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1 700 CF QUALlTY IMPROVEM ENT INCLUDING ASPECTS OF GLOBAL H EALTH

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As a direct result of advances in basic research new therapies have


transformed CF from a disease typically leading to death in early child
hood 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 param
eters. 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 ben
eficial 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 I n itial video seq uences describe establish ment of
the normal perici liary fl uid layer bath ing the su rface a i rway epi
the l i u m with spher presnting chloride and bica rbonate ions

PATHO(i E N ESIS

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 transform
ing growth factor (TGF-) contributes to airway fibrosIS whilil
lack of TGF- may contribute to parenchyma1 inflammat
emphysema. 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 com
prises four interrelated events (Fig. 3 1 4- 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 pul
monary emphysema.
THE ELASTASE:ANTI ELASTASE HYPOTH ESIS

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 mid1 960s 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

secreted through CFTR a n d across the a pical (mucosa l) rspi ratory


su rface. Later video seq uences depict fa i l u re of CFTR a n ion tra n sport
and rsu lting depletion of the peric i l i a ry lay "plasteri ng" of c i l ia
against the m ucosa l su rface and accu m u l ation of m ucus in the a i rway
with resu lting bacteria l i nfection. (Video courtesy of the Cystic Fibrosis

Cigarette smoke

FoundtfOJ

Inflammatory cell recruitment

Chronic Obstructive Pulmonary


Disease
John J. Reilly Jr. Edwin K. Silverman Steven D. Shapiro
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 anatomi
cally 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 condi
tion 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

MMP

Serine
proteinases

Neutrophil

MMP ....
Cysteine ....
proteinases

Macrophage

ltynhibbbit

ECM dadatlon;

Emphysema
FIGURE 314-1

......

Repair

Pathogenesis of emphysema.

U pon long-term expo


sur to clga rtte smoke infl a m matory cI l s a r recru ited to the l u ng;
they release proteinases in excess of i n h i bitors and if repa ir is a bnormal
this 1ads to air space destruction and enlargement or emp hysema
ECM extrace l l u l a r matrix; M M P matrix meta l loproteinase

network of immune and inflammatory cells and additional proteinases


that contribute to emphysema have subsequently been identified.
I N F LAMMATION AND EXTRACELLULAR MATRIX PROTEOLYSIS

Cigarette smoke oxidant-mediated structural cell death


occurs via a variety of mechanisms including rt801 inhibition of mam
malian target of rapamycin (mTOR) leading to cell death as well as
inflammation and proteolysis. Involvement of mTOR and other senes
cence markers has led to the recent concept that emphysema resembles
premature aging of the lung. Uptake 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.
Cell Death

The ability of the adult lung to repair damaged alveoli


appears limited. It is unlikely at the process of septation that is respon
sible 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 appro
priate extracellular matrix particularly functional elastic fibers.
Ineffective Repair

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 AI RWAY

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

1 701

SMALL AI RWAYS

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 sur
factant 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.
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 char
acterized 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 defi
ciency which has a predilection for the lower lobes.
PATHOPHYSI OLOGY

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 ventila
tion and ventilation-perfusion mismatching also occur.
AIRFLOW OBSTRUCTION

Airflow limitation also known as airflow obstruction is typically


determined by spirometry which involves forced expiratory maneu
vers 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 com
mon. 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

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Upon exposure to oxidants from cigarette smoke macrophages and


epithelial cells become activated producing proteinases and chemo
kines that attract other inflammatory and immune cells. One mecha
nism of macrophage activation occurs via oxidant-induced inactiva
tion 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 pro
tein- 10 (IP-lO CXCL-7) which in turn leads to macrophage produc
tion of macrophage elastase (matrix metalloproteinase-12 [MMP- 12]).
Matrix metalloproteinases and serine proteinases most notably neu
trophil 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.

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

volume is readily apparent on the expiratory limb of a flow-rolume


curve. 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.
HYPERI N F LATION

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Lung volumes are also routinely assessed in pulmonary function test


ing. In COPD there is often ir trapping" (increased residual rolume
and increased ratio of residual volume to total lung capacity) and
progressive hyperinflation (increased total lung capacity) late in the
disease. Hyperinflation of the thorax during tidal breathing preserves
maximum expiratory airflow because as lung 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 dia
phragm 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 nor
mally 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 assis
tance from the chest wall recoiling outward toward its resting volume

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
Pao 2 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 Pao 2 at least at rest. An elevation of arterial level of carbon
dioxide (paco ) is not expected until the FEV 1 is <25% of predicted
and even then may not occur. Pulmonary hypertension severe enough
to cause cor pulmonale and right ventricular failure due to COPD typi
cally occurs in individuals who have marked decreases in FEV (<25%
of predicted) and chronic hypoxemia (Pao2 <55 mmHg); however
recent evidence suggests that some patients will develop signicant
pulmonary hypertension independent of COPD severity (Chap. 304) .
Nonuniform ventilation and ventilation-perfusion mismatching
are characteristic of COPD reflecting the heterogeneous nature of the
disease process within the airways and lung parenchyma. Physiologi
studies are consistent with multiple parenchymal compartments having
different rates of ventilation due to regional differences in compliance
and airway resistance. Ventilation-perfusion mismatching accounts for
essentially all of the reduction in Pao2 that occurs in COPD; shunting
is minimal. This finding explains the effectiveness of modest elevations
of inspired oxygen in treating hypoxemia due to COPD and therefore
the need to consider problems other than COPD when hypoxemia is
difficult to correct with modest levels of supplemental 0rgen.
RI SK FACTORS
CI6ARETTE SMOKIN6

By 1 964 the Advisory Committee to the Surgeon General of the


United States had concluded that cigarette smoking was a major
risk factor for mortality from chronic bronchitis and emphysema.
Subsequent longitudinal studies have shown accelerated decline in
FEV 1 in a dose-response relationship to the intensity of garette
smoking which is typically expressed as pack-years (average number
of packs of cigarettes smoked per day multiplied by the total number

o Pack years (945)

1 S D. Mean

nununu
q44l nununu
44l

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20
10
0

40

60 80 100 120
% FEV1

+ 1 S.D.

Median

14

0 160

FI6URE 314-2 Distri butions of forced expi ratory vol u m e i n 1 s


(FEV 1 ) va l ues in a general population sam ple stratified by pack
years of smoking. Mea n s med ians and :t 1 sta ndard deviation of

percent prd icted FEV 1 a re shown for each smoking g roup. Although
a dose-rspons lationship between smoking i ntensity and FEV 1 was
found ma rked va ria bil ity i n p u l lO na ry fu nction was observed among
s u bjects with s i m i l a r smoking histories. (From B Brrows et I: Am Rev
Respir Dis 1 1 5:95 1 977; with permission.)

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 consider
able variability in the response to smoking. Although pack-years of
cigarette smoking is the most highly significant predictor of FEV] (Fig.
3 1 4-2) only 15% of the variability in FEV 1 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 by
products during cigar and pipe smoking.
AI RWAY RESPONSIVEN ESS 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. 309) . However many patients
with COPD also share this feature of airway hyperresponsiveness. The
considerable overlap between persons with asthma and those with
COPD in airway responsiveness airflow obstruction and pulmonary
symptoms led to the formulation of the Dutch hypothesis. This sug
gests that asthma chronic bronchitis and emphysema are variations
of the same basic disease which is modulated by environmental
and genetic factors to produce these pathologically distinct entities.
The alternative British hypothesis contends that asthma and COPD

are fundamentally different diseases: Asthma is viewed as largely an


allergic phenomenon 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.
RESPI RATORY I N F ECTIONS

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 respi
ratory 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.
OCCU PATIONAL EXPOSURES

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 SECO N D-HAND SMOKIN6 EXPOSURE

Exposure of children to maternal smoking results in signicantly


reduced 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 reduc
tions in pulmonary function the importance of this risk factor in the
development of the severe pulmonary function reductions in COPD
remams unertain.
6 E N ETlC CONSIDERATIONS

Although cigarette smoking is the major environmental risk fac


tor 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
<<

Many variants of the protease inhibitor (PI or


SERPINAl ) locus that encodes IAT have been described. The com
mon M allele is associated with normal I AT levels. The S allele associ
ated with slightly reduced AT levels and the Z allele associated with
Antitrypsin Deficiency

Studies of pulmonary function measure


ments performed in general population samples have suggested at
genetic factors other than PI type influence variation in pulmonary
function. Familial aggregation of airflow obstruction within families
of COPD patients has also been demonstrated.
Association studies have compared the distribution of variants in
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 poly
morphism (SNP) of MMP12 (rs2276 109) associated with decreased
MMP 12 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 (FAM1 3A) . 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.
Other 6enetic Risk Factors

NATURAL HISTORY

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 indi
vidual; other environmental factors may have similar effects. Most indi
viduals follow a steady tectory of increasing pulmonary function wi

1 703

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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 FEV 1 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 occu
pational exposures on COPD risk is likely substantially less important
than the effect of cigarette smoking.

markedly reduced IAT levels also occur with frequencies of > 1 % in


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 influ
ence 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 minor
ity 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 nonsmok
ers 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.

1 704

PHYSICAL F I N D I NGS

Early decline

H
nF

100
0
ol
m

o
c

w
LL

75
50

25

......

Respiratory symptoms

10

20

30

40

50

60

70

Rapid decline

80

Age year

FIGURE 314'3
vol u m e in

Hypothetical tracki ng cu rves of forced expi ratory


s (FEV 1 ) for i n d ividuals throughout their l ife spans.

The normal pattern of g rowth and decline with age is shown by


c u rve A. Sig n ifica ntly red uced FEV 1 (<65% of pred icted va l u e at age
20) ca n develop from a normal rate of decl ine after a red uced p u l m o
nary fu nction g rowth phase (cu rve C) rly i n itiation o f p u l monary
fu nction decline after normal g rowth (cu rve B) or accelerated dline
aftr normal g rowth (cu rv 0). (From B Rijcken: Ooctoral dissertatio

1 33 Uiversity of Gronige 1 99 1; with permission.)

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growth during childhood and adolescence followed by a gradual decline


with aging. Individuals appear to track in their quantile of pulmonary
function based on environmentaI and genetic factors that put them on
different tracks. The risk of eventuaI mortality from COPD is closely
associated with reduced levels of FEV!. A graphic depiction of the natu
ral history of COPD is shown as a function of the influences on tracking
curves of FEV 1 in Fig. 314-3. Death 0r disabity from COPD can result
trom a normal rate of decline aftter a reduced growth phase (cue C)
an ea initiation of puIlmonary ftl!I
(curve B) or an accelerated decline after normal growth (curve D). The
rate of decline in pulmonary function can be modified by changing
environmentaI exposures (i quitting smoking) with smoking cessa
tion at an earlier age providing a more beneficial effect than smoking
cessation after marked reductions in pulmonary function have aIready
developed. Genetic factors likely contribute to the level of pulmonary
function achieved during growth and to the rate of decline in response
to smoking and potentially to other environmentaI factors as well.
CU N I CAL PRESENTATION
HISTORY

The three most common snptoms in COPD are cough sputum pro
duction and exertional dyspnea Many patients have such symptoms
for months or years before seeking medicaI attention. Although the
development of airflow obstruction is a gradual process many patients
date the onset of their disease to an acute illness or exacerbation. A
careful history however usually reveals the presence of symptoms
prior to the acute exacerbation The development of exertional dys
pnea often described as increased effort to breathe heaviness air
hunger or gasping can be insidious. It is best eliited by a careful his
tory focused on typial physical activities and how the patient's ability
to perform them has changed Actirities involving significant arm
work particularly at or above shoulder level are particularly difficult
for patients with COPD. Conversely activities that allow the patient
to brae the arms and use accessory muscles of respiration are better
tolerated Examples of such activities include pushing a shopping cart
or walking on a treadmill. As COPD advances the principal feature is
worsening dyspnea on exertion with increasing intrusion on the ability
to perform vocationaI or avocational activities. In the most advanced
stages patients are breathless doing simple activities of daily living
Accompanying worsening airflow obstruction is an increased fre
quency of exacerbations (described below) Patients may also develop
resting hypoxemia and require institution of supplementaI oxygen.

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


physical examination. Current smokers may have signs of active smok
ing 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 of both 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 adi
pose 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 rela
tively 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 I N DI NGS

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 3 1 4- 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 exer
tional hypoxemia. Arterial blood gases provide additional information

GOLD Stage

111

G0lDE(RII T ERm5EvER F
Severity

Spi rometry

Mild
Moderate

F EV/FVC <0.7 and


F EV/FVC <0.7 and
pred icted
F EV/FVC <0.7 and
pred icted
F EV/FVC <0.7 and

Severe

F EV "80% pred icted


F EV "50% but <80%
F EV "30% but <50%

Abbreviations: COPD c h ro n i c obstructive p u l m o n a ry d i sease; GOLD G l o b a l l n itiative for


IV

Very severe

F EV <30% pred icted

Source: From the G l o b a l Strategy for D i a g os i s Maagemet a n d Prevetion of COPD


Lung Disease

20 1 4 iQ G l o b a l l n itiative for C h ro n i c Obstructive L u n g Disease (GOLD) all rig hts reserved


Ava i l a b l e from h ttp//www.goldcopdorg

to i nfluence the natural history of patients with COPD. There is 1 705


cu rrently suggestive but not definitive evidence that the use of
inha led glucocorticoids may a lter morta l ity rate (but not lung fu nction). AII other cu rrent therapies are di rected at im provi ng symptoms and decreasing the freq uency and severity of exacerbations
The institution of these therapies should i nvolve a n assessment of
sym ptoms potentia l risks costs and benefits of thera py. This should
be followed by a n assessment of response to thera py and a decision
should be made whether or not to continue treatment.
PHARMACOTHERAPY
Smoking Cessation (See also Chap. 470)

pr5nti ng emphysematous destruction of the l u ng and mediasti


nal sh ift to the left indicative of hyperinflation.

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 hyper
lucency suggests the presence of emphysema. Increased lung volumes
and flattening of the diaphragm suggest hyperinflation but do not pro
vide information about chronicity of the changes. Computed tomogra
phy (CT) scan is the current definitive test for establishing the presence
or absence of emphysema in living subjects (Fig. 3 1 4-4) . 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 defi
ciency 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 BST R U CT I V E P U l M O N A RY
D I S EA S E
STABLE PHASE COPD

Only three interventions-smoki ng cessation oxygen thera py in


chronica lly hypoxemic patients and l u ng vol ume red uction surgery
in selected patients with em physema-have been demonstrated

Bronchodilators I n general bronchod ilators a re used for sym ptom


atic benefit i n patients with COPD. The inhaled route is preferred for
med ication del ivery beca use the incidence of side effects is lower
than that seen with the use of pa rentera l medication del ivery.
Anticholinergic Agents

Ipratropium brom ide improves sym ptoms


and produces acute improvement in FEV . Tiotropium a long-acti ng
a ntichol i nergic has been shown to improve sym ptoms and red uce
exacerbations. Studies of both ipratropium and tiotropium have
fa iled to demonstrate that either i nfl uences the rate of decline in
FEV . In a large ra ndomized clinical trial there was a trend towa rd
red uced morta l ity rate in the tiotropium-treated patients that
a pproached but did not reach statistica l significa nce. Side effects
a re minor and a trial of inha led anticholinergics is recom mended
in sym ptomatic patients with COPD. Recent retrospective ana lyses
ra ised the possibil ity that anticholinergic use is associated with
i ncreased cardiovascular events i n the COPD popu lation. Th is
was not demonstrated i n a large prospective ra ndom ized tria l of
tiotropium.
Beta Agonists These provide sym ptomatic benefit. The main side
ects are tremor and tachycardia. Long-acting inhaled agonists
such as salmeterol or formoterol have benefits comparable to ipratro
pium bromide. Their use is more convenient than short-acting agents.
The addition of a agonist to inhaled anticholinergic thera py has
been demonstrated to provide incremental benefit. A recent report in
asthma suggests that those patients particularly Africa n Americans
using a long-acting agonist without concomita nt inhaled cortico
steroids have an increased risk of deaths from respiratory causes. The
a pplicability of these data to patients with COPD is unclear.
Inhaled Glucorticoids Althoug h a recent trial demonstrated an
appa rent benefit from the regular use of inhaled glucocorticoids on
the rate of decline of lung fu nction a n u m ber of other wel l-desig ned
ra ndomized trials have not. Patients studied incl uded those with
mild to severe airflow obstruction and current and ex-smokers.
Patients with sig n ificant acute response to i n haled agonists
were excluded from many of these tria ls which may impact the
generaliza bil ity of the fi ndings. Their use has been associated with
increased rates of oropharyngeal ca ndid iasis and an i ncreased rate
of loss of bone density. Available data suggest that i n haled gluco
corticoids reduce exacerbation frequency by -25%. The i m pact of

(28 2H
E Q-v
nCFM
302
z)28

FIGURE 31 4-4 Chest computed tomogra phy scan of a patient


with c h ronic obstructive p u l monary disease who u nderwent a
left sing le-I ung transplant. Note the red uced parenchymal mark
ings i n the right l u ng (left side ofgure) as compa rd to the 1ft l u ng

It has been shown that middle


aged smokers who were able to successfu lly stop smoking experi
enced a sig n ifica nt i m provement in the rate of decl ine in pul monary
fu nction retu rning to annual changes similar to that of nonsmoking
patients. Thus all patients with COPD should be strongly u rged
to q u it smoking and educated a bout the benefits of quitting. An
emerging body of evidence demonstrates that combining phar
macothera py with traditional supportive a pproaches considerably
enha nces the chances of successfu l smoking cessation. There are
three principa l pharmacologic approaches to the problem: bu pro
pion; nicoti ne replacement thera py available as g u m transdermal
patch lozenge inha ler and nasal spray; and va renicli ne a nicotinic
acid receptor agonist/a ntagonist. Cu rrent recommendations from
the u.s. Surgeon Genera l a re that a l l adu lt non preg nant smokers
considering q u itti ng be offered pharmacothera py i n the a bsence of
a ny contraind ication to treatment.

1 706

inhaled corticosteroids on mortal ity rates in COPD is controversial. A


meta-ana lysis and severa l retrospective stud ies suggest a morta l ity
benefit but in a recently publ ished ra ndomized trial d ifferences in
morta lity rate a pproached but did not reach conventional criteria
for statistica l sig n ificance. A trial of inhaled glucocorticoids should
be considered i n patients with freq uent exacerbations defined as
two or more per yea r and in patients who demonstrate a sig nificant
amount of acute reversibil ity in response to inha led bronchodi lators.

50 mg/d L). Typical ly Pil individuals wi l l qual ify although other


ra re types associated with severe deficiency (e.g. n u l l-null) a re a lso
eligi ble. Because only a fraction of individuals with severe AT defi
ciency will develop COPD QAT augmentation thera py is not recom
mended for severely Q AT-deficient persons with normal pulmonary
fu nction and a normal chest CT sca n.

Oral Glucocorticoids

enza vaccine annually. Polyva lent pneumococca l vaccine is also rec


ommended although proof of efficacy in this patient popu lation is
not definitive. 5imilar recommendations and lim itations of evidence
also exist for vacci nation for Bordetella pertussis.

The chronic use of ora l g l ucocorticoids for treat


ment of COPD is not recom mended because of an unfavora ble
benefit/risk ratio. The chronic use of ora l glucocorticoids is associ
ated with significa nt side effects including osteoporosis weight
gain cata racts g l ucose i ntolerance and increased risk of infection.
A recent study demonstrated that patients tapered off chronic low
dose pred nisone (- 1 0 mg/d) did not experience any adverse effect
on the freq uency of exacerbations hea lth-related quality of life or
lung fu nction. On averag patients lost -4.5 kg (- 1 0 I b) when ste
roids were withdrawn.

Theophylline

MOE3 0HYmzg SH
O
M
Z3

Theophyl l i n e produces modest i m p rovements i n


expi ratory flow rates and vita l capacity a n d a slig ht improvement i n
arterial oxygen and carbon d ioxide levels i n patients with moderate
to severe COPD. Na usea is a common side effect; tachyca rdia and
tremor have also been reported. Mon itori ng of blood theophyl line
levels is typica l ly req uired to minimize toxicity. The selective phos
phodiestera 4 (PDE4) inhibitor rofl u m i last has been demonstrated
to reduce exacerbation frequency in COPD patients with chronic
bronchitis and a prior history of exacerbations; its effects on airflow
obstruction and sym ptoms are modest.

Antibiotics

As outli ned below there are strong data impl icati ng


bacterial i nfection as a precipita nt of a su bstantial portion of exacer
bations. Early tria ls of prophylactic or suppressive a nti biotics given
either seasonally or year round fa iled to show a positive i m pact
on exacerbation occu rrence. More recently a random ized cli nical
trial of azithromyci n chosen for both its a nti-inflam matory and
antim icrobia l properties admin istered daily to subjects with a his
tory of exacerbation in the past 6 months demonstrated a red uced
exacerbation freq uency and longer time to first exacerbation i n the
macrolide-treated cohort (hazard ratio 0.73).
Oxygen

Su pplementa l O2 is the only pha rmacologic thera py dem


onstrated to u neq u ivoca l ly decrease morta l ity rates i n patients with
COPD. For patients with resting hypoxemia (resting O2 saturation
:;; 8 8% or <90% with signs of pulmonary hypertension or right heart
fa i l u re) the use of O2 has been demonstrated to have a sign ifica nt
impact on morta l ity rate. Patients meeting these criteria should
be on conti nual oxygen supplementation beca use the morta l ity
benefit is proportional to the n u m ber of hours per day oxygen is
used. Various del ivery systems a re available including portable
systems that patients may ca rry to a l low mobil ity outside the home.
Su pplementa l O2 is commonly prescribed for patients with exer
tional hypoxemia or noctu rnal hypoxemia. Althoug h the rationale
for supplementa l O2 in these settings is physiolog ically sound the
benefits of such thera py a re not wel l su bsta ntiated
Other Agents N-acetyl cysteine has been used in patients with COPD
for both its mucolytic and a ntioxidant properties. A prospective
trial fa iled to fi nd any benefit with respect to decline in l u ng fu nc
tion or prevention of exacerbations. Specific treatment in the form
of IV QAT augmentation thera py is available for individuals with
severe AT deficiency. Despite steril ization proced u res for these
blood-derived prod ucts and the a bsence of reported cases of vira l
infection from therapy some physicia ns recommend hepatitis B
vaccination prior to sta rting augmentation thera py. Although bio
chemica l efficacy of AT augmentation thera py has been shown
a ra ndomized controlled trial of AT augmentation thera py has
not defin itively esta bl ished the efficacy of augmentation thera py in
red ucing decl ine of pulmonary fu nction. Eligibility for AT aug men
tation thera py req uires a serum AT level < 1 1 11M (a pproximately

NON PHARMACOLOG IC THERAPIES


General Medical Care Patients with COPD should receive the infl u

Pulmonary Rehabilitation

This refers to a treatment prog ra m that


i ncorporates ed ucation and card iovascu lar conditioning. In COPD
pu l monary reha bil itation has been demonstrated to i m p rove
hea lth-related qual ity of l ife dyspnea and exercise capacity. It
has also been shown to red uce rates of hospita l ization over a 6- to
1 2-month period .
Lung Volume Reduction Surgery (LVRS) Surgery to red uce the volume
of lung in patients with em physema was fi rst i ntrod uced with mi ni
mal success in the 1 950s and was reintroduced in the 1 990s. Patients
are excluded if they have sig n ifica nt pleura l disease a pulmonary
artery systolic pressu re >45 mm Hg extreme deconditioning con
gestive heart fa i l u re or other severe comorbid conditions. Patients
with an FEV <20% of predicted and either d iffusely distributed
em physema on CT sca n or diusing capacity of lung for carbon
monoxide (DLco) <20% of pred icted have an increased morta l ity rate
after the proced u re and thus are not ca nd idates for LVRS.
The National Em physema Treatment trial demonstrated that
LVRS offers both a morta l ity benefit and a symptomatic benefit
in certai n patients with emphysema. The anatomic distribution of
em physema and post-rehabil itation exercise capacity a re i m porta nt
prog nostic cha racteristics. Patients with upper lobe-predominant
em physema and a low post-rehabil itation exercise capacity are
most likely to benefit from LVRS.
Lung Transplantation (See also Chap. 320e)

COPD is cu rrently the sec


ond leading ind ication for l u ng transpla ntation (Fig. 3 1 4-4). Cu rrent
recommendations are that ca ndidates for lung tra nspla ntation
should have severe disability despite maxi mal medical therapy and
be free of comorbid conditions such as liver renal or ca rd iac dis
ease. I n contrast to LVRS the anatomic d istribution of emphysema
and the presence of pulmonary hypertension are not contraind ica
tions to lung transpla ntation.
EXACERBATIONS OF COPD

Exacerbations are a promi nent featu re of the natural history of


OPD. Exacerbations a re episodes of increased dyspnea and cough
and change in the amount and character of sputu m. They may or
may not be accom panied by other signs of i l l ness including fever
myalg ias and sore th roat. Self-reported hea lth-related qual ity of
life correlates with freq uency of exacerbations more closely than
it does with the degree of a i rflow obstruction. Economic ana lyses
have shown that > 70% of OPD-related health ca re expenditures
go to emergency department visits and hospita l ca re; this translates
to > $ 1 0 billion annually in the U n ited States. The freq uency of exac
erbations increases as a i rflow obstruction increases; patients with
moderate to severe airflow obstruction (GOLD stage or IV; Ta ble
3 1 4-1 ) on average have one to th ree episodes per yea r. However
some individuals with very severe airflow obstruction do not have
frequent exacerbations; the history of prior exacerbations is a strong
pred ictor of future exacerbations. Recently an elevated ratio of the
dia meter of the pulmonary artery to aorta on chest CT has been
associated with increased risk of COPD exacerbations.
The approach to the patient experiencing a n exacerbation
incl udes a n 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 thera py.

111

Precipitating Causes and Strategies to Reduce Frequency of Exacerbations

A va riety of stimuli may result in the fi nal common pathway of air


way i nflam mation and increased sym ptoms that a re cha racteristic of
COPD exacerbations. Stud ies suggest that acquiring a new strain of
bacteria is associated with increased near-term risk of exacerbation
and that bacterial infection/su perinfection 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 significa nt minority of
instances (20-35%) no specific precipitant can be identified.
The role of pharmacothera py i n red ucing exacerbation fre
quency is less wel l studied. Chronic ora l glucocorticoids a re not
recommended for this pu rpose. I n haled g l ucocorticoids red uce the
freq uency of exacerbations by 25-30% i n most analyses. The use of
inhaled glucocorticoids should be considered i n patients with fre
quent exacerbations or those who have an asthmatic component
i.e. significa nt reversibil ity on pulmonary fu nction testi ng or ma rked
sym ptomatic improvement after inha led bronchod ilators. Similar
magnitudes of red uction have been reported for a nticholinerg ic
and long-acti ng -agonist thera py. The influenza vaccine has been
shown to red uce exacerbation rates in patients with COPD. As out
l ined a bove daily azith romycin admin istered to subjects with COPD
and a n exacerbation history red uces exacerbation freq uency.

ACUTE EXACERBATIONS
Bronchodilators Typical ly patients a re treated with an inhaled

agonist often with the add ition of a n a nticholi nergic agent. These
may be admin istered sepa rately or together and the freq uency
of admin istration depends on the severity of the exacerbation.

Antibiotics

Patients with COPD a re freq uently colon ized with


potential respi ratory pathogens and it is ohen d ifficult to identi
conclusively a specific species of bacteria responsible for a pa rticular
clinica l event. Bacteria frequently impl icated i n COPD exacerba
tions include 5treptococcus pneumoniae Haemophilus influenzae
and Moraxella catarrhalis. I n addition Mycoplasma pneumoniae or
Chlamydia pneumoniae are found i n 5-1 0% of exacerbations. The
choice of a ntibiotic should be based on loca l patterns of antibiotic
susceptibil ity of the a bove pathogens as wel l as the patient's clinica l
condition. Most practitioners treat patients with moderate or severe
exacerbations with antibiotics even in the a bsence of data impl icat
ing a specific pathogen.
Glucocorticoids

Among patients admitted to the hospita l the use of


g l ucocorticoids has been demonstrated to red uce the length of stay
hasten recovery and red uce the cha nce of su bseq uent exacerbation
or rela pse for a period of u p to 6 months. One study demonstrated
that 2 weeks of g l ucocorticoid thera py prod uced benefit ind istin
g u ishable from 8 weeks of thera py. The GOLD guidelines recom
mend 30-40 mg of ora l pred n isolone or its equiva lent for a period of
1 0- 1 4 days. Hyperg lycem ia pa rticularly i n patients with preexisting
diag nosis of dia bet is the most freq uently reported acute compli
cation of g l ucocorticoid treatment.
Oxygen

Su pplementa l O2 should be suppl ied to keep a rterial


saturations 90%. Hypoxemic respiratory d rive plays a sma l l role
i n patients with COPD. Studies have demonstrated that i n patients
with both acute and chronic hyperca rbia the administration of
supplementa l O2 does not reduce minute venti lation. It does in
some patients result in modest increases i n a rterial PC02 chiefly by
a ltering venti lation-perfusion relationships with in the lung. This
should not deter practitioners from providing the oxygen needed
to correct hypoxemia.
Mechanical Ventilatory Support

The i n itiation of noni nvasive positive


pressure venti lation (NIPPV) in patients with respiratory fa i l u re
defi ned as Paco2 >45 m m Hg resu lts in a sign ifica nt red uction in mor
ta l ity rate need for intu bation compl ications of thera py and hospi
ta l length of stay. Contraind ications to N I PPV include cardiovascular
insta bil ity impaired mental status or inabil ity to cooperate copious
secretions or the inability to clear secretions craniofacia l a bnorma l i
ties or trauma precluding effective fitting of mask extreme obesity
or significa nt bu rns.
I nvasive (conventional) mechanical venti lation via a n endotra
cheal tube is indicated for patients with severe respi ratory distress
despite initial thera py life-th reatening hypoxem ia severe hyperca r
bia and/or acidosis ma rkedly i m pa i red mental status respi ratory
arrest hemodyna mic instabil ity or other compl ications. The goal
of mechanical venti lation is to correct the aforementioned condi
tions. Factors to consider d u ring mechanical ventilatory su pport
include the need to provide sufficient expi ratory time in patients
with severe airflow obstruction and the presence of auto-PEEP (posi
tive end-expi ratory pressu re) which ca n result in patients having to
generate sig nifica nt respiratory effort to trigger a breath d u ring a
demand mode of ventilation. The morta l ity rate of patients req uir
ing mecha n ical venti latory support is 1 7-30% for that pa rticular
hospita l ization. For patients age >65 admitted to the intensive ca re
unit for treatment the morta l ity rate doubl over the next yea r to
60% regard less of whether mechanical venti lation was req uired.

(28 2H
E Q-v
nCFM
302
z)28

Patient Assessment An attem pt should be made to esta blish 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 wil l req uire hospita l adm ission. The history
should include qua ntification of the deg ree of dyspnea by asking
a bout breath lessness d u ring activities of daily l iving and typical
activities for the patient. The patient should be asked about fever;
change in cha racter of sputum; any ill contacts; and associated
sym ptoms such as nausea vom iting diarrhea myalg ias and chills.
Inquiring a bout the freq uency and severity of prior exacerbations
can provide i m porta nt i nformation.
The physica l exa m ination should incorporate a n assessment of
the degree of distress of the patient. Specific attention should be
focused on tachyca rdia tachypnea use of accessory muscl slgns
of periora l or peri pheral cya nosis the ability to speak in complete
sentences and the patient's mental status. The chest exami nation
should establish the presence or a bsence of foca l fi ndings deg ree of
air movement presence or a bsence of wheezi ng asym metry i n the
chest exa mi nation (suggesting large airway obstruction or pneumo
thorax mimicking an exacerbation) and the presence or a bsence of
pa radoxica l motion of the a bdominal wa l l .
Patients with severe u nderlyi ng COPD w h o a re in moderate or
severe distress or those with foca l fi ndings should have a chest
x-ray. Approximately 25% of x-rays in this clinical situation wi l l be
a bnormal with the most freq uent fi ndings being pneumonia and
congestive heart fa i l u re. Patients with adva nced COPD those with
a history of hyperca rbia those with mental status changes (confu
sion sleepiness) or those i n significa nt distress should have an a rte
ria l blood-gas measurement. The presence of hyperca rbia defi ned
as a Pco2 >45 m m Hg has i m porta nt impl ications for treatment
(discussed below). I n contrast to its util ity i n the management of
exacerbations of asthma measu rement of pulmonary fu nction has
not been demonstrated to be helpfu l in the diag nosis or manage
ment of exacerbations of OPD.
There a re no defi n itive guidelines concerning the need for
i n patient treatment of exacerbations. Patients with respiratory aci
dosis and hyperca rbia sig n ifica nt hypoxem ia or severe underlying
d isease or those whose l iving situation is not conducive to ca refu I
observation and the del ivery of prescribed treatment should be
adm itted to the hospita l .

Patients a re ohen treated initially with nebulized thera py as such 1 707


treatment is often easier to administer in older patients or to those
i n respiratory distress. It has been shown however that conversion
to metered-dose inhalers is eective when accompa n ied by education and training of patients and staff. This a pproach has significa nt
economic benefits and also a l lows a n easier tra nsition to outpatient
ca re. The add ition of methylxa nth ines (such as theophyl line) to
this reg imen can be considered a lthough convi ncing proof of its
efficacy is lacking. If added serum levels should be monitored in an
attempt to minimize toxicity.