Practice Essentials

Asthma, which occurs in adult and pediatric patients, is a chronic inflammatory disorder of
the airways characterized by an obstruction of airflow. Among children and adolescents aged
5-17 years, asthma accounts for a loss of 10 million school days annually and costs caretakers
$726.1 million per year because of work absence. [1]

Signs and symptoms

History

The clinician should establish whether the patient has any of the following symptoms:

 Wheezing: A musical, high-pitched whistling sound produced by airflow turbulence is

one of the most common symptoms of asthma. The wheezing is usually during
exhalation.

 Cough: Usually, the cough is nonproductive and nonparoxysmal; coughing may be

present with wheezing

 Cough at night or with exercise: Coughing may be the only symptom of asthma,
especially in cases of exercise-induced or nocturnal asthma; children with nocturnal
asthma tend to cough after midnight, during the early hours of morning

 Shortness of breath

 Chest tightness: A history of tightness or pain in the chest may be present with or
without other symptoms of asthma, especially in exercise-induced or nocturnal
asthma

Sputum production

In an acute episode of asthma, symptoms vary according to the episode’s severity. Infants and
young children suffering a severe episode display the following characteristics:

 Breathless during rest

 Not interested in feeding

 Sit upright

 Talk in words (not sentences)

 Usually agitated

With imminent respiratory arrest, the child displays the aforementioned symptoms and is also
drowsy and confused. However, adolescents may not have these symptoms until they are in
frank respiratory failure.
Physical examination

Findings during a severe episode include the following:

 Respiratory rate is often greater than 30 breaths per minute

 Accessory muscles of respiration are usually used

 Suprasternal retractions are commonly present

 The heart rate is greater than 120 beats per minute

 Loud biphasic (expiratory and inspiratory) wheezing can be heard

 Pulsus paradoxus is often present (20-40 mm Hg)

 Oxyhemoglobin saturation with room air is less than 91%

Findings in status asthmaticus with imminent respiratory arrest include the following:

 Paradoxical thoracoabdominal movement occurs

 Wheezing may be absent (in patients with the most severe airway obstruction)

 Severe hypoxemia may manifest as bradycardia

 Pulsus paradoxus may disappear: This finding suggests respiratory muscle fatigue

See Clinical Presentation for more detail.

Diagnosis

Tests used in the diagnosis of asthma include the following:

 Pulmonary function tests: Spirometry and plethysmography

 Exercise challenge: Involves baseline spirometry followed by exercise on a treadmill

or bicycle to a heart rate greater than 60% of the predicted maximum, with monitoring
of the electrocardiogram and oxyhemoglobin saturation

 Fraction of exhaled nitric oxide (FeNO) testing: Noninvasive marker of airway

inflammation

 Radiography: Reveals hyperinflation and increased bronchial markings; radiography

may also show evidence of parenchymal disease, atelectasis, pneumonia, congenital
anomaly, or a foreign body

 Allergy testing: Can identify allergic factors that may significantly contribute to
asthma
  Histologic evaluation of the airways: Typically reveal infiltration with inflammatory
cells, narrowing of airway lumina, bronchial and bronchiolar epithelial denudation,
and mucus plugs

See Workup for more detail.

Management

Guidelines from the National Asthma Education and Prevention Program emphasize the
following components of asthma care [2] :

 Assessment and monitoring: In order to assess asthma control and adjust therapy,
impairment and risk must be assessed; because asthma varies over time, follow-up
every 2-6 weeks is initially necessary (when gaining control of the disease), and then
every 1-6 months thereafter

 Education: Self-management education should focus on teaching patients the

importance of recognizing their own level of control and signs of progressively
worsening asthma symptoms; educational strategies should also focus on
environmental control and avoidance strategies, as well as on medication use and
adherence (eg, correct inhaler techniques and use of other devices)

 Control of environmental factors and comorbid conditions

 Pharmacologic treatment

 Pharmacologic treatment

Pharmacologic asthma management includes the use of agents for control and agents for
relief. Control agents include the following:

 Inhaled corticosteroids

 Inhaled cromolyn or nedocromil

 Long-acting bronchodilators

 Theophylline

 Leukotriene modifiers

 Anti-immunoglobulin E (IgE) antibodies (omalizumab)

 Interleukin inhibitors (eg, mepolizumab, benralizumab, dupilumab)

Relief medications include the following:

 Short-acting bronchodilators
  Systemic corticosteroids

 Ipratropium

See Treatment and Medication for more detail.

Background
Asthma is a chronic inflammatory disorder of the airways characterized by an obstruction of
airflow, which may be completely or partially reversed with or without specific therapy.
Airway inflammation is the result of interactions between various cells, cellular elements, and
cytokines. In susceptible individuals, airway inflammation may cause recurrent or persistent
bronchospasm, which causes symptoms that include wheezing, breathlessness, chest
tightness, and cough, particularly at night (early morning hours) or after exercise.

Airway inflammation is associated with airway hyperreactivity or bronchial

hyperresponsiveness (BHR), which is defined as the inherent tendency of the airways to
narrow in response to various stimuli (eg, environmental allergens and irritants). [3]

Asthma affects an estimated 300 million individuals worldwide (see Epidemiology). The
prevalence of asthma is increasing, especially in children. Annually, the World Health
Organization (WHO) has estimated that 15 million disability-adjusted life-years are lost and
250,000 asthma deaths are reported worldwide. [4] Approximately 500,000 annual
hospitalizations (34.6% in individuals aged 18 y or younger) are due to asthma. In the United
States, asthma prevalence, having increased from 1980 to 1996, showed a plateau at 9.1% of
children (6.7 million) in 2007. [5]

The cost of illness related to asthma is around $6.2 billion. Each year, an estimated 1.81
million people (47.8% in individuals aged 18 y or younger) require treatment in the
emergency department. Among children and adolescents aged 5-17 years, asthma accounts
for a loss of 10 million school days and costs caretakers $726.1 million because of work
absence. [1]

Guidelines from the National Asthma Education and Prevention Program provide
recommendations on the diagnosis and treatment of pediatric asthma (see Clinical
Presentation, Workup, and Treatment and Management).

Pathophysiology
Interactions between environmental and genetic factors result in airway inflammation, which
limits airflow and leads to functional and structural changes in the airways in the form of
bronchospasm, mucosal edema, and mucus plugs.

Airway obstruction causes increased resistance to airflow and decreased expiratory flow
rates. These changes lead to a decreased ability to expel air and may result in hyperinflation.
The resulting overdistention helps maintain airway patency, thereby improving expiratory
flow; however, it also alters pulmonary mechanics and increases the work of breathing.
Hyperinflation compensates for the airflow obstruction, but this compensation is limited
when the tidal volume approaches the volume of the pulmonary dead space; the result is
alveolar hypoventilation. Uneven changes in airflow resistance, the resulting uneven
distribution of air, and alterations in circulation from increased intra-alveolar pressure due to
hyperinflation all lead to ventilation-perfusion mismatch.

Vasoconstriction due to alveolar hypoxia also contributes to this mismatch. Vasoconstriction

is also considered an adaptive response to ventilation/perfusion mismatch.

In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is

prevented by the ready diffusion of carbon dioxide across alveolar capillary membranes.
Thus, patients with asthma who are in the early stages of an acute episode have hypoxemia in
the absence of carbon dioxide retention. Hyperventilation triggered by the hypoxic drive also
causes a decrease in PaCO2. An increase in alveolar ventilation in the early stages of an acute
exacerbation prevents hypercarbia.

With worsening obstruction and increasing ventilation-perfusion mismatch, carbon dioxide

retention occurs. In the early stages of an acute episode, respiratory alkalosis results from
hyperventilation. Later, the increased work of breathing, increased oxygen consumption, and
increased cardiac output result in metabolic acidosis. Respiratory failure leads to respiratory
acidosis. Fatigue is also a potential contributor to respiratory acidosis.

Role of inflammation

Chronic inflammation of the airways is associated with increased BHR, which leads to
bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after
exposure to allergens, environmental irritants, viruses, cold air, or exercise. In some patients
with chronic asthma, airflow limitation may be only partially reversible because of airway
remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and subepithelial
fibrosis) that occurs with chronic untreated disease.

New insights in the pathogenesis of asthma suggest that lymphocytes play a role. Airway
inflammation in asthma may represent a loss of normal balance between two "opposing"
populations of T helper (Th) lymphocytes. Two types of Th lymphocytes have been
characterized: Th1 and Th2. Th1 cells produce interleukin (IL)-2 and interferon-α (IFN-α),
which are critical in cellular defense mechanisms in response to infection. Th2, in contrast,
generates a family of cytokines (interleukin-4 [IL-4], IL-5, IL-6, IL-9, and IL-13) that can
mediate allergic inflammation.

The hygiene hypothesis

The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may
explain some of the dramatic increases in asthma prevalence in Westernized countries. [6] This
hypothesis is based on the concept that the immune system of the newborn is skewed toward
Th2 cytokine generation (mediators of allergic inflammation). Over time, environmental
stimuli such as infections activate Th1 responses and bring the Th1/Th2 relationship to an
appropriate balance.

Evidence suggests that the prevalence of asthma is reduced in children who experience the
following events:
  Certain infections (Mycobacterium tuberculosis, measles, or hepatitis A)

 Rural living

 Exposure to other children (eg, presence of older siblings and early enrollment in
childcare

 Less frequent use of antibiotics, including in the first week of life [7]

 Early introduction of fish in the diet [7]

Furthermore, the absence of these lifestyle events is associated with the persistence of a Th2
cytokine pattern.

Under these conditions, the genetic background of the child, with a cytokine imbalance
toward Th2, sets the stage to promote the production of immunoglobulin E (IgE) antibody to
key environmental antigens (eg, dust mites, cockroaches, Alternaria, and possibly cats).
Therefore, a gene-by-environment interaction occurs in which the susceptible host is exposed
to environmental factors that are capable of generating IgE, and sensitization occurs.

A reciprocal interaction is apparent between the two subpopulations, in which Th1 cytokines
can inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an
excessive expression of Th2 cytokines. Alternatively, recent studies have suggested the
possibility that the loss of normal immune balance arises from a cytokine dysregulation in
which Th1 activity in asthma is diminished. [8]

Results of two recently reported cross sectional studies of children growing up on farms in
Central Europe who were exposed to greater variety of environmental microorganisms
showed an inverse relationship between microbial exposure and the probability of asthma. [9]

Genetic factors

Some studies highlight the importance of genotypes in contributing to asthma susceptibility

and allergic sensitization, as well as response to specific asthma treatments. [10, 11, 12, 13]

Through the use of cluster analysis, the Severe Asthma Research Program of the National
Heart, Lung, and Blood Institute identified 5 phenotypes of asthma. [14] Cluster 1 patients have
early-onset atopic asthma with normal lung function treated with two or fewer controller
medications and minimal health care utilization. Cluster 2 patients have early-onset atopic
asthma and preserved lung function but increased medication requirements (29% on three or
more medications) and health care utilization.

Cluster 3 comprises mostly older obese women with late-onset nonatopic asthma, moderate
reductions in pulmonary function, and frequent oral corticosteroid use to manage
exacerbations. Cluster 4 and cluster 5 patients have severe airflow obstruction with
bronchodilator responsiveness but differ in to their ability to attain normal lung function, age
of asthma onset, atopic status, and use of oral corticosteroids. [14]
A recently reported meta-analysis of genome-wide association studies of asthma in ethnically
diverse North American populations identified 5 susceptibility loci. Four were on previously
reported loci on 17q21 and a new asthma susceptibility locus at PYHIN1, which is specific to
the African American population. [15]

An Australian study identified 2 new loci with genome-wide significant association with
asthma risk: rs4129267 in IL6R and rs7130588 on band 11q13.5. The IL6R association
supports the hypothesis that cytokine dysregulation affects asthma risk, hence a specific
antagonist to IL6R may help. The results for the 11q13.5 locus suggest its association with
allergic sensitization and subsequent development of asthma. [16]

Other factors

A study that examined whether the lipid profile is associated with concurrent asthma
concluded that the blood lipid profile is associated with asthma, airway obstruction, bronchial
responsiveness, and aeroallergen sensitization in 7-year-old children. Caution must be applied
before saying that asthma might be a systemic disorder. First, we don't know if the children
with the elevated LDL levels were more likely exposed to higher doses of inhaled, or
systemic corticosteroids. The authors did find that those with worse lung function had higher
LDL levels. However, it could also be that those children exercised less, a potential cause of
obesity and abnormal lipid levels. The BMI was also not reported. [17, 18]

A 2012 study reported a significant association between lung function deficit and bronchial
responsiveness in the neonatal period with development of asthma by age seven years. [19]

Lemanske et al reported that wheezing illnesses caused by rhinovirus infection during infancy
were the strongest predictor of wheezing in the third year of life. [20]

In a study of preschool children with asthma, Guilbert et al found that 2 years of inhaled
corticosteroid therapy did not change the asthma symptoms or lung function during a third,
treatment-free year. This suggests that no disease-modifying effect of inhaled corticosteroids
is present after the treatment is discontinued. [21]

In a study of children in the Cincinnati area, Reponen et al found that a high Environmental
Relative Moldiness Index (ERMI) [22] at age 1 year made asthma at age 7 years more likely.
The ERMI did not predict specific mold allergies at age 7 years. Air conditioning made
asthma less likely. An elevated ERMI at age 7 years had no correlation with current asthma.
Seeing or smelling mold in a home inspection at age 1 year did not correlate with the ERMI
or with the development of asthma. They also found that black race, having a parent with
asthma, and house dust allergy was predictive of a greater likelihood of asthma. [23]

A recent study from Australia reported that obesity is a determinant of asthma control
independent of inflammation, lung function, and airway hyperresponsiveness. [24] A similar
association between increased risk of worse asthma control and obesity was reported in a
recent retrospective study of 32,321 children aged 5-17 years. [25]

A significant inverse relationship between serum vitamin D levels and patient IgE levels,
steroid requirements, and in vitro responsiveness to corticosteroids in children has been
reported. [26]
Parental cigarette smoking has been shown to increase the likelihood of asthma. This is more
true for maternal smoking, though the authors of one study did not correct for primary
caretakers. The more cigarettes the mother smoked, the greater the risk of asthma. [27]

A randomized clinical trial by Sheehan et al evaluated the association in children between

frequent acetaminophen use and asthma-related complications. The study found that among
young children with mild persistent asthma, as-needed use of acetaminophen was not shown
to be associated with a higher incidence of asthma exacerbations or worse asthma control
than was as-needed use of ibuprofen. [28, 29]

Etiology
In most cases of asthma in children, multiple triggers or precipitants are recognized, and the
patterns of reactivity may change with age. Treatment can also change the pattern. Wheeze is
common with respiratory syncytial virus (RSV) bronchiolitis and recurrent wheeze may
persist up to 3-5 years. However, RSV is unlikely the sole explanation for the development of
atopic asthma later in life. On the other hand, infection with human rhinovirus that requires
hospitalization has been associated with future development of asthma (age 6 y).

Respiratory infections

Most commonly, these are viral infections. In some patients, fungi (eg, allergic
bronchopulmonary aspergillosis), bacteria (eg, Mycoplasma, pertussis), or parasites may be
responsible. Most infants and young children who continue to have a persistent wheeze and
asthma have high immunoglobulin E (IgE) production and eosinophilic immune responses (in
the airways and in circulation) at the time of the first viral upper respiratory tract infection
(URTI). They also have early IgE-mediated responses to local aeroallergens.

Allergens and irritants

In patients with asthma, 2 types of bronchoconstrictor responses to allergens are recognized:

early and late. Early asthmatic responses occur via IgE-induced mediator release from mast
cells within minutes of exposure and last for 20-30 minutes.

Late asthmatic responses occur 4-12 hours after antigen exposure and result in more severe
symptoms that can last for hours and contribute to the duration and severity of the disease.
Inflammatory cell infiltration and inflammatory mediators play a role in the late asthmatic
response. Allergens can be foods, household inhalants (eg, animal allergens, molds, fungi,
roach allergens, dust mites), or seasonal outdoor allergens (eg, mold spores, pollens, grass,
trees).

Tobacco smoke, cold air, chemicals, perfumes, paint odors, hair sprays, air pollutants, and
ozone can initiate BHR by inducing inflammation.

Other factors

Asthma attacks can be related to changes in atmospheric temperature, barometric pressure,

and the quality of air (eg, humidity, allergen and irritant content). In some individuals,
emotional upsets clearly aggravate asthma.
Exercise can trigger an early asthmatic response. Mechanisms underlying exercise-induced
asthmatic response remain somewhat uncertain. Heat and water loss from the airways can
increase the osmolarity of the fluid lining the airways and result in mediator release. Cooling
of the airways results in congestion and dilatation of bronchial vessels. During the rewarming
phase after exercise, the changes are magnified because the ambient air breathed during
recovery is warm rather than cool.

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can
significantly increase airway resistance and airway reactivity. Inflammatory conditions of the
upper airways (eg, allergic rhinitis, sinusitis, or chronic and persistent infections) must be
treated before asthmatic symptoms can be completely controlled.

Multiple factors have been proposed to explain nocturnal asthma. Circadian variation in lung
function and inflammatory mediator release in the circulation and airways (including
parenchyma) have been demonstrated. Other factors, such as allergen exposure and posture-
related irritation of airways (eg, gastroesophageal reflux, sinusitis), can also play a role. In
some cases, abnormalities in CNS control of the respiratory drive may be present, particularly
in patients with a defective hypoxic drive and obstructive sleep apnea.

Children exposed to higher maternal stress during the pre- and postnatal period were reported
to be at higher risk for wheeze. This was only true in non-atopic mothers. [30]

A 2012 Danish study reported an association between maternal obesity (BMI ≥35 and
gestational weight gain ≥25 kg) during pregnancy with increased risk of asthma and
wheezing in the offspring. [31]

Results of a prospective birth cohort study of 568 pregnant women and their offspring
showed that postnatal bisphenol A (BPA) exposure in the first years of a child's life is
associated with significantly increased risk for wheeze and asthma. Feeding bottles, sippy
cups, or other containers designed for infants may contain it. The study also found, however,
that fetal exposure to BPA during the third trimester of pregnancy was inversely associated
with risk for wheeze in offspring at age 5 years. [32, 33]

Epidemiology
Approximately 34.1 million people in the United States have been diagnosed with asthma in
their lifetime. According to the most recent US Centers for Disease Control and Prevention
(CDC) Asthma Surveillance Survey, the prevalence of current asthma during 2001-2003
prevalence is estimated at 6.7% in adults and 8.5% in children, and the burden of asthma
increased more than 75% from 1980-1999. [34, 35]

Asthma accounts for more school absences and more hospitalizations than any other chronic
illness. In most children's hospitals in the United States, it is the most common diagnosis at
admission.

Worldwide, 130 million people have asthma. The prevalence is 8-10 times higher in
developed countries (eg, United States, Great Britain, Australia, New Zealand) than in the
developing countries. In developed countries, the prevalence is higher in low-income groups
in urban areas and inner cities than in other groups.
A long-term study of a birth cohort on the Isle of Wight showed that maternal asthma and
eczema were associated with asthma and eczema in their daughters, but not in their sons.
Similarly, paternal asthma and eczema were associated with asthma and eczema in their sons,
but not in their daughters. [36]

Race-, sex-, and age-related demographics

The prevalence of asthma is higher in minority groups (eg, blacks, Hispanics) than in other
groups; however, findings from one study suggest that much of the recent increase in the
prevalence is attributed to asthma in white children. Approximately 5-8% of all black
children have asthma at some time. The prevalence in Hispanic children is reported to be as
high as 15%. In blacks, the death rate is consistently higher than in whites.

Before puberty, the prevalence of asthma is 3 times higher in boys than in girls. During
adolescence, the prevalence is equal among males and females. Adult-onset asthma is more
common in women than in men.

In most children, asthma develops before age 5 years, and, in more than half, asthma
develops before age 3 years.

Among infants, 20% have wheezing with only upper respiratory tract infections (URTIs), and
60% no longer have wheezing by age 6 years. As Martinez et al have pointed out, however,
many of these children are "transient wheezers" whose symptoms subside during the
preschool or early school years. [37, 38] They tend to have no allergies, although their lung
function is often abnormal. These findings have led to the idea that they have small lungs.

Children in whom wheezing begins early in conjunction with allergies are more likely to have
wheezing when they are aged 6-11 years. Similarly, children in whom wheezing begins after
age 6 years often have allergies, and the wheezing is more likely to continue when they are
aged 11 years. [20]

Prognosis
Of infants who wheeze with URTIs, 60% are asymptomatic by age 6 years. However,
children who have asthma (recurrent symptoms continuing at age 6 y) have airway reactivity
later in childhood. Some findings suggest a poor prognosis if asthma develops in children
younger than 3 years, unless it occurs solely in association with viral infections.

Individuals who have asthma during childhood have significantly lower forced expiratory
volume in 1 second (FEV1), higher airway reactivity, and more persistent bronchospastic
symptoms than those with infection-associated wheezing.

Children with mild asthma who are asymptomatic between attacks are likely to improve and
be symptom-free later in life.

Children with asthma appear to have less severe symptoms as they enter adolescence, but half
of these children continue to have asthma. Asthma has a tendency to remit during puberty,
with a somewhat earlier remission in girls. However, compared with men, women have more
BHR.
In a prospective study of 484 Australian children, Tai and colleagues found that having severe
asthma in childhood was associated with an almost 12-fold increased risk of having asthma at
age 50. [39, 40] At age 50, remission of asthma had occurred in 64% of subjects with mild
wheezy bronchitis/wheezy bronchitis at baseline, compared with 47% of those with asthma at
baseline and 15% of those with severe asthma. In a multivariate analysis, factors that
significantly predicted asthma at age 50 were severe childhood asthma (odds ratio [OR]
11.9), childhood hay fever (OR 2.0, and female sex (OR 2.0). [39, 40]

Mortality and morbidity associated with asthma

Globally, morbidity and mortality associated with asthma have increased over the last 2
decades. This increase is attributed to increasing urbanization. Despite advancements in the
understanding of asthma and the development of new therapeutic strategies, the morbidity
and mortality rates due to asthma definitely increased from 1980-1995.

In the United States, the mortality rate due to asthma has increased in all age, race, and sex
strata. In the United States, the mortality rate due to asthma is more than 17 deaths per 1
million population (ie, 5000 deaths per year).

From 1975-1993, the number of deaths nearly doubled in people aged 5-14 years. In the
northeastern and midwestern United States, the highest mortality rate has been among
persons aged 5-34 years. According to the most recent report from the CDC and the National
Center for Health Statistics, 187 children aged 0-17 years died from asthma, or 0.3 deaths per
100,000 children compared with 1.9 deaths per 100,000 adults aged 18 or older in the year
2002. [34]

Non-Hispanic blacks were the most likely to die from asthma and had an asthma death rate
more than 200% higher than non-Hispanic whites and 160% higher than Hispanics.

Patient Education
Patient and parent education should include instructions on how to use medications and
devices (eg, spacers, nebulizers, metered-dose inhalers [MDIs]). The patient's MDI technique
should be assessed on every visit. Discuss the management plan, which includes instructions
about the use of medications, precautions with drug and/or device usage, monitoring
symptoms and their severity (peak flow meter reading), and identifying potential adverse
effects and necessary actions.

Write and discuss in detail a rescue plan for an acute episode. This plan should include
instructions for identifying signs of an acute attack, using rescue medications, monitoring,
and contacting the asthma care team. Parents should understand that asthma is a chronic
disorder with acute exacerbations; hence, continuity of management with active participation
by the patient and/or parents and interaction with asthma care medical personnel is important.
Emphasize the importance of adherence to treatment.

Incorporate the concept of expecting full control of symptoms, including nocturnal and
exercise-induced symptoms, in the management plans and goals (for all but the most severely
affected patients). Avoid unnecessary restrictions in the lifestyle of the child or family. Expect
the child to participate in recreational activities and sports and to attend school as usual.
A systematic review by Coffman and colleagues suggested a benefit school-based asthma
education. Their review included 25 studies in children aged 4-17 years. [41] In most of those
studies, compared with usual care, school-based asthma education improved knowledge of
asthma (7 of 10 studies), self-efficacy (6 of 8 studies), and self-management behaviors (7 of 8
studies). Fewer studies reported favorable effects on quality of life (4 of 8 studies), days of
symptoms (5 of 11 studies), nights with symptoms (2 of 4 studies), and school absences (5 of
17 studies). [41]

For patient education information, see the Asthma Center, as well as Asthma, Asthma FAQs,
Understanding Asthma Medications, Asthma in Children, and Asthma in School Children:
Educational Slides.

History
Guidelines from the National Asthma Education and Prevention Program, which were
updated in 2007, highlight the importance of correctly diagnosing asthma. [2] To establish the
diagnosis of asthma, the clinician must confirm the following:

 Episodic symptoms of airflow obstruction are present

 Airflow obstruction or symptoms are at least partially reversible

 Alternative diagnoses are excluded

Thus, obtaining a good patient history is crucial when diagnosing asthma and excluding other
causes.

The clinician should establish whether the patient has any of the following symptoms:

 Wheezing

 Cough

 Cough at night

 Cough during or after exercise

 Shortness of breath

 Chest tightness

 Sputum production

The clinician should determine the pattern of symptoms, as follows:

 Perennial, seasonal, or both

 Continuous or intermittent
  Daytime or nighttime

 Onset and duration

The clinician should ask whether any of the following precipitate and/or aggravate
symptoms:

 Viral infections

 Environmental allergens

 Irritants (eg, smoke exposure, chemicals, vapors, dust)

 Exercise

 Emotions

 Home environment (eg, carpets, pets, mold)

 Stress

 Drugs (eg, aspirin, beta blockers)

 Foods

 Changes in weather

The presence of other conditions that may affect asthma should be determined. Such
conditions may include the following:

 Thyroid disease

 Pregnancy

 Menses

 Gastroesophageal reflux disease (GERD)

 Sinusitis

 Rhinitis

Questions about the development and treatment of the patient’s disease should touch on the
following:

 Age at onset and diagnosis

 Progression of symptoms (better or worse)

 Improvement with bronchodilators

  Use of oral corticosteroids

The family history should include any history of asthma, allergy, sinusitis, rhinitis, eczema, or
nasal polyps in close relatives, and the social history should cover factors that may contribute
to nonadherence of asthma medications, as well as any illicit drug use.

The history of exacerbations should include the usual prodromal signs or symptoms, rapidity
of onset, associated illnesses, number in the last year, and need for hospitalization. Symptoms
of asthma may include wheezing, coughing, and chest tightness, among others. Patients with
persistent asthmatic symptoms are more likely to experience severe asthma exacerbations. [42]

Wheezing

A musical, high-pitched, whistling sound produced by airflow turbulence is one of the most
common symptoms. The wheezing usually occurs during exhalation.

In the mildest form, wheezing is only end expiratory. As severity increases, the wheeze lasts
throughout expiration. In a more severe asthmatic episode, wheezing is also present during
inspiration. During the most severe episodes, wheezing may be absent because of the severe
limitation of airflow associated with airway narrowing and respiratory muscle fatigue.

Asthma can occur without wheezing when obstruction involves predominantly the small
airways. Thus, wheezing is not necessary for the diagnosis of asthma. Furthermore, wheezing
can be associated with other causes of airway obstruction, such as cystic fibrosis and heart
failure.

Patients with vocal cord dysfunction have a predominantly inspiratory monophonic

wheeze/sound (different from the polyphonic wheeze in asthma), which is heard best over the
laryngeal area in the neck. Patients with bronchomalacia and tracheomalacia also have a
monophonic wheeze.

In exercise-induced or nocturnal asthma, wheezing may be present after exercise or during

the night, respectively.

Coughing and chest tightness

Cough may be the only symptom of asthma, especially in cases of exercise-induced or

nocturnal asthma. Usually, the cough is nonproductive and nonparoxysmal. In addition,
coughing may be present with wheezing. Children with nocturnal asthma tend to cough after
midnight, during the early hours of morning. A history of tightness or pain in the chest may
be present with or without other symptoms of asthma, especially in exercise-induced or
nocturnal asthma.

Other nonspecific symptoms

Infants or young children may have a history of recurrent bronchitis, bronchiolitis, or

pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling. Most
children with chronic or recurrent bronchitis have asthma. Asthma is the most common
underlying diagnosis in children with recurrent pneumonia. Older children may have a
history of chest tightness and/or recurrent chest congestion.
In an acute episode, symptoms vary according to the severity of the episode. During a mild
episode, patients may be breathless after physical activity such as walking. They can talk in
sentences and lie down, and they may be agitated. During a moderate-to-severe episode,
patients are breathless while talking. Infants have feeding difficulties and a softer, shorter cry.

During a severe episode, patients are breathless during rest, are not interested in feeding, sit
upright, talk in words (not sentences), and are usually agitated. With imminent respiratory
arrest (in addition to the aforementioned symptoms), the child is drowsy and confused.
However, adolescents may not have these symptoms until they are in frank respiratory
failure.

Physical Examination
The clinical picture of pediatric asthma varies. Symptoms may be associated with upper
respiratory infections (URTIs), nocturnal or exercise-induced asthmatic symptoms, and status
asthmaticus.

Status asthmaticus, or an acute severe asthmatic episode that is resistant to appropriate

outpatient therapy, is a medical emergency that requires aggressive inpatient management.
This may include admission to an ICU for the treatment of hypoxia, hypercarbia, and
dehydration and possibly for assisted ventilation because of respiratory failure.

Physical findings vary with the absence or presence of an acute episode and its severity.

Findings in the absence of an acute episode

The physical findings between acute episodes vary with the severity of the asthma. During an
outpatient visit, a patient with mild asthma may have normal findings on physical
examination. Patients with more severe asthma are likely to have signs of chronic respiratory
distress and chronic hyperinflation.

Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, ocular
shiners, a transverse crease on the nose due to constant rubbing associated with allergic
rhinitis, and pale violaceous nasal mucosa due to allergic rhinitis, may be present.

The anteroposterior diameter of the chest may be increased because of hyperinflation.

Hyperinflation may also cause an abdominal breathing pattern.

Lung examination may reveal prolongation of the expiratory phase, expiratory wheezing,
coarse crackles, or unequal breath sounds. In a child who is not sick, forced exhalation may
reveal expiratory wheeze. Forced exhalation can be obtained by asking the child to blow hard
(like blowing imaginary birthday candles) or, in the case of toddlers or infants, pushing on the
abdomen may be used to cause forced exhalation. Clubbing of the fingers is not a feature of
straightforward asthma and indicates a need for more extensive evaluation and work-up to
exclude other conditions, such as cystic fibrosis.

Findings during an acute episode

Physical examination during an acute episode may reveal different findings in mild,
moderately severe, and severe episodes and in status asthmaticus with often imminent
respiratory arrest.

Findings during a mild episode include the following:

 Increased respiratory rate

 Accessory muscles of respiration are not used

 The heart rate is less than 100 beats per minute

 Pulsus paradoxus is not present

 Auscultation of chest reveals moderate wheezing, which is often end expiratory

 Oxyhemoglobin saturation with room air is greater than 95%

Findings during a moderately severe episode include the following:

 Increased respiratory rate

 Accessory muscles of respiration typically are used

 Suprasternal retractions are present

 The heart rate is 100-120 beats per minute

 Loud expiratory wheezing can be heard

 Pulsus paradoxus may be present (10-20 mm Hg)

 Oxyhemoglobin saturation with room air is 91-95%

Findings during a severe episode include the following:

 The respiratory rate is often greater than 30 breaths per minute

 Accessory muscles of respiration are usually used

 Suprasternal retractions are commonly present

 The heart rate is greater than 120 beats per minute

 Loud biphasic (expiratory and inspiratory) wheezing can be heard

 Pulsus paradoxus is often present (20-40 mm Hg)

 Oxyhemoglobin saturation with room air is less than 91%.

Findings in status asthmaticus with often imminent respiratory arrest include the following:

 Paradoxical thoracoabdominal movement

 Wheezing may be absent (in patients with the most severe airway obstruction)

 Severe hypoxemia may manifest as bradycardia

 Pulsus paradoxus may disappear; this finding suggests respiratory muscle fatigue

Staging
Asthma severity is defined as "the intensity of the disease process" prior to the initiation of
therapy. Defining asthma severity helps in determining the initiation of therapy in a patient
who is not on any controller medications. [2]

The severity of asthma is classified as intermittent, mild persistent, moderate persistent, or

severe persistent. This classification is based on the impairment and risk related to disease,
which is measured by the following:

 Frequency and severity of symptoms, including nocturnal symptoms

 Characteristics of acute episodes

 Pulmonary function

 Exacerbations

Features of these categories have been divided into 3 charts to reflect classification in
different age groups (0-4 y, 5-11 y, and 12 y and older), according to the 2007 National
Asthma Education and Prevention Program guidelines. [2]

An important point to remember is that the presence of one severe feature is sufficient to
diagnose severe persistent asthma. In addition, the characteristics in this classification system
are general and may overlap because asthma severity varies widely. In addition, a patient’s
classification may change over time .

Patients with asthma of any level of severity may have mild, moderate, or severe
exacerbations.

Some patients with intermittent asthma have severe and life-threatening exacerbations
separated by episodes with almost normal lung function and minimal symptoms; however,
they are likely to have other evidence of increased BHR (eg, on exercise or challenge testing)
due to ongoing inflammation.

Diagnostic Considerations
Problems to be considered include the following:
  Tracheobronchomalacia

 Hyperventilation syndrome

 Vocal cord dysfunction

 Pulmonary edema

 Collagen vascular disease

 Reactive airway disease

Differential Diagnoses
 Aspiration Syndromes

 Bronchiolitis

 Imaging in Bronchopulmonary Dysplasia

 Pediatric Airway Foreign Body

 Pediatric Allergic Rhinitis

 Pediatric Aspergillosis

 Pediatric Bronchiectasis

 Pediatric Gastroesophageal Reflux

 Primary Ciliary Dyskinesia

 Sinonasal Manifestations of Cystic Fibrosis

Approach Considerations
According to the National Asthma Education and Prevention Program guidelines, spirometry
is an essential objective measure for establishing the diagnosis of asthma. Additional studies
are not routinely necessary, but they may be useful when the clinician is considering
alternative diagnoses. [2] Eosinophil counts and IgE levels may be useful when allergic factors
are suspected.

Bronchial provocation tests may be performed to diagnose bronchial hyperresponsiveness

(BHR). These tests are performed in specialized laboratories by specially trained personnel to
document airway hyperresponsiveness to substances (eg, methacholine, histamine).
Increasing doses of provocation agents are given, and FEV1 is measured. The endpoint is a
20% decrease in FEV1 (PC 20 ).

For more information, see the Medscape Reference topic Peak Flow Rate Measurement.
Pulmonary Function Tests
Results of pulmonary function testing are not reliable in patients younger than 5 years. In
young children (3-6 y) and older children who are unable to perform the conventional
spirometry maneuver, newer techniques, such as measurement of airway resistance using
impulse oscillometry system, are used. Measurement of airway resistance before and after a
dose of inhaled bronchodilator may help to diagnose bronchodilator-responsive airway
obstruction.

Spirometry

In a typical case, an obstructive defect is present in the form of normal forced vital capacity
(FVC), reduced forced expiratory volume in 1 second (FEV1), and reduced forced expiratory
flow more than 25-75% of the FVC (FEF 25-75). The flow-volume loop can be concave.
Documentation of reversibility of airway obstruction after bronchodilator therapy is central to
the definition of asthma. FEF 25-75 is a sensitive indicator of obstruction and may be the
only abnormality in a child with mild disease.

In an outpatient or office setting, measurement of the peak flow rate by using a peak flow
meter can provide useful information about obstruction in the large airways. Take care to
ensure maximum patient effort. However, a normal peak flow rate does not necessarily mean
a lack of airway obstruction.

Plethysmography

Patients with chronic persistent asthma may have hyperinflation, as evidenced by an

increased total lung capacity (TLC) at plethysmography. Increased residual volume (RV) and
functional residual capacity (FRC) with normal TLC suggests air trapping. Airway resistance
is increased when significant obstruction is present.

Exercise Challenge
In a patient with a history of exercise-induced symptoms (eg, cough, wheeze, chest tightness
or pain), the diagnosis of asthma can be confirmed with the exercise challenge. In a patient of
appropriate age (usually >6 y), the procedure involves baseline spirometry followed by
exercise on a treadmill or bicycle to a heart rate greater than 60% of the predicted maximum,
with monitoring of the electrocardiogram and oxyhemoglobin saturation.

The patient should be breathing cold, dry air during the exercise to increase the yield of the
study. Spirographic findings and the peak expiratory flow (PEF) rate (PEFR) are determined
immediately after the exercise period and at 3 minutes, 5 minutes, 10 minutes, 15 minutes,
and 20 minutes after the first measurement. The maximal decrease in lung function is
calculated by using the lowest postexercise and highest pre-exercise values. The reversibility
of airway obstruction can be assessed by administering aerosolized bronchodilators.

Methacholine challenge

The degree of airway responsiveness can be assessed by methacholine challenge testing. [43]
Methacholine causes bronchoconstriction via muscarinic acetylcholine receptor M3, and the
resultant decrease in FEV1 is recorded by spirometry. The test can help to confirm the
diagnosis of asthma in a patient with history of asthma but normal spirometry findings.

During the test, the patient inhales increasing concentrations of methacholine aerosol via a
nebulizer; spirometry is performed before and after each dose. A positive response is a 20%
fall in FEV1. The corresponding concentration of methacholine (mg/mL) is called PC 20 . A
PC 20 of greater than 16 mg/mL indicates normal bronchial responsiveness. PC 20 values of 4-
16 mg/mL, 1-4 mg/mL, and < 1 mg/mL indicate borderline, mild, and moderate-to-severe
bronchial hyperresponsiveness, respectively.

Methacholine challenge testing is more useful in excluding a diagnosis of asthma than in

establishing one because its negative predictive power is greater than its positive predictive
power. [43] Other agents (ie, histamine, mannitol) are also used for bronchoprovocation.

Fraction of Exhaled Nitric Oxide Testing

Measuring the fraction of exhaled nitric oxide (FeNO) has proved useful as a noninvasive
marker of airway inflammation, in order to guide adjustment of the dose of inhaled
corticosteroids. In one study involving home monitoring of FeNO and symptom scores, the 2
correlated. Further, in some patients, the FeNO rose before significant exacerbations of the
asthma [44] ; thus, although studies of FeNO in large groups have either shown it to be helpful
or not, it may be a useful method of evaluating therapy in individual patients. Due to the high
cost of equipment, FeNO measurement is used primarily as a research tool at present.

Measuring the level of interleukin-5 in exhaled breath condensate is a possible way of

titrating asthma progress, according to one study. In a longitudinal study of 40 asthmatic
children aged 6-16 years, asthma control score and level of interleukin-5 were significant
predictors of an asthma exacerbation. [45]

Radiography and CT Scan

Include chest radiography in the initial workup if the asthma does not respond to therapy as
expected. In addition to typical findings of hyperinflation and increased bronchial markings, a
chest radiograph may reveal evidence of parenchymal disease, atelectasis, pneumonia,
congenital anomaly, or a foreign body.

In a patient with an acute asthmatic episode that responds poorly to therapy, a chest
radiograph helps in the diagnosis of complications such as pneumothorax or
pneumomediastinum. Consider using sinus radiography and CT scanning to rule out sinusitis.

For more information, see the Medscape Reference topic Imaging in Asthma.

Allergy Testing
Allergy testing can be used to identify allergic factors that may significantly contribute to the
asthma. Once identified, environmental factors (eg, dust mites, cockroaches, molds, animal
dander) and outdoor factors (eg, pollen, grass, trees, molds) may be controlled or avoided to
reduce asthmatic symptoms.
Allergens for skin testing are selected on the basis of suspected or known allergens identified
from a detailed environmental history. Antihistamines can suppress the skin test results and
should be discontinued for an appropriate period (according to the particular agent’s duration
of action) before allergy testing. Topical or systemic corticosteroids do not affect the skin
reaction.

Histologic Findings
Asthma is an inflammatory disease characterized by the recruitment of inflammatory cells,
vascular congestion, increased vascular permeability, increased tissue volume, and the
presence of an exudate. Eosinophilic infiltration, a universal finding, is considered a major
marker of the inflammatory activity of the disease.

Histologic evaluations of the airways in a typical patient reveal infiltration with inflammatory
cells, narrowing of airway lumina, bronchial and bronchiolar epithelial denudation, and
mucus plugs. Additionally, a patient with severe asthma may have a markedly thickened
basement membrane and airway remodeling in the form of subepithelial fibrosis and smooth
muscle hypertrophy or hyperplasia.

Approach Considerations
The National Asthma Education and Prevention Program guidelines highlight the importance
of treating impairment and risk domains of asthma. [2] The goals for therapy are as follows:

 Control asthma by reducing impairment through prevention of chronic and

troublesome symptoms (eg, coughing or breathlessness in the daytime, in the night, or
after exertion)

 Reduce the need for a short-acting beta2-agonist (SABA) for quick relief of
symptoms (not including prevention of exercise-induced bronchospasm)

 Maintain near-normal pulmonary function

 Maintain normal activity levels (including exercise and other physical activity and
attendance at work or school)

 Satisfy patients' and families' expectations for asthma care

Reduction in risk can be achieved by preventing recurrent exacerbations of asthma and

minimizing the need for emergency room visits and hospitalizations, and preventing
progressive loss of lung function. For children, preventing reduced lung growth and
providing optimal pharmacotherapy with minimal or no adverse effects is important.

When a patient has major allergies to dietary products, avoidance of particular foods may
help. In the absence of specific food allergies, dietary changes are not necessary. Unless
compelling evidence for a specific allergy exists, milk products do not have to be avoided.

The goal of long-term therapy is to prevent acute exacerbations. The patient should avoid
exposure to environmental allergens and irritants that are identified during the evaluation.
Components of Asthma Care
The current guidelines emphasize 4 important components of asthma care, as follows [2] :

 Assessment and monitoring

 Education

 Control of environmental factors and comorbid conditions

 Pharmacologic treatment

Assessment and monitoring

Once the patient's condition is classified and therapy has been initiated, continual assessment
is important for disease control. Asthma control is defined as "the degree to which the
manifestations of asthma are minimized by therapeutic intervention and the goals of therapy
are met." [2] Asthma can be classified as well controlled, not well controlled, or very poorly
controlled; classification criteria vary by patient age (view PDF).

In order to assess asthma control and adjust therapy, impairment and risk must be assessed.
Assessment of impairment focuses on the frequency and intensity of symptoms and the
functional limitations associated with these symptoms. Risk assessment focuses on the
likelihood of asthma exacerbations, adverse effects from medications, and the likelihood of
the progression of lung function decline; spirometry should be measured every 1-2 years, or
more frequently for uncontrolled asthma.

Because asthma varies over time, follow-up every 2-6 weeks is initially necessary (when
gaining control of the disease) and then every 1-6 months thereafter.

Education

Patient education continues to be important in all areas of medicine and is particularly

important in asthma. Self-management education should focus on teaching patients the
importance of recognizing their own their level of control and signs of progressively
worsening asthma symptoms.

Both peak flow monitoring and symptom monitoring have been shown to be equally
effective; however, peak flow monitoring may be more helpful in cases in which patients
have a history of difficulty in perceiving symptoms, a history of severe exacerbations, or
moderate-to-severe asthma.

Educational strategies should also focus on environmental control and avoidance strategies
and medication use and adherence (eg, correct inhaler techniques and use of other devices).

Using a variety of methods to reinforce educational messages is crucial in patient

understanding. Providing written asthma action plans in partnership with the patient (making
sure to review the differences between long-term control and quick-relief medications),
education through the involvement of other members of the healthcare team (eg, nurses,
pharmacists, physicians), and education at all points of care (eg, clinics, hospitals, schools)
are examples of various educational tools that are available and valuable for good patient
adherence and understanding.

Control of environmental factors and comorbid conditions

As mentioned above, environmental exposures and irritants can play a strong role in
symptom exacerbations. Therefore, in patients who have persistent asthma, the use of skin
testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once
the offending allergens are identified, counsel patients on avoidance from these exposures. In
addition, education to avoid tobacco smoke (both first-hand and second-hand exposure) is
important for patients with asthma.

Lastly, comorbid conditions that may affect asthma must be diagnosed and appropriately
managed. These include the following:

 Bronchopulmonary aspergillosis

 Gastroesophageal reflux disease (GERD)

 Obesity

 Obstructive sleep apnea

 Rhinitis

 Sinusitis

 Depression

 Stress

 Low vitamin D levels

Based upon reports of an inverse correlation between low vitamin D levels and asthma
control, vitamin D supplementation in children might enhance corticosteroid responses,
control atopy, and improve asthma control. [26] In a long-term study of children with asthma,
those with Vitamin D deficiency or insufficiency responded less well to adequate doses of
inhaled corticosteroids. [46]

A recent clinical trial of lansoprazole in children with poorly controlled asthma without
gastroesophageal symptoms showed no improvement in symptoms or lung function, but was
associated with increased adverse effects. [47]

Inactivated influenza vaccine is indicated for all children with asthma older than 6 months
unless specifically contraindicated.

Pharmacologic treatment
Pharmacologic management includes the use of agents for control and agents for relief.
Control agents include inhaled corticosteroids, inhaled cromolyn or nedocromil, long-acting
bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the
use of the anti-immunoglobulin E (IgE) antibody (omalizumab) or IL-5 monoclonal
antibodies (mepolizumab, benralizumab), or IL-4 receptor alpha monoclonal antibody
(dupilumab) Relief medications include short-acting bronchodilators, systemic
corticosteroids, and ipratropium.

For all but the most severely affected patients, the ultimate goal is to prevent symptoms,
minimize morbidity from acute episodes, and prevent functional and psychological morbidity
to provide a healthy (or near healthy) lifestyle appropriate to the age of child.

A stepwise approach to pharmacologic therapy is recommended to gain and maintain control

of asthma in both the impairment and risk domains. The type, amount, and scheduling of
medication is dictated by asthma severity (for initiating therapy) and the level of asthma
control (for adjusting therapy). Step-down therapy is essential to identify the minimum
medication necessary to maintain control. See table below.

When children are well controlled, it is reasonable to try to reduce their therapy. Whether on
relatively high-dose inhaled steroids, or a combination of steroid/long-acting beta2-agonist, it
is best to try to continue to control them on a lower dose, or on less medication. Reducing
inhaled steroids and/or eliminating the long-acting beta2-agonist could result in a
deterioration in asthma control. When such steps are taken, it is critical to see those children
frequently, monitoring their history, physical examination and spirometry. [48]

For pharmacotherapy, children with asthma are divided into 3 groups based on age: 0-4 y, 5-
11 y, 12 y and older.

For all patients, quick-relief medications include rapid-acting beta2-agonists as needed for
symptoms. The intensity of treatment depends on the severity of symptoms. If rapid-acting
beta2-agonists are used more than 2 days a week for symptom relief (not including use of
rapid-acting beta2-agonists for prevention of exercise induce symptoms), stepping up
treatment may be considered. See the stepwise approach to asthma medications in Table 1,
below.

Table 1. Stepwise Approach to Asthma Medications (Open Table in a new window)

Intermittent
Persistent Asthma: Daily Medication
Asthma

Age Step 1 Step 2 Step 3 Step 4 Step 5 Step 6

< 5 y Rapid- Low-dose Medium-dose Medium-dose High-dose High-dose ICS

acting inhaled ICS ICS plus either ICS plus plus either
beta2- corticosteroid long-acting either LABA LABA or
agonist (ICS) beta2-agonist or montelukast;
(LABA) or Oral systemic
 Alternate
regimen:
prn montelukast montelukast corticosteroid
cromolyn or
montelukast

High-dose ICS
Medium-dose High-dose
plus LABA plus
Low-dose ICS ICS plus ICS plus
oral systemic
LABA LABA
corticosteroid
Either low-
Rapid- dose ICS plus
acting either LABA,
5-11
beta2- Alternate LTRA, or Alternate
y
agonist regimen: theophylline Alternate Alternate
regimen: high-
prn cromolyn, OR Medium- regimen: regimen:
dose ICS plus
leukotriene dose medium-dose high-dose ICS
LRTA or
receptor ICS plus either plus either
theophylline
antagonist LTRA or LABA or
plus systemic
(LTRA), or theophylline theophylline
corticosteroid
theophylline

Low-dose ICS
Medium-dose
plus LABA
Low-dose ICS ICS plus
OR Medium-
LABA High-dose ICS
dose ICS High-dose
Rapid- plus either
ICS plus
acting LABA plus oral
12 y LABA (and
beta2- corticosteroid
or Alternate consider
agonist Alternate (and consider
older Alternate regimen: omalizumab
as regimen: low- omalizumab for
regimen: medium-dose for patients
needed dose ICS plus patients with
cromolyn, ICS plus either with allergies) allergies)
either LTRA,
LTRA, or LTRA,
theophylline,
theophylline theophylline,
or zileuton
or zileuton

In the Salmeterol Multicenter Asthma Research Trial (SMART), salmeterol use in asthma
patients, particularly African Americans, was associated with a small but significantly
increased risk of serious asthma-related events. [49] This trial was a large, double-blind,
randomized, placebo-controlled, safety trial in which salmeterol 42 mcg twice daily or
placebo was added to usual asthma therapy for 28 weeks.

The study was halted following interim analysis of 26,355 participants because patients
exposed to salmeterol (n = 13,176) were found to experience a higher rate of fatal asthma
events compared with individuals receiving placebo (n = 13,179); the rates were 0.1% and
0.02%, respectively. This resulted in an estimated 8 excess deaths per 10,000 patients treated
with salmeterol.
In the post-hoc subgroup analysis, the relative risks of asthma-related deaths were similar
among whites and blacks, although the corresponding estimated excess deaths per 10,000
patients exposed to salmeterol were higher among blacks than whites.

A meta-analysis by Salpeter et al found that LABAs increased the risk for asthma-related
intubations and deaths by 2-fold, even when used in a controlled fashion with concomitant
inhaled corticosteroids. However, the absolute number of adverse events remained small. [50]
The large pooled trial included 36,588 patients, most of them adults.

The US Food and Drug Administration (FDA) has reviewed the data and the issues and has
determined that the benefits of LABAs in improving asthma symptoms outweigh the
potential risks when LABAs are used appropriately with an asthma controller medication in
patients who need the addition of LABAs. The FDA recommends the following measures for
improving the safe use of these drugs [51] :

 LABAs should be used long-term only in patients whose asthma cannot be adequately
controlled on inhaled steroids

 LABAs should be used for the shortest duration of time required to achieve control of
asthma symptoms and discontinued, if possible, once asthma control is achieved;
patients should then be switched to an asthma controller medication

 Pediatric and adolescent patients who require the addition of a LABA to an inhaled
corticosteroid should use a combination product containing both an inhaled
corticosteroid and a LABA to ensure compliance with both medications

Concerns about the safety of long-acting beta2-agonists and resultant drug safety
communications create a question as to the course of treatment if asthma is not controlled by
inhaled corticosteroids. [51] A study by Lemanske et al addressed this question and concluded
that addition of long-acting beta2-agonist was more likely to provide the best response than
either inhaled corticosteroids or leukotriene-receptor antagonists. [52] Asthma therapy should
be regularly monitored and adjusted accordingly.

The CHASE (ChildHood Asthma Safety and Efficacy) international clinical trial further
evaluated the combination of inhaled corticosteroids plus long-acting beta2 agonists. Orally
inhaled budesonide/formoterol (Symbicort) 80/4.5 mcg with orally inhaled budesonide 80
mcg in pediatric patients with asthma aged 6-12 years who were symptomatic on low-dose
inhaled corticosteroids. A statistically significant improvement in lung function (FEV1 at 1 h
postdose) was observed with the children randomized to budesonide/formoterol (n=92)
compared with budesonide alone (n=95) (p ≤0.005). [53]

A systematic review of 18 placebo-controlled clinical trials evaluating monotherapy with

inhaled corticosteroids supports their safety and efficacy in children with asthma. [54] In
addition, the data provide new evidence linking inhaled corticosteroids use in children with
asthma to improved asthma control. A recent study to assess the effectiveness of an inhaled
corticosteroid used as rescue treatment recommends that children with mild persistent asthma
should not be treated with rescue albuterol alone and the most effective treatment to prevent
exacerbations is daily inhaled corticosteroids. This study suggests that inhaled corticosteroids
as rescue medication with albuterol might be an effective step down strategy for children as it
is more effective at reducing exacerbations than is use of rescue albuterol alone. [55] .
Due to concern about oral corticosteroid overuse, Farber et al conducted a study that reported
that of the 69,056 children with asthma reported in the Texas Children’s Health Plan database
from 2011-2015, 42.1% to 44.2% were prescribed oral corticosteroid more than once.
Repeated prescriptions of oral corticosteroids were more common in children younger than 5
years and 81%-83% of children prescribed oral corticosteroids did not have other signs of
poor asthma control (excessive β-agonist refills, emergency department visits, or
hospitalizations for asthma). [56, 57]

A recent Cochrane review concluded that more research is needed to assess the effectiveness
of increased inhaled corticosteroid doses at the onset of asthma exacerbation. [58]

In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse
effects, including growth failure. Recent data from the Childhood Asthma Management
Program (CAMP) study and results of the long-term use of inhaled steroids (budesonide)
suggest that the long-term use of inhaled steroids has no sustained adverse effect on growth in
children. [59, 60]

A review by Rodrigo et al looked at 8 studies of omalizumab in children with moderate to

severe asthma and elevated IgE levels. [61] Children treated with omalizumab were more
significantly able to reduce their use of rescue inhalers and their inhaled and/or oral steroid
dose than patients in the placebo group. Although no significant differences in pulmonary
function were observed, patients receiving omalizumab had fewer exacerbations than the
children receiving placebo. These studies lasted a year or less and did not reveal any
significant adverse effects of the omalizumab.

A randomized trial of omalizumab for asthma in inner-city children showed improved asthma
control, elimination of seasonal peaks in asthmatic exacerbations, and reduced need for other
medications for asthma control. [62]

Another study, by Deschildre et al, indicated that adding omalizumab to maintenance therapy
can improve asthma control in children with severe, uncontrolled allergic asthma. In a study
of 104 such children, Deschildre and colleagues found that adding omalizumab increased the
rate of good asthma control from 0% to 53% and reduced exacerbation and hospitalization
rates by 72% and 88.5%, respectively. By 1-year follow-up, FEV1 (forced expiratory volume
in 1 second) had improved in the study's patients by 4.9%, and inhaled corticosteroid dose
had decreased by 30%. [63, 64]

Additional monoclonal antibodies have been approved for children, but unlike omalizumab,
they target various interleukin (IL) subtypes. Monoclonal antibodies approved for severe
asthma that target IL-5 include mepolizumab and benralizumab. Dupilumab inhibits IL-4
receptor alpha, and thereby blocks IL-4 and IL-13 signaling.

Delivery devices and best route of administration

In pediatric asthma, inhaled treatment is the cornerstone of asthma management. Inhaler

devices currently used to deliver inhaled corticosteroids (ICSs) fall into the following 4
categories:

 Pressurized metered dose inhaler (pMDI) - Propellant used to dispense steroid when
canister is pressed manually
  Dry powder inhaler (DPI) - Does not require hand-breath coordination to operate

 Breath-actuated pMDI - Propellant used to dispense steroid when patient inhales

 Nebulized solution devices

Go to Use of Metered Dose Inhalers, Spacers, and Nebulizers for complete information on
this topic.

In pediatric patients, the inhaler device must be chosen on the basis of age, cost, safety,
convenience, and efficacy of drug delivery. [4]

Based on current research, the preferred device for children younger than 4 years is a pMDI
with a valved holding chamber and age-appropriate mask. Children aged 4-6 years should use
a pMDI plus a valved holding chamber. Lastly, children older than 6 years can use either a
pMDI, a DPI, or a breath-actuated pMDI. For all 3 groups, a nebulizer with a valved holding
chamber (and mask in children younger than 4 y) is recommended as alternate therapy. [4]

Valved holding chambers are important. The addition of a valved holding chamber can
increase the amount of drug reaching the lungs to 20%. The use of a valved holding chamber
helps reduce the amount of drug particles deposited in the oropharynx, thereby helping to
reduce systemic and local effects from oral and gastrointestinal absorption.

A Cochrane review on the use of valved holding chambers versus nebulizers for inhaled
steroids found no evidence that nebulizers are better than valved holding chamber. [65]
Nebulizers are expensive, inconvenient to use, require longer time for administration, require
maintenance, and have been shown to have imprecise dosing.

Newer devices are showing greater efficacy. For MDIs, chlorofluorocarbon (CFC)
propellants (implicated in ozone depletion) have been phased out in favor of the
hydrofluoroalkane-134a (HFA) propellant. Surprisingly, the HFA component is more
environmentally friendly and has proven to be more effective, due to its smaller aerosol
particle size, which results in better drug delivery. MDIs with HFA propellant have better
deposition of drug in the small airways and greater efficacy at equivalent doses compared
with CFC-MDIs.

Treatment of Status Asthmaticus

Treatment goals for acute severe asthmatic episodes (status asthmaticus) are as follows:

 Correction of significant hypoxemia with supplemental oxygen; in severe cases,

alveolar hypoventilation requires mechanically assisted ventilation

 Rapid reversal of airflow obstruction with repeated or continuous administration of an

inhaled beta2-agonist; early administration of systemic corticosteroids (eg, oral
prednisone or intravenous methylprednisolone) is suggested in children with asthma
that fails to respond promptly and completely to inhaled beta2-agonists
  Reduction in the likelihood of recurrence of severe airflow obstruction by intensifying
therapy: Often, a short course of systemic corticosteroids is helpful

Achieving these goals requires close monitoring by means of serial clinical assessment and
measurement of lung function (in patients of appropriate ages) to quantify the severity of
airflow obstruction and its response to treatment. Improvement in FEV1 after 30 minutes of
treatment is significantly correlated with a broad range of indices of the severity of asthmatic
exacerbations, and repeated measurement of airflow in the emergency department can help
reduce unnecessary admissions.

The use of the peak flow rate or FEV1 values, patient's history, current symptoms, and
physical findings to guide treatment decisions is helpful in achieving the aforementioned
goals. When using the peak expiratory flow (PEF) expressed as a percentage of the patient's
best value, the effect of irreversible airflow obstruction should be considered. For example, in
a patient whose best peak flow rate is 160 L/min, a decrease of 40% represents severe and
potentially life-threatening obstruction.

An Australian study by Vuillermin et al found that asthma severity decreased in school-aged

children when parents initiated a short course of prednisolone for acute asthma. [66] Children
who received parent-initiated prednisolone for episodes of asthma had lower daytime and
nighttime asthma scores, reduced risk of health resource use, and reduced school absenteeism
compared with children who received placebo.

Consultations
Any patient with high-risk asthma should be referred to a specialist. The following may
suggest high risk:

 History of sudden severe exacerbations

 History of prior intubation for asthma

 Admission to an ICU because of asthma

 Two or more hospitalizations for asthma in the past year

 Three or more emergency department visits for asthma in the past year

 Hospitalization or an emergency department visit for asthma within the past month

 Use of 2 or more canisters of inhaled short-acting beta2-agonists per month

 Current use of systemic corticosteroids or recent withdrawal from systemic

corticosteroids

Referral to an asthma specialist for consultation or comanagement of the patient is also

recommended if additional education is needed to improve adherence or if the patient
requires step 4 care or higher (step 3 care or higher for children aged 0–4 y). Consider referral
if a patient requires step 3 care (step 2 care for children aged 0–4 y) or if additional testing for
the role of allergy is indicated. [2]

The choice between a pediatric pulmonologist and an allergist may depend on local
availability and practices. A patient with frequent ICU admissions, previous intubation, and a
history of complicating factors or comorbidity (eg, cystic fibrosis) should be referred to a
pediatric pulmonologist. When allergies are thought to significantly contribute to the
morbidity, an allergist may be helpful.

Consider consultation with an ear, nose, and throat (ENT) specialist for help in managing
chronic rhinosinusitis. Consider consultation with a gastroenterologist for help in excluding
and/or treating gastroesophageal reflux.

Long-Term Monitoring
Regular follow-up visits are essential to ensure control and appropriate therapeutic
adjustments. In general, patients should be assessed every 1-6 months. At every visit,
adherence, environmental control, and comorbid conditions should be checked.

If patients have good control of their asthma for at least 3 months, treatment can be stepped
down. However, the patient should be reassessed in 2-4 weeks to make sure that control is
maintained with the new regimen. If patients require step 2 asthma medications or higher,
consultation with an asthma specialist should be considered.

Outpatient visits should include the following:

 Interval history of asthmatic complaints, including history of acute episodes (eg,

severity, measures and treatment taken, response to therapy)

 History of nocturnal symptoms

 History of symptoms with exercise, and exercise tolerance

 Review of medications, including use of rescue medications

 Review of home-monitoring data (eg, symptom diary, peak flow meter readings, daily
treatments)

Patient evaluation should include the following:

 Assessment for signs of bronchospasm and complications

 Evaluation of associated conditions (eg, allergic rhinitis)

 Pulmonary function testing (in appropriate age group)

Address issues of treatment adherence and avoidance of environmental triggers and irritants.
Long-term asthma care pathways that incorporate the aforementioned factors can serve as
roadmaps for ambulatory asthma care and help streamline outpatient care by different
providers.

In the author's asthma clinic, a member of the asthma care team sits with each patient to
review the written asthma care plan and to write and discuss in detail a rescue plan for acute
episodes, which includes instructions about identifying signs of an acute episode, using
rescue medications, monitoring, and contacting the asthma care team. These items are
reviewed at each visit.

One study using directly observed administration of daily preventive asthma medications by a
school nurse showed significantly improved symptoms among urban children with persistent
asthma. [67]

Surgical Care
In a study of 13,506 children with asthma who underwent adenotonsillectomy and 27,012
matched controls with asthma who did not undergo adenotonsillectomy, Bhattacharjee et al
found that those who had the procedure showed significant improvement on several measures
of asthma disease severity, including acute asthma exacerbations and acute status
asthmaticus. [68, 69]

Compared to the year before the procedure, at 1-year postadenotonsillectomy follow-up,

there was a 30.2% reduction in acute asthma exacerbations and a 37.9% reduction in acute
status asthmaticus (P< 0.0001 for both). [68, 69] In addition, asthma-related emergency
department visits were reduced by 25.6% and asthma-related hospitalizations by 35.8%.
Patients who underwent the procedure also had significantly fewer refills of several asthma
medications. In contrast, no significant reductions were observed in any of these outcomes
among children who did not undergo adenotonsillectomy. [68, 69]

Medication Summary
Pharmacologic management includes the use of control agents such as inhaled
corticosteroids, inhaled cromolyn or nedocromil, long-acting bronchodilators, theophylline,
leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E
(IgE) antibodies (omalizumab), IL-5 monoclonal antibodies (mepolizumab, benralizumab),
IL-4 receptor alpha monoclonal antibody (dupilumab), and long-acting antimuscarinic agents
(LAMA) such as tiotropium. Relief medications include short-acting bronchodilators,
systemic corticosteroids, and ipratropium.

Bronchodilators, Beta2-Agonists
Class Summary
These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent
bronchospasm associated with exercise-induced asthma or nocturnal asthma. Several studies
have suggested that short-acting beta2-agonists such as albuterol may produce adverse
outcomes (eg, decreased peak flow or increased risk of exacerbations) in patients
homozygous for arginine (Arg/Arg) at the 16th amino acid position of beta-adrenergic
receptor gene compared with patients homozygous for glycine (Gly-Gly). Similar findings
are reported for long-acting beta2-agonists, such as salmeterol.

Albuterol (AccuNeb, Proventil HFA, Ventolin HFA, Proair

HFA, ProAir RespiClick)

 View full drug information

This beta2-agonist is the most commonly used bronchodilator that is available in multiple
forms (eg, solution for nebulization, MDI, PO solution). This is most commonly used in
rescue therapy for acute asthmatic symptoms. Used as needed. Prolonged use may be
associated with tachyphylaxis due to beta2-receptor downregulation and receptor
hyposensitivity.

Pirbuterol (Maxair Autohaler)

 View full drug information

Pirbuterol is available as a breath-actuated or ordinary inhaler. The ease of administration

with the breath-actuated device makes it an attractive choice in the treatment of acute
symptoms in younger children who otherwise cannot use an MDI. The Autohaler delivers 200
mcg per actuation.

Nonracemic Form of the Beta2-Agonist Albuterol

Class Summary
This nonracemic form of albuterol offers a significant reduction in the adverse effects
associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia,
hypokalemia).

Levalbuterol (Xopenex)

 View full drug information

Nonracemic form of albuterol, levalbuterol (R isomer) is effective in smaller doses and is
reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The
dose may be doubled in acute severe episodes when even a slight increase in the
bronchodilator response may make a big difference in the management strategy (eg, in
avoiding patient ventilation). It is available as an MDI (45 mcg per actuation) or solution for
nebulized inhalation.

Long-Acting Beta2-Agonists
Class Summary
Long-acting bronchodilators (LABA) are not used for the treatment of acute bronchospasm.
They are used for the preventive treatment of nocturnal asthma or exercise-induced asthmatic
symptoms, for example.

Salmeterol is the only single-agent LABA available in the United States that is approved for
asthma. Salmeterol and formoterol are available as combination products with inhaled
corticosteroids that are approved for asthma in the United States (Advair, Symbicort, Dulera).

LABA may increase the chance of severe asthma episodes and death when those episodes
occur. Most cases have occurred in patients with severe and/or acutely deteriorating asthma;
they have also occurred in a few patients with less severe asthma.

LABAs are not considered first-line medications to treat asthma. LABAs should not be used
as isolated medications and should be added to the asthma treatment plan only if other
medicines do not control asthma, including the use of low- or medium-dose corticosteroids. If
used as isolated medication, LABAs should be prescribed by a subspecialist (ie,
pulmonologist, allergist).

Salmeterol (Serevent Diskus)

 View full drug information

This long-acting preparation of a beta2-agonist is used primarily to treat nocturnal or

exercise-induced symptoms. It has no anti-inflammatory action and is not indicated in the
treatment of acute bronchospastic episodes. It may be used as an adjunct to inhaled
corticosteroids to reduce the potential adverse effects of the steroids. The medication is
delivered via a Diskus DPI.

Inhaled Corticosteroids
Class Summary
Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active,
poorly absorbed, and least likely to cause adverse effects. They are used for long-term control
of symptoms and for the suppression, control, and reversal of inflammation. Inhaled forms
reduce the need for systemic corticosteroids.

Inhaled steroids block late asthmatic response to allergens; reduce airway

hyperresponsiveness; inhibit cytokine production, adhesion protein activation, and
inflammatory cell migration and activation; and reverse beta2-receptor downregulation and
subsensitivity (in acute asthmatic episodes with LABA use).

Ciclesonide (Alvesco)

 View full drug information

Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of

asthma as prophylactic therapy in adult and adolescent patients aged 12 y and older. Not
indicated for relief of acute bronchospasm.

Corticosteroids have wide range of effects on multiple cell types (eg, mast cells, eosinophils,
neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids,
leukotrienes, cytokines) involved in inflammation.

Individual patients experience variable time to onset and degree of symptom relief.
Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy.

After asthma stability is achieved, it is best to titrate to lowest effective dosage to reduce the
possibility of adverse effects. For patients who do not adequately respond to the starting dose
after 4 wk of therapy, higher doses may provide additional asthma control.

Beclomethasone (QVAR)

 View full drug information

Beclomethasone inhibits bronchoconstriction mechanisms; causes direct smooth muscle

relaxation; and may decrease the number and activity of inflammatory cells, which, in turn,
decreases airway hyperresponsiveness. It is available as 40 mcg/actuation or 80
mcg/actuation.
Fluticasone (Flovent Diskus, Flovent HFA)

 View full drug information

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a

weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It
is available as an MDI aerosolized product (HFA) or DPI (Diskus).

Fluticasone furoate inhaled (Arnuity Ellipta)

 View full drug information

Synthetic trifluorinated corticosteroid that elicits anti-inflammatory activity. Has low oral
bioavailability owing to extensive first-pass metabolism that is desirable to minimize
systemic exposure. Exhibits high binding affinity for human glucocorticoid receptor (~1.7
times higher than fluticasone propionate). It is indicated for once-daily maintenance treatment
of asthma as prophylactic therapy in children aged ≥5 years.

Budesonide inhaled (Pulmicort Flexhaler or Respules)

 View full drug information

Budesonide has extremely potent vasoconstrictive and anti-inflammatory activity. It has a

weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It
is available as a DPI in 90 mcg/actuation (delivers about 80 mcg/actuation) or 180
mcg/actuation (delivers about 160 mcg/actuation). A nebulized susp (ie, Respules) is also
available for young children.

Mometasone furoate inhalation powder (Asmanex

Twisthaler)

 View full drug information

Mometasone is a corticosteroid for inhalation. It is indicated for asthma as prophylactic
therapy.

Systemic Corticosteroids
Class Summary
These agents are used for short courses (3-10 d) to gain prompt control of inadequately
controlled acute asthmatic episodes. They are also used for long-term prevention of
symptoms in severe persistent asthma as well as for suppression, control, and reversal of
inflammation. Frequent and repetitive use of beta2-agonists has been associated with beta2-
receptor subsensitivity and downregulation; these processes are reversed with corticosteroids.

Higher-dose corticosteroids have no advantage in severe asthma exacerbations, and

intravenous administration has no advantage over oral therapy, provided that GI transit time
or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing
until the FEV1 or peak expiratory flow (PEF) is 50% of the predicted or personal best values;
then, the dose is changed to twice daily. This usually occurs within 48 hours.

Prednisone (Deltasone, Orasone) and prednisolone

(Pediapred, Prelone, Orapred)

 View full drug information

An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease

inflammation by reversing increased capillary permeability and suppressing
polymorphonuclear neutrophil (PMN) activity.

Methylprednisolone (Solu-Medrol)

 View full drug information

Methylprednisolone may decrease inflammation by reversing increased capillary

permeability and suppressing PMN activity.

Dexamethasone (Baycadron, Dexamethasone Intensol)

  View full drug information

Dexamethasone in the ED can provide equivalent relief to a 5-day course of prednisone—and

without the adverse side effect of vomiting—for acute asthma flare-ups in children.
Researchers performed a meta-analysis of 6 studies based in the ED and found that
significantly fewer patients receiving dexamethasone vomited in the ED or at home after
discharge compared with patients receiving oral prednisone or prednisolone. The data suggest
that emergency physicians should consider single or 2-dose dexamethasone regimens over 5-
day prednisone/prednisolone regimens for the treatment of acute asthma exacerbations.

Leukotriene Modifiers
Class Summary
Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal
edema, and inflammatory cell infiltration has led to the concept of modifying their action by
using pharmacologic agents. These are either 5-lipoxygenase inhibitors or leukotriene-
receptor antagonists.

Zafirlukast (Accolate)

 View full drug information

Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.

Montelukast (Singulair)

 View full drug information

The last agent introduced in its class, montelukast has the advantages that it is chewable, it
has a once-a-day dosing, and it has no significant adverse effects.

Methylxanthines
Class Summary
These agents are used for long-term control and prevention of symptoms, especially
nocturnal symptoms.

Theophylline (Theo-24, Theochron, Uniphyl)

 View full drug information

Theophylline is available in short-acting and long-acting formulations. Because of the need to

monitor serum concentrations, this agent is used infrequently. The dose and frequency depend
on the particular product selected.

Combination Inhaled Steroids/Long-Acting Beta2-

Agonists
Class Summary
These combinations may decrease asthma exacerbations when inhaled short-acting beta2-
agonists and corticosteroids have failed. Refer to previous discussion in the LABAs section
regarding increased risk of severe asthma episodes and death with LABAs. In a recent study,
use of combination therapy using fluticasone propionate and salmeterol prolonged time to
first severe asthma exacerbation. [70]

Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by

inhibiting multiple types of inflammatory cells and decreasing production of cytokines and
other mediators involved in the asthmatic response. Available as MDI in 2 strengths; each
actuation delivers formoterol 4.5 mcg with either 80 mcg or 160 mcg.

Budesonide/formoterol (Symbicort)

 View full drug information

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in

conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the
level of inflammation in airways by inhibiting multiple types of inflammatory cells and
decreasing production of cytokines and other mediators involved in the asthmatic response.
This combination is available as an MDI in 2 strengths; each actuation delivers formoterol
4.5-mcg with either 80-mcg or 160-mcg of budesonide. The 80/4.5 mcg strength is approved
for use in children aged 6-12 y, whereas, either strength is approved for children aged ≥12 y.
Mometasone and formoterol (Dulera)

 View full drug information

This is a combination corticosteroid and LABA metered-dose inhaler. Mometasone elicits

local anti-inflammatory effects in the respiratory tract with minimal systemic absorption.
Formoterol elicits bronchial smooth muscle relaxation.

This combination is indicated for prevention and maintenance of asthma symptoms in

patients inadequately controlled with other asthma controller medications (eg, low-dose to
medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of
treatment with 2 maintenance therapies, including a LABA. Available in 2 strengths; each
actuation delivers mometasone/formoterol 100 mcg/5 mcg or 200 mcg/5 mcg.

Salmeterol/fluticasone inhaled (Advair)

 View full drug information

This is a combination corticosteroid and LABA metered-dose inhaler. Fluticasone inhibits

bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may
decrease number and activity of inflammatory cells, in turn decreasing airway hyper-
responsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles
of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or
bronchiectasis and can relieve bronchospasms. Its effect may also facilitate expectoration.
Adverse effects are more likely to occur when administered at high or more frequent doses
than recommended. Two delivery mechanisms are available (ie, powder for inhalation
[Diskus], metered-dose inhaler [MDI]). Diskus is available as a combination of salmeterol 50
mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDI is available as 21 mcg
salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.

Anticholinergic Agents
Class Summary
The long-acting anticholinergic agent, tiotropium, may be considered for long-term
maintenance therapy, but not for acute treatment of asthma exacerbations.
Tiotropium (Spiriva Respimat)

 View full drug information

Tiotropium is a long-acting antimuscarinic agent, often referred to as an anticholinergic.

Inhibits M3-receptors at smooth muscle, leading to bronchodilation. It is indicated for long-
term, once-daily, maintenance treatment of asthma in patients aged ≥6 years.

Ipratropium (Atrovent)

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Chemically related to atropine, ipratropium has antisecretory properties and, when applied
locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. The
MDI delivers 17 mcg/actuation. Solution for inhalation contains 500 mcg/2.5 mL (ie, 0.02%
solution for nebulization). It is not approved for asthma, but off-label use for acute
exacerbations of asthma in addition to beta2-agonist therapy has been described in the
literature. It is a short-acting anticholinergic agent with an onset of 15 minutes.

Monoclonal Antibodies, Anti-asthmatics

Class Summary
Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to
IG-E on the surface of mast cells and basophils. It reduces release of these mediators that
promote an allergic response. Mepolizumab and benralizumab inhibit IL-5 binding to
eosinophils and results in reduced blood, tissue, and sputum eosinophil levels. Dupilumab
inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This in turn
reduces cytokine-induced inflammatory response.

Mepolizumab approval was based on 3 key phase 3 trials (DREAM, MENSA, and SIRIUS).
Each trial demonstrated statistically significant improvement in decreasing asthma
exacerbations and emergency department visits or hospitalization. Mean reduction in
glucocorticoid use was 50% in the mepolizumab group, while also reducing the asthma
exacerbation rate. Significant improvement in FEV1 was also observed compared with
placebo. [71, 72, 73]

Benralizumab approval was based on results from the WINDWARD clinical trial program,
including the Phase III exacerbation trials, SIROCCO and CALIMA, and the Phase III oral
corticosteroid (OCS)-sparing trial, ZONDA. [74, 75, 76] Results for the 8-week benralizumab
dosing regimen from these trials showed significantly reduced annual asthma exacerbation
rate (AAER), improved FEV1, and a 75% median reduction in daily OCS use and
discontinuation of OCS use in 52% of eligible patients compared with placebo.

Approval for dupilumab was based on the LIBERTY QUEST (n=1902) and VENTURE
(n=210) phase 3 clinical trials. In the LIBERTY QUEST trial, patients with moderate-to-
severe uncontrolled asthma were administered dupilumab add-on therapy to current
maintenance therapy every 2 weeks or matched placebo. Those receiving a 200-mg dose
demonstrated a 47.7% lower rate of annualized severe asthma exacerbations compared with
placebo add-on (P < 0.001). The 300-mg dose showed a similar response. [82]

In the LIBERTY VENTURE trial, patients with oral corticosteroid-dependent severe asthma
were administered dupilumab add-on therapy or matched placebo to current maintenance
therapy every 2 weeks for 24 weeks or matched placebo. Corticosteroid doses were gradually
decreased from week 4 to week 20 and then maintained for 4 weeks. Patients receiving
dupilumab had a 70.1% greater corticosteroid dose reduction compared with 41.9% for
placebo add-on (P < 0.001). Additionally, patients receiving dupilumab had a 59% (95% [CI],
37 to 74) lower rate of severe asthma exacerbations than those taking placebo add-on. [83]

Omalizumab (Xolair)

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Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds

selectively to human IgE on surface of mast cells and basophils. It reduces mediator release,
which promotes allergic response. It is indicated for moderate-to-severe persistent asthma in
patients aged 6 years or older who react to perennial allergens in whom symptoms are not
controlled by inhaled corticosteroids.

Mepolizumab (Nucala)

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Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin-5 (IL-
5). Mepolizumab binds to IL-5, and therefore stops IL-5 from binding to its receptor on the
surface of eosinophils. It is indicated for add-on maintenance treatment of patients with
severe asthma aged 12 years or older, and with an eosinophilic phenotype.

Benralizumab (Fasenra)
  View full drug information

Benralizumab is a humanized monoclonal antibody (IgG1/kappa-class) selective for the IL-5

alpha subunit of basophils and eosinophils. It is indicated for add-on maintenance treatment
of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype.

Dupilumab (Dupixent)

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Inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This in turn
reduces cytokine-induced inflammatory response. It is indicated as an add-on maintenance
treatment for moderate-to-severe asthma in patients aged 12 years or older with eosinophilic
phenotype or PO corticosteroid dependent asthma.

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