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The new england journal of medicine c u r r e n t c o n c e p t s
E. Rand Sutherland, M.D., M.P.H., and Reuben M. Cherniack, M.D. hronic obstructive pulmonary disease (copd) is a syndrome of From the Department of Medicine, Nation-al Jewish Medical and Research Center; and progressive airflow limitation caused by chronic inflammation of the air- ways and lung parenchyma. The primary physiological abnormality in COPD is Critical Care Medicine, Department of Med- an accelerated decline in the forced expiratory volume in one second (FEV ) from the icine, University of Colorado Health Sci-ences Center — both in Denver. Address normal rate in adults over 30 years of age of approximately 30 ml per year to nearly 60 reprint requests to Dr. Cherniack at 1400 ml per year.2 As shown in Figure 1, the disease course begins with an asymptomatic Jackson St., J-208, Denver, CO 80206.
phase in which lung function deteriorates without associated symptoms. The onset of the subsequent symptomatic phase is variable but often does not occur until the Copyright 2004 Massachusetts Medical Society. FEV has fallen to approximately 50 percent of the predicted normal value.3 Since sub- stantial deterioration in airflow has already occurred by the time most patients presentwith symptoms, it is reasonable to conclude that the degree of airflow limitation is onlyone of many factors that govern the onset of symptoms.
Hyperinflation, which occurs at rest and worsens with exercise (Fig. 2), is an addi- tional physiological abnormality that is commonly seen in patients with moderate-to-severe COPD. It is manifested primarily by an increase in the functional residualcapacity, which places the muscles of respiration at a mechanical disadvantage, there-by increasing the work of breathing and reducing exercise tolerance. Additional physi-ological abnormalities include a reduction in the diffusing capacity for carbon mon-oxide, hypoxemia, and alveolar hypoventilation.
d i a g n o s i s , s t a g i n g , a n d p r o g n o s i s Because the majority of cases occur in patients who have smoked,4 all current or formersmokers should be considered at increased risk for COPD. Other risk factors, whichaccount for far fewer cases, include a -antitrypsin deficiency,5 airway hyperrespon- siveness,6 and indoor air pollution.7 Since symptoms may not occur until lung func-tion is substantially reduced, early detection is enhanced by spirometric evaluation ofFEV and forced vital capacity (FVC). Guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) state that the airflow limitation in COPD is charac-terized by an FEV value that is less than 80 percent of the predicted normal value and Currently, most guidelines recommend that practitioners use a combination of in- formation about symptoms and evidence of impairment of physiological function indetermining the severity of the disease,3,8-10 although the guidelines differ somewhatwith regard to setting thresholds for mild, moderate, and severe disease (Table 1). Thestage of the disease suggests the prognosis, and follow-up data from longitudinal stud-ies indicate that moderate and severe stages of the disease are associated with highermortality.11 However, in the largely asymptomatic group of patients that GOLD3 cate-gorizes as “stage 0, at risk,” only 18.5 percent of the patients progress to more severe Downloaded from www.nejm.org by ALEXANDRE A. HOLANDA MD on January 30, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine airflow limitation at 15 years,12 which suggests (including both the indolent and progressive na-that more information is required to predict which ture of symptoms), and a knowledge of the distri-patients with incipient disease will progress rapidly bution and potential overlap of physiological dis-to a more advanced stage.
Most guidelines also state that in addition to airflow limitation, patients with COPD have an in- m a n a g e m e n t o f s t a b l e c o p d complete response to albuterol (change in FEV , <200 ml and 12 percent)3,13 and typically do not The major goals of therapy include smoking ces-
have evidence of airway hyperresponsiveness (i.e., sation, symptom relief, improvement in physio-
an abnormal bronchoconstrictor response to a logical function, and limitation of complications,
stimulus such as methacholine). Although these such as abnormal gas exchange and exacerbations
features are helpful in distinguishing COPD from of the disease. As summarized in Figure 3, an inte-
asthma,3 the distinctions are not entirely clear-cut. grated approach to treatment combines health care
Indeed, there is responsiveness to a bronchodila- maintenance and use of drug and supplemental
tor in 23 to 42 percent of patients with COPD, de- therapies in a stepwise fashion as the disease pro-
pending on the criteria used.14 Furthermore, data gresses.
from the Lung Health Study indicate that 59 per-
cent of men and 85 percent of women with mod- health care maintenance
erate disease (mean [±SD] FEV :FVC ratio, 0.63± Regular Assessment of Lung Function
0.055 percent) have airway hyperresponsiveness.15 It is not yet known whether spirometric screeningThus, although guideline-based spirometric criteria for COPD is cost effective, and evidence-based cri-are useful starting points, differentiation of COPD teria for the optimal frequency of such testing infrom asthma requires careful integration of epi- patients with established disease need to be es-demiologic risk factors (including the patient’s age, tablished. Until more data become available, wesmoking status, and family history), clinical status recommend that spirometry be performed in all (% of predicted)
Symptoms
Axis of Progression
Figure 1. Deterioration in Lung Function in Patients with COPD.
Symptoms generally develop only after a significant decline in forced expiratory volume in one second (FEV ) has oc- curred; they progress as lung function deteriorates further.
Downloaded from www.nejm.org by ALEXANDRE A. HOLANDA MD on January 30, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. patients at risk to detect asymptomatic airflow lim- drug therapy
itation; in patients with established disease, spi- Inhaled Bronchodilators
rometry should be performed at least annually, and Inhaled bronchodilators are the foundation of
more frequently if needed, to assess clinical status pharmacotherapy for COPD because of their ca-
or the response to therapy.
pacity to alleviate symptoms, decrease exacerba-tions of disease, and improve the quality of life.21-25 These drugs also improve airflow and hyperinfla- Abstinence from smoking results in a sustained tion (Fig. 2),26,27 thereby decreasing the work of50 percent reduction in the rate of lung-functiondecline in patients with COPD,2 and smoking ces-sation is the only intervention known to be so ef- Total Lung
fective in modifying the disease. Unfortunately, Capacity
achieving and maintaining smoking cessation inpatients with COPD is a challenge. Approximately35 percent of the subjects in the Lung Health Studyachieved abstinence at one year, but only 22 percent reported continued abstinence at five years with a Ventilation
regimen combining nicotine replacement (avail-able in the form of chewing gum, inhaler, spray,and transcutaneous patch), behavioral counsel-ing, and frequent maintenance visits.16 Sustained-release bupropion is also effective, although thelikelihood of sustained abstinence among patients Patients
who have COPD is lower with bupropion than with Patients
with COPD
Patients with COPD
during Exercise
Figure 2. Pulmonary Hyperinflation in Patients with COPD.
Although there is little evidence of a direct benefit As compared with healthy patients, patients with COPD have pulmonary hy- of vaccination in patients with COPD, we recom- perinflation with an increase in functional residual capacity (red) and a de- mend that pneumococcal vaccination and annual crease in inspiratory capacity (blue). This condition increases the volume at influenza vaccination be offered to all patients in which tidal ventilation (oscillating line) occurs and places the muscles of res-piration at mechanical disadvantage. Hyperinflation worsens with exercise an attempt to reduce both disease-specific mortali- and therefore reduces exercise tolerance (dynamic hyperinflation). Inhaled ty and mortality from all causes.18,19 Administra- bronchodilators improve dynamic hyperinflation, as well as hyperinflation at tion of the influenza vaccine does not appear to in- rest (not shown), thereby reducing the work of breathing and increasing exer- crease adverse outcomes in patients with COPD in Table 1. A Comparison of Four Sets of Staging Criteria for COPD.*
American Thoracic Society
European Respiratory Society
British Thoracic Society
(1997)10
GOLD (2003)3
* GOLD denotes Global Initiative for Chronic Obstructive Lung Disease, and FEV forced expiratory volume in one second (shown as a percent- age of the predicted normal value). In the Symptoms columns, NA denotes not applicable (staging is based on physiology only), – no symptoms, ± variable symptoms, + mild-to-moderate symptoms, ++ symptoms that limit exertion, and +++ symptoms that limit daily activities. Downloaded from www.nejm.org by ALEXANDRE A. HOLANDA MD on January 30, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine breathing and improving exercise tolerance. Para- Inhaled bronchodilators can be grouped ac- doxically, improvement in function resulting from cording to mechanism or duration of action (Ta-the administration of bronchodilators is not always ble 2). Short-acting b -adrenergic–receptor agonists reflected by changes in FEV and FVC, and mea- (e.g., albuterol sulfate) and cholinergic-receptor surement of lung volumes or inspiratory capacity antagonists (e.g., ipratropium bromide) result inmay be necessary to document physiological im- bronchodilation for four to six hours.28 Long-act-provement.27 ing b -adrenergic–receptor agonists such as for- Supplemental Therapy
Stepwise Drug Therapy
Combination of anticholinergic and b-agonist bronchodilator Health Care Maintenance
Pneumococcal and annual influenza vaccination Symptoms
Figure 3. An Algorithm for the Treatment of COPD.
The components of COPD therapy include health care maintenance, drug therapy, and supplemental therapy. Because patients with reduced lung function may be asymptomatic, spirometry is indicated to diagnose asymptomatic reduction in lung function in at-risk patients. Treatment should be initiated when reduced lung function is demonstrated, with or without the presence of symptoms. Smoking cessation should be aggressively pursued in patients across the severity spectrum, and vaccination is an important addition to health care maintenance. Patients may initially require only as-needed therapy with a single short-acting anticholinergic agent or b-agonist. For patients with moderate-to-severe dis-ease, or for those with persistent or increasing symptoms with as-needed bronchodilators, a single regularly scheduled, long-acting inhaled bronchodilator of either pharmacologic class or the regularly scheduled combination of a short- or long-acting anticholinergic agent and a b-agonist is preferred. For patients treated with a long-acting inhaled bronchodi-lator, a short-acting agent should be prescribed concurrently for rapid treatment of acute symptoms (box with dashed outline). The addition of pulmonary rehabilitation to treatment regimens will reduce symptoms and improve exercise performance, and the addition of theophylline or an inhaled corticosteroid (or both) to optimal inhaled bronchodilator therapy may provide additional benefits. Patients with moderate or severe disease should be tested for hypoxemia, and it should be aggressively treated if present. Lung-volume–reduction surgery and transplantation are options for a sub-group of patients with very severe disease.
Downloaded from www.nejm.org by ALEXANDRE A. HOLANDA MD on January 30, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. moterol fumarate and salmeterol xinafoate have al improvement in lung function and symptomsan effect for 8 to 12 hours, and the long-acting an- when added to inhaled bronchodilators.35,36 Sinceticholinergic agent tiotropium bromide has a dura- theophylline may be toxic, frequent monitoring fortion of effect of more than 24 hours. In stable dis- supratherapeutic levels, adverse drug reactions, andease, administration by means of a metered-dose drug interactions is critical.
or dry-powder inhaler is preferred.
For patients with mild airflow limitation and in- Inhaled Corticosteroids termittent symptoms, a single short-acting inhaled The appropriate role of inhaled corticosteroids inbronchodilator relieves symptoms and improves COPD is controversial. Many studies have shownairflow. Albuterol and ipratropium are equally ef- that inhaled corticosteroids do not substantiallyfective with regard to bronchodilation, symptom modify airway inflammation in COPD, and fourscores, and the rates of treatment failure and can be large, long-term clinical trials37-40 comparing in-used interchangeably for mild disease as the first haled corticosteroids with placebo found that thesestep in a series of measures for treating patients drugs do not appreciably alter the rate of declinewith COPD (Fig. 3).28-31 in lung function. This absence of physiological Since most patients have at least moderate air- effects, as well as differences in inflammatory phe- flow limitation when first evaluated, they are likely notype between COPD and asthma,41 has led manyto require regularly scheduled bronchodilation3 investigators to conclude that these drugs are inef-and to derive benefit from a long-acting broncho- fective in COPD.
dilator as initial therapy. Formoterol, salmeterol, However, some of the same trials have demon- and tiotropium all have an equivalent peak bron- strated that treatment with inhaled corticosteroidschodilator effect but have a prolonged duration of alleviates patients’ symptoms,40 reduces the fre-effect, which may explain the superiority of these quency of exacerbations,39 and improves health sta-drugs to short-acting bronchodilators in reducing tus.42 These studies relied on FEV as the primary symptoms and the frequency of exacerbations and outcome variable and did not evaluate such physio-in improving the quality of life.22,23,25 Treatment logical variables as hyperinflation, which may havemay be initiated with either a long-acting anticho- a greater effect on clinical status than the FEV does.
linergic agent or a b-agonist, since there is little Moreover, these studies may not have been pow-evidence to suggest clinically significant differenc- ered adequately to detect small differences in thees between pharmacologic classes. Long-acting in- rate of decline in the FEV .43 In fact, the effect of haled bronchodilators are not appropriate for the cigarette smoking in blunting the spirometric re-treatment of acute symptoms, so a short-acting sponse to corticosteroids, as was recently observedbronchodilator should also be prescribed for acute in a study involving patients with asthma,44 mayrelief of symptoms (Fig. 3).
have affected the response to inhaled corticoste- Combination bronchodilator therapy (an anti- cholinergic agent plus a b-agonist) may be consid-ered for patients in whom a single inhaled bron- Table 2. Duration and Administration of Inhaled Bronchodilators.
chodilator has failed to provide adequate relief.
Duration
Usual Dose*
The combination of albuterol and ipratropium Short-acting
provides greater bronchodilation than either drug used alone,28 and similar benefits are obtained by combining long-acting b-agonists with ipratro- pium.32,33 Although the combination of albuterol and ipratropium is commonly prescribed for regu- Long-acting
larly scheduled use, regularly scheduled ipratropi- um combined with albuterol on an as-needed ba- sis has been reported to be equally effective.34 If symptoms continue despite combined inhaled-bronchodilator therapy, theophylline may be pre- * MDI denotes metered-dose inhaler, and DPI dry-powder inhaler.
scribed because of its capacity to provide addition- Downloaded from www.nejm.org by ALEXANDRE A. HOLANDA MD on January 30, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine roids in the studies of COPD, in which smokers received oral prednisolone before fluticasone.39made up 39 to 100 percent of the study population. The overall response to prednisolone was minimalThus, the medical literature suggests that inhaled (a mean increase in FEV of 69 ml) and was unre- corticosteroids provide clinical benefit to some pa- lated to the patients’ baseline FEV , responsiveness tients with COPD and that this effect is indepen- to a bronchodilator, subsequent decline in FEV , dent of the patients’ FEV response, perhaps op- or response to inhaled fluticasone.48 Thus, although erating through an improvement in hyperinflation a trial of oral corticosteroids may be useful in de-or a reduction in the frequency of exacerbations.
tecting coexisting asthma, it is a poor predictor Guidelines recommend that inhaled cortico- of the response to inhaled corticosteroids among steroids be considered for patients with moder- patients with COPD. Oral corticosteroids should
ate-to-severe airflow limitation who have persistent not be used in the routine management of stable
symptoms despite optimal bronchodilator thera- disease.
py.3 This recommendation is based in large part
on the Inhaled Steroids in Obstructive Lung Dis- supplemental therapy
ease in Europe (ISOLDE) trial, in which subjects Pulmonary Rehabilitation
with a mean FEV of approximately 50 percent of Pulmonary rehabilitation improves patients’ exer-
the predicted normal value had a 25 percent rela- cise capacity, reduces dyspnea, improves the qual-tive reduction in frequency of exacerbations when ity of life,49 and reduces the number and durationtreated with inhaled fluticasone propionate.39 Ex- of hospitalizations related to respiratory disease.50acerbations appear to accelerate the rate of lung- It is appropriate for patients with clinically signif-function decline in COPD,45 and the reduction in icant exertional symptoms and is most effectiveexacerbations seen in the ISOLDE trial supports when delivered as a multifaceted program incor-the use of inhaled corticosteroids to modify the porating individually tailored aerobic physical train-frequency of exacerbations, independently of the ing, comprehensive education about the disease,drugs’ effects on underlying airway inflammation. psychosocial counseling, and nutritional support.51In addition, the observation that the combination Although having a low body-mass index is associat-of inhaled corticosteroids and long-acting b-ago- ed with increased mortality from respiratory diseasenists is superior to placebo or either drug alone among patients with COPD,52 there is no evidencewith regard to lung function, frequency of exacer- that enhanced nutrition improves body weight, lungbations, symptoms, and health status46,47 suggests function, exercise capacity, or survival.53that the use of inhaled corticosteroids should be re-stricted to patients in whom optimal bronchodilator Treatment of Abnormal Gas Exchangetherapy has failed to improve the symptoms, physi- Hypoxemia develops as a result of a worsening ven-ological findings, or frequency of exacerbations.
tilation–perfusion mismatch, and aggressive test- It is important to recognize that in older pa- ing for hypoxemia is critical, since clinical trials tients the side effects of inhaled corticosteroids are have shown that mortality is reduced by treatmentnot well understood, and the use of these drugs with supplemental oxygen for 15 or more hours pershould be carefully considered. Since it is difficult to day.54,55 In stable patients, Medicare guidelinespredict accurately which patients will benefit from suggest that oxygen therapy should be initiatedtherapy, clinical and spirometric responses should if the resting partial pressure of arterial oxygen isbe assessed in the months after the initiation of in- 55 mm Hg or lower or if the oxygen saturation ishaled corticosteroids. Treatment should be discon- 88 percent or less. However, these recommenda-tinued if no substantial clinical or physiological tions are based in large part on the inclusion crite-improvement is seen, since there is no evidence ria for the Medical Research Council study54 andthat continuing treatment with inhaled corticoste- the Nocturnal Oxygen Therapy Trial55 and may notroids provides any long-term benefit in such cases. identify all patients who would benefit from sup- plemental oxygen. For example, supplemental ox- ygen substantially improves training intensity and Assessing the spirometric response to a trial of oral exercise tolerance even in patients in whom desat-corticosteroids has been advocated as a means of uration does not occur during exercise.56identifying patients who have a response to inhaled Supplemental oxygen should be adjusted to corticosteroids. In the ISOLDE trial, all subjects maintain an oxygen saturation of at least 90 per- Downloaded from www.nejm.org by ALEXANDRE A. HOLANDA MD on January 30, 2007 . Copyright 2004 Massachusetts Medical Society. All rights reserved. cent at all times. Since patients may have normal therapy alone. In 2000, a small randomized, con-oxygen saturation at rest but hypoxemia with ex- trolled trial that compared lung-volume–reductionertion or sleep, pulse oximetry and oxygen titra- surgery with medical therapy in patients with se-tion should be performed during all three condi- vere emphysema demonstrated improved lungtions. Worsening hypoxemia during air travel must function, exercise capacity, and quality of life 6 tobe considered, and a general recommendation is 12 months after surgery.61 Subsequently, the Na-that patients requiring oxygen should increase tional Emphysema Treatment Trial found that thetheir oxygen flow rate by 2 liters per minute during addition of lung-volume–reduction surgery to op-flight.57 timal medical therapy and rehabilitation led to In advanced disease, hypoxemia and hypercap- an overall improvement in exercise tolerance and nia (alveolar hypoventilation) may occur as a result survival in a subgroup of patients with reduced ex-of an increase in the dead-space fraction, a ventila- ercise tolerance and predominantly upper-lobe em-tion–perfusion mismatch, or an increase in the work physema.62 Overall mortality did not improve,of breathing with enhanced production of carbon however, and mortality was increased in a sub-dioxide. Inhaled bronchodilators can help reduce group of patients with severe physiological impair-the work of breathing and improve gas exchange ment (FEV , ≤20 percent of the predicted normal in some patients with alveolar hypoventilation. value) and homogeneous emphysema or a carbonTrials of noninvasive positive-pressure ventilation monoxide diffusing capacity no more than 20 per-have been conducted in patients with stable COPD, cent of the predicted normal value.63and although hypercapnia can be improved,58 im- Single-lung transplantation is an alternative sur- provement often comes at the cost of increased gical option for patients with end-stage emphyse-hyperinflation.59 A two-year trial of noninvasive ma who have an FEV that is less than 25 percent positive-pressure ventilation in addition to supple- of the predicted normal value after the administra-mental oxygen in patients with alveolar hypoventi- tion of a bronchodilator and who have such com-lation demonstrated improvements in dyspnea and plications as pulmonary hypertension, marked hy-the quality of life but only small improvements in poxemia, and hypercapnia.64 The surgery does notarterial carbon dioxide levels.60 appear to improve survival significantly in thesepatients, however.65 Supported by a grant (K23 HL04385) from the National Heart, Lung-volume–reduction surgery can reduce hyper- Lung, and Blood Institute.
Dr. Cherniack reports having served as a consultant for Glaxo- inflation and should be considered in patients with SmithKline, and Dr. Sutherland having served as a consultant forsevere upper-lobe emphysema and reduced exer- Schering-Plough and having received grant support from Glaxo-cise tolerance who are not faring well with medical SmithKline.
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AS, Bersten AD, McEvoy RD. Effect of CPAP on intrinsic PEEP, inspiratory effort, and paring lung-volume-reduction surgery with Copyright 2004 Massachusetts Medical Society. electronic access to the journal’ s cumulative index
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