45

Wheezing in Older
Children
Asthma
Carolyn M. Kercsmar MS, MD, Karen M. Mcdowell MD

Introduction
Wheezing is a musical, high-pitched, largely expiratory sound,
typically made through the partially obstructed larger airways,
most commonly caused by asthma in school-age children.
Nevertheless, wheezing can also be generated by narrowing in the
distal trachea and by glottic closure. A number of other conditions
can cause both acute and chronic wheezing in children, but many
causes are associated with other symptoms that generally
distinguish them from asthma (Box 45.1). The major focus of this
chapter will be on the diagnosis and treatment of asthma in
children beyond the preschool years.

Box 45.1
Causes of Wheezing in Older Children

2545
 α1-antiprotease deficiency (adolescent, young adult)
Anatomic lesion or airway compression
Angioedema
Aspiration/gastroesophageal reflux
Asthma
Bronchiectasis
Bronchogenic or pulmonary cyst
Congestive heart failure
Cystic fibrosis
Eosinophilic bronchitis
Exercise-induced asthma
Foreign body aspiration
Granulation tissue in intrathoracic airway
Hypersensitivity pneumonitis
Immotile cilia syndrome
Immune deficiency
Infection
Inflammation of lower airway
Irritant inhalation (smoke, illicit drugs, cocaine)
Lymph nodes (mediastinal, paratracheal)
Mycoplasma
Pertussis
Postinfection
Sarcoidosis
Tumor (carcinoid, lymphoma)
Vascular ring
Vasculitis (Wegener granulomatosis, other)
Virus (adenovirus, respiratory syncytial virus [RSV], human
metapneumovirus, parainfluenza, influenza)
Vocal cord adduction/dysfunction

As defined in the National Heart, Lung, and Blood Institute

(NHLBI) guidelines, asthma is characterized by variable, reversible
obstruction of air flow (but not completely so in some patients),
which may improve spontaneously or may subside only after
specific therapy.1 Airway hyperreactivity, defined as the inherent
tendency of the trachea and bronchi to narrow in response to a
variety of stimuli (e.g., allergens, nonspecific irritants, or infection),

2546
is also a prominent feature. Both the airway obstruction and
hyperreactivity may be associated with chronic, dysregulated
airway inflammation that involves many cell types (e.g.,
eosinophils, lymphocytes, neutrophils, epithelial cells, airway
smooth muscle, fibroblasts) and mediators (e.g., cytokines,
chemokines, enzymes, growth factors, IgE). Symptoms of wheeze,
cough, and shortness of breath are episodic in most patients but
may occur daily in some. Asthma is now viewed as an “umbrella
term” for a complex, heterogeneous disorder with numerous
phenotypes and endotypes that differ in children and adults.
Although all asthma phenotypes demonstrate airway obstruction,
the pathophysiological processes, genetics, natural history, and
response to treatment differ widely.
Although there has been an increased awareness of the
prevalence of childhood asthma, substantial physical,
psychological, and socioeconomic morbidity continue to occur.
Among the 7 million children younger than 18 years of age in the
United States with asthma, it is estimated that each year more than
10 million school days are lost, 3 million sick visits are made to
health care providers, and more than 450,000 hospitalizations
occur.2 The annual direct and indirect health care costs for
treatment of asthma were recently estimated at over $50 billion per
year in the United States. Poor, disadvantaged minority children
who reside in central urban areas have both the highest prevalence
and greatest morbidity. Nevertheless, both acute health care
utilization and mortality rates from asthma appear to have
stabilized and for some groups, declined slightly in recent years,
following a steady rise in the period from 1980 to the mid-1990s.2
Mortality remains rare and is declining, and less than 150 children
and adolescents younger than 15 years of age in the United States
die annually from asthma.

Pathology
Examination of postmortem lung specimens of patients who died
from asthma shows marked hyperinflation with smooth muscle
hyperplasia in the bronchial and bronchiolar walls, thick tenacious
mucous plugs often completely occluding the airways, markedly

2547
thickened basement membrane, and variable degrees of mucosal
edema and denudation of bronchial and bronchiolar epithelium
(Fig. 45.1).3 Eosinophilia of the submucosa and secretions is often
prominent whether or not allergic (IgE-mediated) mechanisms are
present. Airway smooth muscle mass is also increased in the
airways by school age and may begin in the preschool years.
Mucous plugs contain layers of shed epithelial cells and
eosinophils, as well as neutrophils and lymphocytes. Although the
exact role of airway eosinophils in causing and perpetuating the
asthma phenotype remains controversial, eosinophil products (e.g.,
major basic protein and other proteases) may play an important
role in the destructive changes observed. The mucosal edema with
separated columnar cells and stratified nonciliated epithelium,
which replaces ciliated epithelium, results in abnormal mucociliary
clearance. Mast cells are increased in airway smooth muscle of
asthmatics. In addition, there is increased mast cell degranulation,
which is often worse in those with more severe asthma. Submucosal
gland hypertrophy and increased goblet cell size are not constant
features of asthma, but mucous metaplasia caused by increased
synthesis and stores frequently occurs across all ranges of asthma
severity. The thickened basement membrane caused by submucosal
deposition of type IV collagen and various other materials is a
striking feature of asthma and has been reported even in mild
asthmatics. Basement membrane thickening is thought to occur
early in the disease, but its pathologic significance remains to be
determined. All of these findings have been observed in symptom-
free asthmatic individuals who died accidental deaths, as well as in
endobronchial biopsy specimens from research subjects (Fig. 45.2).
Significant basement membrane thickening in airway mucosal
biopsies taken from pediatric patients with severe asthma has been
observed in the absence of active eosinophilic or neutrophilic
infiltrates.4,5 Moreover, normal lung function as measured by forced
expiratory volume in 1 second (FEV1) can be achieved by patients
with severe airway remodeling. These observations call into
question the role of inflammation and remodeling in asthma that is
difficult to control. Although an occasional patient may show
localized bronchiectasis and small focal areas of alveolar
destruction, these are not characteristic of asthma, and there is little

2548
evidence that asthma leads to destructive emphysema. However,
the incomplete reversibility of air flow limitation seen in some
asthmatics suggests that a phenotype exists that may be considered
a form of chronic obstructive pulmonary disease (COPD), the so-
called overlap syndrome.6

FIG. 45.1 Sections of asthmatic lung. Top left, Cross-

section of bronchus (original magnification ×66)
showing cartilage (A), thickened basement membrane
(B), epithelium containing many goblet cells (C), area
of many ciliated epithelial cells (D), connective tissue
(E), mucous gland (F), and mucous plug (G). Top right,
Bronchial epithelium (original magnification ×136)
showing mucous glands (A), hyaline basement
membrane (B), goblet cells (C), and ciliated cells (D).
Bottom left, Bronchial epithelium (original magnification
×700) showing goblet cell (A), basement membrane

2549
 (B), connective tissue (C), and ciliated respiratory
epithelial cells (D).

FIG. 45.2 Autopsy specimen from an asthmatic child

who died from toxic ingestion. Note the infiltration of
cells around the bronchus with sloughing of epithelial
cells into the bronchial lumen. The alveoli all appear
normal.

Pathophysiology
Air flow limitation in asthma results from a combination of
obstructive processes, principally mucosal edema, bronchospasm,
loss of alveolar tethering points, and mucous plugging. The relative
roles of these processes in producing obstruction may differ,
however, according to the age of the child, the size and anatomy of
various portions of the airway, the type of agent precipitating
obstruction, and the duration and severity of asthma. An example
of acute bronchoconstriction following bronchial lavage with
normal saline in a child with asthma can be viewed in the video
clip. Note the furrowing of the bronchial mucosa prior to lavage,
which is associated with smooth muscle hypertrophy in the airway
(Video 45.1 ).
Airway obstruction results in increased resistance to air flow

2550
through the trachea and bronchi and in decreased flow rates due to
narrowing and premature closure of the smaller airways. These
changes lead to a decreased ability to expel air and result in
hyperinflation. Although pulmonary overdistention benefits
respiration by helping to maintain airway patency, the work of
breathing increases because of the altered pulmonary mechanics. To
a certain extent, increasing lung volumes can compensate for
pulmonary obstruction, but compensation is limited as tidal
volume approaches the volume of pulmonary dead space, with
resultant alveolar hypoventilation.
Changes in resistance to air flow are not uniform throughout the
tracheobronchial tree, and because of regional differences in this
resistance, the distribution of inspired air is uneven, with more air
flowing to the less resistant portions. In most patients with asthma,
both larger and smaller airways are obstructed, but some patients
may have small airway obstruction primarily, or even exclusively.7
The pulmonary circulation also is affected by hyperinflation, which
induces increased intrapleural and intraalveolar pressures and
uneven perfusion of the alveoli. The increased intraalveolar
pressure, decreased ventilation, and decreased perfusion (the last
through hypoxic vasoconstriction) lead to variable and uneven
ventilation-perfusion relationships within different lung units. The
ultimate result is early reduction in blood oxygenation, even
though carbon dioxide is eliminated effectively because of its ready
diffusibility across alveolar capillary membranes. Thus, early in
acute asthma, hypoxemia occurs in the absence of CO2 retention.
The hyperventilation resulting from the hypoxemic drive causes a
fall in partial pressure of carbon dioxide in alveolar gas (PaCO2).
However, as the obstruction becomes more severe and the number
of alveoli being adequately ventilated and perfused decreases, a
point is reached at which CO2 retention occurs.
Alterations in pH homeostasis result from respiratory and
metabolic factors. Early in the course of acute asthma, respiratory
alkalosis may occur because of hyperventilation. Metabolic acidosis
can occur because of the increased work of breathing, increased
oxygen consumption, and as a result of excessive β-adrenergic
agonist treatment. The metabolic acidosis usually results from lactic
acid accumulation, which most commonly occurs as a result of high

2551
and frequent doses of β-adrenergic agonist use. In such cases, the
acidosis resolves as the β-agonist use is tapered. The mechanism of
β-adrenergic agonist induced lactic acid production is somewhat
controversial, but most likely results as a consequence of the
increased plasma glucose concentration (caused by both beta-
agonist and systemic glucocorticoid administration) and its
conversion via glycolysis to pyruvate, which is then converted to
lactate.8 When respiratory failure is superimposed, respiratory
acidosis may result in a precipitous decrease in pH.
In short attacks of acute asthma, bronchospasm, mucosal edema,
or both can occur. In a minority of asthmatics, acute severe episodes
are characterized by neutrophilic, not eosinophilic infiltration, and
bronchospasm occurs with little mucus secretion. These episodes
may have an abrupt onset and cause severe or life-threatening
symptoms. Mucous secretions become far more important as a
cause of obstruction as the inflammation becomes more intense and
prolonged, and when damage to and sloughing of epithelial cells
impairs mucociliary function and increases reflex
bronchoconstriction.

Inflammatory Cell Biology and

Asthma Etiology and
Pathophysiology
Although tremendous strides have been made in the cellular and
molecular biology of asthma in the past two decades, a complete
understanding of the causative factors and those responsible for
perpetuating the asthmatic state remain inadequately explained.
Current data support the hypothesis that inflammation underlies
the pathophysiology of asthma, and the airway epithelium,
inflammatory leukocytes, multiple immune cells, and other airway
structural cells all play a role.9,10 The mechanisms producing airway
inflammation are legion, cross-talk among various pathways
occurs, and the predominant mechanisms responsible for cellular
dysfunction vary among asthma phenotypes. The cell–cell
communications that initiate and perpetuate asthma likely result
from inhaled stimuli such as inhaled allergens, respiratory viruses,

2552
and air pollutants (particulate and gaseous) that cause airway
epithelial cells to secrete cytokines, interleukins, and other
mediators. In turn, these proinflammatory agents act on resident
cells in the subepithelial layer, (e.g., dendritic cells, mast cells, and
lymphoid cells, including lineage negative innate lymphoid cells) to
recruit other leukocytes and the release of Th2 cytokines such as IL-
4, IL-5, and IL-13. Biologically active neuropeptides and
acetylcholine can also be released from afferent nerves in the
epithelium by similar environmental triggers/irritants. The ongoing
recruitment of T lymphocytes and release of other mediators, such
as IL-17 and IL-33, further enhances the inflammation and
dysfunction of the epithelium and airway smooth muscle.
The propensity to develop IgE-mediated sensitization to
environmental allergens, particularly in association with rhinovirus
infection, coupled with subsequent exposure, is one of the strongest
predictors for the development of childhood asthma. The
persistence and chronic activation of mast cells, dendritic cells,
eosinophils, and lymphocytes in the airways as a result of Th2
cytokine-mediated events (e.g., recruitment of circulating
inflammatory cells, interruption of apoptosis) may be important in
producing chronic asthma. In addition, innate immune responses
modulated by Toll-like receptor recognition and Th17 cells also
may be operative in some asthma phenotypes, such as those with
more severe disease and neutrophilic predominance in the
airways.11 Impaired production of natural airway defense
mediators such as lipoxins, resolvins, and protectins (all important
in the active resolution of airway inflammation) may also promote
a proinflammatory state in the asthmatic airway. Prolonged or
recurrent episodes of inflammation are associated with progressive
structural and functional changes in the airway epithelium,
musculature, and connective tissue. The continued dysregulation of
the cytokine networks perpetuates inflammation in what now may
be the structurally altered airways of chronic asthma. Several
specific effector mechanisms (e.g., IgE, arachidonic acid
metabolites, mast cell proteases, numerous cytokines, thymic
stromal lymphopoietin [TSLP], nitric oxide [NO], the β-adrenergic
receptor [BAR], growth factors, the airway microbiome, and
intrinsic muscular abnormalities) appear to play key roles in airway

2553
inflammation and are discussed further in Chapter 7.

Natural History and Prognosis

Knowledge of the natural history of asthma remains incomplete,
but several longitudinal studies have added substantial insight. The
widespread notion that most children “outgrow” their asthma in
adolescence is only partially true. Between 30% and 70% of children
with episodic asthma have less severe or absent symptoms by late
adolescence, and some features of childhood presentation and
course seem to predict clinical outcome. The presence of allergic
sensitization, female sex, and severe or persistent asthma in early
childhood are predictors of asthma in adulthood. Data from the
Melbourne Asthma Study suggested that mild asthma or infrequent
wheezing associated with viral infections in childhood was not
likely to progress to severe disease in adulthood. In this
longitudinal cohort of approximately 500 subjects, data have been
collected on the symptoms, growth, and lung function for more
than 50 years.12 Subjects were entered in the study at 7 years of age
and were classified as never wheezed (controls), mild wheezy
bronchitis, wheezy bronchitis, and asthma; a cohort with more
severe asthma was added 3 years later. The loss of lung function
seen in the groups with asthma and severe asthma by 10–14 years
of age did not worsen over time. The rate of loss of lung function as
measured by FEV1 had the same rate of decline up to age 50 in all
the groups, even after adjusting for smoking history. Moreover,
asthma remission, defined as no symptoms and no medical
treatment for 3 years, occurred in 64% of those with intermittent
childhood asthma, 47% of those with persistent childhood asthma,
and 15% of those with severe childhood asthma. Data from the
Childhood Asthma Management Program (CAMP) also indicate
that outcomes in children initially diagnosed with moderate asthma
vary and are predicted by certain features.13 During a 7- to 10-year
follow-up period of 909 children initially enrolled in a 4-year-long
clinical trial of placebo versus budesonide (BUD) versus
nedocromil, 6% remitted, 39% had periodic asthma, and 55% had
persistent disease. Prestudy factors associated with disease
remission included lack of allergen sensitivity and exposure to

2554
indoor allergens, milder asthma, older age, less airway
responsiveness (methacholine PC20), and higher prebronchodilator
FEV1. Moreover, there was no effect on disease outcome by
treatment. These results also highlight the lack of current
antiinflammatory treatments' ability to alter disease natural history.
Studies of children with asthma based both on history and on
assessment of pulmonary function indicate that many children who
lose overt symptoms have persistent airway obstruction.
Nonspecific airway hyperreactivity associated with asthma is
present in formerly asthmatic patients who are free from clinical
asthma.14 Individuals who had asthma as children have a
significantly lower FEV1, more airway reactivity, and more frequent
persistence of symptoms than those with infection-induced
wheezing or the controls. In addition, 88% of the adults with
childhood asthma who had persistent symptoms had positive
methacholine challenge test results, as did 42% of the asymptomatic
former asthmatics. The recurrence of overt asthma after years of
freedom from symptoms is not unusual. Thus asthma is often a
lifelong disease with periodic exacerbations and remissions,
although laboratory evidence of decreased pulmonary function,
airway inflammation, and airway hyperresponsiveness may persist,
even when symptoms are quiescent.
In children and adolescents, asthma is frequently a completely
reversible obstructive airways disease, and indeed no abnormalities
in pulmonary functions can be detected in many asthmatic patients
when they become symptom-free. However, recent studies that
examine not only symptoms and pulmonary function but also
indices of airway inflammation and bronchial hyperresponsiveness
suggest that airway inflammation may persist in the absence of
symptoms. In a study of 54 young adults (18–25 years of age) with
atopic asthma or asthma in clinical remission (absence of symptoms
for at least 12 months, median duration 5 years), subjects in
remission were found to have evidence of airway inflammation and
remodeling.14 When compared with normal healthy controls, the
subjects in remission had increased epithelial and subepithelial
major basic protein and reticular basement membrane thickness;
values were close to those of subjects with active asthma. Peripheral
eosinophil counts were also elevated in the remission patients, and

2555
there was a significant correlation between basement membrane
thickness, exhaled NO, and hyperresponsiveness to adenosine
monophosphate. These findings indicate that the airways of some
asymptomatic asthmatics, seemingly in clinical remission, may still
show significant abnormalities and evidence of active
inflammation. It is unclear that continued treatment in the face of
absent symptoms will alter the natural history of the disease in
these patients.
Asthma does appear to progress to chronic obstructive disease in
some individuals, and features of asthma can be found in some
adult patients with COPD (the so-called overlap syndrome).6 The
functional and structural causes of this irreversible airway
obstruction variant of asthma are not understood. A process
referred to as airway remodeling is often suggested as the cause of
chronic obstruction and severe asthma, but data to conclusively
support this hypothesis are lacking. It is believed that chronic
mucous plugging, tracheobronchial ciliary dysfunction, smooth
muscle and goblet cell hyperplasia, and collagen deposition in the
lamina reticularis of the basement membrane occur as a
consequence of persistent inflammation. Genetically determined
dysregulation of inflammatory mediator production with or
without repeated exposure to certain environmental stimuli may
also play a role. Data from animal models demonstrate that even
when inflammation is suppressed and changes consistent with
remodeling are reduced markedly, airway hyperresponsiveness
persists.15 These data suggest that airway remodeling alone is
probably not responsible for severe, irreversible airway obstruction
or bronchial hyperresponsiveness.
The natural history of childhood asthma and the effects of
aggressive long-term management on outcomes remain
incompletely understood, but a great deal of data have come from
the CAMP study.16 CAMP was a well-designed comprehensive
longitudinal study in which the primary objective was to compare
the effects of long-term treatment (4 years) with an inhaled steroid
(BUD) and a nonsteroidal treatment (nedocromil) to placebo in
school-age children (n = 1041) with mild to moderate asthma. The
hypothesis was that treatment with an inhaled steroid would result
in better lung growth compared with no or lesser treatment.

2556
Primary outcome was postbronchodilator FEV1, but a wealth of
other data on atopy, airway reactivity, symptoms, exacerbations,
and linear growth was obtained. After a brief improvement in FEV1
in the BUD group, there was no difference in FEV1 between the
groups over the last 3 years of the study. However, patients in the
BUD group had decreased hospitalizations and urgent care visits
compared with the placebo group. Patients in the nedocromil group
also had fewer emergency visits but not hospitalizations, and both
groups had less oral prednisone use. There was a small, transient
decrease in growth velocity in the BUD group compared with the
placebo and nedocromil groups. These data suggest that long-term
treatment with inhaled steroids in school-aged asthmatics does not
alter pulmonary function over time, even though the symptom
control and airway reactivity improved. Failure to alter the natural
history of asthma, as measured by lung function, in the CAMP
study was thought in part to be caused by beginning treatment too
late after the onset of disease. However, subsequent studies of
inhaled steroid treatment (Fluticasone 88 µg twice a day) in
younger children (2–3 years of age) who had recurrent wheezing
and were at very high risk for developing asthma showed
improvement in clinical symptoms and exacerbations compared
with those receiving placebo. However, the treatment did not
prevent clinical symptoms or alteration in lung function (measured
by impulse oscillometry) in the subsequent year when treatment
was stopped.17 These data again indicate the inability of inhaled
corticosteroids (ICSs) to modify the long-term disease state.

Asthma Mortality
Despite the relatively high prevalence of asthma, mortality rates for
childhood asthma are extremely low and have stabilized and
actually decreased over the past decade.2 This is evident when
adjusting outcome metrics for the population at risk rather than the
overall population.18 Overall, fewer than 4000 individuals (of whom
fewer than 150 are children) die of asthma in the United States each
year. However, death rates are significantly higher in African
Americans of all ages. Analyses of causes of death in children with

2557
asthma suggest that the major causes are the failure of the
physician, parent, or patient to appreciate the severity of asthma,
which results in inadequate or delayed treatment, poor access to
health care, and the use of inappropriate medications (e.g.,
overreliance on β-adrenergic agonists and avoidance of use of
corticosteroids). In fact, recent data from Costa Rica demonstrated
that a 129% increase in the prescription of ICSs over a 7-year period
was associated with an approximately 80% reduction in deaths due
to asthma.19 Labile asthma, regardless of severity, is also a risk
factor, as are respiratory infections, nocturnal asthma, history of
respiratory failure, and marked diurnal variation in air flow
limitation. Some patients cannot perceive severe air flow
obstruction, especially when it occurs gradually, and a small
number may have sudden profound bronchospasm, which can be
fatal. Other factors, such as exposure to allergens (mold),
psychosocial disadvantage, poverty, previous episodes of
respiratory failure, history of hypoxic seizure, previous admission
to an intensive care unit, and psychological factors in both the
patient and family have been implicated in deaths from asthma.

Diagnosis of Asthma
An asthma diagnosis requires demonstration of episodic symptoms
of air flow obstruction, which must be at least partially reversible,
and alternative diagnoses should be excluded. Although airway
hyperresponsiveness is an almost universal feature of asthma, it is
not unique and therefore cannot be used as a defining
characteristic. The methods to establish the diagnosis include a
detailed medical history, a physical examination with a focus on the
respiratory system, and performance of spirometry in children who
are 5 years of age or older. A number of ancillary tests (e.g., allergy
skin tests, inhalation or exercise challenge tests, home peak flow
monitoring) may also be useful and, in some cases, necessary.
Although patients with asthma may present in a variety of ways,
most have certain common historical features, such as intermittent
or recurrent wheezing, an expiratory, musical, high-pitched,
whistling sound produced by air flow turbulence in the large
airways below the thoracic inlet. Many parents and even older

2558
children cannot accurately describe wheezing and may actually
report stridor (from upper airway obstruction), stertor, snoring, or
rhonchorous breathing. Careful explanation or even demonstration
of wheezing is often necessary to obtain an accurate history.
Wheezing can also be generated by adduction of the vocal cords
and forceful inspiration and expiration. Inspiratory wheezing per se
is not characteristic of asthma and suggests obstruction in the
laryngeal area, such as that induced by croup or vocal cord
dysfunction (VCD). However, wheezing also occurs during
inspiration when asthma worsens and may disappear altogether as
obstruction becomes more severe and air flow is limited. Asthma
can occur without wheezing if the obstruction involves
predominantly the small airways. Coughing or shortness of breath
may be the only complaint. However, so-called cough-variant
asthma may be overdiagnosed. Probably no more than 5% of
asthmatic children have cough as the only or primary symptom,
and the cough should resolve with appropriate asthma medications
and recur when the medications are stopped. Older children often
complain of a “tight” chest with colds, recurrent “chest congestion,”
or bronchitis. Usually, symptoms are more severe at night or in the
early morning and improve throughout the day. A history of
symptomatic improvement after treatment with a bronchodilator
suggests the diagnosis of asthma, but a failure of response does not
rule out asthma. When asymptomatic, many asthmatic children will
have normal lung function (FEV1). Reduction of the FEV1/FVC is
considered to be a more reliable indicator of airway obstruction in
children. An inhalation challenge test (e.g., methacholine or
mannitol) should be performed when asthma is suspected but
spirometry is normal or near-normal.
Family history is often positive for asthma or allergy (allergic
rhinitis, eczema) in a first-degree relative. A history of personal
allergy is found in more than two-thirds of children with asthma.

Physical Examination
The physical examination should focus on overall growth and
development; the condition of the entire respiratory tract including
the upper airway, ears, and paranasal sinuses as well as the chest;

2559
and other associated signs of allergic disease. Although severe
asthma can adversely affect linear growth, this is not a common
feature, and its presence should suggest evaluating for alternative
causes of growth failure.
Unless acutely ill, examination of the lungs is frequently normal
in children who are ultimately diagnosed with asthma. In some
cases, particularly during periods with acute symptoms,
auscultation reveals coarse crackles or unequal breath sounds,
which may clear at least partly with coughing. If they persist,
particularly during clinical stability, the possibility of another
diagnosis should be considered. Although wheezing can often be
elicited with a forced expiratory maneuver, occasionally there is
only prolongation of expiration without wheezing. The older child
or adolescent may resist exhaling forcefully to induce latent
wheezes, because such a maneuver may induce coughing, which
can increase bronchospasm. Some patients with severe asthma do
not wheeze because too little air is moving to generate the sound.
Wheezing from the lower respiratory tract should be differentiated
from similar sounds that can emanate from the laryngeal area in
even nonasthmatic children with sufficient forced expiration.
A variety of extrapulmonary signs indicating the presence of
complicating factors or alternative diagnoses (e.g., allergy or cystic
fibrosis) should be sought in all children being evaluated for
asthma. Nasal polyps occur rarely in the child with uncomplicated
asthma, and their presence suggests cystic fibrosis. However, nasal
polyps can occur in highly allergic adolescents or those with aspirin
sensitive asthma. Digital clubbing is not a feature of asthma;
although clubbing may be a nonpathologic familial trait, its
presence suggests cystic fibrosis, congenital heart disease,
inflammatory bowel disease, or another chronic lung disorder. The
conjunctivae should be examined for edema, inflammation, and
tearing, suggesting allergy. Flexor creases and other areas of the
skin should be examined for active or healed atopic dermatitis.
Hyperventilation and VCD syndrome should be considered in
the differential diagnosis of the child with asthma that is apparently
refractory to all therapy, especially if there are no symptoms during
sleep. Both conditions are more likely to occur in adolescence or
later childhood and may be mistaken for asthma, or may coexist

2560
with it. Typically the patient with hyperventilation is anxious and
complains of marked dyspnea and difficulty getting enough air to
breathe in spite of excellent air exchange on auscultation and an
absence of wheezing. Often there are associated complaints of
headache and tingling of the fingers and toes. Pulmonary function
tests (PFTs) are helpful in differentiating hyperventilation
syndrome from asthma; a normal spirogram during or around the
time of symptoms is inconsistent with asthma. Immediate therapy
consists of giving reassurance and having the patient rebreathe into
a paper bag to elevate PaCO2. VCD is another condition that must be
differentiated from true asthma.20 In these patients, wheezing is
often a prominent feature, may occur on inspiration and expiration,
and is typically loudest over the trachea or central, anterior chest.
This condition is more common in older children, adolescents, and
females, and it may also be seen in elite athletes. Most patients with
VCD cannot voluntarily induce an episode, although in many
patients, including highly trained athletes, exercise can precipitate
an attack.20,21 Although VCD was originally described in adults with
psychiatric disorders, in children it is not usually associated with
serious psychological disturbances and should not be labeled as
such. The etiology in children remains poorly understood. The
mechanism involves holding the anterior third of the vocal cords in
a position of relative adduction during inspiration, but also in
expiration. There may also be inward deflection of the supraglottic
structures as well; this condition is sometimes called exercise-
induced laryngomalacia (EILO). A recent study suggested that
EILO in adolescence may be related to a diagnosis of clinically
significant congenital laryngomalacia in infancy.22 The result is
loud, monophonic wheezing in a patient who has normal oxygen
saturation and responds poorly to inhalation of a bronchodilating
aerosol. Patients may appear comfortable or anxious in the face of
loud wheeze. Pulmonary function testing may reveal a pronounced
flattening of the inspiratory loop; however, since some patients
with VCD also have true asthma, there may be evidence of large
and/or small airway obstruction on the expiratory loop as well (Fig.
45.3). An increase in the mid–vital capacity expiratory/inspiratory
flow ratio from the normal value of about 0.9 to a value of greater
than 2 indicates extrathoracic obstruction consistent with VCD. It

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should be noted that most patients with VCD will have normal
pulmonary function testing when asymptomatic. The diagnosis is
confirmed by direct observation of paradoxical vocal cord
movement via flexible laryngoscopy during an acute episode.
Upper and lower airway examination with a flexible bronchoscope
should be considered in patients with atypical reports of wheeze,
dyspnea on exertion, or stridor to identify anatomic lesions such as
cysts, hemangiomas, or laryngotracheomalacia. Older children with
both VCD and asthma often can distinguish the “site” of the
wheezing when the source of the problem is explained to them. The
absence of nocturnal symptoms may also be a diagnostic clue that
VCD is the diagnosis rather than asthma. Effective treatment
consists of appropriate asthma medication (when an asthma
diagnosis has been confirmed), treatment of aggravating conditions
(reflux, rhinitis), and referral to a speech therapist or psychologist
specializing in behavior modification in order to learn relaxation
techniques and alternative breathing strategies. The vast majority of
patients will improve with this treatment.

FIG. 45.3 Flow-volume curve from a patient with vocal

cord dysfunction. The thin line represents the flow at
normal baseline. The thick line represents the flow
during an obstructive episode and depicts a slight
decrease in expiratory flow and a marked decrease in
and flattening of the inspiratory loop.

2562
Asthma Triggers
Many older children will identify more than one precipitating
factor responsible for asthma. Moreover, patterns of reactivity may
change. Thus exercise-induced asthma (EIA) may not be viewed as
a problem in many adolescents or adults with asthma who have
learned in childhood that exercise induces symptoms and have
developed a lifestyle that avoids exercise. Allergic factors that
precipitated asthma in childhood may no longer cause symptoms in
adolescence or adulthood, even though the patient continues to
have asthma. Patterns also may change with treatment or the
institution of environmental control measures. The use of quality-
of-life questionnaires can help uncover latent symptoms and
provide information that may be useful in identifying more subtle
triggers.

Allergens
In the majority of children with asthma, it is possible to induce an
asthmatic reaction to substances in which IgE-mediated reaction is
involved. Allergens that can induce asthma symptoms include
animal allergens, mold spores, pollens, insects (cockroach),
infectious agents (especially Mycoplasma and fungi), and
occasionally drugs and foods. Cockroach and rodent allergens
appear to be potent factors, particularly in inner-city children, and
have been associated with increased health care utilization in
children who are both sensitized and exposed to the allergens.23
Allergic reactions may induce bronchoconstriction directly, may
increase tracheobronchial sensitivity in general, and may be
obvious or subtle precipitating factors. Bronchoconstrictor
responses to allergens via IgE antibody–induced mediator release
from mast cells generally occur within minutes of exposure, last for
a relatively short period of time (20–30 minutes), and resolve. Such
reactions are termed early antigen or asthmatic responses. It is the
“late asthmatic response” (which occurs 4–24 hours after antigen
contact) that results in more severe and protracted symptoms
(lasting hours) and ultimately contributes to the chronicity and
severity of the disease. The late response is due to inflammatory cell
reactions and the release of multiple mediators, including IL-4, IL-5,

2563
and IL-13. Such allergen-induced dual responses can only be
demonstrated in approximately half of all asthmatics challenged in
a laboratory setting.

Irritants
Numerous upper and lower respiratory tract irritants have been
implicated as precipitants of asthma. These include paint odors,
hairsprays, perfumes, chemicals, air pollutants, diesel particulates,
tobacco smoke, cold air, cold water, and cough. Some allergens may
also act as irritants (e.g., molds). Some irritants such as ozone and
industrial chemicals may initiate bronchial hyperresponsiveness by
inducing inflammation, yet they do not produce a late-phase
response. Active and passive exposure to tobacco smoke, in
addition to acting as a precipitant and aggravator of asthma, can
also be associated with an accelerated irreversible loss of
pulmonary function.

Weather Changes
Atmospheric changes are commonly associated with an increase in
asthmatic activity. The mechanism of this effect has not been
defined but may be related to changes in barometric pressure and
alterations in the allergen or irritant content of the air. Grass pollen,
which in its native state is too large to enter the lower airways,
fractionates into numerous small starch granules bearing allergen
when exposed to water, such as during storms. These small
particles, along with fungal spores (Alternaria or Cladisporium) and
PM 2.5 particles readily enter the lower airways and can trigger
severe acute asthma in susceptible individuals; the risk is
particularly high when grass pollen counts exceed 20–50 grains/m3.
A recent outbreak of asthma deaths in Melbourne, Australia,
following thunderstorms during periods of high grass pollen
counts was attributed to this mechanism.23a,23b

Infections
By far, the most common infectious agents responsible for
precipitating or aggravating asthma are viral respiratory pathogens.

2564
It is estimated that up to 85% of asthma exacerbations in school-
aged children are due to viral infections, and rhinovirus has
emerged as a prominent pathogen in causing acute asthma.24
Among the three serotypes of rhinovirus, infection with hRV-C is
more likely to be associated with acute asthma exacerbations than
infection with hRV-A or hRV-B. In addition, there is some evidence
that rhinovirus, detected in nasal lavage, can cause an increase in
daily asthma symptoms apart from significant exacerbations.25 In
some instances, bacterial infections (e.g., pertussis or mycoplasma)
and, more rarely, fungal infections or colonization (e.g.,
bronchopulmonary Aspergillosis) and parasitic infestations (e.g.,
Toxocariasis and Ascariasis) can be triggers. The mechanisms of viral-
induced exacerbations are incompletely understood, but probably
involve some direct respiratory epithelial injury caused by
infection, alteration of host inflammatory responses driven by the
infection, and influence of other cofactors (concomitant allergen
exposure or mediator production). For instance, it is clear that
children who have significant respiratory viral–induced wheezing
are more likely to have elevated IgE and allergen sensitization.26 In
addition, asthmatics may have decreased production of interferons
type I, II, and III, which can be associated with decreased airway
function.

Exercise
Strenuous exercise (i.e., exercise sufficient to cause breathlessness
and hyperventilation) may induce bronchial obstruction in as many
as 90% of individuals with persistent asthma; this phenomenon is
termed exercise-induced bronchospasm (EIB). In addition, exercise can
cause significant bronchospasm in up to 40% of individuals with
allergic rhinitis who do not have persistent asthma. When
otherwise normal individuals develop bronchoconstriction in
response to exercise with hyperventilation, it is often termed EIA;
this may occur in 10%–13% of the general population. Symptoms
induced by exercise range from subtle (mild dyspnea) to significant
coughing, wheezing, and excessive breathlessness. Symptoms
typically begin after 5–10 minutes of vigorous activity and are most
prominent after activity ceases (by contrast with VCD/EILO, in

2565
which symptoms come on during exercise). The mechanisms
underlying EIA remain somewhat uncertain. Recent data indicate
that hyperventilation of cold, dry air causes heat and water loss
from the airways, producing a hyperosmolar lining fluid and
injuring the airway epithelium. Induced sputum obtained from
individuals with EIB demonstrates columnar epithelial cells,
eosinophils, and increased concentrations of leukotrienes. There is
also cytokine release from neutrophils.27 Cooling of the airways has
also been described to result in vascular congestion and dilatation
in the bronchial circulation. The subsequent mucosal swelling as a
result of vascular congestion and edema produces airway
narrowing. Symptoms of EIB usually resolve spontaneously within
1 hour after ceasing exercise, but may require treatment with a
short-acting β agonist (SABA) for complete resolution. There is
typically a refractory period of 1–3 hours following an episode of
EIA/EIB, during which further exercise will not cause significant
bronchospasm. Although studies are conflicting, there is generally
not a late-onset response (8–12 hours postexercise) following the
immediate reaction. A recent study of a cohort of Swedish
adolescents, aged 13–15 years, who underwent exercise challenge
tests and continuous exercise laryngoscopy testing showed that the
prevalence of EIB was 19.2%, the prevalence of EILO was 5.7%, and
5% had both conditions. Of note, 49.4% of those who complained of
exercise-induced dyspnea had neither condition.28 EIA may be both
underdiagnosed when symptoms are subtle, or it may be
overdiagnosed or misdiagnosed due to a number of masquerading
conditions (e.g., VCD, EILO, poor conditioning, or cardiac
dysfunction).

Emotional Factors
Emotional upsets clearly trigger asthma in some individuals;
however, there is no evidence that psychological factors are the
basis for asthma. Coping styles of patients, their families, and their
physicians can intensify or lead to more rapid amelioration of
asthma. Conversely, denial of asthma by patients, parents, or
physicians may delay therapy to the point that reversibility of
obstruction is more difficult. Psychological factors have been

2566
implicated in deaths from asthma in children. The influence of
psychosocial factors on compliance is yet another important factor
related to treatment failure or success. Asthma itself can strongly
influence the emotional state of the patient, the family, and other
individuals associated with the patient. In addition, some studies
indicate that psychosocial stressors, both internal (lack of parental
support) and external (witnessing violence), may modulate
immune responses, increase inflammation, or decrease steroid
responsiveness, leading to poorer asthma control.29,30

Gastroesophageal Reflux
Reflux of gastric contents into the tracheobronchial tree can
aggravate asthma in children and is one of the causes of nocturnal
asthma. Typical symptoms of gastroesophageal reflux (GER)—
heartburn, chest pain, regurgitation, sour brash—may be absent in
many children with asthma; estimates are that reflux may be
“silent” in more than 50% of asthmatic patients. Pediatric studies
have reported a prevalence of GER between 19% and 80%, with a
mean of about 22%.31 However, due to methodological flaws and
absence of longitudinal studies, a clear association between GER
and asthma symptoms in children remains unclear. Although the
exact extent to which reflux exacerbates asthma remains
controversial, it is clear that acid (or even nonacid) reflux of gastric
contents into the distal esophagus can lead to cough and
bronchospasm, presumably via increased vagal activity. Aspiration
of gastric contents in even micro amounts is also presumed to cause
bronchial irritation and bronchospasm. Data from a large double-
blind clinical trial in children did not show benefit to improving
any aspect of asthma control with treatment with proton pump
inhibitor (PPI) in asthmatic patients who did not have symptoms of
GER.32 In addition, the data support possible adverse effects in the
form of increased respiratory infections and symptoms in some
children with asthma treated with lansoprazole.33

Allergic Rhinitis and Sinusitis

Acute or chronic sinusitis can be associated with aggravation of
asthma and can be a cause of recalcitrant asthma. In some patients,

2567
asthma and sinusitis occur at the same time; the nasal symptoms
from the sinusitis may make cough and other symptoms of asthma
worse and less responsive to bronchodilator therapy alone. The
upper airway may be viewed to some extent as a continuum of the
lower airway; inflammatory mediator release in the lower airway
may be triggered as a response to sinus infection. This subject is
discussed in more detail in Chapter 47.

Nonallergic Hypersensitivity to Drugs

and Chemicals
Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs), such
as ibuprofen, can exacerbate asthma in selected individuals by
increasing production of 5-lipoxygenase metabolites, including
leukotrienes. The typical aspirin-sensitive asthmatic has nasal
polyps, urticaria, and chronic rhinitis. Aspirin ingestion may
diminish pulmonary function and produce wheeze, cough, rhinitis,
conjunctivitis, urticaria, and angioedema in 10%–20% of adults with
asthma.34 Although more common after the third decade of life, the
prevalence in children (as determined by a decrease in FEV1 of at
least 20% from baseline following aspirin or NSAID ingestion) has
been reported to be as high as 5% when determined by direct
challenge testing. Although aspirin in particular is rarely given to
children and adolescents because of the risk of Reye syndrome,
there is a very high cross-reactivity to common NSAIDs in aspirin-
susceptible patients. High-dose acetaminophen may also cause
wheezing in a small portion (<2%) of aspirin-sensitive asthmatics.
Some (but not all) studies suggest that early-life use of
acetaminophen may increase the risk of developing asthma, and
one large trial found a reduced risk of an acute care visit for asthma
following treatment with ibuprofen compared with treatment with
acetaminophen.35 However, the data are more compelling for
prenatal exposure to acetaminophen and development of asthma.
Moreover, some studies are “confounded by indication,” and when
adjusted for the incidence of respiratory tract infection, the risk of
developing asthma is greatly attenuated.35,36 The absence of a
history of increased symptoms following NSAID ingestion in

2568
asthmatic children is generally sufficient to warrant safe use of
NSAIDs as needed. A recent trial comparing acetaminophen use
with ibuprofen in children aged 1–5 years found no difference in
the incidence of asthma exacerbations.37 However, aspirin/NSAID
sensitivity should be considered in children and adolescents with
severe or difficult-to-control asthma, who also have chronic rhinitis,
urticaria, and nasal polyps.
Metabisulfite has been reported as a precipitant or aggravator of
asthma, both by allergic and nonallergic mechanisms. Sensitive
individuals should avoid foods containing or preserved using
sulfites (e.g., shrimp, dried fruit, beer, and wine).

Endocrine Factors
Aggravation of asthma and increased pulmonary function
variability occurs in some adolescent and adult women in relation
to the menstrual cycle, beginning shortly before menstruation and
ending shortly after the onset of menses.38 Whether this reflects
changes in water and salt balance, irritability of bronchial smooth
muscle, or other factors is unknown. The use of the oral
contraceptive pill has been reported to both aggravate and
ameliorate premenstrual asthma. Hyperthyroidism has been
reported to worsen or precipitate asthma in an occasional patient,
and treatment of hyperthyroidism usually ameliorates the asthma.
Vitamin D deficiency has gained increasing attention as a
possible contributor to both the development of asthma and a
contributor to its control. Data from the National Health and
Nutrition Examination Survey (NHANES) study indicated a direct
relationship between serum vitamin D concentration and
FEV1/FVC. In addition, several studies demonstrate lower vitamin
D levels in African Americans, Hispanics, and obese individuals, all
groups with increased risk for higher asthma morbidity. Among
asthmatic children, vitamin D insufficiency (defined as serum
concentration ≤30 ng/mL) occurs in approximately one-third of
those studied.39 Among 1024 participants in the CAMP study, 35%
were vitamin D insufficient at study entry. This group had an
increased risk of severe asthma exacerbation (OR 1.5, 1.1–1.9, P =
.01) during the 4 years of the study, after adjusting for numerous

2569
factors (i.e., age, sex, body mass index [BMI], and treatment group).
Those in the BUD treatment group had an even greater effect (OR
1.8, 1.0–3.2, P = .05). These results are similar to those described for
a cohort study (n = 616) of asthmatic Costa Rican children, 28% of
whom were vitamin D insufficient. Serum vitamin D was inversely
associated with serum IgE and peripheral eosinophil count. In
addition, higher vitamin D levels were associated with a significant
decrease in risk of hospitalization in the previous year, a decrease in
the use of antiinflammatory medicines, and borderline decreased
airway hyperresponsiveness. The mechanisms by which vitamin D
influences asthma expression remain unclear, but there are many
possibilities. Vitamin D suppresses bronchial smooth muscle mass
and goblet cell hyperplasia, and serum concentrations are inversely
associated with the frequency of viral respiratory infections.
Vitamin D treatment of T reg cells from steroid-resistant asthmatics
resulted in increased production of the antiinflammatory cytokine
IL-10 with steroid stimulation and also reduced IgE production
from human peripheral B cells.40 Moreover, it has also been
speculated that polymorphisms in the vitamin D receptor play a
role in asthma, but data are inconsistent. Several clinical trials to
demonstrate efficacy of vitamin D in asthma treatment have been
performed in children and adults. In a study of vitamin D3
supplementation in adults with persistent asthma vitamin D
insufficiency, the rate of first treatment failure or exacerbation was
not reduced.41 Data in children are more mixed, with some studies
showing modest effect on exacerbation reduction but little effect on
other clinical outcomes.42 Further research is needed to substantiate
the role of vitamin D in asthma pathophysiology.

Nocturnal Asthma
There is a circadian variation in airway function and bronchial
hyperresponsiveness in most patients with asthma. In individuals
with a normal sleep-wake cycle, the worst peak expiratory flow rate
(PEFR) and the most pronounced reactivity occur at approximately
4 a.m., and the best occur at 4 p.m. Nocturnal asthma is a risk factor
for asthma severity and even death in some asthmatics. Although
nocturnal asthma may result from late-phase reactions to earlier

2570
allergen exposure, GER, or sinusitis in some patients, these
conditions are not present in most patients with severe nocturnal
asthma. Another explanation is an increase in inflammatory cell
infiltrate as an exaggerated normal circadian variation.
Abnormalities in central nervous system control of respiratory
drive, particularly with defective hypoxic drive and obstructive
sleep apnea, as well as physiologic increases in airway
parasympathetic tone, reduction in lung volume, and airway
smooth muscle unloading may also be present in some patients
with nocturnal asthma. Recent work suggests that those with
African ancestry who are obese and have lower lung function may
be at increased risk for nocturnal asthma and reported a twofold
increase compared to European Caucasian counterparts.43

Laboratory Diagnosis
A number of laboratory studies may be useful in confirming the
diagnosis of asthma, and objective measures of pulmonary function
are among the most important.

Lung Function Tests

PFTs, particularly spirometry, are objective, noninvasive, and
extremely helpful in the diagnosis and follow-up of patients with
asthma. Examination of the forced vital capacity (FVC), FEV1, and
forced expiratory flow rate over 25%–75% of the FVC (FEF25–75) is a
reliable way to detect baseline airway obstruction. Examination of
the volume-time curve and shape of the flow-volume loop provides
an estimate of the adequacy of the patient effort in performing the
test. A PFT should be attempted on all children older than 5 years
of age when considering the diagnosis of asthma. However, there is
some controversy regarding the value of repeated measures of lung
function compared with symptom report in improving asthma
outcomes.44 Nevertheless, attempting to achieve and maintain
normal or near normal lung function is a goal for all asthmatic
children.
In children, measurement of FEV1 alone may miss airway

2571
obstruction; the FEV1/FVC has been proposed as a more sensitive
measure of obstruction. FEF25–75 has been proposed as a more
sensitive indicator of airway obstruction, in the small airways in
particular, and a better indicator of a response to bronchodilators
and airway hyperresponsiveness than either FEV1 or FVC.
However, recent data indicate that this information is not entirely
accurate. The FEF25–75 is a highly variable measure that is readily
influenced by expiratory time and change in FVC. Examination of
large data sets including children with asthma and cystic fibrosis
indicates that less than 3% of the test results showed a reduced
FEF25–75% with both FEV1/FVC and FVC within the normal range.45
Documentation of reversibility of air flow obstruction following
inhalation of a bronchodilator is central to the definition of asthma.
If obstruction is demonstrated on a baseline PFT, a bronchodilating
aerosol (albuterol) should be administered and the PFT repeated in
10–20 minutes. An improvement of at least 12% and 200 mL in the
FEV1 is considered a positive response and is indicative of
reversible air flow obstruction; however, in children, an
improvement of 10% may be adequate to indicate significant
improvement. A 10% improvement in the percent predicted FEV1 is
also considered a positive response.
Use of a peak flow meter in the office setting may provide some
useful information about obstruction in the large central airways,
but the test should not be used to diagnose asthma. PEFR is
extremely effort-dependent and is only reflective of obstruction in
the large central airways.
Although standard spirometry has long been considered the gold
standard for use in diagnosing and monitoring change in airway
function in patients with asthma, other modalities may have
particular application in both younger and older children. Forced
oscillation capitalizes on the resonant oscillation properties of the
airways to measure conductance and reactance and, indirectly,
airway resistance.46 The technique requires only tidal breathing on a
mouthpiece for 30 seconds in order to obtain a measurement;
response to a bronchodilator can also be detected. In some studies,
area of reactance (AX) as measured by forced oscillation was able to
discriminate those with asthma, even when FEV1 was not different

2572
between the two groups.47 Widespread adoption of forced
oscillation techniques has not occurred largely due to lack of
reliable normative values.

Bronchial Challenge Tests

Airway hyperreactivity to substances such as methacholine,
histamine, hypertonic saline, adenosine monophosphate, or
mannitol forms the basis of an adjunctive diagnostic test for asthma
(Video 45.2 ). However, the sensitivity and specificity of the tests
vary widely, and bronchoprovocation testing cannot serve as the
sole determinant of an asthma diagnosis. Methacholine and
histamine are considered direct bronchoprovocation agents because
they act directly on smooth muscle. Direct bronchoprovocation
challenge testing with methacholine is very sensitive and has a
better negative than positive predictive value. As such, it is
generally more helpful in excluding than diagnosing asthma
because positive results may be seen in disorders such as cystic
fibrosis, COPD, chronic bronchitis, allergic rhinitis, and even in
some normal individuals. FEV1 is the primary measure used to
assess response, and the concentration of methacholine at which a
20% decrease in FEV1 occurs is recorded (PC20); other methods use
the cumulative dose (PD20). A PC20 of ≤ 4 mg/mL is considered a
positive test result indicative of airway hyperreactivity. However,
there is no universally accepted threshold PC20 value that is
considered diagnostic of asthma (Table 45.1). Accurate
interpretation must account for degree of baseline obstruction (if
any), the pretest probability of asthma, the presence of current
symptoms, and the degree of recovery in postchallenge FEV1. Mild
transient adverse effects (i.e., cough, wheezing, chest tightness, and
dizziness) are uncommon and occur in less than 20% of patients
receiving either histamine or methacholine challenge. Delayed or
prolonged reactions are extremely rare, and fatalities after
methacholine have not been reported. However, methacholine (or
any bronchoprovocation test) should not be performed if the
baseline FEV1 is low (generally less than 60% predicted).48

2573
Table 45.1

Interpretation of Methacholine Challenge Test Results

PC20 (mg/mL) Suggested Interpretation

<1.0 Moderate to severe reactivity (asthma likely)
1–4 Mild reactivity
4–16 Borderline reactivity
>16 Normal (no significant reactivity; asthma unlikely)
Assumes that there is no baseline airway obstruction and that postchallenge
improvement to baseline forced expiratory volume in 1 second occurs.

Indirect bronchoprovocation agents (i.e., hypertonic saline,

adenosine monophosphate [AMP], mannitol) act by inducing
release of inflammatory mediators in the airway, which then cause
bronchoconstriction. In addition, indirect testing is well correlated
with the degree of airway inflammation. Inhalation testing with
dry-powder mannitol has good validity, and a commercial kit is
approved for use in Europe, Australia, and the United States.
Mannitol has the advantage of being safe and easy, and it requires
no special equipment apart from a spirometer. A cut point of 15%
decrease in FEV1 from baseline had a specificity of 98% but a
sensitivity of only 58%.49 Other agents such as allergens and
occupational sensitizers have been used for inhalation challenge
tests, but such challenges may pose significant risk and should only
be performed by experienced physicians and investigators in the
context of specific clinical or research settings. Indeed, bronchial
challenge tests with any inhaled agents should only be performed
in certified pulmonary function laboratories under the direct
supervision of a trained specialist.

Exercise Challenge Test

In individuals 6 years of age through adulthood, a treadmill or
bicycle ergometer exercise test provides useful information about
the presence of EIB or EIA. In children with histories suggestive of
EIB, an exercise challenge test is a more useful diagnostic aid than a
methacholine challenge test (Video 45.3 ). The inhaled air should
be dry, and the child should exercise at maximal level for 4–6
minutes and for a total time of 6–8 minutes. Maximal exercise is

2574
usually determined by heart rate (80%–90% of age maximum) or
maximum voluntary ventilation (FEV1 × 35); the target should be
reached relatively quickly. Pulmonary function should be measured
5 minutes before exercise. Following exercise, serial pulmonary
function measurements should be obtained for at least 20 minutes
(at 5, 10, and 20 minutes postexercise) to determine the presence
and severity of EIA. A decrease in FEV1 of more than 10% is
diagnostic of exercise-induced bronchoconstriction; some sources
suggest a threshold of 15% decrease.48

Other Tests
Complete Blood Cell Count
Often the complete blood cell count is normal and offers little
information in the diagnosis or management of asthma and may be
most useful when searching for other complicating conditions (e.g.,
immunodeficiency states) rather than as a primary diagnostic aid.
However, eosinophilia, if present, most commonly suggests
asthma, allergy, or both. Although there are other causes of
peripheral eosinophilia in children (i.e., gastrointestinal or systemic
eosinophilic disorder, parasitic infection, malignancy, and human
immunodeficiency virus infection), asthma and allergy are the most
likely causes. There has been renewed interest in using peripheral
eosinophil count to both suggest an asthma diagnosis as well as to
assign asthma phenotype.50 Elevated blood eosinophil counts are
not always associated with atopy, but there are data to support that
eosinophil counts of 400/µL and above are more strongly associated
with atopic asthma.51

Cytologic Examination of Sputum

Obtaining induced sputum by inhaling hypertonic saline aerosols
generated by an ultrasonic nebulizer is a useful technique for
helping identify active inflammation in the airways characteristic of
asthma. The presence and number of eosinophils and other
inflammatory cells can provide useful information about disease
phenotype, activity, and response to therapy.52 Improved asthma

2575
control and reduced exacerbations were noted when there were less
than 3% eosinophils in the induced sputum of adult asthmatics, but
results in children are not consistent.53,54 Neutrophilic inflammation
predominates in some patients, while others have a paucity of
inflammatory cells. Using cluster analysis in a study of adults
enrolled in the Severe Asthma Research Program, over 80% of those
in clusters with more severe asthma refractory to treatment with
high-dose inhaled steroids and those with lower lung function had
sputum neutrophilia.55 Those in clusters with mild to moderate
atopic disease had either eosinophilia or minimal inflammatory
cells of any type. However, data from a small study of children
with more severe asthma showed that the absence of blood
eosinophilia did not predict absence of eosinophils in induced
sputum or bronchoalveolar lavage (BAL).56 Although the technique
of obtaining induced sputum is relatively simple, it does require
trained personnel, use of an established protocol, and specimen
processing and is usually only successful in children that are at least
8 or 9 years of age. However, a recent report demonstrated success
in obtaining induced sputum samples in children as young as 7
months using physical activity (or crying) followed by
oropharyngeal suctioning to obtain the sample; 96% of 72 children
aged 7–76 months were able to produce a sample.57

Exhaled Nitric Oxide

NO is an important and widespread regulatory molecule that has
diverse biological functions. NO is synthesized from L-arginine by
three different forms of the enzyme NO synthase (NOS):
constitutive forms—endothelial NOS (eNOS) found in endothelial
cells and nNOS in neuronal tissue—and an inducible form, iNOS.
Although the precise role of NO in the asthmatic airway remains
uncertain, NO can function as a bronchodilator, has antimicrobial
properties, has antiproliferative action on fibroblasts, and is
involved in regulation of ciliary beat frequency and epithelial ion
transport.52 Fractional exhaled NO (FeNO) monitoring has been
proposed as a biomarker useful in asthma diagnosis, monitoring
control and adjusting treatment, and predicting exacerbations. In
many but not all asthma patients, high exhaled NO concentrations,

2576
compared with the nonasthmatic, coupled with a reduction with
inhaled steroid treatment suggest an active or counterregulatory
role in the development or persistence of asthma. Most data
support direct correlation between clinical markers of eosinophilic
airway inflammation or atopy and FeNO, including the degree of
airway hyperresponsiveness as measured by methacholine
challenge.52,58,59 Other measures (e.g., FEV1, bronchodilator
response, and symptom report) correlate only weakly with FeNO.
In a study of 128 school-aged children with asthma and allergic
sensitization, mean FeNO levels were significantly different
between those children with no sensitization and those children
with 1–3, 4–5, and ≥6 positive skin prick tests.60 In addition, those
sensitized to cat, mouse, dust mite, rat, and cockroach had FeNO
levels that were significantly higher compared with those who were
not sensitized. After adjustment for age, sex, ICS use, and asthma
control level, cat and rat allergen remained significant independent
predictors of elevated FeNO.
Although FeNO has proved of value in some situations and
patient populations, a number of limitations exist.61 Weaknesses
include poor ability to identify noneosinophilic inflammation and
lack of specificity for asthma. Elevated FeNO also occurs in
individuals with allergic rhinitis, eosinophilic bronchitis, COPD,
and lung allograft rejection.
The determination of clinical cutoff points for diagnosing asthma,
adjusting treatment, and predicting exacerbations remains
controversial. FeNO levels are affected by many factors, including,
race, age, ingestion of nitrate rich foods (raises), and tobacco smoke
exposure (lowers). If other clinical conditions associated with
elevated FeNO are excluded, a FeNO higher than documented
clinical cutoffs (Table 45.2) can be useful in supporting a diagnosis
of asthma.62 The common presence of atopy in children apart from
asthma limits FeNO as an accurate diagnostic tool.

Table 45.2
Range and Interpretation of Fractional Exhaled Nitric Oxide Values
in Adults and Children. Symptoms Refer to Cough and/or Wheeze
and/or Shortness of Breath

2577
 FeNO < 25 ppb FeNO 25–50
ppb FeNO > 50 ppb
(<20 ppb in
(20–35 ppb in (>35 ppb in Children)
Children)
Children)
DIAGNOSIS
Symptoms present Eosinophilic Be cautious Eosinophilic airway
during past 6 + airway Evaluate inflammation present
weeks inflammation clinical context Likely to benefit from
unlikely Monitor ICS
Alternative change in
diagnoses FeNO over
Unlikely to benefit time
from ICS
MONITORING (IN PATIENTS WITH DIAGNOSED ASTHMA)
Symptoms present Possible Persistent Persistent allergen
alternative allergen exposure
diagnoses exposure Poor adherence or
Unlikely to benefit Inadequate inhaler technique
from increase in ICS dose Inadequate ICS dose
ICS Poor Risk for exacerbation
adherence Steroid resistance
Steroid
resistance
Symptoms absent Adequate ICS Adequate ICS ICS withdrawal or dose
dose dosing reduction may result in
Good adherence Good relapse
ICS taper adherence Poor adherence or
Monitor inhaler technique
change in
FeNO
FeNO, Fraction of exhaled nitric oxide; ICS, inhaled corticosteroid.
Reprinted with permission of the American Thoracic Society. Copyright 2016
American Thoracic Society. The American Journal of Respiratory and Critical Care
Medicine is an official journal of the American Thoracic Society. See reference 53.

A number of studies have used FeNO to adjust treatment with

inhaled steroids with mixed results.63–65 A large trial conducted in
largely black and Hispanic children compared adding FeNO to
usual care (Expert Panel Review [EPR] 2 guideline) in children aged
12–20 years.63 All participants improved during the run-in period,
probably related to the use of guideline care by specialists and the
direct provision of medication to the child. In the intervention
period, using symptom days and exacerbations as outcomes, no
differences between usual care and FeNO groups were noted; but
the use of FeNO resulted in higher doses of ICSs.
In a relatively small study done in seven Belgian hospitals,
children aged 5–14 years with allergic asthma were randomized to
a group managed with symptoms and FEV1 or FeNO.64 In the

2578
FeNO group, a single target value of 20 ppb was used to increase
treatment (>20 ppb) or lower treatment (≤20 ppb). In a 1-year
follow-up period, there was no difference between the groups in
the primary outcome of symptom free days, but there was a
significant decrease in exacerbations. However, the exacerbations
were largely related to an increase in symptoms and unscheduled
medical contact; there was no difference in emergency visits or
hospitalizations. A recent meta-analysis suggested that using FeNO
to guide treatment decisions has little clinical benefit, although this
may result in a decrease in asthma exacerbations.65
Commercial devices are available that permit the rapid,
noninvasive, and easy measurement of eNO (in parts per billion,
ppb) and are priced in the same range as a desktop portable
spirometer.61,67 Although somewhat easier to perform than standard
spirometry, children younger than 6 or 7 years of age are not
consistently able to perform an online FeNO measure; however,
offline collection methods using tidal breathing and Mylar
collection bags have been used in younger children and infants.
A number of studies have demonstrated the presence of a variety
of inflammatory mediators in the liquid condensate from cooled
exhaled air collected over a number of minutes. Cytokines,
leukotrienes, nitrates, and other substances have all been reported
in exhaled breath condensate (EBC), and in some but not all studies,
they correlate with asthma disease activity.68 In addition, an acid
pH in the EBC has also been reported to be a marker of airway
inflammation. More recently, devices that measure volatile organic
compounds in exhaled breath, so-called electronic noses, have been
used to discriminate airway and lung disease states, including
asthma. These devices capitalize in part on measuring metabolomic
airway products that provide a selective “breath print” that
identifies asthma phenotypes.69 However, there is still great
controversy over standardization of the technique, the derivation of
the measured substances (sampling of airway lining fluid rather
than volatilized molecules), and the measurement of mediators.
EBC has yet to prove useful as a noninvasive measure of airway
inflammation, and it is currently a research tool.70

Serum Tests

2579
Determining quantitative levels of immunoglobulin G (and
subclasses), M, and A is useful only to rule out immunodeficiency
syndromes in children with recurrent or chronic infection. In
children with asthma, IgG levels usually are normal, IgA levels are
occasionally low, and IgM levels may be elevated. Systemic
steroids, however, can depress IgG and perhaps IgA levels. Total
serum IgE is often elevated in the child with asthma, atopy, or both;
however, a normal IgE does not rule out asthma as a cause of
symptoms. Although a rare condition in pediatric patients, in the
child with shifting pulmonary infiltrates, a marked elevation of
serum IgE (>1000 IU/mL) should prompt tests for both IgG and
specific IgE antibody to Aspergillus to evaluate for allergic
bronchopulmonary aspergillosis (see Chapter 65).

Sweat Test
A sweat test (determination of chloride concentration in sweat)
should be considered in children with chronic, otherwise
unexplained, respiratory symptoms, including recurrent wheezing,
to rule out cystic fibrosis, even in areas where newborn screening
for the disease is carried out (discussed later). Associated signs and
symptoms that should prompt a sweat test include poor weight
gain and short stature, steatorrhea, nasal polyps, pansinusitis,
hemoptysis, and digital clubbing. Newborn screening for cystic
fibrosis is now universal in the United States, and most cases of
cystic fibrosis are diagnosed in infancy or the preschool years, but
screening does have a false negative rate of approximately 5%,
depending on the cutoff values and the methods chosen. Mutations
conferring pancreatic sufficiency, and other rare mutations are
typically associated with milder pulmonary disease and may
present much later than infancy (see Chapter 50).

Radiographs
Most children with suspected asthma should have a chest
radiograph at some time to rule out parenchymal disease,
congenital anomaly, and (direct or indirect) evidence of a foreign
body, particularly if the asthma diagnosis is questionable.
However, a normal chest radiograph does not rule out other

2580
diagnoses, particularly a retained airway or esophageal foreign
body. A chest radiograph should be considered for the child
admitted to a hospital with asthma, particularly if there are
localized findings on physical examination (i.e., crackles, egophony,
diminished breath sounds), fever, or persistent hypoxemia.
Radiographic findings in asthma may range from normal to
hyperinflation with peribronchial interstitial markings and
atelectasis (Fig. 45.4A); infiltrates, atelectasis, pneumonia, or a
combination of the three (see Fig. 45.4B); and pneumomediastinum
(see Fig. 45.4C), often with infiltrates. Pneumothorax occurs rarely
(see Fig. 45.4D).

2581
 FIG. 45.4 Radiographic findings in asthma. (A)
Hyperinflation with increased bronchial markings. (B)
Atelectasis involving a complete lobe. (C) Massive
pneumomediastinum complicating asthma. (D)
Pneumothorax secondary to paroxysmal coughing in
asthma. Arrows mark air in (C), lung margin in (D).

Paranasal sinus radiographs or screening sinus computed

tomography can also be considered for children with persistent
nocturnal coughing, nasal symptoms, and headaches. Although
acute and chronic rhinosinusitis have long been associated with an
increase in symptoms in children with asthma, a recent study

2582
indicates that long-term treatment with nasal corticosteroids did
not improve asthma control.71 In a 24-week placebo controlled trial
of daily intranasal mometasone, children with asthma and
symptoms of rhinosinusitis did not show improvement in asthma
control or reduction in exacerbations compared to placebo. Nasal
symptoms did improve, but the study results argue against treating
nasal symptoms to improve asthma control.

Allergy Testing
Allergy testing (skin testing or in vitro serum allergen-specific IgE
measure) is indicated in patients in whom specific allergic factors
are believed to be important and in all children with severe asthma.
Numerous allergic factors that might contribute significantly to the
asthma (e.g., pollen, mold, dust mite, cockroach, or dander from
domestic animals) occur in the home or at school. After taking a
detailed environmental history, skin testing should be performed
(usually percutaneous or scratch), limited to the most likely
allergens, as suggested by the history.
Skin test results may vary with age, drug therapy, and inherent
skin factors. Drugs that affect skin test results include H1
antihistamines (which may inhibit skin reactions for up to 72 hours
or longer), tricyclic antidepressants, and some histamine (H2)
blockers. Topical and systemic corticosteroids or montelukast do
not affect skin reactions. Positive (histamine) and negative (saline)
control tests should be included to detect inherent skin factors that
may affect the reaction to allergen, such as dermatographism and
extensive dryness or eczema.
The in vitro measure of allergen-specific IgE (s-IgE) makes use of
the affinity of serum IgE antibody for antigen that has been bound
to a solid phase substrate. The s-IgE is no more specific than the
antigen employed, but it can produce a quantitative result, thus
allowing the degree of sensitization to be measured. The s-IgE test
is significantly more expensive than skin testing, but it can be
performed in commercial laboratories and is useful for situations in
which skin tests are impractical (e.g., for the patient with
generalized dermatitis or dermatographism, or if the patient must
continue to receive medications with antihistaminic activity) or to

2583
better quantify the degree of allergic sensitization (higher value of
s-IgE).

Therapeutic Considerations
Both the most recent US guidelines for the diagnosis and
management of asthma (Expert Panel Report 3) and the
international Global Initiative for Asthma (GINA) guidelines stress
the importance of asthma control as compared with severity.1,72
Asthma severity refers to the intrinsic intensity of the disease and is
typically assigned prior to beginning treatment with controller
medications, and is also reassessed at intervals after treatment to
determine degree of responsiveness to treatment. As a result,
severity becomes defined by the level of treatment necessary to
achieve and maintain adequate control. Identifying children and
adolescents with severe or therapy resistant asthma is important
because the need for close monitoring and aggressive treatment will
be significant. For most other patients, accurate assessment of
control is more important than severity assignment in order to
adequately manage asthma.
Asthma control is divided into two components: impairment or
symptom control and risk. The impairment domain refers to daytime
and nighttime symptoms (i.e., cough, wheeze, exercise limitation),
the need for rescue medication (SABA) for the treatment of
symptoms, deviation from normal levels of activity (i.e., playing,
sleeping, attending work or school), preserving normal or near-
normal lung function, and meeting patient and parent expectations.
The risk domain refers to preventing severe exacerbations that
require medical attention, such as prescription of systemic steroids,
emergency medical treatment or hospitalization, loss of lung
function or impairment of normal lung growth, and adverse effects
caused by medication use. This strategy draws attention to the
management of current symptoms and functional impairment, as
well as the future effects of asthma and its treatment on lung
function and severe exacerbations. It also highlights the very
important observation that asthma treatment strategies that
improve symptoms may not always result in the prevention of
significant exacerbations.

2584
 Asthma is best managed in a continuous fashion by forming a
partnership with a knowledgeable physician or other health care
provider. The concept of expecting a near symptom-free lifestyle
(for all but the most severely affected patients) should be instilled in
patients and their families. Unnecessary restrictions of the child's
and family's lifestyles should be avoided. Participation in
recreational activities, sports, and school attendance should all be
expected. Psychosocial factors such as the child's behavior, social
adjustments in the family and at school, and attitudes toward
managing asthma should also be addressed. Parents should
understand that asthma is a chronic disease with acute
exacerbations that with currently available treatments can be
controlled, but not cured. As better characterization of the
inflammatory processes and pathways that affect the airway in
specific patients and development of real-time noninvasive
monitoring techniques occurs, more precise control of asthma
symptoms or even primary or secondary disease prevention may
become a realistic goal of asthma management.

Classification of Asthma
Over the past decade, increasing awareness has been focused on the
broad heterogeneity of asthma, both with respect to its causes,
manifestations, and response to treatment. Identification of specific
asthma phenotypes is expanding, and the use of biomarkers,
molecular phenotyping, and cluster analysis based on symptoms,
lung function, and comorbidities can help identify specific
subtypes. Age of onset of symptoms, lung function, inflammatory
cell types and mediators in induced sputum, and atopic versus
nonatopic are all markers used to characterize disease severity,
symptom pattern, and response to treatment. Considerable research
is still needed to accurately identify asthma phenotypes and to
determine clinically useful methods for classification.
Although the clinical utility is somewhat questionable, asthma
severity refers to the intrinsic intensity of the disease and may be
classified into broad categories based on frequency of daytime and
nighttime symptoms, play or activity limitation, need for
rescue/reliever treatment, and objective measures of pulmonary

2585
function (PEFR or FEV1) that are typically present before the patient
is treated. In addition, the number, frequency, and intensity of
severe exacerbations—defined as an increase in symptoms
sufficient to warrant treatment with oral corticosteroids or
treatment in the emergency department or inpatient hospital unit—
are considered. Some patients who have relatively well-controlled
symptoms and good functional status may have frequent or intense
exacerbations. Although the correlation between the number and
intensity of exacerbations with severity levels is less clear, the
greater the number and severity (e.g., need for hospitalization,
intensive care treatment), the higher the severity. However, the
degree of severity of asthma often changes in a given individual
with time, response to treatment, airway injury or growth, the
development of newly acquired allergic sensitivities, or change in
exposure to recognized triggers. As a result, determination of
control after treatment has been instituted is of greater significance
than assigning a severity level. Using very similar criteria, asthma is
determined to be well controlled, not well controlled, or very
poorly controlled (Table 45.3). Control is determined at every visit,
and appropriate treatment adjustments are made. The frequency of
physician office visits for assessment of asthma control is variable
and depends on disease activity but typically is every 1–6 months.
Those with poor control or recent exacerbation may require more
frequent visits for treatment monitoring of response and adjustment
and monitoring of lung function. Since asthma is a chronic disorder
that may become clinically obvious only periodically—one in which
the severity of airway obstruction, intensity of symptoms, and
degree of impairment is frequently underestimated by physicians
and patients alike, the use of a standard, validated questionnaire
can help overcome this discrepancy.

Table 45.3
Assessing Asthma Control and Adjusting Therapy in Children 5–
12 Years of Age

CLASSIFICATION OF ASTHMA CONTROL (5–11 YEARS OF AGE)

Components
of Control Not Well Very Poorly
Well Controlled
Controlled Controlled
Impairment Symptoms ≤2 days/week but >2 days/week or Throughout the

2586
 not more than multiple time on day
once on each day. less than 2
days/week
Nighttime ≤1×/month ≥2×/month ≥2×/week
awakenings
Interference with None Some limitation Extremely limited
normal activity
Short acting beta- ≤2 days/week >2 days/week Several times per
agonist use for day
symptom control
(not prevention of
EIB)
Lung function
FEV1 or peak flow >80% 60%–80% <60%
predicted/personal predicted/personal predicted/personal
best best best
FEV1/FVC >80% 75%–80% <75%
Risk Exacerbations 0–1/year ≥2/year (see note)
requiring oral
systemic
corticosteroids
CONSIDER SEVERITY AND INTERVAL SINCE LAST
EXACERBATION
Reduction in lung Evaluation requires long-term follow-up
growth
Treatment related Medication side effects can vary in intensity from none to
adverse effects very troublesome and worrisome. The level of intensity
does not correlate to specific levels of control but should be
considered in the overall assessment of risk.
Recommended Maintain Step up at Consider short
action for current step least 1 step course of oral
treatment Regular and systemic
(See Fig. 45.1B follow-up Reevaluate in corticosteroids
for treatment every 1–6 2–6 weeks Step up at
steps) months For side effects least 1 step
Consider step consider and
down if well alternative Reevaluate in
controlled for treatment 2–6 weeks
at least 3 options For side effects
months consider
alternative
treatment
options
The stepwise approach is meant to assist, not replace, the clinical decision making
required to meet individual patient needs.
The level of control is based on the most severe impairment or risk category. Assess
impairment domain by patient's/caregiver's recall of previous 2–4 weeks and by
spirometry/or peak flow measures. Symptom assessment for longer periods should
reflect a global assessment such as inquiring whether the patient's asthma is better
or worse since the last visit.
At present, there are inadequate data to correspond frequencies of exacerbations
with different levels of asthma control. In general, more frequent and intense
exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU

2587
admission) indicate poorer disease control. For treatment purposes, patients who
had ≥2 exacerbations requiring oral systemic corticosteroids in the past year may be
considered the same as patients who have persistent asthma, even in the absence
of impairment levels consistent with persistent asthma.
Before step up in therapy:
Review adherence to medications, inhaler technique, environmental control, and
comorbid conditions.
If alternative treatment option was used in step, discontinue it and use preferred
treatment for that step.
EIB, Exercise-induced bronchospasm; FEV1, forced expiratory volume in 1 second;
FVC, forced vital capacity.
From NIH Expert Panel Report 3.1

There are several short, self-administered instruments (e.g., the

Asthma Control Test [ACT], Asthma Control Questionnaire,
Asthma Therapy Assessment Questionnaire) that provide a score
indicative of well-controlled, not well-controlled, and poorly
controlled asthma.1 These tools do not assess the risk domain,
which must also be factored into treatment decisions. A newer
measure, the Composite Asthma Severity Index (CASI),
incorporates symptoms, treatment level, exacerbations, and lung
function into a measure that shows better responsiveness than the
ACT or symptom measure alone.73 Further validation will be
necessary to determine its clinical utility.
The most recent NHLBI guidelines classify asthma as either
intermittent or persistent and within the persistent category as mild,
moderate, or severe.1,74,75
The use of cluster analysis techniques shows promise in further
stratifying severe asthma phenotypes into more discrete subtypes
that will help with prospective identification and long-term follow-
up and treatment.76 See Chapter 46 for a detailed discussion of
severe asthma.

Other Measures for Assessing Asthma

Severity and Control
Biomarkers that provide more information on disease activity and
severity could better guide asthma treatment and improve control
or reduce exacerbations. However, currently available tests are

2588
limited in both availability and utility or practicality. Older models
using degree of airway reactivity based on methacholine
responsiveness or proportion of eosinophils contained in induced
sputum, and then adjusting treatment to decrease airway reactivity
or eosinophil counts were shown to achieve better pulmonary
function and fewer exacerbations than monitoring symptoms and
pulmonary function alone in adults.1 However, repeated
methacholine challenge testing or sputum induction is expensive,
time-consuming, and generally impractical in the clinical setting,
especially in the pediatric population. As discussed earlier, FeNO
has been proposed as an easily obtainable measure of eosinophilic
airway inflammation and could therefore be used to titrate
treatment to achieve better control. Although in steroid-naïve
asthmatics FeNO is elevated and in most patients the levels
decrease within 1 week of instituting inhaled steroid treatment,
FeNO remains essentially unchanged in as many as 30%, even
when clinical improvement occurs.59 Moreover, a number of large
randomized, controlled trials that used either daily home or
intermittent in-office FeNO measures to adjust treatment failed to
find a difference in improvement in the number of symptom-free
days or a reduction in ICS dose when compared with standard
treatment using symptom report and pulmonary function
measures.77,78 It has been suggested that FeNO may be useful when
there is discordance between patient-reported symptoms and
airway inflammation.63 However, data from one prospective study
using ACT and FeNO to monitor asthma control and adjust
treatment in school-aged children did not support added benefit
from FeNO measurement.79 In addition, nearly a third of the
patients switched from a concordant to discordant phenotype over
the course of 4 weeks in the trial. Although symptom-free days
improved over a year in those with unstable phenotype, there was
no difference in those in the FeNO group compared with those
without FeNO monitoring. In spite of its limitations, FeNO may be
useful in some settings, such as a diagnostic aid for asthma,
identification of steroid-responsive patients, and (to a lesser extent)
adjusting the dose of controller medications and predicting relapse
during medication taper.
Recently there has been substantial interest in the airway

2589
microbiome, with several lines of evidence supporting a role for the
bacterial ecosystem of the upper and lower airway in both
maintaining pulmonary health and causing chronic conditions,
such as asthma. Although there are data that suggest the airway
microbiome may differ in those with asthma and healthy controls,
as well as differences between degrees of asthma severity,80,81
further research is needed to determine causation and influences of
microbiome on immune dysregulation in the airways. Moreover, it
is likely that there are “fungal-biomes” and “viral-biomes” that may
also influence development and severity of airway disorders, but
little data are currently available.

Pharmacologic Management of
Asthma in Children Older Than 5
Years of Age
The medical treatment of asthma involves the administration of
controller medications designed to prevent asthma symptoms and
the use of rapid-acting reliever medications that quickly abort acute
exacerbations. Controller medications are administered to all
asthmatics other than those with intermittent disease and are
typically, but not uniformly, antiinflammatory in nature (Table
45.4A). Reliever medications are SABA or anticholinergics. Several
immunomodulatory drugs are currently available for treatment of
severe persistent asthma and a number of other such biologics are
under development, discussed in Chapter 48.

Table 45.4A
Usual Dosages for Long-Term Controller Medications

Medication Youth >12 Years Child Dose

SYSTEMIC CORTICOSTEROIDS
Methylprednisolone (chronic 7.5–60 mg 0.25–2 mg/kg1
control) Once daily or every other day
as needed for control
Prednisolone, prednisone (short- 40–60 mg 1–2 mg/kg
course for exacerbation) Administer for 3–10 days once maximum 60
or in 2 divided doses mg/day
Dexamethasone 10–16 mg 0.6 mg/kg,

2590
 Give oral or IM for 1–2 days maximum 16 mg
LONG-ACTING INHALED β-2 AGONISTSa
Salmeterol 50 µg/puff 50 µg q 12 h 50 µg q 12 h
Formoterol 12 µg/capsule 1 capsule q 12 h 1 capsule q 12 h
COMBINATION MEDICATION
Fluticasone/Salmeterol
DPI 100, 250, 500 µg/50 µg 1 inhalation bid 1 inhalation bid
MDI 45/21, 115/21, 230/21 µg 2 inhalations bid 1–2 inhalations bid
Budesonide/formoterol 1–2 inhalations bid 1–2 inhalations bid
MDI 80/4.5; 160/4.5 µg
Mometasone/formoterol 1–2 inhalations bid 1–2 inhalations bid
MDI 100/5 µg; 200/5 µg Adjust dose strength to achieve
control
LEUKOTRIENE MODIFIERS
Montelukast 5 mg daily (6–14 years) 4 mg daily (2–5
10 mg daily (>14 years) years)
5 mg daily (6–14
years)
Zafirlukast 20 mg twice daily 10 mg twice daily
(7–11 years)
Zileuton 1200 mg bid
Methylxanthines
Theophylline, sustained release 300 mg daily 10/mg/kg daily, max
Adjust dose to serum 300 mg
concentration 5–10 mg/mL
a
Should not be used for symptom relief or for exacerbations. Use with inhaled
corticosteroids.
DPI, Dry-powder inhaler; IM, intramuscular; MDI, metered-dose inhaler.

Reliever Medications: Short-Acting β

Agonists
Short acting β2-adrenergic agonists (SABAs) constitute the most
potent bronchodilators currently available for treatment of asthma1
and are used to relieve bronchospasm and its attendant symptoms
of cough, wheezing, and shortness of breath. SABAs bind to the
widely distributed BAR (primarily those located on the bronchial
smooth muscle, airway epithelial cell, and mast cell) and result in
the intracellular conversion of adenosine triphosphate (ATP) to
adenosine 3′, 5′ cyclic monophosphate. The result is relaxation of
airway smooth muscle and improved air flow. Onset of action is
generally within a few minutes, peak action occurs at
approximately 30 minutes, and duration of action is from 4 to 6
hours.1 The preferred route of administration is by inhalation,

2591
because this method results in the most rapid onset and duration of
action while minimizing adverse effects. Inhalation of SABAs can
be accomplished with the use of a small-volume jet nebulizer,
metered-dose inhaler (MDI; usually and ideally with a spacer), or
dry-powder inhaler (DPI).
Several selective SABAs are available for treating acute asthma,
such as terbutaline and albuterol. Racemic albuterol, the
predominant bronchodilator in current use, is a 50 : 50 mixture of
(R)-enantiomers and (S)-enantiomers. Levalbuterol, the (R)-
albuterol isomer, has a 100-fold more potent β2 receptor binding
than (S)-albuterol, and it is responsible for the bronchodilator
effects of the racemate. In vitro, (S)-albuterol has been
demonstrated to increase intracellular Ca2+ to stimulate eosinophil
recruitment and degranulation and recruit other inflammatory
cells. The in vivo effects of (S)-albuterol remain unproven; however,
it has no bronchodilator activity and has a prolonged plasma half-
life, but it does not cause bronchoconstriction or interfere with the
binding of (R)-albuterol to its receptor. When administered in
equivalent doses based on the concentration of (R)-albuterol, there
does not appear to be any consistent clinical advantage to using
levalbuterol versus racemic albuterol as measured by improvement
in clinical symptoms, pulmonary function testing, or adverse effect
profile. Since levalbuterol is typically more expensive than the
racemic drug, the routine use of levalbuterol is generally not
recommended.
Typical adverse effects of SABAs include muscular tremor,
tachycardia, irritability, and with very high doses, hypokalemia,
hypertension, and tachyarrhythmia. Adverse effects are greater
with systemic administration (oral, intravenous [IV], intramuscular
[IM]) compared with the inhaled route. Moreover, the dose
delivered by an MDI is substantially less than that from a small-
volume nebulizer, and since most of the inhaled dose is swallowed
and absorbed by the gastrointestinal tract, annoying side effects are
best minimized by using an MDI with an appropriate spacer.
The clinical significance of serious adverse events that develop as
a result of the chronic administration of inhaled SABAs is, in most
instances, probably less than was once believed. The current
recommendation is for the as-needed use of a SABA for relief of

2592
symptoms or for protection against EIA. A retrospective review of
prescription records in patients in Canada found an increased risk
for asthma death or near-death in patients who used more than one
canister of a SABA per month. However, an association with the
use of a number of other asthma medications was also noted,
suggesting that disease severity might actually be more causative
than overuse of SABAs alone.82 Nonetheless, SABA overuse is a
worrying marker of future risk.
Reports have suggested that repeated use of a SABA may result
in an increase in airway hyperresponsiveness or a decrease in
protection from allergen-induced bronchospasm. The reduction in
beneficial effects of SABA following chronic use may result in part
from receptor desensitization, uncoupling of the receptor from its
signaling G protein, inactivation of receptors, or reduction in
receptor number caused by increased degradation or decreased
synthesis. A well-designed randomized double-blind placebo-
controlled study performed in adults with mild asthma examined
the effects of regularly administered albuterol versus intermittent
administration compared with placebo. There was no significant
difference in any outcome measures between the groups, including
exacerbations, treatment failures, lung function, symptoms, or
methacholine responsiveness.83 However, regular use of albuterol
was also not beneficial to the patients. Finally, there may be specific
subgroups of patients who are at risk for developing adverse
effects, as measured by worsening pulmonary function with
chronic use of SABAs, and this may be related to genetic variability
in the BAR. Nine polymorphisms in the BAR gene have been
described, and several of the more frequent types may have
biological significance. One involves the beta 2AR-16 region, with
replacement of arginine (Arg16) for glycine (Gly16). In a study
involving bronchodilator response in children, those with the
Arg/Arg polymorphism had the highest prevalence (60%) of
bronchodilator response to a single dose of albuterol, whereas
fewer than 30% of those with the Arg/Gly polymorphism responded
and only 13% of those with the Gly/Gly polymorphism were
responders.84 In contrast, data from a prospective study of chronic
albuterol administration to patients segregated by BAR genotype
found that those with the Arg16 homozygous polymorphism had

2593
steadily declining PEFR as compared with those receiving
intermittent treatment or treatment with ipratropium.85 This effect
did not occur in those with the Gly/Gly genotype. Chronic
administration of ipratropium to the Arg/Arg group did not result
in PEFR deterioration. In addition, recent studies point to other
polymorphisms not associated with the BAR but related to smooth
muscle proliferation that are associated with differential
responsiveness to short acting beta-agonists.86–88 Lastly, rare genetic
variants that are associated with ethnicity are also likely
contributors to the variability in response to SABA. A study in
Latino children described a number of such rare genetic variants in
genes associated with membrane ion transport, vascular smooth
muscle adhesion, and TGF-beta pathways.89 These data indicate the
importance of understanding ethnic and ancestral background in
identifying genetic risks for SABA responsiveness.

Anticholinergic Agents
Ipratropium bromide is a quaternary ammonium congener of
atropine and is an anticholinergic compound approved for use as a
bronchodilator. Anticholinergic agents produce bronchodilatation
by antagonizing the activity of acetylcholine at the level of its
receptor, particularly those found on airway smooth muscle in the
large, central airways. The onset of action of ipratropium is
relatively slow (20 minutes), and the peak effect occurs at 60
minutes.1 Ipratropium, unlike atropine, is poorly absorbed across
mucous membranes and has little toxicity at the usual doses. In
particular, ipratropium does not inhibit mucociliary clearance. Data
from several studies conducted in children presenting to the
emergency department for treatment of acute asthma indicate that
when combined with a β-adrenergic agonist, ipratropium improves
pulmonary function and relieves symptoms better than either drug
alone.1 The effect is modest and appears to be most evident in those
who present with the most severe airway obstruction; this may be a
marker for patients who have increased cholinergic tone in the
large central airways. Ipratropium has not been shown to be
effective in the treatment of children hospitalized with acute
asthma, particularly if ipratropium failed to induce improvement

2594
when administered in the emergency department.90

Controller Medications
Inhaled Corticosteroids
ICSs are currently considered the most effective controller
medication available for the treatment of chronic asthma. Most ICSs
have a high topical potency and relatively low systemic effects,
either as a result of poor absorption or rapid and effective
metabolism to inactive compounds. However, all ICSs are absorbed
through the respiratory epithelium to some degree, resulting in the
potential for systemic effects.
The ideal ICS should demonstrate excellent clinical efficacy and
minimal to no toxicity in combination with a convenient and easy-
to-use inhaler device. To achieve such a profile, an ICS should have
the following properties: a high affinity for and potency at the
glucocorticoid receptor (GR); prolonged retention in the lung; a
high level of serum protein binding for the systemically absorbed
fraction; a high volume of distribution; minimal or no oral
bioavailability; and rapid, complete systemic inactivation (e.g., high
first-pass hepatic inactivation, or inactivation in the lung before
systemic absorption).91 Together these properties confer a higher
therapeutic index with prolonged antiinflammatory activity in the
lung and relatively few systemic adverse effects. Pharmacologic
properties alone are not sufficient for optimum clinical effect. The
delivery devices should provide maximal deposition in the lung in
both large and smaller airways, with little to no deposition or
absorption in the oropharynx or gastrointestinal tract. Once-daily
administration is also likely to improve patient adherence.
Inhalation devices should be simple to use, should be acceptable to
a wide age range, and should deliver a consistent dose throughout
the life of the inhaler.

Fluticasone Propionate
Fluticasone propionate (FP) is a potent and poorly orally absorbed
topically active corticosteroid that is extensively metabolized in the

2595
liver to an inactive compound. This highly lipophilic drug
demonstrates an extremely high affinity for lung GRs compared
with beclomethasone (BDP) and shows a slow rate of dissociation
from its receptor. As a result, FP has a negligible oral
bioavailability, and the topical-to-systemic activity ratio is
exceptionally favorable and better than most currently available
ICSs. However, FP is readily absorbed through the respiratory
mucosa and can enter the systemic circulation in this fashion
(without hepatic metabolism). FP is more likely to produce sore
throat and hoarseness than other ICS. In addition, there have been
reports of adrenal suppression in children younger than 12 years of
age who receive more than 400 µg/day of FP, but the data are
inconsistent. FP is therefore considered a high-potency ICS, with
the potential to effectively control symptoms and improve lung
function, but at higher doses it has greater potential to cause
adverse effects. In vivo, FP appears at least twice as potent as BDP
and BUD on a milligram-per-milligram basis. Comparative trials
indicate that fluticasone at half the dose of BUD and BDP results in
a slight improvement of some pulmonary function measures, such
as morning PEFR and end-of-treatment trial FEV1.92 FP is currently
available in MDI and DPI form in three strengths (Table 45.5); it is
approved in the United States for use in children 4 years of age and
older.

Table 45.5
Estimated Comparative Daily Dosages for Inhaled Corticosteroid
in Older Children and Adults

Medium Daily
Drug Low Daily Dose High Daily Dose
Dose
5–11 >12 5–11 >12 5–11 >12
years years years years years years
Beclomethasone HFA 40 or 80 80–160 80–240 >160–320 >240– >320 µg >480 µg
µg/puff µg µg µg 480 µg
Budesonide suspension for 0.5 180–600 1.0 >600– >2.0 >1200
nebulization dry powder (90, 180, mg µg mg 1200 µg mg µg
or 200 µg/inhalation) 180– 400– >800
400 800 µg
µg µg
Flunisolide HFA 80 µg/puff 160 µg 320 µg 320 µg 320–640 ≥ 640 µg >640 µg
µg
Fluticasone dipropionate 88– 88– >176– 264– >352 >440

2596
 HFA/MDI: 44, 110, 220 176 264 352 440 µg µg
µg/puff µg µg µg µg >400 >500
DPI: 50, 100, 250 µg/puff 100– 100– 200– 300– µg µg
200 300 400 500
µg µg µg µg
Fluticasone furoate NA 100 NA 200 NA 400
100, 200 µg/puff µg/day µg/day µg/day
Mometasone DPI 110, 220 µg/puff 110 µg 220 µg 110–220 440 µg >440 µg >880 µg
mcg
Ciclesonide MDI 80, 160 µg/puff NA 160 µg NA 320 µg NA 640 µg
DPI, Dry-powder inhaler; HFA, Hydrofluoroalkane; NA, not approved for this age
group; MDI, metered-dose inhaler.
Adapted from NAEPP Expert Report 3.1

Fluticasone furoate is a new formulation of fluticasone that has

an extended half-life and can be taken once daily. It is available in
the United States as a dry powder inhaler in doses of 100 µg or 200
µg of fluticasone administered once per day and approved for
children and adolescents 12 years of age and older. The dose
response curve is similar to other ICS formulations.93 Fluticasone
furoate is also available with a fixed dose of 25 µg of the long-acting
beta-agonist, vilanterol per inhalation. At the current time, the
combination inhaler has been approved for use only in adults with
COPD and asthma.

Budesonide
BUD has been widely studied and used clinically for many years. It
has moderate potency in vitro and in vivo, with well-documented
clinical efficacy and safety. In addition, the presence of a free C21
hydroxy group on the BUD molecule results in formation of esters
with long-chain fatty acids. This results in an inactive depot of drug
within the airway epithelial cells that is released slowly into an
active state. BUD is currently available in a dry powder inhaler and
a nebulizer suspension. BUD is approved in the United States for
use in children 1 year of age and older. It is available in
combination with formoterol in an MDI form, which is approved in
the United States for use in children age ≥12 years.

Beclomethasone
Although clearly less potent than FP and slightly less so than BUD,

2597
BDP is effective in reducing symptoms and improving pulmonary
function. However, BDP is readily absorbed from the
gastrointestinal tract, and the parent compound (BDP) is
metabolized to the more potent monopropionate. As a result, BDP
has a less favorable topical-to-systemic potency ratio. However,
concerns about its ability to cause adverse effects such as growth
and adrenal suppression have not been substantiated. BDP is
currently available as a fine-particle aerosol dispensed by a
hydrofluoroalkane propellant. This propellant system permits
greater deposition into the lower and smaller airways and a
reduction in the effective dose. The clinical advantage of these
properties remains to be clarified. BDP is approved in the United
States for use in children 5 years of age and older. In low- and
middle-income countries, the low cost of BDP makes it a very
attractive medication.

Mometasone
Mometasone is a potent, highly topically active steroid that has
long been used to treat allergic rhinitis and dermatologic disorders.
It has the advantage of poor systemic absorption and has been
shown to be effective in improving lung function and controlling
symptoms in children with asthma who were previously treated
with other ICSs and SABAs. Mometasone is similar to FP in its high
receptor affinity and half-life. It appears to have a similar safety
profile to other ICSs. Mometasone is approved in the United States
for use in children 4 years of age and older. It is available in both
DPI and MDI forms for treatment of asthma and is labeled for once-
a-day dosing.

Ciclesonide
Ciclesonide is a prodrug that must be metabolized to active form in
the lung, where its metabolite has approximately 100 times greater
receptor affinity. It has essentially no oral bioavailability and is
tightly bound to plasma proteins. Ciclesonide is converted at the
airway epithelial cell into its active metabolite, des-ciclesonide (Des-
CIC); the enzyme responsible for the conversion is only found in
the lower respiratory tract. A recent meta-analysis concluded that

2598
ciclesonide was probably as effective as fluticasone, BUD, and BDP
in equivalent doses at improving pulmonary function and
controlling mild symptoms. Incidence of oral candidiasis was lower
in groups treated with ciclesonide. A single long-term (12-month)
safety study in children compared two doses of ciclesonide to
placebo and concluded that there was no significant effect on linear
growth or adrenal suppression.94 The study was somewhat flawed
in that there was no active comparator, no clinical effect of drug
was seen, and adherence was indirectly measured. Further studies
in children are necessary to assess dose responsiveness and safety.
Ciclesonide is approved in the United States for use in children 12
years of age and older.

Other Inhaled Corticosteroids

Flunisolide is an older, relatively less potent steroid that, while
effective, is less commonly used. It must be given in fairly high
microgram amounts, resulting in a bitter unpleasant taste.

Mechanism of Action and Clinical Use

There are several pathways through which corticosteroids decrease
inflammation. The action of corticosteroids begins as passive
diffusion across the cell membrane and into the cytoplasm where
binding to the GR occurs. The GR exists in the cytoplasm as a large
heterodimeric complex that includes two 90-kD heat shock protein
(HSP) molecules. After hormone binding, the HSPs are shed, the
receptor-steroid complex is translocated to the nucleus, and then
binds as a dimer to a glucocorticoid response element (GRE) on
steroid-responsive genes. The GR acts to regulate transcription of
target genes either directly or indirectly by interaction with other
transcription factors. The binding of the GR complex to GRE results
in either induction or repression of a gene. The number of GREs
and the proximity to transcriptional start sites affects the steroid
inducibility of the gene. Activation of inflammatory genes is
achieved by histone acetylation of the transcription complex. At
low doses, steroids suppress inflammation by recruiting histone
deacetylase-2 (HDAC2) to inactivate transcription of these genes.

2599
GRs may also act independently of binding to GRE by coactivating
other transcription factors (e.g., STAT5). At higher doses,
glucocorticoids control inflammation by increasing histone
acetylation of the transcription complex of antiinflammatory
genes.95
A major mediator of corticosteroid action on genes is the nuclear
transcription factor NFκB (nuclear factor kappa-light-chain-
enhancer of activated B cells). Corticosteroids block NFκB signaling
by preventing it from binding to DNA, which decreases
transcription of proinflammatory cytokines. Corticosteroids may
also inhibit NFκB by directly increasing production of its
cytoplasmic inhibitor protein IκB. IκB proteins bind to NFκB and
keep it anchored in the cytoplasm. In this manner, corticosteroids
inhibit the transcription of a number of cytokines and chemokines
implicated in the pathogenesis of asthma, such as interleukin-1 (IL-
1) through IL-6, tumor necrosis factor alpha (TNFα), granulocyte-
macrophage colony-stimulating factor, IL-13, IL-8, released on
activation, normal T cell expressed and secreted (RANTES), and
eotaxin. Steroids may also inhibit the synthesis of some cytokine
receptors, such as the IL-4 receptor, intracellular adhesion molecule
(ICAM), and vascular cell adhesion molecule (VCAM). In addition
to the action on cytokines, steroids also inhibit the inducible form of
NO synthase, cyclooxygenase, phospholipase A2, and endothelin,
all important factors in the inflammatory cascade relevant to
asthma. Corticosteroids also increase the synthesis of BAR by
increasing gene transcription.75,95
Because topical steroids can also cause rapid effects (e.g., skin
blanching), it is likely that there is also a rapid cellular mechanism
of action with transient vasoconstriction in the microcirculation,
which is independent of the genomic mechanism.96 This action
could involve the generation of vasoconstrictive mediators either at
the point of gluco-corticoid (GC) binding to certain membrane
receptors or at the time of dissociation of the HSP from the
cytoplasmic receptor complex.
ICSs are currently recommended as first-line therapy for children
with persistent asthma. ICSs are the most effective chronic
treatment for asthma and reduce airway reactivity, reduce acute
symptoms and exacerbations, attenuate the late allergen response,

2600
and decrease the need for rescue bronchodilators. In addition, ICSs
decrease deposition of collagen and extracellular matrix
glycoproteins, or tenascins, in the subepithelial basement
membrane. For these reasons, ICSs alone should be used as the
initial treatment for persistent asthma; it is not appropriate, in the
vast majority of cases, to use a fixed-dose combination of ICS plus a
long-acting β-agonist as initial treatment. Withdrawal of ICS
treatment is usually accompanied by a rapid return of airway
hyperresponsiveness and decreased symptom control within
several weeks.
A small but not insignificant proportion of patients do not have a
significant response to ICS. Children and adolescents who are
obese, smoke cigarettes, and have significant and continuous
exposure to certain allergens are relatively refractory to the
beneficial effects of ICSs on symptoms and lung function. The
mechanisms of this relative steroid resistance are not yet fully
understood. Recent data suggest that vitamin D deficiency is
associated with worse asthma control, and the mechanism may
involve induced steroid resistance.97 Vitamin D deficiency is
associated with increased oxidative stress and enhanced expression
of inflammatory mediators such as TNFα and NF-κB in patients
with asthma exacerbations.98 Vitamin D also prevents the
conversion of CD8 T lymphocytes to those that produce IL-13 by
affecting activity of CYP11A1, a steroidogenic enzyme.99,100 Studies
to further examine the role of vitamin D in steroid resistance are
ongoing. Oxidative stress also results in reduced expression and
activity of HDAC2; consequently, transcription of inflammatory
genes is not inactivated and inflammation becomes resistant to the
antiinflammatory actions of glucocorticoids.95
The dose-response curve for ICS treatment reaches a plateau at a
fairly low dose in most patients, and there is little added benefit to
pulmonary function or airway reactivity when doses are as much as
quadrupled. A study performed in adults to evaluate the efficacy
and safety of escalating doses of ICS demonstrated that, for the
majority of patients, maximal improvement in FEV1 and
methacholine responsiveness occurred at low to moderate doses of
FP and BDP, with no added benefit of extremely high doses.101
However, a substantial linear increase in cortisol suppression was

2601
seen as ICS dose increased. Therefore in the majority of patients, the
most clinical benefit with the least risk will occur at low to medium
doses of ICS. However, higher doses of ICS may be required to
effectively decrease serious exacerbations. Patients receiving higher
ICS doses require more careful monitoring for both response to
therapy and emergence of systemic side effects.

Adverse Effects of Inhaled Corticosteroids

Local adverse effects, such as oral candidiasis and dysphonia, are
the most common but least severe complications of ICS treatment.
They are dose-related with some variability depending on steroid
type, and they only occur in a small minority of patients (1%–3%).
Reducing the dose, using a spacer device, and rinsing the mouth
with water after use may minimize both these side effects. The
more serious systemic adverse effects for children include adrenal
suppression and depression of linear growth. A meta-analysis of 15
studies comparing low to medium dose ICS with placebo or
nonsteroidal drugs in a total of more than 5700 children for at least
3 months found a mean reduction in linear growth velocity of 0.48
cm per year and a decrease of 0.6 cm from predicted height over 12
months in children who received ICS. There were no differences in
growth velocity between placebo and ICS groups over subsequent
years in the few studies that reported growth for longer than 1
year.102 Thus the effect of ICSs on linear growth in most patients is
minimal, even after long-term administration of low-dose ICSs.
Most of the decrease in growth velocity appears in the first few
months after initiating steroid treatment. The specific ICS molecule
given was more important than age, delivery device, or dose in
determining the magnitude of the effect.102–104 However, head-to-
head comparisons among ICS molecules are needed to provide
more definitive data. Data on the growth of children in the 4-year-
long CAMP trial demonstrated that there was indeed a significant
decline in growth velocity over the first year of the study, but the
growth rate returned to normal thereafter. Children in the BUD
group were on average 1.1 cm shorter than those in the placebo and
nedocromil groups at the end of the 4-year treatment period.16 In
addition, Agertoft and Pedersen showed that there was no

2602
reduction in final predicted adult height in a group of 142 children
treated with a mean dose of 400 µg/day of BUD for an average of
9.2 years.105 These longer-term studies of chronic low-dose ICSs
point to an excellent safety profile and the potential to reach final
predicted adult height, in spite of short-term decline in height
velocity.
Adrenal suppression has been extensively studied, although the
results are often difficult to interpret owing to flawed design,
previous use of oral corticosteroids, or inappropriate tests used to
assess adrenal function. Nonetheless, adrenal suppression is
unlikely in children receiving less than 400 µg/day of inhaled BUD,
or fluticasone 200 µg/day, even after long-term use.1,16
Adrenal suppression indicated by impaired adrenocorticotropic
hormone stimulation tests can be demonstrated in children
receiving higher doses; however, in most patients, even these
impairments are of no or uncertain clinical significance when the
patient is well. A significant stress (e.g., major illness, surgery)
could warrant administration of exogenous corticosteroids to
prevent an Addisonian response.106
Since there is variability among individual clinical response to
corticosteroids and the predisposition to develop adverse effects,
careful monitoring of each patient's growth during ICS treatment
should be performed, and the dose should be adjusted to the lowest
necessary to achieve good symptom control.

Systemic Corticosteroids
The therapeutic benefits of systemic corticosteroids when used as
chronic therapy are marred by their potential adverse effects, which
include excessive weight gain, hypertension, osteoporosis,
decreased linear growth, metabolic derangement, and cataracts.
Adverse effects from long-term steroid therapy may be reduced,
but not eliminated, by using steroids with shorter half-lives (e.g.,
prednisone, prednisolone, methylprednisolone) at the lowest
possible dose administered in the morning in a single dose and
given every other day.

2603
Long-Acting β Agonists
β-adrenergic agonists that have a prolonged duration of action (8–
24 hours) occupy a unique niche in the asthma treatment
armamentarium, somewhere between that of a controller and a
reliever medication. There are currently two long-acting β agonists
(LABAs) available on the US market and approved for use in
children: salmeterol (approved for patients 4 years of age and older)
and formoterol (approved for patients 12 years of age and older);
others, such as indacaterol and vilanterol, both ultralong acting β2
agonists with a 24-hour duration of action, are available but not
approved for use in children. Indacaterol is approved only for
treatment of COPD, and vilanterol is only approved to treat adults
with asthma.
Formoterol and salmeterol differ in structure, potency, efficacy,
and selectivity for the beta receptor. Salmeterol is a partial agonist,
has a relatively slow onset of action (10–30 minutes), and has
extremely high selectivity for the β2 receptor. Salmeterol is more
than 10,000 times more lipophilic than albuterol, and it also has
three to four times the affinity for the β2 receptor of albuterol.
However, salmeterol diffuses out into the cell membrane somewhat
slowly to approach the β2 adrenoceptor active site, which results in
a slower onset of action. Salmeterol has a long side chain that
interacts with an exosite domain of the β2 receptor. This side chain
attachment allows association and dissociation with the active
receptor site for a prolonged time period and results in the long
duration of drug action (9–12 hours).107,108 Salmeterol is available as
both a dry powder in a Diskus device and in combination with
fluticasone as a MDI in the United States.
Formoterol is a moderately lipophilic, highly effective full agonist
with a very different molecular structure from salmeterol. It is
taken up into the cell membrane to form a dose-dependent depot,
from where it progressively diffuses out to interact with the active
site. It has a rapid onset of action (~5 minutes) comparable to
albuterol, but duration of activity is 12 hours. Formoterol is
dispensed as a DPI or MDI in the United States and is also available
in combination with BUD or mometasone in the United States.
The continued use of LABAs can lead to an alteration in their

2604
biologic effects. Although the mechanisms of tolerance to the
bronchoprotective effect are unclear, downregulation of beta-
receptor number or lack of receptor sensitivity are possibilities.
Following a single dose of salmeterol (25–50 µg), there is sustained
improvement in bronchodilatation for at least 12 hours, as well as a
bronchoprotective effect to the bronchoconstriction caused by both
methacholine and exercise. However, after repeated doses, within a
few days or weeks there is a loss in the degree of bronchoprotection
to methacholine and exercise. However, the loss of
bronchoprotection is greater for exercise than in the response to
methacholine, but it is unclear if this is clinically significant. When
used as monotherapy (which is medical negligence in children),
protection from EIB persists after daily dosing for 2–4 weeks, but in
several studies the duration of action decreases from 9 to 12 hours
to as little as 1 hour. The bronchodilator effect is less likely to
decrease than the bronchoprotective effect following repeated
dosing, and the decline is usually most apparent after a few days of
use, followed by stabilization. Formoterol is likely to behave in a
fashion similar to salmeterol.108 Long-term use of LABAs has been
shown to decrease responsiveness to SABA via β2 adrenoreceptor
downregulation. Similar to the decrease in bronchoprotection, the
clinical significance of the reduction in response to albuterol after
continued use of LABAs is unclear.109–112 At least one study has
demonstrated no loss of asthma control in patients using LABAs,
even when a decrease in bronchoprotection is confirmed.113
The LABAs are not generally considered antiinflammatory
agents, but studies show that salmeterol has either no effect on
airway inflammation or reduces inflammatory cells in the airway
mucosa. It has also been proposed that LABAs may enhance the
actions of ICSs, and the mechanism has been linked to regulator of
G-protein signaling 2 (RGS2) expression, which inhibits the
intracellular influx of Ca2+ triggered by spasmogens.114
Past and recent concerns persist about the use of LABAs as
monotherapy and the risk of adverse events. A study performed by
the Asthma Clinical Research Network demonstrated that the
combination of triamcinolone and salmeterol was effective in
controlling asthma in patients 12–65 years of age.115 However,
complete withdrawal of the ICS and continuation of the LABA

2605
caused significant deterioration in asthma control, as measured by
asthma exacerbations, deterioration in pulmonary function, and the
need for oral corticosteroid treatment. These data and those from
similar studies all suggest that LABAs cannot be used as a
replacement for ICSs and should never be used as monotherapy for
treatment of chronic asthma. Deaths have also been reported in
patients chronically using inhaled salmeterol. It remains uncertain
if there is a direct link between medication use and death, or if the
increase in deaths is a reflection of inappropriate use of a LABA
(e.g., attempt to use it as an acute bronchodilator or in place of a
controller medication). A large trial (>26,000 enrollees) compared
the safety of daily salmeterol or placebo added to usual treatment
for chronic asthma over a 28-week period.116 The Salmeterol
Multicenter Asthma Research Trial (SMART) trial was stopped
early when an interim analysis showed futility in reaching the
required enrollment numbers as well as an association between
salmeterol use and severe or fatal asthma. The risk for asthma-
related death, albeit small (13 of 13,174) in the salmeterol group,
was significantly greater than that in the placebo group (4 of
13,179); RR = 4.37 (95%, CI 1.25–15.34) for combined asthma deaths
or life-threatening experiences. This translates into a death rate of
1.98 per 1000 person-years and is significantly greater than the
expected death rate in the United States asthmatic population of
0.48/1000 person-years. Importantly, the increased risk for death
was stronger in African-American subjects. The African-American
participants were also more likely to have more severe asthma and
less likely to be treated with an ICS. However, the study was not
designed or powered to accurately examine the effects of race or
concomitant use of an ICS on modulating the effect of salmeterol.
Although there were a number of flaws in this trial, the data
resulted in a “black box” warning being placed on the salmeterol
package insert advising of the potential risk of life-threatening
asthma. The results of several subsequent pooled analyses of
adverse effects of LABA have also supported the conclusion that
unopposed LABA use is associated with asthma deaths. As a result,
the US FDA now recommends that (1) LABA not be used as
monotherapy, (2) LABA not be used in patients whose asthma is
well-controlled on ICS alone, (3) LABA be used in combination

2606
with another controller medication, and (4) LABA be discontinued
as soon as possible after asthma control is achieved. In addition, a
recent meta-analysis that used reports of events provided by the
drug manufacturers to the FDA suggests that there is an increased
risk of death with LABA use even with the use of an ICS.117
Reassuring results were obtained in a recent multicenter trial of
11,679 adolescents and adults where there was no increased risk for
an asthma related adverse event when LABA was added to ICS
therapy and delivered by a single inhaler.118 These data remain
controversial, and further large-scale trials are planned to
determine the actual risk.
Some of the risk attributable to chronic LABA use may be
attributed to polymorphisms in the BAR at the 16 position. Similar
to the results obtained with chronic administration of SABA to
those with the Arg/Arg polymorphism, it was suspected that
deterioration in pulmonary function and symptom control might
occur with LABA use, even when given in conjunction with an ICS.
In a prospective randomized crossover 18-week study of ICS
treatment plus LABA or placebo in adult patients stratified by BAR
16 polymorphisms (Arg/Arg or Gly/Gly), there was no difference in
the degree of improvement in PEFR or FEV1 with the addition of
LABA, regardless of genotype. However, those with the Gly/Gly
polymorphism had a higher PC20 with LABA treatment compared
with placebo; there was no difference in PC20 in the Arg/Arg group
between placebo and LABA.119 No difference in adverse effects was
seen in either group. These data suggest that chronic use of LABA
in combination with an ICS is safe in patients with either genotype.
However, longer-duration treatment and larger-scale studies will
be necessary to determine continued efficacy and safety.
A major benefit of LABAs is use in combination with an ICS to
improve asthma control without increasing the steroid dose. A
number of studies that included older children and adults have
demonstrated that the addition of a LABA to a regimen that
includes an ICS results in better asthma control and improved
pulmonary function compared to doubling the dose of ICS.120 More
importantly, the ICS dose can often be reduced by as much as 50%
and still maintain asthma control when the LABA is added.
Although the data are striking and consistent in studies on adults,

2607
there are fewer pediatric studies. An early study suggested that
addition of a LABA to an ICS in pediatric patients may not have the
same steroid-sparing effect or enhancement of steroid effect as that
seen in adults and found the addition of a LABA or higher-dose ICS
conferred no further benefit, but growth suppression occurred at
the higher ICS dose.121 A more recent large multicenter trial
(VIAPAED) compared the effect of salmeterol 50 mg plus
fluticasone 100 µg combination (given in a single inhaler) compared
with fluticasone 200 µg given twice daily for 8 weeks in 441
children 4–16 years of age whose asthma was not well-controlled
while taking an ICS alone.122 Children in the salmeterol plus
fluticasone group had significantly greater improvement in
morning PEFR (improvement of 30.4 ± 34.1 L/min combination vs.
16.7 ± 35.8 L/min fluticasone) and a longer duration of asthma
control (~1 week longer, favoring combination). A meta-analysis of
10 studies examining high-dose ICS compared with low-dose ICS
and LABA concluded that the addition of LABA to ICS allowed a
37%–60% reduction in inhaled steroid dose without loss of asthma
control.120
A study conducted by the Childhood Asthma Research and
Education Network in asthmatic children 6–17 years of age who
were not well controlled on ICS alone examined the response to the
addition of LABA, increasing the dose of ICS, or adding the
leukotriene receptor antagonist (LTRA) montelukast.123 Using a
double-blind randomized triple-crossover design and a composite
of three outcomes (exacerbations, asthma-control days, and FEV1),
this study demonstrated a differential response to the treatment
steps in 161 of the 165 children enrolled. The response to LABA
step-up was most likely to be the best option compared with LTRA
(1.6 relative probability) or increasing the ICS dose (1.7 relative
probability). White race or Hispanic ethnicity predicted a better
response to LABA; African Americans were as likely to respond to
LABA as to ICS step-up therapy and least likely to respond to
LTRA. Although all step-up options provided good symptom
control during the trial, none of the step-up options eliminated
acute asthma flares. The duration of this trial was relatively short
(16 weeks), and issues of safety or long-term maintenance of effect
remain unanswered. Although some would argue that increasing

2608
the dose of ICS may be safer and less expensive than adding a
LABA or LTRA, the more important issue is to carefully and
frequently monitor the patient with poorly controlled asthma who
requires any step-up therapy to ensure both safety and efficacy.
Failure to improve or the development of any adverse effect or
medication intolerance warrants further medication adjustment and
reevaluation.
Overuse (or possibly any use) of LABA could also be detrimental
to some patients, as suggested by a systematic review of adverse
events associated with LABA plus ICS use.124 However, more recent
meta-analyses and systematic reviews have shown that there is no
increased risk for adverse asthma-related events in patients
receiving a combination of inhaled steroid and LABA compared
with those receiving inhaled steroid alone in studies examining
both salmeterol and formoterol.125,126 Similar reassuring results were
obtained in a recent multicenter trial of 11,679 adolescents and
adults, which found there was no increased risk for asthma-related
adverse events when LABA was added to ICS therapy and
delivered by a single inhaler.118 Finally, a multicenter international
pediatric study including over 6200 children age 4–11 years found
no increase in safety events (hospitalizations, intubation, or death)
or decrease in efficacy (time to exacerbation requiring oral steroids)
for fluticasone-salmeterol fixed-dose combination compared with
fluticasone alone over 26 weeks.127 There were no deaths or asthma-
related intubations for any enrollees in the study regardless of
treatment group; however, children with very severe or unstable
asthma were not included in the study. Both of these large-scale
prospective studies examining safety and efficacy of ICS and LABA
provide further evidence that ICS and LABA combinations are safe
for use in the pediatric population.
There are currently four fixed-dose combination-inhaled steroid
and LABA medications available: fluticasone
proprionate/salmeterol, BUD/formoterol, mometasone/formoterol,
and fluticasone furoate/vilanterol. The dosing interval for all but
one is every 12 hours (fluticasone furoate plus vilanterol is once a
day). It is also possible to administer each medication separately
from individual inhalers; however, this is less convenient for the
patient, may be more expensive, and runs the risk of inadvertent

2609
overuse, or even sole use, of LABA. Although use of separate
inhalers does allow more flexibility in adjusting the dose of ICS, this
strategy is not recommended because of the risks associated with
unopposed LABA use. Salmeterol is combined with fluticasone in a
DPI or MDI; the dose of salmeterol is 50 µg per inhalation in the
DPI and 21 µg per inhalation in the MDI, while the fluticasone
component is available in three different concentrations to allow for
flexibility in dosing the ICS while avoiding excessive LABA use. A
combination of formoterol and BUD or mometasone is also
available in DPI or MDI forms. Salmeterol is a partial agonist of the
β receptor compared with formoterol, which results in a flatter dose
response curve and a weaker protective effect against
methacholine-induced airway reactivity for salmeterol.
When the LABA combined with an ICS is formoterol, a different
dosing strategy is possible because of the rapid onset of action of
formoterol. When formoterol is taken in combination with an ICS
for relief of symptoms at the first sign of deterioration, the
additional dose of ICS helps prevent serious exacerbation. This
strategy was examined in a large multicenter trial that evaluated
2760 asthmatics 4–80 years of age who were randomized to
treatment with BUD 320 mg twice daily and terbutaline as reliever,
BUD/formoterol 80/4.5 mg twice daily and terbutaline as reliever, or
BUD/formoterol 80/4.5 mg twice daily both as maintenance and
reliever. The child treatment arm (4–11 years of age) was dosed at
once a day.128,129 Both adults and children in the BUD-formoterol as
maintenance and reliever arm had significantly reduced risk of
exacerbation compared to the other two treatment arms. The child
study showed a significant reduction in severe exacerbations
(defined as sustained fall in morning PEFR, need for oral
corticosteroid, acute care visit or hospitalization); 14% of those in
the combined maintenance plus reliever group had a severe
exacerbation, compared with 38% in the BUD/formoterol plus
SABA group and 26% in the BUD plus SABA group. In addition,
the overall exposure to oral corticosteroids and exacerbations
requiring medical attention was also significantly reduced in the
maintenance plus reliever group. Moreover, linear growth over the
year was approximately 1 cm greater in the groups receiving
BUD/formoterol compared with the higher-dose BUD group.

2610
Although this treatment approach has found acceptance in Europe,
Australia, and Canada (but not in the United States), some concerns
remain about safety and long-term effectiveness. Overuse of the
BUD/formoterol combination can occur, leading some patients to
mask progressing symptoms or delay seeking medical attention.

Leukotriene Antagonists
Leukotrienes are lipid mediators produced by the metabolism of
arachidonic acid via a complex cascade, including the action of
phospholipase A2. The enzyme 5-lipoxygenase catalyzes the
production of leukotrienes, LTB4 and the cysteinyl members LTC4,
LTD4, and LTE4, from arachidonic acid. Arachidonic acid can also
be a precursor for the cyclooxygenase pathway and results in the
production of prostaglandins and thromboxane. However, it is the
cysteinyl leukotrienes (cysLTs) that are the potent mediators which
induce smooth muscle constriction, vascular permeability, mucus
hypersecretion, edema formation, and inflammatory cell
recruitment into the airways. Elevated levels of cysLTs are
recovered from bronchoalveolar lavage fluid, and urinary LTE4
levels are elevated following airway allergen challenge in atopic
asthmatics. CysLTs are produced by a number of cell types found
in the airways, including mast cells, eosinophils, basophils,
macrophages, and neutrophils. Corticosteroids do not directly
inhibit the synthesis or block the action of leukotrienes.
Two basic strategies targeting cysLTs include inhibition of 5-
lipoxygenase and leukotriene receptor antagonism. Because of the
nature of the lipoxygenase synthetic cascade, interruption at an
early level (e.g., at the 5-lipoxygenase) could diminish overall
cysteinyl LT and LTB4 production, both of which are generally
elevated in biological fluids (i.e., blood, bronchoalveolar lavage
fluid, urine) from symptomatic asthmatics. The 5-lipoxygenase
inhibitor zileuton blocks the bronchoconstriction response to
inhaled allergen or cold air challenge, exercise, and aspirin
ingestion in sensitive individuals. However, because the drug can
cause hepatic injury, which is usually reversible, regular liver
enzyme monitoring is necessary. Although previously the drug

2611
required 4 times daily dosing, an extended release form that
permits twice a day dosing is now available.
There are two clinically available LTRAs: zafirlukast and
montelukast. When administered orally, zafirlukast resulted in
significant reduction in daytime and nighttime symptoms and the
need for SABA compared with placebo. Zafirlukast has modest
efficacy at best, must be given twice daily, and in some patients also
results in elevated hepatic enzymes. Montelukast is a LTD4 receptor
antagonist and is administered once daily. It has been shown in a
number of studies to decrease urinary excretion of LTE4, reduce
both circulating and sputum eosinophil counts, and decrease
exhaled NO.1 Clinical effects include improvement in FEV1 and
protection from EIB and allergen-induced bronchospasm.
Improvement in pulmonary function can be detected after the first
dose and reaches a peak after a few weeks of treatment. However,
the montelukast effect on asthma control is not as great as that from
an ICS, as measured by improvement in FEV1, symptom control,
and reduction in inflammatory markers.130 Trials in children with
slightly more severe disease based on lower FEV1 also showed
significantly greater improvement in pulmonary function measures,
symptom reduction, and need for rescue SABA with fluticasone
compared with montelukast.131
Predicting which patients will have a more favorable response to
montelukast versus ICSs has proven difficult. However, a study
examining the rate of response of children with mild asthma to ICS,
montelukast, or both demonstrated that 23% responded to
fluticasone alone, 5% responded to montelukast alone, 17%
responded to both, but 55% responded to neither drug.132 Children
who are older, have had asthma for a longer duration, have a
parental history of asthma, have a higher exhaled NO, and have a
lower PC20 are more likely to respond favorably to ICS treatment
compared with LTRA treatment.133
Montelukast may provide improved asthma control when
combined with other controller medications, such as inhaled
steroids. Although study results are somewhat conflicting, most
show that the addition of montelukast to an ICS results in modest
improvement that is not quite as efficacious as adding an LABA,

2612
particularly on pulmonary function outcomes. One pediatric trial
demonstrated a small improvement in FEV1 (6.0% montelukast,
4.1% placebo, P < .01) and in the need for rescue bronchodilator use
(1.65 puffs/day montelukast, 1.98 puffs/day placebo, P < .013) when
montelukast was added to a regimen of low-dose BUD.134
Adverse effects of montelukast have been relatively minor and
mainly consist of headache, abdominal pain, vivid dreams, and
sleep disruption. Reports of behavioral changes (e.g., moodiness,
depression) and an unsubstantiated association with a suicide
report have led to a label change including behavioral changes as a
possible side effect of treatment with montelukast. There are several
case reports of adults developing Churg-Strauss syndrome when
treatment with montelukast was instituted and ICS treatment
withdrawn. Since the majority of these patients had what was
considered to be severe steroid-dependent asthma, it is believed
that the development of systemic vasculitis was actually the
emergence of an underlying disease as a result of steroid
withdrawal and less likely a result of the direct action of
montelukast. Care should be taken, however, if montelukast is used
in an attempt to decrease or discontinue oral steroids in a patient
with presumed severe asthma.

Long-Acting Muscarinic Antagonists

Short-acting quaternary anticholinergic medications such as
ipratropium bromide have been used for decades as
bronchodilators in the treatment of asthma. Tiotropium, a long-
acting muscarinic receptor antagonist with a duration of action of
24 hours, which has been a mainstay of COPD treatment, has
recently been approved for use in patients with severe persistent
asthma not controlled with ICS. There are five subtypes of
muscarinic receptors, three of which are found in human airways
(M1, M2, M3). All three types of muscarinic receptors mediate
neurally induced bronchoconstriction. Tiotropium has a high
affinity for M receptors but dissociates very slowly from type M1
and M3 receptors, resulting in prolonged prevention of
bronchoconstriction and a 24-hour bronchodilatation effect.96
Although there is a paucity of studies compared to those

2613
examining glucocorticoids, the available data have consistently
shown that tiotropium, when added to ICS or ICS and LABA,
resulted in improved lung function, which was maintained even
after ICS dose reduction and LABA discontinuation.135,136 In fact,
when used in combination with low-dose ICS, tiotropium is more
effective at improving lung function than doubling the ICS dose
and is noninferior to LABA as measured by decrease in symptom
days, improvement in quality of life, and asthma control score.136–138
When added to medium-dose ICS, tiotropium continued to result in
improvement in lung function135,136,138,139 The effect on lung function
is comparable to that of salmeterol, and there may also be acute
bronchodilatation in patients with poorly controlled
symptoms.137,140,141 In addition, tiotropium in combination with ICS
and LABA decreased the risk of severe exacerbations, and extended
the length of time to the first exacerbation.139,142
Most studies of tiotropium in asthma have been conducted with
adults, however more recently there have been trials with children
that show similar benefits and an excellent safety profile.138,139,143,144
Tiotropium has been added as recommended therapy for children
aged ≥ 12 years in steps 4 and 5 of the most recent version of the
GINA guidelines.72 Tiotropium is available in two doses via soft
mist MDI (Respimat), 2.5 µg and 1.25 µg per actuation. Two puffs
of the 1.25 µg dose administered once daily has been approved in
the United States for children with asthma, although higher doses
have been approved for use in COPD.145 Peak effect on FEV1 occurs
within 1–3 hours after dosing. Other anticholinergic agents such as
umeclindinium and aclinidium are currently used in treatment of
COPD but have not yet been adequately studied in asthma.

Methylxanthines: Theophylline
Although methylxanthines have been used for the treatment of
asthma since the early part of the 20th century, their role in
managing acute and chronic asthma has become very restricted.
Theophylline is now considered a second- or third-line medication,
largely because it is a poor acute bronchodilator; it has a narrow
therapeutic index and significant adverse effects, and
antiinflammatory drugs have replaced it. It does have the

2614
advantage of being inexpensive and can be administered in a long-
acting oral formulation. Theophylline is a phosphodiesterase
inhibitor that causes smooth muscle relaxation and
bronchodilatation. However, theophylline can also act centrally as a
respiratory stimulant and may also increase diaphragmatic
contractility and help prevent diaphragmatic fatigue. In addition,
more recent data suggest that it blocks histone deacetylation, which
may be important to the action of corticosteroids and modulation of
inflammatory mediators; further work is necessary to confirm the
clinical relevance of this action. Low-dose theophylline (amounts
sufficient to cause a serum level of 5–10 mg/mL) may be helpful in
some patients for chronic management. The addition of
theophylline to ICSs may have a steroid-sparing effect in some
patients, but it is less effective than adding a long-acting β
agonist.146–149 However, adverse effects, such as tremor, gastric
irritation, gastrointestinal hemorrhage, agitation, and convulsions,
may occur at even relatively low serum concentrations. Also, many
commonly used medications can interfere with theophylline
metabolism, resulting in clinically significant elevation (e.g., some
macrolide and fluoroquinolone antibiotics) or lowering
(carbamazepine) of serum concentrations. Febrile viral illnesses
may also substantially increase serum concentrations. Careful
monitoring of serum concentration is mandatory when doses above
10 mg/kg per day are administered to children and adolescents.

Biologic Therapy for Asthma

Several novel approaches to asthma therapy involve immune
modulation, which may be useful for both the prevention and
treatment of asthma. Use of a humanized monoclonal anti-IgE
antibody (omalizumab) to complex with and lower the circulating
concentration of IgE has demonstrated efficacy in select patients.
This drug is approved by the US Food and Drug Administration for
use in patients 6 years of age and older. Mepolizumab, a
monoclonal antibody to IL-5, resulted in a significant reduction in
exacerbations and improvement in quality of life for patients with
severe eosinophilic asthma. It is approved in the United States for
patients aged 12 years and older. Reslizumab, also an anti-IL-5

2615
antibody, is available in the United States for those asthmatics ≥ 18
years old who have eosinophilic disease. Biologic therapies for
asthma are discussed in more detail in Chapter 48.

Management of Chronic Asthma

The effective management of chronic asthma should focus on (1)
identification and elimination of exacerbating or aggravating
factors, (2) pharmacologic therapy, and (3) education of the patient
and family about the disease and the management skills necessary
to avoid and treat acute exacerbations. The goals of management of
chronic asthma in children include minimizing symptoms and
exacerbations, maintaining normal activities of daily living,
maintaining normal or near-normal pulmonary function, and
avoiding adverse effects from asthma medications. To achieve these
goals, a combination of pharmacologic and nonpharmacologic
modalities must be utilized.
Successful asthma management includes appropriate grading of
disease control (see Table 45.3). Asthma severity, or the intrinsic
intensity of the disease, should be distinguished from asthma
control. Patients may have relatively mild asthma that is poorly
controlled due to multiple factors, such as inadequate treatment,
impaired adherence, or excessive exposure to allergens or irritants.
Once appropriate medical and environmental measures are
instituted, the asthma may become “mild” in terms of absence of
symptoms and normalization of pulmonary function while taking
low doses of a controller medication. Patients who demonstrate a
progressive decline in pulmonary function, frequent exacerbations,
and persistent or recurrent symptoms in spite of regular use of
controller medication and environmental controls have more severe
disease.
The emphasis in most guidelines is now placed on establishing
asthma control, which includes minimizing impairment
(symptoms) and avoiding risk of serious exacerbations, medication
adverse effects, loss of lung function, and (in the case of children)
reduction in lung growth. As discussed earlier in the chapter, other
biomarkers of airway inflammation (eNO, sputum, or peripheral
blood eosinophils) may add additional useful data for grading

2616
asthma severity and guiding treatment to improve control. Several
brief, validated questionnaires can be used in most clinical or
community settings to provide a rapid assessment of asthma
control (see the section on “Other Measures for Assessing Asthma
Severity and Control” earlier in the chapter). Although the utility of
the scores as a single measure is established, the responsiveness to
change over time, collection of data in relation to recent
exacerbations, and seasonal variability all need further evaluation.
The risk domain of control includes exacerbations that are severe
enough to warrant treatment with oral corticosteroids, emergency
medical care, or hospitalizations. There are limited data that are
useful in predicting future exacerbations; however, there is an
inverse relationship between FEV1 and the risk of developing an
exacerbation in the subsequent year. In addition, having one severe
exacerbation is a strong risk factor for a subsequent episode in the
same year. Data are lacking to accurately correlate the number and
severity of exacerbations with degree of asthma control. More than
one exacerbation per year indicates asthma control is inadequate
and the frequency and severity of exacerbations increases with
worsening control. Patients should start treatment at the step most
appropriate to the initial severity grading (or control level for those
already receiving treatment) of their asthma.
The most recent National Asthma Education and Prevention
Program (NAEPP) guidelines continue to list four severity
classifications: intermittent, mild, moderate, and severe persistent,
but have expanded the stepwise treatment algorithm to six steps
while the GINA guidelines have five steps (Fig. 45.5).
Immunotherapy continues to be recommended for children who
are at steps 2–4, have documented allergy, and have persistent
symptoms. However, immunotherapy is most likely to be effective
for those with single allergen sensitization, and this evidence for
efficacy is strongest for animal dander, house dust mites, and
pollen. The two added treatment steps for adolescents and adults
are aimed at those who are allergic, have refractory symptoms in
spite of high-dose ICSs, plus another antiinflammatory controller.
At these steps 5 and 6, recommended additional treatment includes
oral corticosteroids and omalizumab for those older than 12 years
of age who are also allergic. Mepolizumab, which was not available

2617
at the time of publication for the NAEPP guidelines, should now be
considered for patients 12 years of age and older who have
eosinophilic asthma and are not well controlled, with high-dose ICS
and another controller. The GINA guidelines for asthma
management have included tiotropium as add-on therapy for
patients requiring step 4 or step 5 therapies in the 2015 revision.72
The treatment steps are used in conjunction with control levels.
Patients who achieve good control are maintained at the lowest step
level possible. Those with not well-controlled or poorly controlled
asthma receive step-up treatment until control is achieved. Step-
down to a lower treatment level should be attempted once control
is maintained for at least 3 months and no other contraindications
for reducing medication exist (e.g., persistent allergen exposure,
entry into high-risk season). Patient education, environmental
controls, and management of comorbid conditions are stressed at
all steps. In addition, it is critical that all patients and their adult
caregivers be thoroughly trained in the appropriate use of the
specific medication delivery devices and monitoring tools
prescribed (e.g., MDI, DPI, nebulizer, PEFR meter). In addition to
obtaining spirometry at the time of initial assessment, at least
annual monitoring of lung function in children age 5 years and
older is recommended for all levels of asthma severity; however,
spirometry is more likely to be of value for those with more severe
disease and low lung function at baseline. Spirometry should also
be obtained during periods of progressive or prolonged loss of
asthma control.1

2618
 FIG. 45.5 Stepwise treatment algorithm for chronic
treatment of children and adolescents with asthma.
ICS, Inhaled corticosteroids; LABA, long-acting β
agonists. (Figure reproduced with permission from 2016 GINA Report, Global
Strategy for Asthma Management and Prevention, www.ginasthma.org.)

Intermittent Asthma
Children with intermittent asthma or EIA have brief episodes of
wheeze or cough that are easily relieved with SABA treatment and
occur no more frequently than once or twice per week. Treatment is
with the as-needed use of an inhaled SABA agonist.1 The usual dose
of inhaled racemic albuterol is 2–6 puffs (90 µg/puff) every 3–4
hours or 0.15 mg/kg (usual dose 2.5 mg, maximum 5 mg) nebulized

2619
from a small-volume nebulizer in 2 mL of saline. Other SABAs (e.g.,
levalbuterol and terbutaline) may also be used, and it is unlikely
that there is any significant difference in efficacy among the drugs.
Numerous studies have demonstrated that administration of
albuterol by MDI is equally effective as that given by nebulizer.1,65
Moreover, use of an MDI by older children (with or without a
valved holding chamber [VHC]) is far more convenient and less
expensive than a nebulizer. EIA may be prevented to a large extent
with inhalation of albuterol (or formoterol) 5–20 minutes before
exercise. Montelukast taken 1–2 hours before exercise may also help
prevent EIB.

Mild Persistent Asthma

The majority of asthmatics are classified as having mild persistent
asthma, based on symptoms that occur several times per week, but
not daily; infrequent nocturnal symptoms; and normal pulmonary
function. The primary treatment of mild persistent asthma is a low-
dose ICS. Data from multiple studies support the superior efficacy
of ICSs compared with other treatments in improving pulmonary
function, reducing symptoms and need for rescue medications, and
improving bronchial hyperreactivity. As outlined previously, the
safety profile for ICSs given at low dose is excellent. There are few
data to suggest that one type of ICS will offer significantly greater
benefit than the others, but the dose equivalency and ranges for
low, medium, and high doses differ (see Table 45.5). BDP,
fluticasone, and BUD have been extensively studied in children for
many years, are available in easy-to-use devices (MDIs or DPIs), are
well tolerated by most patients, and the adverse event profile is
well understood. Large comparative effectiveness trials,
particularly in children, are sparse. However, a retrospective
observational study that used a large general practice research
database in the United Kingdom examined asthma control in newly
treated asthmatics 5–60 years of age. Using a matched cohort
analysis, more than 2600 patients, including 773 children age 5–12
years of age who were prescribed HFA BDP, or FP, were followed
for 2 years. Although more than 80% of the patients in each group
achieved control, patients who were treated with or received step-

2620
up treatment with BDP were more likely to be controlled (adjusted
odds ratio 1.30; 95% CI, 1.02–1.65).150 However, the control measure
used was a composite of largely risk domain elements (i.e.,
exacerbation, oral steroid use, hospitalization) and probably missed
impairment domain measures (symptoms). Older inhaled steroids
(e.g., flunisolide, triamcinolone) with lower topical potency are
used less frequently. Newer inhaled steroids, such as mometasone
and ciclesonide, are currently labeled for use in the United States
for children 12 years of age and older.
Although chronic daily dosing of ICS is the general
recommendation to maintain good asthma control, other strategies
have been investigated and hold promise as valid alternatives.
There are a few studies that have compared chronic daily inhaled
steroid use with intermittent treatment. There was no difference in
morning PEFR or asthma exacerbations between those that used
daily inhaled steroids and those that used them as needed, but
daily use of inhaled steroids resulted in better asthma control based
on symptom days, asthma control scores, FeNO, and
eosinophils.151,152 This strategy appears to benefit the risk domain
more than the impairment (daily symptom) domain; therefore if
daily symptom burden reduction is more important than infrequent
and mild exacerbation reduction, a daily treatment strategy may be
preferable.
Implications for pediatric asthma management with intermittent
steroid use may be even greater, since the risk of growth
suppression is higher in children. A recent study compared daily
with as needed use of BDP in children with mild asthma who were
previously well controlled while taking daily low-dose ICS. In this
multicenter study, children ages 5–18 were randomly assigned to
one of four treatment groups: placebo twice daily with albuterol
plus placebo as rescue, placebo twice daily with albuterol plus BDP
as rescue, BDP twice daily with albuterol plus placebo as rescue, or
BDP twice daily with BDP plus albuterol as rescue. Children who
received inhaled steroids daily had fewer exacerbations than
children who used no inhaled steroids and albuterol alone as rescue
(28% vs. 49%, P = .03). Children who received BDP daily and as a
rescue (with albuterol) or as rescue (with albuterol) only had fewer
exacerbations than the placebo group, but the results did not reach

2621
statistical significance (31% for BDP daily and as rescue with
albuterol, P = .07; 35% for BDP as rescue only with albuterol, P =
.07). Notably, linear growth was over 1 cm lower in both groups
who received inhaled steroids daily compared with the group
which received no ICS (P < .0001). There was no difference in
growth between the placebo group (no ICS) and those who received
BDP only as a rescue medication (P = .26).153 These data suggest that
some patients with mild asthma of relatively new onset may
achieve adequate control with intermittent ICS use after a period of
stabilization with continuous ICS treatment, and with less risk of
minor growth suppression. However, daily use of an ICS, even
when tapered to low dose, provides the best overall control,
particularly in the exacerbation risk domain.
An alternative treatment is an LTRA, such as montelukast. This
drug has the advantage of once-a-day oral administration and only
uncommon mild adverse effects (i.e., nausea, headache, vivid
dreams). However, numerous comparative studies indicate that
ICSs provide superior asthma control.133,154 Although the current
NAEPP guidelines still list cromolyn, nedocromil, and theophylline
as alternative treatments, nedocromil and cromolyn have limited
availability (neither is available for inhalation in the United States)
and efficacy, while theophylline is less well tolerated.

Moderate Persistent Asthma

Children who have daily symptoms, nocturnal symptoms more
than weekly, and mild obstruction on pulmonary function have
moderate persistent asthma. Children who continue to experience
symptoms or exacerbations while being treated with low-dose ICSs
should have a step up in treatment. Current recommendations for
treatment include increasing the ICS dose to the moderate range, or
continuing the low-dose ICS and adding a second controller drug
with a complimentary mechanism of action. As discussed earlier in
the chapter, the dose response curve for ICSs reaches a plateau at
relatively modest doses, as determined by pulmonary function and
bronchial hyperreactivity measures. However, certain patients may
derive benefit in both the impairment and risk domains when the
ICS dose is increased to the moderate range. LABAs are the current

2622
add-on drugs of choice because of the large body of evidence from
randomized controlled trials that indicate efficacy and effectiveness.
In older children and adults, the addition of a LABA to a low-dose
ICS results in greater improvement in pulmonary function and
reduction in symptoms than a further increase in steroid dose. The
availability of a fixed-dose combination of fluticasone and
salmeterol or BUD and formoterol in a single inhaler make this
combination attractive. An alternative is to raise the dose of the
inhaled steroid alone to the medium range; this is the current
recommended strategy for children younger than 4 years of age,1
but is a secondary option in older children. When concerns exist
about the use of LABA or medium-dose ICSs, the addition of an
LTRA (e.g., montelukast) should be considered. Although the
additive effect of LTRA is more limited, the safety profile may be
viewed as more favorable. LTRA, when added to inhaled BUD in
one study, resulted in a modest improvement in PEFR and a
reduction in need for SABA.134 Low-dose theophylline is another
low-cost add-on medication that may also help improved symptom
control. Data indicate that the latter two add-on medications are
also effective in improving asthma control, but less so than the
addition of a LABA. Use of theophylline as a single daily dose of a
time-release preparation can be well tolerated and is typically less
expensive than using a LABA or LTRA. Any patient who has
deterioration of lung function while using a LABA chronically
should have an alternative medication prescribed. Whatever
combination of medications is used, attempts should be made at
regular intervals to decrease the ICS dose to the lowest level that
adequately controls symptoms and maintains normal pulmonary
function. Children in this category will benefit from referral to a
pulmonologist and may also require ongoing specialty care.

Severe Persistent Asthma

Approximately 5%–10% of patients will have severe persistent
asthma as described by persistent daily symptoms, frequent
nocturnal awakenings, and a moderate or severe obstructive
pattern on pulmonary function testing. These symptoms may occur
in spite of treatment with high-dose ICSs, LABAs, and/or a LTRA or

2623
low-dose theophylline. Patients with the most severe disease have
inadequate response to even high doses of ICS in combination with
other available controller medications. If there is no response, oral
corticosteroids are the next recommended treatment step. It may be
necessary to administer a short course (<10 days) of daily dosing
(40–60 mg/day) and then a longer every-other-day course at the
lowest effective dose (0.5 mg/kg every other day). Before instituting
such therapy, a thorough search for remediable exacerbating factors
or comorbid conditions (e.g., sinusitis, persistent allergen exposure,
poor compliance, GER, VCD) should be sought. As soon as
symptoms are controlled, the lowest possible oral steroid dose at
which symptom control is maintained should be administered.
Although a single morning dose is generally preferred to minimize
systemic side effects, some patients with severe or refractory
symptoms may benefit from twice-daily dosing. Children receiving
chronic oral corticosteroid therapy should be carefully monitored
for development of adverse effects, such as hypertension, cataract
formation, hyperglycemia, loss of bone mineral content, and
impaired linear growth. Systemic corticosteroids may be given in
the presence of acute viral infections, otitis media, or pneumonia
and will not result in worsening infections. However, patients who
develop varicella while taking systemic corticosteroids, or who take
the medication during the incubation period, should have the
steroid dose reduced to the minimum tolerable to control the
asthma and should also be provided adrenal replacement. In
addition, consideration should be given to administering acyclovir
for 5–7 days, and the patient should be carefully observed for signs
of severe or disseminated disease. If there has been a significant
exposure to varicella identified within the previous 96 hours,
passive immunization with varicella zoster immune globulin can be
offered. Children with persistent asthma should receive varicella
vaccine if they have not previously contracted the disease.
A proportion of severe asthmatics may be steroid resistant; in one
series of patients with refractory asthma, 25% were determined to
be steroid resistant. Such patients may have altered steroid
metabolism or receptor dysfunction. A careful evaluation and
specialized pharmacokinetic and cellular studies may be needed to
ascertain the etiology of the defect. Patients deemed to be steroid

2624
resistant may be candidates for alternative therapies, such as
omalizumab, mepolizumab, or other immune modulator
treatments. Children with severe asthma should receive routine
care from a specialist. Frequent visits to assess symptom control,
pulmonary function testing, quality of life, patterns of medication
use, presence of comorbid conditions, adverse effects caused by
treatment, and adherence to treatment regimen are essential. Severe
asthma is discussed in more detail in Chapter 46.

Holding Chambers and Spacer

Devices
A number of studies indicate that as many as 80% of patients use
MDIs incorrectly, even after appropriate instruction, and many
residents, physicians, and nurses are unable to teach patients
correctly. Proper steps are given in Table 45.6. Although there is a
relatively small difference in the amount of medication that reaches
the lower respiratory tract from a properly used MDI alone
compared with an MDI plus a VHC (10% for MDI alone, 15% for
MDI plus holding chamber), a VHC helps ensure that the
maximum possible dose reaches its target. The holding chamber
also minimizes deposition of the medication in the mouth and
oropharynx, a particularly important feature when ICSs are
prescribed. There are several important points to remember when
using a VHC. The child should take a slow deep inspiration and try
to hold his or her breath for 5–10 seconds after inhalation of the
medication. Only one medication should be dispensed into the
chamber at a time, although the same chamber may be used for
other medications. A holding chamber that is of at least 150 mL
volume and that accommodates the MDI canister in its original boot
is preferable to one that requires the canister to be inserted into an
adapter. The latter chambers may not result in accurate dispensing
of medication because of a mismatch between the adapter and the
actuator. Newer holding chambers are made of antistatic plastics or
metal that minimizes static charge, which can cause excessive
retention of medication in the chamber. Washing the chamber with
a mild detergent and air drying can also help prevent static charge.

2625
See www.cdc.gov/asthma/inhaler_video/default.htm for a video
demonstrating proper VHC (spacer) device use.

Table 45.6
Directions for Use of a Metered-Dose Inhaler, With and Without a
Spacer

MDI Use Without Spacer Device MDI Use With Spacer Device
1. Shake canister for 5 s. 1. Shake canister for 5 s.
2. Position finger on top of canister for support. 2. Attach canister to spacer.
3. Patient exhales normally (to FRC). 3. Patient exhales normally (to FRC).
4. Place mouthpiece 2 cm in front of open mouth around 4. Place mouthpiece in mouth and
tube (may place in mouth if coordination is a close lips.
problem).
5. Begin slow inspiration. 5. Activate canister.
6. Activate canister. 6. Begin slow inspiration.
7. Complete inhalation over several seconds. 7. Complete inhalation over several
seconds.
8. Hold breath for 10 s. 8. Hold breath for 10 s.
9. Wait 30–60 s, and repeat steps 2–8 for prescribed 9. Wait 30–60 s, and repeat steps 2–8
number of inhalations. for prescribed number of
inhalations.
FRC, Functional Residual Capacity; MDI, metered-dosed inhaler.

Peak Expiratory Flow Rate Monitoring

Home monitoring of PEFR has been advocated for optimal
management of the patient with moderate to severe persistent
asthma, but the utility remains somewhat limited. PEFR is only
moderately correlated with FEV1, and other measures such as FEF25–
75, FEF50, or mid-maximal expiratory flow (MMEF) that can be used
as a valid measure of obstructive ventilatory defect. The degree of
diurnal and day-to-day PEFR variability has been proposed for
years as a marker of asthma severity and airway hyperreactivity.
However, the correlation between PEFR variability and airway
hyperreactivity is only moderate. Moreover, the correlation of PEFR
variability with other clinical markers of asthma disease activity or
severity remains unclear. PEFR probably has its greatest value
when used repeatedly to indicate severity of an acute asthma
exacerbation and the subsequent response to treatment. Normal
PEFR ranges are determined by the patient's age, sex, and height,

2626
and are readily available. Some patients have PEFR readings well
above, or in some cases below, published standards. For this reason,
an individual patient's personal best reading is often used as a
target. It is important that the personal best be determined only
when efforts have been made to ensure that asthma is optimally
managed at the time the measure is made; this may require short
courses of oral corticosteroids and other antiinflammatory
medications.
Small portable handheld PEFR devices can provide an objective
measure of lung function in the home or school setting. Currently
available devices record measurements electronically and some also
measure FEV1 and FEV6. Patients may use the PEFR reading to alter
medications according to a predetermined plan. Patients and
families must know when and how to use the PEFR meter, how to
interpret the measurement and respond to the reading, and when to
communicate with their physician. Some of these steps can be
obviated with the use of a commercial system that uses a recording
PEFR meter capable of transmitting a longitudinal report via phone
line or the Internet to the managing physician. Although earlier
guideline recommendations were that all patients with asthma use
a PEFR-driven asthma action plan, studies suggest that routine use
of PEFR monitoring is more likely to benefit those with more severe
or unstable disease and is more likely to be used intermittently
(around the time of increased symptoms or seasonally), rather than
continuously.1,72
After determining the target, normal, or personal best PEFR
reading, a care plan incorporating the measure can be made.
Sample plans may be obtained from readily available sources (Fig.
45.6).1

2627
 FIG. 45.6 Sample treatment plan form for management
of chronic asthma. Instructions may use peak
expiratory flow rate monitoring in addition to symptoms
to assess the need for additional treatment.

The zones are generally defined as follows:

2628
 Green: PEFR 80%–100% predicted/personal best; all clear, no
symptoms.
Yellow: PEFR 50%–80% predicted/personal best; indicates
worsening airway obstruction or an impending attack.
Symptoms include slowed play, intermittent cough, wheeze,
and dyspnea.
Red: PEFR less than 50% predicted/personal best; indicates
significant airway obstruction and need for immediate
medical attention. Symptoms include severe dyspnea,
retractions, continuous wheeze, or cough.

There are limitations to PEFR monitoring efficacy. The PEFR is

effort-dependent, and some children learn how to deliberately
adjust the reading artificially high or low by the effort used. In
addition, PEFR only measures obstruction in the large central
airways; many asthmatics have a normal or near-normal PEFR, but
significant obstruction in the small airways or as measured by FEV1
or FEV1/FVC. Moreover, it is unclear that long-term PEFR use as
part of an asthma action plan results in better outcomes than
monitoring symptoms without PEFR and adjusting therapy
accordingly.13 Symptom-based asthma action plans are equally
effective as those based on peak flow monitoring.

Nonpharmacologic Measures
Nonpharmacologic interventions necessary for successful
management include formation of an effective partnership with a
knowledgeable health care provider, frequent monitoring of asthma
symptoms and response to therapy, objective measures of
pulmonary function, and avoidance of asthma triggers. Trigger
avoidance is important, yet patients are often unaware of specific
triggers or how to put environmental controls in place.
Environmental exposures (e.g., diesel particulates, ozone, and
sulfur dioxide) are likely to be more pronounced in those living
near highways, on bus lines, or near certain industrial plants. For
the indoor environment, dust mites, cat and dog dander, mold, and,
in the inner city, cockroach antigen have all been strongly linked to

2629
asthma exacerbations and morbidity. Removal of these allergens
can result in reduced symptoms and airway hyperresponsiveness.
However, it is difficult to reduce indoor allergen burden below the
threshold likely to induce symptoms without a multifaceted
approach. The use of room air filters and special cleaning agents
have some appeal but are not as effective as keeping ambient
humidity low (30%–40%), putting plasticized covers on pillows and
mattresses, washing bedding weekly in hot water, and removing
carpeting. A recent study suggested that application of dust covers
alone is not effective in improving airway function. Removing pets
from the bedroom and ideally from the household is also desirable.
Exterminating roaches is difficult, but the use of integrated pest
management strategies and eliminating water sources can be
effective. For all asthmatics, avoidance of passive exposure to
cigarette smoke is of paramount importance.
The Inner-City Asthma Study utilized a multidimensional
environmental intervention that instructed families on providing a
“safe sleeping zone” for the asthmatic child. Pets, dust, and other
irritants were barred from the sleeping area, and HEPA room filters
and vacuums were provided to all. In addition, specific strategies to
reduce mold and roaches were implemented in households where
dust sampling revealed high levels. This integrated and
individualized strategy resulted in significant allergen reduction
and improvement in symptom-free days over the yearlong
intervention and beyond.155 Another trial optimized asthma medical
care and control and then provided a mold and moisture
remediation program that removed existing mold and repaired
construction defects and leaks that promoted the mold problem.
Compared with those who lived in homes not remediated, the
children in the intervention group had more symptom-free days
and fewer serious exacerbations.156 A multicenter study in Europe
demonstrated that use of a device that provides temperature
controlled, laminar air flow to reduce inhalant allergen exposure is
associated with improved quality of life (as measured by the
Asthma Quality of Life Questionnaire) and decreased FeNO level.157
Use of ancillary personnel (e.g., a social worker who can conduct
formal risk assessment of psychosocial, economic, and school-
related risks) may be of great benefit in improving asthma control.

2630
Social determinants of chronic disease management often relate to,
or operate through, poverty. Substandard housing, limited access to
high-quality medical care, and transportation and child care
barriers can all contribute to poor asthma control in patients from
lower socioeconomic groups. Impaired maternal mental health, lack
of social supports, and child behavior problems may all contribute
to poor adherence and asthma control.
Adherence to a treatment regimen is key to successful asthma
management. Adherence differs from compliance, in that adherence
stresses the role of the patient and family in helping develop a
treatment program and contributing to the strategies necessary to
utilize the treatment plan. Compliance implies that a patient must
utilize a plan derived by the physician; failure to do so indicates
that the patient is at fault and irresponsible. The factors that
contribute to adherence are complex and incompletely understood.
It is difficult to predict which patients will have good adherence,
and it is not well correlated with race, gender, or intelligence.
Moreover, many patients overreport good adherence in an attempt
to please the physician. Adherence to suggested medical treatment
for asthma often ranges from 30% to 70% use of prescribed
medicine. Families should be encouraged to identify areas of a
treatment regimen that might offer difficulty, concerns they have
about medications, and lifestyle issues that might impair adherence.
Physicians must be willing to provide suitable alternatives (e.g.,
medications, dose schedules). Regularly scheduled office visits
should be conducted to evaluate the success of the treatment plan
and offer the patient the opportunity to voice concerns and ask for
help. When a child or the parents fail to adhere, the physician
should try to find out the reasons and to work out a practical
solution that is acceptable to the patient and family. Use of
motivational interviewing techniques and shared decision-making
strategies can often provide better results than direct reminders.
Patients must be given ready access to medical advice (e.g., over
the telephone), including how to deal with school-related asthma
management and behavior problems. Other technologies, such as
text messaging, email, videoconferencing, and social networking,
are also gaining popularity as ways to communicate with patients.
Most importantly, parents and patients must learn that frequent

2631
symptoms and limitation of lifestyle due to illness should not be
accepted; a symptom-free existence should be the goal.

Management of an Acute Episode

Acute asthma in children can occur as a mild illness that responds
promptly to bronchodilators, or it can develop into a medical
emergency over a matter of a few hours or days. Failure to respond
to aggressive home treatment mandates further evaluation and
treatment in the physician's office or a hospital emergency
department. Use of treatment algorithms and guidelines provide
useful infrastructure on which to base treatment, referral, and
admission decisions (Fig. 45.7).

2632
 FIG. 45.7 Treatment algorithm for medical facility
management of acute asthma. FEV1, Forced expiratory
volume in 1 second; ICS, inhaled corticosteroid; MDI,
metered-dosed inhaler; PEF, peak expiratory flow;
SABA, short-acting β agonist; SaO2, oxygen saturation
in arterial blood.

For mild acute asthma (cough, wheeze without dyspnea; PEFR

between 50% and 80% predicted), treatment can begin at home or in

2633
the physician's office, and the drug of choice is an inhaled SABA,
most commonly albuterol, 0.15–0.3 mg/kg per dose (or 2.5–5 mg)
given once from a small-volume nebulizer, or preferably, 2–6 puffs
(90 µg/puff) of albuterol (using a VHC if necessary) every 20
minutes for 1 hour. A recent study of 226 adults found that use of
albuterol plus ipratropium via MDI as rescue medication on an as
needed basis for symptoms provided better bronchodilatation, as
measured by FEV1, than albuterol via MDI (P < .0001).158 If
symptoms resolve, PEFR (if used) improves, and the patient
remains well for 3–4 hours, the short-acting bronchodilator can be
repeated as necessary, routine medications continued, and contact
with the physician considered. Doubling the dose of inhaled
steroids at the onset of an exacerbation is no longer recommended,
because most studies have not found a clear benefit. Higher
(quadruple) doses of inhaled steroids for acute exacerbations may
benefit some patients, but the data are limited thus far.159 Initiating
ICSs as a chronic treatment for a steroid-naïve patient during an
acute episode is appropriate, but other treatment with a SABA and
systemic corticosteroids should still be used as necessary. If
symptoms persist and PEFR improves little after the administration
of albuterol, the dose of inhaled albuterol should be repeated and a
dose of oral steroid (1–2 mg/kg, maximum 60 mg prednisone)
should be given. Physician contact is necessary at this point. For the
patient with progressive symptoms in spite of all of the listed
measures, care should be sought in a medical facility.
In the emergency department, further administration of
nebulized albuterol (2.5–5.0 mg) or 4–6 puffs every 20 minutes may
be continued for another hour, and an oral corticosteroid dose may
be given if not done earlier. Oral steroids commonly administered
for acute asthma exacerbations include prednisone and
prednisolone. A body of evidence supports the use of
dexamethasone. Its longer half-life allows for fewer doses of
medications, thereby facilitating patient adherence.160,161 There is no
benefit to giving IV steroids unless the patient cannot tolerate or
will not take the oral form. Ipratropium (250 or 500 µg) should also
be given every 20–30 minutes by nebulizer for three doses; this may
most likely benefit patients with more severe exacerbations of
airway obstruction. A subcutaneous (SQ) injection of epinephrine

2634
(or terbutaline) can be given if the patient is in severe distress and
unable to comply with aerosol therapy. Studies of continuous
albuterol nebulization (10–15 mg/hour) have yielded mixed results,
although most favor continuous nebulization over intermittent
administration. Significant adverse side effects during continuous
nebulization protocols in severe acute pediatric asthma are rare,
suggesting that this mode of delivery is safe, if not necessarily more
effective, and may be more convenient for patient and staff. A study
compared continuously nebulized levalbuterol to racemic albuterol
and found no significant efficacy or safety advantage, using
pharmacologically equivalent doses.162 These finding were
confirmed in a more recent meta-analysis.163
Other treatments that may be used in the acute hospital setting
include IV magnesium sulfate (MgSO4) and heliox. MgSO4 can act
as a smooth muscle relaxant, possibly by blocking calcium-
mediated contraction, decreasing acetylcholine release from
neuromuscular junctions, and reducing histamine-induced airway
spasm. MgSO4 has been utilized for patients who fail to improve
significantly following administration of inhaled SABA and
systemic corticosteroids. Several studies demonstrate improved
pulmonary function, decreased symptoms, and decreased rate of
hospitalization following a single infusion of 40–75 mg/kg
(maximum 2 g) over a 20-minute period. MgSO4 should strongly be
considered in severely ill patients who are in a monitored unit in an
emergency department and are failing conventional therapy.
Adverse events include flushing, headache, decreased blood
pressure, and weakness; the more significant effects are infrequent
unless the serum magnesium level rises above twice normal.
Heliox, a mixture of helium (80%) and oxygen (20%), is a
specialty gas that is less dense than nitrogen. When administered to
the acutely ill asthmatic, heliox can decrease airway resistance by
restoring laminar flow in obstructed airways where flow has
become more turbulent. Work of breathing is decreased, and the
patient is less likely to fatigue. However, there is no direct curative
action of heliox, and its effect occurs only while in use. It may also
be used to drive a small-volume nebulizer to deliver albuterol, but
this requires a specialized closed delivery system. Current data do
not support the routine use of heliox in the emergency department.

2635
Heliox may be a useful bridge therapy for the severely ill patient in
the intensive care unit who is tiring. It becomes less effective if
concentrations lower than 70% helium are used, making it less
useful in significantly hypoxic patients.
Montelukast administered intravenously or orally as an adjunct
treatment for status asthmaticus, in addition to standard treatment
with a SABA and systemic corticosteroids, has not proven useful in
improving symptoms, pulmonary function, or need for hospital
admission in children.164 The routine use of montelukast for
treatment of status asthmaticus cannot be recommended at this
time.
Failure to clear symptoms (particularly dyspnea, chest wall
retractions, or use of accessory muscles); persistent hypoxemia (O2
saturation < 92% while breathing room air); and improve air
exchange and (if measured) PEFR to above 40% to 50% predicted
are some indicators for hospital admission.

Hospital Management of Asthma

Status asthmaticus, or acute severe asthma that is resistant to
appropriate outpatient therapy, is a significant medical emergency
that requires prompt, systematic, and aggressive management in
the hospital. The initiation of early appropriate therapy shortens
hospitalization and reduces complications for the vast majority of
acutely ill patients. In spite of improved efforts at diagnosing and
treating asthma, status asthmaticus continues to be the one of the
most common discharge diagnoses from children's hospitals,
accounting for 15%–30% of all admissions. The increase in
hospitalizations for asthma reported in all age groups during the
last decade now appears to have slowed.

General Treatment
A physician, nurse, respiratory therapist, and consultant
pulmonologist team should manage the child with status
asthmaticus in a closely monitored inpatient unit. Although the
management of each child with status asthmaticus must be

2636
individualized, certain general principles apply to all patients with
this diagnosis.
Humidified oxygen should be administered (2–3 L/min by nasal
cannula or 30% fraction of inspired oxygen [FIO2] by facemask) to
maintain oxygen saturation in arterial blood (SaO2) greater than 93%
at sea level. The appropriate use of oxygen helps relieve dyspnea,
aids in bronchodilatation, supports the myocardium, and helps
prevent arrhythmias. Failure of improvement in hypoxemia with
modest amounts of oxygen suggests either severe airway
obstruction and impending respiratory failure or a complicating
factor, such as pneumonia, atelectasis, or another diagnosis besides
asthma. IV infusion of fluids is generally not required unless the
patient is unable to take or tolerate oral fluids or requires IV access
for steroids or antimicrobials (if needed for concomitant infection).
PFTs (FEV1 or PEFR) may be performed at the bedside if the child
can cooperate; however, most acutely ill children cannot do
acceptable spirometry. Pulse oximetry (or arterial or capillary blood
gas if hypercarbia or acidosis is suspected) should be measured as
soon as possible and repeated as the patient's condition warrants.
Although not needed on all asthmatics, a chest radiograph provides
information on other pulmonary problems that might complicate
management in patients who do not respond rapidly to treatment
(e.g., pneumonia, atelectasis, pneumomediastinum, or
pneumothorax).
Details about the acute illness (its duration, progression,
manifestations, and initiating factors), information on the duration
and the reports of previous acute episodes, and level of functional
morbidity and medication use at the patient's stable baseline should
be noted. The patient's medication (including the names, dosages,
and exact time of all medications administered within 24 hours)
and any systemic corticosteroid drugs administered within 12
months should be documented. These data will be useful in
constructing a treatment plan upon hospital discharge.
On physical examination, the general appearance and level of
activity, respiratory effort, presence or absence of wheezing,
tachycardia, tachypnea, air exchange, adventitious breath sounds,
use of accessory muscles, dyspnea, and color are important clinical
parameters that provide information about pulmonary dysfunction.

2637
 Although the number of pharmacologic agents for treatment of
status asthmaticus is relatively limited, management strategies are
inconsistent among and within institutions (see Table 45.4A and B).
Evidence-based practice is often replaced by physician personal
experience and preference. Elimination of treatment that adds risk
and cost but does not improve quality of care should be a primary
goal. Status asthmaticus readily lends itself to treatment by the
standardized clinical pathway, and several published studies have
demonstrated shortened hospital stays using such care paths.165
Administration of oral corticosteroids within 75 minutes of arriving
in the emergency department decreases the need for admission.166

Table 45.4B
Adjunct Medications for Severe Episodes

Medication Child (<12 years) Adolescent

MAGNESIUM SULFATE
Intravenous (IV) Bolus: 50 mg/kg per dose (25–75 mg/kg per dose; max 2 g)
Administer over 20 min
SYSTEMIC (INJECTED) β2 AGONISTS
Epinephrine
Intramuscular 0.01 mg/kg (max 0.3–0.5 mg) every 20 0.3–0.5 mg every 20 min for 3
(IM) min for 3 doses doses
1 : 1,000
(1 mg/mL)
Terbutaline
Intravenous (IV) 0.01 mg/kg bolus (max 0.4 mg) over 10 0.01 mg/kg bolus (max 0.75 mg)
min over 10 min
Subcutaneous 0.01 mg/kg (max 0.25 mg) 0.01 mg/kg (max 0.25 mg)
(SQ)
(1 mg/mL) May repeat every 15 min for 3 doses May repeat every 15 min for 3
doses
No advantage has been found for higher-dose corticosteroids in severe asthma
exacerbations.1
There is no advantage for intravenous administration over oral therapy, provided
gastrointestinal function is intact.
Therapy following a hospitalization or emergency department visit is typically 5 days
but may last from 3 to 10 days. Studies indicate that there is no need to taper the
systemic corticosteroid dose when given up to 10 days. Dosages in excess of 1
mg/kg of prednisone or prednisolone have been associated with adverse behavioral
effects in children, whereas 1 mg/kg provides equivalent pulmonary benefit without
the adverse effects in most cases.

Medical management of the hospitalized asthmatic should

include aggressive use of inhaled bronchodilators, most commonly

2638
albuterol, and systemic corticosteroids. The frequency of treatment
should be guided by the patient's condition. In most inpatient,
nonintensive care unit settings, inhalations may be administered as
frequently as every 1–2 hours. In some settings, where close
monitoring is available outside the intensive care unit,
consideration may be given to administering albuterol continuously
(10–15 mg/hour) for short time periods (1–4 hours). Treatments
should be administered only if the patient's respiratory status
indicates need; studies have shown that such assessment-driven
administration of SABAs is as effective as scheduled treatments.
Moreover, patients who are treated on an “as-needed” basis are
likely to receive fewer treatments at less cost. If the patient cannot
tolerate oral therapy, IV administration of corticosteroids should be
ordered. Methylprednisolone, 1–2 mg/kg (maximum 125 mg) may
be given daily. Failure to improve significantly after a maximum of
12 hours of such therapy should prompt a search for other
complicating factors and impending respiratory failure, and
indicates a need for more aggressive monitoring and treatment. If at
any time the patient's condition deteriorates, consideration should
be given to administering immediate intensified treatment, such as
SQ epinephrine (0.01 mL/kg, maximum 0.3 mL), terbutaline, or 500
µg aerosolized ipratropium with 5 mg albuterol. If a favorable
response is observed, the aerosol treatment may be repeated every
20 minutes over the next hour. Patients who fail to sustain
improvement after such treatment should be transferred to the
intensive care unit.
The asthmatic child requiring intensive care should be monitored
carefully for the development of respiratory failure. Physical
findings such as severe dyspnea, inability to lie flat, poor air
exchange, severe wheezing, and use of accessory muscles of
respiration are all indicators of impending respiratory failure.
Continuous cardiorespiratory monitoring and pulse oximetry with
intermittent determination of arterial or venous blood gas
measurement to assess oxygenation, ventilation, serum electrolyte,
and acid-base status are necessary. Treatment should consist of
continuously nebulized albuterol (0.15 mg/kg per hour, maximum
15 mg), ipratropium 500 µg nebulized every 4–6 hours, and
methylprednisolone 1–2 mg/kg (maximum 125 mg) every 24 hours.

2639
Serum potassium concentration should also be closely monitored,
because frequent SABA administration may cause hypokalemia.
A few studies suggest that IV aminophylline may result in the
more rapid resolution of symptoms compared with placebo,
although overall intensive care length of stay was not affected. For
the patient who fails to respond, treatment with a bolus and
possible continuous IV infusion of a β-adrenergic agonist (e.g.,
terbutaline) can be considered (IV albuterol [salbutamol] is not
available in the United States). Delivery of the medication via the
circulation may provide relief of bronchospasm in areas not
receiving medication via the inhaled route due to severe airway
obstruction. However, most studies do not report significant
improvement compared with use of continuous nebulized SABA
treatment. The starting dose of terbutaline is 5 µg/kg, followed by a
continuous infusion of 0.4 µg/kg per minute. The dose is increased
by 0.2 µg/kg per minute to a maximum dose of 12–16 µg/kg per
minute, although higher doses have been used. Baseline and twice-
daily cardiac isoenzymes and continuous electrocardiograms must
be monitored because myocardial toxicity has been reported.
Although every effort should be made to avoid intubation and
mechanical ventilation, a small percentage of severely ill patients
(<10%) may require invasive ventilatory support. It is difficult to
mechanically ventilate an asthmatic, and the complication rate may
exceed 30%. Indications for intubation have become more
conservative and should be reserved for patients who have apnea,
unstable vital signs, impaired level of consciousness, severe
acidosis, extreme fatigue, and failure of noninvasive ventilation. A
trial of noninvasive ventilation using continuous positive airway
pressure (CPAP) or bilevel positive airway pressure (Bi-Pap) may
be successful in some patients. Low levels of H2O pressure (5–10
cm) may be helpful in reducing work of breathing and improving
oxygenation over a several-hour trial. Some patients become
anxious using the tight-fitting facemask necessary for effective
CPAP and may require a modest dose of a short-acting
benzodiazepine to comply with treatment. Risks include gastric
distention, vomiting, aspiration, or air leak.
A skilled intensivist or anesthesiologist using rapid-sequence
induction anesthesia should perform intubation when necessary. It

2640
is important to make certain the patient is adequately hydrated
prior to intubation and not given excessive positive pressure bag
ventilation immediately after. Asthmatic patients are at risk for
significant hypotension following intubation because of extreme
hyperventilation leading to auto-PEEP, which impedes systemic
venous return; this can be further exacerbated by volume depletion
and application of aggressive positive pressure ventilation.
Continuous sedation is usually required during mechanical
ventilation. High peak inspiratory pressures are often noted, and
efforts should be made to reduce them to less than 45 mm Hg. Use
of selective hypoventilation (permissive hypercapnia) must be
practiced, and attempts to immediately normalize ventilation
should be avoided. Relief of hypoxemia, respiratory distress, and
muscle fatigue are the goals. Volume ventilation with a square
wave form and the lowest volume and flow to minimize peak
pressure and volume damage while maximizing expiratory time is
usually recommended, but there are reports of successful use of
pressure-controlled ventilation. Relatively low respiratory rates (8–
10/min), low tidal volumes (6–8 mL/kg), and prolonged expiratory
time should be tried as ventilator strategies. Decreasing the minute
ventilation can maximize expiratory time; this can be best
accomplished by using a lower respiratory rate or tidal volume.
Shortening the inspiratory time by increasing the inspiratory flow
rate can work, but it may be less effective and may contribute to
airway injury caused by high shear forces. As long as metabolic
acidosis is not present, a pH as low as 7.2 can be tolerated. IV
infusion of sodium bicarbonate for more profound acidosis is
controversial and generally not recommended. All medications
should be continued while the patient is mechanically ventilated.
Delivery of aerosolized bronchodilators through the endotracheal
tube using an MDI and spacer device should be continued as well.
Extubation should be considered and attempted using standard
criteria, such as normoxemia with an FIO2 of less than 0.40,
spontaneous tidal volume greater than 5 mL/kg, vital capacity
greater than 15 mL/kg, maximum inspiratory pressure (MIP)
greater than 25 cm H2O, and the ability to protect the airway and
handle secretions. Most patients can be successfully weaned and
extubated within 72 hours.

2641
 Several other therapies for the severely ill asthmatic have been
tried, but they are still considered unproven or experimental. IV
MgSO4 should be tried, particularly if not administered previously.
Heliox has been reported to decrease pulsus paradoxus and
improve air flow in acutely ill, nonintubated asthmatic children,
and can also be administered during mechanical ventilation.
However, this therapy is unproven, and the less-dense gas alters
ventilator function, requiring careful ventilator adjustment and a
knowledgeable respiratory therapist. Administration of inhaled
general anesthetic agents (e.g., enflurane and sevoflurane, which
are bronchodilators) has also been used with some success;
however, reports are anecdotal, and no controlled trials have been
conducted. These agents are also myocardial irritants and may
precipitate serious arrhythmias in the acidotic, hypoxemic
asthmatic. Ketamine infusions can be considered for sedation of the
intubated patient, since the drug also has some bronchodilator
properties. However, the adverse psychoactive effects of ketamine
can be problematic in older children and may only be partially
obviated by the concomitant administration of a benzodiazepine.
Of note, most patients who develop life-threatening asthma and
respiratory failure do so outside the hospital or shortly after
arriving at a medical facility. Most asthma deaths occur prior to
reaching an intensive care unit and institution of successful airway
management. Once successfully stabilized in an intensive care unit
that is familiar with the management of acute severe asthma,
patients who have not experienced respiratory arrest or prolonged
hypoxia are likely to survive intact.

References
1. National Institutes of Health. Guidelines for the Diagnosis and
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