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SECTION 3
RESPIRATORY DISORDERS
27
C HAP T E R
Introduction to Pulmonary
Function Testing
Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
456
may misclassify a small percentage of normal individuals as having inspiratory or expiratory muscles and normally is 40% of TLC. Inspira-
lung dysfunction; it also may miss patients with mild pulmonary tory capacity (IC) is the maximal volume of air that can be inhaled from
SECTION 3
disease. Therefore, clinical correlation and serial pulmonary func- the end of a quiet expiration and is the sum of VT and IRV.
tion testing may be necessary for optimal interpretation of PFTs. FVC, which represents the total amount of air that can be exhaled,
Potential uses of pulmonary function testing include evaluation can be expressed as a series of timed volumes. The forced expiratory
of patients with known or suspected lung disease; evaluation of volume in the first second of expiration (FEV1) is the volume of air
symptoms such as chronic cough, dyspnea, or chest tightness; exhaled during the first second of the FVC maneuver. Although FEV1
monitoring of the effects of exposure to dust, chemicals, or pulmo- is a volume, it conveys information on obstruction because it is
nary toxic drugs; risk stratification prior to surgery; monitoring of measured over a known time interval. FEV1 depends on the volume of
the effectiveness of therapeutic interventions; and objective assess- air within the lung and the effort during exhalation; therefore, it can be
Respiratory Disorders
ment of impairment or disability.1 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
DEFINITIONS OF LUNG VOLUMES is a specific measure of airway obstruction with or without restriction.
AND EXPIRATORY FLOWS Normally, this ratio is ≥75%, and any value <70% to 75% suggests
obstruction.
The air within the lung at the end of a forced inspiration can be Because flow is defined as the change in volume with time, forced
divided into four compartments or lung volumes (Fig. 27–1). The expiratory flow can be determined graphically by dividing the volume
volume of air exhaled during normal quiet breathing is the tidal change by the time change. The forced expiratory flow (FEF) during
volume (VT). The maximal volume of air inhaled above tidal volume 25% to 75% of FVC (FEF25%–75%) represents the mean flow during the
is the inspiratory reserve volume (IRV), and the maximal air exhaled middle half of the FVC. FEF25%–75%, formerly called the maximal
below tidal volume is the expiratory reserve volume (ERV). The midexpiratory flow, is reported frequently in the assessment of small
residual volume (RV) is the amount of air remaining in the lungs airways. The 95% confidence limit is so wide that FEF25%–75% has
after a maximal exhalation. limited utility in the early diagnosis of small airways disease in an
The combinations or sums of two or more lung volumes are individual subject. The peak expiratory flow (PEF), also called maxi-
termed capacities (Fig. 27–1). Vital capacity (VC) is the maximal mum forced expiratory flow (FEFmax), is the maximum flow obtained
amount of air that can be exhaled after a maximal inspiration. It is during FVC. This measurement is used often in the outpatient man-
equal to the sum of IRV, VT, and ERV. When measured on a forced agement of asthma because it can be measured with inexpensive peak
expiration, it is called the forced vital capacity (FVC). When mea- flowmeters.
sured over an exhalation of at least 30 seconds, it is called the slow All lung volumes and flows are compared to normal values
vital capacity (SVC). The VC is approximately 75% of the total lung obtained from healthy subjects. There are significant ethnic and racial
capacity (TLC), and when the SVC is within the normal range, a variations in normal values, and all PFTs should report that race/
significant restrictive disorder is unlikely. Normally, the values for ethnic adjustment factors have been used. The 2005 American Tho-
SVC and FVC are very similar unless airway obstruction is present. racic Society–European Respiratory Society (ATS–ERS) guidelines
TLC is the volume of air in the lung after the maximal inspiration for interpretation of PFT results recommend that, for spirometry in
and is the sum of the four primary lung volumes (IRV, VT, ERV, the United States, the National Health and Nutrition Examination
and RV). Its measurement is difficult because the amount of air Survey (NHANES) III reference be used for subjects aged 8 to 80 years
remaining in the chest after maximal exhalation (RV) must be and the Wang equation used in subjects younger than 8 years.2
measured by indirect methods. The definition of restrictive lung
disease is based on a reduction in TLC (i.e., an inability to get air SPIROMETRY/FLOW–VOLUME LOOP
into the lung or restriction to air movement on inhalation).
The functional residual capacity (FRC) is the volume of air remaining Spirometry is the most widely available and useful PFT. It takes only
in the lungs at the end of a quiet expiration. FRC is the normal resting 15 to 20 minutes, carries no risks, and provides information about
position of the lung; it occurs when there is no contraction of either 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
Maximal inspiratory measurements can be reported in two different formats—standard
level
spirometry (Fig. 27–2) and the flow–volume loop (Fig. 27–3). In stan-
IRV 7
1
IC 6
VC 5
Liters (BPTS)
2
TLC 4
VT 3
3
Resting expiratory level 2 4
ERV
1
FRC
Maximal expiratory level 1 2 3 4 5 6
RV RV Seconds
CHAPTER 27
•
FEF50% (Vmax 50)
the upper airway. In patients with airway obstruction who have
+5 trapped air, dilution techniques will underestimate the actual volume
PEF
Flow (L/s) of the lungs. Planimetry measures the circumference of the lungs on
the posteroanterior view and lateral views of a chest x-ray film and
0 estimates the total lung volume.
TLC FVC RV
Body plethysmography, or body box, is the most accurate tech-
nique for lung volume determinations. It measures all the air in the
−5 PIF
lungs, including trapped air. The principle of the measurement of the
+10 Decreased
overall
+5 RV flows OBSTRUCTIVE LUNG DISEASE
Flow (L/s)
TLC
0 0
Obstructive lung disease implies a reduced capacity to get air
Expiration
−5 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
C D
driving pressure. The most common diseases associated with obstruc-
Decreased Decreased flow with tive pulmonary functions are asthma, emphysema, and chronic bron-
flow at high normal flow–volume
volumes relationship chitis; however, bronchiectasis, infiltration of the bronchial wall by
tumor or granuloma, aspiration of a foreign body, and bronchiolitis
0 0
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
FIGURE 27-4. A. Flow–volume loop depicting mild obstruction charac-
of obstructive and restrictive ventilatory defects should be made using
terized by decrease flow at low lung volumes. B. Moderate airflow
obstruction characterized by a more concave curve. C. Variable intratho- the basic measurements of spirometry.3 A reduction in FEV1 (with
racic obstruction in which peak flow is decreased at higher lung volumes normal FVC) establishes the diagnosis of obstruction. When both
with normalization of curve at lower lung volumes. D. Restrictive lung FEV1 and FVC are reduced, FEV1 cannot be used to assess airway
disease with a curve that is decreased in width but with a normal shape. obstruction because such patients may have either obstruction or
(RV, residual volume; TLC, total lung capacity.) 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 After the diagnosis of obstructive airways disease is established,
volumes (FEV1, FVC, and SVC). In obstructed patients, a better the course and response to therapy are best followed by serial
SECTION 3
measurement is the ratio FEV1/FVC. Patients with restrictive lung spirometry. The multicenter Lung Health Study demonstrated an
disease have reduced FEV1 and use of reduced FVC, but FEV1/FVC abnormally rapid decline (90–150 mL/y) in patients with COPD
remains normal. Although a normal FEV1/FVC ratio is >70% to 75%, who continue to smoke.5 Smoking cessation often resulted in an
the ratio is age dependent, and slightly lower values may be normal in increase in FEV1 during the first year and a near-normal rate of
older patients. Younger children have increased lung elastic recoil and decline (30–50 mL/y) in subsequent years.
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 AIRWAY HYPERREACTIVITY
Respiratory Disorders
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.)
retention), and/or acid–base disorders are suspected clinically. ventilatory or cardiovascular limitations to work, evaluation of
Every time arterial blood gas determinations are ordered, the A–a disability and preoperative assessment before lung resection), exer-
gradient (difference between partial pressure of oxygen in the cise tolerance tests or cardiopulmonary stress testing can be per-
•
alveolus and partial pressure of oxygen in arterial blood) should be formed. Tests include measurement of oxygen consumption (VO2),
• •
calculated. This is accomplished by computer on all automated carbon dioxide production (V CO2), minute volume (V E), VT,
blood gas machines, and a normal P(A–a)O2 can be approximated respiratory rate, SpO2, heart rate, blood pressure, and recording or
•
for sea-level breathing room air by multiplying the age by 0.3. The monitoring of the electrocardiogram. During exercise, VO2 increases
presence of hypoxemia with a normal A–a gradient usually implies with workload in a linear fashion until a maximum oxygen con-
• •
Respiratory Disorders
alveolar hypoventilation (e.g., sedative overdose). Most patients sumption level (VO2max) is reached. Consequently, VO2max is a
11–13
develop hypoxemia secondary to mismatching of ventilation and measure of an individual’s muscular work capacity. Normal
•
perfusion, and P(A–a)O2 will be significantly elevated. VO2max is approximately 1,700 mL/min for a sedentary person and
Oxygen saturation as measured by pulse oximetry (SpO2) is up to 5,800 mL/min for a trained athelete.13 This compares with a
•
widely used in clinical practice for monitoring arterial saturation. A resting VO2 of approximately 250 mL/min. Ventilatory equivalents
pulse oximeter is a small battery-operated device that is placed on for oxygen, carbon dioxide, and O2 pulse are often calculated.
the finger or the earlobe. The device emits and reads the reflected Ventilatory equivalent for oxygen is a measure of the efficiency of
light from capillary blood, and estimates the saturation. Although the ventilatory pump at various workloads11,13,14 and is calculated as
SpO2 is clinically very useful, SpO2 is only an estimate of arterial follows:
saturation. Actual arterial oxygen saturation (SaO2) can be ± 2% to • •
4% of the oximetric reading. The error may be even greater with Ventilatory equivalent for O2 = Ve/Vo2.
saturation <88%. Pulse oximeters do not measure carboxyhemo- A normal ventilatory equivalent for oxygen is 20 to 30.11,13
globin, and SpO2 may be overestimated significantly in patients with O2 pulse is an estimate of oxygen consumption per cardiac cycle
smoke inhalation or in recent smokers. An initial validation of pulse and can be decreased with cardiac problems. O2 pulse can be
oximetry with direct measurement of SaO2 is recommended in any calculated as follows:
critically ill patient.
•
O2 pulse = (VO2 [in L/min] × 1,000)/Heart rate.
EXERCISE TESTING
Cardiopulmonary exercise testing allows for assessment of multiple TABLE 27-4 Indications and Contraindications for Exercise Testing
organs involved in exercise and has benefits over assessment of Indications
either the cardiac system or pulmonary system alone. The major Dyspnea upon exertion
indications for exercise testing are dyspnea on exertion, evaluation Exercise-induced bronchospasm
of exercise-induced bronchospasm, and suspected arterial desatura- Suspected arterial desaturation with exercise
tion during exercise.11–14 Exercise testing also can be useful in the Evaluation of ventilatory limitations to exercise
evaluation of ventilatory or cardiovascular limitations to work, Evaluation of cardiac limitations to exercise
assessment of general fitness or conditioning, evaluation of disabil- Assessment of general fitness or conditioning
ity, establishment of safe levels for exercise, evaluation of drug Evaluation of cardiopulmonary disability
therapy, determining the need and liter flow for supplemental Establishment of safe levels for exercise
oxygen therapy during exercise, assessment of the effects of a Evaluation of drug therapy
Determining appropriate use of supplemental oxygen therapy
rehabilitation program, and preoperative assessment before lung
Establishing an exercise prescription for a rehabilitation program
resection.11–14 Assessment of the effect of a rehabilitation program
Tests for general fitness include the 6-minute walking distance Evaluation of specific disease states or conditions (e.g., asthma, chronic obstructive
and the Harvard step test.11,13–15 For the 6-minute walking distance, pulmonary disease [COPD], interstitial lung disease, pulmonary vascular disor-
the subject simply walks a predetermined route or circuit as fast as ders, coronary artery disease, other vascular disorders, neuromuscular disorders,
possible for 6 minutes. The subject is allowed to stop and rest, but obesity, anxiety-induced hyperventilation)
the clock continues to run. The greater the distance covered, the Assessment before resection
better are the patient’s general fitness and exercise tolerance. For the Assessment before lung volume reduction surgery or lung transplantation
Harvard step test, the subject steps up and down on a 20-inch step Contraindications
at a set rate for 5 minutes. A 1-minute rest period is followed by PaO2 <40 mm Hg on room air
PaCO2 >70 mm Hg
measurement of the subject’s recovery heart rate. The lower the
FEV1 <30% of predicted
recovery heart rate, the better is the subject’s general fitness.
Recent (within 4 weeks) myocardial infarction
Exercise testing sometimes is performed to determine if exercise Unstable angina pectoris
results in arterial oxygen desaturation (SaO2 <90%).12,13 The test Second- or third-degree heart block
may be useful for quantifying the level of exertion the patient can Rapid ventricular/atrial arrhythmias
perform during the activities of daily living as well as determining Orthopedic impairment
appropriate levels of supplemental oxygen therapy. Typically, this Severe aortic stenosis
test is done using a treadmill or cycle ergometer. A baseline mea- Congestive heart failure
surement of arterial blood gas values or pulse oximetry is followed Uncontrolled hypertension
by up to 6 minutes of exercise, during which time the patient is Limiting neurologic disorders
monitored for oxygen desaturation using pulse oximetry. If signifi- Dissecting/ventricular aneurysms
cant desaturation occurs (saturation ≤88%–90%), the test is termi- Severe pulmonary hypertension
Thrombophlebitis or intracardiac thrombi
nated. In the event of oxygen desaturation, the test can be repeated
Recent systemic or pulmonary embolus
to determine the level of supplemental oxygen therapy needed to Acute pericarditis
compensate for the desaturation that otherwise would occur.
461
TABLE 27-5 Typical Findings during Maximum Exercise with Poor FEV1: forced expiratory volume in first second of expiration
CHAPTER 27
Conditioning, Pulmonary Limitations to Exercise, and FEV6: forced expiratory volume in 6 seconds
Cardiac Limitations to Exercise
FIF50%: forced inspiratory flow at 50% of forced vital capacity
Poor Pulmonary Cardiac
Test Parameter Conditioning Limitation Limitation FRC: functional residual capacity
•
VO2max ↓ ↓ ↓ FVC: forced vital capacity
SpO2 N ↓ N IC: inspiratory capacity
O2 pulse N or ↓ N or ↓ ↓
IRV: inspiratory reserve volume
Anaerobic threshold ↓ or N ↓ or N ↓
Ventilatory reservea N ↓ N or ↑ P1V1 = P2V2: Boyle’s gas law
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
463
C HAP T E R
28 Asthma
Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
464
The estimated direct medical cost of asthma in the United States but more recent genome-wide searches have found linkages with
in 2004 was $11.5 billion.3 The societal burden of asthma (indirect genes for metalloproteinases (e.g., ADAM33).10,11 Thus, although
SECTION 3
medical expenditures) in the United States was $4.6 billion. Prescrip- genetic predisposition to atopy is a significant risk factor for
tion drugs were the largest single direct medical expenditure at $5 developing asthma, not all atopic individuals develop asthma, nor
billion, however, the combined costs of emergency care of acute do all asthmatics exhibit atopy.
asthma exacerbations makes up 36% of direct medical costs.3 Almost Environmental risk factors for the development of asthma
$1.5 billion of indirect costs were a result of school days lost, and lost include socioeconomic status, family size, exposure to secondhand
productivity secondary to asthma mortality cost $1.7 billion. tobacco smoke in infancy and in utero, allergen exposure, urbaniza-
The natural history of asthma is still not well defined. Although tion, and decreased exposure to common childhood infectious
asthma can occur at any time, it is principally a pediatric disease, agents.12 The “hygiene hypothesis” proposes that genetically suscep-
Respiratory Disorders
with most patients being diagnosed by 5 years of age and up to 50% tible individuals develop allergies and asthma by allowing the
of children having symptoms by 2 years of age.2 Between 30% and allergic immunologic system (T-helper cell type 2 [TH2]-lympho-
70% of children with asthma will improve markedly or become cytes) to develop instead of the immunologic system used to fight
symptom-free by early adulthood; chronic disease persists in approx- infections (T-helper cell type 1 [TH1]-lymphocytes), and is being
imately 30% to 40% of patients, and generally 20% or less develop used to explain the increase of asthma in Western countries.6,12 The
severe chronic disease.2 Atopic status is the strongest indicator of first 2 years of life appear to be most important for the exposures to
persistence into adulthood, although initial severity also predicts produce an alteration in the immune response system. Support for
severity as an adult.5 Other predictors of persistent adult asthma the hygiene hypothesis for asthma comes from studies demonstrat-
include onset during school age and presence of BHR. Diminished ing a lower risk for asthma in children who live on farms and are
lung growth may occur in children with uncontrolled severe asthma exposed to high levels of bacteria, in those with a large number of
but does not appear to occur in children with mild to moderate siblings, in those with early enrollment into child care, in those with
asthma.6 Most of the deficits in lung function growth occur in exposure to cats and dogs early in life, or in those with exposure to
children whose symptoms begin during the first 3 years of life.6 fewer antibiotics.10,12
In adults, most longitudinal studies have suggested a more rapid Risk factors for early (<3 years of age) recurrent wheezing associ-
rate of decline in lung function in asthmatics than in normal ated with viral infections include low birth weight, male gender, and
volunteers, primarily reflected in forced expiratory volume in 1 parental smoking. However, this early pattern is a result of smaller
second (FEV1).5 However, the annual decline in FEV1 is less than in airways, and these risk factors are not necessarily risk factors for
smokers or in patients with a diagnosis of emphysema. In general, asthma in later life.7 Atopy is the predominant risk factor for children
individuals with less-frequent asthma attacks and normal lung to have continued asthma.7 Asthma can occur in adults later in life.
function on initial assessment have higher remission rates, whereas Occupational asthma in previously healthy individuals emphasizes
smokers have the lowest remission and highest relapse rates.5 The the effect of environment on the development of asthma.13 The
level of BHR tends to predict the rate of decline in FEV1, with a heterogeneity of the asthma phenotype appears most obvious when
greater decline with high levels of BHR.6 Thus airways obstruction listing the diverse triggers of bronchospasm in asthmatic subjects
in asthma not only may become irreversible but also may worsen (Table 28–1).2,6 The various triggers have relative degrees of impor-
over time owing to airway remodeling (see below Remodeling of the tance from patient to patient. This variety should serve as ample
Airway section).7 Many elderly patients with asthma have irrevers- evidence that asthma is likely to be as complex genetically.
ible airways obstruction.5 However, most patients do not die from Environmental exposures are the most important precipitants of
long-term progression of their disease and their life span is not severe asthma exacerbations (see Table 28–1).2,6 Epidemics of severe
different from that of the general population.5 asthma in cities have followed exposures to high concentrations of
Although the prevalence of asthma is increasing in the United aeroallergens.2 Viral respiratory tract infections remain the single
States, measures of significant morbidity (hospital admissions) and most significant precipitant of severe asthma in children, and are an
mortality from acute exacerbations of asthma have reached plateaus important trigger in adults as well.2,6 Other possible factors include
and have been slightly decreasing the past few years.3 Asthma results air pollution, sinusitis, food preservatives, and drugs.
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 TABLE 28-1 List of Agents and Events Triggering Asthma
after hospitalization. The most common cause of death from
Respiratory infection
asthma is inadequate assessment of the severity of airways obstruc-
Respiratory syncytial virus (RSV), rhinovirus, influenza, parainfluenza, Myco-
tion by the patient or physician and inadequate therapy. The most
plasma pneumonia
common cause of death in hospitalized patients is also inadequate Allergens
or inappropriate therapy. Thus the key to prevention of death from Airborne pollens (grass, trees, weeds), house-dust mites, animal danders,
asthma, as advocated by the NAEPP, is education.6 cockroaches, fungal spores
Environment
Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke, wood smoke
ETIOLOGY Emotions
Anxiety, stress, laughter
Asthma is at least a partially heritable complex syndrome that Exercise
requires a gene-by-environment interaction for phenotypic expres- Particularly in cold, dry climate
sion. Epidemiologic studies strongly support the concept of a Drugs/preservatives
genetic predisposition to the development of asthma, yet the picture Aspirin, nonsteroidal antiinflammatory drugs (cyclooxygenase inhibitors),
remains complex and incomplete.9 Genetic factors account for 35% sulfites, benzalkonium chloride, nonselective β-blockers
to 70% of the susceptibility. Asthma represents a complex genetic Occupational stimuli
disorder in that the asthma phenotype is likely a result of polygenic Bakers (flour dust); farmers (hay mold); spice and enzyme workers; printers
(arabic gum); chemical workers (azo dyes, anthraquinone, ethylenediamine,
inheritance or different combinations of genes. Initial searches
toluene diisocyanates, polyvinyl chloride); plastics, rubber, and wood workers
focused on establishing links between atopy (genetically determined
(formaldehyde, western cedar, dimethylethanolamine, anhydrides)
state of hypersensitivity to environmental allergens) and asthma,
465
Inflammation Normal bronchus The late-phase inflammatory reaction occurs 6 to 9 hours after
allergen provocation and involves the recruitment and activation of
CHAPTER 28
T lymphocytes eosinophils, CD4+ T cells, basophils, neutrophils, and macro-
phages.14 There is selective retention of airway T cells, the expression
Eosinophils of adhesion molecules, and the release of selected proinflammatory
mediators and cytokines involved in the recruitment and activation
Lumen
of inflammatory cells.14 The activation of T cells after allergen
Epithelium challenge leads to the release of TH2-like cytokines that may be a key
Mucous
plug 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
Smooth
muscle challenge.
Neutrophils
Goblet
cells
CHRONIC INFLAMMATION
Basement
membrane Airway remodeling Airways inflammation has been demonstrated in all forms of asthma,
and an association between the extent of inflammation and the clinical
FIGURE 28-1. Representative illustration of the pathology found in the
asthmatic bronchus compared with a normal bronchus (upper right). severity of asthma has been demonstrated in selected studies.7,15 It is
Each section demonstrates how the lumen is narrowed. Hypertrophy of accepted that both central and peripheral airways are inflamed.
the basement membrane, mucus plugging, smooth muscle hypertrophy, In asthma, all cells of the airways are involved and become activated
and constriction contribute ( lower section). Inflammatory cells infiltrate, (Fig. 28–2). Included are eosinophils, T cells, mast cells, macrophages,
producing submucosal edema, and epithelial desquamation fills the epithelial cells, fibroblasts, and bronchial smooth muscle cells. These
airway lumen with cellular debris and exposes the airway smooth muscle cells also regulate airway inflammation and initiate the process of
to other mediators (upper left). remodeling by the release of cytokines and growth factors.15
Epithelial Cells
PATHOPHYSIOLOGY
Bronchial epithelial cells traditionally have been considered as a
The major characteristics of asthma include a variable degree of barrier, participating in mucociliary clearance and removal of nox-
airflow obstruction (related to bronchospasm, edema, and hyperse- ious agents. However, epithelial cells also participate in inflamma-
cretion), BHR, and airways inflammation (Fig. 28–1). Evidence of tion by the release of eicosanoids, peptidases, matrix proteins,
inflammation arose from the studies of nonspecific BHR, broncho- cytokines, and nitric oxide (NO). Epithelial cells can be activated by
alveolar lavage, bronchial biopsies, and induced sputum, as well as IgE-dependent mechanisms, viruses, pollutants, or histamine. In
from postmortem observations of patients with asthma who died asthma, especially fatal asthma, extensive epithelial shedding occurs.
from an attack of asthma or from other causes. To understand the The functional consequences of epithelial shedding may include
pathogenetic mechanisms that underlie the many variants of heightened airways responsiveness, altered permeability of the air-
asthma, it is critical to identify factors that initiate, intensify, and way mucosa, depletion of epithelial-derived relaxant factors, and
modulate the inflammatory response of the airways and to deter- loss of enzymes responsible for degrading proinflammatory neu-
mine how these immunologic and biologic processes produce the ropeptides. The integrity of airway epithelium may influence the
characteristic airways abnormalities. Immune responses mediated sensitivity of the airways to various provocative stimuli. Epithelial
by immunoglobulin (Ig) E antibodies are of foremost importance. cells also may be important in the regulation of airway remodeling
and fibrosis.15,16
ACUTE INFLAMMATION
Eosinophils
Inhaled allergen challenge models contribute most to our understand-
Eosinophils play an effector role in asthma by release of proinflamma-
ing of acute inflammation in asthma.14 Inhaled allergen challenge in
tory mediators, cytotoxic mediators, and cytokines.15 Circulating
allergic patients leads to an early phase allergic reaction that, in some
eosinophils migrate to the airways by cell rolling, through interactions
cases, may be followed by a late-phase reaction. The activation of cells
with selectins, and eventually adhere to the endothelium through the
bearing allergen-specific IgE initiates the early phase reaction. It is
binding of integrins to adhesion proteins (vascular cell adhesion
characterized primarily by the rapid activation of airway mast cells
molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-
and macrophages. The activated cells rapidly release proinflammatory
1]). As eosinophils enter the matrix of the membrane, their survival is
mediators such as histamine, eicosanoids, and reactive oxygen species
prolonged by interleukin (IL)-5 and granulocyte-macrophage col-
that induce contraction of airway smooth muscle, mucus secretion,
ony-stimulating factor (GM-CSF). On activation, eosinophils release
and vasodilation.14 The bronchial microcirculation has an essential
inflammatory mediators such as leukotrienes and granule proteins to
role in this inflammatory process. Inflammatory mediators induce
injure airway tissue.15
microvascular leakage with exudation of plasma in the airways.14
Acute plasma protein leakage induces a thickened, engorged, and
Lymphocytes
edematous airway wall and a consequent narrowing of the airway
lumen. Plasma exudation may compromise epithelial integrity, and Mucosal biopsy specimens from patients with asthma contain
the presence of plasma in the lumen may reduce mucus clearance.14 lymphocytes, many of which express surface markers of inflam-
Plasma proteins also may promote the formation of exudative plugs mation. There are two types of T-helper CD4+ cells. TH1 cells
mixed with mucus and inflammatory and epithelial cells. Together produce IL-2 and interferon-γ (INF-γ), both essential for cellular
these effects contribute to airflow obstruction (see Fig. 28–1). defense mechanisms. TH2 cells produce cytokines (IL-4, -5, and -13)
466
IAR LAR Chronic asthma
SECTION 3
FEV1 (L)
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 Mast Cells
inhibit the production of TH2 cytokines, and vice versa. It is
Mast cell degranulation is important in the initiation of immediate
hypothesized that allergic asthmatic inflammation results from a
responses following exposure to allergens.2 Mast cells are found
TH2-mediated mechanism (an imbalance between TH1 and TH2
throughout the walls of the respiratory tract, and increased num-
cells).15
bers of these cells (three- to fivefold) have been described in the
airways of asthmatics with an allergic component. Once binding of
TH1 and TH2 Cell Imbalance allergen to cell-bound IgE occurs, mediators such as histamine;
It has been postulated that the TH1/TH2 imbalance contributes to eosinophil and neutrophil chemotactic factors; leukotrienes (LTs)
the cause and evolution of atopic diseases, including asthma. The C4, D4, and E4; prostaglandins; platelet-activating factor; and others
T-cell population in the cord blood of newborn infants is skewed are released from mast cells (see Fig. 28–2). Histologic examination
toward a TH2 phenotype.7,15 The extent of the imbalance between has revealed decreased numbers of granulated mast cells in the
TH1 and TH2 cells (as indicated by diminished INF-γ production) airways of patients who have died from acute asthma attacks,
during the neonatal phase may predict the subsequent develop- suggesting that mast cell degranulation is a contributing factor in
ment of allergic disease, asthma, or both. It has been suggested that the progression of the disease. Sensitized mast cells also may be
infants at high risk of asthma and allergies should be exposed to activated by osmotic stimuli to account for exercise-induced bron-
stimuli that upregulate TH1-mediated responses in order to restore chospasm (EIB).15
the balance during a critical time in the development of the
immune system and the lung.7 Alveolar Macrophages
The basic premise of the hygiene hypothesis is that the new-
The primary function of alveolar macrophages in the normal airway
born’s immune system is skewed toward TH2 cells and needs timely
is to serve as “scavengers,” engulfing and digesting bacteria and
and appropriate environmental stimuli to create a balanced
other foreign materials. They are found in large and small airways,
immune response. Factors that enhance TH1-mediated responses
ideally located for affecting the asthmatic response. A number of
include infection with Mycobacterium tuberculosis, measles virus,
mediators produced and released by macrophages have been iden-
and hepatitis A virus; increased exposure to infections through
tified, including platelet-activating factor, LTB4, LTC4, and LTD4.15
contact with older siblings; attendance at day care during the first
Additionally, alveolar macrophages are able to produce neutrophil
6 months of life; and a reduction in the production of INF-γ.
chemotactic factor and eosinophil chemotactic factor, which, in
Restoration of the balance between TH1 and TH2 cells may be
turn, amplify the inflammatory process.
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,
Neutrophils
diet, and sensitization to house-dust mites and cockroaches. The role of neutrophils in the pathogenesis of asthma remains
Immune “imprinting” may begin in utero by transplacental trans- somewhat unclear because they normally may be present in the
fer of allergens and cytokines. airways and usually do not infiltrate tissues showing chronic allergic