Pediatric Asthma: Signs and Symptoms

9/23/2018 https://emedicine.medscape.
com/article/1000997-print

emedicine.medscape.com
Pediatric Asthma
Updated: May 22, 2018
Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Kenan Haver, MD
Overview
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 517 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, highpitched 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 exerciseinduced 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
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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 (2040 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, followup every 26 weeks is initially necessary (when gaining control of
the disease), and then every 16 months thereafter
Education: Selfmanagement 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 asthma management includes the use of agents for control and agents for relief. Control agents include the
following:
Inhaled corticosteroids
Inhaled cromolyn or nedocromil
Longacting bronchodilators
Theophylline
Leukotriene modifiers
Antiimmunoglobulin E (IgE) antibodies (omalizumab)
Relief medications include the following:
Shortacting 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 disabilityadjusted 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 517 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 intraalveolar pressure due to hyperinflation
all lead to ventilationperfusion 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 ventilationperfusion 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 ventilationperfusion 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 interferonα (IFNα), which are
critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (interleukin
4 [IL4], IL5, IL6, IL9, and IL13) 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 genebyenvironment 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 earlyonset atopic asthma with normal lung function treated
with two or fewer controller medications and minimal health care utilization. Cluster 2 patients have earlyonset 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 lateonset 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 metaanalysis of genomewide 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 genomewide 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 7yearold
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, treatmentfree year. This suggests that no diseasemodifying
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 517 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
asthmarelated complications. The study found that among young children with mild persistent asthma, asneeded use of
acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control
than was asneeded 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 35 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 IgEmediated 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 IgEinduced mediator release from mast cells within minutes of exposure and last for 2030 minutes.
Late asthmatic responses occur 412 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 exerciseinduced 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 posturerelated 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 nonatopic 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 20012003 prevalence is estimated at 6.7% in adults and 8.5% in children, and the burden of asthma
increased more than 75% from 19801999.[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 810 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
lowincome groups in urban areas and inner cities than in other groups.
A longterm 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 agerelated 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
58% 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. Adultonset 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
611 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 infectionassociated wheezing.
Children with mild asthma who are asymptomatic between attacks are likely to improve and be symptomfree 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 12fold 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 19801995.
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 19751993, the number of deaths nearly doubled in people aged 514 years. In the northeastern and midwestern
United States, the highest mortality rate has been among persons aged 534 years. According to the most recent report from
the CDC and the National Center for Health Statistics, 187 children aged 017 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]
NonHispanic blacks were the most likely to die from asthma and had an asthma death rate more than 200% higher than
nonHispanic 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,
metereddose 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 exerciseinduced 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 schoolbased asthma education. Their review included
25 studies in children aged 417 years.[41] In most of those studies, compared with usual care, schoolbased asthma
education improved knowledge of asthma (7 of 10 studies), selfefficacy (6 of 8 studies), and selfmanagement 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.

Presentation
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, highpitched, 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 exerciseinduced 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 exerciseinduced 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 exerciseinduced 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 moderatetosevere 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 exerciseinduced 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 workup 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 100120 beats per minute
Loud expiratory wheezing can be heard
Pulsus paradoxus may be present (1020 mm Hg)
Oxyhemoglobin saturation with room air is 9195%
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 (2040 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 (04 y, 511 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 lifethreatening 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.

DDx
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
Workup

Workup
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 (36 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 bronchodilatorresponsive 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 2575% of the FVC (FEF 2575). The flowvolume
loop can be concave. Documentation of reversibility of airway obstruction after bronchodilator therapy is central to the
definition of asthma. FEF 2575 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 exerciseinduced 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 preexercise 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 416 mg/mL, 14 mg/mL, and < 1 mg/mL indicate borderline, mild, and moderatetosevere 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 interleukin5 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 616 years, asthma control score and level of interleukin5
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.

Treatment
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 shortacting beta2agonist (SABA) for quick relief of symptoms (not including prevention of
exerciseinduced bronchospasm)
Maintain nearnormal 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 longterm 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
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 12 years, or more frequently for uncontrolled
asthma.
Because asthma varies over time, followup every 26 weeks is initially necessary (when gaining control of the disease) and
then every 16 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 moderatetosevere 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 longterm control and quickrelief
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.
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 firsthand and secondhand 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 longterm 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 management includes the use of agents for control and agents for relief. Control agents include inhaled
corticosteroids, inhaled cromolyn or nedocromil, longacting bronchodilators, theophylline, leukotriene modifiers, and more
recent strategies such as the use of the antiimmunoglobulin E (IgE) antibody (omalizumab) or IL5 monoclonal antibodies
(mepolizumab, benralizumab). Relief medications include shortacting 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). Stepdown 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 highdose inhaled
steroids, or a combination of steroid/longacting beta2agonist, 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 longacting beta2agonist 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: 04 y, 511 y, 12 y and older.
For all patients, quickrelief medications include rapidacting beta2agonists as needed for symptoms. The intensity of
treatment depends on the severity of symptoms. If rapidacting beta2agonists are used more than 2 days a week for
symptom relief (not including use of rapidacting beta2agonists 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
Lowdose
inhaled
corticosteroid Mediumdose
Rapid (ICS) ICS plus Highdose ICS plus
Highdose ICS
acting either long either LABA or
Mediumdose plus either
< 5 y beta2 acting beta2 montelukast; Oral
ICS LABA or
agonist agonist systemic
montelukast
prn Alternate (LABA) or corticosteroid
regimen: montelukast
cromolyn or
montelukast
Highdose ICS plus
Mediumdose
Highdose ICS LABA plus oral
Lowdose ICS ICS plus
plus LABA systemic
LABA
corticosteroid
Either low
Rapid dose ICS plus
acting either LABA,
511
beta2 Alternate LTRA, or
y
agonist regimen: theophylline Alternate
prn OR Medium Alternate Alternate regimen:
cromolyn, regimen:
dose regimen: high highdose ICS plus
leukotriene mediumdose
dose ICS plus LRTA or theophylline
receptor ICS plus
either LABA or plus systemic
antagonist either LTRA or
theophylline corticosteroid
(LTRA), or theophylline
theophylline
12 y Rapid Lowdose ICS Highdose ICS Highdose ICS plus

Mediumdose
or acting plus LABA plus LABA either LABA plus oral
Lowdose ICS ICS plus
older beta2 OR Medium (and consider corticosteroid (and
LABA
agonist dose ICS omalizumab consider omalizumab
as for patients for patients with
needed with allergies) allergies)
Alternate Alternate Alternate

regimen: regimen: low regimen:
cromolyn, dose ICS plus mediumdose
LTRA, or either LTRA, ICS plus
theophylline theophylline, either LTRA,
or zileuton theophylline,
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 asthmarelated events.[49] This trial was a
large, doubleblind, randomized, placebocontrolled, 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 posthoc subgroup analysis, the relative risks of asthmarelated 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 metaanalysis by Salpeter et al found that LABAs increased the risk for asthmarelated intubations and deaths by 2fold,
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 longterm 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 longacting beta2agonists 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 longacting beta2agonist was more likely to provide the best response than either
inhaled corticosteroids or leukotrienereceptor 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 longacting beta2 agonists. Orally inhaled budesonide/formoterol (Symbicort) 80/4.5 mcg with orally
inhaled budesonide 80 mcg in pediatric patients with asthma aged 612 years who were symptomatic on lowdose 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 placebocontrolled 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 20112015, 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, longterm use of highdose 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 longterm use of inhaled
steroids (budesonide) suggest that the longterm 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 innercity 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 1year followup, 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]
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 handbreath coordination to operate
Breathactuated 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 ageappropriate mask. Children aged 46 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 breathactuated 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 hydrofluoroalkane134a (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 CFCMDIs.
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 beta2agonist; 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 beta2agonists
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 lifethreatening
obstruction.
An Australian study by Vuillermin et al found that asthma severity decreased in schoolaged children when parents initiated a
short course of prednisolone for acute asthma.[66] Children who received parentinitiated 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 highrisk 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 shortacting beta2agonists 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.
LongTerm Monitoring
Regular followup visits are essential to ensure control and appropriate therapeutic adjustments. In general, patients should
be assessed every 16 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 24 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 homemonitoring 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.
Longterm 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 1year postadenotonsillectomy followup, 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,
asthmarelated emergency department visits were reduced by 25.6% and asthmarelated 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
Medication Summary
Pharmacologic management includes the use of control agents such as inhaled corticosteroids, inhaled cromolyn or
nedocromil, longacting bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of
antiimmunoglobulin E (IgE) antibodies (omalizumab) and longacting antimuscarinic agents (LAMA) such as tiotropium.
Relief medications include shortacting bronchodilators, systemic corticosteroids, and ipratropium.
Bronchodilators, Beta2Agonists
Class Summary
These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent bronchospasm associated
with exerciseinduced asthma or nocturnal asthma. Several studies have suggested that shortacting beta2agonists 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 betaadrenergic receptor gene compared with patients
homozygous for glycine (GlyGly). Similar findings are reported for longacting beta2agonists, such as salmeterol.
Albuterol (AccuNeb, Proventil HFA, Ventolin HFA, Proair HFA, ProAir
RespiClick)
This beta2agonist 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 beta2receptor downregulation and receptor hyposensitivity.
Pirbuterol (Maxair Autohaler)
Pirbuterol is available as a breathactuated or ordinary inhaler. The ease of administration with the breathactuated 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 Beta2Agonist 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)
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.
LongActing Beta2Agonists
Class Summary
Longacting bronchodilators (LABA) are not used for the treatment of acute bronchospasm. They are used for the preventive
treatment of nocturnal asthma or exerciseinduced asthmatic symptoms, for example.
Salmeterol is the only singleagent 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 firstline 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
mediumdose corticosteroids. If used as isolated medication, LABAs should be prescribed by a subspecialist (ie,
pulmonologist, allergist).
Salmeterol (Serevent Diskus)
This longacting preparation of a beta2agonist is used primarily to treat nocturnal or exerciseinduced symptoms. It has no
antiinflammatory 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 antiinflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to
cause adverse effects. They are used for longterm 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 beta2receptor downregulation and
subsensitivity (in acute asthmatic episodes with LABA use).
Ciclesonide (Alvesco)
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)
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)
Fluticasone has extremely potent vasoconstrictive and antiinflammatory activity. It has a weak hypothalamicpituitary
adrenocortical axis inhibitory potency when applied topically. It is available as an MDI aerosolized product (HFA) or DPI
(Diskus).
Fluticasone furoate inhaled (Arnuity Ellipta)
Synthetic trifluorinated corticosteroid that elicits antiinflammatory 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 oncedaily maintenance treatment of asthma as
prophylactic therapy in children aged ≥5 years.
Budesonide inhaled (Pulmicort Flexhaler or Respules)
Budesonide has extremely potent vasoconstrictive and antiinflammatory activity. It has a weak hypothalamicpituitary
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)
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 (310 d) to gain prompt control of inadequately controlled acute asthmatic
episodes. They are also used for longterm prevention of symptoms in severe persistent asthma as well as for suppression,
control, and reversal of inflammation. Frequent and repetitive use of beta2agonists has been associated with beta2receptor
subsensitivity and downregulation; these processes are reversed with corticosteroids.
Higherdose 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)
An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease inflammation by reversing
increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.
Methylprednisolone (SoluMedrol)
Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Dexamethasone (Baycadron, Dexamethasone Intensol)
Dexamethasone in the ED can provide equivalent relief to a 5day course of prednisone—and without the adverse side
effect of vomiting—for acute asthma flareups in children. Researchers performed a metaanalysis 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 2dose dexamethasone regimens over 5day 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 5lipoxygenase
inhibitors or leukotrienereceptor antagonists.
Zafirlukast (Accolate)
Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.
Montelukast (Singulair)
The last agent introduced in its class, montelukast has the advantages that it is chewable, it has a onceaday dosing, and it
has no significant adverse effects.
Methylxanthines
Class Summary
These agents are used for longterm control and prevention of symptoms, especially nocturnal symptoms.
Theophylline (Theo24, Theochron, Uniphyl)
Theophylline is available in shortacting and longacting 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/LongActing Beta2Agonists
Class Summary
These combinations may decrease asthma exacerbations when inhaled shortacting beta2agonists 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)
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 4.5mcg with either 80mcg or 160mcg
of budesonide. The 80/4.5 mcg strength is approved for use in children aged 612 y, whereas, either strength is approved for
children aged ≥12 y.
Mometasone and formoterol (Dulera)
This is a combination corticosteroid and LABA metereddose inhaler. Mometasone elicits local antiinflammatory 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, lowdose to mediumdose 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)
This is a combination corticosteroid and LABA metereddose inhaler. Fluticasone inhibits bronchoconstriction mechanisms,
produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, in turn decreasing
airway hyperresponsiveness. 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], metereddose 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 longacting anticholinergic agent, tiotropium, may be considered for longterm maintenance therapy, but not for acute
treatment of asthma exacerbations.
Tiotropium (Spiriva Respimat)
Tiotropium is a longacting antimuscarinic agent, often referred to as an anticholinergic. Inhibits M3receptors at smooth
muscle, leading to bronchodilation. It is indicated for longterm, oncedaily, maintenance treatment of asthma in patients
aged ≥6 years.
Ipratropium (Atrovent)
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 offlabel use for acute exacerbations
of asthma in addition to beta2agonist therapy has been described in the literature. It is a shortacting anticholinergic agent
with an onset of 15 minutes.
Monoclonal Antibodies, Antiasthmatics
Class Summary
Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to IGE on the surface of mast cells
and basophils. It reduces release of these mediators that promote an allergic response. Mepolizumab and
benralizumab inhibit IL5 binding to eosinophils and results in reduced blood, tissue, and sputum eosinophil levels.
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 8week 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.
Omalizumab (Xolair)
Omalizumab is a recombinant, DNAderived, 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
moderatetosevere persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by
inhaled corticosteroids.
Mepolizumab (Nucala)
Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin5 (IL5). Mepolizumab binds to IL5,
and therefore stops IL5 from binding to its receptor on the surface of eosinophils. It is indicated for addon maintenance
treatment of patients with severe asthma aged ≥12 y, and with an eosinophilic phenotype.
Benralizumab (Fasenra)
Benralizumab is a humanized monoclonal antibody (IgG1/kappaclass) selective for the IL5 alpha subunit of basophils and
eosinophils. It is indicated for addon maintenance treatment of severe asthma in patients aged ≥12 years who have an
eosinophilic phenotype.

Questions & Answers
Overview
What is pediatric asthma?
Which symptoms help to establish a diagnosis of pediatric asthma?
What are the signs and symptoms of pediatric asthma?
Which physical findings are characteristic of severe episodes of pediatric asthma?
What are the physical findings indicative of status asthmaticus with imminent respiratory arrest in pediatric asthma?
Which tests are performed in the evaluation of pediatric asthma?
What are the National Asthma Education and Prevention Program guidelines for pediatric asthma care?
Which control medications are used in the management of pediatric asthma?
Which relief medications are used in the management of pediatric asthma?
What is pediatric asthma?
What is the prevalence of pediatric asthma?
What is the economic impact of pediatric asthma?
Which organization has published treatment guidelines for pediatric asthma?
What is the role of airway inflammation in the pathophysiology of pediatric asthma?
What is the pathogenesis of pediatric asthma?
What is the pathophysiology of the early stages of pediatric asthma?
What is the role of lymphocytes in the pathophysiology of pediatric asthma?
What is the hygiene hypothesis of the pathophysiology of pediatric asthma?
Which factors have been shown to reduce the prevalence of pediatric asthma?
What is the role of genetics in the pathogenesis of pediatric asthma?
Which loci have been identified as susceptible for asthma?
What is the role of the lipids in the pathogenesis of asthma?
Which early childhood factors may increase the risk for pediatric asthma?
What causes pediatric asthma?
What is the role of respiratory infections in the etiology of pediatric asthma?
What is the role of allergens and irritants in the etiology of pediatric asthma?
What triggers asthma attacks?
How does exercise trigger asthma attacks?
What significantly increase airway resistance and airway reactivity in the pathophysiology of pediatric asthma?
What causes nocturnal asthma?
What factors increase the risk for wheezing in pediatric asthma?
What is the prevalence of pediatric asthma?
What are the racial predilections for pediatric asthma?
How does the prevalence of pediatric asthma vary by sex?
In which age groups is pediatric asthma most prevalent?
What is the prognosis of pediatric asthma?
What is the mortality and morbidity associated with pediatric asthma?
What is included in patient education for pediatric asthma?
What are the benefits of patient education for pediatric asthma?
Presentation
What are the diagnostic criteria for pediatric asthma?
Which factors may precipitate or aggravate symptoms of pediatric asthma?
Which conditions may affect precipitate or aggravate asthma?
What should be the focus of history for pediatric asthma?
What should be included in the family history for pediatric asthma?
What should be included in the history of exacerbations of pediatric asthma?
How is wheezing characterized in pediatric asthma?
How is coughing characterized in pediatric asthma?
What are the nonspecific symptoms of pediatric asthma?
How does the clinical presentation of pediatric asthma vary?
Which physical findings suggest pediatric asthma in the absence of an acute episode?
During an acute episode of pediatric asthma, what will determine the physical findings?
What are the characteristic physical findings during a mild episode of pediatric asthma?
What are the characteristic physical findings during a mild moderately severe episode of pediatric asthma?
What are the characteristic physical findings during a severe episode of pediatric asthma?
What are the characteristic physical findings of status asthmaticus with imminent respiratory arrest?
How is asthma severity defined?
What should be considered when staging pediatric asthma?
DDX
Which conditions should be included in the differential diagnosis of pediatric asthma?
What are the differential diagnoses for Pediatric Asthma?
Workup
What are the diagnostic guidelines for pediatric asthma?
What is the accuracy of pulmonary function tests in the evaluation of pediatric asthma?
What is the role of spirometry in the diagnosis of pediatric asthma?
What is the role of plethysmography in the evaluation of pediatric asthma?
What is the role of exercise challenge testing in the evaluation of pediatric asthma?
What is the role of methacholine challenge testing in the evaluation of pediatric asthma?
What is the role of fraction of exhaled nitric oxide (FeNO) measurement in the evaluation of pediatric asthma?
What is the role of radiography in the evaluation of pediatric asthma?
What is the role of CT scanning in the evaluation of pediatric asthma?
What is the role of allergy testing in the evaluation of pediatric asthma?
Which histologic findings are characteristic of pediatric asthma?
Treatment
What are the goals of therapy for pediatric asthma?
How is the reduction in risk of pediatric asthma achieved?
Which dietary modifications may be beneficial in the treatment of pediatric asthma?
What is the goal of longterm therapy for pediatric asthma?
What are the components of asthma care?
What is included in the assessment and monitoring of pediatric asthma?
What is include in patient education for pediatric asthma?
Which environmental factors and comorbidities must be controlled as part of the management of pediatric asthma?
What is the role of vitamin D supplementation in the treatment of pediatric asthma?
What is the role of lansoprazole and inactivated influenza vaccine in the treatment of pediatric asthma?
What is included in pharmacologic management of pediatric asthma?
What is the goal of pharmacologic treatment of pediatric asthma?
What is the stepwise approach to pharmacologic therapy for pediatric asthma?
What is the role of salmeterol in the treatment of pediatric asthma?
What is the role of longacting betaagonists (LABAs) in the treatment of pediatric asthma?
What are safety concerns regarding the use of longacting beta2agonist in the treatment of pediatric asthma?
How frequently is pediatric asthma treated with oral corticosteroids?
What is the efficacy of increased inhaled corticosteroid doses at the onset of asthma exacerbation in children?
What are the adverse effects of longterm use of highdose steroids for the treatment of pediatric asthma?
What inhaler devices are currently used to deliver inhaled corticosteroids (ICSs) for pediatric asthma?
What is the preferred device for delivery of medications in children younger than 4 years with pediatric asthma?
What is the role of valved holding chambers in the administration of medications for pediatric asthma?
What newer devices have been shown to be effective in the treatment of pediatric asthma?
What are the treatment goals for acute severe asthmatic episodes (status asthmaticus) in pediatric asthma?
Which tests can help guide treatment for acute severe asthmatic episodes (status asthmaticus) in pediatric asthma?
Which factors suggest high risk in pediatric asthma?
Which specialist consultations may be beneficial in the treatment of pediatric asthma?
What is included in longterm monitoring of pediatric asthma?
What should be included in outpatient care for pediatric asthma?
What should be included in the ongoing evaluation of pediatric asthma?
What is the efficacy of monitoring in pediatric asthma?
What is the role of surgery in the treatment of pediatric asthma?
Medications
Which medications are used in the treatment of pediatric asthma?
Which medications in the drug class Monoclonal Antibodies, Antiasthmatics are used in the treatment of Pediatric Asthma?
Which medications in the drug class Anticholinergic Agents are used in the treatment of Pediatric Asthma?
Which medications in the drug class Combination Inhaled Steroids/LongActing Beta2Agonists are used in the treatment of
Pediatric Asthma?
Which medications in the drug class Methylxanthines are used in the treatment of Pediatric Asthma?
Which medications in the drug class Leukotriene Modifiers are used in the treatment of Pediatric Asthma?
Which medications in the drug class Systemic Corticosteroids are used in the treatment of Pediatric Asthma?
Which medications in the drug class Inhaled Corticosteroids are used in the treatment of Pediatric Asthma?
Which medications in the drug class LongActing Beta2Agonists are used in the treatment of Pediatric Asthma?
Which medications in the drug class Nonracemic Form of the Beta2Agonist Albuterol are used in the treatment of Pediatric
Asthma?
Which medications in the drug class Bronchodilators, Beta2Agonists are used in the treatment of Pediatric Asthma?

Contributor Information and Disclosures
Author
Girish D Sharma, MD, FCCP, FAAP Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric
Pulmonology and Rush Cystic Fibrosis Center, Rush Children's Hospital, Rush University Medical Center

Girish D Sharma, MD, FCCP, FAAP is a member of the following medical societies: American Academy of Pediatrics,
American College of Chest Physicians, American Thoracic Society, Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.
Coauthor(s)
Payel Gupta, MD Department of Allergy and Immunology, ENT Faculty Practice

Payel Gupta, MD is a member of the following medical societies: American College of Physicians

Specialty Editor Board
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor
inChief, Medscape Drug Reference

Charles Callahan, DO Professor, Chief, Department of Pediatrics and Pediatric Pulmonology, Tripler Army Medical Center

Charles Callahan, DO is a member of the following medical societies: American Academy of Pediatrics, American College of
Chest Physicians, American College of Osteopathic Pediatricians, American Thoracic Society, Association of Military
Surgeons of the US, Christian Medical and Dental Associations

Chief Editor
Kenan Haver, MD Assistant Professor of Pediatrics, Harvard Medical School; Associate Director of Asthma Program,
Director of Flexible Bronchoscopy Program, Director of Pulmonary Division Asthma Program, CoDirector of Primary Ciliary
Dyskinesia, CoLeader of Empyema Standardized Clinical Assessment and Management Plans (SCAMP), Boston Children’s
Hospital

Kenan Haver, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic
Society

Additional Contributors
Thomas Scanlin, MD Chief, Division of Pulmonary Medicine and Cystic Fibrosis Center, Department of Pediatrics, Rutgers
Robert Wood Johnson Medical School

Thomas Scanlin, MD is a member of the following medical societies: American Association for the Advancement of Science,
Society for Pediatric Research, American Society for Biochemistry and Molecular Biology, American Thoracic Society,
Society for Pediatric Research

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