is available as a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. It helps COPD patients by dilating narrowed airways and keeping them open for 24 hours.

Theophylline (Aminophylline, Theo-24, Theo-Dur, Slo-bid)

Theophylline potentiates exogenous catecholamines. It stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which stimulates bronchodilation. Its popularity has decreased because of its narrow therapeutic range and frequent toxicity. Bronchodilation may require near-toxic (>20 mg/dL) levels. However, clinical efficacy is controversial, especially in the acute setting. Theophylline has been shown to increase exercise capacity, decrease dyspnea, and improve gas exchange. A longer-acting agent is used daily or twice daily. The target concentration is 5-10 µg/mL. Dosing = (target concentration - current level) X 0.5 (ideal body weight). Alternatively, 1 mg/kg results in approximately a 2- µg/mL increase in serum levels.

Aclidinium (Tudorza Pressair)

Aclidinium is an M1-M3 muscarinic agonist (LAMA). It inhibits M3 receptors, leading to smooth muscle relaxation of bronchi; this leads to subsequent bronchodilation. Prevention of acetylcholine-induced bronchoconstriction effects were dose-dependent in in vitro and in vivo studies and lasted longer than 24 hours.


Class Summary

These agents attempt to moderate the inflammatory component of COPD. They should only be added to a regimen that includes a long-acting bronchodilator.

Fluticasone inhaled

Fluticasone inhaled has extremely potent vasoconstrictive and anti-inflammatory activity. It has weak inhibitory effects on the HPA axis when used at high doses for prolonged periods. Its effectiveness is not established in COPD.

Budesonide inhaled

Fluticasone inhaled has extremely potent vasoconstrictive and anti-inflammatory activity. It has weak inhibitory effects on the HPA axis when used at high doses for prolonged periods. Its effectiveness is not established in COPD.  

Phosphodiesterase-4 Inhibitors

Class Summary

Selective phosphodiesterase-4 (PDE-4) inhibitors reduce exacerbations, improve dyspnea, and increase lung function in patients with severe COPD.

Roflumilast (Daliresp)

Roflumilast is a selective phosphodiesterase-4 (PDE-4) inhibitor. The specific mechanism of action is not well defined but is thought to be related to the effects of increased intracellular cyclic AMP in lung cells. It is indicated to decrease the frequency of exacerbations or the worsening of symptoms from severe COPD.

Smoking cessation therapies

Class Summary

These are most effective when used in conjunction with a support program (ie, counseling, group therapy, and behavioral therapy).

Bupropion is used as a non-nicotine aid to smoking cessation. One study demonstrated 23% sustained cessation with bupropion tablets at 1 year, compared with a 12% sustained cessation with placebo. Bupropion also may be effective in patients who do not quit with nicotine replacement therapy.

Varenicline (Chantix) is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. It is used in conjunction with support groups and/or behavioral counseling. Gradually increase dose upward within 1 wk before quit date to 1 mg PO bid pc. Decrease dose with severe renal impairment or end-stage renal disease.

Nicotine transdermal system (Nicotrol, Habitrol, NicoDerm CQ)

Individuals who smoke more than 1 pack/d initially need a 21-mg patch followed by 14- and 7-mg patches.

Nicotine polacrilex (Nicorette)

Nicotine is absorbed through the oral mucosa. It is quickly absorbed and closely approximates the time course of plasma nicotine levels observed after cigarette smoking. It is available as 2- or 4-mg gum in a box containing 96 pieces. Careful adherence to chewing instructions is important for effective use. The manufacturer recommends that the gum not be used longer than 6 months. Individuals who smoke 1 pack/d should use 4-mg pieces. The 2-mg pieces are to be used by individuals who smoke less than 1 pack/d. Instruct patients to chew hourly and for initial cravings for 2 weeks, then gradually reduce the amount chewed over 3 months.

Bupropion (Zyban)

Bupropion is used in conjunction with a support group and/or behavioral counseling. It inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake.

Varenicline (Chantix)

Varenicline is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Its action is thought to be the result of activity at a nicotinic receptor subtype where its binding produces agonist activity, while simultaneously preventing nicotine binding. The agonistic activity is significantly lower than nicotine. It also elicits a moderate affinity for 5-HT3 receptors. Maximum plasma concentrations occur within 3-4 hours after oral administration. Following regular dosing, a steady state is reached within 4 days.


Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Amoxicillin (Amoxil, Trimox, Moxatag)

Amoxicillin interferes with the synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria

Doxycycline (Doryx, Monodox, Doxy, Adoxa)

Doxycycline is a broad-spectrum, synthetically derived bacteriostatic antibiotic in the tetracycline class. It is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. It inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.


Trimethoprim/sulfamethoxazole inhibits bacterial the synthesis of dihydrofolic acid by competing with para-aminobenzoic acid, resulting in inhibition of bacterial growth. The antibacterial activity of trimethoprim/sulfamethoxazole includes common urinary tract pathogens, except Pseudomonas aeruginosa. Like tetracycline, it has in vitro activity against Bartonella pertussis. It is not useful in mycoplasmal infections.

Azithromycin (Zithromax)

Azithromycin is replacing erythromycin as therapy for community-acquired pneumonia. It covers most potential etiologic agents, including Mycoplasma. The newer macrolides offer decreased GI upset and potential for improved compliance through reduced dosing frequency. They also afford improved action against Haemophilus influenzae.