Global INitiative for Asthma 2003 安徽医科大学第一附属医院儿科 王亚亭

Program Objectives Increase appreciation of asthma as a global public health problem Present key recommendations for diagnosis and management of asthma Provide strategies to adapt recommendations to varying health needs, services, and resources Identify areas for future investigation of particular significance to the global community

GINA Workshop Report Developed during workshops conducted in cooperation with the National Heart, Lung, and Blood Institute, NIH and the World Health Organization Evidence-based Implementation oriented Diagnosis Management Prevention Outcomes can be evaluated

GINA Workshop Report Evidence Category Sources of Evidence A Randomized clinical trials Rich body of data B Randomized clinical trials Limited body of data   C Non-randomized trials Observational studies D Panel judgment consensus

GINA Workshop Report Topics: Definition Burden of Asthma Risk Factors Mechanisms Diagnosis and Classification Six Part Asthma Management Plan Education and Delivery of Care Research Recommendations

Definition of Asthma A chronic inflammatory disorder of the airways Many cells and cellular elements play a role Chronic inflammation leads to an increase in airway hyperresponsiveness with recurrent episodes of wheezing, coughing, and shortness of breath Widespread, variable, and often reversible airflow limitation

Definition of Asthma Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role Chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment

Mechanisms Underlying the Definition of Asthma Risk Factors (for development of asthma) INFLAMMATION Airway Hyperresponsiveness Airflow Obstruction Symptoms Risk Factors (for exacerbations)

Mechanisms of Asthma APC Mast Cell TH2 Cells Neutrophil Eosinophil Antigen APC Mast Cell TH2 Cells Neutrophil Eosinophil Mucus plug Epithelia N. Activating E. fibrosis Mucus hypersecretion Sensory nerves activating Vascular dilatation Plasma exudation and edema Smooth muscle contraction and hypertrophy

Acute on chronic inflammation Rapid acting β2 agonist ＋systematic steroid Acute inflammation Attack ICS chronic inflammation ICS ＋LABA＋theophyline Airway reconstruction Time

GINA Workshop Report Topics: Definition Burden of Asthma Risk Factors Mechanisms Diagnosis and Classification Six Part Asthma Management Plan Education and Delivery of Care Research Recommendations

Burden of Asthma Asthma is one of the most common chronic diseases worldwide Prevalence increasing in many countries, especially in children A major cause of school/work absence An overall increase in severity of asthma increases the pool of patients at risk for death

Worldwide Variation in Prevalence of Asthma Symptoms International Study of Asthma and Allergies in Children (ISAAC) Lancet 1998;351:1225

Increasing Prevalence of Asthma in Children/Adolescents { Finland (Haahtela et al) 1966 1989 { Sweden (Aberg et al) 1979 1991 { Japan (Nakagomi et al) 1982 1992 { Scotland (Rona et al) 1982 1992 { UK (Omran et al) 1989 1994 { USA (NHIS) 1982 1992 { New Zealand (Shaw et al) 1975 1989 { Australia (Peat et al) 1982 1992 5 10 15 20 25 30 35 Prevalence (%)

Prevalence of Asthma in Children/Adolescents in China 1990 2000 1.87 0.91 % Total Age

Prevalence of Asthma in Children/Adolescents in China Province / City population investigated Prevalence％ Chongqing 11200 4.63 Shanghai 14468 4.52 Sichuan 10221 4.20 Fujian 10029 4.06 Jiangsu 16282 3.11 Anhui 10901 3.05 Shan(陕)xi 12613 2.71 Beijing 10163 2. 69 Guangxi 11238 2.33 Hubei 9137 1.89 Whole Nation 345446 1.87

Trends in Prevalence of Asthma By Age, U.S., 1985-1996 Rate/1,000 Persons 80 Age (years) 70 <18 18-44 45-64 65+ Total (All Ages) 60 50 40 30 20 85 86 87 88 89 90 91 92 93 94 95 96 Year

Hospitalization Rates for Asthma by Age, U.S., 1974 - 1997 Rate/100,000 Persons 40 35 <15 15-44 45-64 65+ 30 25 20 15 10 5 74 76 78 80 82 84 86 88 90 92 94 96 Year

Death Rates for Asthma By Race, Sex, U.S., 1980-1998 Rate/100,000 Persons 5 Black Female 4 Black Male 3 White Female 2 White Male 1 1980 1985 1990 1995 2000 Year

GINA Workshop Report Topics: Definition Burden of Asthma Risk Factors Mechanisms Diagnosis and Classification Six Part Asthma Management Plan Education and Delivery of Care Research Recommendations

Risk Factors for Asthma Host factors: predispose individuals to, or protect them from, developing asthma Environmental factors: influence susceptibility to development of asthma in predisposed individuals, precipitate asthma exacerbations, and/or cause symptoms to persist

Factors that Exacerbate Asthma Allergens Air Pollutants Respiratory infections Exercise and hyperventilation Weather changes Sulfur dioxide Food, additives, drugs

Risk Factors that Lead to Asthma Development Host Factors Genetic predisposition Atopy Airway hyper- responsiveness Gender Race/Ethnicity Environmental Factors Indoor allergens Outdoor allergens Occupational sensitizers Tobacco smoke Air Pollution Respiratory Infections Parasitic infections Socioeconomic factors Family size Diet and drugs Obesity

GINA Workshop Report Topics: Definition Burden of Asthma Risk Factors Mechanisms Diagnosis and Classification Six Part Asthma Management Plan Education and Delivery of Care Research Recommendations

Mechanisms of Asthma APC Mast Cell TH2 Cells Neutrophil Eosinophil Antigen APC Mast Cell TH2 Cells Neutrophil Eosinophil Mucus plug Epithelia N. Activating E. fibrosis Mucus hypersecretion Sensory nerves activating Vascular dilatation Plasma exudation and edema Smooth muscle contraction and hypertrophy

GINA Workshop Report Topics: Definition Burden of Asthma Risk Factors Mechanisms Diagnosis and Classification Six Part Asthma Management Plan Education and Delivery of Care Research Recommendations

Is it Asthma? Recurrent episodes of wheezing Troublesome cough at night Cough or wheeze after exercise Cough, wheeze or chest tightness after exposure to airborne allergens or pollutants Colds “go to the chest” or take more than 10 days to clear

Asthma Diagnosis History and patterns of symptoms Physical examination Measurements of lung function Measurements of allergic status to identify risk factors

Typical Spirometric (FEV1) Tracings Volume FEV1 Normal Subject Asthmatic (After Bronchodilator) Asthmatic (Before Bronchodilator) 1 2 3 4 5 Time (sec) Note: Each FEV1 curve represents the highest of three repeat measurements

A Simple Index of PEF Variation

Clinical Features Before Treatment Classification of Severity CLASSIFY SEVERITY Clinical Features Before Treatment Nocturnal Symptoms Symptoms FEV1 or PEF Continuous Limited physical activity STEP 4 Severe Persistent  60% predicted Variability > 30% Frequent 60 - 80% predicted Variability > 30% STEP 3 Moderate Persistent Daily Attacks affect activity > 1 time week STEP 2 Mild Persistent > 2 times a month  80% predicted Variability 20 - 30% > 1 time a week but < 1 time a day < 1 time a week Asymptomatic and normal PEF between attacks STEP 1 Intermittent  80% predicted Variability < 20%  2 times a month The presence of one feature of severity is sufficient to place patient in that category.

GINA Workshop Report Topics: Definition Burden of Asthma Risk Factors Mechanisms Diagnosis and Classification Six Part Asthma Management Plan Education and Delivery of Care Research Recommendations

Six-Part Asthma Management Program 1. Educate patients to develop a partnership in asthma management 2. Assess and monitor asthma severity with symptom reports and measures of lung function as much as possible 3. Avoid exposure to risk factors 4. Establish medication plans for chronic management in children and adults 5. Establish individual plans for managing exacerbations 6. Provide regular follow-up care

Goals of Long-term Management Six-part Asthma Management Program Goals of Long-term Management Achieve and maintain control of symptoms Prevent asthma episodes or attacks Maintain pulmonary function as close to normal levels as possible Maintain normal activity levels, including exercise Avoid adverse effects from asthma medications Prevent development of irreversible airflow limitation Prevent asthma mortality

Control of Asthma Minimal (ideally no) chronic symptoms Six-part Asthma Management Program Control of Asthma Minimal (ideally no) chronic symptoms Minimal (infrequent) exacerbations No emergency visits Minimal (ideally no) need for “as needed” use of β2-agonist No limitations on activities, including exercise PEF circadian variation of less than 20 percent (Near) normal PEF Minimal (or no) adverse effects from medicine

. Six-Part Asthma Management Program The most effective management is to prevent airway inflammation by eliminating the causal factors Asthma can be effectively controlled in most patients, although it can not be cured The major factors contributing to asthma morbidity and mortality are under-diagnosis and inappropriate treatment Any asthma more severe than intermittent asthma is more effectively controlled by treatment to suppress and reverse airway inflammation than by treatment only of acute bronchoconstriction and symptoms

Six-part Asthma Management Program Part 1: Educate Patients to Develop a Partnership Patient education involves a partnership between the patient and health care professional(s) with frequent revision and reinforcement Aim is guided self-management – giving patients the ability to control their asthma Interventions, including use of written action plans, have been shown to reduce morbidity in both children and adults

Six-part Asthma Management Program Part 1: Educate Patients to Develop a Partnership Guidelines on asthma management should be available but adapted and adopted for local use by local asthma planning teams Clear communication between health care professionals and asthma patients is key to enhancing compliance

Provide information about asthma Six-part Asthma Management Program Part 1: Educate Patients to Develop a Partnership Educate continually Include the family Provide information about asthma Provide training on self-management skills Emphasize a partnership among health care providers, the patient, and the patient’s family

Medication Usage Patient/Physician Six-part Asthma Management Program Factors Associated with Non-Compliance in Asthma Care Medication Usage Difficulties associated with inhalers Complicated regimens Fears about, or actual side effects Cost Patient/Physician Misunderstanding/lack of information Underestimation of severity Attitudes toward ill health Cultural factors Poor communication

Six-part Asthma Management Program Part 2: Assess and Monitor Asthma Severity with Symptom Reports and Measures of Lung Function Symptom reports Use of reliever medication Nighttime symptoms Activity limitations Spirometry for initial assessment. Peak Expiratory Flow for follow-up: Assess severity Assess response to therapy PEF monitoring at home Important for those with poor perception of symptoms Daily measurement recorded in a diary Assesses the severity and predicts worsening Guides the use of a zone system for asthma self-management Arterial blood gas for severe exacerbations

Typical Spirometric (FEV1) Tracings Volume FEV1 Normal Subject Asthmatic (After Bronchodilator) Asthmatic (Before Bronchodilator) 1 2 3 4 5 Time (sec) Note: Each FEV1 curve represents the highest of three repeat measurements

A Simple Index of PEF Variation

Six-part Asthma Management Program Part 3: Avoid Exposure to Risk Factors Methods to prevent onset of asthma are not yet available but this remains an important goal Measures to reduce exposure to causes of asthma exacerbations (e.g. allergens, pollutants, foods and medications) should be implemented whenever possible

Reduce exposure to indoor allergens Avoid tobacco smoke Six-part Asthma Management Program Part 3: Avoid Exposure to Risk Factors Reduce exposure to indoor allergens Avoid tobacco smoke Avoid vehicle emission Identify irritants in the workplace Explore role of infections on asthma development, especially in children and young infants

Six-part Asthma Management Program Part 4: Establish Medication Plans for Long-Term Asthma Management in Infants and Children At present, inhaled glucocorticosteroids are the most effective controller medications and are recommended for persistent asthma at any step of severity Long-term treatment with inhaled glucocorticosteroids markedly reduces the frequency and severity of exacerbations

Part 4: Establish Medication Plans for Long-Term Asthma Management Six-part Asthma Management Program Part 4: Establish Medication Plans for Long-Term Asthma Management A stepwise approach to pharmacological therapy is recommended The aim is to accomplish the goals of therapy with the least possible medication Although in many countries traditional methods of healing are used, their efficacy has not yet been established and their use can therefore not be recommended

Stepwise Approach to Asthma Therapy Part 4: Long-term Asthma Management Stepwise Approach to Asthma Therapy The choice of treatment should be guided by: Severity of the patient’s asthma Patient’s current treatment Pharmacological properties and availability of the various forms of asthma treatment Economic considerations Cultural preferences and differing health care systems need to be considered.

Pharmacologic Therapy Part 4: Long-term Asthma Management Pharmacologic Therapy Controller Medications: Inhaled glucocorticosteroids Systemic glucocorticosteroids Cromones Methylxanthines Long-acting inhaled β2-agonists Long-acting oral β2-agonists Leukotriene modifiers Anti-IgE

Reliever Medications: Part 4: Long-term Asthma Management Pharmacologic Therapy Reliever Medications: Rapid-acting inhaled β2-agonists Systemic glucocorticosteroids Anticholinergics Methylxanthines Short-acting oral β2-agonists

Estimated Comparative Daily Dosages for Inhaled Glucocorticosteroids Drug Low Daily Dose (g) Adult Child Medium Daily Dose (g) Adult Child High Daily Dose (g) Beclomethasone-CFC 200-500 100-250 500-1000 250-500 > 1000 > 500 Beclomethasone-HFA 100-250 50-200 250-500 200-400 > 500 > 400 Budesonide-DPI 200-600 100-200 600-1000 200- 600 > 1000 > 600 Budesonide-Neb 250-500 500-1000 >1000 Flunisolde 500-1000 500 -750 1000-2000 750-1250 > 2000 > 1250 Fluticasone 100- 250 100-200 250- 500 200- 400 Mometasone furoate 200- 400 400- 800 > 800 Triamcinolone acetonide 400- 1000 400-800 1000-2000 800-1200 > 2000 > 1200

Outcome: Best Possible Results Outcome: Asthma Control Part 4: Long-term Asthma Management Stepwise Approach to Asthma Therapy - Adults Outcome: Best Possible Results Outcome: Asthma Control Controller: Daily inhaled corticosteroid plus Daily long –acting inhaled β2-agonist plus (if needed) When asthma is controlled, reduce therapy Monitor Controller: Daily inhaled corticosteroid plus Daily long-acting inhaled β2-agonist Controller: Daily inhaled corticosteroid Controller: None -Theophylline-SR -Leukotriene -Long-acting inhaled β2- agonist -Oral corticosteroid Reliever: Rapid-acting inhaled β2-agonist prn STEP 1: Intermittent STEP 2: Mild Persistent STEP 3: Moderate Persistent STEP 4: Severe Persistent STEP Down Alternative controller and reliever medications may be considered (see text).

Recommended Asthma Medications Step 1: Adults Severity Daily Controller Medications Other Options (in order of cost) Step 1: Intermittent None Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Recommended Asthma Medications Step 2: Adults Severity Daily Controller Medications Other Options (in order of cost) Step 2: Mild Persistent Low-dose inhaled glucocorticosteroid Sustained-release theophylline, or Cromone, or Leukotriene modifier Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Recommended Asthma Medications Step 3: Adults Severity Daily Controller Medications Other Options (in order of cost) Step 3: Moderate persistent Low- to medium-dose inhaled glucocortico-steroid plus long-acting inhaled β2- agonist Medium-dose inhaled glucocorticosteroid plus sustained- release theophylline, or Medium-dose inhaled glucocorticosteroid plus long-acting inhaled β2- agonist, or High-dose inhaled glucocorticosteroid, or Medium-dose inhaled glucocorticosteroid plus leukotriene modifier Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Recommended Asthma Medications Step 4: Adults Severity Daily Controller Medications Other Options Step 4 Severe persistent High-dose inhaled glucocorticosteroid plus long-acting inhaled β2- agonist plus one or more of the following, if needed: - Sustained-release theophylline - Leukotriene modifier - Long-acting inhaled β2- agonist - Oral glucocorticosteroid Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Allergen-specific Immunotherapy Part 4: Long-term Asthma Management Allergen-specific Immunotherapy Greatest benefit of specific immunotherapy using allergen extracts has been obtained in the treatment of allergic rhinitis A number of questions must be addressed regarding the role of specific immunotherapy in asthma therapy Specific immunotherapy should be considered only after strict environmental avoidance and pharmacologic intervention, including inhaled glucocorticosteroids, have failed to control asthma Perform only by trained physician

Six-part Asthma Management Program Part 4: Establish Medication Plans for Long-Term Asthma Management in Infants and Children Childhood and adult asthma share the same underlying mechanisms. However, because of processes of growth and development, effects of asthma treatments in children differ from those in adults.

Six-part Asthma Management Program Part 4: Establish Medication Plans for Long-Term Asthma Management in Infants and Children Many asthma medications (e.g. glucocorticosteroids, β2- agonists, theophylline) are metabolized faster in children than in adults, and younger children tend to metabolize medications faster than older children

Six-part Asthma Management Program Part 4: Establish Medication Plans for Long-Term Asthma Management in Infants and Children Long-term treatment with inhaled glucocorticosteroids has not been shown to be associated with any increase in osteoporosis or bone fracture Studies including a total of over 3,500 children treated for periods of 1 – 13 years have found no sustained adverse effect of inhaled glucocorticosteroids on growth

Six-part Asthma Management Program Part 4: Establish Medication Plans for Long-Term Asthma Management in Infants and Children Rapid-acting inhaled β2- agonists are the most effective reliever therapy for children These medications are the most effective bronchodilators available and are the treatment of choice for acute asthma symptoms

Recommended Asthma Medications Step 1: Children Younger Than 5yrs Severity Daily Controller Medications Other Options (in order of cost) Step 1: Intermittent None Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Recommended Asthma Medications Step 2: Children Younger Than 5 yrs Severity Daily Controller Medications Other Options (in order of cost) Step 2: Mild Persistent Low-dose inhaled glucocorticosteroid Sustained-release theophylline, or Cromone, or Leukotriene modifier Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Recommended Asthma Medications Step 3: Children Younger Than 5yrs Severity Daily Controller Medications Other Options (in order of cost) Step 3: Moderate persistent Medium-dose inhaled glucocorticosteroid Medium-dose inhaled glucocorticosteroid plus sustained-release theophylline, or Medium-dose inhaled glucocorticosteroid plus long-acting inhaled β2- agonist, or High-dose inhaled glucocorticosteroid, or Medium-dose Inhaled glucocorticosteroid plus leukotriene modifier Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Recommended Asthma Medications Step 4: Children Younger Than 5yrs Severity Daily Controller Medications Other Options Step 4 Severe persistent High-dose inhaled glucocorticosteroid plus one or more of the following, if needed: - Sustained-release theophylline - Leukotriene modifier - Long-acting inhaled β2- agonist - Oral glucocorticosteroid Reliever Medication: Rapid-acting inhaled β2- agonist prn, not more than 3-4 times a day. Once control is achieved and maintained for at least 3 months, gradual reduction of therapy should be tried.

Treatment of exacerbations depends on: The patient Six-part Asthma Management Program Part 5: Establish Plans for Managing Exacerbations Treatment of exacerbations depends on: The patient Experience of the health care professional Therapies that are the most effective for the particular patient Availability of medications Emergency facilities

Primary therapies for exacerbations: Six-part Asthma Management Program Part 5: Establish Plans for Managing Exacerbations Primary therapies for exacerbations: Repetitive administration of rapid-acting inhaled β2-agonist Early introduction of systemic glucocorticosteroids Oxygen supplementation Closely monitor response to treatment with serial measures of lung function

Severe exacerbations are life-threatening medical emergencies Six-part Asthma Management Program Part 5: Managing Severe Asthma Exacerbations Severe exacerbations are life-threatening medical emergencies Care must be expeditious and treatment is often most safely undertaken in a hospital or hospital-based emergency department

Emergency Department Management Acute Asthma Initial Assessment History, Physical Examination, PEF or FEV1 Initial Therapy Bronchodilators; O2 if needed Incomplete/Poor Response Add Systemic Glucocorticosteroids Good Response Discharge Poor Response Admit to Hospital Good Response Observe for at least 1 hour If Stable, Discharge to Home Respiratory Failure Admit to ICU

Continual monitoring is essential to assure that Six-part Asthma Management Program Part 6: Provide Regular Follow-up Care Continual monitoring is essential to assure that therapeutic goals are met. Frequent follow-up visits are necessary to review: Home PEF and symptom records Techniques in use of medications Risk factors and their control Once asthma control is established, follow-up visits should be scheduled (at 1 to 6 month intervals as appropriate)

Six-part Asthma Management Program Special Considerations Special considerations are required to manage asthma in relation to: Pregnancy Surgery Physical activity Rhinitis, sinusitis, and nasal polyps Occupational asthma Respiratory infections Gastroesophageal reflux Aspirin-induced asthma

Six-part Asthma Management Program: Summary Asthma can be effectively controlled, although it cannot be cured Effective asthma management programs include education, objective measures of lung function, environmental control, and pharmacologic therapy A stepwise approach to pharmacologic therapy is recommended. The aim is to accomplish the goals of therapy with the least possible medication

Six-part Asthma Management Program: Summary (continued) Anything more than mild, occasional asthma is more effectively controlled by suppressing inflammation than by only treating acute bronchospasm The availability of varying forms of treatment, cultural preferences, and differing health care systems need to be considered

Outcome: Best Possible Results Outcome: Asthma Control Part 4: Long-term Asthma Management Stepwise Approach to Asthma Therapy Outcome: Best Possible Results Outcome: Asthma Control Controller: Daily inhaled corticosteroid Daily long –acting inhaled β2-agonist plus(if needed) When asthma is controlled, reduce therapy Monitor Controller: Daily inhaled corticosteroid Daily long-acting inhaled β2-agonist Controller: Daily inhaled corticosteroid Controller: None -Theophylline-SR -Leukotriene -Long-acting inhaled β2- agonist -Oral corticosteroid Reliever: Rapid-acting inhaled β2-agonist prn STEP 1: Intermittent STEP 2: Mild Persistent STEP 3: Moderate Persistent STEP 4: Severe Persistent STEP Down Alternative controller and reliever medications may be considered (see text).

Step 1: Intermittent Asthma Stepwise Approach to Asthma Therapy Step 1: Intermittent Asthma Reliever Medications Daily Controller Medications Rapid-acting inhaled 2-agonist for symptoms (but < once a week) Rapid-acting inhaled 2-agonist, cromone, or leukotriene modifier before exercise or exposure to allergen None required Continuously review medication technique, compliance and environmental control Review treatment every three months. Step up if control is not achieved; step down if control is sustained for at least 3 months Preferred treatments are in bold print

Daily Controller Medications Stepwise Approach to Asthma Therapy Step 2: Mild Persistent Asthma Daily Controller Medications Reliever Medications Low-dose inhaled glucocorticosteroid Other options (order by cost): sustained-release theophylline, or Cromone, or leukotriene modifier Rapid-acting inhaled 2-agonist for symptoms (but < 3-4 times/day) Other options: inhaled anticholinergic, or short-acting oral 2-agonist, or short-acting theophylline Continuously review medication technique, compliance and environmental control. Review treatment every three months Step up if control is not achieved; Step down if control is sustained for at least 3 months Preferred treatments are in bold print

Step 3: Moderate Persistent Asthma Stepwise Approach to Asthma Therapy Step 3: Moderate Persistent Asthma Daily Controller Medications Reliever Medications Low- to medium-dose inhaled glucocortico- steroid, plus long-acting inhaled 2-agonist Other options (order by cost): Medium-dose inhaled glucocorticosteroid plus sustained-release theophylline, or Medium-dose inhaled glucocorticosteroid plus long-acting inhaled β2- agonist, or High-dose inhaled glucocorticosteroid, or Medium-dose inhaled glucocorticosteroid plus leukotriene modifier Rapid-acting inhaled 2-agonist for symptoms (but < 3 - 4 times/day) Other options: inhaled anticholinergic or short-acting oral 2-agonist or short-acting theophylline Continuously review medication technique, compliance and environmental control. Review treatment every three months. Step up if control is not achieved; Step down if control is sustained for at least 3 months. Preferred treatments are in bold print.

Step 4: Severe Persistent Asthma Stepwise Approach to Asthma Therapy Step 4: Severe Persistent Asthma Daily Controller Medications Reliever Medications High-dose inhaled glucocorticosteroid, plus long-acting inhaled β2agonist plus one or more of the following, if needed (order by cost): sustained-release theophylline, or leukotriene modifier or oral glucocorticosteroid Rapid-acting inhaled 2-agonist for symptoms (but < 3-4 times/day) Other options: inhaled anticholinergic or short-acting oral 2-agonist or short-acting theophylline Continuously review medication technique, compliance and environmental control. Review treatment every three months. Step up if control is not achieved; Step down if control is sustained for at least 3 months. Preferred treatments are in bold print.

谢 ！