Chronic Obstructive Pulmonary Disease

From Unjustified Nihilism to Evidence-based Optimism

Bartolome R. Celli
Department of Medicine, Tufts University; and Pulmonary and Critical Care Division, St. Elizabeths Medical Center, Boston, Massachusetts

Chronic obstructive pulmonary disease (COPD) has been associated

with a nihilistic attitude. On the basis of current evidence, this
nihilistic attitude is totally unjustified. The disease must be viewed
through the lens of a new paradigm: one that accepts COPD as not
only a pulmonary disease but also as one with important measurable
systemic consequences. COPD is not only preventable but also treatable. Smoking cessation, oxygen for hypoxemic patients, lung reduction surgery for selected patients with emphysema, and noninvasive
ventilation during severe exacerbations have all been shown to impact on mortality. In addition, pulmonary rehabilitation, pharmacologic therapy, and lung transplantation improve patient-centered
outcomes such as health-related quality of life, dyspnea, exercise
capacity, and even exacerbations and hospitalizations. Caregivers
should familiarize themselves with the multiple complementary
forms of treatment and individualize therapy to the particular situation of each patient. The future for patients with this disease is bright
as its pathogenesis and clinical and phenotypic manifestations are
unraveled. The advent of newer and more effective therapies will
lead to a decline in the contribution of this disease to poor world
health.
Keywords: airflow obstruction;
pulmonary disease; emphysema

bronchitis;

chronic

obstructive

The American Thoracic Society and European Respiratory Society have dened chronic obstructive pulmonary disease (COPD)
as a preventable and treatable disease state characterized by
airow limitation that is not fully reversible. The airow limitation is usually both progressive and associated with an abnormal
response of the lungs to noxious particles or gases, primarily
caused by cigarette smoking. Although COPD affects the lungs,
it also produces signicant systemic consequences (1). This denition changes the paradigm that characterized older denitions
(2, 3) in two important aspects. First, it presents a positive attitude toward the disease when it describes it as it is, preventable
and treatable, and second, it points out a salient feature of
COPD, that is, it is frequently associated with systemic manifestations. This review presents the evidence that COPD is an
increasingly important disease and the many problems that make
it so, and that have led to a nihilistic attitude on the part of those
providing treatment. More importantly, evidence is presented
proving that an optimistic attitude is justied, and that there is
hope for patients who suffer from this disease.

HIGHLY PREVALENT, UNDERDIAGNOSED,

UNDERTREATED, AND UNDERPERCEIVED
COPD causes problems for society because of its direct and indirect costs, but more importantly it affects millions of individuals

(Received in original form October 19, 2005; accepted in final form October 23, 2005)
Correspondence and requests for reprints should be addressed to Bartolome R. Celli,
M.D., Pulmonary and Critical Care Division, St. Elizabeths Medical Center, Boston,
MA 02135. E-mail: bcelli@cchcs.org, bcelli@copdnet.org, bcelli@semc.org
Proc Am Thorac Soc Vol 3. pp 5865, 2006
DOI: 10.1513/pats.200510-111JH
Internet address: www.atsjournals.org

by limiting their laboring and functional capacity. It has a long

subclinical phase but once symptoms develop, COPD usually follows a course of progressive dyspnea at ever lower levels of exercise, gas exchange imbalance, and respiratory failure (1, 3). In the
end, death can occur either from the respiratory failure or from
the frequently associated comorbidity such as coronary artery
disease and lung cancer (4, 5). It is difcult to estimate the
exact prevalence of COPD worldwide. Estimates based on the
presence of airow limitation are the most accurate, because
symptoms and self-report or clinician diagnosis lack sensitivity
and specicity. A postbronchodilator FEV1/FVC less than 70%,
in an individual with the appropriate history of exposure to risk
factors such as cigarette smoke, or inhaled wood smoke, and/or
symptoms of cough, sputum production, or dyspnea, conrms
the diagnosis (1). Some of the best data available at present
come from two sources, the third National Health and Nutrition
Examination Survey (NHANES III), a large national survey conducted in the United States between 1988 and 1994 (6, 7) and the
Proyecto Latinoamericano para la Investigacion de la Enfermedad
Obstructiva Cronica, or PLATINO study (8), conducted in ve
cities in Latin America (Caracas, Venezuela; Mexico City, Mexico;
Montevideo, Uruguay; Santiago, Chile; and Sao Paulo, Brazil)
between 2001 and 2004.
In the NHANES III study from the United States (6), for
those aged 2575 yr, the estimated prevalence of COPD was
16%. The prevalence of both mild and moderate COPD was
higher among males than females and among white subjects than
black subjects, and increased steeply with age. The survey reects
the actual strata of the U.S. population and provides invaluable
data in many health aspects.
The prevalence of COPD determined in the PLATINO study
is perhaps the best available data because it was a eld study
representing the cities surveyed. It was designed to evaluate the
disease itself and it included questions specically directed at the
causes of COPD. Finally, and importantly, the survey included
postbronchodilation FEV1 data. The study was conducted in ve
cities and the prevalence uctuated from 7.8% in Mexico City
to 19.7% in Montevideo. The prevalence was higher among men
than women and among less educated than better educated
persons.
Data from other, smaller surveys showed a prevalence of
13.1% in men and 10.5% in Spain (9), 8.4% in Greece (10), and
11.4% in a European study by de Marco and coworkers (11).
Taken together, these studies conrm the widely held concept
that COPD is highly prevalent. Indeed, if we assume the lowest
of these prevalences, 7.8% for the 40% of people more than
40 yr of age, the total number of cases of COPD in the world
approximates close to 280 million persons, a daunting number
that needs to be controlled. It is estimated that COPD, currently
the fourth leading cause of death in the United States, will
become the third cause of death worldwide by 2020.
Unfortunately, COPD remains largely underdiagnosed. Indeed, in the same NHANES III survey, it was clear that less
than 50% of individuals with COPD based on airow limitation
have a doctors diagnosis of COPD at all stages of COPD (6),
that is, even persons with advanced COPD do not know they
suffer from the disease and thus remain untreated.

Celli: COPD: From Nihilism to Optimism

59

For many possible reasons, including self-guilt, patients themselves underperceive the magnitude of their problem and tend
to accept the limitations associated with disease progression as
natural for a person who has smoked. Indeed, in a telephone
survey of more than 3,000 patients with COPD, Rennard and
coworkers reported that more than 50% of patients with the most
severe rating of dyspnea as measured by the Medical Research
Council functional scale (dyspneic when dressing) qualied their
COPD as mild or moderate (12). This leads to little advocacy
from patients and absent recognition in the sufferers, their families, and society of the true magnitude of the problem.

THE AIRFLOW OBSTRUCTION OF COPD

The airow obstruction of COPD, as expressed by the FEV1, is
by denition of the disease poorly reversible (1, 3). In a paradoxical way, we have used this dening physiology as the outcome
to determine the effectiveness of interventions. Indeed, we have
planned many studies to reverse what we have dened as not
fully reversible. It is no surprise that the lack of large response
in FEV1 to different therapies has resulted in a nihilism that is not
deserved (1223). The evidence accumulated suggests otherwise,
and an optimistic attitude toward patients with COPD goes a
long way in relieving patient fears and misconceptions. In contrast to many other diseases, some interventions, such as smoking
cessation (5, 13), long-term oxygen therapy in hypoxemic patients (24, 25), mechanical ventilation in acute respiratory failure
(26, 27), and lung volume reduction surgery (LVRS) for patients
with upper lobe emphysema and poor exercise capacity improve
survival (28), whereas others, such as pharmacologic therapy,
pulmonary rehabilitation, and surgery, improve symptoms and
the quality of a patients life once the diagnosis has been established (1, 3). Table 1 summarizes the available therapeutic options for patients with COPD.

COPD: A PULMONARY DISEASE WITH SYSTEMIC

MANIFESTATIONS
Conventionally, the severity of COPD has been graded on the
basis of the FEV1 (13). However, COPD is associated with a
range of clinical manifestations not closely related to the severity
of airow limitation, such as a worsening dyspnea, reduction in
exercise capacity, pulmonary hypertension, peripheral muscle
weakness, and malnutrition (29, 30). Furthermore, several large
studies have shown that the FEV1 is not the only determinant
of mortality and a number of other risk factors have now been
identied. These include hypoxemia, hypercapnia, the timed
walking distance (31, 32), and a low body mass index (30). Therefore, grading COPD solely on the basis of the FEV1 does not
reect the clinical manifestations of the disease and its ultimate
prognosis.

TABLE 1. THERAPY OF PATIENTS WITH SYMPTOMATIC

STABLE CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Interventions That Improve Survival
Smoking cessation
Oxygen therapy if hypoxemic

Lung volume reduction surgery

Noninvasive ventilation in acute
respiratory failure

Interventions That Improve Symptoms

Pharmacotherapy
Rehabilitation
Education
Training and exercise
Psychologic support
Nutrition
Lung transplant

There is increasing evidence that lung volumes are important

in the genesis of the symptoms and limitations of patients with
more advanced disease. A series of elegant studies has demonstrated that the dyspnea perceived during exercise, even during
walking by patients with COPD, more closely relates to the
development of dynamic hyperination than to the severity of
obstruction (23, 33). Furthermore, the improvement in exercise
brought about by several therapies, including bronchodilators,
oxygen, lung reduction surgery, and even rehabilitation, is more
closely related to delaying dynamic hyperinations than by
changing the degree of airow obstruction. One study also
showed that hyperination, expressed as the ratio of inspiratory
capacity to total lung capacity (IC/TLC), predicted survival better than the FEV1 (34) This not only provides us with new
insights into pathogenesis but also opens the door for new, imaginative ways to alter lung volumes and perhaps impact on disease
progression.
Equally exciting is the increasing number of studies documenting the presence of systemic abnormalities associated with
the disease. Patients with COPD frequently develop skeletal
muscle dysfunction, malnutrition with low body mass index and
loss of muscle mass, osteoporosis, anemia, and depression along
with the better known pulmonary hypertension and heart failure
(5, 32, 33). The systemic involvement of COPD is extremely
important because it may become the object of therapeutic interventions that could inuence outcomes independent of our capacity to modify lung function. As an analogy, patients with
diabetes mellitus who develop microalbuminuria and are treated
with angiotensin-converting enzyme inhibitors improve their
survival. Thus, a treatment that has little to do with the pancreas
or the blood sugar impacted on the long-term survival of patients.
It is entirely conceivable that as we explore the presence and
levels of systemic biomarkers in patients with COPD and their
relation to the systemic manifestations of the disease, we can
develop and apply novel strategies that will in the end improve
the outcome of our patients.
COPD can be described as affecting at least three domains:
the respiratory, perceptive, and systemic domains. We have
integrated the body mass index (B), degree of obstruction (O),
dyspnea (D), and exercise performance (E) scores, using the
6-min walk test to generate a multidimensional index (BODE)
that predicts survival better than the current gold standard, the
FEV1 (5). The multicomponent nature is graphically represented
in Figure 1, in which the pathophysiologic mechanisms of airow
obstruction are represented within a circle and related to hyperination. In addition, related to both but with some independent
features we see the systemic and perceptive domains.

THERAPY IS EFFECTIVE FOR THE RESPIRATORY

MANIFESTATIONS OF COPD
The overall goals of treatment of COPD are to prevent further
deterioration in lung function, to alleviate symptoms, and to
treat complications as they arise (1, 3). Once diagnosed, the
patient should be encouraged to actively participate in disease
management. This concept of collaborative management may
improve self-reliance and esteem. All patients should be encouraged to lead a healthful lifestyle and exercise regularly. Preventive care is extremely important at this time and all patients
should receive immunizations, including pneumococcal vaccine
and yearly inuenza vaccines (1, 3).
Smoking Cessation

Because smoking is the major cause of COPD, smoking cessation

is the most important component of therapy for patients who
still smoke (1, 3). Smoking cessation advice should be provided

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VOL 3 2006

tion will help achieve the desired results. Mucosal deposition in

the mouth will result in local side effects (e.g., thrush with inhaled
steroids) or general absorption and its consequences (e.g., tremor
after -agonists). Finally, the inhaled route is preferred over
oral administration (1, 3) and longer acting bronchodilators may
improve compliance and do provide longer bronchodilation and
symptom relief.
The currently available bronchodilators are as follows:

Figure 1. Nonproportional Venn diagram summarizing some of the

recognized pathophysiologic processes responsible for the airflow limitation (dashed circle) that defines chronic obstructive pulmonary disease
(COPD). Solid circles represent phenotypic expressions of the disease
that are related to outcomes. These phenotypic expressions, although
related to airflow limitation, convey independent predictive information
and are amenable to specific therapy.

to all patients who smoke. Because second-hand smoking is

known to damage lung function, limitation of exposure to involuntary smoke, particularly in children, should be encouraged.
Although most patients agree that smoking is risky, many seem
unaware of its true signicance. The factors that cause patients
to smoke include the addictive potential of nicotine; conditional
responses to stimuli surrounding smoking; psychosocial problems such as depression, poor education, and low income; and
forceful advertising campaigns. Because the causes that drive the
patient to smoke are multifactorial, smoking cessation programs
should also involve multiple interventions. The clinician should
always express strong interest in smoking cessation because a
physicians advice to quit smoking may be the difference between
successful and unsuccessful results (3537).
Pharmacologic Therapy of Airflow Obstruction

The pharmacologic therapy of COPD should be organized according to the severity of the disease, and the tolerance of the
patient for specic drugs (1, 3, 1419). In the outpatient setting,
a stepwise approach similar in concept to that developed for
asthma and systemic hypertension may be helpful. There is no
current evidence that the regular use of any pharmacologic agent
alters the progressive deterioration of lung function in COPD.
However, bronchodilators do provide signicant alleviation of
symptoms, improve exercise tolerance, and improve quality of
lifeall worthwhile goals in COPD.
Bronchodilators. Several important concepts guide the use of
bronchodilators. In some patients, the changes in FEV1 may be
small and symptomatic benet may be experienced through
other mechanisms, such as a decrease in the hyperination of
the lung that occurs as a consequence of increased ventilatory
demand, as during exercise or an exacerbation (23, 33, 38). Older
patients with COPD may have side effects produced by these
drugs. Some older patients with COPD cannot effectively activate metered-dose inhalers, and we should work with these patients to achieve mastery of the metered-dose inhaler. If this is
not possible, use of a spacer to facilitate inhalation of the medica-

-Agonists: -Agonists increase cAMP within many cells and

promote airway smooth muscle relaxation. Other nonbronchodilator effects have been observed but their signicance
is uncertain. In patients with intermittent symptoms, it is
reasonable to initiate drug therapy with a metered-dose inhaler of a short-acting -agonist as needed for relief of symptoms (1). Albuterol should be taken up to a maximum of
four to six times per day or as prophylaxis. In more advanced
disease, it is indicated to use long-acting -agonists (1, 3, 39,
40), at a dose of one or two puffs twice daily. They prevent
nocturnal bronchospasm, increase exercise endurance, and
improve quality of life (18). The effect of salmeterol on
survival is being evaluated in a long-term, large multicenter
trial (41).
Anticholinergics: Anticholinergics act by blocking muscarinic
receptors that are known to be functional in COPD. The
appropriate dosage of the short-acting ipratropium bromide
is two to four puffs three or four times per day, but some
patients require and tolerate larger dosages (1, 3). The therapeutic effect is a consequence of a decrease in exercise-induced increased lung ination or dynamic hyperination (23).
The long-acting quaternary ammonium compound (tiotropium) has been effective in inducing long-term bronchodilation
in patients with COPD (14). In addition, tiotropium shows
a benecial effect on dyspnea, recurrence of exacerbations,
and health-related quality of life when compared with placebo
and even with ipratropium bromide (14, 17). The results of
further clinical trials evaluating its potential role as a diseasemodifying agent (42) will determine its place in the overall
armamentarium of treatments for patients with COPD. At
present, there is an available inhaled combination of ipratropium and a -agonist that has proven effective in the management of COPD (43).
Phosphodiesterase inhibitors: Theophylline is a nonspecic
phosphodiesterase inhibitor that increases intracellular
cAMP within airway smooth muscle. The bronchodilator effects of these drugs are best seen at high doses, with which
there is also a higher risk of toxicity. Its potential for toxicity
has led to a decline in its popularity. Theophylline is of particular value for less compliant or less capable patients who
cannot use aerosol therapy optimally. The previously recommended therapeutic serum levels of 15 to 20 mg/dl are too
close to the toxic range and are frequently associated with
side effects. Therefore, a lower target range of 8 to 13 mg/dl
is safer and still therapeutic (1, 3). The combination of two
or more bronchodilators (theophylline, albuterol, and ipratropium) has some logical rationale as they seem to have
additive effects and can result in maximum benet in stable
COPD (18, 44).
The specic phosphodiesterase E4 inhibitors cilomilast and
roumilast may have an antiinammatory and bronchodilator
effect but less gastrointestinal irritation and thus prove extremely
useful if their theoretical advantages are clinically conrmed.
Data from studies during the rst 6 mo show modest bronchodilation effects and some effect on quality of life (45).

Celli: COPD: From Nihilism to Optimism

Antiinammatory therapy. In contrast to their value in asthma

management, antiinammatory drugs have not been documented to have a signicant role in the routine treatment of
patients with stable COPD (1). Cromolyn and nedocromil have
not been established as useful agents, although they could possibly be helpful if the patient has associated respiratory tract
allergy. The groups of leukotriene inhibitors that have proven
useful in asthma have not been adequately tested in COPD, so
that a nal conclusion about their potential use cannot be drawn.
Corticosteroids. Corticosteroids should be considered in individual patients who continue to have symptoms while receiving
adequate bronchodilator therapy (1, 3). Glucocorticoids act at
multiple points within the inammatory cascade, although their
effects in COPD are more modest compared with bronchial
asthma. Among outpatients, exacerbations necessitate a course
of oral steroids, as we discuss later in this article, but it is important to wean patients quickly because the older COPD population is susceptible to complications such as skin damage, cataracts, diabetes, osteoporosis, and secondary infection. These
risks do not accompany standard doses of inhaled corticosteroid
aerosols, which may cause thrush but pose a negligible risk for
causing pulmonary infection. Several large multicenter trials
evaluated the role of inhaled corticosteroids in preventing or
slowing the progressive course of symptomatic COPD (19, 20,
4650). The results showed minimal if any benets in the rate
of decline of lung function. On the other hand, in the one study
in which it was evaluated, inhaled uticasone decreased the rate
of loss of health-related quality of life and the exacerbations
(19) that are characteristic of patients with severe COPD. In
addition, its regular use was also associated with a decreased
rate of exacerbations. Finally, retrospective analyses of large
databases suggest a possible effect of inhaled corticosteroids on
increased mortality (51, 52). This has prompted the initiation of
a large prospective trial to explore the effect of inhaled corticosteroids on mortality (41). Results of this trial could inuence how
and when to use corticosteroids. Patients with moderate to severe
COPD who have had repeated episodes of acute exacerbation
may be the best candidates for chronic inhaled corticosteroids.
Mucokinetics. Mucokinetics, a loosely dened group of drugs,
aim to decrease sputum viscosity and adhesiveness to facilitate
expectoration. The only controlled study in the United States
suggesting a value for these drugs in the chronic management
of bronchitis was a multicenter evaluation of organic iodide (53).
This study demonstrated symptomatic benets. Oral acetylcysteine is favored in Europe for its antioxidant effects in addition
to its mucokinetic properties. One large trial failed to document
any substantial benet (54). Genetically engineered ribonuclease
seems to be useful in cystic brosis, but is of no value in COPD.
Antibiotics. In patients with evidence of respiratory tract infection, such as fever, leukocytosis, and a change in chest radiograph, antibiotics have proven effective (55). If recurrent infections occur, particularly in winter, continuous or intermittent
prolonged courses of antibiotics may be useful (56, 57). When
an acute bacterial infection is believed to be present, antibiotic
therapy may be justied, but the decision is usually made clinically. In prescribing treatment, scal concerns should be a consideration, because older, less costly agents are often effectivefor
example, tetracycline, doxycycline, amoxicillin, or erythromycin
(1). The major bacteria to be considered are Streptococcus
pneumoniae, Haemophilus inuenzae, and Moraxella catarrhalis.
The antibiotic choice will depend on local experience, supported
by sputum culture and sensitivities if the patient is moderately
ill or needs to be admitted to hospital (56). The introduction of
oral uoroquinolones and macrolides has increased our capacity
to effectively treat patients with acute respiratory tract infections. Quinolones may be favored for patients with more severe

61

disease and for whom gram-negative bacteria with resistance to

many antibiotics seem to be a growing problem (56).
1-Antitrypsin. Although supplemental weekly or monthly
administration of the enzyme 1-antitrypsin may be indicated
in nonsmoking, younger patients with genetically determined
emphysema, in practice such therapy is difcult to initiate. There
is evidence that the administration of 1-antitrypsin is relatively
safe, but the appropriate selection of the candidate for such
therapy is not clear (1, 3, 58). The most likely candidates for
replacement therapy would be patients with mild to moderate
COPD.
Vaccination. Ideally, infectious complications of the respiratory tract should be prevented in patients with COPD by using
effective vaccines (59, 60). Thus, routine prophylaxis with pneumococcal and inuenza vaccines is recommended (1, 3).
Lung Volume Reduction

Multiple operations have been suggested to improve symptoms

in patients with COPD (6164). Of these, bullectomy has proven
useful in patients with large bullae and relatively preserved lung
function (61). Lung transplantation results in normalization of
pulmonary function, exercise capacity, and quality of life, but
its effect on survival remains controversial (65). Several issues
must be considered when evaluating a candidate for lung transplantation. These include the patients pulmonary disability, projected survival without transplantation, comorbid conditions,
and patient preferences. General guidelines include that the
patient be younger than 65 yr without any other medical condition that could shorten predicted survival; not be addicted to
substances such as alcohol, drugs, or cigarettes; be free of persistent bacterial or fungal infections; have no thoracic malformations; or need high-dose corticosteroids.
The other surgical procedure that has received attention is
pneumoplasty, or LVRS. Initially developed by Brantigan and
colleagues (66), Cooper and coworkers (67) reintroduced it as
a valid alternative for selected patients with severe inhomogeneous emphysema who remained severely symptomatic after
optimal comprehensive medical therapy. However, evidence
shows that LVRS improves FEV1 by close to 10%, with larger
improvements in exercise tolerance, dyspnea, and health-related
quality of life (6873). The effect on survival is restricted to a
small group with upper lobe disease and limited exercise performance after rehabilitation (18). There are difculties in patient
selection for LVRS (7477). Current evidence suggests that patients with hyperination and inhomogeneous emphysema, those
with poor but not extremely severe lung function, and those
with limited exercise capacity are the best candidates for this
procedure. LVRS offers new hope to selected patients who have
few other alternatives. Reports evaluating techniques capable
of achieving lung volume reduction, without the surgical risk,
open exciting new avenues of treatment. Indeed, the bronchoscopic placement of one-way valves (78) or biological substances
(79) capable of inducing closure of emphysematous areas may
add to an already exciting armamentarium to treat selected patients with advanced COPD.

THERAPIES THAT ARE EFFECTIVE FOR THE

NONRESPIRATORY MANIFESTATIONS OF COPD
As we have seen above, the most exciting changes in the way we
conceptualize COPD is the recognition of the extrapulmonary
manifestations of COPD. Some of the most important advances
in the therapy of COPD center around our capacity to impact on
the disease without altering lung function. Two of the most proven
forms of therapy for COPD fall within this category: pulmonary
rehabilitation and oxygen therapy. If we add mechanical

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ventilation during exacerbations, the eld is open to explore

even more exciting therapies.
Pulmonary Rehabilitation

Pulmonary rehabilitation is increasingly recognized as an important component in the comprehensive management of patients
with symptomatic lung disease. A somewhat nihilistic approach
became widespread when multiple studies evaluating this therapeutic tool in patients with severe lung disease failed to show
any improvement in conventional pulmonary function tests.
Carefully conducted research studies have shown that pulmonary rehabilitation offers the best treatment option for patients
with symptomatic lung disease (8090). Any patient symptomatic
from respiratory disease is a candidate for rehabilitation (8082).
Patients with moderate to moderately severe disease are preferred targets for treatment to prevent the disabling effects of
end-stage respiratory failure. The rehabilitation program should
have resources available to teach and supervise respiratory therapy techniques (oxygen, use of inhalers, nebulizers, etc.), physical therapy (breathing techniques, chest physical therapy,
postural drainage), exercise conditioning (upper and lower extremities), and activities of daily living (work simplication, energy conservation). Also desirable are services to evaluate and
advise on nutritional needs, psychologic evaluation, and vocational counseling. Exercise training is the most important component of a pulmonary rehabilitation program. Maltais and coworkers (91) documented that the muscle biopsies of trained patients,
but not control subjects, manifested signicant increases in all
enzymes responsible for oxidative muscle function. Pulmonary
rehabilitation can change outcomes that predict survival. Indeed,
in one observational study, rehabilitation improved the BODE
score and the change induced reected outcome prognosis (92).
Home Oxygen Therapy

Results of the Nocturnal Oxygen Therapy Trial and Medical

Research Council studies have established that continuous home
oxygen improves survival in hypoxemic COPD and that survival
is related to the number of hours of supplemental oxygen per
day (25, 26). Other benecial effects of long-term oxygen include
reduction in polycythemia, in pulmonary artery pressures, dyspnea, and rapid eye movementrelated hypoxemia during sleep.
Oxygen also improves sleep, and may reduce nocturnal arrhythmias. Importantly, oxygen can also improve neuropsychiatric
testing (93, 94) and exercise tolerance (9597). The benecial
effects of oxygen are the rst proof that outcomes can be improved without necessarily changing the degree of airow obstruction, providing evidence that the disease can be modied
without changing the rate of decline of FEV1.

PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY

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regimen. Two smaller trials (99, 100) and one large randomized
trial (101) proved the usefulness of corticosteroids. It is important to avoid prolonged ( 2 wk) or high-dose therapy because
older patients are susceptible to severe complications such as
psychosis, uid retention, and vascular necrosis of bones.
Antibiotics such as amoxicillin, doxycycline, erythromycin,
quinolones, and macrolides (clarithromycin and azithromycin)
have been helpful in purulent exacerbations of COPD (52).
The antibiotics used in severe exacerbation must be guided by
knowledge of the prevalent pathogens in that area (102). Exacerbations are to be prevented and treated aggressively because
they have a prolonged and intense effect on health-related
quality of life and can result in accelerated loss of lung function
(103, 104).
Ventilatory support should be considered if patients have
persistent hypoxemia and/or hypercapnia with low pH ( 7.35)
despite maximal medical therapy (1). Several randomized trials
have shown that noninvasive positive pressure ventilation is benecial in selected patients with respiratory failure, decreasing
the need for invasive mechanical ventilation and its complications and, possibly, improving survival (105, 106). Certain conditions would make patients less likely to respond to noninvasive
positive-pressure ventilation. These conditions include respiratory arrest, medical instability (shock, cardiac ischemia), inability
to protect the airway, excessive secretions, agitation or uncooperativeness, craniofacial trauma, or deformity.

CONCLUSIONS
Over the years, our knowledge about COPD and the capacity
to treat it have increased signicantly. Smoking cessation campaigns have resulted in a signicant decrease in smoking prevalence in the United States. Similar efforts in the rest of the world
should have the same impact. The ght against cigarette smoking
should results in a drop in incidence of COPD in the years to
come. The widespread application of long-term oxygen therapy
for hypoxemic patients has resulted in increased survival. During
this time we have expanded our drug therapy armamentarium
and have used drugs to effectively improve dyspnea and quality
of life. Studies have documented the benets of pulmonary rehabilitation. Noninvasive ventilation has offered new alternatives
for patients with acute or chronic failure. The revival of surgery

Exacerbations

An exacerbation of COPD is an event in the natural course of

the disease characterized by a change in the patients baseline
dyspnea, cough, and/or sputum beyond day-to-day variability
and sufcient to warrant a change in management (1, 3, 98). In
the case of an acute exacerbation, pharmacologic therapy is
initiated with the same therapeutic agents available for its
chronic management (1, 3). Care must be taken to rule out
heart failure, myocardial infarction, arrhythmias, and pulmonary
embolism, all of which may present with clinical signs and symptoms similar to exacerbation of COPD.
The most important agents for acute exacerbation of COPD
are anticholinergic and -agonist aerosols as an inhalant solution
by nebulization. Systemic corticosteroids should be added to the

Figure 2. Schematic representation of the possible therapeutic options

for patients at risk for COPD and with established disease. As the disease
progresses (decreasing airflow and worsening of symptoms), the number of therapeutic options increase. Correct staging of the patient helps
identify the best therapeutic options.

Celli: COPD: From Nihilism to Optimism

for emphysema or, in the immediate future, endobronchial lung

volume reduction should provide an alternative to lung transplantation for those patients with severe COPD who are still
symptomatic while receiving maximal medical therapy. With all
these options as shown in Figure 2, a nihilistic attitude toward
the patient with COPD is not justied. The evidence justies a
positive and constructive attitude.
Conflict of Interest Statement : B.R.C. received $3,000 in 2005 and $4,000 in
2003 and 2004 for speaking at conferences sponsored by GlaxoSmithKline (GSK).
He received $3,000 in 2004 and 2005 for serving on an advisory board for GSK.
He has a financial relationship in the laboratory that they direct and work, and
received $180,000 from GSK for 3 yr as research grants for conducting this research.

63

18.

19.

20.

21.

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1. Celli BR, MacNee W. Standards for the diagnosis and treatment of
COPD. Eur Respir J 2004;23:932946.
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