Asthma in Adults

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

• 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

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 guidelines^r8 and American Thoracic Society^r9 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 data^r18 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

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

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

Recommendations for specialist referral

• Refer to asthma specialist (pulmonologist or allergist)
  • Severe, persistent asthma requiring step 4 care or higher^r1
  • 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

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 guidelines^r1) 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

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 exacerbation^r61
• 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)

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