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Allergic and Environmental Asthma

Synonyms and related keywords: reactive airways disease, RAD, occupational asthma,
reversible airway obstruction, increased bronchial reactivity, airway inflammation, passive smoke
inhalation, allergic disease, aeroallergen exposure, viral respiratory illness, allergen-specific
immunoglobulin E, allergen-specific IgE, airway hyperreactivity, AHR, airway remodeling, status
asthmaticus, atopy, asthma triggers, nonallergic rhinitis, early allergic response, EAR, late allergic
response, LAR, mite antigens, cockroach antigens, occupation-induced airway disease,
occupation-induced asthma, industry-induced airway disease, industry-induced asthma, industrial
asthma, occupational asthma, seasonal pollen allergens, mold spore allergens, dust mite
allergens, animal allergens, food allergens, breath-actuated inhaler, BDI, dry-powder inhaler,
DPI, metered-dose inhaler, MDI, breath actuated inhaler, dry powder inhaler, metered dose
inhaler.
Background
Asthma is a clinical syndrome characterized by episodic reversible airway obstruction, increased
bronchial reactivity, and airway inflammation. Asthma results from complex interactions among
inflammatory cells, their mediators, airway epithelium and smooth muscle, and the nervous
system. In genetically susceptible individuals, these interactions can lead to symptoms of
breathlessness, wheezing, cough, and chest tightness.
Risk factors for asthma include a family history of allergic disease, the presence of allergen-
specific immunoglobulin E (IgE), viral respiratory illnesses, exposure to aeroallergens, obesity,
and lower socioeconomic status.
Environmental exposure in sensitized individuals is a major inducer of airway inflammation, which
is a hallmark finding in the asthmatic lung. Although triggers induce inflammation through
different pathways, the resulting effects all lead to increased bronchial reactivity.
Exposure to dust mites within the first year of life is associated with later development of asthma
and, possibly, atopy. Mite and cockroach antigens are common, and exposure and sensitization
has been shown to increase asthma morbidity. Allergies trigger asthma attacks in 60-90% of
children and in 50% of adults. Approximately 75-85% of patients with asthma have positive
(immediate) skin test results. In children, this sensitization is associated with disease activity.
The level of IgE is associated with the prevalence and severity of airway hyperresponsiveness
(AHR) and asthma.
Although most people with asthma have aeroallergen-induced symptoms, some individuals
manifest symptoms with nonallergic triggers. As many as 3-10% of people with asthma are
sensitive to nonsteroidal anti-inflammatory drugs (NSAIDs). Approximately 5-10% of people with
asthma have occupation- or industry-induced airway disease. Many individuals develop symptoms
after viral respiratory tract infections.
Allergen avoidance and other environmental control efforts are feasible and effective. Symptoms,
pulmonary function test findings, and AHR improve with avoidance of environmental allergens.
Removing even one of many allergens can result in clinical improvement. However, patients
frequently are not compliant with such measures.
Pathophysiology
The allergic response in the airway is the result of a complex interaction of mast cells,
eosinophils, T lymphocytes, macrophages, dendritic cells, and neutrophils. Inhalation-challenge
studies with allergens reveal an early allergic response (EAR), which occurs within minutes and
peaks at 20 minutes following inhalation of the allergen. Clinically, the manifestations of the EAR
in the airway include bronchial constriction, airway edema, and mucus plugging. These effects are
the result of mast cell–derived mediators. Four to 10 hours later, one sees the late allergic
response, which is characterized by infiltration of inflammatory cells into the airway and is most
likely caused by cytokine-mediated recruitment and activation of lymphocytes and eosinophils.
Antigen-presenting cells (ie, macrophages, dendritic cells) in the airway capture, process, and
present antigen to helper T cells, which, in turn, become activated and secrete cytokines. Helper
T cells can be induced to develop into T H1 (ie, interferon-gamma, interleukin [IL]–2) or T H2 (ie,
IL-4, IL-5, IL-9, IL-13). Allergens drive the cytokine pattern towards T H2, which promotes B-cell
IgE production and eosinophil recruitment. Subsequently, IgE binds to the high-affinity receptor
for IgE, Fc-epsilon-RI, on the surface of mast cells and, with subsequent exposure to the allergen,
the IgE is cross-linked. This leads to degranulation of the mast cell. Preformed mast cell
mediators, such as histamine and proteases, are released, leading to the EAR.
Newly formed mediators such as leukotriene C4 and prostaglandin D2 also contribute to the EAR.
Proinflammatory cytokines (IL-3, IL-4, IL-5, tumor necrosis factor-alpha) are released from mast
cells and are generated de novo after mast cell activation. These cytokines contribute to the late
allergic response by attracting neutrophils and eosinophils. The eosinophils release major basic
protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase into
the airway, causing epithelial denudation and exposure of nerve endings. The lymphocytes that

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are attracted to the airway continue to promote the inflammatory response by secreting cytokines
and chemokines, which further potentiate the cellular infiltration into the airway. The ongoing
inflammatory process eventually results in hypertrophy of smooth muscles, hyperplasia of
mucous glands, thickening of basement membranes, and continuing cellular infiltration. These
long-term changes of the airway, referred to as airway remodeling, can ultimately lead to fibrosis
and irreversible airway obstruction in some, but not most, patients.
Frequency
 United States: prevalence is difficult to determine because definitions and survey methods
vary, but it is likely increasing as a result of greater sensitization to common allergens and
the redefinition of some nonatopic wheezing as asthma. From 1982-1992, the average age-
adjusted prevalence rate increased 42% (from 34.7/1000 to 49.4/1000). Asthma may affect
31 million people, including 9.2 million children (7.2% of adults by self-report).
 International: asthma affects more than 100 million people worldwide. Some reports suggest
asthma prevalence has peaked at 8-12%, perhaps because of improved management or
because asthma has already been induced in the maximal number of genetically available
individuals.
Mortality/Morbidity
 The death rate from asthma is 17.7 deaths per million people. Mortality has increased,
especially in children who live in inner-city areas, despite advances in disease understanding
and therapy. The number of deaths annually decreased from 5067 (1960-1962) to a low of
1870 (1975-1978) and then increased to 5429 (1993-1995).
 Annually, asthma is responsible for 1.5 million emergency department (ED) visits,
500,000 hospital admissions (third leading preventable cause), and 100 million days of
restricted activity. Medical expenses and lost work and productivity cost an estimated $12.7
billion in 1998. Increased morbidity is multifactorial and may include increased exposure to
indoor allergens, less exposure to viral infections early in life, more environmental pollution,
overuse of short-acting beta-2 agonists, underuse of anti-inflammatory medications, and
limited access to, or education about, health care.
Race
 Females, ethnic minorities, people with a low annual family income (<$20,000/y in the
United States), and persons with poor access to, or education about, health care have worse
outcomes than other individuals.
 Hospitalization and death rates are 3 times greater in African Americans.
 Asthma is rare in Eskimos.

Sex
 Boys have been shown to be at greater risk for asthma than girls. In children younger
than 14 years, the prevalence is twice as high in boys compared with girls.
 The difference narrows with age, and women aged 40 years have a greater prevalence
than men of the same age.
Age
 Disease onset can occur in persons of any age, but children often present when younger
than 6 years. Asthma is the most common chronic disease of childhood.
 Many young children “outgrow” asthma, especially boys who have no personal or family
history of atopy. However, clinical experience shows that many teenagers who become
asthma-free develop asthma again in their 20s and 30s. Perinatal exposure to allergens or
passive smoke has been postulated to make outgrowing asthma less likely.

CLINICAL
History
The classic history consists of wheeze, cough, and dyspnea. The predictive value of any single
parameter is approximately 30% but is much higher when parameters are combined. Chest
discomfort (eg, pain, tightness, congestion, inability to take a full breath) is also common. Some
patients may have cough without other symptoms. Recurrent or refractory chest colds may also
suggest the diagnosis.
 Record the following:
o Age of onset
o Frequency and severity of daytime and nocturnal symptoms
o Symptom triggers, such as exercise, animals, irritants (smoke), and occupation (worse
on workdays)
o Seasonal and geographic variation
o Limits on activity, lost work or school days, and quality of life
o Number of ED and urgent clinic visits, hospital admissions, intensive care unit (ICU)
stays, and need for mechanical ventilation

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o Past treatments, including oral and inhaled steroids, frequency of rescue inhaler use,
immunotherapy, and environmental avoidance
o Family history of asthma
o Personal or family history of atopy, allergy, rhinitis (including nonallergic rhinitis), or
sinusitis
o Gastroesophageal reflux symptoms
o Food allergy
o Growth (children)
o Atopic dermatitis

 All patients should be asked about or should complete a questionnaire regarding


exacerbation of symptoms, as follows:
o Allergic
 Perennial symptoms - Pet in the home (especially in the bedroom, bed,
or both), school, day care, or work environment; moisture, dampness, and
humidifier use; mold and musty odors in any part of the home; cockroaches in the
home; worsening of symptoms after vacuuming rugs (typical of dust mite allergen)
 Seasonal symptoms (may extend beyond one season in temperate or
tropical climates) - Early spring (trees), late spring and summer (grasses), summer
and fall (dry molds), and fall (weeds)

o Environmental
 Personal or secondary tobacco smoke exposure in or out of the home
 Stoves, fireplaces, or heaters used in home
 Sprays or chemical agents at work, home, or with hobbies
 Symptoms only at one place (ie, at work during week with no
symptoms on weekends)
 School or business associates with similar problems
 Symptoms after eating (seafood or dried, canned, or processed food)
 Medications such as beta-blockers (including eye drops), aspirin, or
other NSAIDs
Physical
Physical examination findings are often normal.
 Head and neck: Nasal mucosal swelling, discharge, polyps, or sinus percussion
tenderness may suggest associated allergic rhinitis or sinusitis. Wheezing heard only or
mostly over the neck may suggest vocal cord dysfunction (VCD) or other laryngeal
abnormality, though VCD can be present without a localizing wheeze.
 Cardiac: Findings are normal. Patients with status asthmaticus may have a pulsus
paradoxus greater than 10 mm Hg.
 Respiratory: During an acute asthma exacerbation, lung examination findings may
include wheezing, rhonchi, hyperinflation, or prolonged expiratory time. With severe disease,
lung auscultation may reveal absent breath sounds (indicating poor air movement) or signs
of respiratory distress and failure (eg, nasal flaring, grunting, accessory muscle use,
cyanosis). Focal wheezing may indicate foreign body or other airway obstruction such as a
tumor.
 Skin: Check the patient for atopic dermatitis.
 Extremities: Digital clubbing should not be present.

Causes
The etiology of asthma is likely multifactorial. Genetic factors may control individual
predispositions to asthma and responses to medications. Genetics alone cannot account for the
significant increases in prevalence, as genetic factors take several generations to develop, and
asthma and atopy are not always co-inherited. Several environmental or lifestyle factors have
been implicated.
 A hygienic hypothesis proposes that cleaner environments have led to less
immunological stresses, preventing the development of an asthma-protective T H1 cytokine
phenotype.
 Measles infection, BCG vaccine administration, hepatitis A seropositivity, and other
stimuli that increase production of interferon-gamma and IL-12 may inhibit the T H2 allergic
response.
 In selected series, vaccinations, fewer childhood infections, liberal use of antibiotics,
more processed food in diets, smaller families, and less exposure to day care environments
have been associated with increased atopy and asthma. Asthma, atopy, and AHR are more
prevalent in western Germany, while bronchitis is more common in eastern Germany.

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 One theory to explain the increased prevalence of allergic disease is that with fewer
infectious stimuli in the environment, the in utero T H2 allergic cytokine state never switches
to the TH1 state.
 Causes or triggers of asthma can be divided as follows:
o Allergic: Aeroallergens can include seasonal pollen, mold spores, dust mites,
animal allergens, and food (especially in children). Monosodium glutamate does not
appear to be an allergen.
o Nonallergic: These may include smoke, odors, cold air and weather, chemicals,
medications (eg, aspirin, other NSAIDs, beta-blockers), exercise, hormonal changes (eg,
pregnancy, menstrual cycle), and bisulfite food additives.

DIFFERENTIALS
Bronchiolitis
Bronchitis
Chronic Bronchitis
Emphysema
Foreign Body Aspiration
Immunoglobulin G Deficiency
Mixed Connective-Tissue Disease
Pulmonary Embolism
Sarcoidosis
Sinusitis, Chronic
Undifferentiated Connective-Tissue Disease
Vascular Rings
Other Problems to be Considered
Children and young adults
Cystic fibrosis
Congenital cardiac anomalies
Pulmonary anomalies
Adults
Gastroesophageal reflux
Vocal cord dysfunction
Endobronchial lesion
Churg-Strauss syndrome (allergic angiitis and granulomatosis)
Allergic bronchopulmonary aspergillosis
Reactive airway dysfunction syndrome: This is a distinct entity caused by exposure to a single,
large, inhaled agent leading to asthma symptoms within 24 hours and lasting 3 months or longer

WORKUP
Lab Studies
 The most important tests are pulmonary function tests (see Other Tests). The serum IgE
level is elevated only approximately half the time in patients with allergic disease. Checking
IgE levels is not indicated in most patients with asthma. Levels greater than 1000 ng/mL (1
IU= 2.4 ng) may suggest an alternate diagnosis, such as allergic bronchopulmonary
aspergillosis
 Sputum and serum eosinophilia tests are not routinely performed or required for
diagnosis. Decrease in sputum eosinophilia may suggest asthma control or responsiveness to
inhaled steroids. Note that a finding of greater than 15% serum eosinophilia can indicate
parasites, drug allergies, or eosinophilic pulmonary disorders.
 Exhaled nitric oxide may also predict airway inflammation and asthmatic control but is
more expensive to measure.
 In older patients, an elevated serum brain natriuretic peptide (BNP) level may help
suggest heart failure as a primary or contributing cause of dyspnea and wheezing.
 Skin testing is one of the most useful ways to determine specific allergen sensitivity. A
skin test or in vitro radioallergosorbent assay test (RAST) is very useful in advising patients
about allergen avoidance techniques.
Imaging Studies
 Chest radiographs: These are taken only if pneumonia, large airway lesions, or heart
failure is suggested or if symptoms are atypical or refractory to therapy, if the patient has
unilateral or focal wheezing, or if the patient has new adult-onset asthma.
 Modified or limited sinus CT scans: Consider CT scans of the sinuses if chronic sinusitis is
suggested. About 65% of people with severe asthma have concomitant sinusitis.
 Chest CT scans: These are indicated in select patients to help exclude interstitial lung
disease, bronchiectasis, bronchiolitis, or infection.

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 Echocardiograms: These are performed if congestive heart failure is suggested based on
history and physical examination findings.
Other Tests
 Symptom improvement with asthma therapy is suggestive but not diagnostic of asthma.
Symptoms alone do not necessarily reflect asthma severity. Infants may be treated
empirically. In patients older than 5 years, objectively demonstrating reversible airflow
obstruction with pulmonary function tests is possible and essential.
o Obstruction is defined as a ratio less than 70% of forced expiratory volume in 1
second (FEV1) to forced vital capacity (FVC). FEV 1 is normally greater than 80% of values
predicted by age. Young patients with a supranormal FVC can sometimes have a reduced
FEV1-to-FVC ratio without having obstructive lung disease.
o Reversibility can be shown by administering a short-acting beta-2 agonist
inhaler with a resultant 10-12% and more than 200-mL improvement in FEV 1 or FVC. If
no response, 2-3 weeks of oral or inhaled corticosteroids (20 mg twice daily for the
average patient) may be required to demonstrate an improvement in airflow. Note that
airflow obstruction in some patients with chronic obstructive pulmonary disease may be
partially reversible.
o A 15% drop in FEV1 after 6 minutes of running or other exercise can be
diagnostic of exercise-induced bronchospasm.
o A 20% variation in the peak expiratory flow rate (PEFR) between high and low
values is highly suggestive of asthma, but formal pulmonary function testing (as above)
is recommended because the PEFR is extremely effort-dependent.
o An asthma specialist can perform bronchoprovocation testing with exercise,
histamine, methacholine, or eucapnic voluntary hyperventilation. The results from these
tests have a very high negative predictive value and are useful for excluding the
diagnosis of asthma. The authors most commonly use a challenge with increasing doses
of inhaled methacholine. A 20% decline in FEV 1 with a methacholine concentration of 8
mg/mL or less is considered a positive (abnormal) test result. This testing should be
avoided during pregnancy because of the risk of precipitating an asthma attack and
because methacholine is a class C drug.

 Allergen-inhalation challenges can be performed in selected patients but are generally


not needed or recommended. This test requires an available allergen solution and specialized
centers able to handle potentially significant reactions. A negative test finding may allow
continued exposure to an allergen (eg, family pet); a positive test finding can dramatically
indicate that the patient should avoid a particular allergen. This test is often needed to help
diagnose occupational asthma.

 A trial of allergen avoidance may be diagnostic and therapeutic.

 If restrictive or other lung disease is suggested by history, physical examination, or


pulmonary function testing findings, additional data must be obtained, including complete
lung volumes, respiratory muscle strength, diffusion capacity, and a high-resolution CT scan.

 Perform a barium swallow, endoscopy, or 24-hour pH probe (the Bravo study is now
possible in selected centers) to help diagnose gastroesophageal reflux disease (GERD) if a
patient’s condition is refractory to asthma therapy. Empiric medical therapy is often tried
without performing these tests, especially if a patient has symptoms of GERD.

 Measure oxygenation (ie, with pulse oximetry or arterial blood gas testing) in selected
patients.

 Perform sweat chloride testing for cystic fibrosis or immunoglobulin level testing for
immunodeficiency if these conditions are suggested.

 Skin testing should be performed to help detect the presence of allergen-specific IgE
against environmental triggers that are suggested based on the patient's questionnaire
answers and history information.
o Testing is recommended for antigens to which the patient is exposed rather
than testing with a standard panel.
o Skin test findings have very high positive and negative predictive values;
however, a negative test finding does not rule out the possibility that an allergen is
having an impact on the patient’s asthma. Conversely, a positive test finding does not
mean that a patient is exposed to an allergen or that he or she will react to it in a
natural exposure.
o Antihistamine medications, but not short courses of oral glucocorticoids at
moderate doses, interfere with allergy skin testing.
o Testing should not be performed during an asthma exacerbation, and the
testing site should be equipped for the treatment of rare life-threatening reactions.

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o Skin testing is performed with controls (eg, histamine and saline) to avoid false-
positive (dermatographism) or false-negative results.
o Identification of allergen triggers can assist in formulating an environmental
control strategy.

 An RAST may be used in place of skin testing if dermatologic disease is generalized,


antihistamine or tricyclic antidepressant (TCA) use cannot be suspended (these will not
interfere with RAST results), or skin testing is relatively contraindicated. However, skin
testing is more specific, more sensitive, and usually less expensive than the RAST.

 Staining nasal secretions with Hansel stain is sometimes used to assess for nasal
eosinophilia, which is suggestive of allergy, but the sensitivity and specificity of this stain are
low.

Procedures
 Direct and indirect laryngoscopy are indicated if VCD or another laryngeal abnormality is
suggested. A flow-volume curve on pulmonary function test may demonstrate extrathoracic
obstruction, supporting the diagnosis of VCD.

 Cardiac stress testing, cardiopulmonary exercise testing, or both may be indicated if the
etiology of dyspnea cannot be determined.
Histologic Findings
The diagnosis of asthma is not made histologically. However, autopsy and bronchoscopic biopsy
findings include mucus plugging, inflammatory cell infiltrates and debris, vascular permeability,
mucosal edema, and epithelial exfoliation. Remodeling, consisting of hypertrophy of smooth
muscle, squamous and goblet cell metaplasia, mucous gland hypertrophy, and basement
membrane thickening due to collagen and other matrix protein deposition, is present.
Sputum analysis results show creola bodies (ie, bronchial regenerative cells with nuclear atypia),
Charcot-Leyden crystals (ie, residual product of eosinophils), and Curschmann spirals (ie,
concentric layers of mucous and debris).
Staging
The National Asthma Education and Prevention Program, Expert Panel Report 2 (1997) from the
National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes Health suggests the
following stepwise approach to the diagnosis and treatment of adults and children older than 5
years. Updates were published in 2002. In addition, see Medication.
 Step 1 - Mild intermittent
o Daytime symptoms 2 or fewer times per week
o Nocturnal symptoms 2 or fewer times per month
o PEFR or FEV1 equal to 80% of normal or better
o PEFR variation less than 20%
o Treatment with short-acting inhaled bronchodilators only as needed
o Systemic glucocorticoids for severe exacerbations

 Step 2 - Mild persistent


o Daytime symptoms more than twice per week, but not daily
o Nocturnal symptoms more than twice per month
o PEFR or FEV1 equal to 80% of normal or better
o PEFR variation 20-30%
o Treatment with daily low-dose inhaled glucocorticoids and short-acting inhaled
bronchodilators as needed
o Alternative daily therapy - Mast cell stabilizers (cromolyn or nedocromil) can be
considered before inhaled steroids, especially in children. Leukotriene pathway modifier
agents and even low-dose sustained release theophylline can also be considered, though
these are less firmly established. In selected patients, allergy immunotherapy may be
usefull

 Step 3 - Moderate persistent


o Daily symptoms
o Nocturnal symptoms more than once per week
o PEFR or FEV1 equal to 60-80% of normal
o PEFR variation more than 30%
o Treatment with daily low-to-medium–dose inhaled glucocorticoids - A recent
warning from the US Food and Drug Administration (FDA) about possible adverse effects
observed with combinations of inhaled corticosteroids (ICS) and long-acting beta-

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agonists (LABA) indicates that some caution should be applied with the use of these
products. However, experience indicates that combinations of inhaled CCS and LABA are
extremely effective in step 3 asthmatics. All patients require short-acting bronchodilators
as needed.
o Alternate daily therapy - Increase inhaled glucocorticoids (to medium dose) or
low-to-medium–dose inhaled glucocorticoids and either a leukotriene modifier or
theophylline
o Leukotriene synthesis inhibitors, such as zileuton
o Allergy immunotherapy for appropriately selected patients

 Step 4 - Severe persistent


o Continual daytime symptoms
o Frequent nocturnal symptoms
o PEFR or FEV1 less than or equal to 60% of normal
o PEFR variation more than 30%
o Treatment with daily high-dose inhaled glucocorticoids and daily long-acting
inhaled beta-agonist and short-acting bronchodilators as needed
o Additionally, if needed, oral glucocorticoids at lowest dose and for the shortest
duration required for relief (<2 mg/kg/d, ie, <60 mg/d) or consider alternative or
contributing diagnoses
o Zileuton (may be helpful in some patients)
o Omalizumab (anti-IgE), in allergic patients requiring high-dose inhaled or oral
CCS

 For children younger than 5 years, the guidelines also indicate the preferred therapy for
moderate and severe persistent asthma consists of inhaled corticosteroids with the addition
of long-acting beta-agonists.

TREATMENT
Medical Care
The goals of treatment are to minimize symptoms, improve quality of life, decrease need for
urgent care or hospitalizations, normalize pulmonary function test results, and decrease the
inflammatory process that leads to airway remodeling. For this discussion, treatment is divided
into pharmacotherapy, environmental control, allergen immunotherapy, antibodies against IgE,
and education.
 Pharmacotherapy
o The most important facet of medical care is the use of anti-inflammatory
medication (usually inhaled glucocorticoids) in patients at all stages beyond mild
intermittent asthma. These medications improve the long-term outcomes for children
with asthma and do not appear to have significant adverse effects at moderate doses
(eg, on growth, bone density, eyes, adrenal sufficiency). Unfortunately, in some series,
fewer than half the patients admitted to the hospital for asthma were receiving the
recommended anti-inflammatory medications.
o NHLBI guidelines suggest that initial medical care should be aggressive to
rapidly gain control and then should be tapered as tolerated.
o Severe exacerbations require standard care that includes supplemental oxygen
(goal PaO2 >60 mm Hg, arterial oxygen saturation >90%), nebulized medications,
intravenous fluids, and even noninvasive or invasive ventilatory support. Heliox (helium-
oxygen gas mixture) is an option but has not been systematically shown to be helpful.
o Antibiotics offer no added benefit during an asthma exacerbation.
o In emergency situations, nebulized magnesium sulfate during acute asthma
attacks—when added to short-acting beta-2 agonists—may improve pulmonary function
and reduce admissions, based on a limited number of studies.
o All patients should receive assistance with quitting tobacco use. While smoking
cessation is essential for a number of reasons, it particularly appears to increase
corticosteroid responsiveness in patients with asthma.
o All patients should receive an annual flu shot. A pneumococcal pneumonia
vaccination is not required unless indicated based on age (ie, >65 y). Asthma symptoms
do not increase after these shots because the antigens in the vaccinations are not alive.
o Evaluating and treating patients for associated conditions (eg, rhinitis, GERD,
sinusitis) can be important components of therapy. In one study, treating the GERD
symptoms of patients with asthma with a proton pump inhibitor for 6 months reduced
asthma exacerbations and improved quality of life but did not improve asthma
symptoms or pulmonary function or reduce albuterol usage.

 Environmental control

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o Allergen avoidance takes different forms depending on the specific allergen size
and characteristic. Improvement in symptoms after avoidance of the allergen may take
1-6 months.

o Efforts should focus on the home, where 30-60% of time is spent. Patients
should clean and dust their homes regularly. If patients cannot avoid vacuuming, they
should use a face mask or a double-bagged vacuum with a high-efficiency particulate air
filter. Consideration can be given to moving to a higher floor in the house (less dust and
mold) or different neighborhood (fewer cockroaches) if possible. Active smoking and
exposure to passive smoke must be avoided. Room air ionizers have not been proven
effective to help persons with chronic asthma and the generation of ozone by these
machines may be harmful to some. Other factors related to the home include the
following:
 Dust mites (Dermatophagoides pteronyssinus or "dead skin feeders,"
size 30 µm): The primary allergen is an intestinal enzyme on fecal particles. The
allergen settles on fabric because of its relatively large size; therefore, air filtration
is not as important. Measures to avoid dust mites include using impervious covers
(eg, on mattresses, pillows, comforters), washing other bedding in hot water (130°F
[54.4°C] most effective), removing rugs from the bedroom, limiting upholstered
furniture, reducing the number of window blinds, and putting clothing away in
closets and drawers. Minimize the number of soft toys, and wash them weekly or
periodically put them in the freezer. Decrease room humidity (<50%); this is
difficult in hot, humid climates.
 Cats and other animals (dander or saliva, urine, or serum proteins, size
1-20 µm): Because of its small size, this allergen is predominantly an airborne
indoor allergen. Avoidance involves removing animals from the home (or at least
from the bedroom), using dense filtering material over heating and cooling duct
vents, and washing cats and dogs as often as twice weekly.
 Cockroaches (size 30 µm): Twenty percent of homes without visible
infestation still produce sensitizing levels of allergen. Successful allergen elimination
measures are difficult, especially in poor living conditions. To control cockroaches,
exterminate and use poison baits and traps, keep food out of the bedroom, and
never leave food out in the open.
 Wet molds (size 1-150 µm): Avoidance includes keeping areas dry (eg,
remove carpets from wet floors), removing old wallpaper, cleaning with bleach
products, and storing firewood outdoors.
 Pollen (size 1-150 µm): Avoidance includes closing windows and doors,
using air conditioning and high-efficiency particulate air filters in the car and home,
staying inside during the midday and afternoon when pollen counts are highest,
wearing glasses or sunglasses, and wearing a face mask over the nose and mouth
when mowing the lawn. In addition, consider increasing medications preseason and
vacationing out of the area.

 Allergen immunotherapy
o Repeated injections of small doses of allergen have been used for more than 90
years to treat allergic rhinitis. This treatment is clearly effective, and positive effects may
persist even years after treatment is stopped. This treatment is also considered
mandatory for life-threatening bee and wasp sting reactions. The role of repeated
allergen injections in patients with asthma has been more controversial, ranging from a
relative indication to no indication. Benefit has been shown in individuals with allergy-
induced asthma.
o Supporters argue that compliance can be ensured, and evidence shows that the
underlying disease process can be modified or even prevented (eg, preventing asthma in
children with allergic rhinitis).
o In a 2003 review of 75 randomized controlled trials, Abramson et al reported
that immunotherapy decreased asthma symptoms and need for medication. Another
study showed improved PEFR and decreased use of medications in a highly selected
group of children, but only for the first year of therapy.
o The cost may be $800 for the first year and then $170/y thereafter (1996
estimate). No direct comparisons with medical therapy have been made to allow a cost-
benefit analysis.
o Allergen immunotherapy should be considered if specific allergens have a
proven relationship to symptoms; the individual is sensitized (ie, positive skin test or
RAST findings); the allergen cannot be avoided and is present year-round (eg,
industrial); or symptoms are poorly controlled with medical therapy, and a vaccine to the
allergen is available. As discussed above, this treatment is especially useful if asthma is
associated with allergic rhinitis.
o Referral to an allergist is required. The patient must commit to a course of 3-5
years of therapy (although a trial of several months can be considered).

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o Precautions include serious adverse reactions (occurring in 1 per 30-500 people,
usually within 30 min). The estimated crude annual death rate is 0.7 deaths per million
population. Monitoring and resuscitation personnel and equipment are required. Also,
allergen immunotherapy should be avoided if the patient is taking beta-blockers or is
having an asthma exacerbation (ie, PEFR <70% of patient’s personal best) or has
moderate or worse fixed obstruction. A major risk factor for immunotherapy-related
fatalities includes uncontrolled asthma; therefore, appropriate caution should be
exercised.
o Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per
volume (w/v), or protein nitrogen units (PNU), but "major allergen content" may be a
more standardized and reliable method of dosing and characterizing allergen extracts.
o Sublingual immunotherapy has been shown to improve allergic rhinitis
symptoms, but effectiveness compared with the standard injection type is unclear.
Sublingual immunotherapy and allergoids (modified or peptide-associated allergens) are
not currently used in the United States.

 Antibodies to IgE antibody - Omalizumab


o Omalizumab (Xolair) was approved by the FDA in 2003 for adults and
adolescents (>12 y) with moderate-to-severe persistent asthma who have a positive
skin test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are
inadequately controlled with inhaled corticosteroids.
o This is a humanized murine IgG antibody against the Fc component of the IgE
antibody (the part that attaches to mast cell surfaces). Use of this antibody prevents IgE
from binding directly to the mast cell surface, thereby preventing cell degranulation.
o Therapy has been shown to decrease IgE antibody levels by 99% and cell
receptor sites for IgE antibody by 97%. This decrease, in turn, is associated with
reduced histamine production (90%), early-phase bronchospasm (40%), and late-phase
bronchospasm (70%) and a decrease in the number, migration, and activity of
eosinophils. levels drop quickly and remain low for at least a month.
o This therapy is also effective for allergic rhinitis.
o Multiple phase 3 trials show that, compared to placebo injections, treatment is
associated with larger median inhaled steroid dose reduction (83% vs 50%), higher
percentage of discontinuation of inhaled steroids (42% vs 19%), and fewer asthma
exacerbations (approximately 15% vs 30%). Quality of life and use of rescue inhaler and
the emergency department may also be improved. Omalizumab is approved for
reduction of exacerbations.
o Adverse effects are rare and include upper respiratory infection symptoms,
headache, urticaria (2%) without anaphylaxis, and anaphylaxis (0.1%). Transient
thrombocytopenia has also been noted but not in humans. Antibodies are formed against
the anti-IgE antibody, but these do not appear to cause immune-complex deposition or
other significant problems. To date, decreased IgE levels have not been shown to inhibit
one’s ability to fight infection (including parasites). Registration trials raised a question
of increased risk of malignancy, but this has not been seen in the postmarketing data.
o Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial
serum IgE level and body weight. Patients are usually treated for a trial period lasting at
least 12 weeks. Costs may be $12,000/y, so omalizumab is likely to be cost-effective
only in patients with severe persistent asthma who have frequent exacerbations
requiring hospitalization.
Consultations
 Consult a pulmonologist, allergist/immunologist, or both for any of the following:
o Difficulty controlling disease after 3-6 months, including frequent attacks, need
for rescue inhaler (>1 rescue inhaler used per mo), use of oral steroids more than 2
times per year, or step 4 therapy required (or step 2 or higher if aged <3 y)
o Poor quality of life
o Immunotherapy under consideration
o Intensive education needed
o Refractory cough
o Abnormal chest radiograph findings
o Life-threatening asthma exacerbation
o Patient or parent request

 Appropriate referral is needed if significant psychological, social, or family problems are


present.
Diet: aside from avoiding known food allergens or additives, diet is not restricted.
Activity: maintaining physical activity and exercise is essential to avoid deconditioning.
Susceptible individuals should decrease outdoor activity during midday and afternoon when pollen

9
counts are highest. A short-acting beta-2 agonist and/or cromolyn metered-dose inhaler (MDI)
can be used 15-30 minutes before exercise if needed.

MEDICATION
 Anti-inflammatory medications (especially inhaled glucocorticosteroids) are now the mainstay
of therapy and the single most effective therapy for adults with asthma. Anti-inflammatory
medications are proven to improve lung function (ie, FEV 1, AHR) and to decrease symptoms,
exacerbation frequency, and the need for rescue inhalers.
 Short-acting inhaled beta-2 agonists, as needed, are most effective for rapid relief of asthma
symptoms. No benefit and some risk of developing tolerance occur with regular long-term
use. These agents should still be available to the patient, even if he or she is using a long-
acting beta-2 agonist (eg, salmeterol).
 Of note, the list of medications that combine 2 drugs in a single delivery device in an effort to
increase patient convenience and compliance is expanding. These include a combination of
albuterol and ipratropium bromide (Combivent) and a combination of fluticasone and
salmeterol (Advair). Another combination product, composed of formoterol and budesonide
(Symbicort), may be approved in the United States within 2 years.
 Glucocorticoids may increase cell beta-2 agonist receptors, which, in turn, may enhance the
action of the combination products.
 According to the 1998 Leukotriene Working Group, leukotriene pathway modifiers may be
useful as first-line therapy for mild persistent asthma or as an add-on or glucocorticoid-
sparing medication in others. These agents are less effective than glucocorticoid inhalers but
tend to improve compliance because dosing is oral and once daily, and usage appears more
reasonable for those unable or unwilling to take glucocorticoids. Leukotriene synthesis
inhibitors montelukast, zafirlukast, and zileuton are available.
 When adding to a medication regimen for asthma (referred to as stepping up therapy),
consider adding LABA for persistent symptoms with impaired FEV 1. Patients with symptoms
but normal lung function (especially those with symptomatic allergic rhinitis) might benefit
first from a leukotriene pathway modifier. Of course, some patients will ultimately be treated
with both types of medications for optimum management.
 Mast cell stabilizers can also be used. Cromolyn sodium (Intal) indirectly blocks calcium influx
into mast cells, preventing inflammatory mediator release. Adults can use it in an MDI (2-4
puffs 3-4 times daily) or in a nebulized form (1 ampule 3-4 times daily). Because of its safety
profile, this agent is often tried in children; however, it may take a month to work. The
pediatric dose is 1-2 puffs via an MDI 3-4 times daily or 1 ampule via a nebulizer 3-4 times
daily. Cromolyn sodium tends to work best in young and highly allergic patients.
 Nedocromil (Tilade) has similar effects, although it is structurally distinct. The adult dose is
2-4 puffs via an MDI 2-3 times daily. The pediatric regimen is 1-2 puffs via an MDI 2-4 times
daily. MDIs may be used with a spacer as necessary (mask if <2 y). Patients should activate
the MDI while breathing in slowly, and then they should hold their breath for 10 seconds if
possible.
 Using a spacer or holding the inhaler 2 inches from the mouth may improve delivery. The
recent change from chlorofluorocarbon to hydrofluoroalkane propellants with smaller particle
size may help deliver more medication. The only reliable way to determine if the inhaler is
empty is to count the number of doses. Patients should rinse their mouths with water and
spit after glucocorticoid inhaler use to prevent oral thrush and dysphonia. An alcohol-
containing mouthwash may be more effective than water.
 Breath-actuated inhalers are easier to use for less-coordinated individuals. A dry-powder
inhaler (DPI) allows rapid inhalation. These devices also often have built-in dose counters.
 Consider recommending a nebulizer if the patient is younger than 2 years or is unable to use
an MDI or DPI because of cough, severe dyspnea, or poor coordination.
 Additionally, recombinant DNA-derived humanized immunoglobulin G monoclonal antibodies
to IgE are now available to treat moderate-to-severe persistent asthma in patients who react
to perennial allergens and whose symptoms are not controlled by inhaled corticosteroids.
Drug Category: Bronchodilators
Provide immediate relief of bronchospasm. Preferentially (but not exclusively)
bind beta2-adrenergic receptors, resulting in conversion of ATP to cyclic AMP,
relaxation of bronchial smooth muscle, and decreased release of inflammatory
mediators. Anticholinergic agent ipratropium is included here because it has an
additive beneficial effect when given with bronchodilators in acute, severe
asthma.
Drug Name Albuterol (Proventil, Ventolin, Airet)
Beta-agonist. Relaxes bronchial smooth muscle by action on beta-2
Description
receptors with little effect on cardiac muscle contractility.
Adult Dose 4 mg PO q12h; not to exceed 32 mg/d
MDI: 1-2 puffs q4-6h prn; not to exceed 12 puffs/d

10
Nebulizer: 2.5 mg tid/qid
PO
<12 years: 0.3-0.6 mg/kg/d, not to exceed 8 mg/d
>12 years: Administer as in adults
MDI
Pediatric Dose <4 years: Not established
>4 years: Administer as in adults
Nebulizer
2-12 years: 0.1-0.15 mg/kg/dose, not to exceed 2.5 mg tid/qid prn
>12 years: Administer as in adults
Contraindications Documented hypersensitivity
Beta-adrenergic blockers antagonize effects; inhaled ipratropium may
Interactions increase duration of bronchodilation; cardiovascular effects may increase
with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy C - Safety for use during pregnancy has not been established.
Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders;
used regularly during pregnancy; can cause paradoxical bronchospasm;
Precautions
increasing need for this rescue medication may indicate clinical
destabilization that requires medical reevaluation

Drug Name Ipratropium (Atrovent)


DOC for beta-2 agonist-induced bronchospasm. Chemically related to
atropine and has antisecretory properties. Inhibits vagally mediated
Description reflexes by increasing cyclic GMP, causing local bronchial smooth muscle
dilation. Not effective for exercise-induced symptoms. Additive to, but
slower than, effects of beta-2 agonists.
Nebulizer: 1 U dose vial (500 mcg) q30min for 3 doses, then q2-4h prn
Adult Dose
MDI: 4-8 puffs prn initially; not to exceed 12 puffs/d
Nebulizer: 250 mcg q20min for 3 doses, then q2-4h prn
Pediatric Dose
MDI: 4-8 puffs prn initially; not to exceed 6 puffs/d
Contraindications Documented hypersensitivity
Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity;
Interactions
albuterol may increase effects
Pregnancy B - Usually safe but benefits must outweigh the risks.
Not indicated for acute episodes of bronchospasm; caution in narrow-angle
Precautions
glaucoma, prostatic hypertrophy, and bladder neck obstruction

Drug Name Bitolterol (Tornalate); Pirbuterol (Maxair)


Stimulates beta-2 receptors directly to relax bronchial smooth muscle,
Description
relieving bronchospasm and reducing airway resistance.
Bitolterol: 2 puffs q8h prn
Adult Dose
Pirbuterol: 1-2 puffs q4-6h prn
<12 years: Not established
Pediatric Dose
>12 years: Administer as in adults
Contraindications Documented hypersensitivity; tachycardia resulting from cardiac arrhythmia
Beta-adrenergic blockers antagonize effects; inhaled ipratropium may
Interactions increase duration of bronchodilation; cardiovascular effects may increase
with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy C - Safety for use during pregnancy has not been established.
Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders;
can cause paradoxical bronchospasm; increased need for this rescue
Precautions
medication may indicate clinical destabilization that requires medical
reevaluation

Drug Name Metaproterenol (Alupent, Metaprel)


Relaxes bronchial smooth muscle by action on beta2-adrenergic receptors
Description with little effect on cardiac muscle contractility. Generally not recommended
because of excessive cardiac stimulation, especially in high doses.
MDI: 2-3 puffs q3-4h prn
Adult Dose Nebulizer: 0.01 mg/kg; not to exceed 0.3 mL of 5% solution q4h prn
PO: 20 mg tid/qid

11
<6 years: 2 mg/kg/d PO
Pediatric Dose 6-9 years: 10 mg PO tid/qid
>9 years: Administer as in adults
Contraindications Documented hypersensitivity
Beta-adrenergic blockers antagonize effects; inhaled ipratropium may
Interactions increase duration of bronchodilation; cardiovascular effects may increase
with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy C - Safety for use during pregnancy has not been established.
Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders;
can cause paradoxical bronchospasm; increased need for this rescue
Precautions
medication may indicate clinical destabilization that requires medical
reevaluation

Drug Name Terbutaline (Brethaire, Brethine, Bricanyl)


Acts directly on beta-2 receptors to relax bronchial smooth muscle,
Description
relieving bronchospasm and reducing airway resistance.
MDI: 2 puffs q4-6h prn
Adult Dose SC: 0.25 mg
PO: 5 mg tid
<12 years: Not established
Pediatric Dose 12-15 years: 2.5 mg PO tid
>15 years: Administer as in adults
Documented hypersensitivity; tachycardia resulting from cardiac
Contraindications
arrhythmias
Beta-adrenergic blockers antagonize effects; inhaled ipratropium may
Interactions increase duration of bronchodilation; cardiovascular effects may increase
with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy B - Usually safe but benefits must outweigh the risks.
Through intracellular shunting, may decrease serum potassium levels,
Precautions which can produce adverse cardiovascular effects; decrease is usually
transient and may not require supplementation

Drug Name Salmeterol (Serevent)


Long-acting bronchodilator - works by relaxing smooth muscles of
bronchioles and relieving bronchospasms. Effect may also facilitate
expectoration.
Inhaler does not replace anti-inflammatory medications but can be added to
decrease rescue inhaler use. Evening dose may be useful for nocturnal
symptoms. SR PO albuterol has greater systemic sympathomimetic adverse
Description
effects and is considered an alternate therapy only. WARNING: Data from a
large placebo-controlled US study (SMART trial) that compared the safety of
salmeterol or placebo added to usual asthma therapy showed a small but
significant increase in asthma-related deaths in patients receiving
salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus
those on placebo (3 of 13,179).
PO: 4 mg q12h
Adult Dose
MDI: 2 puffs (or 1 blister pack) q12h
PO: 0.3-0.6 mg/kg/d; not to exceed 8 mg
Pediatric Dose
MDI: 1-2 puffs (or 1 blister pack) q12h
Documented hypersensitivity; angina, tachycardia, and cardiac arrhythmia
Contraindications
associated with tachycardia
Concomitant use of beta-blockers may decrease bronchodilating and
vasodilating effects of beta-agonists; concurrent administration with
Interactions methyldopa may increase pressor response; coadministration with oxytocic
drugs may result in severe hypotension; ECG changes and hypokalemia due
to diuretics may worsen
Pregnancy C - Safety for use during pregnancy has not been established.
Not indicated to treat acute asthmatic symptoms; sympathomimetic
responses (tremor, tachycardia) can occur and may be significant in some
Precautions
patients with cardiovascular disease; onset of action can be delayed (does
not preclude need for short-acting bronchodilators)

Drug Name Theophylline (Theo-24, Theolair, Theo-Dur, Slo-bid)

12
Structurally classified as a methylxanthine, it acts as a bronchodilator.
Potentiates exogenous catecholamines and stimulates endogenous
catecholamine release and diaphragmatic muscular relaxation, which, in
Description turn, stimulates bronchodilation.
For bronchodilation, near toxic (>20 mg/dL) levels are usually required.
Less effective than glucocorticoids but may be glucocorticoid-sparing agent.
Routine drug level monitoring required (goal: 5-15 mcg/mL).
10 mg/kg/d (not to exceed 300 mg) PO initially; not to exceed 800 mg/d
Adult Dose
maintenance
<1 year: 0.2 (times age in wk) plus 5 (estimated in mg/kg/d) maximum PO
Pediatric Dose >1 year: 16 mg/kg/d PO; not to exceed 400 mg/d; alternatively, 10
mg/kg/d IV
Documented hypersensitivity; uncontrolled arrhythmia; peptic ulcers;
Contraindications
hyperthyroidism; uncontrolled seizure disorders
Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop
diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin,
isoniazid, and sympathomimetics may decrease effects
Interactions Effects may increase with allopurinol, beta-blockers, ciprofloxacin,
corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine,
carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and
interferon
Pregnancy C - Safety for use during pregnancy has not been established.
Caution in peptic ulcer, hypertension, tachyarrhythmia, hyperthyroidism,
and compromised cardiac function; do not inject IV solution >25 mg/min;
Precautions
patients diagnosed with pulmonary edema or liver dysfunction are at
greater risk of toxicity because of reduced drug clearance

Drug Category: Monoclonal antibodies


Recombinant, DNA-derived agents inhibit IgE binding to the high-affinity IgE receptor on mast
cells and basophils, causing a decrease in release of mediators of the allergic response.
Drug Name Omalizumab (Xolair)

Recombinant, DNA-derived, humanized IgG monoclonal antibody that binds


selectively to human IgE receptor on surface of mast cells and basophils. By
Description inhibiting IgE binding, release of mediators of allergic response is inhibited.
Indicated for moderate-to-severe persistent asthma in patients who react
to perennial allergens in whom symptoms are not controlled by inhaled
corticosteroids.
150-375 mg SC q2-4wk; inject slowly over 5-10 seconds due to viscosity;
Adult Dose not to exceed 150 mg/injection site
Precise dose and frequency established by serum total IgE level (IU/mL)

Pediatric Dose <12 years: Not established


>12 years: Administer as in adults
Contraindications Documented hypersensitivity

Interactions None reported

Pregnancy C - Safety for use during pregnancy has not been established.

Not effective to treat acute asthma; do not abruptly discontinue inhaled


corticosteroids when initiating omalizumab; malignancy rate among treated
Precautions patients (0.5%) was numerically higher than among control patients
(0.2%); malignancies varied, and further long-term observation needed to
fully assess risk; may cause injection-site reaction

Drug Category: Glucocorticoids


Maintenance medications that decrease inflammatory mediators to limit airway remodeling. Must
be taken regularly to be beneficial. Do not relieve acute bronchospasm; short-acting
bronchodilators must be available. The multiple formulations are not equivalent on a per-dose or
per-mcg basis. Inhaled corticosteroids are one of the most important developments in asthma
management because they decrease inflammation. Proven to improve lung function (ie, FEV 1,
airway hyperactivity) and decrease symptoms, exacerbation frequency, and need
for rescue inhalers. Dose ranges as recommended by NHLBI.
Drug Name Beclomethasone (Beclovent, Vanceril)

13
Inhibits bronchoconstriction, produces direct smooth muscle relaxation,
Description decreases number and activity of inflammatory cells, and decreases airway
hyperresponsiveness.
Low dose: 2-6 puffs (84-mcg MDI) or 4-12 puffs (42-mcg MDI)
Adult Dose Medium dose: 6-10 puffs (84-mcg MDI) or 12-20 puffs (42-mcg MDI)
High dose: >10 puffs (84-mcg MDI) or >20 puffs (42-mcg MDI)
Low dose: 1-4 puffs (84-mcg MDI) or 2-8 puffs (42-mcg MDI)
Pediatric Dose Medium dose: 4-8 puffs (84-mcg MDI) or 8-16 puffs (42-mcg MDI)
High dose: >8 puffs (84-mcg MDI) or >16 puffs (42-mcg MDI)

Contraindications Documented hypersensitivity; bronchospasm, status asthmaticus, other


types of acute episodes of asthma

Interactions Coadministration with ketoconazole may increase plasma levels but does
not appear to be clinically significant
Pregnancy C - Safety for use during pregnancy has not been established.

Not for acute attack; weight gain, increased bruising, cushingoid features,
acneiform lesions, mental disturbances, and cataracts may occur (taper
medication slowly if these changes occur); adverse effects include
Precautions dysphonia and oral thrush (minimize by rinsing mouth); long-term high-
dose use may cause osteoporosis, adrenal suppression, or growth
impairment; universally safer than PO steroids and are necessary to avoid
permanent lung damage in some patients with asthma

Drug Name Budesonide (Pulmicort Respules, Pulmicort Turbuhaler, Rhinocort Aqua


Intranasal)
Inhibits bronchoconstriction mechanisms, produces direct smooth muscle
Description relaxation, and may decrease number and activity of inflammatory cells,
which, in turn, decreases airway hyperresponsiveness.
DPI
Adult Dose Low dose: 200-600 mcg
Medium dose: 600-1200 mcg
High dose: 1200 mcg
Inhalation suspension for children
Pediatric Dose Low dose: 0.5 mg
Medium dose: 1 mg
High dose: 2 mg

Contraindications Documented hypersensitivity; bronchospasm, status asthmaticus, other


types of acute episodes of asthma
Interactions None reported

Pregnancy C - Safety for use during pregnancy has not been established.

Weight gain, increased bruising, cushingoid features, acneiform lesions,


mental disturbances, and cataracts may occur (taper medication slowly if
these changes occur); adverse effects include dysphonia and oral thrush
Precautions (minimize by rinsing mouth); long-term high-dose use may cause
osteoporosis, adrenal suppression, or growth impairment; universally safer
than PO steroids and are necessary to avoid permanent lung damage in
some patients with asthma

Drug Name Flunisolide (AeroBid)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle


Description relaxation, and may decrease number and activity of inflammatory cells,
which, in turn, decreases airway hyperresponsiveness.
Low dose: 2-4 puffs
Adult Dose Medium dose: 4-8 puffs
High dose: >8 puffs
Low dose: 2-3 puffs
Pediatric Dose Medium dose: 4-5 puffs
High dose: >5 puffs
Contraindications Documented hypersensitivity: bronchospasm, status asthmaticus, other

14
types of acute episodes of asthma
Interactions None reported

Pregnancy C - Safety for use during pregnancy has not been established.

Weight gain, increased bruising, cushingoid features, acneiform lesions,


mental disturbances, and cataracts may occur (taper medication slowly if
these changes occur); adverse effects include dysphonia and oral thrush
Precautions (minimize by rinsing mouth); long-term high-dose use may cause
osteoporosis, adrenal suppression, or growth impairment; universally safer
than PO steroids and are necessary to avoid permanent lung damage in
some patients with asthma

Drug Name Fluticasone (Flovent)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a


Description weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when
applied topically.
MDI
Low dose: 88-264 mcg
Medium dose: 264-660 mcg
Adult Dose High dose: >660 mcg
DPI
Low dose: 100-300 mcg
Medium dose: 300-600 mcg
High dose: >600 mcg
MDI
Low dose: 88-176 mcg
Medium dose: 176-440 mcg
Pediatric Dose High dose: >440 mcg
DPI
Low dose: 100-200 mcg
Medium dose: 200-400 mcg
High dose: >400 mcg

Contraindications Documented hypersensitivity; bronchospasm, status asthmaticus, other


types of acute episodes of asthma
Interactions None reported

Pregnancy C - Safety for use during pregnancy has not been established.

Weight gain, increased bruising, cushingoid features, acneiform lesions,


mental disturbances, and cataracts may occur (taper medication slowly if
these changes occur); adverse effects include dysphonia and oral thrush
Precautions (minimize by rinsing mouth); long-term high-dose use may cause
osteoporosis, adrenal suppression, or growth impairment; universally safer
than PO steroids and are necessary to avoid permanent lung damage in
some patients with asthma

Drug Name Triamcinolone (Azmacort)

Description Decreases inflammation by suppressing migration of PMN leukocytes and


reversing capillary permeability.
Low dose: 4-10 puffs
Adult Dose Medium dose: 10-20 puffs
High dose: >20 puffs
Low dose: 4-8 puffs
Pediatric Dose Medium dose: 8-12 puffs
High dose: >12 puffs

Contraindications Documented hypersensitivity, bronchospasm, status asthmaticus, other


types of acute episodes of asthma

Interactions Coadministration with barbiturates, phenytoin, and rifampin decreases


effects
Pregnancy C - Safety for use during pregnancy has not been established.

Precautions Weight gain, increased bruising, cushingoid features, acneiform lesions,


mental disturbances, and cataracts may occur (taper medication slowly if

15
these changes occur); adverse effects include dysphonia and oral thrush
(minimize by rinsing mouth); long-term high-dose use may cause
osteoporosis, adrenal suppression, or growth impairment; universally safer
than PO steroids and are necessary to avoid permanent lung damage in
some patients with asthma

Drug Name Prednisone (Deltasone, Orasone)

Immunosuppressant for treatment of autoimmune disorders. May decrease


inflammation by reversing increased capillary permeability and suppressing
Description PMN activity. Goal is lowest dose and shortest duration effective for disease
control. Conversion: methylprednisolone (Medrol) dose equal to four fifths
of desired prednisone dose.
Prednisolone (Prelone, Pediapred) dose equal to prednisone dose.
40-60 mg/d PO for 3-10 d as burst; 5-60 mg/d PO qd or qod for long-term
Adult Dose use prn for disease control; divided doses (20 mg tid) are more effective
than 60 mg qd but are also associated with more adverse effects

Pediatric Dose 1-2 mg/kg/d PO for 3-10 d as burst; not to exceed 60 mg/d; 0.25-2 mg/kg
qd or qod for long-term use prn for disease control
Documented hypersensitivity; peptic ulcer disease, hepatic dysfunction;
Contraindications viral infection, connective tissue infections, fungal or tubercular skin
infections; GI disease
Coadministration with estrogens may decrease clearance; concurrent use
with digoxin may cause digitalis toxicity secondary to hypokalemia;
Interactions phenobarbital, phenytoin, and rifampin may increase metabolism of
glucocorticoids (consider increasing maintenance dose); monitor for
hypokalemia with coadministration of diuretics
Pregnancy C - Safety for use during pregnancy has not been established.

Category C for methylprednisolone and prednisolone; abrupt


discontinuation may cause adrenal crisis; hyperglycemia, edema, weight
Precautions gain, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia,
osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression,
and infections may occur; qod therapy lessens adverse effects

Drug Category: Leukotriene-modifying agents


Consist of leukotriene receptor antagonists (eg, zafirlukast and montelukast) and
synthesis inhibitors (eg, zileuton).
Drug Name Zafirlukast (Accolate), montelukast (Singulair), zileuton (Zyflo)

Description Leukotriene pathway inhibitors. Not for use in acute episodes of asthma.

Zafirlukast: 20 mg PO bid
Adult Dose Montelukast: 10 mg PO qd
Zileuton: 600 mg PO qid

Pediatric Dose <12 years (zafirlukast and zileuton): Not established


>6 years (montelukast): 5 mg PO qd
Contraindications Documented hypersensitivity

Interactions Warfarin and theophylline levels must be followed closely if coadministered


with zafirlukast or zileuton; do not take with food
Pregnancy B - Usually safe but benefits must outweigh the risks.

Category C for zileuton; association with Churg-Strauss vasculitis


Precautions (zileuton), although may be unrelated and only reflect coincidental
corticosteroid withdrawal; monitor liver enzymes; not a bronchodilator;
have appropriate rescue medication available

FOLLOW-UP
Further Inpatient Care
 Consider admission to a hospital if the patient develops refractory symptoms with a
marked decrease in spirometry or borderline oxygenation. Intravenous or oral corticosteroids
(3- to 10-d course) may be required.

16
o A reduced FEV1 or PEFR to less than 50% of the patient’s personal best,
normocapnia or hypercapnia, severe symptoms, or mental status changes warrants
admission to an ICU.
o If the patient responds to therapy, examination findings are normal 1 hour after
the last medication dose, and the FEV1 or PEFR is greater than 70% of patient’s personal
best, consider discharging the patient home on therapy to include oral steroids and
scheduling a follow-up visit within 1 week.
Further Outpatient Care
 Medical office visits should occur every 6-12 months (every 1-6 mo if severe) and should
include the following assessments:
o Reassess severity, compliance, and response to therapy. Consider giving
patients a written questionnaire. (See ACT scorecard.)
o Objectively measure pulmonary function; initially check office spirometry, then
measure peak flow and review peak-flow log at each visit.
o Reinforce inhaler technique and asthma management plan.
o Ensure compliance with environmental avoidance techniques, and consider
additional efforts (add one at a time).
o Consider arranging a home visit to screen for environmental exposures and
assess compliance with avoidance measures.
Prognosis
 Signs that may indicate a poor prognosis (ie, risk factors for death) are as follows:
o Severe exacerbations - Intubation, ICU stay, 2 or more hospitalizations per
year, 3 or more urgent clinic or ED visits per year
o More than 2 short-acting beta-2 agonist MDIs per month
o Glucocorticoid dependence
o Poor patient perception of airflow obstruction
o Significant medical comorbidities
o Psychiatric disease
o Illicit drug use
o Sensitivity to Alternaria species (a mold)

Patient Education
 The American Lung Association has recently endorsed the Asthma Control Test (ACT), a
5-question self-assessment tool for patients. The ACT asks about symptoms experienced
during the previous 4 weeks. Scores of 19 or less (out of a possible 25) suggest inadequate
asthma control worthy of discussion with a physician.

 Patient compliance rates for medications can be as low as 50%. Compliance with
environmental measures, including mattress covers for dust mites, may be even worse.
Physicians and other health care professionals are also at fault, with only 63% of internists
and only 81% of asthma specialists prescribing inhaled glucocorticoids according to
recommended guidelines. In one study, more than 40% of patients did not feel that their
asthma was well-controlled. Education reduces ED visits, but objective evidence for other
outcome measures is limited. Adequate education programs for parents and/or patients
include the following:
o Asthma disease description
o Proper medication use: Take off the cap and shake the inhaler (not needed for
DPI). Breathe out deeply and hold the inhaler with lips pursed around the orifice or as far
as 2 inches from the face or use a spacer. Depress the inhaler concurrent with slow
inspiration. Hold breath for 10 seconds. Repeat until the desired dose is achieved (wait 1
min for short-acting beta-agonists).
o How to identify and control environmental triggers
o Upper airway allergic symptoms: These can be an early warning system for
allergic asthma.
o Written self-management plan according to PEFR, exposure, and symptoms: For
example, a drop below 80% is considered the yellow zone, and additional intervention is
needed; a drop below 50% is considered the red zone (severe exacerbation), and the
patient should seek medical assistance.
o Parents with a history of allergies: These parents should be advised that some
evidence suggests that environmental control measures may potentially prevent
sensitization in their children. Simple but unproven measures include reducing the
number of bedroom carpets, avoiding passive smoke exposure, venting unvented gas
appliances, increasing fish and vegetable intake, and allowing breastfeeding.

MISCELLANEOUS
Medical/Legal Pitfalls

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 Failure to recognize conditions in the differential diagnosis (eg, foreign body aspiration in
a child)

 Failure to provide sufficient treatment for pregnant women

 Failure to provide short-term rescue agents (eg, inhaled beta-2 agonists) and long-term
maintenance medications

 Failure to refer patients whose conditions are refractory to treatment to specialists and
subjecting them to inappropriate long-term treatment (eg, long-term prednisone when
the patient actually has VCD)
Special Concerns
 Patients dependent on glucocorticoids: These individuals should be referred to a
specialist. The goal is the lowest glucocorticoid dose for the shortest duration possible.
Patients must be screened and then referred or treated for complications such as cataracts
(optometry/ophthalmology screening annually) and osteoporosis (bone densitometry,
supplemental calcium and vitamin D at a minimum if not contraindicated). Excluding
problems that can mimic asthma, such as VCD in "refractory" glucocorticoid-dependent
cases, is important. A truncated inspiratory flow-volume loop on pulmonary function tests
suggests possible VCD.

 Infants and children younger than 5 years: Pulmonary function testing is difficult to
perform because cooperation can be limited and reference ranges are not standardized.
Fewer medications have been studied and approved for patients in this age group.

 Elderly patients: These patients frequently have other medical diseases that can mimic
asthma and are more likely to experience adverse effects from asthma medications.

 Pregnant patients: Asthma affects up to 8% of pregnant women, and these patients


should be treated similarly and possibly even more aggressively than other patients, given
the detrimental effects of hypoxia on maternal and fetal outcomes. Generally during
pregnancy, AHR is stable to improved 69% of the time and worse 31% of the time. The
following are specific interventions:
o Theophylline may be associated with drug toxicity in the newborn because of
poor clearance.
o Beclomethasone is an older and therefore better-studied inhaled steroid for use
during pregnancy. However, budesonide is the only inhaled corticosteroid with an FDA
pregnancy rating of B and should, thus, be the drug of choice.
o Systemic glucocorticoids may increase the risk of preeclampsia and decreased
birth weight but should be used if asthma exacerbation is severe because untreated
asthma bears its own risks on the pregnancy.
o Leukotriene pathway medications generally should not be used because of a
lack of safety information, although montelukast is a category B drug.
o Immunotherapy should not be started nor dosage escalated during pregnancy,
given the rare but significant risk of anaphylaxis.

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