PATHO(i ENESIS Airflow limitation the major physiologic change in COPD can result from both small airway obstruction and emphysema. As described below small airways may become narrowed by cells (hyperplasia and accumulatio mucus and fibrosis. Of note activation of transforming growth factor (TGF-) contributes to airway fibrosIS whilillack of TGF- may contribute to parenchyma1 inflammatemphysema. Largely due to greater similarity of animal air spaces than airways to humans we know more about mechanisms involved in emphysema than small airway obstruction.

The dominant paradigm of the pathogenesis of emphysema comprises four interrelated events (Fig. 314- 1 ) : ( 1 ) Chronic exposure to cigarette smoke leads to inflammatory and immune cell recruitment within the terminal air spaces of the lung. (2) These inflammatory cells release elastolytic and other proteinases that damage the extracellular matrix of the lung. (3) Structural cell death (endothelial and epithelial cells) occurs directly through oxidant-induced cigarette smoke dam age and senescence as well as indirectly via proteolytic loss of matrix attachment. (4) Ineffective repair of elastin and other extracellular matrix components result in air space enlargement that defines pulmonary emphysema.

THE ELASTASE:ANTIELASTASE HYPOTHESIS Elastin the principal component of elastic fibers is a highly stable component of the extracellular matrx 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 enzymes and their inhibitors determines the susceptibility of the lung to destruction resulting in air space enlargement. This hypothesis was based on the clinical observation that patients with genetic deficiency in \ anttryp sin (\AT) the inhibitor of the serine proteinase neutrophil elastase were at increased risk of emphysema and that instillation of elastases including neutrophil elastase into experimental animals results in emphysema. The elastase:antielastase hypothesis remains a prevailing mechanism for the development of emphysema. However a complex

Cigarette smoke

1 700 CF QUALlTY IMPROVEMENT INCLUDING ASPECTS OF GLOBAL HEALTH As a direct result of advances in basic research new therapies have transformed CF from a disease typically leading to death in early childhood to a condition with frequent survival well into the fourth decade of life. It has also become increasingly clear that specified approaches to patient management can have an impact on overall prognosis. For example standardization of clinical intervention throughout the United States has led to remarkable benefit among the CF population Well-defined measures for outpatient care are now established includ ing thresholds for hospital admission antibiotic regimens nutritional guidelines periodicity of diagnostic tests and other clinical parameters. These therapeutic recommendations have become standardized throughout approximately 1 10 specialized CF care centers and 55 affiliated programs. The initiative has improved endpoints such as weight gain body mass index and pulmonary function. Information regarding standardized protocols for CF therapy can be accessed at (www.cjf.org/treatments/reguidelines/) or through a number of excellent reviews.

Newborn screening for CF is now universal throughout the United States most of the Canadian provinces Australia New Zealand and much of Europe and will facilitate ar CF intrntion. Based on data indicating that early nutritional and other therapies can be beneficial newborn diagnosis is expected to significantly promote health in the CF population. Export of quality control measures and novel therapeutics worldwide has become an increasing imperative. For example median survival of individuals with CF is less than 20 years in much of Central and South America (compared to -40 years in the United States and Canada) and efforts to apply state-of-the-art man agement to underdiagnosed and underserved CF patient populations are expected to improve outcome and mitigate CF health disparities in the future.

VIDEO 31 3-1 In it ia l video sequences describe establ ishment of the normal perici l iary fl u id layer bath ing the su rface a i rway epithe l ium with spher presnt ing ch lor ide and bica rbonate ions secreted th rough CFTR and across the ap ica l (mucosa l ) rsp i ratorysu rface. Later video sequences depict fa i l u re of CFTR an ion tran sport and rsu lt ing dep let ion of the peric i l i a ry lay "p lasteri ng" of c i l i a aga inst the mucosa l su rface and accumu l at ion of mucus in the a i rway with resu l t ing bacter ia l i nfect ion . (Video courtesy of the Cystic Fibrosis FoundtfOJ

-MOE3

0HYmzg

SHO

MZ

3

i Inflammatory cell recruitment

MMP .... MMP

Chronic Obstructive Pulmonary Disease John J . Rei l ly J r. Edwin K. Si lverman Steven D. Shapiro

Macrophage

ltynhibbbitECM dadatlon ;

................Emphysema Repair

FIGURE 314-1 Pathogenesis of emphysema. Upon long-term exposu r to c lga rtte smoke infl ammatory c I l s a r recru ited to the l u ng; they re lease prote inases i n excess of i nh i bitors and if repa i r i s a bnormal th i s 1ads to a i r space destruction and en l a rgement or emphysema ECM extrace l l u l a r matrix; MMP matr ix meta l loprote inase

Cysteine .... proteinases

Serine proteinases

Neutrophi l Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by airflow limitation that is not fully reversible (ht://www.goldcopd. com/) . COPD includes emphysema an anatomically defined condition characterized by destruction and enlargement of the lung alveoli; chronic bronchiti a clinially 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 without chronic airflow obstruction is not included within COPD.

COPD is the third leading cause of death and affects > 10 million persons in the United States. 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 of death worldwide by 2020

leading to airflow limitation. Neutrophil influx has been associ- 1 701 ated with purulent sputum of upper respiratory tract infections. Independent of its proteolytic activity neutrophil elastase is among the most potent secretagogues identified.

network of immune and inflammatory cells and additional proteinases that contribute to emphysema have subsequently been 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 with these mucus-secreting cells replacing surfactant-secreting Clara cells. Smooth-muscle hypertrophy may also be present. These abnormalities may cause luminal narrowing by fibrosis excess mucus edema and cellular inmtration. Reduced surfactant may increase surface tension at the air-tissue interface predis posing to airway narrowing or collapse. Respiratory bronchiolitis with mononuclear inflammatory cells collecting in distal airway tissues may cause proteolytic destruction of elastic fibers in the respiratory bron chioles and alveolar ducts where the fibers are concentrated as rings around alveolar entrances. Narrowing and drop-out of small airways precede the onset of emphysematous destruction.

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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. Key parameters obtained from spirometry include the volume of air exhaled within the first second of the forced expiratory maneuver (FEV) and the total volume of air exhaled during the entire spirometric maneuver (forced vital capacity [FVC] ) . Patients with airflow obstruction related to COPD have a chronically reduced ratio of FEV/FVC. In contrast to asthma the redued FEV 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.

Airflow during forced exhalation is the result of the balance between e elastic reo of e 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 resis tance to airflow. The decrease in flow coincident with decreased lung

I NFLAMMATION AND EXTRACELLULAR MATRIX PROTEOLYSIS Upon exposure to oxidants from cigarette smoke macrophages and epithelial cells become activated producing proteinases and chemokines that attract other inflammatory and immune cells. One mechanism of macrophage activation occurs via oxidant-induced inactivation of histone deacetylase-2 ing the balance toward acetylated or loose chromatin exposing nuclear factor-KB sites and resulting in transcription of matrix metalloproteinases proinflammatory cytokines such as interleukin 8 (IL-8) and tumor necrosis factor (TNF ); this leads to neutrophil recruitment. CD8+ T cells are also recruited in response to cigarette smoke and release interferon-inducible protein- 10 (IP - lO CXCL-7) which 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.

Autoimmune mechanisms may promote the progression of dis ease. Increased B cells and lymphoid follicles are present in patients particularly those with advanced disease. Antibodies have been found against elastin fragments as well; IgG autoantibodies with avidity for pulmonary epithelium and the potential to mediate cytotoxicity have been detected.

Concomitant cigarette smoke-induced loss of cilia in the airway epithelium and impaired macrophage phagocytosis predispose to bacterial infection with neutrophilia. 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.

Cell Death Cigarette smoke oxidant-mediated structural cell death occurs via a variety of mechanisms including rt801 inhibition of mammalian target of rapamycin (mTOR) leading to cell death as well as inflammation and proteolysis. Involvement of mTOR and other senescence markers has led to the recent concept that emphysema resembles premature aging of the lung. U ptake of apoptotic cells by macrophages results in production of growth factors and dampens inflammation promoting lung repair. Cigarette smoke impairs macrophage uptake of apoptotic cells limiting repair.

Ineffective Repair The ability of the adult lung to repair damaged alveoli appears limited. It is unlikely at the process of septation that is responsible for alveologenesis during lung development can be reinitiated. The capacity of stem cells to repopate the lung is under active investigation. It appears difficult for an adult human to completely restore an appropriate extracellular matrix particularly functional elastic fibers.

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 obliterated with 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 many macrophages as lavage from non smokers. In smokers' lavage fluid macrophages comprise >95% of the total cell count and neutrophils nearly absent in nonsmokers' lavage account for 1-2% of the cells. T lymphocytes particularly CD8+ cells are also increased in the alveolar space of smokers.

Emphysema is classified into distinct pathologic types e most important being centriacinar and panacinar. Centriacinar emphysema the type most frequently associated with cigarette smoking is characterized by enlarged air spaces found (initially) in association with resprato bronchioles. Centriacinar emphysema is usually most prominent in the upper lobes and superior segments of lower lobes and is often quite focaL Panacinar emphysema refers to abnormally large air spaces evenly distuted within and across acinar units Panacinar emphysema is usually observed in patients with oAT deficiency which has a predilection for the lower lobes.

PATHOLOGY Cigarette smoke exposure may affect the large airways small airways (2 mm diameter) and alveoli. Changes in large airways cause cough and sputum while changes in small airways and alveoli are responsible for physiologic alterations. Emphysema and small airway pathology are both present in most persons with COPD; however they do not appear to be mechanistically related to each other and their relative contributions to obstruction vary from one person to another

LARGE AIRWAY Cigarette smoking often results in mucus gland enlargement and goblet cell hyperplasia leading to cough and mucus production that define chronic bronchitis but these abnormalities are not related to airflow limitation. Goblet cells not only increase in number but in extent through the bronchial tree. Bronchi also undergo squamous metaplasia predisposing to carcinogenesis and disrupting muco ciliary clearance. Although not as prominent as in asthma patients may have smooth-muscle hypertrophy and bronchial hyperreactivity

1 S D. Mean +1 S.D.

4 Median

o Pack years (945) 20 1 0 0

1 702 volume is readily apparent on the expiratory limb of a flow-rolumecurve. In the early stages of COPD 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.

nununu q44l

nununu 44l

80 1 00 120 % FEV1

F I6URE 314-2 Distributions of forced expiratory volume in 1 s (FEV1 ) va l ues in a general population sample stratified by packyears of smoking. Means med ians and :t 1 sta nda rd deviat ion of percent prd icted FEV1 a re shown for each smok ing g roup . A l though a dose-rspons lat ionsh ip between smok ing i ntens ity and FEV1 was found ma rked va r ia b i l ity i n pu llOna ry fu nction was observed among subjects with s im i l a r smok ing h i stories. (From B Brrows et I: Am Rev Respir Dis 1 1 5:95 1 977; with permission.)

1 60 140 60 40

HYPERINFLATION Lung volumes are also routinely assessed in pulmonary function testing. In COPD there is often ir trapping" (increased residual rolumeand 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 rolume increases elastic recoil pressure increases and airways enlarge so that airway resistance decreases.

Despite compensating for airway obstruction 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

of years of smoking) . This dose-response relationship between reduced pulmona function and cigarette smoking intensity accounts for the higher prevalence rates of COPD with increasing age. The histori cally 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.

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 ofFEV] (Fig. 314-2) 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 e development of airflow obstruction.

Although cigar and pipe smoking may also be associated with the development of COPD the evidence supporting such associations is less compelling likely related to the lower dose of inhaled tobacco byproducts during cigar and pipe smoking.

6AS EXCHAN6E Although there is considerable variability in the relationships between the FEV] and other physiologic abnormalities in COPD certain gener alizations may be made. The partial pressure of oxygen in arterial blood Pao2 usually remains near normal until the FEV is decreased to -50% of predicted and even much lower FEV values can be associated with a normal Pao2 at least at rest. An elevation of arterial level of carbon dioxide (paco) is not expected until the FEV1 is

markedly reduced IAT levels also occur with frequencies of > 1 % in 1 703 most white populations. Rare individuals inherit null alleles which lead to the absence of any IAT 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 IAT deficiency

Although only approximately 1% of COPD patients are found to have severe AT deficiency as a contributing cause of COPD these patients demonstrate that genetic factors can have a profound influence on the susceptibility for developing COPD. Piz individuals often develop early-onset COPD but the ascertainment bias in the published series of Piz individuals-which have usually included many Piz sub jects who were tested for IAT deficiency because they had COPD means that the fraction of Piz individuals who will develop COPD and the age-oonset distribution for the development of COPD in Piz subjects remain unknown. Approximately 1 in 3000 individuals in the United States inherits severe AT deficiency but only a small minority of these individuals has been identified. The clinical laboratory test used most frequently to screen for IAT deficiency is measurement of the immunologic level of IAT in serum (see "Laboratory Findings")

A significant percentage of the variability in pulmonary function among PiZ indiviiduals is xplained by cigarette smnoking; cigarette smokers with severe IAT defciency are more likely to develop COPD at early ages. However the development of COPD in Piz subjects even among current or ex-smokers is not absolute. Among PjZ nonsmokers impressive variability has been noted in the development of airflow obstruction. Asthma and male gender also appear to increase the risk of COPD in Piz subjects. Other genetic and/or environmental factors likely contribute to this variabity.

Specific treatment in the form of uAT augmentation therapy is available for severe IAT deficiency as a weekly IV infusion (see "Treatment" below) .

The risk of lung disease in heterozygous PiMZ individuals who have intermediate serum levels of IAT (-60% of PiMM levels) is controver sial. Several recent large 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 Pi'rz subjects are at substantially increased risk for COPD due to other genetic or environmental factors.

are fundamentally different diseases: Asthma is viewed as largely an allergic phenomenon whereas COPD results from smoking-related inflammation and damage. Determination of the validity of the Dutch hypothesis versus the British hypothesis awaits identification of all of the genetic predisposing factors for asthma and/or COPD as well as the interactions between these postulated genetic factors and environ mental 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 slgmcant 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 following an episode of bronchitis or pneumonia. The impact of the effects of childhood respiratory illnesses on the subsequent development of COPD has been difficult to assess due to a lack of adequate longitudinal data. Thus although respiratory infections are irportant causes of exacerbations of COPD the association of both adult and childhood respiratory infections with the development and progression of COPD remains to be proven.

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OCCUPATIONAL EXPOSURES Increased respiratory symptoms and airflow obstruction have been suggested to result from exposure to dust and fumes 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. Although nonsmokers in these occupations can develop some reductions in FEV1 the importance of dust exposure as a risk factor for COPD independent of cigarette smoking is not certain for most of these exposures. However among coal miners coal mine dust exposure was a signicant risk factor for emphysema in both smokers and nonsmokers. In most cases the magnitude of these occupational exposures on COPD risk is likely substantially less important than the effect of cigarette smoking.

Other 6enetic Risk Factors Studies of pulmonary function measurements performed in general population samples have suggested atgenetic 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 candidate genes hypothesized to be involved in the development of COPD in COPD patients and control subjects. However the results have been quite inconsistent often due to underpowered studies. However a well-powered association study omprising 8300 patients and 7 separate cohorts found that a minor allele single nucleotide polymorphism (SNP) of MMP12 (rs2276109) associated with decreased MMP12 expression has a positive effect on lung function in children with asthma and in adult smokers. Recent genome-wide association studies have identified several COPD susceptibility loci including a region near the hedgehog interacting protein (HHIP) gene on chromo some 4 a cluster of genes on chromosome 15 (including components of the nicotinic acetylcholine receptor) and a region within a gene of unknown function (FAM13A) . A regulatory SNP upstream from the HHIP gene has been identified as one potential functional variant; the specc genetic determinants in the other genomic regions have yet to be definitively identified.

AMBIENT AIR POLLUTION Some investigators have reported increased respiratory snptoms in those living in urban compared to rural areas which may relate to increased pollution in the urban settings. However the relationship of air pollution to chronic airflow obstruction remains unproved. Prolonged exposure to smoke produced by biomass combustion-a common mode of cooking in some countries-also appears to be a significant risk factor for COPD among women in those countries. However in most populations ambient air pollution is a much less important risk factor for COPD than cigarette smoking.

PASSIVE OR SECOND-HAND SMOKIN6 EXPOSURE Exposure of children to maternal smoking results in signicantlyreduced lung growth. In utero tobacco smoke exposure also con tributes to signicant redutions 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 remams unertain.

NATURAL HISTORY

6ENETlC 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 IAT deficiency

is a proven genetic risk factor for COPD; there is increasing evidence that other genetic determinants also exist

The effects of cigarette smoking on pulmonary function appear to depend on the illtensity 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. Most individuals follow a steady tectory of increasing pulmonary function wi

PHYSICAL F IND INGS In the early stages of COPD patients usually have an entirely normal physical examination. Current smokers may have signs of active smoking including an odor of smoke or nicotine staining of fingernails. In patients with more severe disease the physicaI examination is notable for a prolonged expiratory phase and may include expiratory wheezing. In addition signs of hyperinflation include a barrel chest and enIarged lung volumes with poor diaphragmatic excursion as assessed by percussion Patients with severe airflow obstruction may aIso exhibit use of accessory muscles of respiration sitting in the characteristic "tripod" position to facilitate the actions of the sternocleidomastoid scalene and intercostaI 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 ele ments ofboth bronchitis and emphysema and that the physical exami nation does not reliably differentiate the two entities

Advanced disease may be accompanied by cachexia 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 move ment 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 pulmonal are relatively infrequent since the advent of supplemental oxygen therapy.

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

LABORATORY F INDINGS The hallmark of COPD is airflow obstruction (discussed above). Pulmonary function testing shows airflow obstruction with a reduction in FEV1 and FEV/FVC (Chap. 306e) . With worsening disease sever ity lung volumes may increase resulting in an increase in total lung capacity functionaI residual capacity and residuaI volume. In patients with emphysema the diffusing capacity may be reduced reflecting the lung parenchymal destruction characteristic of the disease. The degree of airflow obstruction is an important prognostic factor in COPD and is the basis for the GlobaI Initiative for Lung Disease (GOLD) severity classification (Table 314-1 ) . 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 mortaIity rate than pulmonary function alone. In 20 1 1 the GOLD added an additionaI classification system incorporating symptoms and exacerbation history; the utility of this system remains to be defined.

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

...... Rapid decline

Early decl ine

75

1000 ol m H E o c n b F w LL

50

1 704

Respi ratory symptoms 25

40 Age year

F IGURE 314'3 Hypothetical tracki ng cu rves of forced expiratory volume in 1 s (FEV1 ) for individuals throughout their l ife spans. The normal patte rn of g rowth and dec l i ne with age i s shown by cu rve A. S ig n ifica nt ly reduced FEV1 (

to i nfl uence the natural h istory of patients with COPD. There is 1 705 cu rrently suggestive but not defin itive evidence that the use of inha led g lucocorticoids may a lter morta l ity rate (but not lung func-tion). AII other cu rrent therapies a re d i rected at improvi ng symp-toms and decreas ing the frequency and severity of exacerbations The institution of these therapies should i nvolve an assessment of symptoms potentia l r isks costs and benefits of therapy. This should be fol lowed by an assessment of response to therapy and a decis ion should be made whether or not to continue treatment.

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PHARMACOTHERAPY Smoking Cessation (See also Chap. 470) It has been shown that midd le aged smokers who were ab le to successfu l ly stop smoking experi enced a sign ificant improvement in the rate of decl ine in pu lmonary function retu rn ing to annua l changes s imi la r to that of nonsmoking patients. Thus a l l patients with COPD should be strongly u rged to qu it smoking and educated about the benefits of qu itting . An emerg ing body of evidence demonstrates that combin ing pharmacotherapy with tradit ional supportive approaches considerably enhances the chances of successfu l smoking cessation. There a re three pr inc ipa l pharmacologic approaches to the problem: bupropion; n icoti ne replacement therapy ava i l ab le as gum transdermal patch lozenge inha ler and nasal spray; and va ren ic l i ne a n icotin ic acid receptor agonist/antagonist. Cu rrent recommendations from the u.s. Surgeon Genera l a re that a l l adu lt nonpregnant smokers consider ing qu itti ng be offered pharmacotherapy i n the absence of any contra ind ication to treatment.

Bronchodilators I n genera l bronchod i lators a re used for symptomatic benefit i n patients with COPD. The inha led route is preferred for med ication de l ivery because the inc idence of s ide effects is lower than that seen with the use of pa rentera l medication de l ivery.

F IGURE 314-4 Chest computed tomography scan of a patient with chronic obstructive pu lmonary disease who underwent a left sing le-I ung transplant. Note the reduced parenchyma l mark i ngs i n the r ight l u ng (left side ofgure) as compa rd to the 1ft l u ng pr5nti ng emphysematous destruct ion of the l u ng and mediast inal sh ift to the left i nd icative of hyper inflat ion .

Anticholinergic Agents I p ratrop ium bromide improves symptoms and produces acute improvement in FEV . Tiotropium a long-acti ng antichol i nergic has been shown to improve symptoms and reduce exacerbations. Stud ies of both ipratropium and tiotropium have fa i led to demonstrate that either i nfl uences the rate of dec l ine in FEV . In a large randomized c l in ical tr ia l there was a trend toward reduced morta l ity rate in the tiotrop ium-treated patients that approached but d id not reach statistica l s ign ificance. S ide effects a re minor and a tr ia l of i nha led ant ichol inergics is recommended in symptomatic patients with COPD. Recent retrospective ana lyses ra ised the poss ib i l ity that anticho l inergic use is associated with i ncreased cardiovascu la r events i n the COPD popu lat ion. Th is was not demonstrated i n a l a rge prospective randomized tria l of tiotropium.

Beta Agonists These provide symptomatic benefit. The main s ide ects a re tremor and tachycard ia. Long-acting inha led agonists such as sa lmeterol or formoterol have benefits comparable to ipratropium bromide. Their use is more convenient than short-acting agents. The addition of a agonist to inha led antichol inergic therapy has been demonstrated to provide incremental benefit. A recent report in asthma suggests that those patients particu larly African Americans using a long-acting agonist without concomitant inha led corticosteroids have an increased risk of deaths from respi ratory causes. The appl icab i l ity of these data to patients with COPD is unclear.

Inhaled Glucorticoids Although a recent tria l demonstrated an appa rent benefit from the regu la r use of i nha led g lucocorticoids on the rate of dec l ine of lung function a number of other wel l-designed randomized tria l s have not. Patients studied inc l uded those with mi ld to severe a i rflow obstruction and current and ex-smokers. Patients with s ign ificant acute response to i nha led agonists were excluded from many of these tria l s which may impact the genera l izabi l ity of the fi nd ings. Their use has been associated with increased rates of oropharyngeal candid ias is and an i ncreased rate of loss of bone dens ity. Ava i lab le data suggest that i nha led g lucocorticoids reduce exacerbation frequency by -25%. The impact of

about alveolar ventilation and acid-base status by measuring arterial Pco and pH. The change in pH with Pco is 0.08 units/ lO mmHg acutely and 0.03 units/ lO mmHg in the chronic state. Knowledge of the arterial pH therefore allows the classification of ventilatory failure defined as Pco >45 mmHg into acute or chronic conditions. The arterial blood gas is an important component of the eraluation 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 suggests 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. 314-4) . From a prac tical perspective the CT scan currently does little to influene therapy of COPD except in individuals considering surgical therapy for their disease (described below) and as screening for lung cancer.

Recent guidelines have suggested testing for AT deficiency in all subjects with COPD or asthma with chronic airflow obstruction. Measurement of the serum AT level is a reasonable initial test. For subjets with low jAT levels the definitive diagnosis of jAT deficiency requires protease inhibitor (PI) type determination. This is typically performed by isoelectric focusing of serum which reflects the genotype at the PI locus for the common alleles and many of the rare PI alleles as well. Moleular genotyping of DNA an be performed for the common PI alleles (M S and Z).

C H R O N I C O BSTR U CT IVE PU lMONARY D I S EASE

STABLE PHASE COPD Only three interventions-smoking cessation oxygen therapy in chronica l ly hypoxemic patients and l ung vol ume reduction surgery in selected patients with emphysema-have been demonstrated

50 mg/dL) . Typical ly Pil ind ividua l s wi l l qua l ify a lthough other ra re types associated with severe deficiency (e.g. nu l l-nu l l ) a re a lso e l ig ib le . Because only a fraction of ind ividua l s with severe AT defi c iency wi l l develop COPD QAT augmentation therapy is not recom mended for severely QAT-deficient persons with normal pu lmonary function and a normal chest CT scan .

NONPHARMACOLOGIC THERAPIES General Medical Care Patients with COPD shou ld receive the infl u enza vacc ine annua l ly. Polyva lent pneumococca l vacc ine is a l so rec ommended a lthough proof of efficacy in th is patient popu lation is not defin itive. 5 im i la r recommendations and l im itations of evidence a lso exist for vacci nation for Bordetella pertussis.

Pulmonary Rehabilitation This refers to a treatment program that i ncorporates education and card iovascu lar condition ing . In COPD pu lmonary rehab i l itation has been demonstrated to improve hea lth-related qua l ity of l ife dyspnea and exercise capacity. It has a lso been shown to reduce rates of hospita l ization over a 6- to 1 2-month period .

1 706 i nha led corticosteroids on mortal ity rates in COPD is controvers ia l . A meta-ana lysis and severa l retrospective stud ies suggest a morta l ity benefit but in a recently publ ished randomized tr ia l d ifferences in morta l ity rate approached but d id not reach conventional criteria for statistica l s ign ificance. A trial of i nha led g lucocorticoids should be considered i n patients with frequent exacerbations defined as two or more per yea r and in patients who demonstrate a sign ificant amount of acute revers ib i l ity in response to inha led bronchodi lators.

Oral Glucocorticoids The chronic use of ora l g l ucocorticoids for treat ment of COPD is not recommended because of an unfavorable benefit/risk ratio. The chronic use of ora l g lucocorticoids is associated with s ign ificant side effects inc lud ing osteoporosis weight ga in cata racts g l ucose i ntolerance and increased r isk of infect ion. A recent study demonstrated that patients tapered off chronic lowdose prednisone (- 1 0 mg/d) d id not experience any adverse effect on the frequency of exacerbations hea lth-related qua l ity of l ife or lung function. On averag patients lost -4.5 kg (- 1 0 Ib) when steroids were withdrawn.

Lung Volume Reduction Surgery (LVRS) Surgery to reduce the volume of lung in patients with emphysema was fi rst i ntroduced with mi nimal success in the 1 950s and was reintroduced in the 1 990s. Patients a re exc luded if they have sign ificant p leura l d isease a pu lmonary a rtery systol i c pressu re >45 mmHg extreme decondit ioning congestive heart fa i l u re or other severe comorbid conditions. Patients with an FEV $ 1 0 b i l l ion annua l ly in the Un ited States. The frequency of exacerbations increases as a i rflow obstruction increases; patients with moderate to severe a i rflow obstruction (GOLD stage 1 1 1 or IV; Table 3 1 4- 1 ) on average have one to th ree episodes per yea r. However some ind ividua l s with very severe a i rflow obstruction do not have frequent exacerbations; the h istory of prior exacerbations is a strong pred ictor of future exacerbations. Recently an e levated ratio of the d iameter of the pu lmonary a rtery to aorta on chest CT has been associated with increased r isk of COPD exacerbations.

The approach to the patient experienc ing a n exacerbation inc l udes an assessment of the severity of the patient's i l l ness both acute and chronic components; an attempt to identify the precipi tant of the exacerbation; and the institution of therapy.

Oxygen Supplementa l O2 is the only pha rmacologic therapy demonstrated to unequ ivoca l ly decrease morta l ity rates i n patients with COPD. For patients with rest ing hypoxemia (rest ing O2 saturation :;;88% or

Patients a re ohen treated in it ia l ly with nebu l ized therapy as such 1 707 treatment is often easier to admin ister in o lder patients or to those i n respiratory d istress. It has been shown however that conversion to metered-dose inha lers is eective when accompan ied by educa-tion and tra in ing of patients and staff. This approach has s ign ificant economic benefits and also a l lows an easier transit ion to outpatient ca re. The add ition of methylxanth ines (such as theophyl l i ne) to this reg imen can be considered a lthough convinc ing proof of its efficacy is lacking. If added serum levels should be mon itored in an attempt to m in im ize toxicity.

Antibiotics Patients with COPD a re frequently colon ized with potentia l respi ratory pathogens and it is ohen d ifficu lt to identiconclusively a specific species of bacteria respons ib le for a pa rticu lar c l i n ica l event. Bacteria frequently imp l icated i n COPD exacerbations inc lude 5treptococcus pneumoniae Haemophilus influenzae and Moraxella catarrhalis. I n add ition Mycoplasma pneumoniae or Chlamydia pneumoniae are found i n 5-1 0% of exacerbations. The choice of ant ib iotic shou ld be based on loca l patterns of antibiotic suscept ib i l ity of the above pathogens as wel l as the patient's c l i n ica l condit ion. Most practit ioners treat patients with moderate or severe exacerbations with ant ibiotics even in the absence of data imp l icating a specific pathogen.

Precipitating Causes and Strategies to Reduce Frequency of Exacerbations A va riety of stimu l i may resu lt in the fi na l common pathway of a i rway i nflammation and increased symptoms that a re cha racteristic of COPD exacerbations. Stud ies suggest that acqu i ring a new stra in of bacteria is associated with increased near-term risk of exacerbation and that bacteria l infection/superinfection is involved in over 50% of exacerbations. Vi ra l respi ratory infections a re present in approxi mately one-th i rd of COPD exacerbations. In a s ign ificant minority of instances (20-35%) no specific precipitant can be identified.

The ro le of pharmacotherapy i n reduc ing exacerbation frequency is less wel l studied. Chronic ora l g lucocorticoids a re not recommended for this pu rpose. I nha led g l ucocorticoids reduce the frequency of exacerbations by 25-30% in most ana lyses. The use of inha led g lucocorticoids should be considered i n patients with fre quent exacerbations or those who have an asthmatic component i.e. s ign ificant revers ib i l ity on pu lmonary function testi ng or marked symptomatic improvement after inha led bronchod i lators. S im i l a r magnitudes of reduction have been reported for anticho l inerg ic and long-acti ng -agonist therapy. The influenza vacc ine has been shown to reduce exacerbation rates in patients with COPD. As outl ined above da i ly azith romycin admin istered to subjects with COPD and an exacerbation h istory reduces exacerbation frequency.

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Glucocorticoids Among patients admitted to the hospita l the use of g l ucocorticoids 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 g l ucocorticoid therapy produced benefit ind istingu ishab le from 8 weeks of therapy. The GOLD gu ide l ines recommend 30-40 mg of ora l predn isolone or its equ iva lent for a period of 1 0- 1 4 days. Hyperg lycemia pa rticu larly i n patients with preexist ing d iagnosis of d iabet is the most frequently reported acute compl i cation of g l ucocorticoid treatment.

Oxygen Supplementa l O2 shou ld be supp l ied to keep a rteria l saturations 90%. Hypoxemic respi ratory d rive plays a sma l l ro le i n patients with COPD. Stud ies have demonstrated that i n patients with both acute and chronic hyperca rbia the admin istration of supplementa l O2 does not reduce m inute venti lat ion. It does in some patients resu lt in modest increases i n a rteria l PC02 ch iefly by a ltering venti lation-perfus ion relationsh ips with in the lung . Th is shou ld not deter practitioners from provid ing the oxygen needed to correct hypoxemia .

Mechanical Ventilatory Support The i n itiation of noninvasive posit ivepressure venti lation (N IPPV) in patients with respiratory fa i l u re defi ned as Paco2 >45 mmHg resu lts in a s ign ificant reduction in morta l ity rate need for intubation compl ications of therapy and hospi ta l length of stay. Contra ind ications to N I PPV include cardiovascu lar instabi l ity impa i red mental status or inab i l ity to cooperate copious secretions or the inab i l ity to c lear secretions cran iofacia l abnorma l ities or trauma prec lud ing effective fitt ing of mask extreme obesity or s ign ificant bu rns.

I nvasive (conventional) mechanical venti lation via an endotracheal tube is ind icated for patients with severe respi ratory d i stress despite i n it ia l therapy l ife-th reaten ing hypoxemia severe hyperca rbia and/or acidosis markedly impa i red mental status respi ratory arrest hemodynamic instab i l ity or other compl ications. The goal of mechanica l venti lation is to correct the aforementioned condi t ions. Factors to consider du ring mechanica l venti latory support inc lude the need to provide sufficient expi ratory t ime in patients with severe a i rflow obstruction and the presence of auto-PEEP (positive end-expi ratory pressu re) which can resu lt in patients having to generate sign ificant respiratory effort to trigger a breath du ring a demand mode of venti lat ion. The morta l ity rate of patients requ i ring mechan ical venti latory support is 1 7-30% for that pa rticu la r hospita l izat ion. For patients age >65 admitted to the intensive ca re un it for treatment the morta l ity rate doubl over the next yea r to 60% regard less of whether mechanica l venti lation was requ i red.

Patient Assessment An attempt should be made to estab l i sh the severity of the exacerbation as wel l as the severity of preexisti ng COPD. The more severe either of these two components the more l i kely that the patient wi l l requ i re hospita l adm ission. The h istory shou ld inc lude quantification of the degree of dyspnea by asking about breath lessness du ring activities of da i ly l iv ing and typical activities for the patient. The patient should be asked about fever; change in cha racter of sputum; any i l l contacts; and associated symptoms such as nausea vomiting d ia rrhea mya lg ias and ch i l l s . I nqu i ring about the frequency and severity of pr ior exacerbations can provide important i nformation.

The physica l exam ination shou ld incorporate an assessment of the degree of d istress of the patient. Specific attention should be focused on tachyca rdia tachypnea use of accessory muscl s lgnsof periora l or peripheral cyanosis the ab i l ity to speak in complete sentences and the patient's mental status. The chest examination should estab l i sh the presence or absence of foca l fi nd ings deg ree of air movement presence or absence of wheezi ng asymmetry i n the chest examination (suggesting l a rge a i rway obstruction or pneumothorax m imicking an exacerbation) and the presence or absence of pa radoxica l motion of the abdomina l wa l l .

Patients with severe underlyi ng COPD who a re in moderate or severe d i stress or those with foca l fi nd ings shou ld have a chest x-ray. Approximately 25% of x-rays in th is c l in ical situation wi l l be abnormal with the most frequent fi nd ings being pneumonia and congestive heart fa i l u re. Patients with advanced COPD those with a h istory of hyperca rbia those with mental status changes (confusion s leepiness) or those i n s ign ificant d istress should have an a rteria l blood-gas measurement. The presence of hyperca rbia defi ned as a Pco2 >45 mmHg has important imp l ications for treatment (discussed below) . I n contrast to its uti l ity i n the management of exacerbations of asthma measu rement of pu lmonary function has not been demonstrated to be he lpfu l in the diagnosis or management of exacerbations of OPD.

There a re no defin itive gu ide l i nes concern ing the need for i npatient treatment of exacerbations. Patients with resp i ratory acidosis and hyperca rbia s ign ificant hypoxemia or severe underlying d isease or those whose l iv ing situation is not conducive to ca refu I observation and the del ivery of prescribed treatment should be admitted to the hospita l .

ACUTE EXACERBATIONS Bronchodilators Typical ly patients a re treated with an i nha led agonist often with the add ition of an antichol i nerg ic agent. These may be admin istered sepa rately or together and the frequency of admin istration depends on the severity of the exacerbation.