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Asthma in Adults

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Jun.16.2023

Asthma in Adults

Synopsis

Key Points

  • Asthma in adults may be persistence of childhood-onset asthma (usually allergic) or may reflect new onset in adulthood (often nonallergic)
  • Presents with episodic wheezing, chest tightness, difficulty breathing, and cough; cough variant asthma may present with coughing as primary symptom
  • Diagnosis is based on appropriate history plus clinical picture and documented reversibility of airflow obstruction (12% increase or more from baseline in FEV₁; minimum 200 mL) after treatment with an inhaled short-acting bronchodilator r1
  • Classify the asthma initially by frequency of symptoms (intermittent or persistent) and their effect on daily functioning (ie, mild, moderate, severe); initial pharmacotherapy is based on this classification
  • After starting pharmacotherapy, classify the asthma by level of control; pharmacotherapies are stepped up or down based on this level
  • Persistent asthma requires use of a daily controller medication, starting with a low-dose inhaled corticosteroid for mild persistent asthma. There is some evidence that starting inhaled corticosteroids may be beneficial even for mild intermittent asthma
  • Step up to an inhaled long-acting β₂-agonist with increasing doses of inhaled corticosteroids as needed. Leukotriene inhibitors are alternative add-on drugs
  • Begin treatment of an acute exacerbation with an inhaled short-acting β₂-agonist; add steroids that have systemic effects and inhaled anticholinergics for exacerbations classified as severe. On discharge from emergency department, consider initiating corticosteroids in patients who have not previously used them
  • In emergency care setting, discharge goal is improvement to 70% or more of predicted FEV₁ or peak expiratory flow
  • Smoking cessation, education, home monitoring with a peak flow meter, and asthma action plans are important aspects of long-term management

Urgent Action

  • Quickly assess the following in any patient with respiratory distress: vital signs, signs of tiring from work of breathing, lung function, and oxygen saturation. Give supplemental oxygen to maintain SaO₂ of at least 90%
  • Consider alternative diagnoses, such as foreign body aspiration or congestive heart failure, that would require other urgent action
  • FEV₁ or peak expiratory flow measurement is helpful to assess severity of an exacerbation, but do not allow testing to delay treatment
  • Begin treatment of mild to moderate asthma exacerbation with short-acting β₂-agonist via inhaler with spacer or nebulizer; for severe asthma, continuous administration via nebulizer is recommended
  • Give inhaled ipratropium in addition to short-acting β₂-agonist for exacerbations classified as severe or life-threatening r1

Pitfalls

  • Physical examination is not a reliable indicator of the severity of airflow obstruction; wheezing may be inaudible in severe asthma exacerbation
  • Athletes and older adults may underreport symptoms or attribute them to other causes
  • Bronchoprovocation with methacholine, histamine, cold air, or exercise challenge may be useful when asthma is suspected and spirometry results are within reference range or nearly so

Terminology

Clinical Clarification

  • Asthma is a chronic inflammatory airway disease causing episodic, acute airflow obstruction and/or increased airway reactivity that is totally or partially reversible (with or without therapy) in a patient who has normal laryngeal function and lacks an alternative diagnosis r1
  • Clinically presents as recurrent episodes of coughing and wheezing
  • Reversibility is defined as 12% increase or more from baseline in FEV₁ (minimum 200 mL) after treatment with an inhaled short-acting bronchodilator r1

Classification

  • Classification of asthma severity (patients not currently using controller medication) r1
    • Intermittent asthma r1
      • Symptoms occur 2 or fewer days per week
      • No interference with normal activity
      • Nighttime awakenings 2 times per month or less
      • Use of short-acting β₂-agonist for symptom control 2 days per week or less
      • Lung function
        • FEV₁ (predicted within reference range for patient between exacerbations) greater than 80%
        • FEV₁/FVC within reference range
      • 1 or fewer exacerbations per year requiring corticosteroids with systemic effects
        • If patient otherwise meets criteria for intermittent asthma but has at least 2 exacerbations per year that require corticosteroids with systemic effects, this is considered persistent asthma
    • Mild persistent asthma r1
      • Symptoms occur more than 2 days per week, but not daily
      • Minor limitation to normal activity
      • Nighttime awakenings 3 to 4 times per month
      • Use of short-acting β₂-agonist for symptom control more than 2 days per week, but not daily and not more than 1 time on any day
      • Lung function
        • FEV₁ 80% predicted or higher
        • FEV₁/FVC within reference range
      • 2 or more exacerbations per year that require corticosteroids with systemic effects
    • Moderate persistent asthma r1
      • Symptoms occur daily
      • Some limitation to normal activity
      • Nighttime awakenings more than once per week, but not nightly
      • Use of short-acting β₂-agonist for daily symptom control
      • Lung function
        • FEV₁ 60% to 80% predicted
        • FEV₁/FVC is reduced by 5%
      • 2 or more exacerbations per year that require corticosteroids with systemic effects
    • Severe persistent asthma r1
      • Symptoms occur daily and throughout the day
      • Extreme limitation of normal activity
      • Nightly awakenings
      • Use of short-acting β₂-agonist daily for symptom control multiple times per day
      • Lung function
        • FEV₁ less than 60% predicted
        • FEV₁/FVC reduced by more than 5%
      • 2 or more exacerbations per year that require corticosteroids with systemic effects
  • Classification of asthma control (patients using controller medication)
    • Well controlled r1
      • Symptoms occur 2 or fewer days per week
      • No interference with normal activities
      • Nighttime awakenings 2 times per month or less
      • FEV₁ (predicted) or peak expiratory flow (personal best) greater than 80%
    • Not well controlled r1
      • Symptoms occur more than 2 days per week
      • Some limitation of normal activities
      • Nighttime awakenings 1 to 3 times per week
      • FEV₁ (predicted) or peak expiratory flow (personal best) 60% to 80%
    • Very poorly controlled r1
      • Symptoms occur throughout the day
      • Extreme limitation of normal activities
      • Nighttime awakenings 4 or more times per week
      • FEV₁ (predicted) or peak expiratory flow (personal best) less than 60%
  • Classification of acute exacerbations (worsening of baseline function)
    • Mild r1
      • Dyspnea only with activity
      • Peak expiratory flow of 70% or higher of predicted or personal best
    • Moderate r1
      • Dyspnea limits usual activity
      • Peak expiratory flow 40% to 69% of predicted or personal best
    • Severe r1
      • Dyspnea at rest
      • Peak expiratory flow lower than 40% predicted or personal best
    • Life-threatening r1
      • Too dyspneic to speak
      • Peak expiratory flow lower than 25% of predicted or personal best
    • Status asthmaticus
      • Continuous, severe asthma exacerbation resistant to treatment
  • Classification by phenotype r2
    • Intrinsic (nonallergic) r1
      • Common phenotype in late/adult-onset asthma
      • Occurs in patients with no history of allergies
      • May be triggered by upper respiratory tract infection or other factors
    • Allergic asthma
      • Associated with elevated blood IgE level
      • Early/childhood onset
    • Eosinophilic asthma
      • Late/adult onset
      • Associated with airway eosinophilia
      • Blood/sputum eosinophil count is a predictive biomarker for increased severity of asthma attacks
      • Agents targeting eosinophils (interleukin-5 inhibitors) may improve asthma control
    • Aspirin-exacerbated respiratory disease
      • Presents as allergy to NSAIDs
      • Late/adult onset
      • Often severe and may be accompanied by sinusitis and nasal polyposis
    • Neutrophilic asthma
      • Associated with airway neutrophils and elevated levels of interleukin-8
      • Late/adult onset
      • Neutrophils in the airways are associated with reduced lung function and airway wall thickening
      • Usually occurs in patients treated with corticosteroids and presents challenge to management
    • Obesity-associated asthma
      • Late/adult onset
      • Poor response to corticosteroid therapy
      • Weight loss may improve symptoms
    • Exercise-induced asthma
      • Early onset
      • May occur in patients with or without underlying asthma r3
      • Presents intermittently with strenuous exercise
        • FEV₁ or peak expiratory flow decreases 10% to 15% soon after onset of vigorous activity (compared with measurement just before exercise) r1r3
        • May persist up to 30 minutes after exerciser3
    • Severe asthma phenotype
      • Subtype that is difficult to treat and control; estimated to affect approximately 5% to 10% of patients r2r4
      • 50% of patients with severe asthma have evidence of type 2 inflammation and may be candidates for treatment with biologic agents that target this type of inflammation r5
    • Cough variant asthma r6
      • Manifests with nonproductive cough, often without usual wheezing and shortness of breath associated with asthma

Diagnosis

Clinical Presentation

History

  • Episodic dyspnea is the most common symptom c1
    • Present on exertion in mild to moderate asthma c2
    • Present at rest in severe asthma c3
    • Athletes may report decreased exercise tolerance c4
    • Nocturnal dyspnea with awakenings is common c5
    • Inability to take a deep breath c6
  • Cough, especially nocturnal or in the early morning c7c8c9
    • Usually nonproductive; sometimes produces sputum c10c11
  • Chest tightness c12
  • Wheezing may be audible to patient c13
    • Breathlessness, cough, wheezing, and/or sputum production that begin shortly after onset of vigorous exercise are suggestive of exercise-induced asthma c14c15c16c17c18
  • Patient may report recent exposure to common allergic and nonallergic triggers c19
  • Baseline level of disease control may change in patients who adhere to treatment plans
  • Level of short-acting β₂-agonist use, steroid use, and number/severity of exacerbations in the past year are indicative of disease control

Physical examination

  • Results are typically within reference range in a patient with well-controlled asthma
    • There may be evidence of associated diseases, such as nasal secretions and mucosal edema (allergic rhinitis) or rash (atopic eczema) c20c21c22c23
    • Nasal polyps may be present c24
  • During exacerbation
    • General appearance
      • May be anxious c25
      • Labored breathing c26
      • Diaphoresis with increased respiratory effort c27c28
      • Cyanosis with significant hypoxia c29c30
      • Drowsiness with impending respiratory failure c31
    • Vital signs
      • Tachypnea and tachycardia c32c33
      • With severe exacerbation:
        • Sustained tachypnea exceeding 30 breaths per minute and tachycardia exceeding 120 beats per minute c34c35
        • May eventually become apneic c36
        • Pulsus paradoxus (more than 10 mm Hg drop in systemic arterial pressure with inspiration) is often greater than 18 mm Hg but may disappear with fatigue c37
    • Respiratory examination
      • Prolonged expiratory phase c38
      • Use of respiratory accessory muscles/intercostal muscle recession c39c40
      • Wheezing is usually present during exacerbation, but absence of wheezing does not rule out significant bronchospasm c41

Causes and Risk Factors

Causes

  • Underlying causes are incompletely understood; may be environmental in combination with genetic interaction c42c43
  • Exacerbation triggers
    • Aeroallergens (eg, pollen, pet dander, dust mites, mold) c44c45c46c47c48
    • Airborne irritants (eg, cigarette or wood smoke, air pollution, chemical compounds, grain dust) c49c50c51c52
    • Drugs (eg, aspirin, NSAIDs, β-blockers) c53c54c55
    • Ingested substances (eg, foods, sulfites) c56c57
    • Respiratory infection c58
    • Exercise c59
    • Cold air c60
    • Psychological stress c61

Risk factors and/or associations

Age
  • Asthma in adults may be either persistent childhood-onset asthma or new-onset asthma in adulthood c62
Sex
  • Higher prevalence in women c63c64
Genetics
  • Predisposed sensitivity to environmental allergens is strongest risk factor c65
Ethnicity/race
  • Higher prevalence in Hispanic and Black populations than in White population c66c67c68
Other risk factors/associations
  • In females, obesity or increased waist circumference c69c70
    • Large waist circumference (more than 88 cm) is associated with increased asthma prevalence, even among women with a BMI within reference range r7
  • Adjusted odds ratio for adult-onset asthma increases from 1.4 for overweight women to 3.3 for extremely obese women r7c71
  • Presence of the following risk factors increases risk for exacerbations, even if patients have few symptoms r4
    • Previous intubation or intensive care unit admission for asthma
    • 1 or more severe exacerbations in the past year
    • Low FEV₁ (especially if lower than 60% predicted)
    • Exposures
      • Smoking c72
      • Allergens, if sensitized c73
      • Air pollution c74
    • Comorbidities
      • Chronic rhinosinusitis c75
      • Obesity c76
      • Food allergy c77
      • Pregnancy c78
      • Gastroesophageal reflux disease c79
    • Medications
      • Frequent use of short-acting β-agonists c80
      • Inhaled corticosteroids not prescribed or at inadequate dose
      • Poor adherence or inhaler technique c81

Diagnostic Procedures

Primary diagnostic tools

  • New diagnosis
    • History and physical examination suggest the diagnosis r1c82
    • Perform spirometry; obstruction (FEV₁/FVC ratio of 70% or less) with reversibility after bronchodilator administration (12% increase or more from baseline in FEV₁; minimum 200 mL) strongly supports the diagnosis r1c83
      • However, in an asymptomatic patient, normal spirometry results do not rule out an asthma diagnosis
    • Measurement of fractional nitric oxide concentration in exhaled breath (FeNO) may be helpful in the initial diagnosis of asthma as a surrogate marker of eosinophilic airway inflammation c84
      • NICE guidelinesr8 and American Thoracic Societyr9 recommend that this be performed routinely in the diagnostic evaluation of adults
      • Other guidelines suggest utility in confirming asthma when symptoms and signs suggest asthma, but spirometry is not definitive r10r11
      • Measurement of fractional nitric oxide concentration in exhaled breath is also sometimes used as an alternative strategy for guiding therapy, but recent evidence is not supportive of this r4r12
    • Additional testing is not routinely necessary, but it may be helpful in some situations r1
      • Repeated peak flow measures over a period of weeks; variability above 20% within the measurement period supports the diagnosis of asthma r8r10c85
        • Variability less than 20% does not exclude asthma r10
      • Bronchoprovocation when asthma is suspected and spirometry is within (or nearly within) reference range r1r10c86
      • Full pulmonary function testing to differentiate from chronic obstructive pulmonary disease in smokers r1c87
      • Skin testing or in vitro allergy testing to assess sensitivity to perennial indoor allergens for patients with persistent asthma r1c88
      • Peripheral blood eosinophil count and serum IgE level to assess for eosinophilic phenotype, which may later guide therapy; not useful for diagnosis r10r13c89c90
      • Exercise-induced asthma, suggested by respiratory symptoms associated with vigorous exercise, may be confirmed by serial changes in lung function (FEV₁ preferred) after exercise or hyperpnea challenge r3c91
  • Acute exacerbation c92
    • History and physical examination suggest the diagnosis
    • Immediate FEV₁ or peak expiratory flow measurement to determine severity of exacerbation
      • A peak flow rate below 200 L/minute generally indicates severe airway obstruction r1
    • Immediate assessment of oxygenation with pulse oximeter
    • Arterial blood gas measurement is not routine, but it may be helpful in staging exacerbation to guide treatment or if there is poor response to repeated treatments r1c93
    • Obtain chest radiograph if complicating chest infection suspected, hospitalization required, or diagnosis is uncertain r4c94

Laboratory

  • Arterial blood gas level r1c95
    • Rarely indicated; noninvasive SaO₂ monitoring is preferred for monitoring oxygenation in acute exacerbation
    • Can be used in staging severity of asthma exacerbation
      • Mild: decreased PaO₂ and PCO₂ with increased pH level
      • Moderate: decreased PaO₂ with PCO₂ and pH levels within reference range
      • Severe: markedly decreased PaO₂, increased PCO₂, and decreased pH level
      • Results do not correlate with pulmonary function tests or predict clinical outcome
    • Venous blood gas level may be preferable (less painful and lower risk of complication); if PCO₂ is within reference range, arterial hypercarbia is excluded r14c96
  • CBC and differential c97
    • Not required for diagnosis; however, eosinophilia may be a useful predictor of future risk of asthma exacerbations r15
    • Blood eosinophil count of 150/μL or more suggests type 2 inflammation r5
    • Elevated blood eosinophil counts are associated with more severe disease, increased frequency of exacerbations, and asthma mortality r16
  • Other blood tests
    • C-reactive protein, IgE, IgA, IgG, IgM, antineutrophil cytoplasmic antibodies, or fungal precipitins may be considered in cases of difficult-to-treat or severe asthma r5c98c99c100c101c102c103c104

Imaging

  • Chest radiography or high-resolution CT c105
    • Imaging is not routinely required; only used to exclude/support the presence of other conditions or evaluate severe/difficult-to-treat asthma

Functional testing

  • Spirometry c106
    • Measures how an individual inhales or exhales volumes of air as a function of time; reported as either volume or flow
    • Obtain at initial assessment to evaluate for objective signs of reversible airway obstruction (before and after 2-4 inhalations of a short-acting bronchodilator) r1r11
    • Repeat after treatment has begun to assess response, and when symptoms and peak expiratory flow have stabilized
    • Measure during periods of prolonged loss of asthma control and at least every 1 to 2 years for a patient with stable disease r1
    • Relevant measurements are FVC, FEV₁, and FEV₁/FVC ratio
      • Measured values are reported as percent predicted from a set of reference values
        • The 2005 American Thoracic Society and European Respiratory Society published recommendations prefer the third National Health and Nutrition Examination Survey datar18 as reference values for White Americans, African Americans, and Mexican Americans r17
      • Measured from a series of at least 3 forced expiratory curves
      • FVC: volume during an expiration made as forcefully and completely as possible starting from full inspiration
      • FEV₁: volume delivered in the first second of an FVC expiration
      • FEV₁/FVC reference range by age
        • 20 to 39 years: 80% r1
        • 40 to 59 years: 75% r1
        • 60 to 80 years: 70% r1
      • In general, an FEV₁/FVC of less than 70% is considered obstructive r1
      • 12% increase or more from baseline in FEV₁ with a minimum 200 mL increase is considered reversible r1
      • Greater than 400 mL increase in FEV₁ postbronchodilator is highly suggestive of asthma in adults r11
  • Peak expiratory flow c107
    • Maximum expiratory flow achieved from a maximum forced expiration, starting without hesitation from the point of maximal lung inflation r19
      • Teach patient to use a peak flow meter at home to monitor for personal best and for worsening or improvement r1
      • Perform at baseline and when stable to determine personal best r1
      • Do not use for initial diagnosis of asthma because there is wide variability in meters and reference values r1
    • Measured value is in liters per second when part of spirometry, but it is often expressed in liters per minute when using a patient-administered handheld meter r19
  • Serial FEV₁ measurement with exercise (or induced-hyperpnea) challenge c108c109
    • Indicated to confirm exercise-induced asthma
    • Measure FEV₁ (at least 2 reproducible maneuvers) at baseline, before exercise challenge r3
    • Perform exercise challenge or stationary surrogate hyperpnea challenge r3
      • Exercise challenge or surrogate to achieve a high level of ventilation
        • Most protocols recommend breathing dry air with a nose clip in place while running or cycling
        • Heart rate is typically used as a surrogate for high ventilation; 80% to 90% of predicted maximum (predicted maximum heart rate is approximately 220 minus age in years) r3
        • Once this level of exercise is reached, continue exercise at high level for 4 to 6 minutes r3
      • Hyperpnea challenge
        • Protocols vary; include eucapnic voluntary hyperpnea or hyperventilation, inhalation of hyperosmolar aerosols (4.5% saline), and inhalation of dry powder mannitol r3
    • Measure FEV₁ at 5, 10, 15, and 30 minutes after exercise challenge r3
    • Response is expressed as the percentage fall in FEV₁ from the baseline (preexercise) value r3
    • Greater than 10% fall is diagnostic in some guidelines; many laboratories use a criterion of more than 15% decrease because of greater specificity r3
    • Severity grading, based on the percentage fall in FEV₁ from the preexercise level
      • Mild: 10% to 25% r3
      • Moderate: 25% to 50% r3
      • Severe: more than 50% r3
  • Fractional nitric oxide concentration in exhaled breath c110
    • Recommended use in diagnosis
      • A positive test result suggests presence of eosinophilic inflammation and supports an asthma diagnosis but is not conclusive r15
        • A negative test result does not exclude asthma r11
      • British guidelines recommend offering this as a diagnostic test to all adults, with a level of 40 ppb or higher supporting a diagnosis of asthma r8
      • Level of 50 ppb or greater has specificity of greater than 90% for diagnosis of asthma r10
      • A fractional exhaled nitric oxide (FeNO) value less than 40 ppb does not exclude asthma r10
      • National Asthma Education and Prevention Program recommends use as an adjunct to diagnosis only if asthma diagnosis remains uncertain when based on history, clinical findings, clinical course, and spirometry (or if spirometry cannot be performed), including bronchodilator responsiveness testing r20
      • 2020 Global Initiative for Asthma guidelines do not consider this test useful in the diagnosis of asthma r4
    • Recommendations for the use of this test as an alternative strategy for guiding therapy are mixed
      • American Thoracic Society guidelines recommend testing to determine if eosinophilic inflammation is present and to predict steroid responsiveness r12r21
        • Low level (less than 25 ppb) indicates that eosinophilic inflammation and responsiveness to corticosteroids are less likely r21
        • High level (greater than 50 ppb) indicates that eosinophilic inflammation and, in symptomatic patients, responsiveness to corticosteroids are likely r21
        • Midrange levels (25-50 ppb) should be interpreted cautiously in a clinical context r21
      • A Cochrane review did not find a significant change in exacerbation rate when using therapy guided by fractional nitric oxide concentration in exhaled breath (as compared with standard guideline-directed therapy) in adults r12
      • In adults, the 2020 Global Initiative for Asthma guidelines do not recommend using a treatment based on fractional nitric oxide concentration in exhaled breath; can support decision to commence inhaled corticosteroids but should not be used to decide against treatment r4
      • National Asthma Education and Prevention Program recommends use in persistent allergic asthma with uncertainty in choosing, monitoring, or adjusting antiinflammatory therapies based on history, clinical findings, and spirometry r20
        • Use as part of ongoing asthma monitoring and management strategy
  • Bronchoprovocation testing r1c111
    • Performed by an asthma care specialist or trained individual for safety reasons
    • Performed with methacholine, histamine, cold air, or exercise challenge; can be useful when:
      • Asthma is suspected and spirometry is within (or nearly within) reference range
      • There is obstructive spirometry without bronchodilator reversibility, and r8
        • Fractional nitric oxide concentration in exhaled breath is midrange (not clearly low or elevated), and
        • There is less than 20% peak flow variability over 2 to 4 weeks
    • Positive test result is diagnostic for airway hyperresponsiveness, which is characteristic for asthma but can be present in other conditions as well
    • Negative test result is helpful to exclude asthma

Procedures

c112

Differential Diagnosis

Most common

  • Chronic obstructive pulmonary disease c113d1
    • Difficult to clinically distinguish
    • Perform pulmonary function tests with carbon monoxide–diffusing capacity
      • Airway obstruction is more severe with less reversibility in chronic obstructive pulmonary disease
      • Diffusing capacity is lower in chronic obstructive pulmonary disease
  • Congestive heart failure c114
    • History of coronary artery disease, congestive heart failure, or valvular disease
    • Physical examination may reveal wheezing, but other findings (eg, rales, dependent edema, cardiac gallop) suggest heart failure
    • Chest radiograph and ECG aid in diagnosis
  • Chronic cough from other causes (eg, gastroesophageal reflux disease, rhinitis with postnasal drip, adverse effects from ACE inhibitor) c115c116c117c118d2
    • History and physical examination may be suggestive
    • Discontinuing ACE inhibitor or initiating trial of medication for other conditions may eliminate symptoms
    • Bronchoprovocation testing may be helpful when cough variant asthma versus alternative cause of cough is a consideration (result will be negative with a cause other than asthma)
  • Pulmonary embolus c119d3
    • History is sometimes suggestive (eg, previous deep vein thrombosis or pulmonary embolus, recent immobilization resulting from travel or surgery)
    • D-dimer testing and/or appropriate imaging to diagnose
  • Mechanical obstruction of airway (eg caused by foreign body or tumor) c120
    • History suggestive of benign or malignant tumor may include constitutional symptoms, weight loss, difficulty swallowing, and hemoptysis
    • Chest radiograph, CT scan, soft tissue radiograph of the neck, and/or endoscopic visualization to diagnose
  • Vocal cord dysfunction (paradoxical vocal cord motion disorder) c121
    • May mimic asthma but will be unresponsive to bronchodilators
    • Consider in atypical asthma and in athletes who have exercise-related dyspnea that is unresponsive to asthma medication
    • Spirometry demonstrates extrathoracic airway obstruction on flow-volume loops (truncated inspiratory loop)
    • Laryngoscopy confirms abnormal adduction

Treatment

Goals

  • Reduce current impairment r1
    • Prevent symptoms
    • Decrease need for short-acting β₂-agonist inhaler to 2 or fewer days per week
    • Maintain normal activity levels
    • Maintain near-normal pulmonary function (measured by FEV₁ or peak expiratory flow)
  • Reduce future risk r1
    • Prevent exacerbations
    • Prevent structural changes in airways and decline in pulmonary function
    • Minimize risks/adverse effects of therapy

Disposition

Admission criteria

Base admission decisions on serial assessment of lung function (using FEV₁ or peak expiratory flow) after the patient receives 3 doses of an inhaled bronchodilator (at least 1 hour after initiation of treatment); use pulse oximetry if patient is unable to comply with FEV₁ or peak expiratory flow measurement

  • Criteria for discharge from urgent care/emergency department
    • Patient is not in distress, physical examination results are normal, and FEV₁ is at least 70% of personal best (or predicted value) r1
    • Response sustained at least 1 hour after last treatment r1
  • Criteria for keeping in observation unit (if available) or admitting to hospital ward (individualized decision)
    • After 1 to 3 hours of treatment with short-acting β₂-agonist treatments and oral corticosteroids, patient has mild to moderate symptoms, and FEV₁ or peak expiratory flow is 40% to 69%
  • More severe disease requires ICU admission
Criteria for ICU admission
  • Impending (or actual) respiratory arrest
  • Drowsiness or confusion
  • FEV₁ or peak expiratory flow less than 25% before treatment often predicts need for ICU r1
  • FEV₁ or peak expiratory flow less than 40% after multiple or continuous nebulized albuterol and ipratropium treatments with oral corticosteroids r1
  • PCO₂ of 42 mm Hg or higher on arterial blood gas after multiple treatmentsr1

Recommendations for specialist referral

  • Refer to asthma specialist (pulmonologist or allergist)
    • Severe, persistent asthma requiring step 4 care or higherr1
    • Poorly controlled asthma with frequent absence from school or work
    • Consideration of immunotherapy or omalizumab treatment
    • Patient has required more than 2 rounds of oral steroids or high-dose inhaled corticosteroids in past year r1
    • Patient required hospitalization in past year
    • Diagnosis is uncertain or symptoms are atypical

Treatment Options

Acute asthma exacerbation

  • Exacerbation with peak expiratory flow remaining at 50% or more of personal best can often be managed at home with use of inhaled short-acting β₂-agonist with or without a short course of oral corticosteroids r1
    • Patients may be advised to quadruple maintenance dose of inhaled corticosteroids at the onset of an asthma attack and for up to 14 days to reduce the risk of needing oral corticosteroids r15
  • Exacerbation with peak expiratory flow less than 50% of predicted or personal best requires immediate medical care in urgent care facility or emergency department; if peak expiratory flow is less than 40%, patient should go to emergency department r1
  • Emergent clinical setting
    • For mild to moderate exacerbation
      • Supplemental oxygen by nasal cannula or face mask if SaO₂ is lower than 90% r1
      • Immediately start treatment with inhaled short-acting β₂-agonist drug; start with repeated doses via metered dose inhaler r22
      • Give oral corticosteroids if there is no immediate response to inhaled short-acting β₂-agonist drug or if patient recently took oral corticosteroids r1
      • Reassess
        • Continue inhaled short-acting β₂-agonist drug treatments for 1 to 3 hours; make admission decision within 4 hours r1
    • For severe exacerbation
      • Provide supplemental oxygen by nasal cannula or face mask if SaO₂ is lower than 90% r1
      • Immediately start treatment with inhaled short-acting β₂-agonist drug; give continuous (instead of intermittent) nebulized short-acting β₂-agonist r23
        • Injected epinephrine or terbutaline is no more effective than inhaled short-acting β₂-agonist r1r24
      • Give ipratropium by nebulizer along with short-acting β₂-agonist r1
      • Administer corticosteroids that have systemic effects r1
      • Reassess
        • Repeat administration of inhaled short-acting β₂-agonist with ipratropium as necessary r1
        • Consider adjunctive therapies if FEV₁ remains lower than 40% r1
          • IV magnesium sulfate reduces hospital admissions and improves lung function in adults when inhaled short-acting medications and IV steroids have failed; not for routine use r25
    • For severe exacerbation with impending or actual respiratory arrest
      • Some authors advocate for noninvasive positive pressure ventilation for severe exacerbation when attempting to avoid intubation;r14r26however, evidence of benefit is limitedr27
        • Based on observational studies, this therapy is considered safe and well tolerated; is associated with a reduction in endotracheal intubation and in-hospital mortality r28
      • Intubation and mechanical ventilation with 100% oxygen are required if respiratory arrest is occurring or impending, signaled by:
        • Paradoxical thoracoabdominal movement
        • Absence of wheeze
        • Peak expiratory flow lower than 25% r1
        • If arterial blood gas is obtained, PCO₂ of 42 mm Hg or higherr1
        • Cyanosis
        • Drowsiness
        • Bradycardia
      • Immediately start treatment with continuous inhaled short-acting β₂-agonist plus inhaled ipratropium r1
      • Give IV corticosteroids r1
      • Consider adjunctive therapies
        • Magnesium sulfate if FEV₁ remains less than 40% r1
          • Recent trials of nebulized inhaled magnesium sulfate have not shown significant benefit r29
    • For all patients before discharge from emergency department or hospital
      • Ensure that the patient will receive these critical components of asthma management as an outpatient: r1
        • Ongoing clinical assessment and home monitoring
        • Education and asthma action plan
        • Control of environmental factors and comorbid conditions
        • Ongoing controller medication

Chronic asthma

  • Pharmacotherapy is prescribed using stepwise approach;r20r1 initial step is determined by disease severity classification (for newly diagnosed patients not on controller medications) or by disease control classification (for patients currently using controller medications)
    • Adjustments are based on the ongoing level of control
    • Therapy can be both stepped up and stepped down; step-down can be considered after 3 months of good control
  • 3 types of medications may be used r4
    • Controllers
      • Inhaled corticosteroid-containing controller medications reduce airway inflammation and symptoms, reduce future exacerbations and decline in lung function
      • The Single Maintenance and Reliever Treatment (SMART) strategy using a combination of inhaled corticosteroid (ICS) plus formoterol in a single inhaler therapy is the preferred treatment of steps 3 and 4 r4r15r20
    • Relievers
      • Used as needed to alleviate breakthrough symptoms
      • Once a mainstay of asthma therapy, short-acting β-agonists are no longer recommended as the preferred reliever for symptomatic patients and should not be used as monotherapy because of safety concerns and poor outcomes r30
        • An inhaled corticosteroid combined with fast onset, long-acting β-agonist (ie, formoterol) are the preferred relievers
      • Reduction or elimination of need for use is a major goal of asthma treatment
    • Add-on medications
      • A variety of agents may be considered when symptoms persist or exacerbations occur despite optimal therapy with controllers
  • Step 1 (intermittent asthma; infrequent symptoms less than twice per month and no risk factors for exacerbations) r1
    • Global Initiative for Asthma and National Asthma Education and Prevention Program recommend using a low-dose inhaled corticosteroid plus the inhaled long-acting β₂-agonist, formoterol, in a single inhaler, as required to alleviate symptoms r4r20
      • As an alternative to a fixed dose combination, give a dose of low-dose inhaled corticosteroid whenever inhaled short-acting β₂-agonist is used to relieve symptoms
      • Inhaled corticosteroid-containing reliever medications are superior to short-acting β₂-agonists alone and significantly reduce risks of severe asthma exacerbation r31r32
      • As required, inhaled corticosteroid plus formoterol reduced exacerbations, hospital admissions or unscheduled healthcare visits, and need for corticosteroids with systemic effects compared to use of a fast-acting β₂-agonist alone; combination is as effective as regular inhaled corticosteroids used alone in patients with mild asthma r33r34
      • Global Initiative for Asthma no longer recommends as-needed inhaled short-acting β₂-agonist monotherapy for such symptoms r35
    • British guidelines recommend use of an inhaled short-acting β₂-agonist as reliever therapy for patients with symptomatic asthma who have infrequent, short-lived wheeze and normal lung function r8r15
  • Step 2 (asthma symptoms or need for reliever medication more than twice per month)
    • Global Initiative for Asthma recommends either: r4
      • As-needed low-dose inhaled corticosteroid plus formoterol in a single inhaler, to alleviate symptoms
      • Low-dose inhaled corticosteroid maintenance therapy plus as-needed inhaled short-acting β₂-agonist to alleviate symptoms
      • Alternatives
        • Daily leukotriene receptor antagonist
        • Low dose of inhaled corticosteroid whenever inhaled short-acting β₂-agonist is used to relieve symptoms
    • British guidelines recommend low-dose inhaled corticosteroids as maintenance therapy for patients with asthma-related symptoms 3 times a week or more, or causing waking at night or asthma that is uncontrolled with a reliever alone r8r15
  • Step 3 (asthma symptoms on most days or waking because of asthma symptoms once per week or more)
    • Global Initiative for Asthma recommends either: r4
      • Low-dose inhaled corticosteroid plus inhaled long-acting β₂-agonist as maintenance therapy, and low-dose inhaled corticosteroid plus formoterol single inhaler as needed to alleviate symptoms (preferred by National Asthma Education and Prevention Program)r20
      • Low-dose inhaled corticosteroid plus inhaled long-acting β₂-agonist as maintenance therapy, and as-needed inhaled short-acting β₂-agonist as reliever
      • Alternatives:
        • Medium-dose inhaled corticosteroid plus as-needed inhaled short-acting β₂-agonist to alleviate symptoms
        • Low-dose inhaled corticosteroid maintenance therapy plus leukotriene receptor antagonist
        • Addition of house dust mite sublingual immunotherapy for sensitized patients with allergic rhinitis and FEV₁ greater than 70% predicted
        • Low-dose inhaled corticosteroid plus a long-acting muscarinic antagonist, tiotropium (National Asthma Education and Prevention Program recommended) r20
          • Do not use long-acting muscarinic antagonists without concomitant inhaled corticosteroids because it increases risk of severe exacerbations r4
    • British guidelines recommend add-on therapy with inhaled long-acting β₂-agonist or a leukotriene receptor antagonist r8r15
      • If asthma control still remains suboptimal, then medium-dose inhaled corticosteroid or combined low-dose inhaled corticosteroid plus inhaled long-acting β₂-agonist as maintenance therapy, and low-dose inhaled corticosteroid plus formoterol single inhaler as needed to alleviate symptoms
  • Step 4 (asthma symptoms on most days, waking because of asthma symptoms once per week or more, or low lung function)
    • Global Initiative for Asthma recommends medium-dose inhaled corticosteroid plus inhaled long-acting β₂-agonist as maintenance therapy, with as-needed low-dose inhaled corticosteroid plus formoterol single inhaler (preferred by National Asthma Education and Prevention Program) r20or inhaled short-acting β₂-agonist to alleviate symptoms r4
      • Alternatives
        • High-dose inhaled corticosteroid
        • Add-on tiotropium bromide, a long-acting muscarinic antagonist r20
          • Compared to dual therapy, add-on tiotropium bromide is associated with fewer severe asthma exacerbations and improvements in asthma control in patients with moderate to severe asthma r36
        • Add-on leukotriene receptor antagonist
        • Add-on house dust mite sublingual immunotherapy for sensitized patients with allergic rhinitis and FEV₁ greater than 70% predicted
    • British guidelines recommend 1 of the following if asthma control remains inadequate on medium-dose inhaled corticosteroid plus a long-acting β₂-agonist or a leukotriene receptor antagonist: r15
      • High-dose inhaled corticosteroids
      • Addition of a leukotriene receptor antagonist (if not already using)
      • Addition of tiotropium bromide, a long-acting muscarinic antagonist
      • Addition of theophylline (rarely used nowadays)
  • Step 5 (severe uncontrolled asthma) r1
    • Referral to asthma specialist is recommended
    • Address any factors that may contribute to suboptimal control (eg, poor adherence to therapy, incorrect inhaler technique, comorbidities, modifiable risk factors such as smoking) r5
    • Use high-dose inhaled corticosteroid plus inhaled long-acting β₂-agonist with as-needed low-dose inhaled corticosteroid plus formoterol single inhaler or inhaled short-acting β₂-agonist to alleviate symptoms
    • Consider screening for adrenal insufficiency if patient is on maintenance oral corticosteroids or high-dose inhaled corticosteroids r37
    • Assess asthma phenotype for type 2 airway inflammation during high-dose inhaled corticosteroid treatment r5
      • Biologic therapies that reduce eosinophil count can significantly reduce asthma symptoms, oral corticosteroid use, and exacerbation frequency, and improve lung function in patients with type 2 airway inflammation r16
      • Type 2 airway inflammation is defined by the presence of 1 or more of the following:
        • Blood eosinophil count of 150/μL or more
          • If not elevated initially, repeat testing up to 3 times, at least 1 to 2 weeks after stopping or reducing to lowest possible oral corticosteroid dose r37
        • Fractional nitric oxide concentration in exhaled breath of 20 ppb or more
          • If not elevated initially, repeat testing up to 3 times, at least 1 to 2 weeks after stopping or reducing to lowest possible oral corticosteroid dose r37
        • Sputum eosinophil concentration of 2% or more
        • Asthma that is clinically caused by allergens
        • Dependent on oral corticosteroid
      • If no evidence of type 2 inflammation, consider the following:
        • Add-on tiotropium bromide, a long-acting muscarinic antagonist r38
        • Add-on macrolide antibiotic (eg, azithromycin) r38
          • Consider in adults aged 50 to 70 years who have persistent symptoms despite more than 80% adherence to high-dose inhaled steroids (over 800 mcg/day) and 1 or more exacerbations requiring oral steroids in the past year r39
          • Treat for a minimum of 6 to 12 months to assess efficacy in reducing exacerbations r39
          • Macrolides may reduce severe exacerbations and symptoms r40
        • Course of low-dose oral corticosteroid
        • Bronchial thermoplasty may be considered for some patients with severe asthma despite optimal medical therapy r4r5r15
        • Add-on interleukin-4 (dupilumab) or thymic stromal lymphopoietin antibodies (tezepelumab) r37
      • If there is evidence of type 2 airway inflammation, consider addition of biologic agents (refer to local eligibility criteria and published guidelines for use) r5r41
        • Before considering biologic therapy: r37
          • Investigate for causes other than asthma, such as strongyloidiasis in patients with a blood eosinophil count of 300/µL or higher
          • Investigate for conditions such as eosinophilic granulomatosis with polyangiitis in patients with a blood eosinophil count of 1500/µL or higher
        • Evaluate response to the biologic agent after 4 months and, if favorable, continue treatment with reevaluation every 3 to 6 months; switch to a different agent if response to the initial agent is inadequate r41
        • Monoclonal antibodies to interleukin-5/interleukin-5 receptor (mepolizumab, benralizumab, reslizumab) can be prescribed for severe asthma with an eosinophilic phenotype, ascertained by either sputum or peripheral blood eosinophilia r42
          • Anti–interleukin-5 agents reduce exacerbations and improve lung function in patients with severe eosinophilic asthma r38r43r44
          • Mepolizumab and benralizumab are effective in reducing oral steroid doses in patients with corticosteroid-dependent asthma
          • A blood eosinophil count threshold of 150/μL or more can be used to guide initiation of anti–interleukin-5 agents r5r38
        • Omalizumab, a monoclonal antibody to IgE, may be used to treat allergic asthma with documented sensitivity to a perennial aeroallergen and elevated total IgE level
          • A blood eosinophil count of 260/μL or more and fractional nitric oxide concentration in exhaled breath of 20 ppb or more identify patients most likely to benefit from anti-IgE treatment r5r38
        • Anti–interleukin-4 receptor agents may reduce exacerbations in adults with moderate to severe uncontrolled asthma who have not responded to other therapies r45
          • Dupilumab, a monoclonal antibody to the interleukin-4 receptor, is indicated for patients with severe eosinophilic asthma or a fractional nitric oxide concentration in exhaled breath of 25 ppb or more, and those requiring maintenance oral corticosteroids regardless of blood eosinophil levels r5r38
        • Thymic stromal lymphopoietin antibodies r46
          • Tezepelumab, a human monoclonal antibody that blocks thymic stromal lymphopoietin, reduces exacerbations and improves lung function in patients with severe uncontrolled asthma, regardless of asthma phenotype r47
          • Greater benefit observed in patients with higher blood eosinophil levels and/or higher fractional exhaled nitric oxide (FeNO) r37
      • Investigational agents
        • Interleukin-33 antibodies
          • Astegolimab may be a promising treatment for patients with severe asthma who do not respond to conventional biologic agents r48
        • Interleukin-13 antibodies r46
          • Lebrikizumab and tralokinumab have demonstrated only modest benefits compared to other biologic agents
    • Guidelines have been developed to aid evaluation and management of difficult-to-treat and severe asthma r5r37r38r41

Exercise-induced asthma r3r49

  • Use inhaled short-acting β₂-agonist 15 minutes before exercise r3r15
    • An alternative is combination low-dose inhaled corticosteroid plus formoterol used as required and before exercise r49
  • Ensure training and warm-up is sufficient r4
  • For patients who require an inhaled short-acting β₂-agonist daily or more frequently, add low-dose inhaled corticosteroids r4r15
  • Review and optimize asthma treatment for patients whose exercise-induced asthma reflects overall poorly controlled asthma r15
  • If exercise remains a specific problem in patients who are otherwise well controlled on low-dose inhaled corticosteroids, consider adding 1 of the following therapies: r3r15
    • Daily leukotriene antagonist r3
    • Cromolyn sodium before exercise r3
    • Inhaled anticholinergic before exercise r49
    • Long-acting β₂-agonists (only used with an inhaled corticosteroid)
    • Theophylline
  • Use antihistamine only if there are definite allergies r3
  • Consider adding inhaled anticholinergic (weak evidence, but can be tried if other options are inadequate) r3

Cough variant asthma r6

  • Low-dose inhaled corticosteroids are considered first line treatment
  • If response is incomplete, inhaled corticosteroid dose may be increased and/or leukotriene antagonist added

Drug therapy

  • Chronic asthma
    • Relief of episodic wheezing (relievers)
      • Short-acting β₂-agonists
        • Albuterol c122
          • Albuterol Pressurized inhalation, suspension; Adults: 90 to 180 mcg (1 to 2 actuations of 90 mcg/actuation) inhaled by mouth every 4 to 6 hours as needed. Max: 1,080 mcg/day (12 actuations/day).
          • Albuterol Inhalation powder; Adults: 90 to 180 mcg (1 to 2 actuations of 90 mcg/actuation) inhaled by mouth every 4 to 6 hours as needed. Max: 1,080 mcg/day (12 actuations/day).
          • Albuterol Sulfate Nebulizer solution; Adults: 2.5 mg inhaled by nebulizer 3 to 4 times daily as needed. Usual Max: 10 mg/day.
          • Some guidelines recommend simultaneous administration of low-dose inhaled corticosteroids when albuterol is used to relieve symptoms
            • Fluticasone c123
              • Fluticasone Propionate Pressurized inhalation, suspension; Adults: GINA recommends 88 mcg (2 oral inhalations of 44 mcg/actuation) or 110 mcg to 220 mcg (1 to 2 oral inhalations of 110 mcg/actuation) or 220 mcg (1 oral inhalation of 220 mcg/actuation) as needed whenever short-acting beta-2 agonist (SABA) is given. NAEPP only recommends as-needed ICS/SABA as an option for patients with mild persistent asthma. FDA-approved Max: 1,760 mcg/day.
              • Fluticasone Furoate Inhalation powder; Adults: GINA recommends 100 mcg (1 oral inhalation of 100 mcg/actuation) as needed whenever short-acting beta-2 agonist (SABA) is given. NAEPP only recommends as-needed ICS/SABA as an option for patients with mild persistent asthma. FDA-approved Max: 200 mcg/day.
            • Budesonide c124
              • Budesonide Inhalation powder; Adults: GINA recommends 180 to 360 mcg (1 to 2 oral inhalations of 180 mcg/actuation) as needed whenever short-acting beta-2 agonist (SABA) is given. NAEPP only recommends as-needed ICS/SABA as an option for patients with mild persistent asthma. FDA-approved Max: 1,440 mcg/day.
          • Inhaled corticosteroid plus fast onset, long-acting β₂-agonist
            • Budesonide and formoterol combination product c125
              • Budesonide, Formoterol Fumarate Pressurized inhalation, powder; Adults: NAEPP recommends 1 or 2 oral inhalations (total per dose = 160 to 320 mcg budesonide with 4.5 to 9 mcg formoterol) as needed in addition to daily maintenance dosing; may repeat after 5 minutes if needed. Max per NAEPP: formoterol 54 mcg/day or 12 oral inhalations of a product containing 4.5 mcg/actuation of formoterol. GINA recommends 100 mcg budesonide/6 mcg formoterol (1 oral inhalation) as needed in addition to a daily maintenance dose; may repeat after 5 minutes. GINA Max: 12 oral inhalations/day (do not exceed formoterol 72 mcg/day).
        • Levalbuterol (for patients intolerant of albuterol) c126
          • Levalbuterol Tartrate Pressurized inhalation, suspension; Adults: 45 to 90 mcg (1 to 2 actuations of 45 mcg/actuation) inhaled by mouth every 4 to 6 hours as needed. Max: 540 mcg/day (12 actuations/day).
          • Levalbuterol Hydrochloride Nebulizer solution; Adults: 0.63 or 1.25 mg inhaled by nebulizer 3 times daily as needed. Max: 3.75 mg/day.
    • Maintenance treatment (controllers)
      • Inhaled corticosteroids (preferred)
        • Fluticasone c127
          • Fluticasone Propionate Pressurized inhalation, suspension; Adults: 88 mcg (2 actuations of 44 mcg/actuation) inhaled by mouth twice daily. May increase the dose after 2 weeks if the response is not adequate. Max: 880 mcg (4 actuations of 220 mcg/actuation) twice daily. Use the lowest effective dose once stable.
          • Fluticasone Propionate Inhalation powder; Adults: 55 mcg (1 actuation of 55 mcg/actuation) inhaled by mouth twice daily. May increase the dose after 2 weeks if the response is not adequate. Max: 232 mcg (1 actuation of 232 mcg/actuation) twice daily. Use the lowest effective dose once stable.
        • Budesonide c128
          • Budesonide Inhalation powder; Adults: 360 mcg (2 actuations of 180 mcg/actuation) inhaled by mouth twice daily; 180 mcg (1 actuation of 180 mcg/actuation) twice daily may be appropriate for some patients. Max: 720 mcg (4 actuations of 180 mcg/actuation) twice daily. Use the lowest effective dose once stable.
          • Budesonide Nebulizer suspension; Adults†: Not FDA-approved in U.S. in adults. European usual dose for severe asthma is 1 to 2 mg via nebulizer twice daily. Usual maintenance dose is 0.5 to 1 mg via nebulizer twice daily; may increase during exacerbations or severe asthma. Max: 4 mg/day. Titrate to lowest effective dose once stable.
      • Inhaled corticosteroid plus long-acting β₂-agonists (preferred)
        • Budesonide and formoterol combination product c129
          • Budesonide, Formoterol Fumarate Pressurized inhalation, suspension; Adults: 160 mcg budesonide/9 mcg formoterol (2 actuations of 80 mcg budesonide/4.5 mcg formoterol/actuation) or 320 mcg budesonide/9 mcg formoterol (2 actuations of 160 mcg budesonide/4.5 mcg formoterol/actuation) inhaled by mouth twice daily. Base starting dose on prior asthma therapy and disease severity. Max: 640 mcg budesonide/18 mcg formoterol/day.
          • Single maintenance and reliever therapy (SMART); same inhaler is used for both regular maintenance dosing and as needed to alleviate symptoms
            • Only use budesonide plus formoterol as a reliever when this combination is also used as maintenance therapy r20
        • Fluticasone and salmeterol combination product c130
          • Fluticasone Propionate, Salmeterol Pressurized inhalation, suspension; Adults: 90 mcg fluticasone/42 mcg salmeterol (2 actuations of 45 mcg fluticasone/21 mcg salmeterol/actuation) or 230 mcg fluticasone/42 mcg salmeterol (2 actuations of 115 mcg fluticasone/21 mcg salmeterol/actuation) or 460 mcg fluticasone/42 mcg salmeterol (2 actuations of 230 mcg fluticasone/21 mcg salmeterol/actuation) inhaled by mouth twice daily. Max: 920 mcg fluticasone/84 mcg salmeterol/day.
          • Fluticasone Propionate, Salmeterol Inhalation powder; Adults: 100 mcg fluticasone/50 mcg salmeterol (1 actuation of 100 mcg fluticasone/50 mcg salmeterol) or 250 mcg fluticasone/50 mcg salmeterol (1 actuation of 250 mcg fluticasone/50 mcg salmeterol) or 500 mcg fluticasone/50 mcg salmeterol (1 actuation of 500 mcg fluticasone/50 mcg salmeterol) inhaled by mouth twice daily. Max: 1,000 mcg fluticasone/100 mcg salmeterol/day.
          • Fluticasone Propionate, Salmeterol Inhalation powder; Adults: 55 mcg fluticasone/14 mcg salmeterol (1 actuation of 55 mcg fluticasone/14 mcg salmeterol) or 113 mcg fluticasone/14 mcg salmeterol (1 actuation of 113 mcg fluticasone/14 mcg salmeterol) or 232 mcg fluticasone/14 mcg salmeterol (1 actuation of 232 mcg fluticasone/14 mcg salmeterol) inhaled by mouth twice daily. Max: 464 mcg fluticasone/28 mcg salmeterol/day.
        • Fluticasone and vilanterol combination product c131
          • Fluticasone Furoate Inhalation powder, Vilanterol Inhalation powder; Adults: 1 oral inhalation of either 100/25 (100 mcg of fluticasone and 25 mcg of vilanterol per actuation) or 200/25 (200 mcg fluticasone and 25 mcg vilanterol per actuation) once daily. Choose dose based on asthma severity and previous therapy. Max: 200 mcg fluticasone with 25 mcg vilanterol per day.
      • Leukotriene receptor antagonists (second line)
        • Montelukast c132
          • Montelukast Sodium Oral tablet; Adults: 10 mg PO once daily in the evening.
          • FDA has issued a warning regarding serious neuropsychiatric adverse effects. r4
        • Zafirlukast c133
          • Zafirlukast Oral tablet; Adults: 20 mg PO twice daily.
    • Maintenance therapy; add-on agents for steps 4 and 5 in disease control classification
      • Long-acting muscarinic antagonist
        • Tiotropium c134
          • Tiotropium Respiratory spray, solution; Adults: 2.5 mcg (2 actuations of 1.25 mcg/actuation) inhaled by mouth once daily.
      • Leukotriene synthesis inhibitor
        • Zileuton c135
          • Zileuton Oral tablet; Adults: 600 mg PO 4 times daily.
          • Zileuton Oral tablet, biphasic release; Adults: 1,200 mg PO twice daily.
      • Macrolide antibiotic
        • Azithromycin c136
          • Azithromycin Oral tablet; Adults: 250 to 500 mg PO 3 days per week.
      • Biologic agents r41
        • Benralizumab c137
          • Benralizumab Solution for injection; Adults: 30 mg subcutaneously every 4 weeks for 3 doses, then 30 mg subcutaneously every 8 weeks.
        • Mepolizumab c138
          • Mepolizumab Solution for injection; Adults: 100 mg subcutaneously every 4 weeks.
        • Omalizumab c139
          • Omalizumab (Hamster) Solution for injection; Adults: 150 to 375 mg subcutaneously every 2 weeks or every 4 weeks. Dosage and frequency determined by baseline IgE (units/mL) and weight (kg). Adjust doses for significant changes in body weight. Do not administer more than 150 mg per injection site.
            • Risk of serious hypersensitivity reactions or anaphylaxis, and omalizumab hypersensitivity may occur after any dose of omalizumab. Omalizumab is derived from Chinese hamster ovarian cells and may be inappropriate for use by patients with known hamster protein hypersensitivity. Omalizumab is contraindicated for use by patients who have experienced a severe omalizumab hypersensitivity reaction, including anaphylaxis or a history of angioedema with the drug. Administration of omalizumab requires a specialized care setting that is equipped and prepared to manage serious hypersensitivity reactions, including anaphylaxis that can be life-threatening.
        • Reslizumab c140
          • Reslizumab Solution for injection; Adults: 3 mg/kg IV infusion once every 4 weeks. Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis.
        • Dupilumab c141
          • For eosinophilic phenotype moderate to severe asthma
            • Dupilumab Solution for injection; Adults: 400 mg subcutaneously as a single dose, then 200 mg subcutaneously every other week or 600 mg subcutaneously as a single dose, then 300 mg subcutaneously every other week.
          • For oral corticosteroid-dependent moderate to severe asthma
            • Dupilumab Solution for injection; Adults: 600 mg subcutaneously as a single dose, then 300 mg subcutaneously every other week.
      • Oral corticosteroid
        • Prednisone c142
          • Prednisone Oral tablet; Adults: 7.5 to 60 mg PO once daily or every other day. Use the lowest effective dose.
  • Acute exacerbation of asthma
    • Inhaled short-acting β₂-agonist
      • Albuterol c143
        • Albuterol Pressurized inhalation, suspension; Adults: 360 to 900 mcg (4 to 10 actuations of 90 mcg/actuation) inhaled by mouth every 20 minutes for the first hour, then 360 to 900 mcg (4 to 10 actuations of 90 mcg/actuation) every 3 to 4 hours up to 540 to 900 mcg (6 to 10 actuations of 90 mcg/actuation) every 1 to 2 hours, or more often.
        • Albuterol Sulfate Nebulizer solution; Adults: 2.5 mg inhaled by nebulizer every 20 minutes for the first hour, then 2.5 mg every 3 to 4 hours up to 2.5 mg every 1 to 2 hours, or more often. Usual dose: 2.5 mg inhaled by nebulizer 3 to 4 times daily.
      • Levalbuterol (for patients intolerant of albuterol) c144
        • Levalbuterol Hydrochloride Nebulizer solution; Adults: 1.25 mg inhaled by nebulizer every 20 minutes for the first hour, then 1.25 mg every 3 to 4 hours and up to 1.25 mg every 1 to 2 hours, or more often. Usual dose: 0.63 to 1.25 mg inhaled by nebulizer 3 times daily, every 6 to 8 hours.
    • Mast cell stabilizer
      • Cromolyn c145
        • Cromolyn Sodium Nebulizer solution; Adults: 20 mg inhaled by nebulizer 4 times daily. Usual maintenance dose: 20 mg inhaled by nebulizer 3 times daily.
    • Inhaled anticholinergics
      • Ipratropium c146
        • Ipratropium Bromide Pressurized inhalation, solution; Adults: 136 mcg (8 actuations of 17 mcg/actuation) inhaled by mouth every 20 minutes as needed for up to 3 hours.
        • Ipratropium Bromide Nebulizer solution; Adults: 500 mcg inhaled by nebulizer every 20 minutes for 3 doses, then as needed for up to 3 hours.
      • Ipratropium and albuterol combination product c147
        • Ipratropium Bromide, Albuterol Sulfate Nebulizer solution; Adults: 0.5 mg ipratropium bromide/2.5 mg albuterol (3 mL) inhaled by nebulizer every 20 minutes for 3 doses, then as needed, usually every 4 to 6 hours.
    • Smooth muscle relaxant
      • Magnesium sulfate c148
        • Magnesium Sulfate Solution for injection; Adults: 2 g IV as a single dose.
    • Corticosteroids with systemic effects
      • Prednisone c149
        • For mild exacerbation (outpatient)
          • Prednisone Oral tablet; Adults: 40 to 60 mg/day PO in 1 to 2 divided doses for 3 to 10 days or until the patient achieves peak expiratory flow (PEF) of 80% of personal best or symptoms resolve. Another recommendation is 40 to 50 mg/day usually for 5 to 7 days (or 1 mg/kg/day); Max: 50 mg/day.
        • For moderate to severe exacerbation (emergency department or inpatient)
          • Prednisone Oral tablet; Adults: One recommendation is 40 mg/day or 1 mg/kg/day for 5 to 7 days; Max: 50 mg/day. Alternatively, 40 to 80 mg/day PO in 1 to 2 divided doses until peak expiratory flow is 70% of predicted or personal best; total course: 3 to 10 days.
      • Methylprednisolone c150
        • For mild exacerbation (outpatient)
          • Methylprednisolone Oral tablet; Adult: 40 to 60 mg/day PO in 1 to 2 divided doses for 5 to 10 days.
        • For moderate to severe exacerbation (emergency department or inpatient)
          • Methylprednisolone Oral tablet; Adults: 40 mg PO once daily in the morning for 5 to 7 days. Alternatively, 40 to 80 mg/day PO in 1 to 2 divided doses until peak expiratory flow is 70% of predicted or personal best; total course of treatment may range from 3 to 10 days.
          • Methylprednisolone Sodium Succinate Solution for injection; Adults: 40 mg IV/IM once daily each morning for 5 to 7 days is adequate for most patients. Alternatively, 40 to 80 mg/day IV/IM in 1 to 2 divided doses until peak expiratory flow is 70% of predicted or personal best. Change to oral therapy as soon as feasible.
  • Exercise-induced asthma
    • Take as required before exercise; maintenance low-dose inhaled corticosteroids may also be indicated
    • Inhaled short-acting β₂-agonist
      • Albuterol c151
        • Albuterol Pressurized inhalation, suspension; Adults: 180 mcg (2 actuations of 90 mcg/actuation) via oral inhalation 15 to 30 minutes before exercise.
        • Albuterol Inhalation powder; Adults: 180 mcg (2 actuations of 90 mcg/actuation) via oral inhalation 15 to 30 minutes before exercise.
      • Levalbuterol (for patients intolerant of albuterol) c152
        • Levalbuterol Tartrate Pressurized inhalation, suspension; Adults: 90 mcg (2 actuations of 45 mcg/actuation) via oral inhalation 15 minutes (range, 5 to 20 minutes) before exercise.
    • Inhaled corticosteroid plus long-acting β₂-agonists
      • Budesonide and formoterol combination product c153
        • Budesonide, Formoterol Fumarate Pressurized inhalation, suspension; Adults: 1 oral inhalation of 160/4.5 (160 mcg budesonide with 4.5 mcg formoterol per actuation) 5 to 20 minutes before exercise has been used and was efficacious in a clinical trial. FDA-approved Max: 2 oral inhalations of 160/4.5 twice daily.
    • Leukotriene receptor antagonists
      • Montelukast c154
        • Montelukast Sodium Oral tablet; Adults: 10 mg PO once, given at least 2 hours before exercise. Max: 10 mg/24 hours. Patients receiving daily montelukast for another indication should not take an additional dose to prevent EIB. Rescue medications (e.g., beta-agonists) should be available.
    • Mast cell stabilizer
      • Cromolyn c155
        • Cromolyn Sodium Nebulizer solution; Adults: Inhale 20 mg via nebulization not more than 1 hour before anticipated exercise or other precipitating factor. Effective prophylaxis lasts approximately 1 to 2 hours.

Nondrug and supportive care

Patient education about self-management establishes a partnership with the patient and is a major component of care c156

  • Self-monitoring symptoms and peak flow meter use
  • Use of control chart (sample available within the National Asthma Education and Prevention Program guidelinesr1) and written asthma action plan, emphasizing difference between controller and reliever medications (sample plan available from the NIH National Heart, Lung, and Blood Institute)
  • Supported self-management involving at least 2 hours of scheduled follow-up with health care providers significantly reduced use of health care services and improved quality of life compared to less intensive review r50
  • Multidisciplinary case management may be needed for patients with severe, difficult-to-treat disease

Reduce exposure to allergen, irritant, and air pollution triggers

  • Multicomponent allergen-specific intervention strategies are recommended over single component interventions in patients who are known to be sensitized or become symptomatic on exposure to specific allergens r20
    • For rodents and/or cockroaches, integrated pest management including measures to block infestation (eg, filling holes in walls) and abatement (eg, traps)
    • For dust mites, combination of dust mite–impermeable pillow and mattress covers, HEPA (high-efficiency particulate air) filter–equipped vacuum cleaner, carpet and curtain removal, and cleaning products
    • For mold, use of HEPA (high-efficiency particulate air) purifiers and mold abatement

Breathing exercises c157

  • Breathing exercise programs can be considered as adjuvants to pharmacologic treatment r15

Smoking cessation c158

Physical activity r51c159

Weight-loss interventions c160

  • Weight loss may help overweight and obese patients to improve asthma control r15

Supplemental oxygen c161

  • Indicated for SaO₂ lower than 90%
  • Nasal cannula or Venturi mask (Ventimask) to maintain SaO₂ of at least 90%
  • Noninvasive positive pressure ventilation decreases hospital admissions, but evidence base is not strong r27
Procedures
Bronchial thermoplasty r20c162
General explanation
  • Procedure using radiofrequency energy to reduce airway smooth muscle mass
  • Administered in 3 sessions as part of a bronchoscopy
  • Variable outcomes; no consistent improvement in asthma control or reduction in hospitalization, but improved quality of life and a small decrease in exacerbations
  • Moderate risk of adverse effects
  • National Asthma Education and Prevention Program recommends against its use in patients with persistent asthma; however, it remains an option for treatment of poorly controlled asthma

Comorbidities

  • Obesity c163
    • Associated with increased risk of asthma, worsening symptoms, and decreased responsiveness to therapies r52
    • Weight loss may improve asthma control and should be encouraged
  • Allergic rhinitis c164
    • Common comorbidity that is managed with intranasal corticosteroids, antihistamines, and/or immunotherapy r1
  • Chronic rhinosinusitis with nasal polyposis c165c166
    • In patients with this condition, better management of rhinosinusitis can decrease asthma exacerbation
    • A subset of these patients have aspirin sensitivity that can result in severe bronchospasm; referral to specialist is indicated
  • Gastroesophageal reflux disease c167
    • Unclear role in causing asthma; uncontrolled gastroesophageal reflux disease may worsen asthma symptoms, and management of the disease is important
  • Allergic bronchopulmonary aspergillosis r1c168
    • Consider in patients who have asthma and a history of pulmonary infiltrates, IgE sensitization to aspergillus, and/or corticosteroid dependency
    • Treat with prednisone and azole antifungal agents
  • COVID-19 infection c169
    • In patients with well-controlled asthma, it does not appear to significantly increase their risk of contracting COVID-19 infection, the severity of disease, or the death rate r4r53r54r55
    • However, some studies have found higher rates of intubation and prolonged mechanical ventilation in patients with asthma r56
    • Regular asthma medications should be continued during the COVID-19 pandemic r4r57
    • Nonsevere asthma exacerbations may be managed via telehealth with a low threshold for face-to-face assessment r57
    • Usual guidelines for initiation of corticosteroids that have systemic effects for asthma exacerbations should be followed
    • If possible, patients with COVID-19 infection should be given inhaled asthma medications via inhaler rather than nebulizer to prevent aerosolizing the virus r4
    • Avoid spirometry in patients with known or suspected COVID-19 infection; if possible, postpone spirometry and peak flow measurements while community transmission rates are concerning r4

Special populations

  • Pregnant patients
    • Asthma symptoms may change during pregnancy; can improve or worsen r58
    • Monthly monitoring is recommended because of the unpredictable course of asthma during pregnancy r58
    • Asthma is undertreated during pregnancy compared with prepregnancy treatment rates
    • Maternal asthma is associated with increased risk of low birthweight, preeclampsia, gestational diabetes, cesarean delivery, perinatal mortality, and neonatal hospitalization at birth r58
      • Uncontrolled asthma, in particular, is associated with poor perinatal outcomes
    • Use stepwise approach to therapy for chronic asthma r59
      • General principles
        • Inhaled medications should be continued; many have been used for decades without demonstrated adverse effects on the fetus r58
          • Albuterol is classified as a pregnancy risk category C drug but has a good safety profile r59
          • Guidelines recommend use of whichever inhaled corticosteroid formulation was effective prepregnancy r59
          • Budesonide has the most safety documentation
        • Monoclonal antibodies should be continued during pregnancy if required for asthma control r58
        • Minimal data exists on leukotriene receptor antagonists and long-acting β₂-agonists
      • Mild intermittent asthma: short-acting β₂-agonist as needed r59
      • Mild persistent asthma: low-dose inhaled corticosteroid r59
      • Moderate persistent asthma: low-dose inhaled corticosteroid and a long-acting β₂-agonist or low-dose inhaled corticosteroid and either theophylline or leukotriene receptor antagonist r59
      • Severe persistent asthma: high-dose inhaled corticosteroid and a long-acting β₂-agonist; if needed, add long-term oral corticosteroid or high-dose inhaled corticosteroid and sustained-release theophylline r59
    • Treat asthma exacerbations according to guidelines without modification;r60undertreatment with avoidance of oral corticosteroids results in increased return visits for exacerbationr61
  • Adults older than 65 years r62
    • Asthma is associated with higher morbidity and mortality in this group; reasons for this are not clearly understood
    • May not be recognized if overlapping with chronic obstructive pulmonary disease (ie, asthma–chronic obstructive pulmonary disease overlap syndrome)
    • Diagnosis is the same as with younger adults
      • Use age-adjusted values when interpreting the FEV₁/FVC ratio to avoid overdiagnosing respiratory impairment
      • Frail patients usually cannot adequately complete spirometric maneuvers; alternative monitoring with effort-independent testing may be better (eg. forced oscillation testing, if available)
    • Treatment guidelines were developed from studies of younger adults, with little data available on older patients
      • Carefully monitor inhaler technique as cognition and dexterity decline
      • In older adults, short-acting anticholinergic medications may be useful bronchodilators without the cardiac adverse effects of β₂-agonists, but there are other potential risks (eg, cognitive impairment, falls, symptomatic urinary outlet obstruction, closed-angle glaucoma)
      • Inhaled corticosteroids appear to be underused and should be used as directed by guidelines. Patients on higher doses should be monitored for cataracts and decreased bone density
      • There are no studies specifically focused on the safety of inhaled long-acting β₂-agonists in older adults
      • Pharmacologic treatment of comorbidities may worsen asthma (eg, β-blockers, aspirin and nonsteroidal agents, cholinergic agents)

Monitoring

  • Periodic monitoring of asthma control guides decisions for maintaining or adjusting therapy
    • Home self-monitoring r1
      • Instruct all patients to monitor at home; symptom-based monitoring or peak flow monitoring are similarly beneficial c170c171
      • For patients with moderate or severe persistent asthma, peak flow monitoring is preferred r1
    • Office monitoring
      • Assess asthma control, medication technique, asthma action plan, adherence, and patient concerns at every patient visit c172c173
      • Schedule office visits at 2- to 6-week intervals when starting a new treatment or changing treatment; perform spirometry when patient is stable after medication change r1c174c175
      • Schedule office visits at 1- to 6-month intervals, after asthma control is achieved r1c176
      • Schedule office visits at 3-month intervals, if step-down therapy is likely r1c177
      • Review treatment of established stable patients regularly (eg, at least every 12 months) r35
      • Perform spirometry at least every 1 to 2 years r1c178
      • A Cochrane review suggests that adults with frequent exacerbations and severe asthma may benefit from sputum eosinophil monitoring to guide need for corticosteroid initiation or step-up therapy r63c179
  • Urgent asthma review is indicated in the following circumstances: r35
    • Patient's asthma symptoms worsen despite appropriate use of controller medications
    • Patient experiences an asthma exacerbation, especially if associated with emergency department visit or urgent care, hospitalization, nocturnal awakening, difficulty in speaking, or marked impairment in activities of daily living
    • Patient has not had a routine review in the last 12 months
    • Patient has been prescribed more than 1 short-acting β-agonist inhaler in the last 4 months or 3 or more during the previous year
    • Patient has been prescribed a new course of oral corticosteroids (eg, in secondary care)
  • Consider periodic ophthalmologic monitoring for cataracts and bone densitometry for patients treated with high-dose inhaled corticosteroids (longer than 1 year) and/or repeated courses of oral corticosteroids r1c180c181

Complications and Prognosis

Complications

  • Complications of disease
    • Respiratory failure c182
    • Pneumothorax c183
    • Pneumomediastinum c184
    • Airway remodeling over time with worsening airflow obstruction c185c186
    • Death c187
  • Complications during surgical procedures
    • Assess asthma control and maximize lung function before planned surgery
    • Inform anesthesiologist of recent corticosteroid use
  • Complications of steroid pharmacotherapy
    • Inhaled corticosteroids
      • Increased incidence of pneumonia, especially at higher doses r64
      • May increase risk of cataracts and osteoporosis
      • Increased risk of oral candidiasis
    • Oral corticosteroids
      • Increased risk of oral candidiasis, osteoporosis, cataracts, and hyperglycemia
    • To reduce steroid complications: r1
      • Advise patient to use spacers with non–breath-activated metered dose inhalers
      • Advise patient to rinse mouth (rinse and spit) after inhalation
      • Use lowest dose of inhaled or oral corticosteroid that maintains asthma control
      • Consider calcium and vitamin D supplementation, especially for perimenopausal women

Prognosis

  • Good with mild intermittent disease or persistent disease (if well controlled)
  • Risk factors for death from asthma include: r1
    • Previous exacerbations requiring ICU admission and/or intubation
    • 3 or more emergency department visits for asthma and/or 2 or more hospitalizations for asthma in the past year r1
    • Hospitalization or emergency department visit in the past 30 days r1
    • Use of more than 2 canisters of short-acting β₂-agonist per month r1
    • Current or recent use of corticosteroids that have systemic effects
    • Patient has difficulty perceiving severity of exacerbations

Screening and Prevention

Screening c188

At-risk populations

  • A 2007 American Thoracic Society report concluded that there was insufficient evidence to support the adoption of population-based asthma screening r65
  • No universally accepted screening guideline exists for exercise-induced asthma in athletes, although some sporting organizations have established screening programs for their internationally competitive athletes r3

Prevention

  • Avoid known triggers of exacerbation r1c189c190
  • Smoking cessation c191
  • Annual influenza vaccine to prevent influenza-induced exacerbation r1c192
  • Pneumococcal vaccination (PPSV23 unless patient has criteria for PCV13 as well) if not previously administered r66c193
  • Education regarding the use of inhalers, peak flow meters, spacers, asthma action plans, and adherence to recommended treatments c194
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