GUIDELINE SYNTHESIS

Asthma Treatment

Guidelines

1. National Heart, Lung, and Blood Institute (U.S.) (NHLBI). Expert Panel Report 2: guidelines for the diagnosis and management of asthma. Bethesda (MD): U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute; 1997 Jul. 146 p. [79 references]

2. World Health Organization (WHO) and National Heart, Lung, and Blood Institute (U.S.) (NHLBI). Global Initiative for Asthma. Bethesda (MD): Global Initiative for Asthma, National Heart, Lung, and Blood Institute; 1995 Jan (revised 1998). 249 p. [544 references]

3. Institute for Clinical Systems Improvement (ICSI). Diagnosis and management of asthma. Bloomington, MN: Institute for Clinical Systems Improvement; 1999 Jun. 32 p. [28 references]

4. University of Michigan Health System (UMHS). Asthma. Ann Arbor (MI): University of Michigan Health System; 2000 Jan. 14 p. [14 references]

5. American Academy of Allergy, Asthma and Immunology (AAAAI); American College of Allergy, Asthma and Immunology (ACAAI); Joint Council of Allergy, Asthma, and Immunology (JCAAI). Practice parameters for the diagnosis and treatment of asthma. J Allergy Clin Immunol 1995 Nov;96(5 Pt 2):707-870. [1195 references]

INTRODUCTION:

Clinical practice guidelines on asthma issued by NHLBI, WHO/NHLBI, ICSI, UMHS, and AAAAI/ACAAI/JCAAI are compared in the following table. The comparison is restricted to recommendations for treatment of asthma and does not include recommendations concerning diagnosis or other issues. It should be noted that certain recommendations that originated in the NHLBI guideline were subsequently incorporated into the WHO/NHLBI, ICSI, and UMHS guidelines. The WHO/NHLBI guideline extends and interprets NHLBI’s original guideline in a global context. The NHLBI classification scheme for asthma severity and the stepwise approach to pharmacological therapy was also endorsed by ICSI and adapted for use in their medical groups.

Following the content comparison table and discussion, the areas of agreement and differences among the guidelines are identified. In general, the timing of the guideline with respect to available data is an important factor to consider when evaluating areas of differences among guidelines. The rationale behind disparate recommendations that cannot be attributed to the evidence base available and considered during guideline development is also explored in the discussion of areas of differences.

Abbreviations used in the text and tables follow:

· AAAAI, American Academy of Allergy, Asthma and Immunology

· ACAAI, American College of Allergy, Asthma and Immunology

· DPI, dry powder inhaler

· FEV, forced expiratory volume

· ICSI, Institute for Clinical Systems Improvement

· JCAAI, Joint Council of Allergy, Asthma, and Immunology

· MDI, metered dose inhaler

· NHLBI, National Heart, Lung, and Blood Institute

· NSAID, nonsteroidal anti-inflammatory drugs

· PEF, peak expiratory flow

· PEFR, peak expiratory flow rate

· UMHS, University of Michigan Health System

· URI, upper respiratory infection

· WHO, World Health Organization

Note: To print the following large tables, users may have to change their printer settings to landscape, print on legal size paper, and/or use a small font size.

	NHLBI (1997)	WHO/NHLBI (1998)	ICSI (1999)	UMHS (2000)	AAAAI/ACAAI/JCAAI (1995)
OBJECTIVE AND SCOPE	To improve asthma care and the quality of life for patients with asthma and their families.	To facilitate the successful management of asthma; to prevent chronic disability and premature death due to asthma; and to facilitate productive and fulfilling lives for people with asthma. To extend the relevance of and impact of the National Heart, Lung, and Blood Institute's (NHLBI) "International Consensus Report on Diagnosis and Management of Asthma," by adapting the recommendations for the clinical management of asthma in order to ensure their appropriateness throughout the global community. To deliver information to public health officials about the costs of asthma, prevention activities, and education methods; so that they can develop asthma care services and programs responsive to the particular needs and circumstances of their countries. To develop information, recommendations and tools to assist health care professionals and public health officials in appreciating the magnitude of the asthma problem in their countries and in designing and delivering effective asthma management and prevention programs in their communities. To identify areas for future research investigations.	To promote the accurate assessment of asthma severity through the use of objective measures of lung function (spirometry and PEFR). To promote long-term control of persistent asthma through the use of anti-inflammatory drug therapy. To promote the partnership of patients and parents with health care professionals through education and use of written action plans.	To improve the patient's quality of life by achieving and maintaining control of symptoms; attaining normal lung function; minimizing need for as-needed beta2-agonists; avoiding adverse effects from asthma medications; preventing exacerbations; attaining normal activity levels, including exercise; and preventing emergency visits and hospitalizations.	· To provide scientific information to the health care community and foster improvement in the overall quality of the diagnosis and treatment of patients who suffer from asthma.
TARGET POPULATION	United States Infants, children, adolescents, and adults with asthma	International Patients of all ages with asthma	United States Patients 5 years of age and older who present with asthma-like symptoms and/or have been diagnosed with asthma The guideline is intended for treatment of outpatients, not critically ill patients	United States Children, adolescents, and adults with asthma	United States Children, adolescents and adults with asthma
INTENDED USERS	Physicians; Nurses; Nurse Practitioners; Physician Assistants; Health Plans	· Physicians; Nurses; Nurse Practitioners; Health Care Providers; Public Health Departments	· Physicians; Nurses; Nurse Practitioners; Physician Assistants; Allied Health Care Practitioners	· Physicians; Nurses; Nurse Practitioners; Physician Assistants; Respiratory Care Practitioners; Pharmacists	· Physicians (primary care and specialists)
INTERVENTIONS AND PRACTICES CONSIDERED	Periodic assessment and monitoring of signs and symptoms, pulmonary function (spirometry, peak flow monitoring) quality of life/functional status, history of asthma exacerbations, pharmacotherapy, patient-provider communication and patient satisfaction Control factors contributing to asthma severity Pharmacological therapy for managing asthma long term: The stepwise approach to identify minimum amount of medication necessary to maintain control. Long-term medications: Corticosteroids Long-acting beta2-agonists Cromolyn sodium and nedocromil Methylxanthines (theophylline) Leukotriene modifiers Quick-relief medications: Short-acting beta2-agonists Anticholinergics Systemic corticosteroids Management of asthma exacerbations: Beta2-agonist (inhaled) Systemic corticosteroid (moderate-to-severe exacerbations) Oxygen to relieve hypoxia (moderate-to-severe exacerbations) Monitoring response to therapy with serial measurement of lung function Referral to an asthma specialist Patient education	A six-part asthma management program, including the following elements: Assess and monitor asthma severity with both symptom reports and, as much as possible, measurements of lung function (using peak expiratory flow or PEF information). Measurement of arterial blood gases is also considered, especially for patients in the emergency department. Avoid or control asthma triggers: controlling exposure to allergens, pollutants, and pharmacologic agents. Influenza vaccination and specific immunotherapy are also considered. Establish individual medication plans for long-term management. Long-term preventive (controller) medications: Corticosteroids, inhaled and systemic Sodium cromoglycate Nedocromil sodium Sustained-release theophylline Long-acting beta2-agonists; inhaled and oral Ketotifen Antileukotrienes Quick-relief (reliever) medications: Short-acting inhaled beta2-agonists Systemic corticosteroids Inhaled anticholinergics Short-acting theophylline Short-acting oral beta2-agonists Epinephrine/adrenaline injection Traditional methods of healing or therapies (i.e., alternative and complementary medicines) Establish plans for managing exacerbations: including assessment of the severity of the exacerbation, and: Home management of exacerbations: action plan and treatment including bronchodilators and corticosteroids; and additional care (continued medications). Hospital-based management of exacerbation: including assessment of the patient; treatment (including oxygen, beta2-agonists, epinephrine, additional bronchodilators, and corticosteroids); and considerations of other treatments. Provide regular follow-up care. Educate patients to develop a partnership in asthma management.	Chronic management of asthma with interval evaluation, including history and physical examination, measurement of pulmonary function, PEFR. Step care of pharmacologic treatment: Control of asthma symptoms with the least amount of medication necessary. Long term medications include: Systemic corticosteroids Cromolyn and nedocromil Long-active beta2-agonists Methylxanthines (theophylline) Leukotriene modifiers Management of acute asthma 1. Emergency care Beta-agonists Corticosteroids 2. Home-based care Beta-agonists (inhaled) Corticosteroids (inhaled or oral) Cromolyn/ nedocromil Leukotriene modifiers Antibiotics for bacterial infection Consultation with an asthma specialist Patient education	Education of patients to develop a partnership in asthma management Assessment of asthma severity with objective measures of lung function (PEFR monitoring) Avoidance or control of asthma triggers: Indoor allergens (domestic mites, animal allergens, cockroach allergens, fungi, occupational allergens and irritants) Outdoor allergens (pollens, molds) Food additives (sulfites, tartrazine [yellow dye], parabens, monosodium glutamate) Indoor air pollution (tobacco or other smoke, air pollutants) Medications (aspirin, NSAIDs, beta-blockers) Exercise Concurrent medical conditions: infections [e.g., viral upper respiratory infection, bronchitis, sinusitis]; allergic rhinitis; gastroesophageal reflux disease Establishment of medication plans for chronic management Anti-inflammatory medications: Inhaled corticosteroids Systemic corticosteroids: Leukotriene modifier agents: Non-steroidal drugs with anti-inflammatory properties (mast cell stabilizers) Bronchodilator medications: Inhaled, short-acting beta2-agonists Inhaled, long-acting beta2-agonists Methylxanthines Anticholinergics Use of bronchodilators: pediatric considerations and home nebulizers Establishment of plans for managing exacerbations Regular follow-up care and consideration of consultation or referral	Classification of asthma severity Environmental avoidance Airborne triggers Food hypersensitivity Pharmacotherapy Beta-adrenergic agonist bronchodilators Theophylline Anticholinergic agents Antihistamines Cromolyn and nedocromil Corticosteroids Hydration and pharmacomucolytic agents Alternative therapy (troleandomycin, methotrexate, gold and intravenous globin therapy) Antibiotics for bacterial infection Polypharmacy Influenza immunization for patients with moderately severe or severe asthma Allergen immunotherapy Management of severe acute intractable asthma Administration of oxygen Use of beta2-agonists (sympathomimetics) Use of corticosteroids Monitoring blood levels and cardiopulmonary function after administration of aminophylline/ theophylline Fluid hydration and danger of overhydration Possible need for mechanical ventilation and intubation Consultation with an asthma specialist Patient education
TREATMENT RECOMMENDATIONS
	NHLBI (1997)	WHO, NHLBI (1998)	ICSI (1999)	UMHS (2000)	AAAAI, ACAAI, JCAAI (1995)
Goals of Asthma Therapy	The goals of therapy are as follows: Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness in the night, in the early morning, or after exertion) Maintain (near) "normal" pulmonary function Maintain normal activity levels (including exercise and other physical activity) Prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations Provide optimal pharmacotherapy with minimal or no adverse effects Meet patients’ and families’ expectations of, and satisfaction with, asthma care	The primary goal of asthma management is to achieve control of asthma, which is defined as: Minimal (ideally no) chronic symptoms, including nocturnal symptoms Minimal (infrequent) exacerbations No emergency visits Minimal (ideally no) need for p.r.n. (as needed) beta2-agonist No limitations on activities, including exercise Peak expiratory flow (PEF) circadian variation of less than 20 percent (Near) normal PEF Minimal (or no) adverse effects from medicine Additional goals include: Prevention of development of irreversible airflow limitation Prevention of asthma mortality	The goal of managing patients with acute asthma exacerbation is prompt evaluation and treatment to improve symptoms in the short term, prevent recurrence of symptoms and provide for follow-up. The aim of pharmacological therapy is to achieve and maintain control of chronic asthma using the least amount of medication necessary and hence minimizing the risk for adverse effects.	Goals of treatment include: Symptomatic relief Normalization of lung function. Minimization of need for as needed beta2-agonists Avoidance of adverse effects from asthma medication Prevention of exacerbations Attainment of normal activity levels, including exercise Prevention of emergency visits and hospitalizations Patient self-management, including ability to measure their peak expiratory flow rate (PEFR) at home and modify their therapy or seek help based on their performance relative to their personal best peak flow value.	Individualized treatment aimed at the following outcome goals: Reduction in emergency care Reduction in hospitalization Prevention of nocturnal symptoms Tolerance of physical activity appropriate for the patient’s age Improvement in pulmonary function Minimization of time lost from work, school, and daily activities Improved self-image based on a full understanding of the disease and confidence in outlined approaches to treatment Optimal control of asthma with the use of the least amount of medication possible, administered in a manner that permits the most normal lifestyle, and is associated with minimal side effects General improvement in patients’ quality of life
Asthma Trigger Avoidance	Allergens Reduce or eliminate exposure to allergen(s) the patient is sensitive to, including: Animal dander: Remove animal from home or: keep pet out of patient’s bedroom, keep door closed, consider placing dense filtering material over forced air outlets, either remove upholstered furniture or try to keep pet away from them. House-dust mites: Essential control measures include encasing bed mattress in allergen-impermeable cover, encase pillow likewise or wash weekly, and wash sheets and blankets on patient’s bed weekly in hot water (>130° F). Desirable control measures: reduce indoor humidity to <50%; remove carpets from bedroom, avoid sleeping or lying on upholstery; remove carpets laid on concrete. Cockroaches: Use poison bait or traps to control. Do not leave food or garbage exposed. Pollens and outdoor molds: Stay indoors with windows closed during allergy season, especially during afternoon. Indoor mold: Fix leaks and eliminate water sources associated with mold growth; clean moldy surfaces. Consider reducing indoor humidity to <50%. Indoor/Outdoor Pollutants and Irritants Tobacco Smoke: advise patients and others in the home to stop smoking or smoke outside the home Discuss ways to reduce exposure to the following: Wood-burning stoves or fireplaces Unvented stoves or heaters Other irritants (e.g., perfumes, cleaning agents, sprays) Other Factors That Can Influence Asthma Severity Aspirin sensitivity: patients who have experienced a reaction to aspirin or other NSAIDs should be advised to use alternative medications Non-selective beta-blockers should be avoided Sulfite sensitivity: patients with asthma symptoms associated with shrimp, dried fruit, beer, wine, or processed potatoes should avoid these products Annual influenza vaccinations are recommended for patients with persistent asthma Rhinitis/sinusitis and gastroesophageal reflux are often associated with asthma	Avoidance or Control of Asthma Triggers Domestic mites: Mattresses, box springs, and pillows should receive allergen-proof casing. Bed linens and blankets should be washed once a week in hot water (> 55° C). Ideally, carpets should be replaced with vinyl or polished wooden floor boards. If carpet cannot be removed, cover with polyethylene sheeting. Children’s soft toys should be removed, washed in hot water, or deep frozen once a week. Fabric-covered furniture should be eliminated. Maintaining low humidity (< 50%) with dehumidifiers or air conditioning is desirable. Animal allergens: Animals should be removed from home or, at minimum, from sleeping area. Washing cat fur weekly appears to reduce allergen load. Cockroaches: Control by regular cleaning and pesticides. Asthmatic persons should not be present when spray is used. Fungi: Remove or clean mold-laden objects. Maintain low humidity (< 50%) and clean dehumidifier frequently. Air conditioning is also recommended. In tropical and subtropical climates fungi may grow on walls; they should be tiled or cleaned as necessary. Outdoor allergens (pollen and mold spores): Reduce exposure by closing windows and doors, remaining indoors when pollen and mold counts are highest, and using air conditioning if available. Viral respiratory infections: Primarily cause asthma in children and are difficult to avoid. Indoor air pollutants: Avoid passive and active smoking. Parents of asthmatics should be advised to not smoke and not allow smoking in rooms their children use. Vent all furnaces to the outdoors, maintain heating systems adequately. Gas appliances should have sufficient flues or ducts. Avoid wood smoke, household sprays, and volatile organic compounds (e.g. polishes and cooking oils). Outdoor air pollutants: Pollutants such as ozone, nitrogen oxides, acidic aerosols, and particulate matter can reach intense local concentrations in defined geographic areas. During such episodes, patients are advised to avoid unnecessary physical activity, avoid smoking and smoke-filled rooms, avoid exposure to dust and other irritants, avoid exposure to respiratory infectious agents, and try to stay indoors in a clean environment. If possible, leave polluted area temporarily. Avoid occupational exposures Food avoidance: Foods containing sulfites should be avoided by sensitive patients. Specific food allergies may occur in children and must be diagnosed carefully before food avoidance is recommended. Avoidance of certain drugs: Aspirin and other NSAIDs should be avoided by patients with a history of reacting to these agents. Beta-blocker drugs should not be used by patients with asthma. Influenza vaccination: Asthma patients might be advised to receive this vaccination to avoid respiratory illness. Concomitant Conditions That May Influence Asthma Severity Rhinitis, sinusitis, and nasal polyps: These upper airway disorders may increase asthma severity. Gastroesophageal reflux: Condition commonly found in asthma patients.	Asthma Triggers Viral respiratory infections Environmental allergens Exercise, temperature, humidity Occupational and recreational allergens or irritants Environmental irritants (perfume, tobacco smoke, wood-burning stoves) Drugs (aspirin, NSAIDs, beta-blockers) and food (sulfites) Asthma triggers are mentioned in the context of diagnosis of asthma and interval evaluation. The stepwise approach calls for patient education regarding appropriate environmental control measures to avoid exposure to known allergens and irritants. Specific recommendations on avoidance of triggers in patients diagnosed with asthma are not presented.	Measures for avoiding or controlling asthma triggers: House dust mites. Effective mite control measures include washing (every 1-2 weeks) bedding materials in hot water to denature mite allergens, encasing the mattress and box spring, reducing humidity to less than 50% and treating carpets and furniture with acaricides (to kill dust mites) or tannic acid (to denature dust mite allergen). Mite-allergic patients should avoid the environment when it is being cleaned or vacuumed as this causes dispersion of allergen. Warm-blooded pets (especially cats, but also including dogs, rodents, and birds). Remove animals from the patient’s environment. The perceived benefit may not be immediate because animal allergens may linger for months after animal removal. Occupational trigger exposure. PEFR monitoring on and off the job and Material Safety Data Sheets can help identify occupational triggers. Outdoor allergens (pollens and molds): Reduce exposure by closing windows and doors and by using air-conditioning and filtering devices, especially during peak pollen and mold seasons. Food triggers. Avoid food triggers, such as sulfites, the yellow dye tartrazine, parabens, and monosodium glutamate. Be educated in self-administration of epinephrine for inadvertent food exposures. Indoor air pollution. Avoid tobacco smoke, smoke from wood stoves or heating, aerosols, household sprays, volatile organic compounds, strong odors and scents, and air pollutants. Medications. In certain patients aspirin and NSAIDs can cause severe exacerbations, but may be useful for those without contraindications. Exercise. Anti-inflammatory therapy often results in the disappearance of exercise-induced symptoms. The inhalation of a beta2-agonist 10 to 20 minutes before exercise is often the most effective means of preventing exercise-induced asthma exacerbations. Cromolyn inhalers and oral montelukast are also of demonstrated efficacy for exercise-induce asthma. Training and sufficient warm up also reduce the incidence and severity of exercise-induced asthma. Concurrent medical conditions Concurrent medical conditions that can exacerbate asthma include infections (e.g., viral upper respiratory infections, bronchitis, sinusitis), allergic rhinitis, and gastroesophogeal reflux disease.	Airborne Triggers House-dust mites Cockroaches Domestic animals Tree, grass, and weed pollen Molds and fungi Nonallergic environmental triggers (tobacco smoke, chemical irritants, or strong odors) Recommendations to minimize exposure: Minimize house-dust mite exposure in mite-allergic patients with asthma Lessen exposure to domestic animals Do not allow smoking in the home Avoid strong odors and chemical fumes Install kitchen and bathroom exhaust fans Use humidifiers with caution in homes with mite- and mold-sensitive patients Use air conditioners in bedrooms and family rooms when appropriate Use high-efficiency particulate air filters or electrostatic air purifiers Install a dehumidifier and reduce water entry in damp basements Initiate other measures for specific allergies as appropriate Food Allergies Evaluation of food hypersensitivity should be considered in patients with chronic symptoms Other Factors That Can Influence the Severity of Asthma Concomitant conditions (obesity, sleep apnea, tuberculosis, diabetes, hyperthyroidism, Addison’s disease, hypertension and heart disease, peptic ulcer, gastritis, and esophagitis, fixed obstructive disorders, bronchiolitis obliterans) Anaphylaxis – may be induced by food, insect venom, allergenic extracts or drugs such as beta-blockers Nasal and sinus disease (sinusitis, nasal polyps) Gastroesophageal reflux Aspirin/NSAID/ preservative sensitivity (preservatives include sulfites, Azo dyes and monosodium glutamate)
Allergen Immunotherapy	Allergen Immunotherapy may be considered for asthma patients when: There is clear evidence of relationship between symptoms and exposure to an unavoidable allergen to which the patient is sensitive Symptoms occur all year or during a major portion of the year There is difficulty controlling symptoms with pharmacologic management For safety reasons, immunotherapy should only be performed in a physician’s office where facilities and personnel are available to treat a rare, but possible, life-threatening reaction.	Allergen Immunotherapy May be considered when avoiding allergens is not possible or when appropriate medication is not available or fails to control asthma symptoms. Can be dangerous and should only be performed by health care professionals especially trained for this form of treatment. Factors to be considered when comparing immunotherapy to other therapies: Potential severity of allergic asthma to be treated Efficacy of available immunotherapy Cost and availability of each type of treatment Risk of morbidity and mortality due to asthma compared to the risk of the treatments To minimize risk and improve efficacy, the following suggestions are made: Patients with multiple allergen sensitivities and/or nonallergic triggers may not benefit from specific immunotherapy Specific immunotherapy is more effective in children and young adults than later in life Patient should be asymptomatic at time of injections because lethal and adverse reactions more often occur in patients with severe airflow limitation. Patients should remain in provider’s office under close supervision for 30 minutes following administration of the allergen extract. FEV or PEV1 with pharmacological treatment should be > 70% of predicted value for both efficacy and safety reasons.	Allergen immunotherapy is not addressed.	Desensitization injections (allergy shots) are not indicated for most patients, but they may have a place in the management of a subset of selected patients with extrinsic (allergic) asthma.	Allergen Immunotherapy Allergen immunotherapy can be effective in patients with asthma and may lessen the effect of chronic allergen stimulation on hyperresponsive airways Allergen immunotherapy should be considered a long-term therapeutic modality. It should be part of a well-planned program that includes pharmacotherapy and avoidance measures Patient compliance is essential for effective and safe application Immediate and delayed local and systemic reactions may occur in the course of allergen immunotherapy; patients should be informed of the relative risks. Patients and medical personnel should be instructed in detail about prevention and treatment of reactions to allergen immunotherapy
Assessment of Asthma Severity	The NHLBI stepwise classification scheme considers clinical features before treatment: Step 4: Severe Persistent Continual symptoms Limited physical activity Frequent nighttime symptoms Frequent exacerbations FEV1 or PEF <60% predicted PEF variability >30% Step 3: Moderate Persistent Daily symptoms Daily use of inhaled short-acting beta2-agonist Exacerbations affect activity Exacerbations >2 times a week; may last days Nighttime symptoms >1 time a week FEV1 or PEF >60% - < 80% predicted PEF variability >30% Step 2: Mild Persistent Symptoms >2 times a week but <1 time per day Exacerbations may affect activity Nighttime symptoms >2 times per month FEV1 or PEF >80% predicted PEF variability 20-30% Step 1: Mild Intermittent Symptoms <2 times per week Asymptomatic and normal PEF between exacerbations Exacerbations brief (from a few hours to a few days); intensity may vary Nighttime symptoms <2 times per month FEV1 or PEF >80% predicted PEF variability <20%	From NHLBI Expert Panel Report 2: Step 4: Severe Persistent Continual symptoms Limited physical activity Frequent nighttime symptoms Frequent exacerbations FEV1 or PEF < 60% predicted FEV1 or PEF variability > 30% Step 3: Moderate Persistent Daily symptoms Daily use of inhaled short-acting beta2-agonist Exacerbations affect activity and sleep Nighttime symptoms > 1 time a week FEV1 or PEF > 60% - < 80% predicted FEV1 or PEF variability > 30% Step 2: Mild Persistent Symptoms > 2 times a week but < 1 time per day Exacerbations may affect activity and sleep Nighttime symptoms > 2 times per month FEV1 or PEF > 80% predicted FEV1 or PEF variability 20-30% Step 1: Mild Intermittent Intermittent symptoms < 1 time per week Asymptomatic and normal lung function between exacerbations Exacerbations brief (from a few hours to a few days) Nighttime symptoms < 2 times per month FEV1 or PEF > 80% predicted FEV1 or PEF variability < 20%	From NHLBI Expert Panel Report 2: Step 4: Severe Persistent Continual symptoms Limited physical activity Frequent nighttime symptoms Frequent exacerbations FEV1 or PEF < 60% predicted PEF variability > 30% Step 3: Moderate Persistent Daily symptoms Daily use of inhaled short-acting beta2-agonist Exacerbations affect activity Exacerbations >2 times a week; may last days Nighttime symptoms <1 time a week FEV1 or PEF > 60% - <80% predicted PEF variability >30% Step 2: Mild Persistent Symptoms >2 times a week but <1 time per day Exacerbations may affect activity Nighttime symptoms >2 times per month FEV1 or PEF >80% predicted PEF variability 20-30% Step 1: Mild Intermittent Symptoms < 2 times per week Asymptomatic and normal PEF between exacerbations Exacerbations brief (from a few hours to a few days); intensity may vary Nighttime symptoms < 2 times per month FEV1 or PEF > 80% predicted PEF variability < 20%	Adapted from the NHLBI Expert Panel Report 2: Step 4: Severe Persistent Continual symptoms Limited physical activity Frequent nighttime symptoms Frequent exacerbations FEV1< 60% predicted PEF diurnal variability >30% Step 3: Moderate Persistent Daily symptoms Daily use of short-acting B2-agnoist Exacerbations affect activity, sleep Nighttime symptoms > 1/week FEV1> 60% but less than 80% predicted PEF diurnal variability >30% Step 2: Mild Persistent Symptoms >2/week but < 1/day Exacerbations may affect activity and sleep Nighttime symptoms > 2/month FEV1 > 80% predicted PEF diurnal variability 20-30% Step 1: Mild Intermittent Symptoms <2 times per week asymptomatic, normal lung function between exacerbations Brief exacerbations Nighttime symptoms <2/month FEV1 >80% predicted PEF diurnal variability <20%	There is no recommended classification scheme, because of difficulty in applying one toward an individualized treatment approach. Instead, the following characteristics of asthma that deserve consideration in assessment of asthma severity are discussed: Symptoms – can be ranked on the basis of duration throughout the day or night, as well as persistence throughout the week Restriction of activity – can be based on inability to work or attend school, as well as how many days per week or month the restriction is present Pulmonary function tests – can be used to assess severity of asthma based on the predicted normal value or patient’s best attainable value Nonspecific bronchial hyperresponsiveness Hospitalization and emergency care visits Medication use
Long-Term Pharmacologic Treatment for Patients Older Than 5 Years (preferred treatments are in bold type)	Stepwise Approach Step 4: Severe Persistent Daily medications: Anti-inflammatory; inhaled corticosteroid (high dose) Long-acting bronchodilator; either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting beta2-agonist tablets and Corticosteroid tablets or syrup long term (2 mg/kg/day, generally do not exceed 60 mg per day) Step 3: Moderate Persistent Daily medication: Anti-inflammatory: inhaled corticosteroid (medium dose) or Inhaled corticosteroid (low-medium dose) and add a long-acting bronchodilator, especially for nighttime symptoms: either long-acting inhaled beta2-agonist, sustained release theophylline, or long-acting beta2-agonist tablets If needed: anti-inflammatory inhaled corticosteroids (medium-high dose) and Long-acting bronchodilator, especially for nighttime symptoms; either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting beta2-agonist tablets Step 2: Mild Persistent One daily medication: Anti-inflammatory: either inhaled corticosteroid (low doses) or cromolyn or nedocromil (usually begun in children) Sustained-release theophylline to serum concentration of 5-15 mcg/ml is an alternative, but not preferred, therapy. Zafirlukast or zileuton may also be considered for patients > 12 years of age, although their position in therapy is not fully established. Step 1: Mild Intermittent No daily medication needed Review treatment every 1-6 months; a gradual stepwise reduction in treatment may be possible. If control is not maintained, consider stepwise increase in treatment. First review patient medication technique, adherence and environmental control (avoidance of allergens or other factors that contribute to asthma severity).	Based on NHLBI Expert Panel Report 2: Stepwise Approach Step 4: Severe Persistent Daily medications: Anti-inflammatory; inhaled corticosteroid (high dose) Long-acting bronchodilator; either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting beta2-agonist tablets and Oral corticosteroid tablets or syrup long term in lowest possible dose (alternate or single daily dose after a 3- to 7-day burst) Step 3: Moderate Persistent Daily medication: Anti-inflammatory: inhaled corticosteroid (medium dose, 800-2000 mcg) or Inhaled corticosteroid (low-medium dose, 800-2000 mcg) and add a long-acting bronchodilator, especially for nighttime symptoms: either long-acting inhaled beta2-agonist, sustained release theophylline, or long-acting beta2-agonist tablets or syrup (long acting beta2-agonist may provide more effective symptom control when added to low-medium dose steroid compared to increasing the steroid dose) Consider adding anti-leukotriene, especially for aspirin-sensitive patients and for preventing exercise-induced bronchospasm. Step 2: Mild Persistent One daily medication: Anti-inflammatory: either inhaled corticosteroid (low doses, 200-500mcg) or cromolyn or nedocromil (usually begun in children) Sustained-release theophylline to serum concentration of 5-15 mcg/mL is an alternative, but not preferred, therapy. If needed, increase inhaled corticosteroids. If inhaled corticosteroids currently equal 500 mcg, increase the dosage to 800 mcg or add long-acting bronchodilator (especially for nighttime symptoms): either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting oral beta-agonist. Anti-leukotrienes may be considered, but their position in therapy has not been fully established. Step 1: Intermittent No daily medication needed. Review treatment every 3 to 6 months. If control is sustained for at least 3 months, a gradual stepwise reduction in treatment may be possible. If control is not achieved, consider step-up. But first: review patient medication technique, compliance, and environmental control (avoidance of allergens or other trigger factors).	Based on NHLBI Expert Panel Report 2: Stepwise Approach Step 4: Severe Persistent Daily medications: Anti-inflammatory; inhaled corticosteroid (high dose) Long-acting bronchodilator; either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting beta2-agonist tablets and Corticosteroid tablets or syrup long term (2 mg/kg/day, generally do not exceed 60 mg per day). Step 3: Moderate Persistent Daily medication: Anti-inflammatory: inhaled corticosteroid (medium dose) or Inhaled corticosteroid (low-medium dose) and add a long-acting bronchodilator, especially for nighttime symptoms: either long-acting inhaled beta2-agonist, sustained release theophylline, or long-acting beta2-agonist tablets. If needed: Anti-inflammatory inhaled corticosteroids (medium-high dose) and Long-acting bronchodilator, especially for nighttime symptoms; either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting beta2-agonist tablets. Step 2: Mild Persistent One daily medication: Anti-inflammatory: either inhaled corticosteroid (low doses) or cromolyn or nedocromil (usually begun in children) Sustained-release theophylline to serum concentration of 5-15 mcg/ml is an alternative, but not preferred, therapy. Zafirlukast or zileuton may also be considered for patients > 12 years of age, although their position in therapy is not fully established. Step 1: Mild Intermittent No daily medication needed Review treatment every 1-6 months; a gradual stepwise reduction in treatment may be possible. If control is not maintained, consider stepwise increase in treatment. First review patient medication technique, adherence and environmental control (avoidance of allergens or other factors that contribute to asthma severity).	Adapted from the NHLBI Expert Panel Report 2: Stepwise Approach Step 4: Severe Persistent Daily medications: Anti-inflammatory: inhaled corticosteroids, 800-2000 mcg and Long-acting bronchodilator; either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting beta2-agonist tablets (inhaled beta2-agonists preferred due to lower toxicity) and Corticosteroid tablets or syrup long term (2mg/kg/day, max 60 mg/day) Step 3: Moderate Persistent Daily medication: Either Anti-inflammatory: inhaled corticosteroid (medium dose) or Inhaled corticosteroid (low-medium dose) and add a long-acting bronchodilator, especially for nighttime symptoms: either long-acting inhaled beta2-agonist, sustained-release theophylline, or long-acting beta2-agonist tablets If needed: Anti-inflammatory: inhaled corticosteroids (medium-high dose) and Add a long-acting bronchodilator, especially for nighttime symptoms either long-acting inhaled beta2-agoinst, sustained-release theophylline, or long-acting beta2-agonist tablets. Step 2: Mild Persistent Daily medications: Anti-inflammatory; either inhaled corticosteroid, 200-400 mcg, cromolyn sodium, or nedocromil (children begin with trial of cromolyn or nedocromil). Sustained-release theophylline to serum concentration of 5-15 mcg/mL is an alternative, but not preferred, therapy. Zafirlukast or zileuton may also be considered for patients >12 years of age; Montelukast may be used in patients >6 years of age, although their position in therapy is not fully established. Step 1: Mild Intermittent None needed	Inhaled beta2-agonists, preferable to oral beta2 agonists in the treatment of chronic asthma because they have a rapid onset of action, are generally more effective than other routes of administration, and infrequently produce adverse reactions. Inhaled beta2-agonists may be more effective when administered on an as-needed basis rather than a regular basis in the treatment of many patients with chronic asthma. If more than 8 inhalations per day (or approximately one canister per month) are needed, the addition of cromolyn, nedocromil, or inhaled corticosteroids should be considered. Sustained-release oral beta2-agonists may be indicated when long duration of effect is desired or patient does not tolerate inhaled beta2-agonists. It is generally felt that inhaled corticosteroids should be used as primary therapy in patients with moderate and severe chronic asthma. Long-term administration of systemic (oral) corticosteroids should be considered only in patients with inadequate control of asthma despite maximal use of other treatments. Prolonged use can generate significant side effects. Cromolyn can be effective in many patients (alone or in conjunction with bronchodilators) in preventing the symptoms of mild-to-moderate asthma. Nedocromil sodium is clinically useful in the preventive treatment of mild and moderate asthma Nedocromil sodium is indicated primarily as a preventive drug in the management of asthma-associated chronic inflammation. If used appropriately, it is effective in improving symptom scores and reducing use of bronchodilators and, in some cases, other concomitant medications such as inhaled corticosteroids or cromolyn. Maintenance therapy with theophylline is effective in reducing the frequency and severity of the symptoms of chronic asthma. It may be similar in effectiveness to cromolyn or beta2-agonists, and long-acting preparations allow for effective control of nocturnal symptoms. Inhaled anticholinergic agents such as ipratropium may be indicated in patients in whom alternative agents have not been sufficiently effective, are inappropriate because of other medical conditions, or have produced unacceptable side effects. Adequate hydration is recommended for asthma patients, but overhydration must be prevented by careful monitoring of fluid and electrolyte balance, especially in infants, severely ill patients, and the elderly. Patients who do not respond to systemic corticosteroids may benefit from alternatives such as troleandomycin, methotrexate, gold, and intravenous g -globulin therapy. Certain of these regimens are contraindicated in some patients and/or may be associated with significant adverse effects.
Quick-Relief Medication (Initial Treatment) for Acute Exacerbations in Patients Older Than 5 Years	Same treatment for all patients (no step-wise approach) Short-acting bronchodilator: inhaled beta2-agonists as needed for symptoms. Intensity of treatment will depend on severity of exacerbation Use of short-acting inhaled beta2-agonists on a daily basis, or increasing use, indicates the need for additional long-term-control therapy. Anticholinergics (ipratropium bromide) are an alternative for patients with intolerance to beta2-agonists. They are the treatment of choice in patients with bronchospasm due to beta-blocker medication. Systemic corticosteroids are sometimes used for moderate-to-severe-exacerbations to speed recovery and prevent recurrence of exacerbations. Exercise-Induced Asthma Short-acting inhaled beta2-agonists may prevent exercise-induced bronchospasm if taken just prior to exercise. Cromolyn and nedocromil are also acceptable for preventing exercise-induced bronchospasm.	Step 4: Severe Persistent Short-acting bronchodilator: inhaled beta2-agonist as needed for symptoms. Step 3: Moderate Persistent Short-acting bronchodilator: inhaled beta2-agonist as needed for symptoms, not to exceed 3-4 times in one day Step 2: Mild Persistent Short-acting bronchodilator: inhaled beta2-agonist as needed for symptoms, not to exceed 3-4 times in one day Step 1: Intermittent Short-acting bronchodilator: inhaled beta2-agonist as needed for symptoms, but less than once a week Intensity of treatment will depend on severity of exacerbation Additional reliever medications: Systemic corticosteroids may be used for acute severe exacerbations to prevent progression of the exacerbation, prevent early relapse, and reduce morbidity of illness. Oral therapy for 3 to 10 days is preferred. Anticholinergics – Inhaled ipratropium bromide may have an additive effect when nebulized together with short-acting beta2-agonist. Short acting oral beta2-agonists are appropriate for use in patients unable to use inhaled medication. Exercise-induced asthma Inhaled beta2-agonist or cromoglycate or nedocromil before exercise or exposure to allergen	Same treatment for all patients (no step-wise approach) Short-acting bronchodilator: inhaled beta2-agonists as needed for symptoms. Intensity of treatment will depend on severity of exacerbation Use of short-acting inhaled beta2-agonists on a daily basis, or increasing use, indicates the need for additional long-term control therapy.	Step 4: Severe Persistent Short-acting bronchodilator: inhaled beta2-agonist as needed for symptoms Increasing use of beta2-agonist indicates the need for assessment and increasing inflammatory therapy. Step 3: Moderate Persistent Short-acting bronchodilator: inhaled beta2-agonist as needed for symptoms, not to exceed 3-4 times in one day Increasing use of beta2-agonist indicates the need for assessment and increasing inflammatory therapy. Step 2: Mild Persistent Short-acting bronchodilator: inhaled beta2-agonist as needed for symptoms, not to exceed 3-4 times in one day Step 1: Mild Intermittent Short-acting bronchodilator: inhaled beta2-agonist as needed, but < 1/week Intensity of treatment will depend on severity of exacerbation Inhaled beta2-agonist, cromolyn, or nedocromil before exercise or exposure to allergen With viral infection: Inhaled beta2-agonist q 4-6 hrs. up to 24 hrs. (longer with physician consult) but no more than once every 6-8 wks Systemic corticosteroid if severe attack or history of severe attacks with infection Exercise-induced asthma The inhalation of a beta2-agonist 10 to 20 minutes before exercise is often the most effective means of preventing exercise-induced asthma exacerbations. Cromolyn inhalers and oral montelukast are also of demonstrated efficacy for exercise-induce asthma.	Inhaled beta2-agonists are generally the safest and most effective treatment for acute asthma. Oral beta2-agonists should not be administered for the treatment of acute severe asthma. Systemic corticosteroids should be considered in the management of acute asthma when the patient does not respond readily to bronchodilators. Early use of corticosteroids shortens the course of asthma, prevents relapses, and reduces the need for hospitalization. The early use of corticosteroids is of particular importance in patients who have a history consistent with fatality-prone asthma. Intravenous corticosteroids may be lifesaving in the treatment of severe intractable asthma. After episodes of severe intractable asthma, complete restoration of pulmonary function may require weeks of treatment. Therefore after such events, corticosteroids should be continued at least until symptoms are controlled and pulmonary function is restored. Inhaled anticholinergic medication may provide benefit when combined with a beta2-agonist or other primary therapeutic agent in patients with acute severe asthma. Nedocromil sodium is not indicated in the treatment of acute asthma Exercise-induced asthma Inhaled beta2-agonists, when administered 15 to 30 minutes before exercise, prevent exercise-induced bronchospasm in many patients. Inhaled beta2-agonists are generally the agent of choice for this purpose. Cromolyn can be effective in preventing or diminishing exercise-induced asthma when given 15 to 30 minutes before exercise.
Long-Term Pharmacologic Treatment for Infants and Young Children	Stepwise Approach Step 4: Severe Persistent Daily anti-inflammatory medication: Inhaled corticosteroid (high dose) with spacer/holding chamber and face mask If needed, add systemic corticosteroids (2 mg/kg/day and reduce to lowest daily or alternate day use that stabilizes symptoms) Step 3: Moderate Persistent Daily anti-inflammatory medication. Either: Inhaled corticosteroid (medium dose) with spacer/holding chamber and face mask or, once control is established: Inhaled corticosteroid (medium dose) and nedocromil or Inhaled corticosteroid (medium dose) and long-acting bronchodilator (theophylline) Step 2: Mild persistent Daily anti-inflammatory medication. Either: Cromolyn (nebulizer is preferred, or MDI) or nedocromil (MDI only) Infants and young children usually begin with a trial of cromolyn or nedocromil or Inhaled corticosteroid (low dose) with spacer/holding chamber and face mask Step 1: Mild Intermittent No daily medication needed Review treatment every 1-6 months; If control is sustained for 3 months, a gradual stepwise reduction in treatment may be possible. If control is not maintained, consider stepwise increase in treatment. First review patient medication technique, adherence and environmental control (avoidance of allergens or other factors that contribute to asthma severity).	Stepwise Approach Step 4: Severe Persistent Daily medications: Nebulized budesonide (corticosteroid) > 1 mg twice a day If needed, add oral corticosteroids in lowest possible dose on an alternate day, early morning schedule Step 3: Moderate Persistent Daily medication: Nebulized budesonide (corticosteroid) < 1 mg twice a day Step 2: Mild persistent Daily medication: Either inhaled corticosteroids or cromoglycate (use MDI with a spacer and face mask or use a nebulizer) Step 1: Intermittent No controller medication needed Review treatment every 3 to 6 months. If control is sustained for at least 3 months, a gradual stepwise reduction in treatment may be possible. If control is not achieved, consider step-up. But first: review patient medication technique, compliance, and environmental control (avoidance of allergens or other trigger factors).	Outside scope of guideline	MDIs can be used in infants and smaller children with appropriate spacer devices and masks. Infants and smaller children need MDI doses equivalent to adult doses because they inhale aerosols during tidal breathing without a breath hold, thus decreasing retention time and effective drug delivery to the lungs. Pediatric patients may be uncooperative with inhaled medication delivery. Compressed air-driven, wet nebulizers are commonly available for home administration of beta2-agonists, cromolyn sodium, ipratropium bromide, and corticosteroids. Complete nebulization of medication is time consuming.	In general, treatment recommendations for infants and young children are not specified.
Quick-Relief Medication (Initial Treatment) for Acute Exacerbations in Infants and Young Children	Step 4: Severe Persistent Medication: Bronchodilator as needed for symptoms up to 3 times a day. Intensity of treatment will depend upon severity of exacerbation. Either: Inhaled short-acting beta2-agonist by nebulizer or face mask and spacer/holding chamber or Oral beta2-agonist for symptoms With viral respiratory infection Bronchodilator q 4-6 hours up to 24 hours (longer with physician consult) but, in general, repeat no more than once every 6 weeks Consider systemic corticosteroid if current exacerbation is severe or patient has history of previous severe exacerbations Step 3: Moderate Persistent Medication: See Step 4 Step 2: Mild Persistent Medication: Bronchodilator as needed for symptoms <2 times a week. See Step 4 for more details. Step 1: Mild Intermittent Medication: See Step 2	Step 4: Severe Persistent Medication: Inhaled short-acting bronchodilator: inhaled beta2-agonist or ipratropium bromide or oral beta2-agonist as needed for symptoms, not to exceed 3-4 times in one day Step 3: Moderate Persistent Medication: See Step 4 Step 2: Mild Persistent Medication: See Step 4 Step 1: Intermittent Medication: Inhaled short-acting bronchodilator: inhaled beta2-agonist or ipratropium bromide or oral beta2-agonist as needed for symptoms, but not more than 3 times a week	Outside scope of guideline	Not stated	Medications: Use short-acting beta2-agonists as needed to relieve acute symptoms. Systemic corticosteroids are used in short bursts (usually days) for acute severe asthma
Home and Emergency/ Hospital Management of Acute Exacerbations	Home Management Assess Severity Measure PEF: Value <50% personal best or predicted suggests severe exacerbation. Note other signs and symptoms. Initial Treatment Inhaled short-acting beta2-agonist: up to three treatments of 2-4 puffs by MDI at 20-minute intervals or single nebulizer treatment. Good Response Mild exacerbation PEF > 80% predicted or personal best No wheezing or shortness of breath Response to beta2-agonist sustained for 4 hours (may continue beta2-agonist every 3-4 hours for 24-48 hours. For patients on inhaled corticosteroids, double dose for 7-10 days. Contact clinician for follow-up instructions. Incomplete Response Moderate Exacerbation PEF 50-80% predicted or personal best Persistent wheezing and shortness of breath Add oral corticosteroid Continue beta2-agonist Contact clinician urgently (this day) for instructions Poor Response Severe Exacerbation PEF <50% predicted or personal best Marked wheezing and shortness of breath Add oral corticosteroid Repeat beta2-agonist immediately If distress is severe and non-responsive, call your doctor and proceed to emergency department; consider calling ambulance or 9-1-1. Emergency Department or Hospital Management Assess Severity If impending or actual respiratory arrest: Intubation and mechanical ventilation with 100% O2 Nebulized beta2-agonist and anticholinergic agent Intravenous corticosteroid Admit to hospital intensive care (see below) If FEV1 or PEF >50% (moderate exacerbation): Inhaled beta2-agonist by metered-dose inhaler or nebulizer, up to three doses in first hour Oxygen to achieve O2 saturation >90% Oral systemic corticosteroids if no immediate response or if patient recently took oral systemic corticosteroid If FEV1 or PEF <50% (severe exacerbation): Inhaled high-dose beta2-agonist and anticholinergic by nebulization every 20 minutes or continuously for 1 hour Oxygen to achieve O2 saturation >90% Oral systemic corticosteroid For moderate or severe exacerbation, repeat assessment (symptoms, physical examination, PEF, O2 saturation, other tests as needed) Moderate Exacerbation (FEV1 or PEF 50-80% predicted/personal best. Physical exam shows moderate symptoms.) Inhaled short-acting beta2-agonist every 60 minutes Systemic corticosteroid Continue treatment 1-3 hours, provided there is improvement Severe Exacerbation (FEV1 or PEF <50% predicted/personal best. Physical exam shows severe symptoms at rest, accessory muscle use, chest retraction. History indicates high-risk. No improvement after initial treatment) Inhaled short-acting beta2-agonist, hourly or continuous + inhaled anticholinergic agent Oxygen Systemic corticosteroid Assess response in patients with moderate or severe exacerbation Good Response FEV1 or PEF >70% Response sustained 60 minutes after last treatment No distress Physical exam normal Discharge home (continue treatment with inhaled beta2-agonist, continue course of oral systemic corticosteroids, educate patient) Incomplete Response FEV1 or PEF >50% but <70% Mild-to-moderate symptoms Either discharge home (continue treatment as described under good response) or Admit to hospital ward Inhaled beta2-agonist + inhaled anticholinergic Systemic (oral or intravenous) corticosteroid Oxygen Monitor FEV1 or PEF, O2 saturation, pulse If patient improves, discharge home (continue treatment as described under good response) Poor Response FEV1 or PEF <50% PCO2 >42 mm Hg Physical exam shows severe symptoms, drowsiness, confusion Admit to hospital intensive care Inhaled beta2-agonist hourly or continuously + inhaled anticholinergic Intravenous corticosteroid Oxygen Possible intubation and mechanical ventilation When patient stabilizes, admit to hospital ward (see above) and when patient improves discharge home (see above).	Home Management Assess Severity Measure PEF: Value < 80% personal best or predicted suggests exacerbation. Clinical features include coughing, breathlessness, wheezing, chest tightness, use of accessory muscles, and suprasternal retractions. Initial Treatment Inhaled short-acting beta2-agonist: up to three treatments of 2-4 puffs at 20-minute intervals for the first hour. Good Response Mild episode If PEF > 80% predicted or personal best, and response to beta2-agonist sustained for 4 hours: May continue beta2-agonist every 3-4 hours for 24-48 hours. Contact clinician for follow-up instructions. Incomplete Response Moderate Episode If PEF 60-80% predicted or personal best: Add oral corticosteroid Continue beta2-agonist Contact clinician urgently (this day) for instructions Poor Response Severe Episode If PEF < 60% predicted or personal best: Add oral corticosteroid Repeat beta2-agonist immediately Immediate transport to hospital emergency department, consider ambulance. Emergency Department or Hospital Management Assess Severity History, physical examination, PEF or FEV1, oxygen saturation, arterial blood gas of patient in extremis, and other tests as indicated Initial Treatment Inhaled short-acting beta2-agonist, usually by nebulization, one dose every 20 minutes for 1 hour Oxygen to achieve O2 saturation >90% (95% children) Systemic corticosteroids if no immediate response or if patient recently took oral steroid, or if episode is severe Sedation is contraindicated in the treatment of exacerbations Repeat assessment (symptoms, physical examination, PEF, O2 saturation, other tests as needed) Moderate Episode PEF 60-80% predicted/personal best Physical exam shows moderate symptoms, accessory muscle use Inhaled short-acting beta2-agonist every 60 minutes Consider corticosteroids Continue treatment 1-3 hours, provided there is improvement Severe Episode PEF < 60% predicted/personal best Physical exam shows severe symptoms at rest, chest retraction History indicates high-risk No improvement after initial treatment Inhaled short-acting beta2-agonist (hourly or continuous) + inhaled anticholinergic agent Oxygen Systemic corticosteroid Consider subcutaneous, intramuscular, or intravenous beta2-agonist Assess response Good Response PEF > 70% Response sustained 60 minutes after last treatment No distress Physical exam normal If good response, discharge home (continue treatment with inhaled beta2-agonist, continue course of oral systemic corticosteroids, educate patient) Incomplete Response FEV1 or PEF > 50% but < 70% History indicates high-risk Mild-to-moderate symptoms O2 saturation not improving If incomplete response within 1-2 hours: Admit to hospital ward Inhaled beta2-agonist + inhaled anticholinergic Systemic (oral or intravenous) corticosteroid Oxygen Monitor FEV1 or PEF, O2 saturation, pulse Discharge home If PEF > 70% predicted or personal best and sustained on oral/inhaled medication Continue treatment as described under good response. Admit to intensive care (see below) if no improvement within 6-12 hours. Poor Response PEF < 30% PCO2 > 45 mm Hg PO2 < 60 mm Hg History indicates high-risk Physical exam shows severe symptoms, drowsiness, confusion If poor response within 1 hour: Admit to hospital intensive care Inhaled beta2-agonist hourly or continuously + inhaled anticholinergic Intravenous corticosteroid Consider subcutaneous, intramuscular, or intravenous beta2-agonists Oxygen Consider intravenous aminophylline Possible intubation and mechanical ventilation Rehydration may be necessary for infants and young children	Home Management Medications Inhaled beta2-agonist every 2-6 hours Initiate or increase anti-inflammatory medication (inhaled corticosteroids or cromolyn/nedocromil). A course of oral corticosteroids should be given serious consideration in patients with acute asthma exacerbation. Emergency Management Assess Severity Based on history and physical exam (vital signs, auscultation of chest, use of accessory muscles, alertness, color, peak flow rate or FEV1 Initial Treatment Short acting nebulized beta2-agonist (Albuterol, Terbutaline) 2.5-5 mg q 20 min up to 3 doses. Alternatives: Epinephrine (Adult: 0.3-0.5 mg subq q 20 min up to 3 doses; Peds: 0.01 mg/kg subq q 20 min up to 3 doses) Terbutaline (Adult: 0.25 mg subq q 20 min up to 3 doses; Peds: 0.01 mg/kg subq q 20 min up to 3 doses Good Response Peak flow or FEV1 >70% predicted normal No wheezing on auscultation Transfer to home treatment Incomplete Response Peak flow or FEV1 50-70% predicted normal Mild wheezing Consider hospitalization, particularly for high risk patients, if the following conditions apply: Past history of sudden severe exacerbation Prior intubation for asthma Two or more hospitalizations for asthma in the past year Three or more emergency care visits for asthma within the past year Hospitalization or an emergency care visit for asthma within the past month Use of > 2 canisters per month of inhaled short-acting beta2-agonists Current use of systemic corticosteroids or recent withdrawal from systemic corticosteroids Difficulty perceiving airflow obstruction or its severity Comorbidity, as from cardiovascular disease or chronic obstructive pulmonary disease Serious psychiatric disease or psychosocial problems Low socioeconomic status and urban residence Illicit drug use Sensitivity to Alternaria Poor Response Peak flow or FEV1 < 50% predicted normal No improvement in respiratory distress Strongly consider hospitalization Continue inhaled beta-agonist q 60 minutes Consider starting prednisone (Adult: short course "burst" 40-60 mg/day as single or 2 divided doses for 3 to 10 days; Child: short course "burst" 1-2 mg/kg day, maximum 60 mg/day for 3 to 10 days)	Home Management Assess Severity: Home PEFR Monitoring Using the System of PEFR Zones Green Zone (80-100% of personal best) = "all clear" no change in therapy; or if asymptomatic for a prolonged period, consider a reduction in medication with continued monitoring. Yellow Zone (50-80% of personal best) = "caution" indicating suboptimal control or early exacerbation. Red Zone (<50% of personal best) = "alert" indicating need for initiation of more intense treatment, often involving a course of corticosteroids. Treatment Follow a written action plan based on signs and symptoms (Asthma Treatment Plan) . For rapid reversal of airflow obstruction, repetitive or continuous administration of an inhaled beta2-agonist. Emergency Management Assess severity of asthma For rapid reversal of airflow obstruction, repetitive or continuous administration of an inhaled beta2-agonist. Early administration of systemic corticosteroids in patients with severe attacks or in patients who fail to respond promptly and completely to an inhaled beta2-agonist. Correction of hypoxemia by administrating supplemental oxygen. Close monitoring of the patients' conditions by serial measurement of lung function.	This guideline does not differentiate home management from hospital management in summary statements concerning severe acute intractable asthma. The following recommendations seem to be most relevant to emergency department or hospital management. Prompt recognition and intervention is needed History must establish features of current attack and the presence of medical conditions that could complicate treatment of intractable asthma. Oxygen administration is indicated A PaCO2 of 40 torr may be a sign of severe asthma Early in treatment, parenteral and sympathomimetic agents may be indicated for patients who are not ventilating well enough to deliver adequate amounts of nebulized drug to the lower respiratory tract. Patients with severe acute intractable asthma will require corticosteroid administration. Early use is recommended because a lag time of several hours may occur before any clinical effect is noted. If aminophylline theophylline is used, it is especially important to monitor blood levels and cardiopulmonary function. Overhydration may increase vascular hydrostatic pressure and decrease plasma colloid pressure, increasing the possibility of pulmonary edema, which is also favored by large negative peak inspiratory intrapleural pressures associated with acute asthma. The need for mechanical ventilation should be anticipated. Intubation may be difficult and, if possible, should be done by an individual experienced in such procedures.
Guidelines for Referral to an Asthma Specialist	Referral for consultation or care to a specialist in asthma care is recommended when: Patient has had a life-threatening asthma exacerbation Patient is not meeting the goals of asthma therapy Signs and symptoms are atypical or there are problems in differential diagnosis Other conditions complicate asthma or its diagnosis (e.g., sinusitis, nasal polyps, aspergillosis, severe rhinitis, vocal cord dysfunction, gastroesophageal reflux, chronic obstructive pulmonary disease). Additional diagnostic testing is indicated (e.g., allergy skin testing, rhinoscopy, complete pulmonary function studies, provocative challenge, bronchoscopy) Patient requires additional education and guidance on complications of therapy, problems with adherence, or allergen avoidance Patient is being considered for immunotherapy Patient has severe persistent asthma, requiring step 4 care (referral may be considered for patients requiring step 3 care) Patient requires continuous oral corticosteroid therapy or high-dose inhaled corticosteroids or has required more than two bursts of oral corticosteroids in 1 year Patient is under age 3 and requires step 3 or 4 care. When patient is under age 3 and requires step 2 care or initiation of daily long-term therapy, referral should be considered. Patient requires confirmation of a history that suggests that an occupational or environmental inhalant or ingested substance is provoking or contributing to asthma. Depending on the complexities of diagnosis, treatment, or the intervention required in the work environment, it may be appropriate in some cases for the specialist to manage the patient over a period of time or comanage with the primary care provider	Although most asthma care should be provided at the primary care level, consultation with an asthma specialist may be appropriate for those patients who do not respond favorably to treatment. More specific reasons for referral are not provided.	Specialty consultation is recommended for: Adults with severe asthma; also consider referral for those with moderate asthma. Children with moderate to severe asthma; also consider referral for those with mild persistent asthma. Specialty consultation is also recommended when: Patient has poorly controlled or complex asthma including previous life-threatening asthma exacerbations, or asthma exacerbations requiring more than 2 bursts of oral corticosteroids in one year, or asthma complicated by other medical or psychosocial conditions. Patient needs additional diagnostic evaluations and/or testing (e.g., allergy skin testing, bronchoprovocation). Testing is recommended for patients with persistent asthma who are exposed to perennial indoor antigens. Patient needs evaluation and treatment of allergy for occupational asthma, environmental counseling, or immunotherapy. Patients need additional or intensive asthma education not otherwise available	Some situations may warrant a referral or consultation with a specialist in asthma care. These include cases with: Diagnosis in doubt. Signs and symptoms are atypical, or there are problems in differential diagnosis. Additional diagnostic testing indicated. (e.g., skin testing, provocative challenge, rhinoscopy, bronchoscopy, complete pulmonary function studies). Inadequate response to asthma therapy. For example, patients considered to have mild or moderate asthma who are hospitalized for exacerbations, or who make more than two emergency room visits a year. Severe refractory asthma, particularly if the clinician cares for very few such patients. Other chronic pulmonary disease complicating management. Immunotherapy or other complications of therapy. Special cases meriting consultation with health care team members include: Occupational-related asthma. In this situation either the primary care physician or the consultant may benefit from consultation with a physician expert in occupational medicine. Patients who chronically do not adhere to their treatment regimen may benefit from an intensive asthma health behavior/health education intervention. Significant psychiatric or family problems interfering with treatment. Additional consideration should be given to consultation or referral in the following situations: When the cost of care for a patient becomes excessive. When patient disability is substantial despite adequate therapy.	A number of reasons exist for recommending that a patient consult an asthma specialist early in the treatment program. These include: Instability of the patient’s asthma; uncontrolled asthma may be associated with widely variable pulmonary functions and possibly high morbidity and mortality. Early intervention may prevent these events. A long-term treatment plan should be developed. A patient response to treatment that is limited, incomplete, or very slow and poor control interferes with the patient’s quality of life. In spite of regular use of anti-inflammatory medications, the patient must use an inhaled beta2-agonist frequently, exclusive of its use in exercise-induced asthma If there is a need for frequent adjustments of therapy because of unstable asthma For identification of allergens or other environmental factors that may be causing the patient’s disease When allergen immunotherapy is a consideration. When the patient and primary caregiver need intensive education in the role of allergens and other environmental factors When family dynamics interfere with patient care and/or there is a need for further family education about asthma When a patient has a chronic cough, refractory to usual therapy When coexisting illnesses and/or their treatment complicate the management of asthma When the patient has recurrent absences from school or work due to asthma. When the patient experiences continuing nocturnal episodes of asthma When the patient is unable to participate in normal daily activities and sports because of limited exercise ability despite use of inhaled beta2-agonists before exercise When the patient requires multiple medications on a long-term basis When frequent bursts of oral corticosteroids or daily oral corticosteroids are required When the patient exhibits excessive lability of pulmonary function, such as highly variable peak flow rates When the diagnosis of asthma is in doubt When there is concern about side effects that have occurred or may occur, for example, with use of oral or orally inhaled corticosteroids in children When preventive measures need to be considered for the high-risk, predisposed infant with a family history of asthma or atopy Sudden severe attacks of asthma Hospitalization of the patient for asthma Severe episodes of asthma resulting in loss of consciousness Seizures, near-death episodes, or respiratory failure requiring artificial respiration When emergency visits are required to control the patient’s asthma When the patient asks for a consultation
Patient Education	Patient education is described in the context of the stepwise plan based on asthma severity: Step 1: Mild Intermittent Teach basic facts about asthma Teach inhaler/spacer/holding chamber technique Discuss roles of medications Develop self-management plan Develop action plan for when and how to take rescue actions, especially for patients with a history of severe exacerbations Discuss appropriate environmental control measures to avoid exposure to known allergens and irritants Step 2: Mild Persistent Step 1 actions plus: Teach self-monitoring Refer to group education if available Review and update self-management plan Step 3: Moderate Persistent Steps 1 and 2 actions Step 4: Severe Persistent Steps 2 and 3 actions plus: Refer to individual education/counseling	Patients should be actively involved in managing their asthma to prevent problems and can live productive, physically active lives. Asthma patients can learn to: Take medications correctly Understand the difference between "quick-relief" and "long-term preventive" medications Avoid triggers Monitor their status using symptoms and, if available, PEF indicators Recognize signs that asthma is worsening and take action Seek medical help as appropriate. Patients and their health care teams should prepare a written asthma management plan that is not only medically appropriate but also practical. Such an asthma management plan should cover: Prevention steps for long-term control What daily medication to take What asthma triggers to avoid Action steps to stop attacks How to recognize worsening asthma. List indicators such as increasing cough, chest tightness, wheeze, difficult breathing, sleep disturbance, or PEF measurements below personal best despite increased use of medications. How to treat worsening asthma. List the names and doses of quick-relief bronchodilator medications and steroid tablets and when to use them. How and when to seek medical attention. List indicators such as feeling panicky, an attack with sudden onset, shortness of breath while resting or speaking a few words, PEF readings below a specified level, or a history of severe attacks. List the name, location, and telephone number of the physician's office or clinic.	Patient education is essential for successful management of asthma. It should begin at the time of diagnosis and be ongoing. The following patient education is recommended: Basic facts about asthma Role of medications (quick relief vs. long-term controller medications) Skills (use of inhalers, peak flow monitoring, monitoring of symptoms) Environmental control measures (to avoid asthma triggers) When and how to take actions (responding to changes in asthma severity). A written action plan should be offered to patients. Emphasize need for regular follow-up visits	Patient education is described in the context of the stepwise plan based on asthma severity: Step 1: Mild Intermittent Teach basic facts about asthma Teach inhaler/spacer technique Discuss roles of medications Develop self-management plan Develop action plan for when and how to take rescue actions Discuss appropriate environmental control measures to avoid exposure to known triggers Step 2: Mild Persistent Step 1 actions plus: Teach self-monitoring Refer to group education if available Review and update self-management plan Step 3: Moderate Persistent Same as Step 2 actions Step 4: Severe Persistent Step 2 and 3 actions plus: Refer to individual education/ counseling	Cooperative management through education involves the following: Educating asthmatic patients, parents, and family about asthma and treatment methods is essential for effective control of asthma Educational programs have been successful in increasing patient understanding and decreasing morbidity. Patients should be educated to effectively monitor their asthmatic status and know how to respond to changes Patients should learn how to effectively use inhalers Physicians must recognize and resolve patient concerns by increasing patient confidence in the management approach. Asthma education requires an understanding of basic concepts related to pathophysiology and treatment but must also be individualized for each patient. Education can be important for improving patient compliance with the treatment program.
BENEFITS OF TREATMENT
	NHLBI (1997)	WHO/NHLBI (1998)	ICSI (1999)	UMHS (2000)	AAAAI, ACAAI, JCAAI (1995)
Potential Benefits	Effective asthma management, reflected by the following components: Use of objective measures of lung function to assess the severity of asthma and to monitor the course of therapy Environmental control measures to avoid or eliminate factors that precipitate asthma symptoms or exacerbations Comprehensive pharmacologic therapy for long-term management designed to reverse and prevent the airway inflammation characteristic of asthma as well as pharmacologic therapy to manage asthma exacerbations Patient education that fosters a partnership among the patient, his or her family, and clinicians	Primary prevention methods have considerable potential to prevent the development of asthma. Effective management of asthma results in benefits including achievement and maintenance of control of symptoms, prevention of asthma exacerbations; maintenance of pulmonary function as close to normal levels as possible; maintenance of normal activity levels, including exercise; avoidance of adverse effects from asthma medications; prevention of the development of irreversible airflow limitation; and prevention of asthma mortality. Additional benefits include decreased health care costs, increased productivity, increased participation in family life and a decrease of chronic disability and premature death. Patient education increases the likelihood of lifelong success in treating asthma	Accurate diagnosis and assessment of asthma severity Effective long-term control of persistent asthma through the use of anti-inflammatory medication Effective partnership of patients and parents with health care professionals through education and use of written action plans	Patients with asthma gain symptomatic relief and functional benefit from several classes of anti-inflammatory and bronchodilator medications and from education in self-management of the disease.	Prevention of long-term effects of airway inflammation Improved patient compliance to therapeutic regimen by participating in patient education program Reduction of the number of emergency room visits and hospitalizations due to the exacerbation of asthma symptoms Improved quality of life Prevention of morbidity and mortality due to asthma Improved tolerance of physical activity/exercise Minimization of time lost from work, school, daily activities Improved self-image with control of asthma symptoms
Subgroup(s) Most Likely to Benefit	Not stated	Infants: Reducing exposure to indoor allergens, particularly domestic mites, is one of the most promising measures for future preventive action, especially for infants. Avoidance of passive smoking is also very likely to be beneficial.	Not stated	Not stated	Persistent asthmatics
POTENTIAL HARMS OF TREATMENT
	NHLBI (1997)	WHO, NHLBI (1998)	ICSI (1999)	UMHS (2000)	AAAAI, ACAAI, JCAAI (1995)
Potential Harms	Side effects of medications: Long-Term Controller Medications Inhaled Corticosteroids Cough, dysphonia, oral thrush In high doses, systemic effects may occur, such as potential impairment of a child's linear growth, skin thinning and easy bruising, risk of osteoporosis and fracture with long-term use Systemic Corticosteroids Short-term use: reversible abnormalities in glucose metabolism, fluid retention, weight gain, mood alteration, hypertension, peptic ulcer, and rarely aseptic necrosis of femur. Long-term use: adrenal axis suppression, growth suppression, dermal thinning, hypertension, diabetes, Cushing’s syndrome, cataracts, muscle weakness, and, in rare instances, impaired immune function. Coexisting conditions such as herpes virus infections, varicella, tuberculosis, hypertension, peptic ulcer, and Strongyloides could be worsened by systemic corticosteroids Long-Acting Beta2-Agonists Tachycardia, skeletal muscle tremor, hypokalemia, prolongation of QTc interval in overdose Methylxanthines (Theophylline) Dose-related acute toxicities include tachycardia, nausea and vomiting, tachyarrhythmias (SVT), central nervous system stimulation, headache, seizures, hematemesis, hyperglycemia, and hypokalemia Adverse effects at usual therapeutic doses include insomnia, gastric upset, aggravation of ulcer or reflux, increase in hyperactivity in some children, difficulty in urination in elderly males with prostatism. Leukotriene Modifiers Zileuton tablets have been associated with elevation of liver enzymes. Limited case reports of reversible hepatitis and hyperbilirubinemia. Nedocromil Fifteen to 20% of patients complain of unpleasant taste. Quick-Relief Medications Short-Acting Inhaled Beta2-Agonists Tachycardia, skeletal muscle tremor, hypokalemia, increased lactic acid, headache, hyperglycemia. Patients with preexisting cardiovascular disease (especially the elderly) may have adverse cardiovascular reactions. Anticholinergics (ipratropium bromide) Drying of mouth and respiratory secretions, increased wheezing in some individuals, blurred vision if sprayed in eyes. Systemic Corticosteroids See under long-term controller medications Allergen Immunotherapy Some patients (particularly those with poorly-controlled asthma) may experience adverse or life-threatening reaction (e.g., bronchoconstriction)	Side effects of medications: Controller Medications Inhaled corticosteroids: Local adverse effects from inhaled corticosteroids include oropharyngeal candidiasis, dysphonia, and occasional coughing from upper airway irritation. Sodium cromoglycate: Minimal side effects include cough upon inhalation. Systemic corticosteroids: Long-term use may produce systemic effects including osteoporosis, arterial hypertension, diabetes, hypothalamic-pituitary-adrenal axis suppression, cataracts, obesity, skin thinning leading to cutaneous striae and easy bruisability, and muscle weakness. Theophylline: Sustained-release theophylline has the potential for significant adverse effects. The signs and symptoms of theophylline intoxication involve many different organ systems. Gastrointestinal symptoms, nausea, and vomiting are the most common early events. Theophylline intoxication can result in seizures and even death. Cardiopulmonary effects include tachycardia, arrhythmias, and occasionally, stimulation of the respiratory center. Beta2-agonists: Long-acting inhaled beta2-agonists are associated with systemic adverse effects (although fewer than oral therapy) such as cardiovascular stimulation, skeletal muscle tremor, anxiety, pyrosis, headache, and hypokalemia. Long-acting oral beta2-agonists may cause cardiovascular stimulation, anxiety, pyrosis, and skeletal tremor. Ketotifen: The most frequent side effect is sedation, especially in the initial treatment period and in adults. Ketotifen may also cause weight gain. Anti-leukotrienes: Elevation of liver enzymes is possible. Limited case reports of reversible hepatitis and hyperbilirubinemia exist. Reliever Medications: Beta2-agonists: Short-acting inhaled beta2-agonists may cause systemic adverse effects (although fewer than oral therapy) such as cardiovascular stimulation, skeletal muscle tremor, and hypokalemia. Oral beta2-agonists are associated with the potential for cardiovascular stimulation, skeletal muscle tremor, hypokalemia, and irritability. Systemic corticosteroids: Potential side effects include systemic adverse effects such as cardiovascular stimulation, skeletal muscle tremor, headache, irritability, and hypokalemia; reversible abnormalities in glucose metabolism; increased appetite; fluid retention; weight gain; rounding of the face; mood alteration; hypertension; peptic ulcer; and aseptic necrosis of the femur. Anticholinergics: Inhalation of ipratropium or oxitropium can cause a dryness of the mouth and a bad taste. Short-acting theophylline: Theophylline has the potential for significant adverse effects. The signs and symptoms of theophylline intoxication involve many different organ systems. Gastrointestinal symptoms, nausea, and vomiting are the most common early events. Theophylline intoxication can result in seizures and even death. Cardiopulmonary effects include tachycardia, arrhythmias, and occasionally, stimulation of the respiratory center. Epinephrine/adrenaline: Epinephrine/adrenaline injection is associated with similar, but more significant effects than beta2-agonists. In addition, convulsions, chills, fever, and hallucinations may occur. Nontraditional Methods of Healing Acupuncture has been associated with hepatitis B, bilateral pneumothorax, and burns. Homeopathy treatments may contain potent pharmacological agents that may lead to adverse effects. Herbal medicines are potentially dangerous and toxic. Allergen Immunotherapy Adverse or fatal reactions can occur, particularly in patients with severe airflow obstruction	Side effects of medications: Risk of adverse effects is associated with asthma pharmacotherapy. Specific adverse effects are not described.	Side effects associated with pharmacotherapy: Anti-inflammatory agents Inhaled corticosteroids: There is a dose-dependent reduction of short-term growth with the use of conventional doses of beclomethasone dipropionate. Inhaled corticosteroids in doses as high as 800 mcg/d exert much less short-term growth suppression than low-dose oral corticosteroids. High doses of inhaled corticosteroids may cause systemic side effects (though to a much lesser extent than oral steroids will). Risk of side effects with high-dose inhaled steroids can be minimized by having the patient rinse his/her mouth immediately after inhalation and before swallowing and by using a spacer device. Systemic corticosteroids: Chronic systemic corticosteroid therapy may be associated with obesity, moon faces, supraclavicular and nuchal fat pads, striae, easy bruisability, weakness, hypertension, and glucose intolerance. Long-term (>2 weeks) corticosteroid therapy may cause suppression of the hypothalamic-pituitary-adrenal axis. Full recovery of the axis can take up to 12 months depending on the dose, frequency, and duration of antecedent therapy. Adrenal insufficiency can evolve into acute adrenal crisis precipitated by severe infection, trauma, or surgery. Systemic corticosteroid therapy can cause osteopenia. Leukotriene modifier agents: The U.S. Food and Drug Administration (FDA) mandates monitoring hepatic enzymes with use of the 5-lipoxygenase-inhibitor zileuton. Churg-Strauss Vasculitis has rarely been reported in association with montelukast or zafirlukast in patients tapering chronic systemic corticosteroid. Inhaled, short-acting beta2-agonists: Several epidemiologic studies have found an association between excess use of beta2-agonist inhalers and asthma mortality. A causal relationship has not been demonstrated, and it is possible that beta2-agonists represent a mere marker for the severity of disease, being more frequently prescribed for patients with life-threatening asthma. If beta2-agonists do have a causative role, it may be an indirect one, such as delaying presentation until airway obstruction is more severe. Drug interactions: Leukotriene modifier agents: Both zafirlukast and zileuton can potentiate warfarin and theophylline as well as interact with several other medications.	Side effects of medications: Beta2-Agonists Cardiovascular effects (increased blood pressure and pulse rate, arrhythmias, myocardial necrosis). Elderly patients or patients with underlying cardiac disease must be closely monitored. Tremor and central nervous system effects (headache and irritability). Paradoxical bronchospasm may occur in some patients. Hypoxemia Metabolic effects: hypokalemia Increased bronchial hyperresponsiveness Systemic Corticosteroids Long-term use associated with risk of adrenal suppression, central nervous system complications (pseudotumor cerebri, psychiatric reactions), posterior subcapsular cataracts, glaucoma, myopathy, osteoporosis, aseptic necrosis of bone, nephrocalcinosis, nephrolithiasis, hypertension, aggravation of congestive heart failure, growth retardation, hyperglycemia (steroid diabetes), hypercalciuria, hyperlipidemia, and various cutaneous and subcutaneous manifestations. Fatal varicella has been reported with high-dose therapy. Patients exposed to chickenpox or measles should be carefully monitored. Theophylline At doses above 20 mcg/ml, side effects can include nausea, vomiting, diarrhea, headache, nervousness, tachycardia, insomnia, cardiac arrhythmias, and seizures which can result in permanent brain damage or death. Side effects can occur at lower doses in infants and older patients with sustained fever or influenza, or after medications which decrease the rate of theophylline metabolism. Cromolyn Inhaled cromolyn has the potential, in rare instances, to produce life-threatening bronchospasm associated with acute cough, chest tightness and/or other symptoms Nedocromil Occasional headaches, nausea, vomiting, dizziness, and a bad taste. Allergen immunotherapy In rare instances, allergen immunotherapy can produce a life-threatening reaction. Fatalities have occasionally been reported.
Subgroup(s) Most Likely to be Harmed	· Children taking systemic corticosteroids are vulnerable to growth suppression · Patients with coexisting conditions are more vulnerable to adverse effects of systemic corticosteroids Elderly patients or those with underlying cardiovascular disease are particularly vulnerable to side effects from beta2-agonists	· Children taking inhaled corticosteroids may experience minor growth delay or suppression (average 1 cm). · Patients with comorbid conditions (tuberculosis, parasitic infections, osteoporosis, glaucoma, hypertension, diabetes, severe depression, or peptic ulcers) may experience side effects with the use of systemic corticosteroids. Some patients exposed to herpes virus have developed fatal infections while using systemic corticosteroids, even short bursts. Patients taking a combination of beta2-agonists and theophylline have experienced adverse cardiovascular reactions.	Not stated	1. Anti-inflammatory agents Long-term linear growth does not appear to be affected by moderate doses (400-800 mcg/day) of inhaled corticosteroids, except in prepubertal males. Children may exhibit growth failure from chronic systemic corticosteroid therapy. In pregnancy, both leukotriene receptor antagonists zafirlukast and montelukast are category B while zileuton is category C. 2. Beta2-agonists: Safety and efficacy of the inhaled, long-acting beta2-agonist salmeterol has not been established in children less than 12 years of age.	· Children younger than two years of age or at puberty are particularly vulnerable to steroid-induced growth suppression when taking systemic corticosteroids. Patients exposed to chickenpox or measles should be carefully monitored when taking systemic corticosteroids. Elderly patients or those with underlying cardiac disease should be carefully monitored when taking beta2-agonists.

GUIDELINE CONTENT COMPARISON

NHLBI, WHO/NHLBI, ICSI, UMHS and AAAAI/ACAAI/JCAAI present recommendations for the diagnosis and treatment of asthma. Four of these guidelines are interrelated. NHLBI extended its original recommendations in a global initiative with WHO, resulting in the NHLBI/WHO guideline. ICSI also cites the original NHLBI guideline with regard to several aspects of treatment, discussed in greater detail below. UMHS adapted their guideline from the original NHLBI guideline.

There are several points of comparison where one or two guidelines lack information that appears in three or four of the other guidelines. ICSI does not present recommendations concerning allergen immunotherapy, prevention of exercise-induced asthma, or measures to avoid asthma triggers. ICSI also does not provide specific information concerning adverse effects of pharmacotherapy. Furthermore, ICSI does not formulate recommendations concerning pharmacologic treatment of infants and young children (under 5 years of age).. Although UMHS provides broad recommendations concerning long-term pharmacologic treatment of infants and young children (under 5 years of age), they do not formulate recommendations for pharmacologic treatment of acute exacerbations in this age group. NHLBI, WHO/NHLBI, ICSI clearly differentiate home management of acute exacerbations of asthma from emergency room/hospital management of acute exacerbations, while UMHS and AAAAI/ACAAI/JCAAI do not clearly differentiate. In discussions of pharmacologic therapy, the AAAAI/ACAAI/JCAAI guideline is the only guideline that does not discuss leukotriene modifiers (e.g., zileuton).). Zileuton did not receive FDA approval until 1996, which explains its absence in the original guideline. Leukotriene antagonists are included in an algorithm that complements and updates the guideline, issued by AAAAI/ACAAI/JCAAI in 1998 (Ann Allergy Asthma Immunol 1998;81:415-420). The AAAAI/ACAAI/JCAAI guideline contains the most comprehensive list of factors that can influence the severity of asthma. The NHLBI guideline is the only guideline to compare different aerosol delivery devices in terms of technique and therapeutic issues.

Areas of Agreement

There are few areas of agreement that encompass all guidelines. However, the four guidelines are in general agreement regarding preferred long-term controller medications and quick-relief medications. In addition, all guidelines agree on the value of patient education in the therapeutic process and the types of education that should be provided. The NHLBI guideline has integrated patient education into its model for stepwise treatment based on asthma severity.

Areas of agreement occur more often among four out of five guidelines. All guidelines, except the AAAAI/ACAAI/JCAAI guideline, generally agree on a classification scheme for asthma severity and a consequent stepwise approach to asthma treatment. As mentioned earlier, these recommendations originated in the NHLBI guideline and were subsequently adopted in the ICSI, UMHS and WHO/NHLBI guidelines. The contrasting viewpoints in the AAAAI/ACAAI/JCAAI guideline will be discussed under Areas of Differences, below. The four guidelines that report on prevention of exercise-induced asthma, NHLBI, WHO/NHLBI, UMHS, and AAAAI/ACAAI/JCAAI, generally agree on the appropriate medications to be used (although the AAAAI/ACAAI/JCAAI guideline does not mention nedocromil). The guidelines that report side effects of medications generally agree on the types of side effects that may occur with a given medication, although the range of reported side effects differs slightly among these documents. These guidelines also agree on the subgroups of patients most vulnerable to adverse effects from pharmacotherapy (children, the elderly, and patients with comorbidities). The same four guidelines are in overall agreement concerning measures to avoid asthma triggers, although the joint guideline issued by AAAAI/ACAAI/JCAAI contains less detail in their recommendations compared to the other documents.

Areas of Differences

The discussion of areas of difference among the guidelines will focus primarily on substantial differences in philosophy and implementation of therapeutic approaches. These guidelines contain a number of minor differences that would require an inordinate amount of space to enumerate (e.g., PEF >70% vs. PEF >80% in defining a good treatment response). In most cases, the overall treatment plans have more similarities than differences; therefore, noting minor differences among studies creates a false impression. The interested reader can identify relatively minor differences among guidelines in the comparison table.

Most of the major differences in recommendations among these guidelines appear when contrasting recommendations from the joint guideline issued by AAAAI/ACAAI/JCAAI with those of the other guidelines. This is mainly because the WHO/NHLBI, UMHS, and ICSI guidelines were at least partially derived from the NHLBI guideline. The most significant difference appears when comparing long-term therapeutic approaches. Whereas the other four guidelines present a stepwise plan for pharmacologic treatment based on assessment of asthma severity, the AAAAI/ACAAI/JCAAI guideline states that classifications of asthma severity are often difficult to apply toward an individualized treatment approach. For example, patients may not fit neatly into a specific category, with the results of pulmonary function tests placing them in one category and nocturnal symptoms assigning them to another. Therefore, a classification scheme is not adopted by AAAAI/ACAAI/JCAAI; instead, characteristics of asthma that deserve consideration in assessment of asthma severity are discussed. The individualized treatment philosophy expressed by AAAAI/ACAAI/JCAAI translates into a treatment plan that is not as rigidly defined as what appears in the other guidelines. This may also reflect disagreement among asthma specialists concerning what is the best widely applicable treatment program.

Another major difference occurs in the comparison of home and hospital treatments for acute asthma exacerbations. Unlike the other guidelines, the AAAAI/ACAAI/JCAAI and UMHS guidelines do not clearly differentiate home treatment from hospital treatment, and the recommendations of AAAAI/ACAAI/JCAAI seem to be based on emergency department/hospital treatment. Neither guideline provides any definition of response to therapy (e.g. good, incomplete, poor) while the other guidelines provide detailed definitions. In general, the other three guidelines provide a comprehensive treatment plan for acute exacerbations while the AAAAI/ACAAI/JCAAI guideline provides general suggestions and important issues to be considered. Among the guidelines with comprehensive plans, the ICSI guideline provides a less-detailed plan for home management of exacerbations than the other two guidelines.

Among the four guidelines providing recommendations that include infants and young children, the AAAAI/ACAAI/JCAAI and UMHS guidelines do not provide specific recommendations, and UMHS does not provide any recommendations for managing acute exacerbations in this age group. Instead, the recommendations include children of all age groups with asthma, with a few specific notations concerning infants and young children. The NHLBI and WHO/NHLBI guidelines provide specific treatment recommendations for infants and young children as one group and older children/adults as another group.

In the context of acute asthma management, the ICSI guideline is the only guideline to specifically state that critically ill patients are beyond the scope of the guideline. UMHS does not reference critically ill patients.. The other guidelines all provide some reference to treatment for critically ill patients, although they devote less space to this particular subgroup of patients. Among the four guidelines that discuss allergen immunotherapy, the AAAAI/ACAAI/JCAAI guideline does not specify the circumstances under which a patient should receive such therapy. However, this group has published a separate parameter focusing specifically on allergen immunotherapy (Practice parameters for allergen immunotherapy. J Allergy Clin Immunol 1996 Dec;98[6 Pt 1]:1001-11). The WHO/NHLBI guideline provides the most specific statements concerning when immunotherapy should be considered and issues that should be evaluated before initiating therapy. UMHS suggests that allergen immunotherapy is not indicated for most patients, but that it may have a place in the management of a subset of selected patients with extrinsic (allergic) asthma.

Although the WHO/NHLBI guideline makes a general statement concerning when to refer a patient to an asthma specialist, it is the only guideline that does not contain a list of specific recommendations concerning this issue. This may reflect the global perspective of this document; the other four guidelines were issued exclusively by organizations based in the United States. The WHO/NHLBI guideline also states that most asthma care should be provided at the primary care level. Although not specifically stated, the implication in the WHO/NHLBI guideline is that in some countries, asthma specialists are unlikely to play a significant role in asthma management. The other guidelines are in general agreement concerning the conditions under which a specialist consult is desirable, although the joint guideline produced by AAAAI, ACAAI, and JCAAI contains the most comprehensive list of conditions.

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This Synthesis was prepared by ECRI on June 12, 2000. It was reviewed by the guideline developers as of August 14, 2000.The UMHS guideline was added to this Synthesis by ECRI on December 6, 2000. It has been reviewed by UMHS as of March 8, 2001.

Internet citation: National Guideline Clearinghouse (NGC). Guideline synthesis: Asthma treatment. In: National Guideline Clearinghouse (NGC) [website]. Rockville (MD): 2000 Aug 14 (updated 2001 Mar 23). [cited YYYY Mon DD]. Available: http://www.guideline.gov.

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Edward E. Rylander,M.D.

D.A.B.F.P. AND D.A.B.P.M.