2184 PART 7 Disorders of the Respiratory System

airway responsiveness is clearly a significant predictor of subsequent

decline in pulmonary function. A study from the Childhood Asthma

Management Program identified four lung function trajectories in children with persistent asthma. Asthmatics with reduced lung function

early in life were more likely to meet spirometric criteria for COPD in

early adulthood. Both asthma and airway hyperresponsiveness are risk

factors for COPD.

■ RESPIRATORY INFECTIONS

The impact of adult respiratory infections on decline in pulmonary

function is controversial, but significant long-term reductions in pulmonary function are not typically seen following an individual episode

of acute bronchitis or pneumonia. However, respiratory infections are

important causes of COPD exacerbations, and recent results from the

COPDGene and ECLIPSE studies suggest that COPD exacerbations

are associated with increased loss of lung function longitudinally,

particularly among those individuals with better baseline lung function levels. The impact of the effects of childhood respiratory illnesses

on the subsequent development of COPD has been difficult to assess

due to a lack of adequate longitudinal data, but recent studies have

suggested that childhood pneumonia may lead to increased risk for

COPD later in life.

■ OCCUPATIONAL EXPOSURES

Increased respiratory symptoms and airflow obstruction have been

suggested to result from exposure to dust and fumes. Several specific

occupational exposures, including coal mining, gold mining, and cotton textile dust, have been implicated as risk factors for chronic airflow

obstruction. Although nonsmokers in these occupations can develop

some reductions in FEV1

, the importance of dust exposure as a risk

factor for COPD, independent of cigarette smoking, is not certain for

most of these exposures. However, among coal miners, coal mine dust

exposure was a significant risk factor for emphysema in both smokers

and nonsmokers. In most cases, the magnitude of these occupational

exposures on COPD risk is likely substantially less important than the

effect of cigarette smoking.

■ AMBIENT AIR POLLUTION

Some investigators have reported increased respiratory symptoms in

those living in urban compared to rural areas, which may relate to

increased pollution in the urban settings. However, the relationship

of air pollution to chronic airflow obstruction remains unproved.

Prolonged exposure to smoke produced by biomass combustion—a

common mode of cooking in some countries—also appears to be a

significant risk factor for COPD, particularly among women.

■ PASSIVE, OR SECOND-HAND, SMOKING

EXPOSURE

Exposure of children to maternal smoking results in significantly

reduced lung growth. In utero, tobacco smoke exposure also contributes to significant reductions in postnatal pulmonary function.

Although passive smoke exposure has been associated with reductions

in pulmonary function, the importance of this risk factor in the development of the severe pulmonary function reductions often observed in

COPD remains uncertain.

■ GENETIC CONSIDERATIONS

Although cigarette smoking is the major environmental risk factor for the development of COPD, the development of airflow

obstruction in smokers is highly variable. Severe α1

AT deficiency

is a proven genetic risk factor for COPD; there is increasing evidence

that other genetic determinants also exist.

α1

 Antitrypsin Deficiency Many variants of the protease inhibitor (PI or SERPINA1) locus that encodes α1

AT have been described.

The common M allele is associated with normal α1

AT levels. The S

allele, associated with slightly reduced α1

AT levels, and the Z allele,

associated with markedly reduced α1

AT levels, also occur with frequencies of >1% in most white populations. Rare individuals inherit

null alleles, which lead to the absence of any α1

AT production through

a heterogeneous collection of mutations. Individuals with two Z alleles

or one Z and one null allele are referred to as PiZ, which is the most

common form of severe α1

AT deficiency.

Although only ~1% of COPD patients are found to have severe α1

AT

deficiency as a contributing cause of COPD, these patients demonstrate

that genetic factors can have a profound influence on the susceptibility

for developing COPD. PiZ individuals often develop early-onset COPD,

but the ascertainment bias in the published series of PiZ individuals—

which have usually included many PiZ subjects who were tested for

α1

AT deficiency because they had COPD—means that the fraction of

PiZ individuals who will develop COPD and the age-of-onset distribution for the development of COPD in PiZ subjects remain unknown.

Approximately 1 in 3000 individuals in the United States inherits

severe α1

AT deficiency, but only a small minority of these individuals

has been identified. The clinical laboratory test used most frequently

to screen for α1

AT deficiency is measurement of the immunologic level

of α1

AT in serum (see “Laboratory Findings”).

A significant percentage of the variability in pulmonary function

among PiZ individuals is explained by cigarette smoking; cigarette

smokers with severe α1

AT deficiency are more likely to develop COPD

at early ages. However, the development of COPD in PiZ subjects, even

among current or ex-smokers, is not absolute. Among PiZ nonsmokers,

impressive variability has been noted in the development of airflow

obstruction. Asthma and male gender also appear to increase the risk

of COPD in PiZ subjects. Other genetic and/or environmental factors

likely contribute to this variability.

Specific treatment in the form of α1

AT augmentation therapy is

available for severe α1

AT deficiency as a weekly IV infusion (see “Treatment,” below).

The risk of lung disease in heterozygous PiMZ individuals, who have

intermediate serum levels of α1

AT (~60% of PiMM levels), has been controversial. Several recent studies have demonstrated that PiMZ subjects

who smoke are likely at increased risk for the development of COPD.

However, α1

AT augmentation therapy is not recommended for use in

PiMZ subjects.

Other Genetic Risk Factors Studies of pulmonary function measurements performed in general population samples have indicated

that genetic factors other than PI type influence variation in pulmonary function. Familial aggregation of airflow obstruction within families of COPD patients has also been demonstrated.

GWAS have identified >80 regions of the genome that contain

COPD susceptibility loci, including a region near the HHIP gene

on chromosome 4, a cluster of genes on chromosome 15 (including

components of the nicotinic acetylcholine receptor and another gene,

IREB2, related to mitochondrial iron regulation), and a region within

a gene of unknown function (FAM13A). As with most other complex

diseases, the risk associated with individual GWAS loci is modest, but

these genetic determinants may identify important biological pathways

related to COPD. Gene-targeted murine models for HHIP, FAM13A,

and IREB2 exposed to chronic cigarette smoke had altered emphysema

susceptibility, suggesting that those genes are likely to be involved in

COPD pathogenesis.

NATURAL HISTORY

The effects of cigarette smoking on pulmonary function appear to

depend on the intensity of smoking exposure, the timing of smoking exposure during growth and development, and the baseline lung

function of the individual; other environmental factors may have

similar effects. Most individuals follow a steady trajectory of increasing

pulmonary function with growth during childhood and adolescence,

followed by a plateau in early adulthood, and then gradual decline

with aging. Individuals appear to track in their quantile of pulmonary

function based on environmental and genetic factors that put them

on different tracks. The risk of eventual mortality from COPD is

closely associated with reduced levels of FEV1

. A graphic depiction of

the natural history of COPD is shown as a function of the influences

on tracking curves of FEV1

 in Fig. 292-4. Death or disability from

COPD can result from a normal rate of decline after a reduced growth

2185Chronic Obstructive Pulmonary Disease CHAPTER 292

phase (curve C), an early initiation of pulmonary function decline

after normal growth (curve B), or an accelerated decline after normal

growth (curve D). Although accelerated rates of lung function decline

have classically been associated with COPD, recent analyses of several

population-based cohorts demonstrated that many subjects meeting

the spirometric criteria for COPD had reduced growth but normal

rates of lung function decline. The rate of decline in pulmonary

function can be modified by changing environmental exposures (i.e.,

quitting smoking), with smoking cessation at an earlier age providing a

more beneficial effect than smoking cessation after marked reductions

in pulmonary function have already developed. The absolute annual

loss in FEV1

 tends to be highest in mild COPD and lowest in very

severe COPD. Multiple genetic factors influence the level of pulmonary

function achieved during growth.

In chronic smokers, substantial chest CT changes (emphysema and

airway wall thickening) have been identified in subjects with normal

physiology (normal FEV1

 and FEV1

/FVC). COPD in these subjects

commonly progresses in two primary patterns. Subjects with an

emphysema-predominant pattern show emphysema early and classically progress through GOLD 1 to GOLD 2–4. Subjects with an airway

disease–predominant pattern typically show initial evidence of airway

inflammation and progress with little emphysema early as FEV1

 falls

while retaining a normal FEV1

/FVC ratio. This is termed preserved

ratio–impaired spirometry (PRISm) physiology. These subjects tend to

develop emphysema late and can progress directly to GOLD 3 and 4

with severe, end-stage COPD.

CLINICAL PRESENTATION

■ HISTORY

The three most common symptoms in COPD are cough, sputum production, and exertional dyspnea. Many patients have such symptoms

for months or years before seeking medical attention. Although the

development of airflow obstruction is a gradual process, many patients

date the onset of their disease to an acute illness or exacerbation.

A careful history, however, usually reveals the presence of respiratory symptoms prior to the acute exacerbation. The development of

exertional dyspnea, often described as increased effort to breathe,

heaviness, air hunger, or gasping, can be insidious. It is best elicited

by a careful history focused on typical physical activities and how the

patient’s ability to perform them has changed. Activities involving

significant arm work, particularly at or above shoulder level, are particularly difficult for many patients with COPD. Conversely, activities

that allow the patient to brace the arms and use accessory muscles of

respiration are better tolerated. Examples of such activities include

pushing a shopping cart or walking on a treadmill. As COPD advances,

the principal feature is worsening dyspnea on exertion with increasing

intrusion on the ability to perform vocational or avocational activities.

In the most advanced stages, patients are breathless doing basic activities of daily living.

Accompanying worsening airflow obstruction is an increased frequency of exacerbations (described below). Patients may also develop

resting hypoxemia and require institution of supplemental oxygen.

■ PHYSICAL FINDINGS

In the early stages of COPD, patients usually have an entirely normal

physical examination. Current smokers may have signs of active smoking, including an odor of smoke or nicotine staining of fingernails.

In patients with more severe disease, the physical examination of the

lungs is notable for a prolonged expiratory phase and may include expiratory wheezing. In addition, signs of hyperinflation include a barrel

chest and enlarged lung volumes with poor diaphragmatic excursion

as assessed by percussion. Patients with severe airflow obstruction

may also exhibit use of accessory muscles of respiration, sitting in the

characteristic “tripod” position to facilitate the actions of the sternocleidomastoid, scalene, and intercostal muscles. Patients may develop

cyanosis, visible in the lips and nail beds.

Traditional teaching is that patients with predominant emphysema,

termed “pink puffers,” are thin, noncyanotic at rest, and have prominent use of accessory muscles, and patients with chronic bronchitis are

more likely to be heavy and cyanotic (“blue bloaters”). However, current evidence demonstrates that most patients have elements of both

chronic bronchitis and emphysema and that the physical examination

does not reliably differentiate the two entities.

Advanced disease may be accompanied by cachexia, with significant weight loss and diffuse loss of subcutaneous adipose tissue. This

syndrome has been associated with both inadequate oral intake and

elevated levels of inflammatory cytokines (TNF-α). Such wasting

is an independent poor prognostic factor in COPD. Some patients

with advanced disease have paradoxical inward movement of the rib

cage with inspiration (Hoover’s sign), the result of alteration of the

vector of diaphragmatic contraction on the rib cage due to chronic

hyperinflation.

Signs of overt right heart failure, termed cor pulmonale, are relatively

infrequent since the advent of supplemental oxygen therapy.

Clubbing of the digits is not a sign of COPD, and its presence should

alert the clinician to initiate an investigation for causes of clubbing.

In COPD patients, the development of lung cancer is the most likely

explanation for newly developed clubbing.

■ LABORATORY FINDINGS

The hallmark of COPD is airflow obstruction (discussed above). Pulmonary function testing shows airflow obstruction with a reduction

in FEV1

 and FEV1

/FVC (Chap. 285). With worsening disease severity, lung volumes may increase, resulting in an increase in total lung

capacity, functional residual capacity, and residual volume. In patients

with emphysema, the diffusing capacity may be reduced, reflecting the

lung parenchymal destruction characteristic of the disease. The degree

of airflow obstruction is an important prognostic factor in COPD and

is the basis for the GOLD spirometric severity classification (Table

292-1). Although the degree of airflow obstruction generally correlates

with the presence and severity of respiratory symptoms, exacerbations,

emphysema, and hypoxemia, the correlations are far from perfect.

Thus, clinical features should be carefully assessed in each individual

patient with COPD to determine the most appropriate therapies. It has

been shown that a multifactorial index (BODE), incorporating airflow

obstruction, exercise performance, dyspnea, and body mass index, is

a better predictor of mortality. Recently, GOLD added additional elements to their COPD classification system incorporating respiratory

symptoms and exacerbation history; these metrics are used to guide

COPD treatment (see below).

Arterial blood gases and oximetry may demonstrate resting or exertional hypoxemia. Arterial blood gases provide additional information

about alveolar ventilation and acid-base status by measuring arterial

Age, year

Respiratory symptoms

Reduced growth

Rapid decline

Early decline

Normal

A

B

C

D

FEV1, % normal level at age 20

50

100

80

75

25

0 10 706050403020

FIGURE 292-4 Hypothetical tracking curves of forced expiratory volume in 1 s

(FEV1

) for individuals throughout their life spans. The normal pattern of growth

and decline with age is shown by curve A. Significantly reduced FEV1

 (<65% of

predicted value at age 20) can develop from a normal rate of decline after a reduced

pulmonary function growth phase (curve C), early initiation of pulmonary function

decline after normal growth (curve B), or accelerated decline after normal growth

(curve D). (From B Rijcken: Doctoral dissertation, p 133, University of Groningen,

1991; with permission.)

2186 PART 7 Disorders of the Respiratory System

Pco2

 and pH. The change in pH with Pco2

 is 0.08 units/10 mmHg

acutely and 0.03 units/10 mmHg in the chronic state. Knowledge of

the arterial pH therefore allows the classification of ventilatory failure,

defined as Pco2

 >45 mmHg, into acute or chronic conditions with

acute respiratory failure being associated with acidemia. The arterial

blood gas is an important component of the evaluation of patients

presenting with symptoms of an exacerbation. An elevated hematocrit

suggests the presence of chronic hypoxemia, as does the presence of

signs of right ventricular hypertrophy.

Radiographic studies may assist in the classification of the type of

COPD. Increased lung volumes and flattening of the diaphragm suggest hyperinflation but do not provide information about chronicity

of the changes. Obvious bullae, paucity of parenchymal markings,

or hyperlucency on chest x-ray suggests the presence of emphysema.

Chest CT scan is the current definitive test for establishing the presence

or absence of emphysema, the pattern of emphysema, and the presence

of significant disease involving medium and large airways (Fig. 292-2).

It also enables the discovery of coexisting interstitial lung disease and

bronchiectasis. Smokers with COPD are at high risk for development

of lung cancer, which can be identified on a chest CT scan. In advanced

COPD, CT scans can help determine the possible value of surgical

therapy (described below).

Recent guidelines have suggested testing for α1

AT deficiency in

all subjects with COPD or asthma with chronic airflow obstruction.

Measurement of the serum α1

AT level is a reasonable initial test. For

subjects with low α1

AT levels, the definitive diagnosis of α1

AT deficiency requires PI type determination. This is typically performed by

isoelectric focusing of serum or plasma, which reflects the genotype

at the PI locus for the common alleles and many of the rare PI alleles

as well. Molecular genotyping can be performed for the common PI

alleles (M, S, and Z), and DNA sequencing can detect other rare deficiency variants.

TREATMENT

Chronic Obstructive Pulmonary Disease

STABLE PHASE COPD

The two main goals of therapy are to provide symptomatic relief

(reduce respiratory symptoms, improve exercise tolerance, and

improve health status) and reduce future risk (prevent disease progression, prevent and treat exacerbations, and reduce mortality).

The institution of therapies should be based on symptom assessment, benefits of therapy, potential risks, and costs. Figure 292-5

provides the currently suggested categories of COPD patients based

on respiratory symptoms and risk for exacerbations. Response to

therapy should be assessed, and decisions should be made whether

or not to continue or alter treatment.

Three interventions—smoking cessation, oxygen therapy in

chronically hypoxemic patients, and lung volume reduction surgery

(LVRS) in selected patients with emphysema—have been demonstrated to improve survival of patients with COPD. Recent studies

indicate that triple inhaled therapy (long-acting beta agonist bronchodilator, long-acting muscarinic antagonist bronchodilator and

inhaled corticosteroid) reduces mortality in selected patients with

COPD. There is a suggestion that inhaled LAMA bronchodilators

may reduce mortality.

PHARMACOTHERAPY

Smoking Cessation (See also Chap. 454) It has been shown that

middle-aged smokers who were able to successfully stop smoking

experienced a significant improvement in the rate of decline in

pulmonary function, often returning to annual changes similar

to that of nonsmoking patients. In addition, smoking cessation

improves survival. Thus, all patients with COPD should be strongly

urged to quit smoking and educated about the benefits of quitting.

An emerging body of evidence demonstrates that combining pharmacotherapy with traditional supportive approaches considerably

enhances the chances of successful smoking cessation. There are

three principal pharmacologic approaches to the problem: nicotine

replacement therapy available as gum, transdermal patch, lozenge,

inhaler, and nasal spray; bupropion; and varenicline, a nicotinic

acid receptor agonist/antagonist. Current recommendations from

the U.S. Surgeon General are that all adult, nonpregnant smokers

considering quitting be offered pharmacotherapy, in the absence of

any contraindication to treatment. Smoking cessation counseling

is also recommended and free counseling is available through state

Smoking QuitLines.

Bronchodilators In general, bronchodilators are the primary

treatment for almost all patients with COPD and are used for

symptomatic benefit and to reduce exacerbations. The inhaled

route is preferred for medication delivery, because side effects

are less than with systemic medication delivery. In symptomatic

patients, both regularly scheduled use of long-acting agents and

as-needed short-acting medications are indicated. Figure 292-6

provides suggestions for prescribing inhaled medication therapy

based on grouping patients by severity of symptoms and risk of

exacerbations.

Muscarinic Antagonists Short-acting ipratropium bromide

improves symptoms with acute improvement in FEV1

. Long-acting

muscarinic antagonists (LAMA, including aclidinium, glycopyrrolate, glycopyrronium, revefenacin, tiotropium, and umeclidinium)

improve symptoms and reduce exacerbations. In a large randomized clinical trial, there was a trend toward reduced mortality rate in

tiotropium-treated patients that approached statistical significance.

Side effects are minor; dry mouth is the most frequent side effect.

Beta Agonists Short-acting beta agonists ease symptoms with

acute improvements in lung function. Long-acting beta agonists

(LABAs) provide symptomatic benefit and reduce exacerbations,

though to a lesser extent than an LAMA. Currently available

long-acting inhaled beta agonists are arformoterol, formoterol,

indacaterol, olodaterol, salmeterol, and vilanterol. The main side

effects are tremor and tachycardia.

Combinations of Beta Agonist–Muscarinic Antagonist The combination inhaled long-acting beta agonist and muscarinic antagonist therapy has been demonstrated to provide improvement in

Exacerbation History

COPD Severity Group

C

Low

symptoms,

High risk

D

High

symptoms,

High risk

A

Low

symptoms,

Low risk

B

High

symptoms,

Low risk

mMRC 0–1

or

CAT <10

mMRC ≥2

or

CAT ≥10

≥2

or

≥1 with hospital admission

0 or 1

(without hospital admission)

Symptoms

FIGURE 292-5 Chronic obstructive pulmonary disease (COPD) severity assessment.

COPD severity categories are based on respiratory symptoms (based on the

Modified Medical Research Council Dyspnea Scale [mMRC] or COPD Assessment

Test [CAT]) and annual frequency of COPD exacerbations. The mMRC provides a

single number for degree of breathlessness: 0—only with strenuous activity; 1—

hurrying on level ground or walking up a slight hill; 2—walk slower than peers or

stop walking at their own pace; 3—walking about 100 yards or after a few minutes

on level ground; 4—too breathless to leave the house or when dressing. The CAT is

an eight-item COPD health status measure with Likert scale responses for questions

about cough, phlegm, chest tightness, dyspnea on one flight of stairs, limitation

in home activities, confidence in leaving the home, sleep, and energy. Range of

total score is 0–40. Both mMRC and CAT are available from Global Strategy for

the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic

Obstructive Lung Disease (GOLD) 2017. (Reproduced with permission from Global

Strategy for Diagnosis, Management and Prevention of COPD 2017, ©.)

2187Chronic Obstructive Pulmonary Disease CHAPTER 292

LAMA

LAMA or

LAMA + LABA* or

ICS + LABA**

A Long Acting Bronchodilator

(LABA or LAMA)

A Bronchodilator

mMRC 0–1, CAT <10

≥2 moderate

exacerbations or ≥1

leading to

hospitalization

0 or 1 moderate

exacerbations

(not leading to

hospital admission)

mMRC ≥2, CAT ≥10

Group C

INITIAL PHARMACOLOGICAL TREATMENT

A

Group A

Group D

Group B

*Consider if highly symptomatic (e.g. CAT >20)

**Consider if eos ≥300

LABA or LAMA

LABA + LAMA LABA + ICS

• Consider LABA + LAMA + ICS

switching

inhaler device

or molecules

• Investigate

(and treat)

other causes

of dyspnea

Consider the predominant treatable trait to target (dyspnea or exacerbations)

– Use exacerbation pathway if both exacerbations and dyspnea need to be targeted

Place patient in box corresponding to current treatment & follow indications

Assess response, adjust and review

These recommendations do not depend on the ABCD assessment at diagnosis

FOLLOW-UP PHARMACOLOGICAL TREATMENT

B

DYSPNEA EXACERBATIONS

LABA or LAMA

LABA + LAMA LABA + ICS

LABA + LAMA + ICS

Roflumilast

FEV1 <50% &

chronic bronchitis Azithromycin

In former smokers

Consider if

eos < 100

Consider if

eos ≥ 100

1. IF RESPONSE TO INITIAL TREATMENT IS APPROPRIATE, MAINTAIN IT.

2. IF NOT:

FIGURE 292-6 Medication therapy for stable chronic obstructive pulmonary disease (COPD). Initial pharmacological therapy (Panel A) is based on both COPD exacerbations

and respiratory symptoms (assessed through the modified Medical Research Council (mMRC) dyspnea questionnaire or the COPD Assessment Test (CAT)). Follow-up

pharmacological therapy (Panel B) is based on response to treatment initiation and reassessment of symptoms and exacerbations. Global Strategy for the Diagnosis,

Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2021. *

For Panel B: consider if eos ≥300 or eos ≥100 AND ≥2 moderate

exacerbations/1 hospitalization. **Consider de-escalation of ICS or switch if pneumonia, inappropriate original indication or lack of response to ICS. CATTM, COPD Assessment

TestTM; Eos, blood eosinophil count in cells per microliter; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; LAMA,

long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea questionnaire. (Reproduced with permission from the Global Strategy for Diagnosis,

Management and Prevention of COPD 2021, ©.)

lung function that is greater than either agent alone and reduces

exacerbations.

Inhaled Corticosteroids The main role of ICS is to reduce exacerbations. In population studies, patients with an eosinophil count

of <100 cells per microliter do not benefit, while benefit increases

as eosinophil counts rise above 100. ICS are never used alone in

COPD due to little symptomatic benefit but, rather, are combined

with a LABA or used with a LABA and LAMA. Their use has been

associated with increased rates of oropharyngeal candidiasis and

pneumonia and in some studies an increased rate of loss of bone

density and development of cataracts. A trial of ICS should be

considered in patients with frequent exacerbations, defined as two

or more per year or in patients hospitalized with one exacerbation.

In stable patients without exacerbations, ICS withdrawal may be

considered. Patients who continue to smoke cigarettes do not

benefit as greatly from ICS use. Although ICS withdrawal does not

lead to an increase in exacerbations, there may be a small decline

in lung function.

Oral Glucocorticoids The chronic use of oral glucocorticoids for

treatment of COPD is not recommended because of an unfavorable

benefit/risk ratio. The chronic use of oral glucocorticoids is associated with significant side effects, including osteoporosis, weight

2188 PART 7 Disorders of the Respiratory System

gain, cataracts, glucose intolerance, and increased risk of infection.

A study demonstrated that patients tapered off chronic low-dose

prednisone (~10 mg/d) did not experience any adverse effect on

the frequency of exacerbations, health-related quality of life, or

lung function.

Theophylline Theophylline produces modest improvements in

airflow and vital capacity, but is not first-line therapy due to side

effects and drug interactions. Nausea is a common side effect;

tachycardia and tremor have also been reported. Monitoring of

blood theophylline levels is required to minimize toxicity.

PDE4 Inhibitors The selective phosphodiesterase 4 (PDE4) inhibitor roflumilast has been demonstrated to reduce exacerbation

frequency in patients with severe COPD, chronic bronchitis, and a

prior history of exacerbations; its effects on airflow obstruction and

symptoms are modest, and side effects (including nausea, diarrhea,

and weight loss) are common.

Antibiotics There are strong data implicating bacterial infection

as a precipitant of a substantial portion of exacerbations. A randomized clinical trial of azithromycin, chosen for both its antiinflammatory and antimicrobial properties, administered daily

to subjects with a history of exacerbation in the past 6 months

demonstrated a reduced exacerbation frequency and longer time

to first exacerbation in the macrolide-treated cohort (hazard ratio,

0.73). Azithromycin was most effective in older patients and milder

GOLD stages; there was little benefit in current smokers.

Oxygen Supplemental O2

 is the only pharmacologic therapy

demonstrated to unequivocally decrease mortality in patients with

COPD. For patients with resting hypoxemia (resting O2

 saturation

≤88% in any patient or ≤89% with signs of pulmonary arterial

hypertension, right heart failure or erythrocytosis), the use of O2

has been demonstrated to have a significant impact on mortality.

Patients meeting these criteria should be on continuous oxygen

supplementation because the mortality benefit is proportional

to the number of hours per day oxygen is used. Various delivery

systems are available, including portable systems that patients may

carry to allow mobility outside the home.

A recent study failed to demonstrate mortality benefits to COPD

patients with moderate hypoxemia at rest or with hypoxemia only

with activity.

`1

AT Augmentation Therapy Specific treatment in the form of IV

α1

AT augmentation therapy is available for individuals with severe

α1

AT deficiency. Despite sterilization procedures for these bloodderived products and the absence of reported cases of viral infection

from therapy, some physicians recommend hepatitis B vaccination prior to starting augmentation therapy. Although biochemical efficacy of α1

AT augmentation therapy has been shown,

the benefits of α1

AT augmentation therapy are controversial. A

randomized study suggested a reduction in emphysema progression in patients receiving α1

AT augmentation therapy. Eligibility

for α1

AT augmentation therapy requires a serum α1

AT level

<11 μM (~50 mg/dL). Typically, PiZ individuals will qualify,

although other rare types associated with severe deficiency (e.g.,

null-null) are also eligible. Because only a fraction of individuals

with severe α1

AT deficiency will develop COPD, α1

AT augmentation therapy is not recommended for severely α1

AT-deficient persons with normal pulmonary function and a normal chest CT scan.

NONPHARMACOLOGIC THERAPIES

Patients with COPD should receive the influenza vaccine annually.

Pneumococcal vaccines and vaccination for Bordetella pertussis are

recommended.

Pulmonary Rehabilitation This refers to a comprehensive treatment program that incorporates exercise, education, and psychosocial and nutritional counseling. In COPD, pulmonary rehabilitation

has been demonstrated to improve health-related quality of life,

dyspnea, and exercise capacity. It has also been shown to reduce

rates of hospitalization over a 6- to 12-month period.

Lung Volume Reduction Surgery In carefully selected patients with

emphysema, surgery to remove the most emphysematous portions

of lung improves exercise capacity, lung function, and survival. The

anatomic distribution of emphysema and postrehabilitation exercise capacity are important prognostic characteristics. Patients with

upper lobe–predominant emphysema and a low postrehabilitation

exercise capacity are most likely to benefit from LVRS.

Patients with an FEV1

 <20% of predicted and either diffusely

distributed emphysema on CT scan or diffusing capacity of lung

for carbon monoxide (DlCO) <20% of predicted have increased

mortality after the procedure, and thus are not candidates for LVRS.

Methods of achieving lung volume reduction by using bronchoscopic techniques have recently been approved by the U.S. Food

and Drug Administration; they appear to be beneficial in selected

emphysema patients.

Lung Transplantation (See also Chap. 298) COPD is currently the

second leading indication for lung transplantation. Current recommendations are that candidates for lung transplantation should

have very severe airflow obstruction, severe disability despite maximal medical therapy, and be free of significant comorbid conditions

such as liver, renal, or cardiac disease.

EXACERBATIONS OF COPD

Exacerbations are a prominent feature of the natural history of

COPD. Exacerbations are episodic acute worsening of respiratory

symptoms, including increased dyspnea, cough, wheezing, and/

or change in the amount and character of sputum. They may or

may not be accompanied by other signs of illness, including fever,

myalgias, and sore throat. The strongest single predictor of exacerbations is a history of a previous exacerbation. The frequency

of exacerbations increases as airflow obstruction worsens; patients

with severe (FEV1

 <50% predicted) or very severe airflow obstruction (FEV1

 <30% predicted) on average have 1–3 episodes per year.

However, some individuals with very severe airflow obstruction do

not have frequent exacerbations. Other factors, such as an elevated

ratio of the diameter of the pulmonary artery to aorta on chest CT

and gastroesophageal reflux, are also associated with increased risk

of COPD exacerbations. Economic analyses have shown that >70%

of COPD-related health care expenditures are due to emergency

department visits and hospital care for COPD exacerbations; this

translates to over $10 billion annually in the United States.

Precipitating Causes and Strategies to Reduce Frequency of

Exacerbations A variety of stimuli may result in the final common pathway of airway inflammation and increased respiratory

symptoms that are characteristic of COPD exacerbations. Studies

suggest that acquiring a new strain of bacteria is associated with

increased near-term risk of exacerbation and that bacterial infection/

superinfection is involved in >50% of exacerbations. Viral respiratory infections are present in approximately one-third of COPD

exacerbations. In a significant minority of instances (20–35%), no

specific precipitant can be identified.

Patient Assessment An attempt should be made to establish the

severity of the exacerbation as well as the severity of preexisting

COPD. The more severe either of these two components, the more

likely that the patient will require hospital admission. The history

should include quantification of the degree and change in dyspnea

by asking about breathlessness during activities of daily living and

typical activities for the patient. The patient should be asked about

fever; change in character of sputum; and associated symptoms

such as wheezing, nausea, vomiting, diarrhea, myalgias, and chills.

Inquiring about the frequency and severity of prior exacerbations

can provide important information; the single greatest risk factor

for hospitalization with an exacerbation is a history of previous

hospitalization.

The physical examination should incorporate an assessment of

the degree of distress of the patient. Specific attention should be

focused on tachycardia, tachypnea, use of accessory muscles, signs

of perioral or peripheral cyanosis, the ability to speak in complete

2189Chronic Obstructive Pulmonary Disease CHAPTER 292

sentences, and the patient’s mental status. The chest examination

should establish the presence or absence of focal findings, degree of

air movement, presence or absence of wheezing, asymmetry in the

chest examination (suggesting large airway obstruction or pneumothorax mimicking an exacerbation), and the presence or absence

of paradoxical motion of the abdominal wall.

Patients with severe underlying COPD, who are in moderate

or severe distress, or those with focal findings should have a chest

x-ray or chest CT scan. Approximately 25% of x-rays in this clinical

situation will be abnormal, with the most frequent findings being

pneumonia and congestive heart failure. Patients with advanced

COPD, a history of hypercarbia, or mental status changes (confusion, sleepiness) or those in significant distress should have an arterial blood gas measurement. The presence of hypercarbia, defined

as a Pco2

 >45 mmHg, has important implications for treatment

(discussed below). In contrast to its utility in the management of

exacerbations of asthma, measurement of pulmonary function has

not been demonstrated to be helpful in the diagnosis or management of exacerbations of COPD. Pulmonary embolus (PE) should

also be considered, as the incidence of PE is increased in COPD

exacerbations.

The need for inpatient treatment of exacerbations is suggested by

the presence of respiratory acidosis and hypercarbia, new or worsening hypoxemia, severe underlying disease, and those whose living

situation is not conducive to careful observation and the delivery of

prescribed treatment.

TREATMENT OF ACUTE EXACERBATIONS

Bronchodilators Typically, patients are treated with inhaled beta

agonists and muscarinic antagonists. These may be administered

separately or together, and the frequency of administration depends

on the severity of the exacerbation. Patients are often treated initially

with nebulized therapy, as such treatment is often easier to administer in those in respiratory distress. It has been shown, however, that

conversion to metered-dose inhalers is effective when accompanied

by education and training of patients and staff. This approach has

significant economic benefits and also allows an easier transition

to outpatient care. The addition of methylxanthines (theophylline)

to this regimen can be considered, although convincing proof of

its efficacy is lacking. If methylxanthines are added, serum levels

should be monitored in an attempt to minimize toxicity.

Antibiotics Patients with COPD are frequently colonized with

potential respiratory pathogens, and it is often difficult to identify

conclusively a specific species of bacteria responsible for a particular clinical event. Bacteria frequently implicated in COPD exacerbations include Streptococcus pneumoniae, Haemophilus influenzae,

Moraxella catarrhalis, and Chlamydia pneumoniae; viral pathogens

are also common etiologies of exacerbations. The choice of antibiotic should be based on local patterns of antibiotic susceptibility of

the above bacterial pathogens as well as the patient’s clinical condition. Patients with moderate or severe exacerbations are usually

treated with antibiotics, even in the absence of data implicating a

specific pathogen.

In patients admitted to the hospital, the use of systemic glucocorticoids reduces the length of stay, hastens recovery, and reduces the

chance of subsequent exacerbation or relapse. One study demonstrated that 2 weeks of glucocorticoid therapy produced benefit

indistinguishable from 8 weeks of therapy. Current recommendations

suggest 30–40 mg of oral prednisolone or its equivalent typically for

a period of 5–10 days in outpatients. Hyperglycemia, particularly in

patients with preexisting diagnosis of diabetes, is the most frequently

reported acute complication of glucocorticoid treatment.

Oxygen Supplemental O2

 should be supplied to maintain oxygen saturation ≥90%. Studies have demonstrated that in patients

with both acute and chronic hypercarbia, the administration of

supplemental O2

 does not reduce minute ventilation. It does, in

some patients, result in modest increases in arterial Pco2

, chiefly

by altering ventilation-perfusion relationships within the lung. This

should not deter practitioners from providing the oxygen needed to

correct hypoxemia.

Mechanical Ventilatory Support The initiation of noninvasive

positive-pressure ventilation (NIPPV) in patients with respiratory failure, defined as Paco2

 >45 mmHg, results in a significant

reduction in mortality rate, need for intubation, complications of

therapy, and hospital length of stay. Contraindications to NIPPV

include cardiovascular instability, impaired mental status, inability

to cooperate, copious secretions or the inability to clear secretions,

craniofacial abnormalities or trauma precluding effective fitting of

mask, extreme obesity, or significant burns.

Invasive (conventional) mechanical ventilation via an endotracheal tube is indicated for patients with severe respiratory distress

despite initial therapy, life-threatening hypoxemia, severe hypercarbia and/or acidosis, markedly impaired mental status, respiratory

arrest, hemodynamic instability, or other complications. The goal of

mechanical ventilation is to correct the aforementioned conditions.

Factors to consider during mechanical ventilatory support include

the need to provide sufficient expiratory time in patients with

severe airflow obstruction and the presence of auto-PEEP (positive

end-expiratory pressure), which can result in patients having to

generate significant respiratory effort to trigger a breath during a

demand mode of ventilation. The mortality rate of patients requiring mechanical ventilatory support is 17–30% for that particular

hospitalization. For patients aged >65 admitted to the intensive care

unit for treatment, the mortality rate doubles over the next year to

60%, regardless of whether mechanical ventilation was required.

Following a hospitalization for COPD, about 20% of patients are

rehospitalized in the subsequent 30 days and 45% are hospitalized

in the next year. Mortality following hospital discharge is about 20%

in the following year.

■ FURTHER READING

Agusti A, Hogg JC: Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med 381:1248, 2019.

Celli BR, Wedzicha JA: Update on clinical aspects of chronic

obstructive pulmonary disease. N Engl J Med 381:1257, 2019.

Global Strategy for the Diagnosis, Management and Prevention of COPD: Global Initiative for Chronic Obstructive Lung

Disease (GOLD) 2021. Available from: http://goldcopd.org.

Lange P et al: Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 373:111, 2015.

The Long-Term Oxygen Treatment Trial Research Group: A

randomized trial of long-term oxygen for COPD with moderate

desaturation. N Engl J Med 375:1617, 2016.

Lowe KE et al: COPDGene 2019: Redefining the diagnosis of chronic

obstructive pulmonary disease. Chronic Obstr Pulm Dis 6:384, 2019.

Lynch D et al: CT definable subtypes of COPD: A statement of the

Fleischner Society. Radiology 277:192, 2015.

McDonough JE et al: Small-airway obstruction and emphysema in

chronic obstructive pulmonary disease. N Engl J Med 365:1567, 2011.

Regan E et al: Clinical and radiologic disease in smokers with normal

spirometry. JAMA Intern Med 175:1539, 2015.

Rennard SI, Drummond MB: Early chronic obstructive pulmonary

disease: Definition, assessment, and prevention. Lancet 385:1778, 2015.

Sakornsakolpat P et al: Genetic landscape of chronic obstructive

pulmonary disease identifies heterogeneous cell-type and phenotype

associations. Nat Genet 51:494, 2019.

Sandhaus RA et al: The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis 3:668, 2016.

Spruit MA et al: An official American Thoracic Society/European

Respiratory Society statement: Key concepts and advances in pulmonary rehabilitation. Am J Resp Crit Care Med 188:e13, 2013.

Young KA et al: Pulmonary subtypes exhibit differential GOLD

spirometry stage progression: The COPDGene Study. Chronic Obstr

Pulm Dis 6:414, 2019.

Young KA et al: Subtypes of COPD have unique distributions and

differential risk of mortality. Chronic Obstr Pulm Dis 6:400, 2019.

2190 PART 7 Disorders of the Respiratory System

Diffuse parenchymal lung diseases include a large number (>200) of

heterogeneous conditions that affect the lung parenchyma with varying

degrees of inflammation and fibrosis. While remodeling of the interstitial space, the region between the epithelium and endothelium, tends

to be the dominant site of involvement for most of the interstitial lung

diseases (ILDs), it is important to recognize the prominent role of the

alveolar epithelium and endothelial cells (including both airways and

vessels) in the pathogenesis of these ILDs.

Despite the diverse array of conditions, most patients ultimately

diagnosed with an ILD will come to medical attention with reports

of progressive exertional dyspnea or a persistent dry cough. However,

because some ILDs are part of multisystem disorders, some patients

will be identified based on nonrespiratory symptomatology (e.g., skin

thickening in the setting of systemic sclerosis, Chap. 359) or physical

examination findings (e.g., ulnar deviation of the fingers in the setting

of rheumatoid arthritis [RA], Chap. 358). Additionally, ILDs can also

be identified incidentally based on the results of abnormal pulmonary

function tests, chest x-rays (CXRs), computed tomography (CT) studies of both the chest and abdomen (which can both visualize, at least a

portion, of the lung parenchyma), and positron emission tomography

(PET) scans. It is important to remember that ILDs can be associated

with high rates of morbidity and mortality, and although prognosis

depends on both disease extent and specificity, this fact makes these

important disorders to recognize in a timely manner.

Owing to a variety of clinical presentations, as well as overlapping

imaging and histopathologic findings (Table 293-1), ILDs can be

difficult to diagnose. A generally accepted central tenet of ILD diagnosis is that the combined weight of clinical data, laboratory studies,

293 Interstitial Lung Disease

Gary M. Hunninghake, Ivan O. Rosas

pulmonary function testing, imaging findings, and histopathology (if

obtained) are jointly required to make a confident diagnosis. No single

piece of data confers a diagnosis alone. For example, a lung biopsy

demonstrating a usual interstitial pneumonia (UIP) pattern is helpful

in diagnosing a patient with idiopathic pulmonary fibrosis (IPF) but

can also be present in some connective tissue diseases (CTDs) (e.g.,

RA-associated ILD, Chap. 358). In light of this challenge, most ILD

centers recommend a multidisciplinary approach to the diagnosis (and

in some cases the management) of ILDs. An example of a multidisciplinary approach might include a conference attended by pulmonologists, rheumatologists, radiologists, and pathologists where all of the

data generated on a patient can be discussed and reviewed jointly by

those with unique sets of expertise in the care of patients with ILD.

While there are numerous ways to categorize the ILDs, one classic

approach is to divide the ILDs into those of known and unknown

causes (Fig. 293-1). Although even this approach has limitations (e.g.,

genetic studies demonstrate that a significant portion of familial pulmonary fibrosis and IPF [classically described as diseases of unknown

cause] may be explained, in part, by genetic factors), it is a useful place

to start. Known causes of ILD include occupational exposures (e.g.,

asbestosis), medications (e.g., nitrofurantoin), and those related to an

underlying systemic disease (e.g., cryptogenic organizing pneumonia

[COP] in the setting of polymyositis). Unknown causes of ILD include

groups of rare disorders often with classic presentations (e.g., a spontaneous pneumothorax in a young female with diffuse cystic changes on

a chest CT might suggest lymphangioleiomyomatosis [LAM]) and the

most common group of ILDs, the idiopathic interstitial pneumonias

(IIPs). Granulomatous lung diseases straddle both known (e.g., hypersensitivity pneumonitis [HP] due to chronic bird exposure, Chap. 288)

and unknown (e.g., sarcoidosis, Chap. 367) causes and are often separated due to their unique presentations, imaging findings, and diagnostic evaluation. Equally important to knowledge of disease classification

is knowledge of disease prevalence. Although there is variability within

different demographic groups, most studies demonstrate that IPF,

TABLE 293-1 Common Interstitial Lung Disease (ILD) Findings

IPF

NONSPECIFIC

INTERSTITIAL

PNEUMONIA

RESPIRATORY

BRONCHIOLITIS

ASSOCIATED ILD

SYSTEMIC SCLEROSIS

ASSOCIATED ILD SARCOIDOSIS

Clinical symptoms Gradual onset of SOB, dry

cough. Unusual in older

adults.

Subacute onset of SOB,

dry cough. Frequently

associated with other

conditions.

Can be asymptomatic, or

have SOB and cough.

Gradual onset of SOB, dry

cough. Fatigue, tightening

of skin, exaggerated cold

response, reflux, and

difficulty swallowing.

Can be asymptomatic,

or have SOB and cough.

Can also have fatigue,

palpitations, eye, skin,

and joint findings.

Physical exam

findings

Frequent rales at lung bases;

digital clubbing is common.

Frequent rales. Clubbing

is less common.

Rales common. Clubbing

is rare.

Can have rales in

isolation. Also skin

thickening, joint swelling,

and telangiectasias.

Can be normal; rales may

be present. Can have skin

findings, joint pain, and

enlarged lymph nodes.

Exposures Idiopathic but many exposed

to smoke. Genetic findings

may explain more than

one-third of the risk of the

disease.

Can be idiopathic

but should prompt

consideration for

associated conditions.

Strong association with

smoking.

Mostly unknown; some

debate about solvent and

silicate exposures.

Mostly unknown, although

silicate dusts thought to

play a role in some cases.

HRCT findings Bilateral subpleural reticular

changes most prominent in

lower, posterior lung zones.

Traction bronchiectasis and

honeycombing common.

Classic usual interstitial

pneumonia (UIP) pattern is

considered diagnostic.

Peripheral subpleural

ground glass and

reticular patterns.

Traction bronchiectasis

is common, but

honeycombing is rare.

HRCT not diagnostic.

Diffuse patchy

centrilobular ground glass

nodules.

Can have UIP or

nonspecific interstitial

pneumonia (NSIP)

patterns, also dilated

esophagus, occasional

mediastinal calcifications,

and pulmonary vascular

enlargement.

Can have mediastinal and

hilar lymphadenopathy.

Peribronchovascular

reticular-nodular findings.

Histopathology UIP pattern including

fibroblastic foci, temporal

and spatial heterogeneity,

honeycombing.

Cellular or fibrotic pattern

of NSIP. More uniform

than a UIP pattern.

Respiratory bronchiolitis

with adjacent inflammatory

and fibrosing changes.

Pigment-laden

macrophages.

Both UIP or NSIP patterns

can occur.

Noncaseating

granulomas.

Clinical course 50% 3- to 5-year mortality. 18% 5-year mortality. 25% 7-year mortality. 20–30% 10-year mortality. Generally low but varies

by state.

Abbreviations: HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; SOB, shortness of breath.