Treatment of allergic asthma

Treatment of Allergic Asthma

Henry Lin, MD, Thomas B. Casale, MD

Asthma is a chronic inflammatory disorder of theairways that causes recurrent episodes of wheezing,breathlessness, chest tightness, and coughing, par-ticularly at night or in the early morning. The airwayinflammation also increases bronchial hyperrespon-siveness to a variety of stimuli. After evaluation thatincludes spirometry, patients with intermittentasthma are treated with a short-acting bronchodila-tor on an as-needed basis. Patients with persistentasthma should receive inhaled corticosteroids asfirst-line anti-inflammatory therapy and long-actinginhaled �2-agonists as preferred adjunctive therapy.Leukotriene modifiers can be used as maintenancetherapy in patients with mild persistent asthma, oradded to the regimen of patients with moderate orsevere persistent asthma. In patients with asthmaand concomitant allergic rhinitis, antihistamines maybe useful as adjunctive therapy. Am J Med. 2002;113(9A):8S–16S. © 2002 by Excerpta Medica, Inc.

Despite significant pharmacologic advances inasthma therapy, the past 2 decades have seen analarming increase in the prevalence of asthma

worldwide.1 In the United States alone, asthma affects�14 million individuals. The prevalence of asthma in theadult population is about 5%,2 and the estimated preva-lence in children is 5% to 15%.3 The incidence of asthmain the United States is about 0.2% per year.4 The GlobalInitiative for Asthma defines asthma as a chronic inflam-matory disorder of the airways that causes recurrent epi-sodes of wheezing, breathlessness, chest tightness, andcoughing, particularly at night or in the early morning.1

The airway inflammation also increases bronchial hyper-responsiveness to a variety of stimuli.

MAKING THE DIAGNOSIS

As with any disease, the key to the diagnosis is a detailedmedical history and physical examination. Typical symp-toms of asthma are sudden or recurrent episodes ofcoughing and wheezing and/or shortness of breath,which are often worse at night. Depending on the suscep-tibilities of the individual patient, symptoms may developor worsen in response to exercise, viral infection, changesin the weather, emotional stress, menses, airborne chem-icals, dust, or a variety of allergens, including animal dan-der, house dust mites, and mold. A number of other pre-disposing factors have been identified, including a familyhistory of allergy or asthma,5 presence of bronchial hy-perresponsiveness, atopy, viral respiratory illness,6,7 cig-arette smoking or passive exposure to tobacco smoke,8,9

low socioeconomic status, and African American or His-panic American ethnicity.10,11

The physical examination should focus on assessmentof the upper respiratory tract, chest, and skin. Inspiratoryand expiratory rhonchi and wheezes, a prolonged exha-lation phase, and hyperexpansion of the thorax are typi-cal findings. Depending on the degree of airway obstruc-tion, tachycardia, tachypnea, use of accessory muscles onbreathing, and pulsus paradoxus (an exaggerated de-crease of systolic blood pressure on inspiration) may alsobe observed. Patients with concomitant rhinitis may ex-hibit increased nasal secretions, increased nasal mucosalswelling, and occasionally nasal polyps. Atopic dermatitisor eczema is common, especially in younger patients.

SpirometryThe clinical diagnosis of asthma is made by demonstrat-ing reversible airflow obstruction on spirometry. The fol-lowing parameters are measured before and after the pa-tient inhales a short-acting bronchodilator: forced expi-

From the Division of Allergy/Immunology, Department of Medicine,Creighton University, Omaha, Nebraska, USA.

Requests for reprints should be addressed to Thomas B. Casale, MD,Department of Medicine, Creighton University, 601 North 30th Street,Suite 5850, Omaha, Nebraska 68131. E-mail: [email protected].

8S © 2002 by Excerpta Medica, Inc. 0002-9343/02/$22.00All rights reserved. PII S0002-9343(02)01432-8

ratory volume in 1 second (FEV1), forced vital capacity(FVC), and FEV1/FVC. Clinically significant reversibilityis defined as an increase of �12% and 200 mL in FEV1

after inhalation of a short-acting bronchodilator or aftertreatment with corticosteroids.1 The National AsthmaEducation and Prevention Program guidelines from 1997recommend that spirometry be performed at the initialassessment and after the patient’s symptoms have beenstabilized with medical treatment to document attain-ment of near-normal airway function.12 Spirometryshould then be performed at least every 1 to 2 years there-after to assess maintenance of airway function. A peakflow meter is useful for short-term monitoring, recogniz-ing exacerbations, and daily long-term monitoring by thepatient with moderate to severe persistent asthma.

Carbon Monoxide Diffusing Capacity TestAdditional studies may be needed to rule out other pos-sible diagnoses (Table 1).12 Especially in older smokers,the carbon monoxide diffusing capacity test is helpful fordifferentiating between asthma and emphysema. Patientswith asthma have a normal or elevated diffusing capacity,whereas patients with emphysema have a low diffusingcapacity resulting from the destruction of the alveoli.When spirometry is normal in a patient with a high clin-ical suspicion of asthma, bronchoprovocation withmethacholine or cold-air or exercise challenge is helpfulfor the diagnosis.

Allergy TestingSuch testing and consultation by an allergist/immunolo-gist are helpful in patients with a suspected allergic com-ponent. Once the allergens are identified, further specific

therapies may be instituted, such as allergen avoidance,the administration of antihistamines, or allergen immu-notherapy, in addition to the traditional asthma treat-ments. Patients with asthma, especially those with persis-tent disease, should be questioned about exposure to in-halant allergens. Appropriate skin testing or in vitrotesting can be performed to investigate the possible con-tributions of allergens.

TREATMENT OF ASTHMA

Asthma is classified according to the severity and fre-quency of symptoms. The main goals of asthma therapyare to prevent chronic and troublesome symptoms, tomaintain near-normal pulmonary function, to maintainnormal activity levels, and to prevent recurrent asthmaexacerbations and minimize the need for emergencydepartment visits or hospitalizations.12 A stepped-careapproach is recommended (Tables 2 and 3).13 Regularmonitoring of the patient’s symptoms and pulmonaryfunction is necessary so that once control of asthma isestablished, the dose of medication can be adjusted to theminimal effective dose.

Avoidance of exposure to the offending allergen is themost important step in controlling allergen-inducedasthma. Allergen exposure can cause a worsening ofasthma symptoms. Antihistamines may provide a mildbenefit, especially in patients with concomitant allergicrhinitis. Immunotherapy may be considered when thereis a clear correlation between symptoms and exposure tothe allergens, and when symptoms are chronic and unre-sponsive to pharmacotherapy.12 The duration of immu-notherapy is usually 3 to 5 years. Such therapy is generallynot recommended for patients with severe persistentasthma and FEV1 values �70% of predicted.

Comorbid conditions, such as sinusitis or seasonal al-lergic rhinitis, should also be treated. Coexisting gastro-esophageal reflux should be treated as well, especially inpatients with frequent nocturnal symptoms. Patientswith aspirin sensitivity should avoid taking nonsteroidalanti-inflammatory drugs. In general, individuals withasthma should avoid taking �-blockers. Annual influenzavaccination is recommended for those with persistentasthma.

Short-acting �2-Adrenergic Receptor AgonistsShort-acting �2-receptor agonists, such as albuterol, pir-buterol, bitolterol, metaproterenol, and terbutaline, areindicated for the relief of bronchospasm or for acute ex-acerbations of asthma. The inhalation of a short-acting �-agonist improves pulmonary function within 15 minutes,with the maximum improvement seen in approximately60 to 90 minutes, according to findings in controlled clin-ical trials.14 The therapeutic effect persists for 3 to 4 hoursin most patients and for �6 hours in others. The use of�1 canister in 1 month, or the increasing use of a short-

Table 1. Differential Diagnosis of Asthma12

Adults Children

Postnasal dripGERDCOPDCHFPulmonary hypertensionPulmonary embolismLaryngeal dysfunctionVocal cord dysfunctionMechanical obstruction

of the airwaysEosinophilic infiltration

of lungsDrug-induced coughCarcinoid tumor

Viral bronchiolitisCystic fibrosisBronchopulmonary dysplasiaObliterative bronchiolitisHeart diseaseForeign body in trachea or

bronchusVocal cord dysfunctionVascular ringsLaryngeal websLaryngotracheomalaciaTracheal stenosisBronchostenosisMechanical obstruction of the

airwaysAllergic rhinitisSinusitis

CHF � congestive heart failure; COPD � chronic obstructive pulmo-nary disease; GERD � gastroesophageal reflux disease.

A Symposium: Treatment of Allergic Asthma/ Lin and Casale

December 16, 2002 THE AMERICAN JOURNAL OF MEDICINE� Volume 113 (9A) 9S

Table 2. Stepwise Approach for Managing Infants and Young Children (�5 Years of Age) with Acute or Chronic Asthma

Clinical Features Before Treatment or Adequate Control

Classificationof Severity

Symptoms/Day

Medications Required to Maintain Long-Term ControlSymptoms/Night

Step 4 Continual Daily medicationsSevere persistent Frequent ● Preferred treatment

High-dose inhaled corticosteroids and long-acting inhaled �2-agonists and, if needed, corticosteroid tablets or syrup long term(2 mg/kg/day, generally do not exceed 60 mg/day). Make repeatattempts to reduce systemic corticosteroids and maintaincontrol with high-dose inhaled corticosteroids.

Step 3 Daily ● Preferred treatmentModerate persistent �1 night/wk Low-dose inhaled corticosteroids and long-acting inhaled �2-

agonists or medium-dose inhaled corticosteroids● Alternative treatment

Low-dose inhaled corticosteroids and either leukotriene receptorantagonist or theophylline.

If needed (particularly in patients with recurring severe exacerbations)● Preferred treatment

Medium-dose inhaled corticosteroids and long-acting �2-agonists● Alternative treatment

Medium-dose inhaled corticosteroids and either leukotrienereceptor antagonist or theophylline

Step 2 �2/wk but �1�/day ● Preferred treatmentMild persistent �2 nights/mo Low-dose inhaled corticosteroid (with nebulizer or MDI with

holding chamber with or without face mask or DPI)● Alternative treatment (listed alphabetically)

Cromolyn (nebulizer is preferred or MDI with holding chamber)or leukotriene receptor antagonist

Step 1 �2 days/wk ● No daily medication neededMild intermittent �2 nights/mo

Quick relief, all patients● Bronchodilator as needed for symptoms. Intensity of treatment will depend on severity of exacerbation.

Preferred treatment: short-acting inhaled �2-agonists by nebulizer or face mask and space/holding chamberAlternative treatment: oral �2-agonist

● With viral respiratory infectionBronchodilator every 4–6 hr up to 24 hr (longer with physician consult); in general, repeat no more than once every 6 wk

● Consider systemic corticosteroid if exacerbation is severe or patient has history of previous severe exacerbations● Use of short-acting �2-agonists �2 �/wk in intermittent asthma (daily, or increasing use in persistent asthma) may indicate

the need to initiate (increase) long-term control therapy.

Step down: Review treatment every 1–6 mo; a gradual stepwise reduction in treatment may be possible.Step up: If control is not maintained, consider step up. First, review patient medication technique, adherence, and environmental

control.

Goals of therapy: asthma control● Minimal or no chronic symptoms day or night● Minimal or no exacerbations● No limitations on activities; no school/parent’s work missed● Minimal use of short-acting inhaled �2-agonist (�1 �/day, �1 canister/mo)● Minimal or no adverse effects from medications

(Continued)


10S December 16, 2002 THE AMERICAN JOURNAL OF MEDICINE� Volume 113 (9A)

acting �2-receptor agonist, indicates inadequate controland the need for intensified anti-inflammatory therapy.Short-acting �2-agonists can also be used to preventbronchoconstriction resulting from a variety of stimuli.Common side effects of �2-agonists include tremors, diz-ziness, nervousness, headache, insomnia, and, rarely,bronchospasm.

Long-acting �2-AgonistsLong-acting �2-agonists, such as salmeterol and formot-erol, are indicated for maintenance therapy of asthmaand the prevention of bronchospasm. Drugs in this classare administered twice daily. They are not indicated foran acute exacerbation. The median time to onset of clin-ically significant bronchodilation for salmeterol rangesfrom 30 to 48 minutes. The majority of patients exhibitimprovement by 1 hour. Maximum improvement inFEV1 generally occurs within 180 minutes, and clinicallysignificant improvement continues for 12 hours in mostpatients.15,16 Combination therapy with inhaled cortico-steroids and long-acting �-agonists is now considered thetreatment of choice for patients �5 years with moderateto severe persistent asthma.13 When added to anti-in-flammatory therapy,17 long-acting �-agonists are helpfulin patients with nocturnal symptoms of asthma.18,19 Ad-verse reactions to salmeterol and formoterol includetachycardia, arrhythmias, palpitations, headache,tremor, nervousness, paradoxical bronchospasm, hypo-kalemia, and hyperglycemia.

Inhaled CorticosteroidsInhaled corticosteroids, which possess potent anti-in-flammatory activity, are considered to be the most effec-tive available long-term therapies for persistent asthma,13

whether it is mild, moderate, or severe. This is apparent inTables 2 and 3, which document the stepped-care treat-ment of asthma.13 The estimated comparative daily dos-ages for inhaled corticosteroids in adults and children areprovided in Table 4.13 Inhaled corticosteroids block thelate-phase reaction to allergens, reduce airway hyperre-sponsiveness, and inhibit cytokine production, adhesion

protein expression, and inflammatory cell migration andactivation. The maximum therapeutic benefit may not beachieved for 1 to 2 weeks or longer after initiation oftreatment, although some improvement has been ob-served within the first 24 hours of therapy.20 Inhaled cor-ticosteroids can reduce the need for oral corticosteroidswith their potentially serious side effects. In 1 trial, a highdose of inhaled fluticasone was reportedly as effective asoral prednisone for treating acute asthma exacerba-tions.21

Except in very young children, corticosteroids can beinhaled by means of metered-dose inhalers or dry-pow-der inhalers. In certain instances, dry-powder inhalersoffer better lung deposition, and they are less effort de-pendent. Nebulizers or metered-dose inhalers with spac-ers and face masks are typically used to deliver corticoste-roids to very young children.

Systemic availability. The systemic availability of an in-haled corticosteroid depends on the amount deposited inthe lungs and the oral bioavailability of the portion swal-lowed. In theory, nearly all of the corticosteroid depositedin the lung is absorbed systemically. The systemic effectsof the swallowed corticosteroid depend on its bioavail-ability and metabolism. However, the delivery device caninfluence the bioavailability of the inhaled drug. Using ametered-dose inhaler, approximately 10% to 30% of thedose of inhaled corticosteroid is deposited in the lungs,with the remainder largely deposited in the oropharynxor swallowed. The corticosteroid that is deposited in theoropharynx or the upper airways can produce local ad-verse effects, such as oral candidiasis, dysphonia, and re-flex cough. The risk of oral candidiasis (thrush) can beminimized by using a spacer, less frequent dosing, andrinsing the mouth after inhalation.22 A topical or oralantifungal agent is indicated in the presence of active in-fection. Anywhere from 5% to 50% of patients will de-velop dysphonia associated with vocal stress and in-creased dosage. Treatment involves using a spacer or dry-powder inhaler and giving the vocal cords a rest. Reflex

Table 2. Continued

Notes● The stepwise approach is intended to assist, not replace, the clinical decision making required to meet individual patient needs.● Classify severity: assign patient to most severe step in which any feature occurs.● There are very few studies on asthma therapy for infants.● Gain control as quickly as possible (a course of short systemic corticosteroids may be required); then step down to the least

medication necessary to maintain control.● Provide parent education on asthma management and controlling environmental factors that make asthma worse (e.g.,

allergies and irritants).● Consultation with an asthma specialist is recommended for patients with moderate or severe persistent asthma. Consider

consultation for patients with mild persistent asthma.

DPI � dry-powder inhaler; MDI � metered-dose inhaler.Adapted from Executive Summary of National Asthma Education and Prevention Program Expert Panel Report 2002.13



Table 3. Stepwise Approach for Managing Asthma in Adults and Children �5 Years of Age: Treatment

Clinical Features BeforeTreatment or Adequate Control

Classificationof Severity

Symptoms/Day PEF ov FEV1 Medications Required to MaintainLong-Term ControlSymptoms/Night PEF Variability

Step 4 Continual �60% Daily medicationsSevere persistent Frequent �30% ● Preferred treatment

High-dose inhaled corticosteroids and long-actinginhaled �2-agonists and, if needed, corticosteroidtablets or syrup long term (2 mg/kg/day, generally donot exceed 60 mg/day). Make repeat attempts to reducesystemic corticosteroids and maintain control withhigh-dose inhaled corticosteroids.

Step 3 Daily �60%–�80% ● Preferred treatmentModerate persistent �1 night/wk �30% Low- to medium-dose inhaled corticosteroids and long-

acting inhaled �2-agonists.● Alternative treatment (listed alphabetically)

Increase inhaled corticosteroids within medium-doserange or low- to medium-dose inhaled corticosteroidsand either leukotriene modifier or theophylline

If needed (particularly in patients with recurring severeexacerbations)

● Preferred treatmentIncrease inhaled corticosteroids within medium-dose

range and add long-acting inhaled �2-agonists.● Alternative treatment (listed alphabetically)

Increase inhaled corticosteroids within medium-doserange and add either leukotriene modifier ortheophylline.

Step 2 �2/wk but �1�/day �80% ● Preferred treatmentMild persistent �2 nights/mo 20%–30% Low-dose inhaled corticosteroids

● Alternative treatment (listed alphabetically):Cromolyn, leukotriene modifier, nedocromil orsustained-release theophylline to serum concentration of

5–15 �g/mL

Step 1 �2 days/wk �80% ● No daily medication neededMild intermittent �2 nights/mo �20% ● Severe exacerbations may occur, separated by long periods

of normal lung function and no symptoms. A course ofsystemic corticosteroids is recommended.

Quick relief, all patients● Short-acting bronchodilator: 2–4 puffs short-acting inhaled �2-agonists as needed for symptoms.● Intensity of treatment will depend on severity of exacerbation; up to 3 treatments at 20-minute intervals or a single nebulizer

treatment as needed. Course of systemic corticosteroids may be needed.● Use of short-acting �2-agonists �2�/wk in intermittent asthma (daily, or increasing use in persistent asthma) may indicate

the need to initiate (increase) long-term control therapy.

Step down: Review treatment every 1–6 mo; a gradual stepwise reduction in treatment may be possible.Step up: If control is not maintained, consider step up. First, review patient medication technique, adherence, and environmental

control.Goal of therapy: asthma control● Minimal or no chronic symptoms day or night● Minimal or no exacerbations● No limitations on activities; no school/parent’s work missed● Maintain (near) normal pulmonary function● Minimal use of short-acting inhaled �2-agonist (�1�/day, �1 canister/mo)● Minimal or no adverse effects from medications

(Continued)



cough and bronchospasm can be treated by slowing therate of inhalation, using a spacer, or pretreating with al-buterol.

Growth suppression in children. A possible suppres-sion of linear growth in children with asthma who aretreated with inhaled corticosteroids has received consid-erable attention. Data suggest that there is no effect onfinal adult height.23,24 The clinical implications of osteo-porosis and fracture after the long-term use of inhaledcorticosteroids are still unknown.25,26 Data suggest thatosteoporosis and accelerated bone loss may occur withdoses �1,000 �g/day (beclomethasone equivalent). Con-current calcium supplements (1,000 to 1,500 mg/day)and vitamin D (400 IU/day) are recommended for theprevention and treatment of osteoporosis. Inhaled corti-costeroids can cause dose-related hypothalamic pitu-itary-adrenal axis suppression, in general at doses of�800 �g (beclomethasone equivalent) in adults and�400 �g in children, but the clinical significance of thesebiochemical changes is not clear. Other systemic adverseeffects include skin thinning, ocular hypertension, andcataract formation, with the latter 2 events being rare.

Combination with long-acting �2-agonists. In manypatients, the dose–response curves for inhaled corticoste-roids are relatively steep and then reach a plateau. Addinga long-acting �-agonist to a moderate dose of inhaledcorticosteroids has been shown to improve the FEV1

more than does doubling the dose of the inhaled cortico-steroid.27 A combination of salmeterol and fluticasone iscurrently marketed as salmeterol 50 �g plus fluticasone,100 �g, 250 �g, or 500 �g. The most common adverseevents associated with the combination are headache,throat irritation, hoarseness, and candidiasis.

Oral or Parenteral CorticosteroidsCorticosteroids administered by the oral or parenteralroute exhibit potent anti-inflammatory activity. Onset ofaction depends on the route of administration but gener-ally occurs within 24 hours. The indications for oral cor-ticosteroids are for short-term (3 to 10 days) therapy for

asthma exacerbations or for the prompt control of inad-equately controlled persistent asthma. Oral corticoster-oids reduce the risk of death from asthma exacerba-tions.28 The other indication is for longer-term treatmentof severe persistent asthma in selected patients, but cau-tion is advised because long-term use is associated withsignificant side effects. Side effects of short-term cortico-steroids include reversible abnormalities in glucose me-tabolism, increased appetite, fluid retention, weight gain,mood alteration, hypertension, peptic ulcer, and, rarely,aseptic necrosis of the femur. Long-term use of systemiccorticosteroids is associated with hypothalamic pituitary-adrenal axis suppression, osteoporosis, growth suppres-sion, dermal thinning, hypertension, diabetes, Cushingsyndrome, cataracts, and muscle weakness.

Leukotriene ModifiersLeukotriene modifiers can be used for long-term controland prevention of symptoms in mild persistent asthma oras additional therapy in patients with moderate and se-vere persistent asthma. These agents are also useful intreating exercise-induced asthma. There are 2 classes ofleukotriene modifiers: leukotriene receptor antagonists(e.g., zafirlukast, montelukast) and leukotriene synthesisinhibitors (e.g., zileuton). Leukotriene receptor antago-nists are selective competitive inhibitors of CysLT1 recep-tors. Peak plasma concentrations are achieved within 3hours after dosing. Zileuton inhibits 5-lipoxygenase, theenzyme that catalyzes the formation of leukotrienes fromarachidonic acid. Studies have shown significant im-provement from baseline in FEV1 within 2 hours of ad-ministration. The main side effect of zileuton is elevationof liver enzymes. Therefore, the patient’s liver functionneeds to be monitored. Leukotriene modifiers have beenshown to have both a steroid-sparing (allow steroid re-duction) and a steroid-additive (enhance control oversteroids alone) effect. They are especially useful for aspi-rin-sensitive patients because of the inhibition of the ef-fects of leukotriene D4. The most recent National AsthmaEducation and Prevention Program guidelines recom-mend leukotriene modifiers as alternative therapy to low-

Table 3. Continued

Notes● The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.● Classify severity: assign patient to most severe step in which any feature occurs (PEF is % of personal best; FEV1 is %

predicted).● Gain control as quickly as possible (consider a short course of systemic corticosteroids); then step down to the least medication

necessary to maintain control.● Provide education on self-management and controlling environmental factors that make asthma worse (e.g., allergens and

irritants).● Refer to an asthma specialist if there are difficulties controlling asthma or if step 4 care is required. Referral may be considered

if step 3 care is required.

FEV1 � forced expiratory volume in 1 second; PEF � peak expiratory flow.Adapted from Executive Summary of National Asthma Education and Prevention Program Expert Panel Report 2002.13



dose inhaled corticosteroids in patients with mild persis-tent asthma.13 Recent data indicate that leukotriene mod-ifiers can also inhibit symptoms of concomitant allergicrhinitis.29

Cromolyn Sodium and Nedocromil (Cromones)The mechanisms of action of cromolyn and nedocromilinclude interference with chloride channels,30 stabilizingmast cell membranes, and inhibiting the activation andrelease of mediators from eosinophils and epithelial cells.Cromolyn and nedocromil are indicated for long-termprevention of asthmatic symptoms. They inhibit acuteresponses to exercise, cold dry air, and SO2. Cromolynand nedocromil block both the early and late reaction toallergen. Beneficial effects as maintenance therapy oftenoccur within 2 weeks but may take up to 4 to 6 weeks.These agents can be used as an alternative, albeit less ef-fective, therapy to low-dose inhaled corticosteroids in pa-tients with mild persistent asthma. The main side effect isan unpleasant taste, reported by 15% to 20% of patientsusing nedocromil.

Methylxanthines (Theophylline)Theophylline produces airway smooth muscle relaxationand bronchodilation by means of inhibition of phospho-diesterase and, possibly, the antagonism of adenosine.This drug also increases contractility of the diaphragmand mucociliary clearance. Theophylline is indicated forthe long-term control and prevention of asthmatic symp-toms, especially nocturnal symptoms. It is not generallyrecommended for treating exacerbations, because it of-fers little or no benefit over that achieved with short-acting �-agonists. Theophylline exhibits some steroid-sparing effects. Because this agent has a narrow therapeu-tic index, it is essential to maintain peak levels between 5and 15 �g/mL. Dose-related acute toxicities include nau-sea, vomiting, epigastric pain, hematemesis, diarrhea,headache, irritability, restlessness, insomnia, reflex hy-

perexcitability, muscle twitching, seizures, palpitations,tachycardia, extrasystoles, flushing, hypotension, circula-tory failure, and supraventricular and ventricular tachy-arrhythmias.

Anticholinergic AgentsIpratropium bromide is an anticholinergic (parasympa-tholytic) agent that inhibits vagally mediated reflexes byantagonizing the action of acetylcholine, the transmitteragent released from the vagus nerve. Anticholinergicagents ameliorate acetylcholine-mediated bronchocon-striction and mucus production but are generally less po-tent bronchodilators than �-agonists. Further, ipratro-pium has not demonstrated significant long-term benefitin the management of asthma,31 although when used inaddition to albuterol, it can be useful in treating asthmaexacerbations and status asthmaticus in the emergencyroom.32,33 The main side effects of ipratropium are dry-ness of the oropharynx, cough, and nervousness.

Treatment of Acute Asthma ExacerbationsThe patient with an acute exacerbation of asthma re-quires urgent care and should immediately contact thephysician for instructions. Current guidelines1 for treat-ing acute asthma exacerbations at home recommend, asinitial treatment, the use of an inhaled short-acting �2-agonist by means of a metered-dose inhaler or nebuliza-tion, with or without an inhaled anticholinergic, every 20minutes for 1 hour. Episodes are considered moderate ifthe patient has peak flow values of 60% to 80% and severeif peak flow values are �60%. A good sustained response60 minutes after the last treatment and peak flow values�80% of baseline indicate that the patient can remain athome, given a careful review of an action plan with closemedical follow-up. Oral corticosteroids should bestrongly considered along with a �2-agonist if peak flowvalues are between 60% and 80% of the predicted or per-sonal best. The starting dose of prednisone should be

Table 4. Estimated Comparative Daily Dosages for Inhaled Corticosteroids

Drug

Low Daily Dose Medium Daily Dose High Daily Dose

Adult Child* Adult Child* Adult Child*

Beclomethasone CFC (42 or 84 �g/puff) 168–504 �g 84–336 �g 504–840 �g 336–672 �g � 840 �g � 672 �gBeclomethasone HFA (40 or 80 �g/puff) 80–240 �g 80–160 �g 240–480 �g 160–320 �g � 480 �g � 320 �gBudesonide DPI (200 �g/inhalation) 200–600 �g 200–400 �g 600–1,200 �g 400–800 �g � 1,200 �g � 800 �gInhalation suspension for

nebulization (child dose) 0.5 mg 1.0 mg 2.0 mgFlunisolide (250 �g/puff) 500–1,000 �g 500–750 �g 1,000–2,000 �g 1,000–1,250 �g � 2,000 �g � 1,250 �gFluticasone

MDI: 44, 110, or 220 �g/puff 88–264 �g 88–176 �g 264–660 �g 176–440 �g � 660 �g � 440 �gDPI: 50, 100, or 250 �g/inhalation 100–300 �g 100–200 �g 300–600 �g 200–400 �g � 600 �g � 400 �g

Triamcinolone acetonide (100 �g/puff) 400–1,000 �g 400–800 �g 1,000–2,000 �g 800–1,200 �g � 2,000 �g � 1,200 �g

CFC � chlorofluorocarbon; DPI � dry-powder inhaler; HFA � hydrofluoroalkane; MDI � metered-dose inhaler.* Children �12 years of age.Adapted from Executive Summary of National Asthma Education and Prevention Program Expert Panel Report 2002.13



about 1.0 mg/kg body weight. If the patient does not ad-equately respond to �2-agonist therapy and has peak flowvalues of �60% of the predicted or personal best, pred-nisone should be initiated immediately, with emergencytherapy sought. The extent of care provided at home de-pends on the patient’s (or parent’s) experience with treat-ing an exacerbation, and the availability of medicationsand of emergency care.1 Specific plans for home treat-ment should be based on the patient’s past history ofasthma and his/her risk for asthma-related death. A pa-tient who develops a severe exacerbation and who is athigh risk for asthma-related death should be treated as amedical emergency.

H1 AntihistaminesA growing body of evidence supports an apparent patho-physiologic relation between allergic rhinitis and asthma,although the importance of rhinitis as a risk factor forasthma has not been definitively determined.34 It is inter-esting that both rhinitis and asthma are improved bytreatment with systemic agents, such as antihistaminesalone or in combination with decongestants, leukotrienemodifiers, corticosteroids, or other systemic agents. Ifconfirmed, the relation between asthma and rhinitiswould provide a rationale for the use of certain treat-ments, especially those with systemic benefits.

H1 antihistamines selectively inhibit peripheral H1 re-ceptors, thus blocking histamine’s effects, such as smoothmuscle contraction, increased vascular permeability, andstimulation of parasympathetic nerves. H1 antihista-mines are indicated for treatment of symptoms related toallergic rhinitis. The potential role of antihistamines inasthma has been under investigation for more than half acentury. Some studies have suggested that H1 antihista-mines may have an adjunctive role in patients with aller-gic asthma, especially if used in doses higher than thoserecommended for treatment of allergic rhinitis. Cur-rently, results on the use of H1 antihistamines in asthmaremain inconclusive. Nonetheless, these agents haveshown benefits as adjunctive therapy in patients withconcomitant allergic rhinitis, suggesting that the role ofantihistamines in asthma remains a promising avenue ofresearch.

CONCLUSION

Asthma is a chronic inflammatory disease that requirescareful diagnosis, avoidance of exacerbating factors, andearly and aggressive prevention and treatment with ap-propriate medications. Once the disease is under control,a stepped approach is recommended to achieve effectivemaintenance therapy. The minimum effective dose ofbronchodilator, inhaled corticosteroid, and other agentsshould be chosen to minimize the risk of side effects.Treatment of asthma is a team approach involving pa-tients, family members, nurses, and physicians, with the

goals of obtaining normal daily activity levels and mini-mizing the need for emergency room visits and hospital-izations.

REFERENCES1. National Heart, Lung, and Blood Institute/World Health

Organization (NHLBI/WHO) Workshop Report. Global Initia-tive for Asthma: Global Strategy for Asthma Managementand Prevention. Bethesda, MD: National Institutes ofHealth, 2002. NIH publication 02-3659.

2. Adams PF, Marano MA. Current Estimates from the Na-tional Health Interview Survey,1994. Vital and Health Sta-tistics, series 10; 1995 Hyattsville, MD: US Dept of Healthand Human Services publication PHS 96-1521.

3. Neddenriep D, Schumacher MJ, Lemen RJ. Asthma inchildhood. Curr Probl Pediatr. 1989;19:325–388.

4. McWhorter WP, Polis MA, Kaslow RA. Occurrence, predic-tors, and consequences of adult asthma in NHANESI andfollow-up survey. Am Rev Respir Dis. 1989;139:721–724.

5. Young S, Le Souef PN, Geelhoed GC, et al. The influence ofa family history of asthma and parental smoking on airwayresponsiveness in early infancy. N Engl J Med. 1991;324:1168–1173.

6. Busse WW. The role of respiratory infection in airway hy-perresponsiveness and asthma. Am J Respir Crit Care Med.1994;150:S77–S79.

7. Martinez FD. Viral infections and the development ofasthma. Am J Respir Crit Care Med. 1995;151:1644–1648.

8. Chilmonczyk BA, Salmun LM, Megathlin KN, et al. Associ-ation between exposure to environmental tobacco smokeand exacerbations of asthma in children. N Engl J Med.1993;328:1665–1669.

9. Ehrlich RI, Du Toit D, Jordaan E, et al. Risk factors forchildhood asthma and wheezing: importance of maternaland household smoking. Am J Respir Crit Care Med. 1996;154:681–688.

10. Lang DM, Polansky M. Patterns of asthma mortality inPhiladelphia from 1969 to 1991. N Engl J Med. 1994;331:1542–1546.

11. Beckett WS, Belanger K, Gent JF, et al. Asthma amongPuerto Rican Hispanics: a multiethnic comparison study ofrisk factors. Am J Respir Crit Care Med. 1996;154:894–899.

12. National Asthma Education and Prevention Program. Ex-pert Panel Report 2: Guidelines for the Diagnosis and Man-agement of Asthma. Bethesda, MD: National Institutes ofHealth; 1997. NIH publication 97-4051.

13. Executive Summary of the National Asthma Education andPrevention Program (NAEPP). Expert Panel Report: Guide-lines for the Diagnosis and Management of Asthma—Up-date on Selected Topics 2002. Bethesda, MD: NationalInstitutes of Health; June 2002. NIH publication 02-5075.

14. Barnes PJ. Neural control of human airways in health anddisease. Am Rev Respir Dis. 1986;134:1289–1314.

15. Palmqvist M, Persson G, Lazer L, et al. Inhaled dry-powderformoterol and salmeterol in asthmatic patients: onset ofaction, duration of effect and potency. Eur Respir J. 1997;10:2484–2489.

16. van Noord JA, Smeets JJ, Raaijmakers JA, et al. Salmeterolversus formoterol in patients with moderately severeasthma: onset and duration of action. Eur Respir J. 1996;9:1684–1688.

17. Yates DH, Sussman HS, Shaw MJ, Barnes PJ, Chung KF.Regular formoterol treatment in mild asthma. Effect on



bronchial responsiveness during and after treatment. Am JRespir Crit Care Med. 1995;1523:1170–1174.

18. Fitzpatrick MF, Mackay T, Driver H, Douglas NH. Salmet-erol in nocturnal asthma: a double-blind, placebo-con-trolled trial of a long-acting inhaled beta2-agonist. BMJ.1990;301:1365–1368.

19. Maesen FP, Smeets JJ, Gubbelmans HL, Zweers PG. For-moterol in the treatment of nocturnal asthma. Chest. 1990;98:866–870.

20. Szefler SJ, Boushey HA, Pearlman DS, et al. Time to onsetof effect of fluticasone propionate in patients with asthma.J Allergy Clin Immunol. 1999;103:780–788.

21. Manjra AI, Price J, Lenney W, Hughes S, Barnacle H. Effi-cacy of nebulized fluticasone propionate compared withoral prednisolone in children with an acute exacerbation ofasthma. Respir Med. 2000;12:1206–1214.

22. Selroos O, Halme M. Effect of a volumatic spacer andmouth rinsing on systemic absorption of inhaled cortico-steroids from a metered dose inhaler and dry powder in-haler. Thorax. 1991;46:891–894.

23. Allen DB, Mullen M, Mullen B. A meta-analysis of the effectof oral and inhaled corticosteroids on growth. J Allergy ClinImmunol. 1996;98:S102–S106.

24. Ninan TK, Russell G. Asthma, inhaled corticosteroid treat-ment, and growth. Arch Dis Child. 1992;67:703–705.

25. Jennings BH, Anderson KE, Johansson SA. Assessment ofsystemic effects of inhaled glucocorticosteroids: compari-son of the effects of inhaled budesonide and oral pred-nisolone on adrenal function and markers of bone turnover.Eur J Clin Pharmacol. 1991;40:77–82.

26. Pouw EM, Prummel MF, Oosting H, Roos CM, Ender E.Beclomethasone inhalation decreases serum osteocalcinconcentrations. BMJ. 1991;302:627–628.

27. Greening AP, Ind PW, Northfield M, Shaw G. Added sal-meterol versus higher-dose corticosteroid in asthma pa-tients with symptoms on existing inhaled corticosteroid.Lancet. 1994;344:219–224.

28. Abramson MJ, Bailey MJ, Fiona J, et al. Are asthma med-ications and management related to deaths from asthma?Am J Respir Crit Care Med. 2001;163:12–18.

29. Baki H, Casale TB. The role of leukotrienes in allergicrhinitis: clinical and experimental evidence. Leukotriene ResClin Rev. 2001;2:4–7.

30. Alton E, Norris AA. Chloride transport and the actions ofnedocromil sodium and cromolyn sodium in asthma. JAllergy Clin Immunol. 1996;98:S102–S106.

31. Gross NJ. Ipratropium bromide. N Engl J Med. 1988;319:486–494.

32. Schuh S, Johnson DW, Callahan S, Canny G, Levison H.Efficacy of frequent nebulized ipratropium bromide addedto frequent treatment of children with acute asthma. Pedi-atrics. 1993;22:1842–1846.

33. Reisman T, Galdes-Sebalt M, Kazim F, Canny G, LevisonH. Frequent administration of salbutamol and ipratro-pium bromide in the initial management of severe acuteasthma in children. J Allergy Clin Immunol. 1993;104:1325–1328.

34. Dubuske LB. The link between allergy and asthma. AllergyAsthma Proc. 1999;20:341–345.



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