455
SECTION 3
RESPIRATORY DISORDERS
27
C HAP T E R
Introduction to Pulmonary
KEY CONCEPTS
 Normal ventilation–perfusion ratio. The function of the lungs
is to maintain PaO2 and PaCO2 within normal ranges. This goal
is accomplished by matching 1 mL mixed venous blood with
• • •
1 mL fresh air ( V/Q = 1). Normally, ventilation (V) is less than
• • •
perfusion (Q ), and V/Q ratio is 0.8.
 The air in the lung is divided into four compartments: tidal vol-
ume—air exhaled during quiet breathing; inspiratory reserve vol-
ume—maximal air inhaled above tidal volume; expiratory reserve
volume—maximum air exhaled below tidal volume; and residual
volume—air remaining in the lung after maximal exhalation. The
sum of all four components is the total lung capacity.
 Obstructive lung disease is defined as an inability to get air out
of the lung. It is identified on spirometry when FEV1/FVC (force
expiratory volume in the first second of expiration/forced vital
capacity [total amount of air that can be exhaled during a
forced exhalation]) is <70% to 75%.
 Reversible airway obstruction is common in asthma and chron-
ic obstructive pulmonary disease. An increase in FEV1 of 12%
(and >0.2 L in adults) after an inhaled β-agonist suggests an
acute bronchodilator response.
 Restrictive lung disease is defined as an inability to get air into
the lung and is best defined as a reduction in total lung capac-
ity. It is suspected when FVC is low and FEV1/FVC is normal.
 Restrictive lung disease can be produced by a number of de-
fects, such as increased elastic recoil (interstitial lung disease),
respiratory muscle weakness (myasthenia gravis), mechanical
restrictions (pleural effusion or kyphoscoliosis), and poor effort.
The primary function of the respiratory system is to maintain nor-
mality of arterial blood gases, that is, arterial pressure of oxygen
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Function Testing
JAY I. PETERS AND STEPHANIE M. LEVINE
(PaO2) and arterial pressure of carbon dioxide (PaCO2). To achieve
this goal, several processes must be accomplished, including alveolar
ventilation, pulmonary perfusion, ventilation–perfusion matching,
and gas transfer across the alveolar–capillary membrane. Alveolar
ventilation is achieved by the cyclic process of air movement in and
out of the lung. During inspiration, the inspiratory muscle contracts
and generates negative pressure in the pleural space. This pressure
gradient between the mouth and the alveoli draws fresh air (tidal
volume) into the lung. Approximately one third of the inspired gas
stays in the conducting airways (dead space), and two thirds reaches
the alveoli.
 The human lung contains a series of branching, progressively
tapering airways that originate at the glottis and terminate in a matrix
of thin-walled alveoli. Coursing through this matrix of alveoli is a rich
network of capillaries that originates from the pulmonary arterioles
and terminates in the pulmonary venules. The adequacy of respiration
in each gas exchange unit depends on the opposition of a thin film of
mixed venous blood with just the right amount of fresh alveolar gas.
During “ideal” gas exchange, blood flow and ventilation are uniform;
accordingly, there is no alveolar–arterial difference (or gradient) in the
partial pressure of oxygen [P(A–a)O2, sometimes called the A–a gradi-
ent]. However, gas exchange is not perfect, even in the normal lung.
Normally, alveolar ventilation is less than pulmonary blood flow, and
the overall ventilation–perfusion ratio is 0.8 (not 1.0).
Normal expiration is a passive process, and when the inspiratory
muscles end their contraction, the elastic recoil of the lung pulls the
lung back to its original size and shape. This process makes the
alveolar pressure positive relative to the pressure at the mouth, and air
flows out of the lung. During inspiration, the respiratory muscles
must overcome the elastic properties of the lung (elastic recoil) and
the resistance to airflow by the airways. During expiration, the flow of
air is determined primarily by the elastic recoil and airway resistance.
Different pulmonary function tests (PFTs) are used to evaluate
the physiologic processes of the respiratory system. Physiologic
abnormalities that can be measured by pulmonary function testing
include obstruction to airflow, restriction of lung size, and decrease
in transfer of gas across the alveolar–capillary membrane. Abnormal
values on PFTs are outside the range of values obtained from a
group of normal individuals matched according to age, height, sex,
and race. A PFT is labeled abnormal when the results fall outside the
range in which 95% of people the same age, height, and sex would
be found (95% confidence interval). This definition is arbitrary and
 456
may misclassify a small percentage of normal individuals as having
lung dysfunction; it also may miss patients with mild pulmonary
SECTION 3
disease. Therefore, clinical correlation and serial pulmonary func-
tion testing may be necessary for optimal interpretation of PFTs.
Potential uses of pulmonary function testing include evaluation
of patients with known or suspected lung disease; evaluation of
symptoms such as chronic cough, dyspnea, or chest tightness;
monitoring of the effects of exposure to dust, chemicals, or pulmo-
nary toxic drugs; risk stratification prior to surgery; monitoring of
the effectiveness of therapeutic interventions; and objective assess-
Respiratory Disorders
ment of impairment or disability.1
DEFINITIONS OF LUNG VOLUMES
AND EXPIRATORY FLOWS
 The air within the lung at the end of a forced inspiration can be
divided into four compartments or lung volumes (Fig. 27–1). The
volume of air exhaled during normal quiet breathing is the tidal
volume (VT). The maximal volume of air inhaled above tidal volume
is the inspiratory reserve volume (IRV), and the maximal air exhaled
below tidal volume is the expiratory reserve volume (ERV). The
residual volume (RV) is the amount of air remaining in the lungs
after a maximal exhalation.
The combinations or sums of two or more lung volumes are
termed capacities (Fig. 27–1). Vital capacity (VC) is the maximal
amount of air that can be exhaled after a maximal inspiration. It is
equal to the sum of IRV, VT, and ERV. When measured on a forced
expiration, it is called the forced vital capacity (FVC). When mea-
sured over an exhalation of at least 30 seconds, it is called the slow
vital capacity (SVC). The VC is approximately 75% of the total lung
capacity (TLC), and when the SVC is within the normal range, a
significant restrictive disorder is unlikely. Normally, the values for
SVC and FVC are very similar unless airway obstruction is present.
TLC is the volume of air in the lung after the maximal inspiration
and is the sum of the four primary lung volumes (IRV, VT, ERV,
and RV). Its measurement is difficult because the amount of air
remaining in the chest after maximal exhalation (RV) must be
measured by indirect methods. The definition of restrictive lung
disease is based on a reduction in TLC (i.e., an inability to get air
into the lung or restriction to air movement on inhalation).
The functional residual capacity (FRC) is the volume of air remaining
in the lungs at the end of a quiet expiration. FRC is the normal resting
position of the lung; it occurs when there is no contraction of either
Maximal inspiratory
level
IRV
IC
VC
TLC
VT
Resting expiratory level
ERV
FRC
Maximal expiratory level
RV RV
FIGURE 27-1. Lung volumes and capacities. (ERV, expiratory reserve
volume; FRC, functional residual capacity; IC, inspiratory capacity; IRV,
inspiratory reserve volume; RV, residual volume; TLC, total lung capacity;
VC, vital capacity; VT, tidal volume.)
inspiratory or expiratory muscles and normally is 40% of TLC. Inspira-
tory capacity (IC) is the maximal volume of air that can be inhaled from
the end of a quiet expiration and is the sum of VT and IRV.
FVC, which represents the total amount of air that can be exhaled,
can be expressed as a series of timed volumes. The forced expiratory
volume in the first second of expiration (FEV1) is the volume of air
exhaled during the first second of the FVC maneuver. Although FEV1
is a volume, it conveys information on obstruction because it is
measured over a known time interval. FEV1 depends on the volume of
air within the lung and the effort during exhalation; therefore, it can be
diminished by a decrease in TLC or by a lack of effort. A more sensitive
way to measure obstruction is to express FEV1 as a ratio of FVC. This
ratio is independent of the patient’s size or TLC; therefore, FEV1/FVC
is a specific measure of airway obstruction with or without restriction.
Normally, this ratio is ≥75%, and any value <70% to 75% suggests
obstruction.
Because flow is defined as the change in volume with time, forced
expiratory flow can be determined graphically by dividing the volume
change by the time change. The forced expiratory flow (FEF) during
25% to 75% of FVC (FEF25%–75%) represents the mean flow during the
middle half of the FVC. FEF25%–75%, formerly called the maximal
midexpiratory flow, is reported frequently in the assessment of small
airways. The 95% confidence limit is so wide that FEF25%–75% has
limited utility in the early diagnosis of small airways disease in an
individual subject. The peak expiratory flow (PEF), also called maxi-
mum forced expiratory flow (FEFmax), is the maximum flow obtained
during FVC. This measurement is used often in the outpatient man-
agement of asthma because it can be measured with inexpensive peak
flowmeters.
All lung volumes and flows are compared to normal values
obtained from healthy subjects. There are significant ethnic and racial
variations in normal values, and all PFTs should report that race/
ethnic adjustment factors have been used. The 2005 American Tho-
racic Society–European Respiratory Society (ATS–ERS) guidelines
for interpretation of PFT results recommend that, for spirometry in
the United States, the National Health and Nutrition Examination
Survey (NHANES) III reference be used for subjects aged 8 to 80 years
and the Wang equation used in subjects younger than 8 years.2
SPIROMETRY/FLOW–VOLUME LOOP
Spirometry is the most widely available and useful PFT. It takes only
15 to 20 minutes, carries no risks, and provides information about
obstructive and restrictive disease. Spirometry allows for measure-
ment of all lung volumes and capacities except RV, FRC, and TLC;
it also allows assessment of FEV 1 and FEF 25%–75% . Spirometry
measurements can be reported in two different formats—standard
spirometry (Fig. 27–2) and the flow–volume loop (Fig. 27–3). In stan-
7
1
6
5
Liters (BPTS)
2
4
3
3
2 4
1
1 2 3 4 5 6
Seconds
FIGURE 27-2. Standard spirometry. Curve 1 is for a normal subject with
normal FEV1; curve 2 is for a patient with mild airways obstruction; curve
3 is for a patient with moderate airways obstruction; curve 4 is for a
patient with severe airways obstruction. (BPTS, body temperature satu-
rated with water vapor.)

FEF50% (Vmax 50)
+5
PEF
Flow (L/s)
0 estimates the total lung volume.
TLC FVC
−5 PIF
0 2
Volume (L)
FIGURE 27-3. Normal flow–volume loop. Flows are measured on the
vertical (y) axis, and lung volumes are measured on the horizontal (x)
axis. Forced vital capacity (FVC) can be read from the tracing as the
•
maximal horizontal deflection. Instantaneous flow ( Vmax ) at any point in
FVC also can be measured directly. (FEF50%, forced expiratory flow at
50% of forced vital capacity; PEF, peak expiratory flow; PIF, peak
inspiratory flow; RV, residual volume; TLC, total lung capacity.)
dard spirometry, the volumes are recorded on the vertical (y) axis and
the time on the horizontal (x) axis. In flow–volume loops, volume is
plotted on the horizontal (x) axis, and flow (derived from volume/
time) is plotted on the vertical (y) axis. The shape of the flow–volume
loop can be helpful in differentiating obstructive and restrictive
defects and in diagnosing upper airway obstruction (Fig. 27–4). This
curve gives a visual representation of obstruction because the expira-
tory descent becomes more concave with worsening obstruction.
LUNG VOLUMES
Spirometry measures three of the four basic lung volumes but cannot
measure RV. RV must be measured to determine TLC. TLC should
be measured anytime VC is reduced. In the setting of chronic
obstructive pulmonary disease (COPD) and a low VC, measurement
of TLC can help to determine the presence of a superimposed
restrictive disorder. The four methods for measuring TLC are helium
dilution, nitrogen washout, body plethysmography, and chest x-ray
A B
Inspiration
+10
+5 RV
Flow (L/s)
TLC
0 0
Expiration
−5
C D
Decreased
flow at high
volumes
0 0
FIGURE 27-4. A. Flow–volume loop depicting mild obstruction charac-
terized by decrease flow at low lung volumes. B. Moderate airflow
obstruction characterized by a more concave curve. C. Variable intratho-
racic obstruction in which peak flow is decreased at higher lung volumes
with normalization of curve at lower lung volumes. D. Restrictive lung
disease with a curve that is decreased in width but with a normal shape.
(RV, residual volume; TLC, total lung capacity.)
457
measurement (planimetry). The first two methods are called dilution
techniques and only measure lung volumes in communication with
CHAPTER 27
•
the upper airway. In patients with airway obstruction who have
trapped air, dilution techniques will underestimate the actual volume
of the lungs. Planimetry measures the circumference of the lungs on
the posteroanterior view and lateral views of a chest x-ray film and
RV
Body plethysmography, or body box, is the most accurate tech-
nique for lung volume determinations. It measures all the air in the
lungs, including trapped air. The principle of the measurement of the
Introduction to Pulmonary Function Testing
body box is Boyle’s gas law (P1V1 = P2V2): A volume of gas in a closed
system varies inversely with the pressure applied to it. The changes in
4 6
alveolar pressure are measured at the mouth, as well as pressure
changes in the body box. The volume of the body box is known. Lung
volumes can be determined measuring the changes in pressures
caused by panting against a closed shutter.2 Measurement of lung
volumes provides useful information about elastic recoil of the lungs.
If elastic recoil is increased (as in interstitial lung disease), lung
volumes (TLC) are reduced. When elastic recoil is reduced (as in
emphysema), lung volumes are increased.
CARBON MONOXIDE DIFFUSING CAPACITY
The diffusing capacity of the lungs (DL) is a measurement of the
ability of a gas to diffuse across the alveolar–capillary membrane.
Carbon monoxide is the usual test gas because normally it is not
present in the lungs and is much more soluble in blood than in lung
tissue. When the diffusing capacity is determined with carbon
monoxide, the test is called the diffusing capacity of lung for carbon
monoxide (DLCO). Because DLCO is directly related to alveolar
volume (VA), it frequently is normalized to the value DL/VA, which
allows for its interpretation in the presence of abnormal lung
volumes (e.g., after surgical lung resection).
The diffusing capacity will be reduced in all clinical situations
where gas transfer from the alveoli to capillary blood is impaired.3
Common conditions that reduce DLCO include lung resection,
emphysema (loss of functioning alveolar–capillary units), and inter-
stitial lung disease (thickening of the alveolar–capillary membrane).
Normal PFTs with reduced DLCO should suggest the possibility of
pulmonary vascular disease (e.g., pulmonary embolus) but also can
be seen with anemia, early interstitial lung disease, and mild Pneu-
mocystis carinii pneumonia (PCP) infection in patients with acquired
immune deficiency syndrome.
Decreased
overall
flows OBSTRUCTIVE LUNG DISEASE
 Obstructive lung disease implies a reduced capacity to get air
through the conducting airways and out of the lungs. This reduction
in airflow may be caused by a decrease in the diameter of the airways
(bronchospasm), a loss of their integrity (bronchomalacia), or a
reduction in elastic recoil (emphysema) with a resulting decrease in
driving pressure. The most common diseases associated with obstruc-
Decreased flow with tive pulmonary functions are asthma, emphysema, and chronic bron-
normal flow–volume
relationship chitis; however, bronchiectasis, infiltration of the bronchial wall by
tumor or granuloma, aspiration of a foreign body, and bronchiolitis
also cause obstructive PFTs. The standard test used to evaluate airway
obstruction is the forced expiratory spirogram.
Standard spirometry and flow–volume loop measurements include
many variables; however, according to ATS guidelines, the diagnosis
of obstructive and restrictive ventilatory defects should be made using
the basic measurements of spirometry.3 A reduction in FEV1 (with
normal FVC) establishes the diagnosis of obstruction. When both
FEV1 and FVC are reduced, FEV1 cannot be used to assess airway
obstruction because such patients may have either obstruction or
restriction. In restrictive lung disease, the patient has an inability to
 458
get air into the lung, which results in a reduction of all expiratory
volumes (FEV1, FVC, and SVC). In obstructed patients, a better
SECTION 3
measurement is the ratio FEV1/FVC. Patients with restrictive lung
disease have reduced FEV1 and use of reduced FVC, but FEV1/FVC
remains normal. Although a normal FEV1/FVC ratio is >70% to 75%,
the ratio is age dependent, and slightly lower values may be normal in
older patients. Younger children have increased lung elastic recoil and
may have higher ratios. Children with asthma often have FEV1/FVC
>90% despite obstructive lung disease. In children, the improvement
in FEV1 after use of an inhaled bronchodilator often is the only way
Respiratory Disorders
to document mild-to-moderate obstructive lung disease. Caution
should be used in interpreting obstruction when FEV1/FVC is below
normal, but FEV1 and FVC both are within the normal range because
this pattern can be seen with healthy, athletic subjects. In screening
spirometry performed in office practice, FEV6 (forced expiratory
volume in 6 seconds) can be used in place of FVC. FEV6 is a more
reproducible number when obtained by less skilled personnel. The
measurement of FEF25%–75% also is abnormal in patients with obstruc-
tive airways disease. In general, this test has so much variability that it
adds little to the measurement of FEV1 and FEV1/FVC. FEF25%–75%
has been of value in monitoring lung transplant patients for graft
rejection,4 and a reduced value may be an early indicator of acute
rejection.
Although there is no standardization for interpretation of severity
of obstruction, most pulmonary laboratories state that FEV1/FVC
<70% of the predicted value is diagnostic for obstruction, and the
degree of obstruction then is based on the percent predicted of FEV1.
FEV1 <60% of the predicted value is moderate obstruction, and
<40% of the predicted value is severe obstruction. In patients with
obstruction, a dose of a bronchodilator (e.g., albuterol or isoproter-
enol) by metered-dose inhaler is given during the initial examina-
tion. An increase in FEV1 of >12% and >0.2 L suggests an acute
bronchodilator response.3 Because bronchodilator responsiveness is
variable over time, the lack of an acute bronchodilator response
should not preclude a 6- to 8-week trial of bronchodilators and/or
corticosteroids.
Although all patients with obstructive lung disease of any etiology
will have reduced flow rates on forced exhalation, the pattern on PFTs
may be helpful in differentiating among the various etiologies (Table
27–1). Asthma is characterized by variable obstruction that often
improves or resolves with appropriate therapy. Because asthma is an
inflammatory disorder of the airways (predominantly large airways),
DLCO is normal. Most patients with acute asthma have a bronchodi-
lator response >15% to 20%; however, this response is also seen in
20% of patients with COPD. These patients are said to have asthmatic
bronchitis. Chronic bronchitis may be limited to the airways, but the
vast majority of patients with chronic bronchitis and airway obstruc-
tion have a mixture of bronchitis and emphysema and have a
reduction in DLCO. Therefore, DLCO is the best PFT for separating
asthma from COPD.
TABLE 27-1 Specific Patterns of Pulmonary Function in Patients
with Chronic Obstructive Pulmonary Disease
COPD
Asthma Chronic Bronchitis
Decreased FEV1 ++++ ++++
Decreased FEV1/FVC ++++ ++++
Increased airway resistance ++++ ++++
Decreased DLCO — —/++a
Response to bronchodilators ++++ +b
DLCO, diffusing capacity of carbon monoxide; FEV1, forced expiratory volume in the first second of
expiration; FVC, forced vital capacity.
a
Most smokers with chronic bronchitis have reduced DLCO.
b
Twenty percent of patients with chronic obstructive pulmonary disease (COPD) have a large (++++)
bronchodilator response.
After the diagnosis of obstructive airways disease is established,
the course and response to therapy are best followed by serial
spirometry. The multicenter Lung Health Study demonstrated an
abnormally rapid decline (90–150 mL/y) in patients with COPD
who continue to smoke.5 Smoking cessation often resulted in an
increase in FEV1 during the first year and a near-normal rate of
decline (30–50 mL/y) in subsequent years.
AIRWAY HYPERREACTIVITY
 Airway hyperreactivity or hyperresponsiveness is defined as an
exaggerated bronchoconstrictor response to physical, chemical, or
pharmacologic stimuli. Individuals with asthma, by definition, have
hyperresponsive airways. The Lung Health Study Group observed
nonspecific hyperresponsiveness in a significant number of patients
with COPD. This group of patients with airway hyperreactivity
appears to have a worse prognosis and an accelerated rate of decline
in FEV1.6
Some patients with asthma (especially cough-variant asthma)
present with no history of wheezing and normal PFTs. The diagno-
sis of asthma still can be established by demonstrating hyperrespon-
siveness to provocative agents. The two agents used most widely in
clinical practice are methacholine and histamine. Other agents used
for bronchial provocation include distilled water, cold air, and
exercise. During a typical bronchoprovocation test, baseline FEV1 is
measured after inhalation of isotonic saline, then increasing doses of
methacholine are given at set intervals. Hyperresponsiveness is
defined as a decline in FEV1 ≥20% and reversibility of obstruction
to bronchodilators. The result can best be expressed as the provoc-
ative concentration needed to cause a 20% fall in FEV1 (PC20). A test
is considered positive if either methacholine or histamine demon-
strates a PC20 for FEV1 ≤8 mg/mL or <60 to 80 cumulative breath
units.7 This test is used most frequently to establish a diagnosis of
asthma in patients with normal PFTs, but it also may be useful in
following patients with occupational asthma, establishing the sever-
ity of asthma, and assessing the response to treatment.
UPPER AIRWAY OBSTRUCTION
Obstruction of airflow by abnormalities in the upper airway often
goes undiagnosed or misdiagnosed because of improper interpreta-
tion of PFTs. Patients have obstructive physiology and often are
misclassified as having asthma or COPD. The shape of the flow–
volume loop, which includes inspiratory and expiratory flow–
volume curves, and the ratio of forced expiratory and inspiratory
flow at 50% of vital capacity (FEF50%/FIF50%) may be useful in the
diagnosis of upper airway obstruction.8
The shape of the flow–volume curve differs depending on whether
the obstruction is fixed or variable (Fig. 27–5). Fixed lesions, as in
strictures from previous intubations or tracheostomy, cause a uniform
caliber of airway during inspiration and expiration. With variable
lesions, the airway caliber changes with changes in intrathoracic pres-
sure. Variable lesions are subclassified into variable intrathoracic and
Emphysema
variable extrathoracic. If the lesion is intrathoracic, as with tumors of
the trachea, the negative pressure generated during inspiration opens
++++ the obstruction, whereas the positive pressure during expiration wors-
++++
ens the obstruction. If the lesion is a variable extrathoracic obstruction,
+
++++
as with vocal cord dysfunction, the negative pressure within the airways
—b will pull the vocal cord toward the midline and potentiate the obstruc-
tion. In this case, there will be a plateau on the inspiratory limb of the
flow–volume loop, and FEF50%/FIF50% will be >1. Typical flow–volume
curves from upper airway obstruction are shown in Fig. 27–4.
Another test used to distinguish upper airway obstruction from
COPD and asthma is FEV1/FEV0.5 (FEV at 0.5 second). This ratio
 459

CHAPTER 27
Expiratory Expiratory Expiratory
flow flow flow

TLC RV RV TLC RV
Inspiratory Inspiratory TLC Inspiratory FIGURE 27-5. Maximum expiratory flow–volume curves
flow flow flow from patients with fixed obstruction, variable extrathoracic
Fixed obstruction Variable extrathoracic Variable intrathoracic obstruction, and variable intrathoracic obstruction. (RV,
obstruction obstruction residual volume; TLC, total lung capacity.)

usually is >1.5 in patients with upper airway obstruction.9 This is so

Introduction to Pulmonary Function Testing

develop a moderately severe restrictive lung disease while maintain-
because FEV0.5 is proportionately more reduced in upper airway ing TLC within the normal range. On flow–volume loop, patients
obstruction because forced expiration measured at 0.5 second better with restrictive disease have normal-shaped curves with a reduction
reflects obstruction at high lung volumes. The abnormality seen on in the height and width of the curve because peak expiratory flow
the flow–volume loop has been referred to as “straightening” of the rate and VC both depend on the amount of air within the lung prior
curve during early expiration. to performance of expiratory maneuvers (Fig. 27–3).
 Restrictive lung function can be produced by increased elastic
recoil of the lung parenchyma (interstitial lung disease), respiratory
RESTRICTIVE LUNG DISEASE muscle weakness, mechanical restrictions (chest wall deformities),
and/or poor effort. Table 27–2 lists common causes of restrictive
 Restrictive lung disease is defined as an inability to get air into the lung disease.
lungs and to maintain normal lung volumes. Restrictive lung disease Restrictive lung function from parenchymal lung disease usually
reduces all the subdivisions of lung volumes (IRV, VT, ERV, and can be differentiated from processes causing mechanical restriction as
RV) without reducing airflow. Patients have normal airway resis- a result of chest bellows malfunction (Table 27–3). Restrictive paren-
tance and FEV1/FVC >75%. chymal diseases are associated with a reduction in alveolar volume
Although restriction could be defined as a reduction in vital and an increase in lung elastic recoil. All lung volumes, as well as
capacity (VC or FVC) with normal FEV1/FVC, poor effort also will DLCO, are reduced. RV/TLC (normal ≤30%) and measurements of
reduce FVC with normal FEV1/FVC. A reduction in TLC is the most maximal inspiratory pressure (normal = –75 cm H2O in males, –50
accurate measurement of restrictive lung function. TLC can be cm H2O in females) remain normal. In addition, patients exhibit mild
measured by various techniques. The gas dilution methods (e.g.,
resting hypoxemia that worsens with exercise. Monitoring gas
helium dilution and nitrogen washout) are unable to measure gas
exchange during exercise may be the most sensitive test for detecting
trapped in cysts or bullae and may underestimate the true lung
progression of interstitial lung disease.10
volume. Therefore, TLC is best measured by plethysmography.
Mechanical restriction caused by chest bellows malfunction may
Most restrictive lung disease is associated with impairment or
result from chest wall or skeletal deformity, loss of neuromuscular
destruction of the alveolar–capillary membrane; therefore, DLCO is
function, fibrosis of the pleural space, and abdominal overdisten-
reduced in most patients with restrictive lung disease. The reduction sion causing upward displacement of the diaphragm, as well as
in DLCO may occur prior to a reduction in lung volumes and is used decreased diaphragm movement. The most common pulmonary
as a marker of early interstitial (restrictive) lung disease. DLCO may function pattern seen in these patients is a decrease in TLC and VC
be abnormal even with a normal chest x-ray film, and thin-cut with only a slight decrease in RV. RV is maintained in these diseases
computed tomographic scans of the chest may be required to because lung compliance remains normal. DLCO is normal or only
diagnose early interstitial lung disease. Because peribronchiolar
minimally reduced, and DLCO/VA (corrected for alveolar volume) is
inflammation and fibrosis occur in patients with restrictive paren-
normal. RV/TLC often is increased in patients with restrictive chest
chymal lung disease, FEF25%–75% may be reduced and fail to respond
bellows disease. Patients with neuromuscular disease have reduced
to bronchodilators. respiratory muscle function with a reduction in maximal inspira-
The severity of restrictive disease has not been standardized; tory pressure.
however, many laboratories classify patients with reduced TLC as
mild (TLC ≤80%), moderate (TLC ≤65%), or severe (TLC ≤50%).
These definitions are completely arbitrary because a patient with PULMONARY GAS EXCHANGE
obstructive lung disease may start with TLC 120% and subsequently
The essential function of the lungs is to maintain blood gas homeo-
stasis. Arterial blood gas measurement plays an important role in
TABLE 27-2 Causes of Restrictive Lung Disease
Interstitial lung diseases Chest wall diseases TABLE 27-3 Patterns of Pulmonary Function
Idiopathic pulmonary fibrosis Kyphoscoliosis Obstructive Restrictive
Sarcoidosis Ankylosing spondylitis Lung Disease Lung Disease
Collagen vascular disease Neuromuscular disease
Pneumoconiosis Miscellaneous causes Parenchymal Chest Bellows
Drug-induced lung disease Obesity Asthma COPD Disease Disease
Pulmonary edema Pregnancy FVC Nl or I Nl or I D D
Infiltrative lung diseases Ascites FEV1 D D D D
Granulomatosis Paralyzed diaphragm FEV1/FVC <75% <75% ≥75% ≥75%
Tumor Lung resection TLC Nl or I Nl or I D D
Pleural diseases RV/TLC Nl or I Nl or I Nl I
Pleural effusion Airway resistance I I Nl Nl
Fibrothorax DLCO Nl D D Nl
Pneumothorax
D, decreased; I, increased; Nl, normal.
 460
the diagnosis and management of patients with pulmonary disease
and should be ordered whenever hypoxemia, hypercapnia (CO2
SECTION 3
retention), and/or acid–base disorders are suspected clinically.
Every time arterial blood gas determinations are ordered, the A–a
gradient (difference between partial pressure of oxygen in the
alveolus and partial pressure of oxygen in arterial blood) should be
calculated. This is accomplished by computer on all automated
blood gas machines, and a normal P(A–a)O2 can be approximated
for sea-level breathing room air by multiplying the age by 0.3. The
presence of hypoxemia with a normal A–a gradient usually implies
Respiratory Disorders
alveolar hypoventilation (e.g., sedative overdose). Most patients
develop hypoxemia secondary to mismatching of ventilation and
perfusion, and P(A–a)O2 will be significantly elevated.
Oxygen saturation as measured by pulse oximetry (SpO2) is
widely used in clinical practice for monitoring arterial saturation. A
pulse oximeter is a small battery-operated device that is placed on
the finger or the earlobe. The device emits and reads the reflected
light from capillary blood, and estimates the saturation. Although
SpO2 is clinically very useful, SpO2 is only an estimate of arterial
saturation. Actual arterial oxygen saturation (SaO2) can be ± 2% to
4% of the oximetric reading. The error may be even greater with
saturation <88%. Pulse oximeters do not measure carboxyhemo-
globin, and SpO2 may be overestimated significantly in patients with
smoke inhalation or in recent smokers. An initial validation of pulse
oximetry with direct measurement of SaO2 is recommended in any
critically ill patient.
EXERCISE TESTING
Cardiopulmonary exercise testing allows for assessment of multiple
organs involved in exercise and has benefits over assessment of
either the cardiac system or pulmonary system alone. The major
indications for exercise testing are dyspnea on exertion, evaluation
of exercise-induced bronchospasm, and suspected arterial desatura-
tion during exercise.11–14 Exercise testing also can be useful in the
evaluation of ventilatory or cardiovascular limitations to work,
assessment of general fitness or conditioning, evaluation of disabil-
ity, establishment of safe levels for exercise, evaluation of drug
therapy, determining the need and liter flow for supplemental
oxygen therapy during exercise, assessment of the effects of a
rehabilitation program, and preoperative assessment before lung
resection.11–14
Tests for general fitness include the 6-minute walking distance
and the Harvard step test.11,13–15 For the 6-minute walking distance,
the subject simply walks a predetermined route or circuit as fast as
possible for 6 minutes. The subject is allowed to stop and rest, but
the clock continues to run. The greater the distance covered, the
better are the patient’s general fitness and exercise tolerance. For the
Harvard step test, the subject steps up and down on a 20-inch step
at a set rate for 5 minutes. A 1-minute rest period is followed by
measurement of the subject’s recovery heart rate. The lower the
recovery heart rate, the better is the subject’s general fitness.
Exercise testing sometimes is performed to determine if exercise
results in arterial oxygen desaturation (SaO2 <90%).12,13 The test
may be useful for quantifying the level of exertion the patient can
perform during the activities of daily living as well as determining
appropriate levels of supplemental oxygen therapy. Typically, this
test is done using a treadmill or cycle ergometer. A baseline mea-
surement of arterial blood gas values or pulse oximetry is followed
by up to 6 minutes of exercise, during which time the patient is
monitored for oxygen desaturation using pulse oximetry. If signifi-
cant desaturation occurs (saturation ≤88%–90%), the test is termi-
nated. In the event of oxygen desaturation, the test can be repeated
to determine the level of supplemental oxygen therapy needed to
compensate for the desaturation that otherwise would occur.
When more formal exercise testing is needed for some of the
indications previously listed (e.g., dyspnea evaluation, evaluation of
ventilatory or cardiovascular limitations to work, evaluation of
disability and preoperative assessment before lung resection), exer-
cise tolerance tests or cardiopulmonary stress testing can be per-
•
formed. Tests include measurement of oxygen consumption (VO2),
• •
carbon dioxide production (V CO2), minute volume (V E), VT,
respiratory rate, SpO2, heart rate, blood pressure, and recording or
•
monitoring of the electrocardiogram. During exercise, VO2 increases
with workload in a linear fashion until a maximum oxygen con-
• •
sumption level (VO2max) is reached. Consequently, VO2max is a
11–13
measure of an individual’s muscular work capacity. Normal
•
VO2max is approximately 1,700 mL/min for a sedentary person and
up to 5,800 mL/min for a trained athelete.13 This compares with a
•
resting VO2 of approximately 250 mL/min. Ventilatory equivalents
for oxygen, carbon dioxide, and O2 pulse are often calculated.
Ventilatory equivalent for oxygen is a measure of the efficiency of
the ventilatory pump at various workloads11,13,14 and is calculated as
follows:
• •
Ventilatory equivalent for O2 = Ve/Vo2.
A normal ventilatory equivalent for oxygen is 20 to 30.11,13
O2 pulse is an estimate of oxygen consumption per cardiac cycle
and can be decreased with cardiac problems. O2 pulse can be
calculated as follows:
•
O2 pulse = (VO2 [in L/min] × 1,000)/Heart rate.
TABLE 27-4 Indications and Contraindications for Exercise Testing
Indications
Dyspnea upon exertion
Exercise-induced bronchospasm
Suspected arterial desaturation with exercise
Evaluation of ventilatory limitations to exercise
Evaluation of cardiac limitations to exercise
Assessment of general fitness or conditioning
Evaluation of cardiopulmonary disability
Establishment of safe levels for exercise
Evaluation of drug therapy
Determining appropriate use of supplemental oxygen therapy
Establishing an exercise prescription for a rehabilitation program
Assessment of the effect of a rehabilitation program
Evaluation of specific disease states or conditions (e.g., asthma, chronic obstructive
pulmonary disease [COPD], interstitial lung disease, pulmonary vascular disor-
ders, coronary artery disease, other vascular disorders, neuromuscular disorders,
obesity, anxiety-induced hyperventilation)
Assessment before resection
Assessment before lung volume reduction surgery or lung transplantation
Contraindications
PaO2 <40 mm Hg on room air
PaCO2 >70 mm Hg
FEV1 <30% of predicted
Recent (within 4 weeks) myocardial infarction
Unstable angina pectoris
Second- or third-degree heart block
Rapid ventricular/atrial arrhythmias
Orthopedic impairment
Severe aortic stenosis
Congestive heart failure
Uncontrolled hypertension
Limiting neurologic disorders
Dissecting/ventricular aneurysms
Severe pulmonary hypertension
Thrombophlebitis or intracardiac thrombi
Recent systemic or pulmonary embolus
Acute pericarditis

TABLE 27-5 Typical Findings during Maximum Exercise with Poor
Conditioning, Pulmonary Limitations to Exercise, and
Cardiac Limitations to Exercise
Poor Pulmonary
Test Parameter Conditioning Limitation
•
VO2max ↓ ↓
SpO2 N ↓
O2 pulse N or ↓ N or ↓
Anaerobic threshold ↓ or N ↓ or N
Ventilatory reservea N ↓
(MVV – VEmax)
a
Ventilatory reserve = Maximum voluntary ventilation (MVV) – Minute volume during maximum
exercise (VEmax).
N, normal.
Adapted from Madama VE. Pulmonary Function Testing and Cardiopulmonary Stress Testing.
Albany, NY: Delmar, 1993.
A normal O2 pulse is 2.5 to 4.0 mL per beat at rest and increases to
10 to 15 mL per beat during strenuous exercise.11,13
The anaerobic threshold is the point during strenuous exercise at
which anaerobic metabolism and lactic acid production begin.11,13,14
• •
VCO2max increases with exercise at about the same rate as VO2 until
the subject’s anaerobic threshold is reached. From that point on, V
•
•
CO2 increases faster than V O2, and this change can be used to
estimate the anaerobic threshold. A breath-by-breath plot of the
ventilatory equivalents for O2 and CO2 also can be used to deter-
mine the anaerobic threshold. Anaerobic threshold is a measure of
fitness in normal subjects, and aerobic training can delay the anaer-
obic threshold.11,13
For exercise tolerance testing, the patient typically is subjected to
either a constant workload (steady-state tests) or an increasing
workload (progressive multistage tests) using a cycle ergometer or
treadmill.11,13 With progressive multistage tests, the patient exer-
cises to exhaustion or the occurrence of an adverse reaction, at
which point the test is stopped. Safety during exercise testing is of
major importance, and rigorous guidelines for termination of the
test should be followed. Both types of tests can be used to determine
• •
VO2max. A limit to exercise, as indicated by a decrease in VO2max,
can result from (1) poor conditioning, (2) pulmonary limitation,
(3) cardiac limitation, or (4) poor effort. In the case of poor
conditioning, SpO2 and O2 pulse will be normal. With a pulmonary
limitation to exercise, SpO2 will be reduced, and O2 pulse will be
normal. With a cardiac limitation to exercise, SpO2 will be normal,
and O2 pulse will be reduced. Table 27–4 summarizes the indica-
tions and contraindications for exercise testing. Table 27–5 sum-
marizes the findings during maximum exercise associated with
poor conditioning, pulmonary limitations to exercise, and cardiac
limitations to exercise.
ABBREVIATIONS
COPD: chronic obstructive pulmonary disease
DL: diffusing capacity of lung
DLCO: diffusing capacity of lung for carbon monoxide
ERV: expiratory reserve volume
FEF: forced expiratory flow
FEF25%–75%: forced expiratory flow during 25% to 75% of forced
vital capacity
FEF50%: forced expiratory flow at 50% of forced vital capacity
FEFmax: maximum forced expiratory flow
FEV0.5: forced expiratory volume at 0.5 second
461
FEV1: forced expiratory volume in first second of expiration
CHAPTER 27
FEV6: forced expiratory volume in 6 seconds
FIF50%: forced inspiratory flow at 50% of forced vital capacity
Cardiac
Limitation FRC: functional residual capacity
↓ FVC: forced vital capacity
N IC: inspiratory capacity
↓
IRV: inspiratory reserve volume
↓
N or ↑ P1V1 = P2V2: Boyle’s gas law
Introduction to Pulmonary Function Testing
P(A–a)O2: alveolar–arterial difference in partial pressure of oxygen
PaCO2: arterial partial pressure of carbon dioxide
PaO2: arterial partial pressure of oxygen
PC20: provocative concentration needed to cause a 20% fall in FEV1
PCP: Pneumocystis carinii pneumonia
PFT: pulmonary function test
PO2: partial pressure of oxygen
RV: residual volume
SaO2: arterial oxygen saturation
SpO2: oxygen saturation as measured by pulse oximetry
SVC: slow vital capacity
TLC: total lung capacity
VA: alveolar volume
VC: vital capacity
VT: tidal volume
REFERENCES
1. Renzessi AA Jr, Bleeker, ER, Eppler, GR, et al. Evaluation of impair-
ment/disability secondary to respiratory disorders. Am Rev Respir Dis
1986;133:1205–1209.
2. Pelligrino R, Viegi G, Brusasco V, et al. Series ATS/ERS Task Force:
Standardization of lung function testing; interpretative strategies for
lung function tests. Eur Respir J 2005;26:319–338.
3. Crapo RO, Hankinson JL, Irvin C, et al. American Thoracic Society
statement: Standardization of spirometry—1994 update. Am J Respir
Crit Care Med 1995;152:1107–1136.
4. Levine SM, Peters JI, Jenkinson SG. Lung transplantation and lung
volume reduction surgery. In: George RB, Light RW, Matthaw MA, eds.
Chest Medicine: Essentials of Pulmonary and Critical Care Medicine,
4th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:208–232.
5. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking
intervention and the use of an inhaled anticholinergic bronchodilator
on the rate of decline of FEV1: The Lung Health Study. JAMA
1994;272:1497–1505.
6. Tashkin DP, Altose MD, Bleeker ER, et al. The Lung Health Study:
Airway responsiveness to inhaled methacholine in smokers with mild
to moderate airflow limitation. Am Rev Respir Dis 1992;145:301–310.
7. Crapo RO, Casaburi R, Coates AL, et al. American Thoracic Society
statement: Guidelines for methacholine and exercise challenge test-
ing—1999. Am J Respir Crit Care Med 2000;161:309–329.
8. Aboussouan LS, Stoller JK. Diagnosis and management of upper
airway obstruction. Clin Chest Med 1994;15:35–53.
9. Bright P, Miller MR, Franklyn JA, et al. The use of a neural network to
detect upper airway obstruction caused by goiter. Am J Respir Crit
Care Med 1998;157:1885–1891.
10. Leith DE, Brown R. ERS/ATS Workshop Series: Human lung volumes
and the mechanisms that set them. Eur Respir J 1999;13:468–472.
11. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles
of Exercise Testing and Interpretation: Including Pathophysiology and
Clinical Applications, 4th ed. Philadelphia: Lippincott Williams &
Wilkins, 2004.
 462
12. Ruppel GE. Manual of Pulmonary Function Testing. St. Louis: Mosby, 14. Weisman IM, Zeballos RJ. Clinical exercise testing. Clin Chest Med
1994. 2001;22:679–701.
SECTION 3

13. ATS/ACCP statement on cardiopulmonary exercise testing. Am J 15. ATS Statement: Guidelines for the six-minute walk test. Am J Respir
Respir Crit Care Med 2003;167:211–277. Crit Care Med 2002;166:111–117.
Respiratory Disorders

C HAP T E R
28
KEY CONCEPTS
 Asthma is a disease of increasing prevalence that is a result of
genetic predisposition and environmental interactions; it is one
of the most common chronic diseases of childhood.
 Asthma is primarily a chronic inflammatory disease of the air-
ways of the lung for which there is no known cure or primary
prevention; the immunohistopathologic features include cell
infiltration by neutrophils, eosinophils, T-helper type 2 lympho-
cytes, mast cells, and epithelial cells.
 Asthma is characterized by either the intermittent or persistent
presence of highly variable degrees of airflow obstruction from
airway wall inflammation and bronchial smooth muscle con-
striction; in some patients, persistent changes in airway struc-
ture occur.
 The inflammatory process in asthma is treated most effectively
with corticosteroids, with the inhaled corticosteroids having the
greatest efficacy and safety profile for long-term management.
 Bronchial smooth muscle constriction is prevented or treated
most effectively with inhaled β2-adrenergic receptor agonists.
 Variability in response to medications requires individualiza-
tion of therapy within existing evidence-based guidelines for
management.
 Ongoing patient education, for a partnership in asthma care, is
essential for optimal patient outcomes and includes trigger
avoidance and self-management techniques.
Asthma has been known since antiquity, yet it is a disease that still
defies precise definition. The word asthma is of Greek origin and
means “panting.” More than 2,000 years ago, Hippocrates used the
word asthma to describe episodic shortness of breath; however, the
first detailed clinical description of the asthmatic patient was made
by Aretaeus in the second century.1 An expert panel of the National
Institutes of Health, the National Asthma Education and Prevention
Program (NAEPP), has provided the following working definition
of asthma2:
Asthma is a chronic inflammatory disorder of the airways in
which many cells and cellular elements play a role: in particular,
Learning objectives, review questions,
and other resources can be found at
www.pharmacotherapyonline.com.
Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
463
Asthma
H. WILLIAM KELLY AND CHRISTINE A. SORKNESS
mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils,
and epithelial cells. In susceptible individuals, this inflammation
causes recurrent episodes of wheezing, breathlessness, chest tight-
ness, and coughing, particularly at night or in the early morning.
These episodes are usually associated with widespread but variable
airflow obstruction that is often reversible either spontaneously or
with treatment. The inflammation also causes an associated increase
in the existing bronchial hyperresponsiveness (BHR) to a variety of
stimuli. Reversibility of airflow limitation may be incomplete in
some patients with asthma.
This definition encompasses the important heterogeneity of the
clinical presentation of asthma by describing the scientific and
clinically accepted characteristics of asthma.
EPIDEMIOLOGY
 An estimated 20.5 million persons in the United States have
asthma (approximately 7% of the population).3 Asthma is the most
common chronic disease among children in the United States, with
approximately 6.5 million children affected. The prevalence of
asthma in the United States and worldwide has continued to
increase. The prevalence rate is highest in children 5–17 years at
9.6%.3 In the United States, as in other Western industrialized
countries, the prevalence of asthma has reached epidemic propor-
tions. Asthma accounts for 1.6% of all ambulatory care visits (13.7
million physician office visits and 1.0 million hospital outpatient
visits) and results in more than 497,000 hospitalizations and 1.8
million emergency department visits per year.3 Although asthma is
the third leading cause of preventable hospitalization in the United
States, hospitalizations for asthma have decreased only slightly over
the past 10 years to 17 per 10,000 population.4 Children younger
than 15 years of age have the highest rate of hospitalization at 31 per
10,000 population. Asthma accounts for more than 10 million
missed school days per year.3 The prevalence of disabling asthma in
children has increased 232% over the past 20 years compared with
a 113% increase from all other chronic conditions in childhood.4 In
young children (0 to 10 years of age), the risk of asthma is greater in
boys than in girls, becomes about equal during puberty, and then is
greater in women than in men.3
Ethnic minorities continue to share the burden of asthma dispro-
portionately. African Americans have a higher prevalence than
whites, but this appears to be a result of urbanization and not race or
socioeconomic status.4 African Americans are three times as likely to
be hospitalized and approximately 2.5 times more likely to die from
asthma.3 In addition, African Americans and Puerto Ricans living in
inner cities are four times more likely to experience emergency
department visits than whites.3 These patterns are likely a result of
poor access to care as Hispanics in general have a lower prevalence
than African Americans or whites.
 464
The estimated direct medical cost of asthma in the United States
in 2004 was $11.5 billion.3 The societal burden of asthma (indirect
SECTION 3
medical expenditures) in the United States was $4.6 billion. Prescrip-
tion drugs were the largest single direct medical expenditure at $5
billion, however, the combined costs of emergency care of acute
asthma exacerbations makes up 36% of direct medical costs.3 Almost
$1.5 billion of indirect costs were a result of school days lost, and lost
productivity secondary to asthma mortality cost $1.7 billion.
The natural history of asthma is still not well defined. Although
asthma can occur at any time, it is principally a pediatric disease,
Respiratory Disorders
with most patients being diagnosed by 5 years of age and up to 50%
of children having symptoms by 2 years of age.2 Between 30% and
70% of children with asthma will improve markedly or become
symptom-free by early adulthood; chronic disease persists in approx-
imately 30% to 40% of patients, and generally 20% or less develop
severe chronic disease.2 Atopic status is the strongest indicator of
persistence into adulthood, although initial severity also predicts
severity as an adult.5 Other predictors of persistent adult asthma
include onset during school age and presence of BHR. Diminished
lung growth may occur in children with uncontrolled severe asthma
but does not appear to occur in children with mild to moderate
asthma.6 Most of the deficits in lung function growth occur in
children whose symptoms begin during the first 3 years of life.6
In adults, most longitudinal studies have suggested a more rapid
rate of decline in lung function in asthmatics than in normal
volunteers, primarily reflected in forced expiratory volume in 1
second (FEV1).5 However, the annual decline in FEV1 is less than in
smokers or in patients with a diagnosis of emphysema. In general,
individuals with less-frequent asthma attacks and normal lung
function on initial assessment have higher remission rates, whereas
smokers have the lowest remission and highest relapse rates.5 The
level of BHR tends to predict the rate of decline in FEV1, with a
greater decline with high levels of BHR.6 Thus airways obstruction
in asthma not only may become irreversible but also may worsen
over time owing to airway remodeling (see below Remodeling of the
Airway section).7 Many elderly patients with asthma have irrevers-
ible airways obstruction.5 However, most patients do not die from
long-term progression of their disease and their life span is not
different from that of the general population.5
Although the prevalence of asthma is increasing in the United
States, measures of significant morbidity (hospital admissions) and
mortality from acute exacerbations of asthma have reached plateaus
and have been slightly decreasing the past few years.3 Asthma results
in a little more than 4,000 deaths per year.3 Despite the relatively low
number of asthma deaths, 80% to 90% are preventable.2,8 Most
deaths from asthma occur outside the hospital, and death is rare
after hospitalization. The most common cause of death from
asthma is inadequate assessment of the severity of airways obstruc-
tion by the patient or physician and inadequate therapy. The most
common cause of death in hospitalized patients is also inadequate
or inappropriate therapy. Thus the key to prevention of death from
asthma, as advocated by the NAEPP, is education.6
ETIOLOGY
 Asthma is at least a partially heritable complex syndrome that
requires a gene-by-environment interaction for phenotypic expres-
sion. Epidemiologic studies strongly support the concept of a
genetic predisposition to the development of asthma, yet the picture
remains complex and incomplete.9 Genetic factors account for 35%
to 70% of the susceptibility. Asthma represents a complex genetic
disorder in that the asthma phenotype is likely a result of polygenic
inheritance or different combinations of genes. Initial searches
focused on establishing links between atopy (genetically determined
state of hypersensitivity to environmental allergens) and asthma,
but more recent genome-wide searches have found linkages with
genes for metalloproteinases (e.g., ADAM33).10,11 Thus, although
genetic predisposition to atopy is a significant risk factor for
developing asthma, not all atopic individuals develop asthma, nor
do all asthmatics exhibit atopy.
 Environmental risk factors for the development of asthma
include socioeconomic status, family size, exposure to secondhand
tobacco smoke in infancy and in utero, allergen exposure, urbaniza-
tion, and decreased exposure to common childhood infectious
agents.12 The “hygiene hypothesis” proposes that genetically suscep-
tible individuals develop allergies and asthma by allowing the
allergic immunologic system (T-helper cell type 2 [TH2]-lympho-
cytes) to develop instead of the immunologic system used to fight
infections (T-helper cell type 1 [TH1]-lymphocytes), and is being
used to explain the increase of asthma in Western countries.6,12 The
first 2 years of life appear to be most important for the exposures to
produce an alteration in the immune response system. Support for
the hygiene hypothesis for asthma comes from studies demonstrat-
ing a lower risk for asthma in children who live on farms and are
exposed to high levels of bacteria, in those with a large number of
siblings, in those with early enrollment into child care, in those with
exposure to cats and dogs early in life, or in those with exposure to
fewer antibiotics.10,12
Risk factors for early (<3 years of age) recurrent wheezing associ-
ated with viral infections include low birth weight, male gender, and
parental smoking. However, this early pattern is a result of smaller
airways, and these risk factors are not necessarily risk factors for
asthma in later life.7 Atopy is the predominant risk factor for children
to have continued asthma.7 Asthma can occur in adults later in life.
Occupational asthma in previously healthy individuals emphasizes
the effect of environment on the development of asthma.13 The
heterogeneity of the asthma phenotype appears most obvious when
listing the diverse triggers of bronchospasm in asthmatic subjects
(Table 28–1).2,6 The various triggers have relative degrees of impor-
tance from patient to patient. This variety should serve as ample
evidence that asthma is likely to be as complex genetically.
Environmental exposures are the most important precipitants of
severe asthma exacerbations (see Table 28–1).2,6 Epidemics of severe
asthma in cities have followed exposures to high concentrations of
aeroallergens.2 Viral respiratory tract infections remain the single
most significant precipitant of severe asthma in children, and are an
important trigger in adults as well.2,6 Other possible factors include
air pollution, sinusitis, food preservatives, and drugs.
TABLE 28-1 List of Agents and Events Triggering Asthma
Respiratory infection
Respiratory syncytial virus (RSV), rhinovirus, influenza, parainfluenza, Myco-
plasma pneumonia
Allergens
Airborne pollens (grass, trees, weeds), house-dust mites, animal danders,
cockroaches, fungal spores
Environment
Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke, wood smoke
Emotions
Anxiety, stress, laughter
Exercise
Particularly in cold, dry climate
Drugs/preservatives
Aspirin, nonsteroidal antiinflammatory drugs (cyclooxygenase inhibitors),
sulfites, benzalkonium chloride, nonselective β-blockers
Occupational stimuli
Bakers (flour dust); farmers (hay mold); spice and enzyme workers; printers
(arabic gum); chemical workers (azo dyes, anthraquinone, ethylenediamine,
toluene diisocyanates, polyvinyl chloride); plastics, rubber, and wood workers
(formaldehyde, western cedar, dimethylethanolamine, anhydrides)

Inflammation Normal bronchus
T lymphocytes
Eosinophils
Lumen
Epithelium
Mucous
plug
Smooth
muscle
Neutrophils
Goblet
cells
Basement
membrane Airway remodeling
FIGURE 28-1. Representative illustration of the pathology found in the
asthmatic bronchus compared with a normal bronchus (upper right).
Each section demonstrates how the lumen is narrowed. Hypertrophy of
the basement membrane, mucus plugging, smooth muscle hypertrophy,
and constriction contribute ( lower section). Inflammatory cells infiltrate,
producing submucosal edema, and epithelial desquamation fills the
airway lumen with cellular debris and exposes the airway smooth muscle
to other mediators (upper left).
PATHOPHYSIOLOGY
 The major characteristics of asthma include a variable degree of
airflow obstruction (related to bronchospasm, edema, and hyperse-
cretion), BHR, and airways inflammation (Fig. 28–1). Evidence of
inflammation arose from the studies of nonspecific BHR, broncho-
alveolar lavage, bronchial biopsies, and induced sputum, as well as
from postmortem observations of patients with asthma who died
from an attack of asthma or from other causes. To understand the
pathogenetic mechanisms that underlie the many variants of
asthma, it is critical to identify factors that initiate, intensify, and
modulate the inflammatory response of the airways and to deter-
mine how these immunologic and biologic processes produce the
characteristic airways abnormalities. Immune responses mediated
by immunoglobulin (Ig) E antibodies are of foremost importance.
ACUTE INFLAMMATION
Inhaled allergen challenge models contribute most to our understand-
ing of acute inflammation in asthma.14 Inhaled allergen challenge in
allergic patients leads to an early phase allergic reaction that, in some
cases, may be followed by a late-phase reaction. The activation of cells
bearing allergen-specific IgE initiates the early phase reaction. It is
characterized primarily by the rapid activation of airway mast cells
and macrophages. The activated cells rapidly release proinflammatory
mediators such as histamine, eicosanoids, and reactive oxygen species
that induce contraction of airway smooth muscle, mucus secretion,
and vasodilation.14 The bronchial microcirculation has an essential
role in this inflammatory process. Inflammatory mediators induce
microvascular leakage with exudation of plasma in the airways.14
Acute plasma protein leakage induces a thickened, engorged, and
edematous airway wall and a consequent narrowing of the airway
lumen. Plasma exudation may compromise epithelial integrity, and
the presence of plasma in the lumen may reduce mucus clearance.14
Plasma proteins also may promote the formation of exudative plugs
mixed with mucus and inflammatory and epithelial cells. Together
these effects contribute to airflow obstruction (see Fig. 28–1).
465
The late-phase inflammatory reaction occurs 6 to 9 hours after
allergen provocation and involves the recruitment and activation of
CHAPTER 28
eosinophils, CD4+ T cells, basophils, neutrophils, and macro-
phages.14 There is selective retention of airway T cells, the expression
of adhesion molecules, and the release of selected proinflammatory
mediators and cytokines involved in the recruitment and activation
of inflammatory cells.14 The activation of T cells after allergen
challenge leads to the release of TH2-like cytokines that may be a key
mechanism of the late-phase response.14 The release of preformed
cytokines by mast cells is the likely initial trigger for the early
Asthma
recruitment of cells. This cell type may recruit and induce the more
persistent involvement by T cells.14 The enhancement of nonspecific
BHR usually can be demonstrated after the late-phase reaction but
not after the early phase reaction following allergen or occupational
challenge.
CHRONIC INFLAMMATION
Airways inflammation has been demonstrated in all forms of asthma,
and an association between the extent of inflammation and the clinical
severity of asthma has been demonstrated in selected studies.7,15 It is
accepted that both central and peripheral airways are inflamed.
In asthma, all cells of the airways are involved and become activated
(Fig. 28–2). Included are eosinophils, T cells, mast cells, macrophages,
epithelial cells, fibroblasts, and bronchial smooth muscle cells. These
cells also regulate airway inflammation and initiate the process of
remodeling by the release of cytokines and growth factors.15
Epithelial Cells
Bronchial epithelial cells traditionally have been considered as a
barrier, participating in mucociliary clearance and removal of nox-
ious agents. However, epithelial cells also participate in inflamma-
tion by the release of eicosanoids, peptidases, matrix proteins,
cytokines, and nitric oxide (NO). Epithelial cells can be activated by
IgE-dependent mechanisms, viruses, pollutants, or histamine. In
asthma, especially fatal asthma, extensive epithelial shedding occurs.
The functional consequences of epithelial shedding may include
heightened airways responsiveness, altered permeability of the air-
way mucosa, depletion of epithelial-derived relaxant factors, and
loss of enzymes responsible for degrading proinflammatory neu-
ropeptides. The integrity of airway epithelium may influence the
sensitivity of the airways to various provocative stimuli. Epithelial
cells also may be important in the regulation of airway remodeling
and fibrosis.15,16
Eosinophils
Eosinophils play an effector role in asthma by release of proinflamma-
tory mediators, cytotoxic mediators, and cytokines.15 Circulating
eosinophils migrate to the airways by cell rolling, through interactions
with selectins, and eventually adhere to the endothelium through the
binding of integrins to adhesion proteins (vascular cell adhesion
molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-
1]). As eosinophils enter the matrix of the membrane, their survival is
prolonged by interleukin (IL)-5 and granulocyte-macrophage col-
ony-stimulating factor (GM-CSF). On activation, eosinophils release
inflammatory mediators such as leukotrienes and granule proteins to
injure airway tissue.15
Lymphocytes
Mucosal biopsy specimens from patients with asthma contain
lymphocytes, many of which express surface markers of inflam-
mation. There are two types of T-helper CD4+ cells. TH1 cells
produce IL-2 and interferon-γ (INF-γ), both essential for cellular
defense mechanisms. TH2 cells produce cytokines (IL-4, -5, and -13)
 466
IAR LAR Chronic asthma
SECTION 3

FEV1 (L)

Minutes Hours Days

Respiratory Disorders

Bronchoconstriction Submucosal edema, Epithelial cell damage,

hyperresponsiveness mucus hypersecretion,
hyperresponsiveness

Histamine, PAF, LTC4, MBP,

PGD2, LTC4, ECP, etc.
LTD4, PAF PAF, LTC4, MBP,
cytokines, etc.
LTB4
PAF

IL-5,
FIGURE 28-2. Diagrammatic presentation Mast cell Neutrophil Macrophage GM-CSF Lymphocyte
of the relationship between inflammatory
cells, lipid and preformed mediators, inflam- Antigen
matory cytokines, and proposed pathogene- Eosinophil Eosinophil
sis and clinical presentation in asthma. See
Antigen-presenting cell IL-3,
text for details. (ECP, eosinophil cationic Monocyte GM-CSF
protein; GM-CSF, granulocyte-macrophage IL-8, etc.
colony-stimulating factor; IAR, immediate IL-4, etc.
IFN-γ, etc.
asthmatic reaction; IFN, interferon; IL, inter-
leukin; LAR, late asthmatic response; LT, Preeosinophil
leukotriene; MBP, major basis protein; PAF, (bone marrow)
Lymphocyte Eosinophilopoesis
platelet-activating factor; PG, prostaglandin.)

that mediate allergic inflammation. It is known that TH1 cytokines
inhibit the production of TH2 cytokines, and vice versa. It is
hypothesized that allergic asthmatic inflammation results from a
TH2-mediated mechanism (an imbalance between TH1 and TH2
cells).15
TH1 and TH2 Cell Imbalance
It has been postulated that the TH1/TH2 imbalance contributes to
the cause and evolution of atopic diseases, including asthma. The
T-cell population in the cord blood of newborn infants is skewed
toward a TH2 phenotype.7,15 The extent of the imbalance between
TH1 and TH2 cells (as indicated by diminished INF-γ production)
during the neonatal phase may predict the subsequent develop-
ment of allergic disease, asthma, or both. It has been suggested that
infants at high risk of asthma and allergies should be exposed to
stimuli that upregulate TH1-mediated responses in order to restore
the balance during a critical time in the development of the
immune system and the lung.7
The basic premise of the hygiene hypothesis is that the new-
born’s immune system is skewed toward TH2 cells and needs timely
and appropriate environmental stimuli to create a balanced
immune response. Factors that enhance TH1-mediated responses
include infection with Mycobacterium tuberculosis, measles virus,
and hepatitis A virus; increased exposure to infections through
contact with older siblings; attendance at day care during the first
6 months of life; and a reduction in the production of INF-γ.
Restoration of the balance between TH1 and TH2 cells may be
impeded by frequent administration of oral antibiotics, with con-
comitant alterations in gastrointestinal flora. Other factors favoring
the TH2 phenotype include Western lifestyle, urban environment,
diet, and sensitization to house-dust mites and cockroaches.
Immune “imprinting” may begin in utero by transplacental trans-
fer of allergens and cytokines.
Mast Cells
Mast cell degranulation is important in the initiation of immediate
responses following exposure to allergens.2 Mast cells are found
throughout the walls of the respiratory tract, and increased num-
bers of these cells (three- to fivefold) have been described in the
airways of asthmatics with an allergic component. Once binding of
allergen to cell-bound IgE occurs, mediators such as histamine;
eosinophil and neutrophil chemotactic factors; leukotrienes (LTs)
C4, D4, and E4; prostaglandins; platelet-activating factor; and others
are released from mast cells (see Fig. 28–2). Histologic examination
has revealed decreased numbers of granulated mast cells in the
airways of patients who have died from acute asthma attacks,
suggesting that mast cell degranulation is a contributing factor in
the progression of the disease. Sensitized mast cells also may be
activated by osmotic stimuli to account for exercise-induced bron-
chospasm (EIB).15
Alveolar Macrophages
The primary function of alveolar macrophages in the normal airway
is to serve as “scavengers,” engulfing and digesting bacteria and
other foreign materials. They are found in large and small airways,
ideally located for affecting the asthmatic response. A number of
mediators produced and released by macrophages have been iden-
tified, including platelet-activating factor, LTB4, LTC4, and LTD4.15
Additionally, alveolar macrophages are able to produce neutrophil
chemotactic factor and eosinophil chemotactic factor, which, in
turn, amplify the inflammatory process.
Neutrophils
The role of neutrophils in the pathogenesis of asthma remains
somewhat unclear because they normally may be present in the
airways and usually do not infiltrate tissues showing chronic allergic