++
The primary goal of therapy is to achieve asthma control by reducing
impairment and reducing risk. Reducing impairment is focused on
prevention of symptoms, resulting in decreased need for relief use
of a short-acting bronchodilator, maintenance of normal activity
level, normal pulmonary function, and patient satisfaction with
control. Reducing risk is focused on prevention of exacerbations
and loss of lung function. Treatment should include identification
and education regarding the individual patient’s asthma
triggers, as well as pharmacologic treatment optimized for maximal effectiveness
with minimal or no side effects.
++
There are 2 types of asthma medications: controller medications,
which are taken daily to provide long-term control, and quick-relief
medications. Patients who have persistent asthma require both classes
of medication. Long-term control medications include inhaled corticosteroids,
inhaled long-acting bronchodilators, leukotriene modifiers, cromolyn, theophylline,
and immunomodulators. These medications act predominantly by decreasing
airway inflammation. A summary of a childhood asthma treatment plan algorithm
is shown in Figure 512-4.
+++
Controller Medications
+++
Inhaled Corticosteroids
++
Inhaled corticosteroids (ICS) are the most effective long-term
therapy available for patients with persistent asthma. Corticosteroids exert
their effects by binding to glucocorticoid receptors in the cytoplasm
of target cells. ICS have a variety of anti-inflammatory effects
on many different cell types, which may contribute to their success
in the treatment of asthma. These include modulation of anti-inflammatory
proteins including cytokines, adrenergic receptor expression, cytokine
expression, inflammatory receptors, and adhesion molecules. In addition, steroids
markedly reduce the number of circulating eosinophils by decreasing
their survival. They inhibit the release of inflammatory mediators
from alveolar macrophages, the production of inflammatory cytokines
and chemokines by human airway epithelial cells, and inhibit mucous
secretion by goblet cells.
++
ICS are very effective as preventive therapy, leading to reduced symptom
severity, improvement in asthma control and quality of life, improvement
in lung function measures, diminished airway hyperresponsiveness, and
prevention of exacerbation frequency and severity. Sensitivity to
ICS varies among patients. Corticosteroid responsiveness is decreased in
smokers and persons who have asthma with predominantly neutrophilic inflammation.
In addition, African American children with poorly controlled asthma
are at increased risk for corticosteroid insensitivity.6
++
Studies comparing ICS therapy to other single-control medications
reveal that in patients with mild or moderate persistent asthma,
treatment with ICS demonstrates greater improvements in lung function,
symptom scores, frequency and severity of exacerbations, and relief
use of bronchodilators. According to the Expert Panel Report 3,
in patients 12 years and older who require more than low-dose ICS
alone to control asthma (ie, step 3 care or higher), combination
therapy with a long-acting β-agonist along with
ICS is preferred. Alternative, adjunctive therapies include leukotriene
receptor antagonists, or theophylline. For children 0 to 11 years
of age, long-acting β-adrenergic agonists or leukotriene receptor
antagonists, and, in children 5 to 11 years of age, theophylline,
may be considered as adjunctive therapies in combination with ICS.
It is important to note that although studies have examined adjunctive
therapy in adults, adjunctive therapy has
not been studied adequately in children. Studies in adults support
that the addition of a long-acting β-agonist to
ICS leads to greater improvement in lung function and symptoms than
increasing the dose of ICS or using leukotriene receptor antagonists
as adjunctive therapy. Several studies show that for patients who
have mild or moderate persistent asthma, use of higher dose ICS
negligibly improves asthma control compared with lower doses.14 However,
in other studies, higher doses have demonstrated added benefit.
Once the asthma is well controlled for at least 3 months, stepdown
of the therapy should be considered. Several studies have shown
that for most patients whose asthma has been well controlled by
high-dose ICS alone, a 50% reduction in dose can be tolerated
without peak expiratory flow loss of control.14 However,
there is significant variability in response, and the ICS should
be decreased cautiously. The patient and family should be given
a plan if symptoms worsen while the ICS are being decreased. Each
patient and family should be given a written asthma action plan
based on signs and symptoms and/or peak expiratory flow,
especially those with moderate or severe asthma or those at higher
risk for exacerbations.
++
ICS are well tolerated and safe at the recommended dosages. Oral
candidiasis (thrush) is uncommon in patients on low-dose
ICS, but it is a common adverse effect of high-dose ICS.6 In
order to minimize this risk, use the lowest dose of ICS that provides
control and advise patients to rinse their mouths (rinse and spit)
after inhalation of the ICS. In addition, use of a spacer or valved holding
chamber with a non-breath-activated metered-dose inhaler will reduce
the risk of thrush. Dysphonia is another side effect
of ICS therapy, especially at higher doses, although it is less
common in children. Use of a spacer or valved holding chamber minimizes
risk. Reflex cough and bronchospasm have
been reported after use of ICS. These effects can be reduced by
optimizing inhaler technique and the use of a spacer or valved holding
chamber. The side effect that is most worrisome in children is the
potential effect on linear growth. Longitudinal
studies have shown that a reduction in growth
velocity may occur in children or adolescents as a result of ICS
therapy, but they are difficult to interpret because poorly controlled
asthma may delay growth in children. Per the Expert Panel Report
3, the available cumulative data regarding children suggest that
although low to medium ICS doses may decrease growth velocity, the
effects are small, nonprogressive, and may be reversible. Combination
therapy should be initiated when high-dose ICS are necessary to
control symptoms in order to reduce the dose of ICS and minimize
possible dose-related long-term effects on growth. Low- and medium-dose ICS
appear to have no serious adverse effects on bone mineral density
in children. Cases have been reported of children who have severe,
persistent asthma and are taking immunosuppressive doses of systemic
corticosteroids developing disseminated varicella.
Children on immunosuppressive doses of corticosteroids who have not
been immunized against varicella and are exposed to varicella infection
are candidates for oral antiviral therapy. In children, low- and
medium-dose ICS therapy has not been found to have a significant
effect on the incidence of subcapsular cataracts or glaucoma.
In a study of children, ICS at dosages from 400 to 1,000 mcg/day (budesonide)
did not affect fasting glucose or glycosylated hemoglobin.
+++
Oral Systemic
Corticosteroids
++
Because of the considerable side effects of systemic steroids,
oral systemic corticosteroids should be used only for the most severe
asthma patients who are not controlled by the other modes of therapy.
Other modes of therapy should be maximized in order to minimize
the systemic steroid dose. It is necessary, therefore, to monitor
for the development and progression of adverse effects and to take
appropriate steps to minimize the risk and impact of adverse corticosteroid
effects.
+++
Leukotriene
Modifiers
++
Leukotrienes (LT) are products of arachidonic acid metabolism
released from mast cells, eosinophils, and basophils. Via the cyclooxygenase
pathway, arachidonic acid is converted to prostaglandins and thromboxanes. Through
the action of 5-lipoxygenase, arachidonic acid is converted to LTA4 (leukotriene
A4), which can then be converted to LTB4 (leukotriene
B4) through the action of the LTA4 hydrolase or
to LTC4 via LTC4 synthase. LTC4 can then
be converted to LTD4 and LTE4. LTB4 is
produced by a variety of cell types and is strongly chemoattractive
for neutrophils. To a lesser extent, it is also chemoattractive
for eosinophils. The effects of LTB4 are mediated by the
LTB4 receptor.
++
In 1983, Samuelson identified the slow-reacting substance of
anaphylaxis (SRS-A) as the cysteinyl leukotrienes LTC4,
D4, and E4. The cysteinyl leukotrienes are potent
bronchoconstrictors of human smooth muscle, stimulate mucous production,
and increase vascular permeability, resulting in exudation of plasma
into the airway walls and lumen. Patients with asthma are very sensitive
to the bronchospastic effects of inhaled leukotrienes.
++
Three leukotriene modifiers—montelukast, zafirlukast,
and zileuton—are available as oral tablets for the treatment
of asthma. There are 2 classes of compounds: 5-lipoxygenase pathway
inhibitors (eg, zileuton), and leukotriene receptor antagonists
(eg, montelukast and zafirlukast, which block the effects of the
CysLT1 receptor). Only montelukast (for children as young as 1 year)
and zafirlukast (for children as young as 7 years) are approved
for use in children. Three randomized, controlled, double-blind
studies in children 5 to 15 years of age demonstrated greater effectiveness
of ICS compared to montelukast.15 Although ICS are the
preferred controller therapy for persistent asthma, leukotriene
receptor antagonists are an alternative treatment for mild, persistent
asthma in children under 12 years. They can also be used as adjunct
therapy with ICS for children under 12 years. In children 12 years
or older, the preferred adjunct therapy is long-acting β-agonists.
The use of leukotriene receptor antagonists as adjunctive therapy
in moderate or severe asthma has not been studied adequately in
children. Hepatic dysfunction has been reported as a side effect
of zafirlukast, including some cases of fulminate hepatic failure.
Patients should stop taking zafirlukast if any signs or symptoms
of hepatitis occur.
+++
Long-Acting β2-Adrenergic
Agonists
++
Salmeterol and formoterol are β2-agonists,
which bind to β2-adrenergic receptors
and result in relaxation of airway smooth muscle. Both produce clinically
relevant cardiovascular effects (tachycardia, QTc interval prolongation,
and hypokalemia) at doses approximately 4 to 5 times those recommended.
Due to their increased lipophilicity prolonging retention in lung
tissue, a single dose results in a bronchodilation effect for about
12 hours. Formoterol has a more rapid onset of bronchodilation (similar
to albuterol).
++
They should not be used alone for treatment of persistent asthma
but rather in combination with ICSs for long-term control and prevention of
symptoms in moderate or severe persistent asthma (step 3 or higher
in children Å 5 years of age). These drugs should not be used for
the treatment of an acute exacerbation.
++
Long-acting β2-agonists have been associated with
an increased risk of asthma-related deaths and an increased number
of severe asthma exacerbations. Thus, all preparations containing
a long-acting β2-agonist carry a black
box warning. The beneficial effects of long-acting β2-agonists
in combination therapy for patients who require more therapy than
low-dose ICS alone to control asthma (ie, require step 3 care or
higher) should be weighed against the increased risk of severe exacerbations,
although uncommon, associated with the daily use of long-acting β2-agonists.
In children 5 years or older who have moderate, persistent asthma
that is not well controlled on ICS, the option to increase the ICS
dose should be given equal weight to the option of adding a long-acting β2-agonist.6 Long-acting β2-agonists
may be used to prevent exercise-induced symptoms; however, it is
important to note that chronic, regular use of long-acting β2-agonists
has been shown to result in a decrease in the duration of action
to less than 5 hours.
++
Omalizumab is a recombinant DNA–derived humanized monoclonal
antibody to the Fc portion of IgE. It blocks the ability of IgE to
bind to its high-affinity receptor (FcεRI) on mast
cells and basophils. The use of this antibody results in reduction
of the serum concentration of free IgE and attenuates the allergic
response to inhaled allergens in sensitized individuals. It may
be considered as adjunctive therapy in patients 12 years or older
who have allergies and severe, persistent asthma (step 5) that is not
controlled with the combination of high-dose ICS and long-acting β2-agonists.
++
In clinical trials of patients with moderate or severe persistent
allergic asthma (IgE > 30 IU/mL) incompletely controlled
with ICS, addition of omalizumab to ICS therapy produced a reduction
in asthma exacerbations, improved quality of life, and showed a
small improvement in lung function in some studies.6 Omalizumab
appears to have a modest steroid-sparing effect and is the only
adjunctive therapy to demonstrate added efficacy in patients who
are already on high-dose ICS and long-acting β2-agonists.
++
Anaphylactic reactions are estimated to occur in 0.2% of
treated patients, which resulted in a US Food and Drug Administration
alert (FDA 2007; http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/ucm103291.htm). These
reactions occur for the most part within 2 hours of the first 3
injections of omalizumab injection, but reactions can occur at any time.
Thus, administration of omalizumab should be performed only in settings
equipped for the identification and treatment of anaphylaxis (FDA
2007). Adverse effects reported from omalizumab in the trials have
also included injection-site pain and bruising in up to 20% of
patients.16
++
These agents are mast cell stabilizers. They are not the preferred treatment
for any category of asthma but can be used as an alternative treatment
for mild, persistent asthma. They may also be efficacious as preventive
treatment prior to exercise, cold air, or unavoidable exposure to
known allergens.6 However, these agents are less effective
than ICS in improving outcomes measures.
+++
Treatment of
Acute Episodes
++
Asthma remains a leading cause of emergency department visits
by children. Severe exacerbations of asthma are potentially life
threatening. Care must be prompt, and rapid recognition of a severe
exacerbation is critical, as this requires close observation for
deterioration, frequent treatment, and transfer to an emergency
department. The assessment of the severity of an acute asthma exacerbation
is an important guide to treatment. All clinicians treating patients
who have asthma should be prepared to treat an asthma exacerbation,
be familiar with the symptoms and signs of severe and life-threatening
exacerbations, and have procedures for facilitating immediate transfer
to an emergency department. Clinical signs characterizing a severe
episode include the use of accessory muscles, limited ability to
speak, preference to sit upright, a paradoxical pulse greater than
25 mm Hg, a heart rate greater than 130/min, a respiratory
rate of more than 25 breaths/min, a peak expiratory flow
of less than 50% of predicted, and an oxygen saturation
less than 92%. If any of these signs are present, the patient should
be transferred to an emergency department immediately.
++
A brief history should include ascertainment of the onset of
the exacerbation, identification of any potential triggers, current
medications and timing of the most recent dose, comorbid conditions,
and the number of previous emergency department visits and hospitalizations
(including intensive care unit and need for intubation) for asthma.
The physical examination should focus on assessment of the severity
of the exacerbation and possible complications, including pneumonia,
pneumothorax, or pneumomediastinum. Most patients who have an asthma
exacerbation do not require any initial laboratory studies. Chest
radiography is not recommended for routine assessment but should
be obtained if a complicating process is suspected, such as a pneumothorax,
pneumomediastinum, pneumonia, or lobar atelectasis. The differences
in the anatomy and physiology of the lungs of infants and young
children place them at greater risk for respiratory failure, so
it is important to monitor arterial oxygen saturation (SaO2)
by pulse oximetry.
++
According to the Expert Panel Report 3, initial treatment for
an acute exacerbation should include oxygen to maintain an SaO2 greater
than 92% and 3 treatments of a short-acting β2-adrenergic
agonist (each 2.5–5.0 mg albuterol by nebulizer or 4–8 puffs
of metered-dose inhaler) spaced every 20 to 30 minutes should be
given.6 Ipratropium bromide (0.25–0.5 mg nebulizer
solution or 4–8 puffs by metered-dose inhaler in children)
should be added for patients who have severe exacerbations. Systemic
corticosteroids (1–2 mg/kg/day up to
a maximum 60 mg/day for 3–10 days) are recommended
for patients who have moderate or severe exacerbations and do not
respond completely to initial therapy. Oral administration of prednisone
has been shown to be as effective as intravenous methylprednisolone.
A 5- to 10-day course following emergency department discharge is
recommended to prevent early relapse. Improvement from an asthma
exacerbation is usually gradual, and even when symptoms have resolved,
evidence of inflammation in the airways has been shown to continue
for up to 2 to 3 weeks. Intramuscular depot injections of corticosteroids
have been shown to be effective in preventing relapse after discharge
from the emergency department. Thus, this option may be considered
as an alternative to oral corticosteroids for patients who are at
high risk of noncompliance. Systemic corticosteroids can speed resolution
of airflow obstruction and reduce the rate of relapse but may be
associated with considerable side effects. Little information is
available regarding the side effects of brief courses of systemic
corticosteroids. One epidemiologic study suggests that children
4 to 17 years of age who require more than 4 courses of oral corticosteroids
(average duration 6.4 days) as treatment for underlying disease
have an increased risk of fracture. Another study concluded that
multiple short courses of oral corticosteroids (median 4 courses in
the preceding year) in the treatment of asthma in children 2 to
17 years of age were not associated with any lasting effect on bone metabolism,
bone mineralization, or adrenal function.18 In another
study, children who received 4 or more bursts of oral corticosteroids
for acute asthma exacerbations in the previous year demonstrated
a subnormal response of the hypothalamic-pituitary-adrenal axis
to hypoglycemic stress or adrenocorticotrophic hormone.
+++
Quick-Relief
Medications
++
Quick-relief medications are used to provide prompt relief of
acute asthma symptoms, including cough, chest tightness, and wheezing. These
medications include short-acting β2-adrenergic
agonists and anticholinergics (ipratropium bromide). Short-acting β2-agonists
(albuterol, levalbuterol, pirbuterol, etc.) relax airway smooth
muscle, resulting in a rapid increase in airflow and symptomatic
relief. These agents exist as racemic mixtures, and the (R)-enantiomers
have been shown to possess the majority of the therapeutic activity.
However, there has been no consistent added benefit of the (R)-enantiomer
versus the racemic mixture. Short-acting β2-agonists
are very effective in the treatment of acute symptoms, but regular
use is not recommended because it has not been shown to have added
benefit when compared to use when needed with regard to asthma control.
Use of short-acting β2-agonists more than
2 times per week may signify that the asthma is not well controlled,
and controller therapy should be adjusted accordingly. Increasing
use of short-acting β2-agonists has been
associated with increased risk of acute exacerbation requiring hospitalization
and increased risk for death. Several common genetic polymorphisms have
been identified in the β2-adrenergic receptor
gene, some of which may be relevant to the function of the receptor.
Two studies have shown that patients who are homozygous for arginine
at position 16 (Arg/Arg 16) are more likely than patients
who are homozygous for glycine (Gly/Gly 16) to experience
decline in lung function when taking regularly scheduled daily albuterol
treatment.17 Additional studies are needed to delineate
the clinical utility of these observations.
+++
Other Treatment
Considerations
++
According to the Expert Panel Report 3, allergen immunotherapy
should be considered for patients who have persistent asthma, evidence of
allergen sensitization, and a history supporting a relationship
between asthma symptoms and allergen exposure.6 Clinical
studies have demonstrated that immunotherapy is effective in reducing
asthma symptoms caused by exposure to grass, cat, house-dust mite,
ragweed, Cladosporium, and Alternaria.
A meta-analysis of 75 randomized, placebo-controlled studies confirmed
the effectiveness of immunotherapy in asthma, with a significant
reduction in asthma symptoms and medication and with improvement
in bronchial hyperreactivity.19 Furthermore, immunotherapy may
prevent the development of asthma in children with allergic rhinitis.20 The
duration of a course of allergen immunotherapy is typically of 3
to 5 years. Immunotherapy carries a risk of allergic reactions,
including severe anaphylaxis, and these are more frequent among
patients with poorly controlled asthma. Thus, immunotherapy should be
administered only in a physician’s office equipped to handle anaphylaxis.
+++
Environmental
Allergen Avoidance
++
Environmental allergen avoidance is one of the goals of asthma
management. Allergic sensitization is very common among asthmatics: 60% in
adults and as high as 90% of children. Sensitized asthmatic patients,
challenged with extracts of the aeroallergens to which they are
sensitive, display symptoms of acute asthma. Asthmatic symptoms
and objective measurements of lung function improve when patients
avoid allergens to which they are sensitive.21
++
Specific strategies for allergen avoidance are dependent on the
allergen. The allergen that has been best studied is the house dust
mite. The key target for control of dust mite exposure is bedding
because of the high level of mite allergen exposure in mattresses
as well as the proximity of the patient to the source of dust mite
and the prolonged period of time that is spent in this one site.
In studies examining the effectiveness of dust mite–proof
encasings for bedding, there were long-term reductions in the amount
of allergen recovered as well as in the allergen concentrations.
Another recommendation is weekly washing of all sheets and bedding
in hot water at a temperature of greater than 130°Cin order to
kill dust mites. Other recommendations for decreasing dust mite
exposure include removal of wall-to-wall carpeting and replacement
with hardwood floors or tiled floor surfaces and using methods to
decrease humidity.
++
Pet allergen control represents a unique problem. Almost all
residences contain detectable cat and dog allergen regardless of
whether there is a cat or dog in the home. Although the mean level in
houses without cats is significantly lower than that found in houses
with pets, the lower level is still sufficient to cause symptoms
in some individuals. Optimal strategy for cat allergen control is
relocation of the cat to another environment. This results in a
drop in allergen levels by up to 70%, although it takes
years for the levels to decline to levels found in homes without
a cat. Other measures, such as frequent washing of the cat, air
filtration, and treatment with drugs or emollients have not been
shown to be effective.
++
Cockroach sensitivity and exposure are common among patients
who have asthma and live in inner cities. In a study of asthma in
an inner-city area, asthma severity increased with increasing levels
of cockroach antigen in the bedrooms of sensitized children. Cockroach
control measures are recommended if the patient is sensitive to
cockroaches and infestation is present in the home.6 The
data for other environmental control measures, including control
of molds, are still not definitive but support that decreasing exposure
may be beneficial. As a routine part of their asthma care, patients
and families should be counseled concerning the negative effects
of smoking and environmental tobacco smoke. Notably, smoking out
of doors does not adequately reduce exposure for children. There
is insufficient evidence to recommend indoor air cleaning devices.
++
For severe exacerbations unresponsive to the initial treatments,
adjunct treatments (magnesium sulfate or heliox) can be considered.
Studies in children and adults have demonstrated that adjunct intravenous
magnesium sulfate (25–75 mg/kg up to 2 g in children)
reduces hospitalization rates in emergency department patients with
severe asthma exacerbations. Magnesium sulfate has not been shown
to be beneficial in mild or moderate exacerbations.
+++
Use of Metered-Dose
Inhalers
++
An important component of asthma management is education. This includes
education regarding the goals of therapy, the different types of
medication (controller versus quick relief), the importance of taking
the medications as prescribed, the actions to be taken for worsening
symptoms, and the correct inhaler technique.
+++
Spacers and
Valved Holding Chambers
++
Both spacers and valved holding chambers are intended to retain large
particles emitted from the metered-dose inhaler, reduce deposition
in the oropharynx, and promote inhalation of a higher proportion
of small, respirable particles. In vitro and in vivo studies comparing
various spacers and valved holding chambers with the same metered-dose
inhaler have demonstrated a 2- to 6-fold variation in the respirable
dose emitted from the devices and a 2- to 5-fold difference in systemic
availability of the drug. Valved holding chambers are preferred
in children because they have one-way valves that do not allow the
child to exhale into the device. Thus, the child does not need to
coordinate actuation and inhalation.