Emphysema and chronic bronchitis by emedicine.medscape.

com

Emphysema and chronic bronchitis are airflow-limited states contained within the disease state known
as chronic obstructive pulmonary disease (COPD). 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. [1]

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.
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. [2] 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.

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 is finding its way into journals and literature reviews. This entity seeks 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. Although not clearly
defined as of yet, ACOS encompasses a challenge to answer, specifically because of the lack of evidence-
based guidelines to support its naming, recognition, and management.

Risk factors

The risk factors thought to be responsible for the development of COPD are all associated with an
accelerated decline in FEV1 over time. Leading this list is cigarette smoking: 15-20% of 1 pack-per-day
smokers and 25% of 2 pack-per-day smokers develop COPD. Next are cigars and pipe smoke, followed by
secondhand and thirdhand smoke. Occupational, inhalational, and environmental exposures, including
biomass fuel cooking, also are included on the list.

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. Throughout the world, COPD is a disease of occupation and environmental pollutants too,
including but not limited to organic and inorganic dusts, isocyanates, and phosgenes.

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.

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.

Genetic risk factors for the development of COPD are also thought to exist. The most well-studied is
alpha-1-antitrypsin (AAT) deficiency (also known as alpha-1 antiprotease deficiency).

Alpha-1-antitrypsin 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.

Lifetime nonsmokers who are homozygous for the Z allele rarely develop emphysema. Hence, cigarette
smoking is the most important risk factor for emphysema development. The American Thoracic
Society/European Respiratory Society (ATS/ERS) Guidelines recommend screening for AAT deficiency if
emphysema is suspected in any patient younger than 45 years and with any of the following:

Absence of recognized emphysema risk factors such as smoking or occupational inhalational exposure

Unexplained liver disease

Family history of AAT deficiency, COPD, bronchiectasis, or panniculitis

Positive c-ANCA (anti-neutrophilic cytoplasmic antibody) vasculitis

Unclear/idiopathic bronchiectasis

Asthma with persistent, fixed-airways obstruction despite therapy

Pathophysiology

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
pateints. [10] 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.
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). 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.

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.

Morphology

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

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.

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.

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.

Epidemiology

Frequency

United States
The National Health Interview Survey reports the prevalence of emphysema at 18 cases per 1000
persons and chronic bronchitis at 34 cases per 1000 persons. While the rate of emphysema has stayed
largely unchanged since 2000, the rate of chronic bronchitis has decreased. This 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. This is felt to be an underestimation because most patients do not present for
medical care until the disease is in its later stages.

International

The Burden of Obstructive Lung Disease (BOLD) study showed that the worldwide prevalence of COPD
(stage II or higher) was 10.1%. 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.

Sex

In the past, COPD was more prevalent among men; however, this was attributed to the difference in
smoking rates of men versus women. With the increase in smoking among women over the past 30
years, the sex difference has declined. Some studies have suggested women may be even more
susceptible to the development of emphysema.

Prognosis

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.

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

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)

Six-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

BODE's approximate 4-year survival is as follows:

0-2 points = 80%

3-4 points = 67%

5-6 points = 57%

7-10 points = 18%

Mortality/morbidity

A US Centers for Disease Control and Prevention (CDC) Morbidity Mortality Weekly Report study of the
National Vital Statistics System reported an age-standardized death rate from COPD in the United States
for adults older than 25 years of 64.3 deaths per 100,000 population. [23] This rate varied by location,
with the lowest rate in Hawaii (27.1 deaths per 100,000 population) and the highest rate in Oklahoma
(93.6 deaths per 100,000 population).

Patient Education

For patient education resources, visit the Lung Disease and Respiratory Health Center. Also, see the
patient education articles Cigarette Smoking and Emphysema.

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 Milimeter Merkuri (Hydrargyrum), compared with 159 Milimeter Merkuri (Hydrargyrum) 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 Milimeter Merkuri (Hydrargyrum) 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.

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 Milimeter Merkuri (Hydrargyrum) but demonstrate substantial
nocturnal hypoxemia should be prescribed oxygen supplementation for use during sleep.

History

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

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.

Causes

Cigarette smoking

Smoking is by far the single most clearly established environmental risk factor for emphysema/chronic
bronchitis. One in five persons who smokes develops COPD, and 80-90% of COPD patients have a
smoking history.
AAT deficiency syndromes

This syndrome leads to protease-antiprotease imbalance and unopposed action of neutrophil elastases.

Intravenous drug user

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.

Immune deficiency syndromes

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.

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

Vasculitis

Hypocomplementemic vasculitis urticaria syndrome (HVUS) may be associated with obstructive lung
disease.

Other sequellae include angioedema, nondeforming arthritis, sinusitis, conjunctivitis, and pericarditis.

Connective-tissue disorders
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

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.

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

Bronchiectasis

Bronchitis

Lymphangioleiomyomatosis

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.

Serum alpha1-antitrypsin: 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 most common severe variant is the Z allele, which accounts for 95% of the clinically
recognized cases of severe AAT deficiency. The diagnosis of severe AAT deficiency is confirmed when the
serum level falls below the protective threshold value (ie, 3-7 mmol/L). Specific phenotyping is reserved
for patients in whom serum levels are 7-11 mmol/L or when genetic counseling or family analysis is
needed.

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.

Staging

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):

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).

Medical Care

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. 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. [26] Treatments
should be added in a stepwise fashion to reach these goals.

Smoking cessation

Smoking cessation is the single most effective therapy for most COPD patients. [26] 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.

Physician intervention

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 [26] :

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.

Pharmacologic intervention

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.

The most recent drug to receive approval for smoking cessation is varenicline. Varenicline 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.

Pharmacologic therapy for emphysema

Bronchodilators

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 2 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. [27] 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.

LABA

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. [28] 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. [29] 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.

LAMA

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. [30] The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial
studied the effects of use over a 4-year period. [31] 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. [32, 33] 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. [32]

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). [34]

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

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. [35]

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). [36]

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. [37] 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%. [38] 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. [39] 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). [39]

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. [40]

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. [41]

Antibiotics

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. [42] 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 [41] ; 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. [43]

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. [44] 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. [45]

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. [46]

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.

Vaccination

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. [47, 48] 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. [49]

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. [9, 50]

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. [51] 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.

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.

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. [42]
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.

Bullectomy

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).

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.

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.

Consultations

Consultation with a pulmonary specialist is recommended when the diagnosis is suspected, and
specifically when mild obstruction is diagnosed.

Diet

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

Long-Term Monitoring

Pulmonary rehabilitation

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

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. This multidisciplinary approach emphasizes
the following:

Patient and family education

Smoking cessation

Medical management (including oxygen and immunization)

Respiratory and chest physiotherapy

Physical therapy with bronchopulmonary hygiene, exercise, and vocational rehabilitation

Psychosocial support

Pulmonary rehabilitation programs usually are conducted in an inpatient or outpatient setting. A

rehabilitation program may include a number of components and should be tailored to the needs of the
individual patient. All patients who complete the program should be provided guidelines for home
continuation of the program. 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 recent evidence suggests benefit in the addition of anabolic
steroidsduring pulmonary rehabilitation.

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 and the clinical guideline summary, Pulmonary Rehabilitation: Joint
ACCP/AACVPR Evidence-Based Clinical Practice Guidelines.