Chronic Obstructive Pulmonary Disease Hariison.docx

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Chronic Obstructive Pulmonary Disease: Introduction

Chronic obstructive pulmonary disease (COPD) has been defined by the Global Initiative for

Chronic Obstructive Lung Disease (GOLD), an international collaborative effort to improve

awareness, diagnosis, and treatment of COPD, as a disease state characterized by airflow

limitation that is not fully reversible (http://www.goldcopd.com/). COPD includes emphysema,

an anatomically defined condition characterized by destruction and enlargement of the lung

alveoli; chronic bronchitis, a clinically defined condition with chronic cough and phlegm; and

small airways disease, a condition in which small bronchioles are narrowed. COPD is present

only if chronic airflow obstruction occurs; chronic bronchitis withoutchronic airflow obstruction

is notincluded within COPD.

COPD is the fourth leading cause of death and affects >16 million persons in the United States.

COPD is also a disease of increasing public health importance around the world. GOLD

estimates suggest that COPD will rise from the sixth to the third most common cause of death

worldwide by 2020.

Risk Factors

Cigarette Smoking

By 1964, the Advisory Committee to the Surgeon General of the United States had concluded

that cigarette smoking was a major risk factor for mortality from chronic bronchitis and

emphysema. Subsequent longitudinal studies have shown accelerated decline in the volume of

air exhaled within the first second of the forced expiratory maneuver (FEV1) in a dose-response

relationship to the intensity of cigarette smoking, which is typically expressed as pack-years

(average number of packs of cigarettes smoked per day multiplied by the total number of years

of smoking). This dose-response relationship between reduced pulmonary function and cigarette

smoking intensity accounts for the higher prevalence rates for COPD with increasing age. The

historically higher rate of smoking among males is the likely explanation for the higher

prevalence of COPD among males; however, the prevalence of COPD among females is

increasing as the gender gap in smoking rates has diminished in the past 50 years.
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Although the causal relationship between cigarette smoking and the development of COPD has

been absolutely proved, there is considerable variability in the response to smoking. Although

pack-years of cigarette smoking is the most highly significant predictor of FEV1 (Fig. 254-1),

only 15% of the variability in FEV1 is explained by pack-years. This finding suggests that

additional environmental and/or genetic factors contribute to the impact of smoking on the

development of airflow obstruction.

Figure 254-1

Distributions of forced expiratory volume in 1 s (FEV1) values in a general population

sample, stratified by pack-years of smoking. Means, medians, and 1 standard deviation of

percent predicted FEV1 are shown for each smoking group. Although a dose-response

relationship between smoking intensity and FEV1 was found, marked variability in pulmonary

function was observed among subjects with similar smoking histories. (From R Burrows et al:

Am Rev Respir Dis 115:95, 1977; with permission.)

Although cigar and pipe smoking may also be associated with the development ofCOPD, theevidence supporting such associations is less compelling, likely related to the lower dose of

inhaled tobacco byproducts during cigar and pipe smoking.

Airway Responsiveness and COPD

A tendency for increased bronchoconstriction in response to a variety of exogenous stimuli,

including methacholine and histamine, is one of the defining features of asthma (Chap. 248).

However, many patients with COPD also share this feature of airway hyperresponsiveness. Theconsiderable overlap between persons with asthma and those with COPD in airway

responsiveness, airflow obstruction, and pulmonary symptoms led to the formulation of the

Dutch hypothesis. This suggests that asthma, chronic bronchitis, and emphysema are variations

of the same basic disease, which is modulated by environmental and genetic factors to produce


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these pathologically distinct entities. The alternative British hypothesis contends that asthma and

COPD are fundamentally different diseases: Asthma is viewed as largely an allergic

phenomenon, while COPD results from smoking-related inflammation and damage.

Determination of the validity of the Dutch hypothesis vs. the British hypothesis awaits

identification of the genetic predisposing factors for asthma and/or COPD, as well as the

interactions between these postulated genetic factors and environmental risk factors.

Longitudinal studies that compared airway responsiveness at the beginning of the study to

subsequent decline in pulmonary function have demonstrated that increased airway

responsiveness is clearly a significant predictor of subsequent decline in pulmonary function.

Thus, airway hyperresponsiveness is a risk factor forCOPD.

Respiratory Infections

These have been studied as potential risk factors for the development and progression of COPD

in adults; childhood respiratory infections have also been assessed as potential predisposing

factors for the eventual development of COPD. 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 episode of bronchitis or pneumonia. The impact of

the effects of childhood respiratory illnesses on the subsequent development of COPD has beendifficult to assess due to a lack of adequate longitudinal data. Thus, although respiratory

infections are important causes of exacerbations of COPD, the association of both adult and

childhood respiratory infections to the development and progression of COPD remains to be

proven.

Occupational Exposures

Increased respiratory symptoms and airflow obstruction have been suggested as resulting from

general exposure to dust at work. Several specific occupational exposures, including coal

mining, gold mining, and cotton textile dust, have been suggested as risk factors for chronic

airflow obstruction. However, although nonsmokers in these occupations developed some

reductions in FEV1, the importance of dust exposure as a risk factor forCOPD, independent o


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cigarette smoking, is not certain. Among workers exposed to cadmium (a specific chemical

fume), FEV1, FEV1/FVC, and DLCO were significantly reduced (FVC, forced vital capacity;

DLCO, carbon monoxide diffusing capacity of the lung; Chap. 246), consistent with airflow

obstruction and emphysema. Although several specific occupational dusts and fumes are likely

risk factors forCOPD, the magnitude of these effects appears to be 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 unproven. Prolonged

exposure to smoke produced by biomass combustiona common mode of cooking in some

countriesalso appears to be a significant risk factor for COPD among women in those

countries. However, in most populations, ambient air pollution is a much less important risk

factor forCOPD than cigarette smoking.

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 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 1

antitrypsin ( 1AT) deficiency is a proven genetic risk factor for COPD; there is increasing

evidence that other genetic determinants also exist.


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1 Antitrypsin Deficiency

Many variants of the protease inhibitor (PI or SERPINA1) locus that encodes 1AT have

been described. The common M allele is associated with normal 1AT levels. The S allele,

associated with slightly reduced 1AT levels, and the Z allele, associated with markedly

reduced 1AT levels, also occur with frequencies >1% in most Caucasian populations. Rare

individuals inherit null alleles, which lead to the absence of any 1AT 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 1AT deficiency.

Although only 12% of COPD patients are found to have severe 1AT deficiency as a

contributing cause ofCOPD, 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 individualswhich have usually

included many PiZ subjects who were tested for 1AT 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 ofCOPD in PiZ subjects remain unknown. Approximately 1 in

3000 individuals in the United States inherits severe 1AT deficiency, but only a small

minority of these individuals has been recognized. The clinical laboratory test used most

frequently to screen for 1AT deficiency is measurement of the immunologic level of

1AT in serum (see "Laboratory Findings," below).

A significant percentage of the variability in pulmonary function among PiZ individuals is

explained by cigarette smoking; cigarette smokers with severe 1AT deficiency are more


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likely to develop COPD at early ages. However, the development ofCOPD in Pi subjects, even

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

been noted in the development of airflow obstruction. Other genetic and/or environmental factors

likely contribute to this variability.

Specific treatment in the form of 1AT augmentation therapy is available for severe 1AT

deficiency as a weekly intravenous infusion (see "Treatment," below).

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

1AT (~60% of PiMM levels), is controversial. Although previous general population surveys

have not typically shown increased rates of airflow obstruction in PiMZ compared to PiMM

individuals, case-control studies that compared COPD patients to control subjects have usually

found an excess of PiMZ genotypes in the COPD patient group. Several recent large population

studies have suggested that PiMZ subjects are at slightly increased risk for the development of

airflow obstruction, but it remains unclear if all PiMZ subjects are at slightly increased risk for

COPD or if a subset of PiMZ subjects are at substantially increased risk forCOPD due to other

genetic or environmental factors.

Other Genetic Risk Factors

Studies of pulmonary function measurements performed in general population samples have

suggested 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.

Association studies have compared the distribution of variants in genes hypothesized to be

involved in the development of COPD in COPD patients and control subjects. However, the

results have been quite inconsistent, and no genetic determinants of COPD other than severe

1AT deficiency have been definitively proven using this approach. Genome scan linkage

analyses of early-onset COPD families have found evidence for linkage of spirometric

phenotypes to several chromosomal regions, but the specific genetic determinants in those


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regions have yet to be definitively identified.

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 the baseline lung

function of the individual; other environmental factors may have similar effects. Although rare

individuals may demonstrate precipitous declines in pulmonary function, most individuals follow

a steady trajectory of increasing pulmonary function with growth during childhood and

adolescence, followed by a gradual decline with aging. Individuals appear to track in their

quartile of pulmonary function based upon 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 ofCOPD is shown as a function of theinfluences on tracking curves of FEV1 in Fig. 254-2. Death or disability from COPD can result

from a normal rate of decline after a reduced growth phase (curve C), an early initiation of

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

growth (curve D). 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. Genetic factors likely contribute to the level of pulmonary

function achieved during growth and to the rate of decline in response to smoking and potentially

to other environmental factors as well.

Figure 254-2

Hypothetical tracking curves of FEV1 for individuals throughout their life spans. The

normal pattern of growth and decline with age is shown by curve A. Significantly reduced

FEV1 (


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(From B Rijcken: Doctoral dissertation, p 133, University of Groningen, 1991; with

permission.)

Pathophysiology

Persistent reduction in forced expiratory flow rates is the most typical finding in COPD.

Increases in the residual volume and the residual volume/total lung capacity ratio, nonuniform

distribution of ventilation, and ventilation-perfusion mismatching also occur.

Airflow Obstruction

Airflow limitation, also known as airflow obstruction, is typically determined by spirometry,

which involves forced expiratory maneuvers after the subject has inhaled to total lung capacity

(see Fig. 246-4). Key phenotypes obtained from spirometry include FEV1 and the total volume o

air exhaled during the entire spirometric maneuver (FVC). Patients with airflow obstruction

related to COPD have a chronically reduced ratio of FEV1/FVC. In contrast to asthma, the

reduced FEV1 in COPD seldom shows large responses to inhaled bronchodilators, although

improvements up to 15% are common. Asthma patients can also develop chronic (not fully

reversible) airflow obstruction. Maximal inspiratory flow can be relatively well preserved in the

presence of a markedly reduced FEV1.

Airflow during forced exhalation is the result of the balance between the elastic recoil of the

lungs promoting flow and the resistance of the airways limiting flow. In normal lungs, as well as

in lungs affected by COPD, maximal expiratory flow diminishes as the lungs empty because the

lung parenchyma provides progressively less elastic recoil and because the cross-sectional area

of the airways falls, raising the resistance to airflow. The decrease in flow coincident with

decreased lung volume is readily apparent on the expiratory limb of a flow-volume curve. In the

early stages ofCOPD, the abnormality in airflow is only evident at lung volumes at or below the

functional residual capacity (closer to residual volume), appearing as a scooped-out lower part of

the descending limb of the flow-volume curve. In more advanced disease the entire curve has

decreased expiratory flow compared to normal.


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Hyperinflation

Lung volumes are also routinely assessed in pulmonary function testing. In COPD there is often

"air trapping" (increased residual volume and increased ratio of residual volume to total lung

capacity) and progressive hyperinflation (increased total lung capacity) late in the disease.

Hyperinflation of the thorax during tidal breathing preserves maximum expiratory airflow,

because as lung volume increases, elastic recoil pressure increases and airways enlarge so that

airway resistance decreases.

Hyperinflation helps to compensate for airway obstruction. However, hyperinflation can push the

diaphragm into a flattened position with a number of adverse effects. First, by decreasing the

zone of apposition between the diaphragm and the abdominal wall, positive abdominal pressure

during inspiration is not applied as effectively to the chest wall, hindering rib cage movement

and impairing inspiration. Second, because the muscle fibers of the flattened diaphragm are

shorter than those of a more normally curved diaphragm, they are less capable of generating

inspiratory pressures than normal. Third, the flattened diaphragm (with increased radius of

curvature, r) must generate greater tension (t) to develop the transpulmonary pressure (p)

required to produce tidal breathing. This follows from Laplace's law, p = 2t/r. Also, because the

thoracic cage is distended beyond its normal resting volume, during tidal breathing the

inspiratory muscles must do work to overcome the resistance of the thoracic cage to further

inflation instead of gaining the normal assistance from the chest wall recoiling outward toward

its resting volume.

Gas Exchange

Although there is considerable variability in the relationships between the FEV1 and other

physiologic abnormalities in COPD, certain generalizations may be made. The PaO2 usually

remains near normal until the FEV1 is decreased to ~50% of predicted, and even much lower

FEV1s can be associated with a normal PaO2, at least at rest. An elevation of PaCO2 is not

expected until the FEV1 is


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together with chronic hypoxemia (PaO2


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activity, neutrophil elastase is among the most potent secretagogues identified.

Small Airways

The major site of increased resistance in most individuals with COPD is in airways 2 mm

diameter. Characteristic cellular changes include goblet cell metaplasia and replacement of

surfactant-secreting Clara cells with mucus-secreting and infiltrating mononuclear inflammatory

cells. Smooth-muscle hypertrophy may also be present. These abnormalities may cause luminal

narrowing by excess mucus, edema, and cellular infiltration. Reduced surfactant may increase

surface tension at the air-tissue interface, predisposing to airway narrowing or collapse. Fibrosis

in the wall may cause airway narrowing directly or, as in asthma, predispose to hyperreactivity.

Respiratory bronchiolitis with mononuclear inflammatory cells collecting in distal airway tissues

may cause proteolytic destruction of elastic fibers in the respiratory bronchioles and alveolar

ducts where the fibers are concentrated as rings around alveolar entrances.

Because small airway patency is maintained by the surrounding lung parenchyma that provides

radial traction on bronchioles at points of attachment to alveolar septa, loss of bronchiolar

attachments as a result of extracellular matrix destruction may cause airway distortion and

narrowing in COPD. Although the significance of alveolar attachments is not resolved, the

concept of decreased alveolar attachments leading to small airway obstruction is appealing

because it underscores the mechanistic relationship between loss of elastic recoil and increased

resistance to airflow in small airways.

Lung Parenchyma

Emphysema is characterized by destruction of gas-exchanging airspaces, i.e., the respiratory

bronchioles, alveolar ducts, and alveoli. Their walls become perforated and later obliterated with

coalescence of small distinct airspaces into abnormal and much larger airspaces. Macrophages

accumulate in respiratory bronchioles of essentially all young smokers. Bronchoalveolar lavage

fluid from such individuals contains roughly five times as many macrophages as lavage from

nonsmokers. In smokers' lavage fluid, macrophages comprise >95% of the total cell count, and

neutrophils, nearly absent in nonsmokers' lavage, account for 12% of the cells. T lymphocytes,


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particularly CD8+ cells, are also increased in the alveolar space of smokers.

Emphysema is classified into distinct pathologic types, the most important being centriacinar and

panacinar. Centriacinar emphysema, the type most frequently associated with cigarette smoking,

is characterized by enlarged airspaces found (initially) in association with respiratory

bronchioles. Centriacinar emphysema is most prominent in the upper lobes and superior

segments of lower lobes and is often quite focal. Panacinar emphysema refers to abnormally

large airspaces evenly distributed within and across acinar units. Panacinar emphysema is

usually observed in patients with 1AT deficiency, which has a predilection for the lower

lobes. Distinctions between centriacinar and panacinar emphysema are interesting and may

ultimately be shown to have different mechanisms of pathogenesis. However, garden-variety

smoking-related emphysema is usually mixed, particularly in advanced cases, and these

pathologic classifications are not helpful in the care of patients with COPD.

Pathogenesis

Airflow limitation, the major physiologic change in COPD, can result from both small airway

obstruction and emphysema, as discussed above. Pathologic findings that can contribute to small

airway obstruction are described above, but their relative importance is unknown. Fibrosis

surrounding the small airways appears to be a significant contributor. Mechanisms leading to

collagen accumulation around the airways in the face of increased collagenase activity remain an

enigma. Although seemingly counterintuitive, there are several potential mechanisms whereby a

proteinase can predispose to fibrosis, including proteolytic activation of transforming growth

factor (TGF- ) and insulin-like growth factor (IGF) binding protein degradation

releasing profibrotic IGF. Largely due to availability of suitable animal models, we know much

more about mechanisms involved in emphysema than small airway obstruction.

The pathogenesis of emphysema can be dissected into four interrelated events (Fig. 254-3): (1)

Chronic exposure to cigarette smoke may lead to inflammatory cell recruitment within the

terminal airspaces of the lung. (2) These inflammatory cells release elastolytic proteinases which

damage the extracellular matrix of the lung. (3) Loss of matrix-cell attachment leads to apoptosis

of structural cells of the lung. (4) Ineffective repair of elastin and perhaps other extracellular


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matrix components result in airspace enlargement that defines pulmonary emphysema.

Figure 254-3

Pathogenesis of emphysema. Upon long-term exposure to cigarette smoke, inflammatory cells

are recruited to the lung; they release proteinases in excess of inhibitors, and if repair is

abnormal, this leads to airspace destruction and enlargement or emphysema.

The Elastase:Antielastase Hypothesis

Elastin, the principal component of elastic fibers, is a highly stable component of the

extracellular matrix that is critical to the integrity of both the small airways and the lung

parenchyma. The elastase:antielastase hypothesis proposed in the mid-1960s states that the

balance of elastin-degrading enzymes and their inhibitors determines the susceptibility of the

lung to destruction resulting in airspace enlargement. This hypothesis was based on the clinical

observation that patients with genetic deficiency in 1AT, the inhibitor of the serine

proteinase neutrophil elastase, were at increased risk of emphysema, and that instillation of

elastases, including neutrophil elastase, to experimental animals results in emphysema. To this

day, the elastase:antielastase hypothesis is the prevailing mechanism for the development of

emphysema. However, a complex network of inflammatory cells and additional proteinases that

contribute to emphysema have subsequently been identified.

Inflammation and Extracellular Matrix Proteolysis

Macrophages patrol the lower airspace under normal conditions. Upon exposure to oxidants from

cigarette smoke, histone deacetylase-2 is inactivated, shifting the balance toward acetylated or

loose chromatin, exposing nuclear factor B sites and resulting in transcription of matrix

metalloproteinase-9, proinflammatory cytokines interleukin 8 (IL-8), and tumor necrosis factor


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(TNF- ); this leads to neutrophil recruitment. CD8+ T-cells are also recruited in

response to cigarette smoke and release interferon inducible protein-10 (IP-10, CXCL-7) that in

turn leads to macrophage production of macrophage elastase [matrix metalloproteinase-12

(MMP-12)]. Matrix metalloproteinases and serine proteinases, most notably neutrophil elastase,

work together by degrading the inhibitor of the other, leading to lung destruction. Proteolytic

cleavage products of elastin also serve as a macrophage chemokine, fueling this destructive

positive feedback loop.

Concomitant cigarette smoke-induced loss of cilia in the airway epithelium predisposes to

bacterial infection with neutrophilia. Surprisingly, in end-stage lung disease, long after smoking

cessation there remains an exuberant inflammatory response, suggesting that mechanisms of

cigarette smoke-induced inflammation that initiate the disease differ from mechanisms that

sustain inflammation after smoking cessation.

Collagen turnover in COPD is complex. The three collagenases (MMP-1, MMP-8, and MMP-

13) that initiate the cleavage of interstitial collagens are also induced in both inflammatory cells

and structural cells in COPD. While collagen is disrupted as alveolar units are obliterated, overall

there is a net increase in collagen content in the COPD lung, with prominent accumulation in the

airway submucosa.

Cell Death

Airspace enlargement with loss of alveolar units obviously requires disappearance of both

extracellular matrix and cells. Traditional theories suggest that inflammatory cell proteinases

degrade lung extracellular matrix as the primary event, with subsequent loss of cell anchoring

leading to apoptosis. Animal models have used endothelial and epithelial cell death as a means to

generate transient airspace enlargement. Whether apoptosis is a primary or secondary event in

COPD remains to be determined.

Ineffective Repair

The ability of the adult lung to repair damaged alveoli appears limited. Whether the process of


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septation that is responsible for alveogenesis during lung development can be reinitiated is not

clear. In animal models, treatment with all-trans retinoic acid has resulted in some repair. Also,

lung resection results in compensatory lung growth in the remaining lung in animal models. In

addition to restoring cellularity following injury, it appears difficult for an adult to completely

restore an appropriate extracellular matrix, particularly functional elastic fibers.

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 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 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, walking on a treadmill, or pushing a wheelchair. 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

simple 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.


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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 is notable

for a prolonged expiratory phase and 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.

Although traditional teaching is that patients with predominant emphysema, termed "pink

puffers," are thin and 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"),current evidence demonstrates that most patients have elements of both bronchitis and

emphysema and that the physical examination does not reliably differentiate the two entities.

Advanced disease may be accompanied by systemic wasting, with significant weight loss,

bitemporal wasting, and diffuse loss of subcutaneous adipose tissue. This syndrome has been

associated with both inadequate oral intake and elevated levels of inflammatory cytokines (TNF-

). 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 as a result

of 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 ofCOPD, and its presence should alert the clinician to initiate

an investigation for causes of clubbing. In this population, the development of lung cancer is the

most likely explanation for newly developed clubbing.

Laboratory Findings


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The hallmark of COPD is airflow obstruction (discussed above). Pulmonary function testing

shows airflow obstruction with a reduction in FEV1 and FEV1/FVC (Chap. 246). 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 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 disease classification (Table 254-1). More recently it has been shown that a

multifactorial index incorporating airflow obstruction, exercise performance, dyspnea, and body

mass index is a better predictor of mortality than pulmonary function alone.

Table 254-1 Gold Criteria forCOPD Severity

GOLD

Stage

Severity Symptoms Spirometry

0 At Risk Chronic cough, sputum

production

Normal

I Mild With or without chronic

cough or sputum production

FEV1/FVC


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predicted

or

FEV1 45 mmHg, into acute or chronic conditions. 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. Obvious bullae,

paucity of parenchymal markings, or hyperlucency suggest the presence of emphysema.

Increased lung volumes and flattening of the diaphragm suggest hyperinflation but do not

provide information about chronicity of the changes. Computed tomography (CT) scan is the

current definitive test for establishing the presence or absence of emphysema in living subjects

(Fig. 254-4). From a practical perspective, the CT scan does little to influence therapy of COPD

except in those individuals considering surgical therapy for their disease (described below).

Figure 254-4


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Chest CT scan of a patient with COPD who underwent a left single-lung transplant. Note

the reduced parenchymal markings in the right lung (left side of figure) as compared to the left

lung, representing emphysematous destruction of the lung, and mediastinal shift to the left,

indicative of hyperinflation.

Recent guidelines have suggested testing for 1AT deficiency in all subjects with COPD or

asthma with chronic airflow obstruction. Measurement of the serum 1AT level is a

reasonable initial test. For subjects with low 1AT levels, the definitive diagnosis of 1AT

deficiency requires PI type determination. This is typically performed by isoelectric focusing o

serum, which reflects the genotype at the PI locus for the common alleles and many of the rare

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

(M, S, and Z).

Chronic Obstructive Pulmonary Disease: Treatment

Stable Phase COPD

Only three interventionssmoking cessation, oxygen therapy in chronically hypoxemic patients,

and lung volume reduction surgery in selected patients with emphysemahave been

demonstrated to influence the natural history of patients with COPD. There is currently

suggestive, but not definitive, evidence that the use of inhaled glucocorticoids may alter

mortality (but not lung function). All other current therapies are directed at improving symptoms

and decreasing the frequency and severity of exacerbations. The institution of these therapies

should involve an assessment of symptoms, potential risks, costs, and benefits of therapy. This

should be followed by an assessment of response to therapy, and a decision should be made

whether or not to continue treatment.

Pharmacotherapy


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Smoking Cessation (See Also Chap. 390)

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, returning to

annual changes similar to that of nonsmoking patients. Thus, all patients with COPD should be

strongly urged to quit 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 two principal

pharmacologic approaches to the problem: bupropion, originally developed as an antidepressant

medication, and nicotine replacement therapy. The latter is available as gum, transdermal

patches, inhaler, and nasal spray. Current recommendations from the U.S. Surgeon General are

that all adult, nonpregnant smokers considering quitting be offered pharmacotherapy, in theabsence of any contraindication to treatment.

Bronchodilators

In general, bronchodilators are used for symptomatic benefit in patients with COPD. The inhaled

route is preferred for medication delivery as the incidence of side effects is lower than that seen

with the use of parenteral medication delivery.

Anticholinergic Agents

While regular use of ipratopium bromide does not appear to influence the rate of decline of lung

function, it improves symptoms and produces acute improvement in FEV1. Tiotropium, a long-

acting anticholinergic, has been shown to improve symptoms and reduce exacerbations. Side

effects are minor, and a trial of inhaled anticholinergics is recommended in symptomatic patients

with COPD.

Beta Agonists

These provide symptomatic benefit. The main side effects are tremor and tachycardia. Long-

acting inhaled agonists, such as salmeterol, have benefits comparable to ipratopium


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bromide. Their use is more convenient than short-acting agents. The addition of a agonist to

inhaled anticholinergic therapy has been demonstrated to provide incremental benefit. A recent

report in asthma suggests that those patients, particularly African Americans, using a long-acting

agonist without concomitant inhaled corticosteroids have an increased risk of deaths from

respiratory causes. The applicability of these data to patients with COPD is unclear.

Inhaled Glucocorticoids

Several trials have failed to find a beneficial effect for the regular use of inhaled glucocorticoids

on the rate of decline of lung function, as assessed by FEV1. Patients studied included those with

mild to severe airflow obstruction and current and ex-smokers. Patients with significant acute

response to inhaled agonists were excluded from these trials. Their use has been associated

with increased rates of oropharyngeal candidiasis and an increased rate of loss of bone density.

Some analyses suggest that inhaled glucocorticoids reduce exacerbation frequency by ~25%. A

more recent meta-analysis suggests that they may also reduce mortality by ~25%. A definitive

conclusion regarding the mortality benefits awaits the results of ongoing prospective trials. A

trial of inhaled glucocorticoids should be considered in patients with frequent exacerbations,

defined as two or more per year, and in patients who demonstrate a significant amount of acute

reversibility in response to inhaled bronchodilators.

Oral Glucocorticoids

The chronic use of oral glucocorticoids for treatment ofCOPD 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 gain, cataracts, glucose intolerance, and

increased risk of infection. A recent 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. On average, patients lost ~4.5 kg

(~10 lb) when steroids were withdrawn.


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Theophylline

Theophylline produces modest improvements in expiratory flow rates and vital capacity and a

slight improvement in arterial oxygen and carbon dioxide levels in patients with moderate to

severe COPD. Nausea is a common side effect; tachycardia and tremor have also been reported.

Oxygen

Supplemental O2 is the only pharmacologic therapy demonstrated to decrease mortality in

patients with COPD. For patients with resting hypoxemia (resting O2 saturation


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proven the efficacy of augmentation therapy in reducing decline of pulmonary function.

Eligibility for 1AT augmentation therapy requires a serum 1AT level 45 mmHg, extreme

deconditioning, congestive heart failure, or other severe comorbid conditions. Recent data

demonstrate that patients with an FEV1


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emphysema on CT scan or DLCO $10 billion annually in the

United States. The frequency of exacerbations increases as airflow obstruction increases; patients

with moderate to severe airflow obstruction [GOLD stages III,IV (Table 254-1)] have 13

episodes per year.

The approach to the patient experiencing an exacerbation includes an assessment of the severity


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of the patient's illness, both acute and chronic components; an attempt to identify the precipitant

of the exacerbation; and the institution of therapy.

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 symptoms that are characteristic ofCOPD exacerbations. Bacterial infections play a

role in many, but by no means all, episodes. 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.

Despite the frequent implication of bacterial infection, chronic suppressive or "rotating"

antibiotics are not beneficial in patients with COPD. This is in contrast to their apparent efficacy

in patients with significant bronchiectasis. In patients with bronchiectasis due to cystic fibrosis,

suppressive antibiotics have been shown to reduce frequency of hospital admissions.

The role of anti-inflammatory therapy in reducing exacerbation frequency is less well studied.

Chronic oral glucocorticoids are not recommended for this purpose. Inhaled glucocorticoids did

reduce the frequency of exacerbations by 2530% in some analyses. The use of inhaled

glucocorticoids should be considered in patients with frequent exacerbations or those who have

an asthmatic component, i.e., significant reversibility on pulmonary function testing or marked

symptomatic improvement after inhaled bronchodilators.

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 of

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; any ill

contacts; and associated symptoms such as nausea, vomiting, diarrhea, myalgias, and chills.

Inquiring about the frequency and severity of prior exacerbations can provide important


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information.

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 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. 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, those with a history of hypercarbia, those with 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 ofCOPD.

There are no definitive guidelines concerning the need for inpatient treatment of exacerbations.

Patients with respiratory acidosis and hypercarbia, significant hypoxemia, or severe underlying

disease or those whose living situation is not conducive to careful observation and the delivery of

prescribed treatment should be admitted to the hospital.

Acute Exacerbations

Bronchodilators

Typically, patients are treated with an inhaled agonist, often with the addition of an

anticholinergic agent. These may be administered separately or together, and the frequency of

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


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with nebulized therapy, as such treatment is often easier to administer in older patients or to

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 (such as theophylline) to this regimen can be considered,

although convincing proof of its efficacy is lacking. If 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, and Moraxella catarrhalis. In addition, Mycoplasma pneumoniae or

Chlamydia pneumoniae are found in 510% of exacerbations. The choice of antibiotic should be

based on local patterns of antibiotic susceptibility of the above pathogens as well as the patient's

clinical condition. Most practitioners treat patients with moderate or severe exacerbations with

antibiotics, even in the absence of data implicating a specific pathogen.

Glucocorticoids

Among patients admitted to the hospital, the use of glucocorticoids has been demonstrated to

reduce the length of stay, hasten recovery, and reduce the chance of subsequent exacerbation or

relapse for a period of up to 6 months. One study demonstrated that 2 weeks of glucocorticoid

therapy produced benefit indistinguishable from 8 weeks of therapy. The GOLD guidelines

recommend 3040 mg of oral prednisolone or its equivalent for a period of 1014 days.

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 keep arterial saturations 90%. Hypoxic respiratory


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drive plays a small role in patients with COPD. 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, need for

intubation, complications of therapy, and hospital length of stay. Contraindications to NIPPV

include cardiovascular instability, impaired mental status or 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

hypercapnia 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 theneed 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 of patients requiring mechanical ventilatory support is 1730% for that particular

hospitalization. For patients age >65 admitted to the intensive care unit for treatment, the

mortality doubles over the next year to 60%, regardless of whether mechanical ventilation was

required.

Further Readings

American Thoracic Society/European Respiratory Society Task Force: Standards for the

diagnosis and management of patients with COPD [Internet]. Version 1.2. New York: American

Thoracic Society; 2004 [updated 2005 September 8]. Available from:


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http://www.thoracic.org/sections/copd/index.html

Fiore MC et al: Treating Tobacco Use and Dependence, Clinical Practice Guideline. Rockville,

MD: U.S. Department of Health and Human Services. Public Health Service, June 2000

Ito K et al: Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N

Engl J Med 352:1967, 2005 [PMID: 15888697]

Mannino DM, Buist AS: Global burden of COPD: Risk factors, prevalence, and future trends.

Lancet 370:765, 2007 [PMID: 17765526]

Rabe KF et al: Global strategy for the diagnosis, management and prevention of chronic

obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176:532,

2007 [PMID: 17507545]

et al: Update in chronic obstructive pulmonary disease 2006. Am J Respir Crit Care Med

175:1222, 2007

Sin DD et al: Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease.

Thorax 60:992, 2005 [PMID: 16227327]

Wise RA, Tashkin DP: Optimizing treatment of chronic obstructive pulmonary disease: Anassessment of current therapies. Am J Med 120:S4, 2007

Bibliography

Celli BR et al: The body-mass index, airflow obstruction, dyspnea, and exercise capacity index

in chronic obstructive pulmonary disease. N Engl J Med 350:1005, 2004 [PMID: 14999112]

Hersh CP et al: Chronic obstructive pulmonary disease, in Respiratory Genetics, EK Silverman

et al, eds. London, Hodder-Arnold, 2005

Pauwels RA et al: Global strategy for the diagnosis, management, and prevention of chronic

obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung

Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 163:1256, 2001 [PMID:
http://www.thoracic.org/sections/copd/index.htmlhttp://www.thoracic.org/sections/copd/index.htmlhttp://www.thoracic.org/sections/copd/index.htmlhttp://www.thoracic.org/sections/copd/index.htmlhttp://www.thoracic.org/sections/copd/index.html


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