BRONCHIAL ASTHMA
Asthma
affects between 5% and 15% of the population in most countries where this has
been evaluated. Asthma is a clinical syndrome characterized by variable airflow
obstruction, increased responsiveness of the airway to constriction induced by
nonspecific inhaled stimuli (airway hyperresponsiveness), and cellular inflammation.
Asthmatic symptoms are characteristically epi- sodic and consist of dyspnea,
wheezing, cough, and chest tightness caused by airflow obstruction because of
airway smooth muscle constriction, airway wall edema, airway inflammation, and
hypersecretion by mucous glands. A major feature of the airflow obstruction of
asthma is that it is partially or fully reversible either spontaneously or as a
result of treatment.
Clinical Forms of Bronchial
Asthma
Asthma is a syndrome because, although the clinical
presentation is often quite characteristic, its etiologic factors vary.
Previous descriptors of asthma included the terms extrinsic asthma,
implying that an external stimulus was responsible for causing the disease, and
intrinsic asthma, in which no obvious external cause could be identified.
It is now recognized that likely all asthma is initiated by some external
stimulus, the most commonly identified of which are environmental allergens.
Allergic Asthma
Allergic asthma most often affects children and young
adults (Plate 4-14). A personal history of other allergic manifestations
(atopy), such as allergic rhinitis, conjunctivitis, or eczema is common, as is
a family history of atopy. Atopy is identified by positive dermal responses to
environmental and occupational allergens and elevated serum immunoglobulin E (IgE)
levels.
Nonallergic Asthma
Nonallergic asthma is usually identified in patients
who develop asthma symptoms as adults (see Plate 4-15). The symptoms may
develop after a respiratory tract infection, and occasionally infective agents
such as Chlamydia pneumoniae or Mycoplasma spp. are implicated.
Occupational sensitizers are other important causes of nonallergic asthma, and
a detailed occupational history is a critical component of the evaluation of the
patient. Nonallergic asthma is also commonly associated with comorbidities such
as chronic sinusitis, obesity, or gastroesophageal reflux.
Inducers and Inciters of Asthma
An important distinction needs to be made between
stimuli that are inducers of asthma (cause the disease), such as
environmental allergens and occupational sensitizers, and inciters of asthma,
which are stimuli that cause exacerbations or transient symptoms (see Plate
4-16).
Respiratory Viral Infections
Viral infections are important inducers of asthma and
have been associated with a number of important clinical consequences in people
with asthma, including the development of wheezing-associated illnesses in
infants and small children; the development of asthma in the first decade of
life; causing acute asthma exacerbations (particularly rhinovirus); and inducing
changes in airway physiology, including increasing airway responsiveness.
Environmental Allergens
Allergens are known to both induce asthma and be
inciters of asthma symptoms. Indeed, some people with asthma only experience
seasonal symptoms when they are exposed to allergens. Patients with allergen
sensitivity can experience acute bronchoconstriction within 10 to 15 minutes
after allergen inhalation, which usually resolves with 2 hours (the early
asthmatic response); however, the bronchoconstriction can recur between 3 to 6
hours later (the late asthmatic response), which develops more slowly and is
characterized by severe bronchoconstriction and dyspnea. The late response
occurs because of progressively increasing influx of inflammatory cells, particularly
basophils and eosinophils, into the airways. The bronchoconstriction usually
resolves within 24 hours, but patients are left with increased airway
responsiveness, which may persist for more than 1 week.
Occupational Sensitizing Agents
Occupational asthma is a common cause of adult- onset
asthma. More than 200 agents have been identified in the workplace, including
allergens such as animal dander, wheat flour, psyllium, and enzymes, which cause
airway narrowing through IgE-mediated responses, and chemicals (often small
molecular weight, e.g., toluene diisocyanate), which cause asthma through
non–IgE-mediated mechanisms. Work-related exposures and inhalation accidents
are a significant risk for new-onset asthma. When occupational chemical
sensitizers are inhaled by a sensitized subject in the laboratory, an early
asthmatic response can often be elicited, similar to that induced by allergen.
This can be followed by a late asthmatic response. The airway inflammatory
responses caused by occupational sensitizers do not appear to differ
substantially from other causes of asthma, such as environmental allergens.
Exercise
Exercise is a very commonly experienced asthma
inciter. Bronchoconstriction occurs after exercise, becoming maximal 10 to 20
minutes after the end of exertion, and generally resolves within 1 hour.
Bronchoconstriction very rarely occurs during exercise. Bronchoconstriction is
caused by the cooling and drying of the airways because the large volumes of
air inhaled during exercise are conditioned to body temperature and are fully saturated. Similar
symptoms can be experienced by people with asthma who inhale very cold, dry
air. Exercise-induced bronchoconstriction can usually be prevented by
pretreatment with inhaled β2-agonists 5 to 10 minutes before exercise.
Atmospheric Pollutants
A variety of atmospheric pollutants are asthma
inciters. These include nitrogen dioxide (NO2), sulfur dioxide (SO2),
ozone, and inhaled particles smaller than 10 μm in diameter (PM10). Other environmental
irritants that can incite asthma symptoms include strong smells, such as perfume, car
exhaust fumes, and secondhand tobacco smoke.
Aspirin Sensitivity
A triad of aspirin sensitivity, asthma, and nasal
polyposis (Samter triad) has been recognized in approximately 5% of individuals
with asthma (although nasal polyposis is not invariably present in asthmatics with aspirin sensitivity).
Symptoms of asthma develop within 20 minutes of ingestion of aspirin, which may be very severe and
occasionally life threatening. This sensitivity exists to all drugs that are cyclo-oxygenase (COX-1) inhibitors and
sometimes also to tartrazine. Acetaminophen and COX-2 inhibitors appear to be safe to use in most
aspirin-sensitive individuals with asthma.
Symptoms and Clinical Findings
Symptoms and signs of asthma range from mild, discrete
episodes of shortness of breath, wheezing, and cough, which are very
intermittent, usually after exposure to an asthma trigger, followed by
significant remission, to continuous, chronic symptoms that wax and wane in
severity. For any patient, symptoms may be mild, moderate, or severe at any
given time, and even patients with mild, intermittent asthma can have severe
life-threatening exacerbations. An asthmatic exacerbation can be a terrifying
experience, especially for patients who are aware of its potentially
progressive nature.
Symptoms of an asthmatic exacerbation most often
develop gradually but occasionally can be sudden in onset. Most often asthma
exacerbations are preceded by viral upper respiratory tract infections. Many
patients complain of a sensation of retrosternal chest tightness. Expiratory
and often inspiratory wheezing is audible and is associated with variable
degrees of dyspnea. Cough is likely to be present and may be productive of
purulent sputum.
In severe asthma exacerbations, the patient prefers to
sit upright; visible nasal alar flaring and use of the accessory respiratory
muscles reflect the increased work of breathing. Anxiety and apprehension generally relate
to the intensity of the exacerbation. Tachypnea may be the result of fear,
airway obstruction, or changes in blood and tissue gas tensions or pH.
Hypertension and tachy- cardia both reflect increased catecholamine output,
although a pulse rate greater than 110 to 130 beats/min may indicate significant
hypoxemia (PaO2 <60 mm Hg) and the seriousness of the episode. Pulsus
paradoxus (<10 mm Hg) accompanies pulmonary hyperinflation, occurring when the
forced expiratory volume in 1 second (FEV1) is usually below 30% of predicted
normal. If severe hypoxemia and hypercapnia with respiratory acidosis occur,
the patient is usually cyanotic, fatigued, confused, and agitated. Chest
examination reveals a hyperresonant percussion note, a low-lying diaphragm, and
other evidence of hyperinflation. Expiration is prolonged. The patient has
generalized inspiratory and expiratory wheezing. With low-grade obstruction,
wheezing may be slight or even absent but may be accentuated by rapid, deep breathing. When airflow is
severely reduced, the chest may become paradoxically silent. This
ominous finding may be inadvertently induced or worsened by administration of hypnotics,
tranquilizers, or sedatives, which depress respiration. At the point where airflow is so
decreased that the chest becomes silent, cough becomes ineffective, and ventilatory
failure supervenes. This requires immediate and intensive therapy.
DIAGNOSIS OF ASTHMA
Because asthma is a lifelong disease in most patients,
it is important to
make the correct diagnosis when symptoms first present. Unfortunately, this is sometimes not done, and patients
are inappropriately treated. None of the symptoms of asthma are pathognomonic, and the adage “all that
wheezes is not asthma” serves as a reminder that wheezing but also cough, chest
tightness, and dyspnea are symptoms of other respiratory or cardiac diseases.
The diagnosis of asthma must be made by the presence of the characteristic symptoms
associated with the presence of variable airflow obstruction or airway
hyperresponsiveness to inhaled bronchoconstrictor mediators.
Variable airflow obstruction is best measured using
spirometry with a flow-volume loop and demonstrating a reduced FEV1 and ratio of
FEV1 to forced vital capacity (FVC), which improves after inhalation of β2-agonists (Plate 4-17). An improvement in FEV1 of more than 12%, with a minimal
change of 200 mL, is usually accepted as documentation of reversible airflow
obstruction. Some clinics may not have access to spirometry, so variability in
peak expired flow (PEF) measurements can also be used for both diagnosis and
monitoring asthma. An improvement of more than 20% (or <60 L/min)
after inhalation of a β2-agonist or diurnal variation in PEF of more than 20%
over 2 weeks of measurements also confirms variable airflow obstruction.
AIRWAY HYPERRESPONSIVENESS
For patients with symptoms consistent with asthma but normal lung
function, measurements of airway responsiveness to direct airway challenges (e.g.,
inhaled methacholine and
histamine) or indirect airway challenges (e.g., inhaled mannitol or exercise challenge) may help establish
a diagnosis of asthma (Plate 4-17). Measurements of airway responsiveness reflect the “sensitivity” of
the airways to factors that can cause asthma symptoms, and the test results are usually expressed as the
provocative concentration (or dose) of the agonist causing a given decrease in FEV1. These tests are
sensitive for a diagnosis of asthma but have limited specificity. This means that a negative test
result can be useful to
exclude a diagnosis of persistent asthma in a patient who is not taking inhaled
glucocorticosteroid treatment, but a positive test result does not always mean that a
patient has asthma. This is because airway hyperresponsiveness has been described in patients
with allergic rhinitis
and in those with airflow limitation caused by conditions other than asthma, such as cystic fibrosis,
bronchiectasis, and chronic obstructive pulmonary disease (COPD).
Radiography
The primary value of radiography is to exclude other
diseases and to determine whether pneumonia, atelectasis, pneumothorax,
pneumomediastinum, or bronchiectasis exists. In mild asthma, the chest
radiograph shows no abnormalities. With severe obstruction, however, a
characteristic reversible hyperlucency of the lung is evident, with widening of
costal interspaces, depressed diaphragms, and increased retrosternal air. In
contrast to pulmonary emphysema, in which vascular branching is attenuated and
distorted, vascular caliber and distribution in asthma are generally
undisturbed.
Focal atelectasis, a complication of asthma, is caused
by impaction of mucus. In children, even complete collapse of a lobe may be
observed. Atelectatic shadows may be transient as mucus impaction shifts from
one lung zone to another. When sputum is mobilized, these patterns resolve.
Radiography is also useful in evaluating coexisting
sinusitis. An upper gastrointestinal series may be indicated if
gastroesophageal reflux is suspected. A lung ventilation-perfusion scan or
computed tomography angiogram may be required if pulmonary emboli are believed to mimic
asthma.
Sputum
Spontaneously produced as well as induced sputum can
be helpful in confirming the diagnosis of asthma and in deciding treatment
requirements (Plate 4-18). Spontaneously produced sputum may be mucoid,
purulent, or a mixture of both. Importantly, purulent sputum does not always
indicate the presence of a bacterial infection in asthmatic patients.
Thin spiral bronchiolar casts (Curschmann spirals) in
sputum, measuring up to several centimeters in length, are strongly indicative
of asthma. Ciliated columnar bronchial epithelial cells are frequently found.
Creola bodies are clumps of such bronchial epithelial cells with moving cilia
and are seen in severe asthma.
In asthma, both sputum eosinophils and neutrophils may
be increased or the cellular infiltrate may be pre-dominantly eosinophilic or
neutrophilic or occasionally paucigranulocytic. The importance of a sputum
eosinophilia is that it indicates inadequate treatment with or poor adherence
to inhaled corticosteroids (ICS). Acute exacerbations of asthma are usually
associated with an increase in eosinophil or neutrophil cell numbers in sputum.
Skin Prick Tests
It is important to establish the presence of atopy in
asthmatic subjects, particularly, whether environmental allergens are
important triggers of asthma symptoms.
Preferably,
skin tests are performed by a skin prick using aqueous extracts of common antigens,
such as molds, pollens, fungi, house dusts, feathers, foods, or animal dander
technique (Plate 4-19). If skin-sensitizing antibodies to the antigen are
present, a wheal-and-flare reaction develops within 15 to 30 minutes; a control
test with saline diluent should show little or no reaction.
Optimally, both the history and dermal reactivity will
give corresponding results. However, some patients have positive histories but
negative skin test results. In other patients, negative histories and positive skin
test results indicate immunologic reactivity that is clinically insignificant.
Blood Tests
Blood tests are rarely of value in the diagnosis of
asthma, but radioallergosorbent tests (RASTs) are used to identify the presence
of allergy to specific allergens. Also, blood eosinophil counts may be increased
in asthmatic patients, but they are neither sensitive nor specific for a
diagnosis.
Exhaled Nitric Oxide
Elevated levels of exhaled nitric oxide (eNO) may
indicate eosinophilic inflammation associated with asthma in the right clinical
setting, but the clinical utility of this test is still uncertain.
Differential Diagnosis
Diseases to be considered in the differential
evaluation are depicted in Plate 4-20. In children, diseases that may be misdiagnosed
as asthma also include chronic rhinosinusitis, gastroesophageal reflux, cystic
fibrosis, bronchopulmonary dysplasia, congenital mal-formation causing narrowing
of the intrathoracic airways, foreign body aspiration, primary ciliary
dyskinesia syndrome, immune deficiency, and congenital heart disease. In adult
patients, pulmonary disorders, other than those illustrated in Plate 4-20,
include cystic fibrosis, pneumoconiosis, and systemic vasculitis involving the
lungs.
Physiologic Abnormalities in Asthma
Spirometry and Ventilatory Function in Asthma
In asthma, the prime physiologic disturbance is
obstruction to airflow, which is more marked in expiration. This obstruction is
variable in severity and in its site of involvement and is, by definition, reversible to some
degree. Various combinations of smooth muscle constriction, inflammation, edema,
and mucus hypersecretion produce this airflow impediment. In addition, low lung
volumes with terminal airspace collapse may compound the airway obstruction. In
the larger airways, the rigid cartilaginous rings help maintain patency. In the
peripheral airways, however, there is little opposition to the smooth
muscle action because of the paucity of cartilage. Instead, the patency of
these airways is influenced by lung volume because they are imbedded in and
partially supported by the lung parenchyma.
At the onset of an asthmatic attack, or in mild cases,
obstruction is not extensive. As asthma progresses, airways resistance
significantly increases. Although inspiratory resistance also increases, the
abnormality is more pronounced during expiration because of narrowing or
closure of the airways as the lung empties. At this point, further expiratory
effort does not produce any increase in expiratory flow rate and may even
intensify airway collapse.
Because of these mechanical resistances, the respiratory
muscles must produce a greater degree of chest expansion. More important, the
elastic recoil of the lungs is insufficient for “passive” expiration. The respiratory
muscles, therefore, must now play an active role in expiration. If obstruction
is severe, air trapping will occur, with an increase in residual volume (RV)
and functional residual capacity (FRC).
Airway obstruction is uneven and results in unequal
distribution of gases to alveoli. This and other stimuli result in tachypnea
and a consequently shortened respiratory cycle even though the bronchial
obstruction requires a lengthened respiratory time for adequate ventilation.
These conflicting demands cannot be reconciled while the asthmatic attack
continues.
The severity of the obstruction is reflected in the
spirometric measurements of expiratory volume and airflow. The FEV1, FVC, and
inspiratory capacity (IC) are all reduced during an acute attack.
The peripheral airways have a proportionately large
total cross-sectional area. For this reason, the resistance of the peripheral
airways normally accounts for only 20% of the total airway resistance. Thus,
extensive obstruction in these smaller airways may go undetected if the
physician relies only on clinical findings. The reduction in FVC and FEV1 shows
a good correlation with the decrease in PaO2, although carbon dioxide retention
does not occur until the FEV1 is about 1 L or 25% of the level predicted.
With progressive obstruction, expiration becomes
increasingly prolonged. Increases in RV and FRC occur (see Plate 4-39). These
volume changes may represent an inherent physiologic response by the patient
because breathing at higher lung volumes prevents the closure of terminal
airways. The overall effect of these events is alveolar hyperinflation, which
tends to further increase the diameter of the airways by exerting a greater
lateral force on their walls. This hyperinflation may partially preserve gas
exchange. It is disadvantageous because much more work is required, resulting
in an increase in O2 consumption. Moreover, such a state compromises
IC and vital capacity (VC). The symptoms of dyspnea and fatigue may also arise
in part from this process.
Finally, the effectiveness of cough is impaired because the velocity of
respiratory airflow is seriously reduced.
As a result of the nonhomogeneous airway obstruction
in asthma, the distribution of inspired air to the terminal respiratory units
is not uniform throughout the lungs. Alveoli that are hypoventilated because
they are supplied by obstructed airways are interspersed with normal or
hyperventilated alveoli; hence, the severity of asthma
is directly related to the ratio of poorly ventilated to well-ventilated
alveolar groups. Arterial hypoxemia, which is the primary defect in gas exchange in asthma,
is caused by this V· A Q· C nonhomogeneity (Plate 4-21). As the population
of alveolar units with a low V· A Q· C ratio increases (because of advancing obstruction),
the degree of arterial hypoxemia also intensifies. The V· A
Q· C disturbance is compounded if
some airways are completely obstructed. The right-to-left intrapulmonary shunt effect results
in arterial hypoxemia.
Carbon dioxide elimination is not impaired when the number
of alveolar-capillary units with normal V· A
Q· C ratios remains large
relative to the number of those with low V· A
Q· C ratios. As airway obstruction progresses, there are more and
more hypoventilated alveoli. Simultaneously, appropriate increases in respiratory
work, rate, and depth occur. Such a response initially minimizes the increase in
physiologic dead space but eventually becomes limited, and alveolar ventilation
finally fails to support the metabolic needs of the body. Carbon dioxide retention
now occurs together with increasing hypoxemia. This is a state of ventilatory failure,
and it monly arises when the FEV1 is less than 25% predicted.
PATHOGENESIS OF ASTHMA
Genetics
Genetic and environmental factors interact in a
complex manner to produce both asthma susceptibility and asthma expression.
Several genes on chromosome 5q31-33 may be important in the development or progression
of the inflammation associated with asthma and atopy, including the cytokines
interleukin-3 (IL-3), IL-4, IL-5, IL-9, IL-12, IL-13, and granulocyte-macrophage
colony-stimulating factor (GM-CSF). In addition, a number of other genes may
play a role in the development of asthma or its pathogenesis, including the
corticosteroid receptor and the β2-adrenergic receptor. Chromosome 5q32
contains the gene for the β2-adrenoceptor, which is highly polymorphic, and a
number of variants of this gene have been discovered that alter receptor
functioning and response to β-agonists.
Other chromosome regions linked to the development of
allergy or asthma include chromosome 11q, which contains the gene for the β chain of the highaffinity
IgE receptor (FcεRIβ). Chromosome 12 also contains several candidate genes,
including interferon-γ (INF-γ), stem cell factor (SCF), IGF-1, and the constitutive
form of nitric oxide synthase (cNOS). The ADAM 33 gene (a disintegrin
and metalloproteinase 33) on chromosome 20p13 has been significantly associated
with asthma. ADAM proteins are membrane- anchored proteolytic enzymes. The
restricted expression of ADAM 33 to mesenchymal cells and its close
association with airways hyperresponsiveness (AHR) suggests it may be operating
in airway smooth muscle or in events linked to airway remodeling.
Cellular Inflammation
Persistent airway inflammation is considered the characteristic
feature of severe, mild, and even asymptomatic asthma. The characteristic
features include infiltration of the airways by inflammatory cells, hypertrophy
of the airway smooth muscle, and thickening of the lamina reticularis just
below the basement membrane (see Plate 4-22).
An important feature of the airway inflammatory
infiltrate in asthma is its multicellular nature, which is mainly composed of
eosinophils but also includes neutrophils, lymphocytes, and other cells in
varying degrees. Whereas neutrophils, eosinophils, and T lymphocytes are recruited from the circulation, mast
cells are resident cells of the airways. Histologic evidence of mast cell
degranulation and eosinophil vacuolation reveals that the inflammatory cells are
activated. The mucosal mast cells are not increased but show signs of granule
secretion in asthmatic patients. Postmortem studies have shown an apparent
reduction in the number of mast cells in the asthmatic bronchi as well as in
the lung parenchyma, which reflects mast cell degranulation rather than a true
reduction in their numbers.
Eosinophils are considered to be the predominant and
most characteristic cells in asthma, as observed from both bronchoalveolar
lavage (BAL) and bronchial biopsy studies. The bronchial epithelium is
infiltrated by eosinophils, which is evident in both large and small airways,
with a greater intensity in the proximal airways in acute severe asthma.
However, some studies report the virtual absence of eosinophils in severe or
fatal asthma, suggesting some heterogeneity in this process. Alveolar
macrophages are the most prevalent cells in the human lungs, both in normal
subjects and in asthmatic patients and, when activated, secrete a wide array of
mediators. Lymphocytes are critical for the development of asthma and are found
in the airways of asthmatic subjects in relationship to disease severity. The
function and contribution of lymphocytes in asthma are multifactorial and
center on their ability to secrete cytokines. Activated T cells are a source of
Th2 cytokines (e.g., IL-4,
IL-13), which may
induce the activated B cell to
produce IgE and enhance expression of cellular adhesion molecules, in
particular vascular cell adhesion molecule-1 (VCAM-1) and IL-5, which is
essential for eosinophil development and survival in tissues.
IMMUNOLOGIC ABNORMALITIES
Allergic asthma and other allergic diseases, such as
allergic rhinitis and anaphylaxis, develop as a result of sensitization to
environmental allergens and subsequent immunologically mediated responses when
the allergens are encountered. These allergic reactions take place in specific
target organs, such as the lungs, gastrointestinal tract, or skin. These immune
processes leading to allergic reactions represent the disease state referred to
clinically as “atopy.” The immune sequence consists of the sensitization phase
followed by a challenge reaction, which produces the clinical syndrome
concerned (see Plate 4-23).
Sensitization to an allergen occurs when the other-
wise innocuous allergen is encountered for the first time. Professional
antigen-presenting cells (APCs) such as monocytes, macrophages, and immature
dendritic cells capture the antigen and degrade it into short immunogenic
peptides. Cleaved antigenic fragments are presented to naïve CD4+ T-helper (Th) cells on MHC class II molecules.
Depending on a multitude of factors, particularly the cytokine
microenvironment, these naïve T-helper cells are subsequently polarized into
Th1 or Th2 lymphocytes. Th1 lymphocytes pre- dominantly secrete IL-2, INF-γ,
and tumor necrosis factor (TNF)-β to induce a cellular immune response. In
contrast, Th2 lymphocytes secrete IL-4, IL-5, IL-9, and IL-13 cytokines to induce a humoral immune
response, particularly the B-cell class switch to allergen-specific
immunoglobulin E (IgE) production. In allergic asthma, an imbalance exists
between Th1 and Th2 lymphocytes, with a shift in immunity from a Th1 pattern
toward a Th2 profile. Accordingly, allergic asthma is often referred to a Th2-mediated
disorder, with a persistent Th2-skewed immune response to inhaled allergens
(Plate 4-23).
IgE is a γ-l-glycoprotein and is the least abundant
antibody in serum, with a concentration of 150 ng/mL compared with 10 mg/mL for
IgG in normal individuals. However, IgE concentrations in the circulation may
reach more than 10 times the normal level in “atopic” individuals. IgE levels
are also increased in patients with parasitic infestations and
hyper-IgE-syndrome. Increased serum concentration is not necessarily a specific
indicator of the extent or severity of allergy in the individual concerned. The
IgE molecules attach to the surfaces of the mast cells or other cells such as
basophils. The mast cells containing IgE are distributed in the mucosa of the
upper and lower respiratory tract and perivascular connective tissues of the
lung.
After sensitization to an allergen has occurred, reexposure
of the patient to the allergen may result in an acute allergic reaction, also
known as an immediate hypersensitivity reaction (Plate 4-23). IgE-sensitized
mast cells in contact with the specific antigen secrete preformed and newly
synthesized mediators, including histamine, cysteinyl leukotrienes, kinins,
prostaglandins and thromboxane, and platelet activating factor. Also, mast
cells are sources of proinflammatory cytokines. Each antigen molecule has to
bridge at least two of the IgE molecules bound to the surface of the cell. The
subsequent airway smooth muscle contraction, vasoconstriction, and hypersecretion
of mucus, together with an inflammatory response of increased capillary
permeability and cellular infiltration with eosinophils and neutrophils
follows, producing asthma symptoms.
PATHOLOGIC CHANGES IN ASTHMA
The initial knowledge of the pathology of asthma came
from postmortem studies of fatal asthma or airways of patients with
asthma who have died of other causes or who had undergone lung resections. All
showed similar, although variably severe, pathologic changes and provided key
directives as to the causes and consequences of the inflammatory reactions in
the airway (see Plate 4-24).
The characteristic mucus plugs in asthmatic airways
can cause airway obstruction, leading to ventilation-perfusion mismatch and
contributing to hypoxemia. Mucus plugs are composed of mucus, serum proteins,
inflammatory cells, and cellular debris, which include desquamated epithelial
cells and macrophages often arranged in a spiral pattern (Curschmann spirals).
The excessive mucus production in fatal asthma is attributed to hypertrophy and
hyperplasia of the submucosal glands. The mucus also contains increased
quantities of nucleic acids, glycoproteins, and albumin, making it more
viscous. This altered mucous rheology, coupled with the loss of ciliated epithelium, impairs
mucociliary clearance.
The airway wall thickness is increased in asthma and
is related to disease severity. Compared with non-asthmatic subjects, the
airway wall thickness is increased from 50% to 300% in patients with fatal
asthma and from 10% to 100% in nonfatal asthma. The greater thickness results
from an increase in most tissue compartments, including smooth muscle,
epithelium, submucosa, adventitia, and mucosal glands. The inflammatory edema
involves the whole airway, particularly the submucosal layer, with marked
hypertrophy and hyperplasia of the submucosal glands and goblet cell
hyperplasia. Goblet cell hyperplasia and hypertrophy accompany the loss of
epithelial cells. There is hyperplasia of the muscularis layer and
microvascular vasodilation in the adventitial layers of the airways. Also,
morphometric studies have shown that the bronchial lamina propria of asthmatic
subjects had a larger number of vessels occupying a larger percentage area than
in nonasthmatic subjects and in some circumstances correlated with the severity
of disease.
LONG-TERM MANAGEMENT OF ASTHMA
Asthma treatment guidelines have been remarkably
consistent in identifying the goals and objectives of asthma treatment. These
are to (1) minimize or eliminate asthma symptoms, (2) achieve the best possible
lung function, (3) prevent asthma exacerbations, (4) do the above with the
fewest possible medications, (5) minimize short- and long-term adverse effects,
and (6) educate the patient about the disease and the goals of management. One
other important objective should be the prevention of the decline in lung
function and the development of fixed airflow obstruction, which occur in some
asthmatic patients. In addition to these goals and objectives, each of these
documents has described what is meant by the term asthma control. This
includes the above objectives but also includes minimizing the need for rescue
medications, such as inhaled β2- agonists, to less than daily use;
minimizing the variability of flow rates that is characteristic of asthma; and
having normal activities of daily living. Achieving this level of asthma
control should be an objective from the very first visit of the patient to the
treating physician.
The pharmacologic treatment of patients with asthma
must only be considered in the context of asthma education and avoidance of
inducers of the disease (see Plate 4-25).
Mild Persistent Asthma
Low doses of inhaled corticosteroids (ICS) can often
provide ideal asthma control and reduce the risks of severe asthma
exacerbations in both children and adults with mild persistent asthma, and they
should be the treatment of choice. ICS are the most effective anti-inflammatory
medications for asthma treatment. The mechanisms of action of asthma
medications are depicted in Plate 4-26. There is no convincing evidence that
regular use of combination therapy with ICS and inhaled long-acting β2-agonists
(LABA) provides any additional benefit. Leukotriene receptor antagonists
(LTRAs) are another treatment option in this population, but they are also less
effective than low-dose ICS. There are considerable inter- and intraindividual
differences in responses to any therapy. This is also true for response to
treatment with ICS and LTRAs in both adults and in children. Although on
average, ICS improve almost all asthma outcomes more than LTRAs some patients
may show a greater response to LTRAs. Currently, it is not possible to
accurately identify these responders based on their clinical, physiologic, or
pharmacogenomic characteristics.
The other issue that needs to be considered when
making a decision to start ICS treatment in patients with mild asthma is the
potential for side effects. ICS are not metabolized in the lungs, and every
molecule of ICS that is administered into the lungs is absorbed into the
systemic circulation. All of the studies in patients with mild persistent
asthma have used low doses of ICS (maximal doses, 400 µg/d). A wealth of data
are available demonstrating the safety of these low doses, even used long term,
in adults. However, a significant reduction in growth velocity has been
demonstrated with low doses of ICS in children. This is unlikely to have any
effect on the final height of these children because the one study that has
followed children treated with ICS to final height did not show any detrimental
effect even with a moderate daily ICS doses.
Moderate Persistent Asthma
These patients have asthma that is not well controlled
on low doses of ICS. Asthma treatment guidelines recommend that combination
therapy with ICS and a LABA is the preferred treatment option in these
patients. This is because the use of combination treatment of ICS and LABA for
moderate persistent asthma has also been demonstrated to improve all indicators
of asthma control compared with ICS alone. It is important to note that the
evidence of the enhanced benefit of combination therapy with ICS and LABA in
moderate persistent asthma exists mainly in adults with asthma. Another
recently described treatment approach for the management of patients with
moderate asthma is the use of an inhaler containing the combination of the ICS
budesonide and the LABA formoterol, both as maintenance and as relief therapy,
which has been shown to reduce the risk of severe asthma exacerbations compared with
the other approaches studied with an associated reduction in oral
corticosteroid use.
Several studies have compared the clinical benefit when
LTRAs are added to ICS in patients with moderate persistent asthma in both
adults and children. The addition of LTRAs to ICS may modestly improve asthma
control compared with ICS alone, but this strategy cannot be recommended as a substitute for
increasing the dose of ICS. In addition, LTRAs have been shown to be less
effective than LABAs when combined with ICS. Low-dose theophylline has also
been evaluated as an add-on therapy to ICS. The magnitude of benefit achieved is
less than for LABAs. Another potential treatment option for patients with
moderate asthma is omalizumab, which is a recombinant humanized monoclonal antibody against IgE. This anti-IgE
antibody forms complexes with free IgE, thus blocking the interaction between IgE and effector cells and
reducing serum concentrations of free IgE. Compared with placebo in patients on moderate to high doses of
ICS, omalizumab reduces asthma exacerbations and enables a small but statistically signifycant
reduction in the dose of ICS. However, this treatment has not been compared with proven additive therapies such as
LABAs that are less expensive. Therefore, this therapy is currently recommended in international guidelines for
patients with moderate to severe asthma.
Severe Persistent Asthma
Patients with severe asthma are those who do not respond adequately
to even high doses of ICS and LABAs. This population disproportionately consumes health care
resources related to asthma. Physiologically, these patients often have air trapping, airway
collapsibility, and a high degree of AHR. Patients with severe difficult-to-treat
asthma are most often adult patients with signifi cant comorbidities, including severe
rhinosinusitis, gastroesophageal reflux, obesity, and anxiety disorders. Often
this population requires oral corticosteroids in addition to ICS in an effort to achieve asthma control.
TREATMENT OF SEVERE ASTHMA
EXACERBATIONS
Episodes of acute severe asthma (asthma exacerbations) are episodes of
progressive increase in shortness of breath, cough, wheezing, chest tightness, or some
combination and are characterized by airflow obstruction that can be
quantified by measurement of PEF or FEV1. These measurements are more reliable indicators of the severity of
airflow limitation than is the degree of symptoms. Severe exacerbations are potentially life threatening, and
their treatment requires close supervision. Patients with severe exacerbations should be encouraged to see
their physicians promptly or to proceed to the nearest hospital that provides
emergency access for patients with acute asthma. Close objective monitoring of the
response to therapy is essential.
The primary therapies for severe asthma exacerbations include repetitive
administration of rapid-acting inhaled β2-agonists, 2 to 4 puffs every 20
minutes for the first hour
(see Plate 4-27). After the first hour, the dose of β2-agonists required
depends on the severity of the exacerbation and the response of the previously
administered inhaled β2-agonists. A combination of inhaled β2-agonist with an
anticholinergic (ipratropium bromide) may produce better
bronchodilation than either drug alone. Oxygen should be administered by
nasal cannula or by mask and should be titrated against pulse oximetry to maintain a satisfactory
oxygen saturation of 90% or above (≥95% in children).
Systemic glucocorticosteroids speed resolution of exacerbations and
should be used in all but the mildest exacerbations, especially if the initial rapid-acting inhaled β2-agonist
therapy fails to achieve lasting improvement. Oral glucocorticosteroids are usually as effective as those
administered intravenously and are preferred because this route of delivery is less
invasive. The aims of treatment are to relieve airflow obstruction and hypoxemia as
quickly as possible and to plan the prevention of future relapses. Sedation should be strictly avoided
during exacerbations of asthma because of the respiratory depressant effect of anxiolytic and hypnotic drugs.
Patients at high risk of asthma-related death should be encouraged to
seek urgent care early in the course of their exacerbations. These patients include those with a previous
history of near-fatal asthma requiring intubation and mechanical ventilation, who have had a hospitalization or
emergency care visit for asthma in the past year, who are currently using or have recently stopped using oral
glucocorticosteroids, who are overdependent on rapid-acting inhaled β2-agonists, who have a history of
psychiatric disease or psychosocial problems, and who have a history of noncompliance with an asthma
medication plan.
The response to treatment may take time, and patients should be
closely monitored using clinical as well as objective measurements. The increased
treatment should continue until measurements of lung function return to their previous best level or there
is a plateau in the
response to the inhaled β2-agonists, at which time a decision to admit or discharge the patient can be
made based on these values. Patients who can be safely discharged will have responded within the first 2
hours, at which time decisions regarding patient disposition can be made. Patients with a pretreatment FEV1 or
peak expiratory flow (PEF) below 25% percent predicted or those with a
posttreatment FEV1 or PEF below 40% percent predicted usually require hospitalization. Patients with
posttreatment lung function of 40% to 60% predicted can often be discharged from
the emergency setting provided that adequate follow-up is available in the community and their
compliance with treatment is assured.
For patients discharged from the emergency department,
a minimum of a 7-day course of oral glucocorticosteroids for adults and a
shorter course (3-5 days) for children should be prescribed along with
continuation of bronchodilator therapy. The bronchodilator can be used on an
as-needed basis, based on both symptomatic and objective improvement. Patients should initiate or
continue inhaled glucocorticosteroids. The patient’s inhaler technique and use
of peak flow meter to monitor therapy at home should be reviewed. The factors
that precipitated the exacerbation should be identified and strategies for their
future avoidance implemented. The patient’s response to the exacerbation should
be evaluated, and an asthma action plan should be reviewed and written guidance
provided.
