Chronic obstructive pulmonary disease

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Chronic Obstructive Pulmonary Disease: Clinical Review and

Update on Consensus Guidelines

Journal: Hospital Practice

Manuscript ID: Draft

Manuscript Type: Review Article

Therapeutic Area: Respiratory, Chronic lung disease, Chronic obstructive pulmonary disease, Emphysema, Chronic bronchitis, Pulmonary, Diagnosis, Therapeutics

Keywords – Click <a href="http://www.ncbi.nlm.nih.gov/mesh" target="_blank">here</a> to find your

MeSH keywords.:

Pulmonary Disease, Chronic Obstructive, Practice Guideline, Chronic bronchitis, Emphysema, COPD, Diagnosis, Therapeutics

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Chronic Obstructive Pulmonary Disease: Clinical Review and Update on Consensus Guidelines

Abstract

In the past two decades, chronic obstructive pulmonary disease (COPD) has gained increasing

recognition as a major public health problem. Since the introduction of the Global Initiative for Chronic

Obstructive Lung Disease (GOLD) in 1998, increasing interest in the pathogenesis and management of

COPD has led to notable improvements in patient care and quality of life. Despite increasing recognition

surrounding the importance of this common preventable disease and the development of major

therapeutic advances during this period, the global impact of COPD is still strikingly large. We aim to

provide an evidence-based clinical review of the diagnosis, management, and treatment of COPD with a

focus on internists as the target audience. We will also summarize key updates from the GOLD executive

summary and joint clinical practice guideline on diagnosis and management of stable COPD from the

American College of Physicians (ACP), American College of Chest Physicians (ACCP), American

Thoracic Society (ATS), and European Respiratory Society (ERS).

Keywords: Chronic obstructive pulmonary disease; COPD; chronic bronchitis; practice guidelines;

emphysema; diagnosis; therapeutics; GOLD guidelines.

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INTRODUCTION

Chronic obstructive pulmonary disease (COPD) places a significant socioeconomic burden on the

healthcare system. It is now projected to rank third in terms of leading causes of mortality by the year

2020.1,2

Despite major therapeutic advances in the management of COPD during the past two decades

the disease remains a major public health problem. The Global Initiative for Chronic Obstructive Lung

Disease (GOLD) was formed in 1998 in an effort to bring attention to the management and prevention of

this important disease. In February of 2013, GOLD released its second 5-year revision to its consensus

statement, Global Strategy for the Diagnosis, Management, and Prevention of COPD, originally published

in 2001.3,4

We aim to provide clinicians with a review of new updates to the 2013 GOLD executive

summary as well as the 2011 joint clinical practice guideline on diagnosis and management of stable

COPD from the ACP, ACCP, ATS, and ERS. The article will focus on internists as the target audience.

We also provide an evidence-based clinical review of COPD, highlighting the importance of inpatient and

outpatient management of this important disease.

MATERIALS AND METHODS

We performed a comprehensive literature search of the available evidence was performed by the authors

using PubMed, MEDLINE, and the Cochrane Database (English Language). Articles were critically

evaluated by the authors and/or were independently rated as high quality by an established evaluation

process, such as Cochrane Collaboration or cited by evidence-based consensus statements on COPD

from GOLD, ACP, ACCP, ATS, or ERS.

OVERVIEW

Definitions

COPD is a preventable and treatable condition characterized by progressive airflow limitation caused by

airway and/or parenchymal lung inflammation.5 Clinically, chronic bronchitis is defined as the presence of

chronic productive cough for at least three consecutive months in two consecutive years. Pathologically, it

is the end-result of obstructive bronchiolitis involving small airways caused by a chronic inflammatory

response to the exposure of noxious inhaled agents such as cigarette smoke, industrial fumes, and other

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environmental pollutants. Emphysema refers to an abnormal enlargement of the airspaces distal to the

terminal bronchioles accompanied by destruction of their walls without obvious fibrosis visualized on

computed tomography or in pathologic analysis of lung specimens. GOLD defines COPD as a disease

state characterized by persistent airflow limitation that is usually progressive and associated with an

enhanced inflammatory response in the airways and the lung to noxious particles or gases.3

Risk Factors

Cigarette smoking remains the most common and important risk factor for the development of COPD.

Smoking has been shown to accelerate the rate of decline in lung function over time; however, individual

susceptibility to the harmful effects of smoking varies considerably from person to person. Clinically, lung

function is measured by use of spirometry and severity of obstructive lung disease is classified based on

forced expiratory volume in 1 second (FEV1) percent predicted. It remains unclear why some smokers

develop an exaggerated loss of FEV1 and others do not. It is postulated that differences in susceptibility to

tobacco smoke injury may be related to individual genetic differences.6 Major risk factors for the

development of COPD are summarized in Table 1.

Epidemiology and Natural History

Data collected by Fletcher et al in the 1970s estimated that approximately 15% of smokers

eventually develop COPD (a figure corresponding with moderate disease by current GOLD staging).3,7

However, it is likely that 15% is an underestimate of those truly affected by the disease.8 This is

supported by population-based studies indicating that approximately 15 million Americans report a

diagnosis of COPD, but as many as 50% of those affected by the disease are unaware of it.9,10

Furthermore, COPD is an independent risk factor for cardiac mortality and many patients who are heavy

smokers may die as a result of complications related to atherosclerotic vascular disease, leaving the

diagnosis of COPD in these individuals largely unknown.11–13

In normal nonsmoking individuals, pulmonary function peaks in the early to mid-20s and gradually

declines in a predictable linear fashion over the course of a lifetime. After the age of 35 years old, the

average decline in FEV1 is approximately 25-30 mL/year. Decline in FEV1 is used as a marker for

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progression of COPD and in active smokers loss of FEV1 occurs in a dose-dependent fashion with regard

to pack-years smoked, averaging approximately 50-55 mL/year, a rate nearly twice that seen in

nonsmokers.14,15

However, there is marked variation in the susceptibility of smokers with regard to loss of

lung function. Additionally, in most persons with a history of smoking fewer than 20 pack-years, there is

little, if any noticeable change in FEV1.13,16

Moreover, in persons with COPD that stop smoking, the rate of

decline in FEV1 returns to that seen in nonsmokers.17

A graphical comparison of the natural history of

pulmonary function in smokers and nonsmokers is depicted in Figure A.

Pathophysiology

Chronic inflammation in the walls and lumens of airways in response to repeated exposures to inhaled

particles—from tobacco smoke or other noxious gases—are the main underlying cause of the pathologic

changes, symptoms, complications, and pulmonary function abnormalities in COPD. The chronic

inflammatory response appears to be a pathologic enhancement of the normal, physiological,

inflammatory response of the respiratory tract to chronic irritants. This process is amplified in persons who

develop COPD for poorly understood reasons. Ultimately, the process leads to destruction of

parenchymal lung tissue and obstructive bronchiolitis resulting in emphysema and fibrotic narrowing of

small airways and a state of progressive obstructive airflow limitation and air trapping.3,6,18

Causes of Mortality

It was once thought that risk of death in patients with COPD was closely correlated with measured FEV1,

as reported by Fletcher and Peto’s landmark 1977 study.17

Since then, numerous other factors have been

identified as important causes of mortality in patients with COPD. Furthermore, the presence of certain

co-morbid medical conditions have been identified with increasing prevalence in those affected by COPD,

including coronary artery disease, lung cancer, osteoporosis, myopathy, anemia, and mood disorders, all

playing an important role in the natural course of the disease.19,20

Their presence adds increasing

complexity in the prediction of mortality among individual patients.

The Lung Health Study,21

sponsored by the National Heart, Lung, and Blood Institute (NHLBI)

served a prominent role in the identification of causes of mortality in persons affected by mild to moderate

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COPD. The cohort included nearly 6,000 men and women who were cigarette smokers between 35 and

60 years of age and found the most common causes of mortality were cancer (33%), cardiovascular

disease (22%), and respiratory disease (8%). In patients with more severe lung disease, such as those

identified in the TOward a Revolution in COPD Health (TORCH) study, the leading cause of mortality was

respiratory illness (35%), followed by cardiovascular disease (27%), and cancer (21%).22

ASSESSMENT AND DIAGNOSIS

Clinical Manifestations

COPD is characterized by symptoms of dyspnea, chronic cough, and chronic sputum production in

persons with a history of exposure to risk factors, such as smoking cigarettes. Dyspnea is initially

intermittent and only with exertion, but later becomes persistent. Chronic cough can be intermittent,

productive, or non-productive. Any pattern of sputum production may be described.3

Several questionnaires are available to assess severity of symptoms. GOLD recommends use of

the Modified British Medical Research Council (MMRC) questionnaire on breathlessness23

or the COPD

Assessment Test (CAT)24

for this purpose.3 A high symptom burden is suggested by an MMRC grade ≥ 2

or a CAT score ≥ 10. The MMRC questionnaire on breathlessness categorizes severity of symptoms in

grades 0 to 4 based on answers to the following statements:

• MMRC Grade 0: I only get breathless with strenuous exercise;

• MMRC Grade 1: I get short of breath when hurrying on level ground or walking up a slight hill;

• MMRC Grade 2: I walk slower than people of the same age on level ground because of

breathlessness, or I have to stop for breath when walking on my own pace on level ground;

• MMRC Grade 3: I stop for breath after walking about 100 meters or after a few minutes on level

ground; and

• MMRC Grade 4: I am too breathless to leave the house or I am breathless when dressing or

undressing.

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History and Examination

Patients with suspected COPD should have a detailed medical history and physical examination. History

of present illness should include review of current respiratory symptoms and their development over time.

It should also include assessment of physical activity level but clinicians are cautioned to be especially

aware of have gradually limited their activity level over time to compensate due to symptoms of dyspnea.

Medical history should focus on prior history of lung disease, exposure to risk factors, family history of

chronic respiratory disease or COPD, pattern of symptom development, prior history of hospitalizations

for exacerbations or other respiratory disorders, medical co-morbidities, and risk factor reduction such as

smoking cessation.3

Clinicians should also determine each patient’s cumulative number of pack-years smoked (packs

of cigarettes smoked per day multiplied by the number of years) when evaluating patients as the

magnitude of decline in FEV1 is dose-dependent.13

A reported history of smoking ≥ 70 pack-years of

cigarettes is the single most specific indicator of airway obstruction (positive likelihood ratio [LR] =

8.0).25,26

However, a combination of findings is more useful for diagnosing airflow obstruction than any

individual sign, symptom, or piece of historical information. However, the presence of two or more of the

following findings (history of smoking ≥ 70 pack-years, history of COPD, and/or the auscultation of

decreased breath sounds) is more useful for predicting airflow obstruction than any individual sign,

symptom, or piece of historical information (positive LR = 34).26

Moreover, absence of all three items

strongly suggests against underlying obstructive airway disease (negative LR = 0.02).26,27

A systematic review28

found the following historical elements to have the strongest independent

diagnostic value for detecting COPD: > 40 pack years of smoking (positive LR = 11.6); self-reported

history of COPD (positive LR = 4.4); wheezing (odds ratio [OR] = 4.4); and symptoms provoked by

allergens (OR = 4.5). Examination tests found to have strong independent diagnostic value include

prolonged expiration (OR = 3.7), forced expiratory time > 9 seconds (positive LR =4.6), and maximum

laryngeal height (the distance between the top of the thyroid cartilage and suprasternal notch) of < 4 cm

(positive LR = 3.6).28

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The majority of characteristic exam findings associated with COPD are typically not seen until late

in the course of disease. This emphasizes the importance of obtaining spirometry for screening purposes

in smokers ≥ 40 years old with respiratory symptoms. Early diagnosis of COPD may result in improved

patients outcomes through lifestyle changes such as smoking cessation, by use of appropriate

pharmacological therapies, and implementation of preventative health practices such as immunizations

against influenza and pneumococcal infection.3

Ancillary Testing

GOLD recommends pulse oximetry should be used to assess all stable patients with FEV1 < 35% of

predicted or those with clinical signs suggestive of respiratory failure or right heart failure.3 In patients with

an oxygen saturation < 92%, arterial blood gas (ABG) measurement is suggested because pulse oximetry

loses sensitivity for detecting hypoxia below this cut-off.29

ABG measurement is useful in determining

need for chronic oxygen therapy, ascertaining the presence of hypercapnia, and classifying severity of

acute exacerbations and/or need for non-invasive or invasive ventilatory strategies during exacerbations.3

An electrocardiogram (ECG) can aid in the diagnosis of coexisting cardiac problems. Chest radiography

may show evidence of hyperinflation, flattening of the diaphragmatic contour, bullous disease, or

increased depth of the retrosternal air space.

Co-morbidities

Co-morbidities in patients with COPD should be routinely screened for and treated in the same manner

as in patients without COPD. Commonly encountered co-morbid medical conditions include depression

and anxiety, osteoporosis, cardiovascular disease, diabetes, and lung cancer.3 Osteoporosis is present in

up to 60% of patients with advanced COPD.30

Accelerated bone loss is associated with smoking, use of

glucocorticoids, vitamin D deficiency, low body mass index, hypogonadism, and sedentary lifestyle.

Recognition and screening for the presence of underlying bone disease in patients with COPD is

important because many patients remain undiagnosed until their first fracture. Management involves

vitamin D and calcium supplementation and bisphosphonates when indicated.30

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Alpha 1-Antitrypsin Deficiency

COPD is the most prevalent clinical disorder associated with alpha 1-antitrypsin (AAT) deficiency, an

inherited disorder characterized by panacinar basilar emphysema, often presenting at a young age (< 45

years old). Up to 3% of patients with COPD have AAT deficiency and among Caucasians in North

America, AAT deficiency is as common as cystic fibrosis.31

Approximately 95% of patients with severe

AAT deficiency are homozygotes for the protease inhibitor (PI), type ZZ allele (designated PI*ZZ).

Cigarette smoking is the most significant risk factor for the development of emphysema in patients with

AAT deficiency, usually developing by the third or fourth decade of life. However, in homozygotes who

are nonsmokers, few develop clinically significant lung disease and the disorder often goes clinically

unrecognized.32

The World Health Organization (WHO) recommends screening for the disorder in

patients with COPD from areas with a high prevalence of AAT deficiency (particularly Caucasians of

Northern European ancestry) using a quantitative test. Serum levels of AAT in PI*ZZ homozygotes is

approximately 15% of normal (30-40 mg/dL—compared with normal serum values of 150-350 mg/dL).

Those with abnormal results on screening should undergo PI typing and if positive should be offered

genetic counseling.33

Spirometry

Post-bronchodilator spirometry is recommended for the diagnosis of COPD in patients with respiratory

symptoms and a history of exposure to risk factors by GOLD and the ACP, ACCP, ATS, and ERS joint

practice guideline.3,26

The presence of a post-bronchodilator FEV1/FVC ratio < 0.70 is characteristic of

obstructive airway disease. The ACP, ACCP, ATS, and ERS joint practice guideline recommend against

use of spirometry to screen for airflow obstruction in individuals without respiratory symptoms.26

GOLD

recommends that spirometry should be performed in individuals > 40 years of age with respiratory

symptoms suggestive of COPD. Spirometry should be repeated annually in patients diagnosed with

COPD.3

Measurements of lung volumes and diffusing capacity are not essential to patient management,

but may help to identify air trapping or concomitant restrictive lung disease and characterize the severity

of alveolar destruction. Early in the course of disease, patients with COPD exhibit gas trapping, reflected

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by an increased residual volume. As airflow limitation progresses, static hyperinflation occurs, reflected by

an increase in total lung capacity. Destruction of lung parenchyma, as occurs in emphysema, may be

reflected by a reduced diffusing capacity of carbon monoxide.

Classifying Severity of Disease

In patients with a post-bronchodilator FEV1/FVC ratio of < 0.70, the degree of airflow obstruction in COPD

is determined by spirometric measurement of post-bronchodilator FEV1. Accordingly, GOLD organizes

patients into the following stages of severity:3

• GOLD 1 (Mild): FEV1 ≥ 80% predicted;

• GOLD 2 (Moderate): FEV1 50-79% predicted;

• GOLD 3 (Severe): FEV1 30-49% predicted; or,

• GOLD 4 (Very Severe): FEV1 < 30% predicted.

Although it is important to determine the magnitude of reduction in FEV1 to determine disease

severity, other disease severity indices such as the BODE index (Table 2) may be more reliable

predictors of hospitalization from COPD than FEV1 alone.34,35

Recognizing that worsening airflow

limitation alone is not the most reliable means of assessing disease severity, a major revision was

introduced in the updated GOLD guideline, recommending use of a novel tool, the combined COPD

assessment (Figure B), which utilizes an MMRC grade ≥ 2 or a CAT score ≥ 10 as an indication of

severe symptom burden.3 Categorization of patients in this manner allows practitioners to stratify

individual patients according to risk of exacerbations and apply recommended therapeutic strategies for

each patient group, as recommended by GOLD in Table 3. According to GOLD,3 in patients where there

is a discrepancy between risk category assessed by spirometry and that derived from exacerbation

history and symptoms based on the combined COPD assessment, the highest risk group should be

chosen. Based on the combined COPD assessment, groups can be organized into the following

categories:

• Patient group A—low risk, less symptoms: GOLD 1-2 (mild or moderate airflow limitation) and

0-1 exacerbations per year and MMRC grade 0-1 or CAT score < 10.

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• Patient group B—low risk, more symptoms: GOLD 1-2 (mild or moderate airflow limitation)

and 0-1 exacerbations per year and MMRC grade ≥ 2 or CAT score ≥10.

• Patient group C—high risk, less symptoms: GOLD 3-4 (severe or very severe airflow

limitation) and/or ≥ 2 exacerbations per year and/or ≥ 1 hospitalized exacerbations per year and

MMRC grade 0-1 or CAT score < 10.

• Patient group D—high risk, more symptoms: GOLD 3-4 (severe or very severe airflow

limitation) and/or ≥ 2 exacerbations per year and/or ≥ 1 hospitalized exacerbations per year and

MMRC grade ≥ 2 or CAT score ≥ 10.

MANAGEMENT

Stable COPD

GOLD now recommends that management strategy of stable COPD should consider individualized

symptoms and future risk for exacerbation in addition to FEV1, as FEV1 alone is a poor descriptor of

disease status.3 Use of the new Combined COPD Assessment tool from GOLD can be used for this

purpose (Figure B). Treatment of stable COPD should be largely focused at reducing symptoms in an

effort to improve quality of life, minimizing risk factors, and preventing exacerbations. Interventions shown

to be effective at reducing exacerbations include, evaluating knowledge of current therapy, such as

proper inhaler technique, smoking cessation, annual influenza vaccination, pulmonary rehabilitation, and

maintenance medications including long-acting bronchodilators (long-acting beta agonists [LABAs] or

long-acting anticholinergics such as tiotropium), inhaled corticosteroids (ICS), and phosphodiesterase

type-4 inhibitors (roflumilast).3

Inhaled Bronchodilators

Inhaled bronchodilators are preferred over oral bronchodilators and long-acting formulations are preferred

over short-acting formulations for both anticholinergics and β2-agonists.3 Long-acting bronchodilators

including LABAs and/or long-acting anticholinergics (tiotropium) are recommended in patients with

moderate to very severe disease. LABAs can be used alone or in combination with ICS. Use of LABAs as

monotherapy has been shown to reduce frequency in exacerbations and slow decline in FEV1.22

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In patients with moderate to very severe disease, addition of tiotropium (18 mcg inhaled once

daily) to standard medications used to treat COPD (excluding the short-acting anticholinergic

ipratropium), has been shown to reduce the risk of exacerbations, related hospitalizations, and respiratory

failure.36

When used as monotherapy, tiotropium is superior to ipratropium.37

The ACP, ACCP, ATS, and

ERS joint guideline recommends treatment with inhaled bronchodilators for stable COPD patients with

respiratory symptoms and FEV1 < 60% predicted.26

They also recommend that monotherapy using either

long-acting inhaled anticholinergics or inhaled LABAs should be prescribed to symptomatic patients with

COPD and FEV1 < 60% predicted with choice of specific monotherapy based on patient preference, cost,

and adverse effect profile.26

Inhaled Corticosteroids

Use of inhaled corticosteroids as maintenance therapy in COPD has been shown to reduce the frequency

of exacerbations in patients with an FEV1 < 50% of predicted. Their use may also slow decline in FEV1

when used alone, but more so when used in combination with a long-acting β2-agonist. Unlike asthma

therapy, long-term monotherapy with ICS is not recommended in patients with COPD because it is less

effective than the combination of ICS with LABAs.3 Despite the benefits seen with ICS use in COPD

management, their use (alone or in combination with LABA) has been linked to an increased risk of

pneumonia.38

GOLD recommends that long-term treatment with ICS is recommended for patients with

FEV1 < 50% of predicted and/or frequent exacerbations that are not adequately controlled by long-acting

bronchodilators.3 The ACP, ACCP, ATS, ERS joint guideline suggests administering combination inhaled

therapies (long-acting inhaled anticholinergics, LABAs, or ICS) for symptomatic patients with stable

COPD and FEV1 < 60% predicted.26

Continuous Oxygen

Supplemental oxygen therapy has been shown to be improve survival when used for ≥ 15 hours daily to

maintain an arterial PaO2 > 60 mm Hg in patients with COPD who have severe resting hypoxemia (mean

resting arterial PaO2 ≤ 55 mm Hg) or arterial oxygen saturation ≤ 88%.39,40

Continuous oxygen therapy is

recommended by both guidelines for patients with COPD with a resting PaO2 ≤ 55 mm Hg or SaO2 ≤ 88%

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(during rest, exercise, or sleep).3,26

Long-term continuous oxygen therapy should also be considered for

patients with a resting PaO2 of 56 to 59 mm Hg and evidence of right heart failure (cor pulmonale) and/or

secondary polycythemia (hematocrit > 55%).3

Roflumilast

Addition of roflumilast (a type-4 phosphodiesterase inhibitor) to standard therapy can be considered in

patients with an FEV1 < 50% predicted, chronic bronchitis, and frequent exacerbations (two or more per

year) that are not adequately controlled by long-acting bronchodilators.3 In this patient population, it has

been shown to reduce frequency of exacerbations.41,42

Common adverse reactions (≥ 2%) associated

with its use include nausea, diarrhea, weight loss, and psychiatric disturbance (including suicidal ideation

and behavior).43

Because some patients develop significant weight loss with its use, it is recommended

that weight be monitored regularly with its use. Its use is contraindicated in patients with moderate to

severe liver impairment.43

Smoking Cessation

Smoking cessation remains the most important preventative strategy in the management of COPD. In

addition to improving respiratory symptoms, smoking cessation has been shown to slow disease

progression, as evidenced by a decrease in the rate of decline in the FEV1, and decrease long-term

mortality in patients with COPD.15,21,44

Patients should be counseled on smoking cessation at regular

intervals during follow up visits.

Nicotine replacement therapy in any form (e.g., nicotine gum, inhaler, nasal spray, sublingual

tablet, lozenge, or transdermal patch) has been shown to increase long-term smoking cessation rates.45–

47 Other pharmacologic options that have been shown to improve long-term smoking cessation rates

include varenicline, bupropion, and nortriptyline.48–50

Many patients are anxious to try cigarette

substitutes, or “electronic cigarettes”, but safety of the propellant has not been established, though

presumably it is safer than the known toxins of inhaled tobacco smoke.51

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Vaccinations

Annual influenza vaccination is recommended in all persons age 50 or older and those with chronic

pulmonary disease (including COPD and asthma).52

Annual vaccination against influenza can reduce the

risk of serious lower respiratory tract infections and death in patients with COPD.3 Pneumococcal

vaccination is recommended for all persons 65 years of age or older, all persons with COPD, and all

active smokers. Vaccination decreases risk of serious invasive disease with the pathogen Streptococcus

pneumoniae.53

Pulmonary Rehabilitation

Maintenance of physical activity and pulmonary rehabilitation is clinically useful in all patients with

symptomatic COPD and after exacerbations. Exercise rehabilitation has been shown to improve exercise

tolerance, decrease symptoms of dyspnea and fatigue, and improve quality of life in patients with

COPD.54,55

Regular physical activity is recommended for all patients with COPD.3 The ACP, ACCP, ATS,

ERS joint guideline recommends that pulmonary rehabilitation be prescribed for symptomatic patients

with an FEV1 < 50% predicted and considered for symptomatic or exercise-limited patients with an FEV1

> 50% predicted.26

Perioperative Risk Assessment

Increased severity of postoperative complications in COPD may vary with underlying baseline disease

severity; however, the most important predictor of outcome is proximity of the surgical site to the

diaphragm. The closer the incision is to the diaphragm, the higher the risk. Most reports conclude that

epidural or spinal anesthesia have lower risk in comparison to general anesthesia, although results are

not uniform. Postoperative complications include lung infections, atelectasis, and worsened airflow

limitation that may lead to respiratory failure.3

Acute COPD Exacerbations

An exacerbation of COPD is defined as an acute event characterized by a worsening of the patient’s

respiratory symptoms that is beyond normal day-to-day variations requiring a change in medication.56–58

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Nearly 50% of patients with COPD experience at least one exacerbation annually.59

The hallmark of

exacerbations is a change in the character and/or severity in one or more of the three cardinal symptoms

of COPD—dyspnea, chronic cough, and/or sputum production. Exacerbations have numerous

precipitating causes but are most commonly related to viral and/or bacterial respiratory tract infections.3,5

Frequent COPD exacerbations are defined as ≥ 2 exacerbations per year and are seen in

approximately 10% of patients with COPD.59

Although frequent exacerbations are more common with

increasing severity of the disease, a considerable number of patients with moderate disease (i.e., FEV1 >

50% predicted, GOLD stage 2) are affected by frequent exacerbations.59

The single best predictor for risk

of frequent exacerbations, across all GOLD stages of COPD, is a history of previously treated

exacerbations.59

Patients should be considered at high risk for exacerbations if they meet GOLD 3 or

GOLD 4 (severe to very severe disease) severity airflow obstruction, or if they have a history of ≥ 2

exacerbations in the preceding year.3

Exacerbations play a significant role in the course of disease and are associated with significant

mortality. It may take several weeks or even months following an exacerbation for patients to improve to

baseline from a symptomatic and pulmonary function standpoint.3 The in-hospital mortality is

approximately 10% for patients admitted with exacerbations complicated by acidosis and hypercapnic

respiratory failure. In-hospital mortality rates are as high as 20% among those admitted to the ICU.60,61

Exacerbations of COPD are commonly managed with a combination of inhaled short-acting

bronchodilators, systemic corticosteroids, and antibiotics. Severity of exacerbations is usually classified

as mild when respiratory symptoms require change of inhaled treatment by the patient, moderate when

respiratory symptoms require medical interventions such as antibiotics and/or oral corticosteroids, and

severe when respiratory symptoms require hospitalization for management.3

Potential indications for hospital admission for management of exacerbation include severe

baseline underlying disease, onset of new signs suggestive of severe disease, frequent exacerbations,

older age, insufficient home support, failure to respond to outpatient medical management, and presence

of serious co-morbidities such as heart failure or arrhythmias.3 Signs suggestive of severe exacerbations

include use of accessory respiratory muscles, paradoxical chest wall movements, worsening or new onset

central cyanosis, development of peripheral edema, hemodynamic instability, and altered mental status.3

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Indications for ICU admission include hemodynamic instability, need for invasive mechanical ventilation,

changes in mental status (e.g., confusion, lethargy, coma), persistent or worsening hypoxemia (arterial

PaO2 < 40 mm Hg) and/or severe or worsening respiratory acidosis (pH < 7.25) despite supplemental

oxygen and NIV.3

Systemic Corticosteroids

The beneficial effects of corticosteroid use for the treatment of exacerbations was established in 1999

with the Department of Veterans Affairs Cooperative Study Group Trial.62

Beneficial effects of

corticosteroids include a reduction in exacerbation treatment failure, shorter hospital stays, improvement

in lung function and oxygenation, and shortened recovery times.33,63,64

Although their role in COPD

management remains important, corticosteroids are associated with significant adverse effects including

hyperglycemia, myopathy, adrenal suppression, cataract formation, peptic ulcer disease, psychosis,

hyperadrenocorticism, increased risk of infection, and osteoporosis.65

Thus, duration and dosage required

for an adequate clinical response is of clinical importance but remains a matter of debate.

GOLD recommends prednisone (or equivalent) 40 mg/day by mouth for 10-14 days during

exacerbations.3 The REDuction in the Use of Corticosteroids in Exacerbated COPD (REDUCE)

66 trial

found a short-term (5 days) course of corticosteroids non-inferior to conventional (14 days) treatment. The

main outcome measure of the trial was time to next exacerbation within 180 days, which was similar in

both groups. The REDUCE trial provides strong evidence supporting use of a 5-day course of

corticosteroids (irrespective of disease severity) for treatment of exacerbations.66

In most circumstances,

corticosteroids used for a duration of < 2 weeks can be discontinued safely without tapering.62

Antibiotics

Although conflicting data exists regarding the role of antibiotics in exacerbations, antibiotics are often

utilized empirically, even in the absence of supportive data implicating a bacterial pathogen.67

The most

common bacterial pathogens implicated in exacerbations include Streptococcus pneumoniae,

Haemophilus influenzae, and Moraxella catarrhalis.68

In patients with more severe disease (GOLD 3 and

GOLD 4), Pseudomonas aeruginosa can be implicated as a causative pathogen in exacerbations.3

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GOLD recommends that antibiotics should be given to patients with COPD exacerbations who

have three cardinal symptoms (increase in dyspnea, sputum volume, and sputum purulence); patients

with two of the cardinal symptoms, if increased purulence of sputum is present; or those who require

invasive or noninvasive mechanical ventilation.3 Addition of antibiotics (e.g., a respiratory quinolone) to

standard treatment in patients with severe exacerbations requiring need for mechanical ventilation

(noninvasive or invasive) has been shown to reduce the risk of inhospital death, shorten the duration of

mechanical ventilation and hospital stay, and reduce the need for additional courses of antibiotics.69

The

recommended duration of antibiotics is 5-10 days and selection should be based on local bacterial

resistance patterns.3 Evidence supports a shorter antibiotic course (≤ 5 days) in patients with mild to

moderate exacerbations.70

Inhaled Bronchodilators

Short-acting bronchodilators play a key role in symptom management in patients with exacerbations.

Their use is associated with acute improvements in FEV1, but have little effect on FEV1 with chronic use.

Commonly utilized short-acting bronchodilators include albuterol sulfate, a short-acting β2-agonist

(SABA), and the short-acting anticholinergic ipratropium bromide. Both provide acute symptomatic

improvement with their use. With long-term use, there is no significant difference in outcomes when

comparing metered dose inhalers with nebulizers. However, both are commonly administered via

nebulized preparations during exacerbations. No studies have evaluated the use of inhaled long-acting

bronchodilators with/without ICS during exacerbations.3

SABAs produce bronchodilation primarily due to their ability to relax airway smooth muscle.

Systemic absorption of the drug can cause unwanted side effects, most commonly tachycardia, and

palpitations.71

Their short half-lives limits their use in the chronic treatment of COPD, though they are

commonly used as rescue medications during acute exacerbations. Controversy exists regarding optimal

dosing of inhaled SABA, and ideally they should be utilized at the lowest dose and frequency required to

achieve clinical response.71

Anticholinergics such as ipratropium bromide also work by inhibiting

bronchoconstriction resulting in symptomatic improvement in addition to reducing mucus secretion. The

two drugs can be used alone or in combination, and produce similar effects in terms of bronchodilation

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and combination of SABA and ipratropium do not appear to increase the effect on FEV1 more than either

used alone.72

Noninvasive Ventilation

Acute hypercapnic respiratory failure in the setting of COPD exacerbation is the most common indication

for noninvasive positive-pressure ventilation (NIPPV).73

Use of NIPPV has been shown to improve blood

gas exchange, reduce the need for intubation, and decrease mortality when properly applied as a first line

treatment for respiratory failure resulting complicating COPD exacerbations. Its use has also been shown

to decrease length of hospital stay, reduce ventilator-induced lung injury, and lower rates of nosocomial

infections (e.g., ventilator associated pneumonia).74,75

The ideal candidate for NIPPV is an alert patient

with increased work of breathing, tachypnea, and moderate respiratory acidosis (pH 7.10–7.35).74

Indications for initiation of NIPPV in patients with hypercapnic respiratory failure include one or

more of the following: respiratory acidosis (arterial pH ≤ 7.35 and/or PaCO2 ≥ 45 mm Hg) or severe

dyspnea with signs of respiratory muscle fatigue and/or increased work of breathing (e.g., use of

accessory respiratory muscles, paradoxical abdominal motion, or intercostal muscle retraction).3,73–77

Contraindications to NIV include altered mental status, nausea/vomiting, upper gastrointestinal

hemorrhage or recent abdominal surgery, hemodynamic instability, and inability to clear secretions.76

Proper NIPPV settings and early institution of the therapy is of utmost importance in order to

achieve successful outcomes with its use. We suggest use of Bi-level Positive Airway Pressure (BiPAP)

mode with the following initial settings: Inspiratory Positive Airway Pressure (IPAP) at 8 cm H2O,

Expiratory Positive Airway Pressure at 4 cm H2O, Fraction of inspired oxygen (FiO2) set at 60% and

titrated to obtain a goal oxygen saturation of 88-92%. IPAP should be titrated upwards in 2 cm H2O

increments at the bedside in order to obtain a goal tidal volume of 6-8 mL/kg of ideal body weight (IBW).

Invasive Mechanical Ventilation

Indications for invasive mechanical ventilation (IMV) include: failure of an initial trial of NIV; respiratory or

cardiac arrest; massive aspiration; diminished or loss of consciousness; respiratory pauses with loss of

consciousness; psychomotor agitation inadequately controlled by sedation; inability to remove/tolerate

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secretions; hemodynamic instability; severe ventricular arrhythmias; and life-threatening hypoxemia in

patients unable to tolerate NIV.3,78

Major complications of IMV in patients with COPD include development of barotrauma, failure to

wean to spontaneous ventilation, and risk of ventilator-acquired pneumonia.3 When IMV is required for

the management of respiratory failure complicating COPD exacerbations, the most appropriate setting is

in the intensive care unit in consultation with appropriately trained specialists. We recommend intubation

with a relatively large endotracheal tube (internal diameter 7.5-8.5 mm) and use assist-control mode with

the following initial ventilator settings: delivered tidal volume of 8 mL/kg of IBW; respiratory rate 10-14

breaths per minute; FiO2 of 35% (titrated to maintain a goal oxygen saturation of 88-92%); positive end-

expiratory pressure (PEEP) of 5 cm H2O. Moderate sedation may be achieved with agents such as

propofol, fentanyl, or midazolam, with scheduled withdrawal of sedatives on a daily basis. The use of

paralytics should be avoided.78

In all patients with severe exacerbations requiring NIV or IMV, ABG measurements, chest

radiographs, fluid balance, and nutritional status should be monitored closely. Usual therapy for

exacerbations should be continued, including as systemic corticosteroids, antibiotics, and inhaled

bronchodilators. Additionally, co-morbid medical conditions (e.g., heart failure, arrhythmias, infections)

should the same as in patients without COPD. Venous thromboembolism prophylaxis should be utilized in

all patients without contraindications and the head of the bed should be kept elevated at ≥ 45 degrees at

all times to minimize the risk of aspiration.3,78

Weaning and discontinuation of ventilatory support should

take place via a standardized protocol.

Hospital Discharge and Outpatient Follow Up

Prior to discharge, patients should be started on long-acting bronchodilators (anticholinergics and/or β2-

agonists), with or without ICS. Inhaler technique should be reassessed to ensure proper use. Patients

should be educated about their maintenance regiment and given instructions regarding completion of

steroid therapy and antibiotics, if prescribed. Counseling on smoking cessation should also take place

prior to discharge, and routinely at all follow up visits. Pulse oximetry or ABG measurements should be

utilized to assess need for long-term oxygen therapy. Patients should also be screened for need of a

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home nebulizer.3 Early outpatient pulmonary rehabilitation after hospitalization for exacerbations should

also be considered. Its use is safe and has been shown to result in clinically significant improvements in

exercise capacity and health status at 3 months.79

Finally, vaccination status should be updated and a

plan for management and follow up of co-morbidities should be arranged.3

Patients hospitalized for exacerbations should be seen in the outpatient setting four to six weeks

after discharge. Outpatient visits should focus on smoking cessation counseling, proper inhaler

techniques, symptoms, and status of co-morbidities. The MMRC or CAT can be utilized to re-assess

symptom severity. Spirometry should be utilized for measurement of post-bronchodilator FEV1. Patients

should be questioned about their ability to cope in their normal living environment, current exercise

capacity, and physical ability to perform activities of daily living. Screening for need of long-term oxygen

therapy and/or a home nebulizer should also take place.3

CONCLUSION

COPD remains an important preventable cause of death and places a significant socioeconomic burden

on the healthcare system. Management of the disease is complex, often involving a multidisciplinary

approach to achieve optimal outcomes. Patients often have multiple co-morbid medical conditions that

impact mortality and pose a significant challenge to practitioners managing the disease. A new GOLD

combined COPD assessment tool has been introduced, which serves to help practitioners in the

assessment of disease severity, estimate risk of future exacerbations, and guide selection of appropriate

pharmacotherapy. GOLD now requires use of spirometry and characteristic findings in the diagnosis of

COPD. Despite the introduction of multiple new drug therapies for COPD in the past two decades,

smoking cessation remains the single most important method of reducing mortality.

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72. McCrory DC, Brown CD. Anti-cholinergic bronchodilators versus beta2-sympathomimetic agents for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev Online. 2002;(4):CD003900. doi:10.1002/14651858.CD003900.

73. Hill NS, Brennan J, Garpestad E, Nava S. Noninvasive ventilation in acute respiratory failure. Crit Care Med. 2007;35(10):2402–2407. doi:10.1097/01.CCM.0000284587.36541.7F.

74. Plant P, Owen J, Elliott M. Non-invasive ventilation in acute exacerbations of chronic obstructive pulmonary disease: long term survival and predictors of in-hospital outcome. Thorax. 2001;56(9):708–712. doi:10.1136/thorax.56.9.708.

75. Lightowler JV. Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003;326(7382):185–185. doi:10.1136/bmj.326.7382.185.

76. Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, copd, and nocturnal hypoventilation—a consensus conference report*. Chest J. 1999;116(2):521–534. doi:10.1378/chest.116.2.521.

77. Ram FSF, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev Online. 2004;(1):CD004104. doi:10.1002/14651858.CD004104.pub2.

78. Conti G, Antonelli M, Navalesi P, et al. Noninvasive vs. conventional mechanical ventilation in patients with chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial. Intensive Care Med. 2002;28(12):1701–1707. doi:10.1007/s00134-002-1478-0.

79. Man WD-C, Polkey MI, Donaldson N, Gray BJ, Moxham J. Community pulmonary rehabilitation after hospitalisation for acute exacerbations of chronic obstructive pulmonary disease: randomised controlled study. BMJ. 2004;329(7476):1209. doi:10.1136/bmj.38258.662720.3A.

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Table 1. Risk factors for COPD

Risk factor Comments

Cigarette smoking The most common and important risk factor, exposure seen in 85% to 95% of cases. Less commonly, inhalation of pipe and cigar smoke.

Passive exposure to smoke Also referred to as “second hand smoke” or environmental tobacco smoke.

Occupational exposures Professions with exposure to dusts, gases and/or fumes (coal workers, hard rock miners, tunnel workers, and concrete manufacturing).

AAT deficiency Over 90% caused by homozygous phenotype.

Childhood illnesses Low birth weight, respiratory infections, and childhood asthma

Indoor and outdoor air pollutants

Low socioeconomic status

Reference: Data from Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. The Lancet. 1;370(9589):765–773. doi:10.1016/S0140-6736(07)61380-4.

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Table 2. Variables and Point Values Used for the Computation of the Body-Mass Index, Degree of Airflow Obstruction and Dyspnea, and Exercise Capacity (BODE) Index.*

Variable Points on BODE Index

0 1 2 3

FEV1 (% of predicted) ≥ 65 50-64 36-64 ≤ 35

Distance walked in 6 min (m) ≥ 350 250-349 150-249 ≤ 149

MMRC dyspnea scale 0-1 2 3 4

Body-mass index (kg/m2) > 21 ≤ 21

* The cutoff values for the assignment of points are shown for each variable. The total possible values range from 0 to 10. FEV1 denotes forced expiratory volume in one second.

† The forced expiratory volume in 1 second (FEV1) categories are based on stages identified by the American Thoracic Society.

‡ Scores on the modified Medical Research Council (MMRC) dyspnea scale can range from 0 to 4, with a score of 4 indicating that the patient is too breathless to leave the house or becomes breathless when dressing or undressing.

§ The values for body-mass index were 0 or 1 because of the inflection point in the inverse relation between survival and body-mass index at a value of 21.

Reference: Reproduced with permission from Celli BR, Cote CG, Marin JM, et al. The Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease. N Engl J Med. 2004;350(10):1005–1012. doi:10.1056/NEJMoa021322.

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Table 3. Initial Pharmacologic Management of COPD*

Patient Group Recommended First Choice Alternative Choice Other Possible Treatments†

A

Short-acting anticholinergic prn

or

Short-acting β2-agonist prn

Long-acting anticholinergic

or

Long-acting β2-agonist

or

Short-acting anticholinergic and short-acting β2-agonist

Theophylline

B

Long-acting anticholinergic

or

Long-acting β2-agonist

Long-acting anticholinergic and long-acting β2-agonist

Short-acting anticholinergic

and/or

Short-acting β2-agonist

and/or

Theophylline

C

Inhaled corticosteroid and long-acting β2-agonist

or

Long-acting anticholinergic

Long-acting anticholinergic and long-acting β2-agonist

Phosphodiesterase-4 inhibitor

and/or

Short-acting anticholinergic

and/or

Short-acting β2-agonist

and/or

Theophylline

D

Inhaled corticosteroid and long-acting β2-agonist

or

Long-acting anticholinergic

Inhaled corticosteroid, long-acting β2-agonist, and long-acting anticholinergic

or

Inhaled corticosteroid, long-acting β2-agonist, and phosphodiesterase-4

inhibitor

or

Long-acting anticholinergic and long-acting β2-agonist

or

Long-acting anticholinergic and phosphodiesterase-4 inhibitor

Carbocysteine

and/or

Short-acting anticholinergic

and/or

Short-acting β2-agonist

and/or

Theophylline

Definition of abbreviation: COPD = chronic obstructive pulmonary disease.

* Medications in each cell are mentioned in alphabetical order and therefore not necessarily in order of preference.

† Medications in this column can be used alone or in combination with other options in the First and Alternative Choice columns.

Reproduced with permission from the Global Initiative for Chronic Obstructive Lung Disease (GOLD), www.goldcopd.org, Copyright 2013. [4]

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225x136mm (72 x 72 DPI)

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Figure A. Natural history of chronic obstructive pulmonary disease (COPD)

References: Reproduced from The natural history of chronic airflow obstruction, Fletcher C, Peto R, ©

1977 BMJ, Volume 1:1645–1648, British Medical Journal with permission from BMJ Publishing Group Ltd

and Pathophysiology of airflow limitation in chronic obstructive pulmonary disease, Hogg JC, Lancet,

2004; 364(9435):709–721, © Elsevier 2004.

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Figure B. Model of Symptom/Risk of Evaluation of COPD [4]

When assessing risk, choose the highest risk according to GOLD grade or exacerbation history.

(One or more hospitalizations for COPD exacerbations should be considered high risk.)

Patient Characteristic Spirometric Classification

Exacerbations per year

mMRC CAT

A Low Risk

Less Symptoms GOLD 1-2 ≤ 1 0-1 < 10

B Low Risk

More Symptoms GOLD 1-2 ≤ 1 ≥ 2 ≥ 10

C High Risk

Less Symptoms GOLD 3-4 ≥ 2 0-1 < 10

D High Risk

More Symptoms GOLD 3-4 ≥ 2 ≥ 2 ≥ 10

Abbreviations: CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; GOLD, the Global Initiative for Chronic Obstructive Lung Disease; mMRC, Modified British Medical Research Council scale.

Reference: Reprinted with permission from the Global Strategy for Diagnosis, Management and Prevention of COPD 2011, http://www.goldcopd.org. © 2011 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved.

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