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Chronic Obstructive Pulmonary Disease: Introduction

Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized byairflow limitation that is not fully reversible (http://www.goldcopd.com/). COPD includesemphysema, an anatomically defined condition characterized by destruction and enlargementof the lung alveoli; chronic bronchitis, a clinically defined condition with chronic cough andphlegm; 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 >10 million persons in the UnitedStates. COPD is also a disease of increasing public health importance around the world.Estimates suggest that COPD will rise from the sixth to the third most common cause odeath worldwide by 2020.Risk Factors

Cigarette Smoking

By 1964, the Advisory Committee to the Surgeon General of the United States had concludedthat cigarette smoking was a major risk factor for mortality from chronic bronchitis andemphysema. Subsequent longitudinal studies have shown accelerated decline in the volumeof 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 aspack-years (average number of packs of cigarettes smoked per day multiplied by the totalnumber of years of smoking). This dose-response relationship between reduced pulmonaryfunction and cigarette smoking intensity accounts for the higher prevalence rates for COPDwith increasing age. The historically higher rate of smoking among males is the likelyexplanation for the higher prevalence of COPD among males; however, the prevalence oCOPD among females is increasing as the gender gap in smoking rates has diminished in thepast 50 years.

Although the causal relationship between cigarette smoking and the development of COPDhas 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 FEV 1(Fig. 260-1), only 15% of the variability in FEV1 is explained by pack-years. This findingsuggests that additional environmental and/or genetic factors contribute to the impact o


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smoking on the development of airflow obstruction.

Figure 260-1

Distributions of forced expiratory volume in 1 s (FEV1) values in a general populationsample, stratified by pack-years of smoking.Means, medians, and 1 standard deviationof percent predicted FEV1 are shown for each smoking group. Although a dose-responserelationship between smoking intensity and FEV1 was found, marked variability inpulmonary function was observed among subjects with similar smoking histories. (From BBurrows et al: Am Rev Respir Dis 115:95, 1977; with permission.)


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Although cigar and pipe smoking may also be associated with the development of COPD, theevidence supporting such associations is less compelling, likely related to the lower dose oinhaled tobacco by-products 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. 254).However, many patients with COPD also share this feature of airway hyperresponsiveness.The considerable overlap between persons with asthma and those with COPD in airwayresponsiveness, airflow obstruction, and pulmonary symptoms led to the formulation of theDutch hypothesis. This suggests that asthma, chronic bronchitis, and emphysema arevariations of the same basic disease, which is modulated by environmental and geneticfactors to produce these pathologically distinct entities. The alternative British hypothesiscontends that asthma and COPD are fundamentally different diseases: Asthma is viewed as

largely an allergic phenomenon, while COPD results from smoking-related inflammation anddamage. Determination of the validity of the Dutch hypothesis vs. the British hypothesisawaits identification of the genetic predisposing factors for asthma and/or COPD, as well asthe interactions between these postulated genetic factors and environmental risk factors. Onote, several genes related to the proteinase-antiproteinase hypothesis have been implicatedas genetic determinants for both COPD and asthma, including ADAM33 and macrophageelastase (MMP12) as described below.

Longitudinal studies that compared airway responsiveness at the beginning of the study tosubsequent decline in pulmonary function have demonstrated that increased airwayresponsiveness is clearly a significant predictor of subsequent decline in pulmonary function.

Thus, airway hyperresponsiveness is a risk factor 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 followingan episode of bronchitis or pneumonia. The impact of the effects of childhood respiratoryillnesses on the subsequent development of COPD has been difficult to assess due to a lack oadequate longitudinal data. Thus, although respiratory infections are important causes oexacerbations of COPD, the association of both adult and childhood respiratory infections tothe development and progression of COPD remains to be proven.

Occupational Exposures

Increased respiratory symptoms and airflow obstruction have been suggested to result fromgeneral exposure to dust and fumes at work. Several specific occupational exposures,including coal mining, gold mining, and cotton textile dust, have been suggested as riskfactors for chronic airflow obstruction. Although nonsmokers in these occupations developed


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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, arecent study found that coal mine dust exposure was a significant risk factor for emphysemain both smokers and nonsmokers. In most cases, the magnitude of these occupationalexposures 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 urbancompared 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 combustiona common mode ocooking in some countriesalso appears to be a significant risk factor for COPD amongwomen in those countries. However, in most populations, ambient air pollution is a much lessimportant risk factor for COPD than cigarette smoking.

Passive, or Second-Hand, Smoking Exposure

Exposure of children to maternal smoking results in significantly reduced lung growth. Inutero tobacco smoke exposure also contributes to significant reductions in postnatalpulmonary function. Although passive smoke exposure has been associated with reductionsin pulmonary function, the importance of this risk factor in the development of the severepulmonary function reductions in COPD remains uncertain.

Genetic Considerations

Although cigarette smoking is the major environmental risk factor for the development oCOPD, the development of airflow obstruction in smokers is highly variable. Severe 1antitrypsin (1AT) deficiency is a proven genetic risk factor for COPD; there is increasingevidence that other genetic determinants also exist.

1Antitrypsin Deficiency

Many variants of the protease inhibitor (PI or SERPINA1) locus that encodes 1AT have beendescribed. 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 markedlyreduced 1AT levels, also occur with frequencies >1% in most white populations. Rare

individuals inherit null alleles, which lead to the absence of any 1AT production through aheterogeneous collection of mutations. Individuals with two Z alleles or one Z and one nullallele 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 acontributing cause of COPD, these patients demonstrate that genetic factors can have aprofound influence on the susceptibility for developing COPD. PiZindividuals often develop


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early-onset COPD, but the ascertainment bias in the published series of Pi individualswhich have usually included many PiZsubjects who were tested for 1AT deficiency becausethey had COPDmeans that the fraction of PiZindividuals who will develop COPD and theage-of-onset distribution for the development of COPD 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 testused most frequently to screen for 1AT deficiency is measurement of the immunologic levelof 1AT in serum (see "Laboratory Findings").

A significant percentage of the variability in pulmonary function among PiZ individuals isexplained by cigarette smoking; cigarette smokers with severe 1AT deficiency are more likelyto develop COPD at early ages. However, the development of COPD in PiZ subjects, evenamong current or ex-smokers, is not absolute. Among PiZnonsmokers, impressive variabilityhas been noted in the development of airflow obstruction. Asthma and male gender alsoappear to increase the risk of COPD in PiZ subjects. Other genetic and/or environmentalfactors likely contribute to this variability.

Specific treatment in the form of 1AT augmentation therapy is available for severe 1ATdeficiency as a weekly IV infusion (see "Treatment," below).

The risk of lung disease in heterozygous PiMZ individuals, who have intermediate serumlevels of 1AT (~60% of Pi

MMlevels), is controversial. Although previous general populationsurveys have not typically shown increased rates of airflow obstruction in PiMZcompared toPiMMindividuals, case-control studies that compared COPD patients to control subjects haveusually found an excess of PiMZgenotypes in the COPD patient group. Several recent largepopulation studies have suggested that PiMZ subjects are at slightly increased risk for thedevelopment of airflow obstruction, but it remains unclear if all PiMZsubjects are at slightly

increased risk for COPD or if a subset of PiMZsubjects 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 havesuggested that genetic factors other than PI type influence variation in pulmonary function.Familial aggregation of airflow obstruction within families of COPD patients has also beendemonstrated.

Association studies have compared the distribution of variants in candidate genes

hypothesized to be involved in the development of COPD in COPD patients and controlsubjects. However, the results have been quite inconsistent, often due to underpoweredstudies. However, a recent association study comprising 8300 patients and 7 separate cohortsfound that a minor allele SNP of MMP12 (rs2276109) associated with decreased MMP-12expression has a positive effect on lung function in children with asthma and in adultsmokers. Recent genome-wide association studies have identified several COPD loci,including a region near the hedgehog interacting protein (HHIP) gene on chromosome 4 and


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a cluster of genes on chromosome 15 (including components of the nicotinic acetylcholinereceptor) that likely contain COPD susceptibility determinants, but the specific geneticdeterminants in those regions have yet to be definitively identified.Natural History

The effects of cigarette smoking on pulmonary function appear to depend on the intensity osmoking exposure, the timing of smoking exposure during growth, and the baseline lungfunction of the individual; other environmental factors may have similar effects. Mostindividuals follow a steady trajectory of increasing pulmonary function with growth duringchildhood and adolescence, followed by a gradual decline with aging. Individuals appear totrack in their quartile of pulmonary function based upon environmental and genetic factorsthat put them on different tracks. The risk of eventual mortality from COPD is closelyassociated with reduced levels of FEV1. A graphic depiction of the natural history of COPDis shown as a function of the influences on tracking curves of FEV 1in Fig. 260-2. Death ordisability 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 pulmonaryfunction can be modified by changing environmental exposures (i.e., quitting smoking), withsmoking cessation at an earlier age providing a more beneficial effect than smoking cessationafter marked reductions in pulmonary function have already developed. Genetic factors likelycontribute to the level of pulmonary function achieved during growth and to the rate odecline in response to smoking and potentially to other environmental factors as well.

Figure 260-2


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Hypothetical tracking curves of FEV1for individuals throughout their life spans.Thenormal pattern of growth and decline with age is shown by curve A.Significantly reducedFEV1(


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which involves forced expiratory maneuvers after the subject has inhaled to total lungcapacity. Key parameters obtained from spirometry include FEV1and the total volume of airexhaled during the entire spirometric maneuver [forced vital capacity (FVC)]. Patients withairflow obstruction related to COPD have a chronically reduced ratio of FEV1/FVC. Incontrast to asthma, the reduced FEV1 in COPD seldom shows large responses to inhaled

bronchodilators, although improvements up to 15% are common. Asthma patients can alsodevelop chronic (not fully reversible) airflow obstruction.

Airflow during forced exhalation is the result of the balance between the elastic recoil of thelungs promoting flow and the resistance of the airways limiting flow. In normal lungs, as wellas in lungs affected by COPD, maximal expiratory flow diminishes as the lungs emptybecause 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 flowcoincident with decreased lung volume is readily apparent on the expiratory limb of a flow-volume curve. In the early stages of COPD, the abnormality in airflow is only evident at lungvolumes 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 advanceddisease the entire curve has decreased expiratory flow compared to normal.

Hyperinflation

Lung volumes are also routinely assessed in pulmonary function testing. In COPD there isoften "air trapping" (increased residual volume and increased ratio of residual volume to totallung capacity) and progressive hyperinflation (increased total lung capacity) late in thedisease. Hyperinflation of the thorax during tidal breathing preserves maximum expiratoryairflow, because as lung volume increases, elastic recoil pressure increases, and airwaysenlarge so that airway resistance decreases.

Despite compensating for airway obstruction, hyperinflation can push the diaphragm into aflattened position with a number of adverse effects. First, by decreasing the zone oapposition between the diaphragm and the abdominal wall, positive abdominal pressureduring inspiration is not applied as effectively to the chest wall, hindering rib cage movementand impairing inspiration. Second, because the muscle fibers of the flattened diaphragm areshorter than those of a more normally curved diaphragm, they are less capable of generatinginspiratory pressures than normal. Third, the flattened diaphragm (with increased radius ocurvature, 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, becausethe 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 furtherinflation instead of gaining the normal assistance from the chest wall recoiling outwardtoward its resting volume.

Gas Exchange

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


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physiologic abnormalities in COPD, certain generalizations may be made. The PaO2usuallyremains near normal until the FEV1is decreased to ~50% of predicted, and even much lowerFEV1values can be associated with a normal PaO2, at least at rest. An elevation of arteriallevel of carbon dioxide (PaCO2) is not expected until the FEV1is


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phagocytes is also prominent. Smooth-muscle hypertrophy may also be present. Theseabnormalities may cause luminal narrowing by fibrosis, excess mucus, edema, and cellularinfiltration. Reduced surfactant may increase surface tension at the air-tissue interface,predisposing to airway narrowing or collapse. Respiratory bronchiolitis with mononuclearinflammatory cells collecting in distal airway tissues may cause proteolytic destruction o

elastic fibers in the respiratory bronchioles and alveolar ducts where the fibers areconcentrated as rings around alveolar entrances.

Because small airway patency is maintained by the surrounding lung parenchyma thatprovides radial traction on bronchioles at points of attachment to alveolar septa, loss obronchiolar attachments as a result of extracellular matrix destruction may cause airwaydistortion and narrowing in COPD.

Lung Parenchyma

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

bronchioles, alveolar ducts, and alveoli. Their walls become perforated and later obliteratedwith coalescence of small distinct air spaces into abnormal and much larger air spaces.Macrophages accumulate in respiratory bronchioles of essentially all young smokers.Bronchoalveolar lavage fluid from such individuals contains roughly five times as manymacrophages as lavage from nonsmokers. In smokers' lavage fluid, macrophages comprise>95% of the total cell count, and neutrophils, nearly absent in nonsmokers' lavage, accountfor 12% of the cells. T lymphocytes, particularly CD8+ cells, are also increased in thealveolar space of smokers.

Emphysema is classified into distinct pathologic types, the most important being centriacinarand panacinar. Centriacinar emphysema, the type most frequently associated with cigarette

smoking, is characterized by enlarged air spaces found (initially) in association withrespiratory bronchioles. Centriacinar emphysema is usually most prominent in the upperlobes and superior segments of lower lobes and is often quite focal. Panacinar emphysemarefers to abnormally large air spaces evenly distributed within and across acinar units.Panacinar emphysema is usually observed in patients with 1AT deficiency, which has apredilection for the lower lobes. Distinctions between centriacinar and panacinar emphysemaare interesting and may ultimately be shown to have different mechanisms of pathogenesis.However, garden-variety smoking-related emphysema is usually mixed, particularly inadvanced cases, and these pathologic classifications are not helpful in the care of patientswith COPD.Pathogenesis

Airflow limitation, the major physiologic change in COPD, can result from both small airwayobstruction and emphysema, as discussed above. Pathologic findings that can contribute tosmall airway obstruction are described above, but their relative importance is unknown.Fibrosis surrounding the small airways appears to be a significant contributor. Mechanismsleading to collagen accumulation around the airways in the face of increased collagenaseactivity remain an enigma. Although seemingly counterintuitive, there are several potential


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mechanisms whereby a proteinase can predispose to fibrosis, including proteolytic activationof transforming growth factor (TGF-). Largely due to greater similarity of animal air spacesthan airways to humans, we know much more about mechanisms involved in emphysemathan small airway obstruction.

The dominant paradigm of the pathogenesis of emphysema comprises four interrelated events(Fig. 260-3): (1) Chronic exposure to cigarette smoke may lead to inflammatory cellrecruitment within the terminal air spaces of the lung. (2) These inflammatory cells releaseelastolytic proteinases that damage the extracellular matrix of the lung. (3) Structural celldeath results from oxidant stress and loss of matrix-cell attachment. (4) Ineffective repair oelastin and other extracellular matrix components result in air space enlargement that definespulmonary emphysema.

Figure 260-3

Pathogenesis of emphysema.Upon long-term exposure to cigarette smoke, inflammatorycells are recruited to the lung; they release proteinases in excess of inhibitors, and if repair isabnormal, this leads to air space destruction and enlargement or emphysema. ECM,extracellular matrix; MMP, matrix metalloproteinase.


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The Elastase:Antielastase Hypothesis

Elastin, the principal component of elastic fibers, is a highly stable component of theextracellular matrix that is critical to the integrity of the lung. The elastase:antielastase

hypothesis proposed in the mid-1960s states that the balance of elastin-degrading enzymesand their inhibitors determines the susceptibility of the lung to destruction resulting in airspace enlargement. This hypothesis was based on the clinical observation that patients withgenetic deficiency in 1AT, the inhibitor of the serine proteinase neutrophil elastase, were atincreased risk of emphysema, and that instillation of elastases, including neutrophil elastase,to experimental animals results in emphysema. The elastase:antielastase hypothesis remains aprevailing mechanism for the development of emphysema. However, a complex network oimmune and inflammatory cells and additional proteinases that contribute to emphysemahave subsequently been identified.

Inflammation and Extracellular Matrix Proteolysis

Macrophages patrol the lower air space under normal conditions. Upon exposure to oxidantsfrom cigarette smoke, macrophages become activated, producing proteinases and chemokinesthat attract other inflammatory cells. One mechanism of macrophage activation occurs viaoxidant-induced inactivation of histone deacetylase-2, shifting the balance toward acetylatedor loose chromatin, exposing nuclear factor B sites and resulting in transcription of matrixmetalloproteinases, proinflammatory cytokines such as interleukin 8 (IL-8), and tumornecrosis factor (TNF-); this leads to neutrophil recruitment. CD8+ T cells are also recruited inresponse to cigarette smoke and release interferon inducible protein-10 (IP-10, CXCL-7) thatin 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 thisdestructive positive feedback loop.

Autoimmune mechanisms have recently been identified in COPD and may promote theprogression of disease. Increased B cells and lymphoid follicles are present in patients,particularly those with advanced disease. Antibodies have been found against elastinfragments, as well; IgG autoantibodies with avidity for pulmonary epithelium and thepotential to mediate cytotoxicity have been detected.

Concomitant cigarette smokeinduced loss of cilia in the airway epithelium and impaired

macrophage phagocytosis predispose to bacterial infection with neutrophilia. In end-stagelung disease, long after smoking cessation there remains an exuberant inflammatory response,suggesting that mechanisms of cigarette smokeinduced inflammation that initiate the diseasediffer from mechanisms that sustain inflammation after smoking cessation.

Cell Death


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Air space enlargement with loss of alveolar units obviously requires disappearance of bothextracellular matrix and cells. Cell death can occur from increased oxidant stress both directlyfrom cigarette smoke and from inflammation. Animal models have used endothelial andepithelial cell death as a means to generate transient air space enlargement. Uptake oapoptotic cells by macrophages results in production of growth factors and dampens

inflammation, promoting lung repair. Cigarette smoke impairs macrophage uptake ofapoptotic cells, limiting repair.

Ineffective Repair

The ability of the adult lung to repair damaged alveoli appears limited. It is unlikely that theprocess of septation that is responsible for alveologenesis during lung development can bereinitiated. The capacity of stem cells to repopulate the lung is under active investigation. Itappears difficult for an adult human 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 exertionaldyspnea. Many patients have such symptoms for months or years before seeking medicalattention. Although the development of airflow obstruction is a gradual process, manypatients 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. Thedevelopment 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 ontypical physical activities and how the patient's ability to perform them has changed.

Activities involving significant arm work, particularly at or above shoulder level, areparticularly difficult for patients with COPD. Conversely, activities that allow the patient tobrace the arms and use accessory muscles of respiration are better tolerated. Examples osuch activities include pushing a shopping cart, walking on a treadmill, or pushing awheelchair. As COPD advances, the principal feature is worsening dyspnea on exertion withincreasing intrusion on the ability to perform vocational or avocational activities. In the mostadvanced 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 osupplemental 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 nicotinestaining of fingernails. In patients with more severe disease, the physical examination isnotable for a prolonged expiratory phase and may include expiratory wheezing. In addition,


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signs of hyperinflation include a barrel chest and enlarged lung volumes with poordiaphragmatic excursion as assessed by percussion. Patients with severe airflow obstructionmay 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 "pinkpuffers," are thin and noncyanotic at rest and have prominent use of accessory muscles, andpatients with chronic bronchitis are more likely to be heavy and cyanotic ("blue bloaters"),current evidence demonstrates that most patients have elements of both bronchitis andemphysema 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 beenassociated 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 ribcage as a result of chronic hyperinflation.

Signs of overt right heart failure, termed cor pulmonale, are relatively infrequent since theadvent of supplemental oxygen therapy.

Clubbing of the digits is not a sign of COPD, and its presence should alert the clinician toinitiate an investigation for causes of clubbing. In this population, the development of lungcancer is the most likely explanation for newly developed clubbing.

Laboratory Findings

The hallmark of COPD is airflow obstruction (discussed above). Pulmonary function testingshows airflow obstruction with a reduction in FEV1 and FEV1/FVC (Chap. 252). Withworsening disease severity, lung volumes may increase, resulting in an increase in total lungcapacity, functional residual capacity, and residual volume. In patients with emphysema, thediffusing capacity may be reduced, reflecting the lung parenchymal destruction characteristicof the disease. The degree of airflow obstruction is an important prognostic factor in COPDand is the basis for the Global Initiative for Lung Disease (GOLD) redundant classification(Table 260-1). More recently it has been shown that a multifactorial index incorporatingairflow obstruction, exercise performance, dyspnea, and body mass index is a better predictor

of mortality rate than pulmonary function alone.

Table 260-1 Gold Criteria for COPD Severity


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GOLD

Stage

Severity Symptoms Spirometry

0 At Risk Chronic cough, sputumproduction

Normal

I Mild With or without chroniccough or sputum production

FEV1/FVC


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Figure 260-4

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 tothe left lung, representing emphysematous destruction of the lung, and mediastinal shift tothe left, indicative of hyperinflation.

Recent guidelines have suggested testing for 1AT deficiency in all subjects with COPD orasthma with chronic airflow obstruction. Measurement of the serum 1AT level is a reasonableinitial test. For subjects with low 1AT levels, the definitive diagnosis of 1AT deficiencyrequires protease inhibitor (PI) type determination. This is typically performed by isoelectricfocusing of serum, which reflects the genotype at the PI locus for the common alleles andmany of the rare PI alleles as well. Molecular genotyping of DNA can be performed for thecommon PI alleles (M, S, and Z).

Treatment: Chronic Obstructive Pulmonary Disease

Stable Phase COPD

Only three interventionssmoking cessation, oxygen therapy in chronically hypoxemic


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patients, and lung volume reduction surgery in selected patients with emphysemahave beendemonstrated to influence the natural history of patients with COPD. There is currentlysuggestive, but not definitive, evidence that the use of inhaled glucocorticoids may altermortality rate (but not lung function). All other current therapies are directed at improvingsymptoms and decreasing the frequency and severity of exacerbations. The institution o

these therapies should involve an assessment of symptoms, potential risks, costs, and benefitsof therapy. This should be followed by an assessment of response to therapy, and a decisionshould be made whether or not to continue treatment.

Pharmacotherapy

Smoking Cessation (See Also Chap. 395)

It has been shown that middle-aged smokers who were able to successfully stop smokingexperienced a significant improvement in the rate of decline in pulmonary function, returningto 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 emergingbody of evidence demonstrates that combining pharmacotherapy with traditional supportiveapproaches considerably enhances the chances of successful smoking cessation. There arethree principal pharmacologic approaches to the problem: bupropion, originally developed asan antidepressant medication; nicotine replacement therapy available as gum, transdermalpatch, inhaler, and nasal spray; and varenicline, a nicotinic acid receptor agonist/antagonist.Current recommendations from the U.S. Surgeon General are that all adult, nonpregnantsmokers considering quitting be offered pharmacotherapy, in the absence of anycontraindication to treatment.

Bronchodilators

In general, bronchodilators are used for symptomatic benefit in patients with COPD. Theinhaled route is preferred for medication delivery as the incidence of side effects is lower thanthat seen with the use of parenteral medication delivery.

Anticholinergic Agents

Ipratropium bromide improves symptoms and produces acute improvement in FEV1.Tiotropium, a long-acting anticholinergic, has been shown to improve symptoms and reduceexacerbations. Studies of both ipratropium and tiotropium have failed to demonstrate thateither influences the rate of decline in FEV1. In a large randomized clinical trial, there was a

trend toward reduced mortality rate in the tiotropium-treated patients that approached, but didnot reach, statistical significance. Side effects are minor, and a trial of inhaledanticholinergics is recommended in symptomatic patients with COPD.

Beta Agonists

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


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acting inhaled agonists, such as salmeterol, have benefits comparable to ipratropium bromide.Their use is more convenient than short-acting agents. The addition of a agonist to inhaledanticholinergic therapy has been demonstrated to provide incremental benefit. A recent reportin asthma suggests that those patients, particularly African Americans, using a long-actingagonist 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

Although a recent trial demonstrated an apparent benefit from the regular use of inhaledglucocorticoids on the rate of decline of lung function, a number of other well-designedrandomized trials have not. Patients studied included those with mild to severe airflowobstruction and current and ex-smokers. Patients with significant acute response to inhaledagonists were excluded from many of these trials, which may impact the generalizability othe findings. Their use has been associated with increased rates of oropharyngeal candidiasisand an increased rate of loss of bone density. Available data suggest that inhaled

glucocorticoids reduce exacerbation frequency by ~25%. The impact of inhaledcorticosteroids on mortality rates in COPD is controversial. A meta-analysis and severalretrospective studies suggest a mortality benefit, but in a recently published randomized trial,differences in mortality rate approached, but did not reach, conventional criteria for statisticalsignificance. A trial of inhaled glucocorticoids should be considered in patients with frequentexacerbations, defined as two or more per year, and in patients who demonstrate a significantamount of acute reversibility in response to inhaled bronchodilators.

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 withsignificant side effects, including osteoporosis, weight gain, cataracts, glucose intolerance,and increased risk of infection. A recent study demonstrated that patients tapered off chroniclow-dose prednisone (~10 mg/d) did not experience any adverse effect on the frequency oexacerbations, health-related quality of life, or lung function. On average, patients lost ~4.5kg (~10 lb) when steroids were withdrawn.

Theophylline

Theophylline produces modest improvements in expiratory flow rates and vital capacity and aslight 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 beenreported. Monitoring of blood theophylline levels is typically required to minimize toxicity.

Oxygen

Supplemental O2is the only pharmacologic therapy demonstrated to unequivocally decreasemortality rates in patients with COPD. For patients with resting hypoxemia (resting O2


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saturation 88% or


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Surgery to reduce the volume of lung in patients with emphysema was first introduced withminimal success in the 1950s and was reintroduced in the 1990s. Patients are excluded if theyhave significant pleural disease, a pulmonary artery systolic pressure >45 mmHg, extremedeconditioning, congestive heart failure, or other severe comorbid conditions. Patients withan FEV1


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A variety of stimuli may result in the final common pathway of airway inflammation andincreased symptoms that are characteristic of COPD exacerbations. Bacterial infections play arole in many, but by no means all, episodes. Viral respiratory infections are present inapproximately one-third of COPD exacerbations. In a significant minority of instances (2035%), 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 efficacy inpatients with bronchiectasis due to cystic fibrosis, in whom suppressive antibiotics have beenshown to reduce frequency of hospital admissions.

The role of pharmacotherapy in reducing exacerbation frequency is less well studied. Chronicoral glucocorticoids are not recommended for this purpose. Inhaled glucocorticoids reducethe frequency of exacerbations by 2530% in most analyses. The use of inhaledglucocorticoids should be considered in patients with frequent exacerbations or those whohave an asthmatic component, i.e., significant reversibility on pulmonary function testing or

marked symptomatic improvement after inhaled bronchodilators. Similar magnitudes oreduction have been reported for anticholinergic and long-acting beta-agonist therapy. Theinfluenza vaccine has been shown to reduce exacerbation rates in patients with COPD.

Patient Assessment

An attempt should be made to establish the severity of the exacerbation as well as the severityof preexisting COPD. The more severe either of these two components, the more likely thatthe patient will require hospital admission. The history should include quantification of thedegree of dyspnea by asking about breathlessness during activities of daily living and typicalactivities 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 canprovide important information.

The physical examination should incorporate an assessment of the degree of distress of thepatient. Specific attention should be focused on tachycardia, tachypnea, use of accessorymuscles, 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 orabsence of focal findings, degree of air movement, presence or absence of wheezing,asymmetry in the chest examination (suggesting large airway obstruction or pneumothoraxmimicking 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 withfocal findings should have a chest x-ray. Approximately 25% of x-rays in this clinicalsituation will be abnormal, with the most frequent findings being pneumonia and congestiveheart failure. Patients with advanced COPD, those with a history of hypercarbia, those withmental status changes (confusion, sleepiness), or those in significant distress should have an


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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 themanagement of exacerbations of asthma, measurement of pulmonary function has not beendemonstrated to be helpful in the diagnosis or management of exacerbations of COPD.

There are no definitive guidelines concerning the need for inpatient treatment oexacerbations. Patients with respiratory acidosis and hypercarbia, significant hypoxemia, orsevere underlying disease or those whose living situation is not conducive to carefulobservation 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 ananticholinergic agent. These may be administered separately or together, and the frequency o

administration depends on the severity of the exacerbation. Patients are often treated initiallywith nebulized therapy, as such treatment is often easier to administer in older patients or tothose in respiratory distress. It has been shown, however, that conversion to metered-doseinhalers is effective when accompanied by education and training of patients and staff. Thisapproach has significant economic benefits and also allows an easier transition to outpatientcare. The addition of methylxanthines (such as theophylline) to this regimen can beconsidered, although convincing proof of its efficacy is lacking. If added, serum levels shouldbe monitored in an attempt to minimize toxicity.

Antibiotics

Patients with COPD are frequently colonized with potential respiratory pathogens, and it isoften difficult to identify conclusively a specific species of bacteria responsible for aparticular clinical event. Bacteria frequently implicated in COPD exacerbations includeStreptococcus pneumoniae,Haemophilus influenzae, andMoraxella catarrhalis. In addition,

ycoplasma pneumoniae or Chlamydia pneumoniae are found in 510% of exacerbations.The choice of antibiotic should be based on local patterns of antibiotic susceptibility of theabove pathogens as well as the patient's clinical condition. Most practitioners treat patientswith moderate or severe exacerbations with antibiotics, even in the absence of dataimplicating a specific pathogen.

Glucocorticoids

Among patients admitted to the hospital, the use of glucocorticoids has been demonstrated toreduce the length of stay, hasten recovery, and reduce the chance of subsequent exacerbationor relapse for a period of up to 6 months. One study demonstrated that 2 weeks ofglucocorticoid therapy produced benefit indistinguishable from 8 weeks of therapy. TheGOLD guidelines recommend 3040 mg of oral prednisolone or its equivalent for a period o1014 days. Hyperglycemia, particularly in patients with preexisting diagnosis of diabetes, is


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the most frequently reported acute complication of glucocorticoid treatment.

Oxygen

Supplemental O2should be supplied to keep arterial saturations 90%. Hypoxemic respiratory

drive plays a small role in patients with COPD. Studies have demonstrated that in patientswith both acute and chronic hypercarbia, the administration of supplemental O2 does notreduce 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 deterpractitioners from providing the oxygen needed to correct hypoxemia.

Mechanical Ventilatory Support

The initiation of noninvasive positive-pressure ventilation (NIPPV) in patients withrespiratory failure, defined as PaCO2>45 mmHg, results in a significant reduction in mortalityrate, need for intubation, complications of therapy, and hospital length of stay.

Contraindications to NIPPV include cardiovascular instability, impaired mental status orinability to cooperate, copious secretions or the inability to clear secretions, craniofacialabnormalities or trauma precluding effective fitting of mask, extreme obesity, or significantburns.

Invasive (conventional) mechanical ventilation via an endotracheal tube is indicated forpatients 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 tocorrect the aforementioned conditions. Factors to consider during mechanical ventilatorysupport 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 canresult in patients having to generate significant respiratory effort to trigger a breath during ademand mode of ventilation. The mortality rate of patients requiring mechanical ventilatorysupport is 1730% for that particular hospitalization. For patients age >65 admitted to theintensive care unit for treatment, the mortality rate 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 thediagnosis and management of patients with COPD [Internet]. Version 1.2. New York:American Thoracic Society; 2004 [updated September 8, 2005]. Available from http://www-

test.thoracic.org/copd/

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, June2000

Hunninghake GM et al: MMP12, lung function, and COPD in high-risk populations. N Engl J


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Ito K et al: Decreased histone deacetylase activity in chronic obstructive pulmonary disease.N Engl J Med 352:1967, 2005[PMID: 15888697] [Full Text]

Mannino DM, Buist AS: Global burden of COPD: Risk factors, prevalence, and future trends.Lancet 370:765, 2007[PMID: 17765526] [Full Text]

Rabe KF et al: Global strategy for the diagnosis, management and prevention of chronicobstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med176:532, 2007[PMID: 17507545] [Full Text]

et al: Update in chronic obstructive pulmonary disease 2006. Am J Respir Crit CareMed 175:1222, 2007

Sin DD et al: Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease.Thorax 60:992, 2005[PMID: 16227327] [Full Text]

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

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