Asthma

Asthma is a respiratory disease that is characterized by chronic airway inflammation and manifests with variable respiratory symptoms and expiratory airflow limitation. Allergic asthma usually develops in childhood and is triggered by allergens such as pollen, dust mites, and certain foods. Nonallergic asthma typically develops in patients aged > 40 years; triggers include cold air, medications (e.g., aspirin), exercise, and viral infections. Typical clinical features of asthma include dyspnea, end-expiratory wheezing, and persistent dry cough that worsens at night and/or on exposure to triggers. Symptoms remit in response to antiasthmatic medications or resolve spontaneously upon removal of the trigger. Diagnosis is confirmed in individuals who present with asthma symptoms that vary in severity and demonstrate variable expiratory airflow limitation on pulmonary function tests (PFTs), e.g., ↓ FEV₁ and ↓ FEV₁/FVC ratio. Additional tests may be utilized to identify asthma triggers and comorbidities that increase the risk of acute exacerbations. Treatment regimens differ based on the severity of asthma but primarily consist of an inhaled corticosteroid (ICS) combined with a long-acting beta agonist (LABA), e.g., budesonide/formoterol. Systemic glucocorticoids are usually reserved for the treatment of acute asthma exacerbations but may also be used in patients with severe persistent asthma. Avoidance of asthma triggers and management of comorbidities (e.g., rhinosinusitis) are important to achieve symptomatic control and minimize the risk of exacerbations. Frequent follow-up is essential for monitoring response to therapy and for stepwise adjustment of treatment regimens.

“Acute asthma exacerbations” and “Exercise-induced bronchoconstriction” are discussed separately.

• Asthma: a respiratory disease that is characterized by chronic airway inflammation and manifests with variable respiratory symptoms and expiratory airflow limitation.
• Acute asthma exacerbation: a reversible worsening of the clinical features of asthma that develops over a short period of time and can progress to life-threatening asthma.

• Prevalence
  • 5–10% of the US population
  • More common in Black than in White individuals
  • For unknown reasons, the prevalence of asthma has been increasing over the past 20 years. ^[1]
• Sex: differs depending on age of onset
  • ♂ > ♀ in patients < 18 years
  • ♀ > ♂ in patients > 18 years
• Age of onset
  • Allergic asthma: typically in childhood
  • Nonallergic asthma: typically > 40 years

References:^[2]

Epidemiological data refers to the US, unless otherwise specified.

• The exact etiology of asthma remains unknown.
• Risk factors for asthma include:
  • Atopy
  • Allergies
  • Genetic predisposition
  • Environmental and socioeconomic factors that increase exposure to asthma triggers, e.g., pollution from heating and cooking sources

Childhood exposure to secondhand smoke increases the risk of developing asthma.

Common underlying pathophysiology

Asthma is an inflammatory disease driven by T-helper type 2 cells (Th2-cell) that manifests in individuals with a genetic predisposition. It consists of the following three pathophysiologic processes:

1. Bronchial hyperresponsiveness
2. Bronchial inflammation
   • Symptoms are primarily caused by inflammation of the terminal bronchioles, which are lined with smooth muscle but lack the cartilage found in larger airways.
   • Overexpression of Th2-cells → inhalation of antigen results in production of cytokines (IL-3, IL-4, IL-5, IL-13) → activation of eosinophils and induction of cellular response (B-cell IgE production) → bronchial submucosal edema and smooth muscle contraction → bronchioles collapse ^[4][5]
3. Endobronchial obstruction caused by:
   • Increased parasympathetic tone
     • Reversible bronchospasm
     • Increased mucus production
     • Mucosal edema and leukocyte infiltration into the mucosa with hyperplasia of goblet cells
   • Hypertrophy of smooth muscle cells

Type-specific pathophysiology

• Allergic asthma
  • IgE-mediated type 1 hypersensitivity to a specific allergen
  • Characterized by mast cell degranulation and release of histamine after a prior phase of sensitization
• Nonallergic asthma
  • Irritant asthma: irritant enters lung → ↑ release of neutrophils → submucosal edema → airway obstruction
  • Aspirin-exacerbated respiratory disease is characterized by the Samter triad:
    • Inhibition of COX-1 → ↓ PGE₂; → ↑ leukotrienes and inflammation → submucosal edema → airway obstruction
    • Chronic rhinosinusitis with nasal polyposis
    • Asthma symptoms

• Typical features: The following features are usually variable and can occur either sporadically or in response to an asthma trigger.
  • Persistent, dry cough that worsens at night, with exercise, or on exposure to triggers/irritants (e.g., cold air, allergens, smoke)
  • End-expiratory wheezes
  • Dyspnea (shortness of breath)
  • Chest tightness
  • Prolonged expiratory phase on auscultation
  • Hyperresonance to lung percussion
• Atypical features: See “Subtypes and variants.”
• Features of common comorbid conditions: : e.g., atopic conditions like allergic rhinitis or eczema
• Acute asthma exacerbations: covered in detail separately

Characteristic examination findings may not be present between episodes of asthma exacerbation!

The following is a list of asthma phenotypes and variants.

• Allergic asthma
  • Most common phenotype
  • Begins with intermittent symptoms in childhood
  • Triggered by allergens
  • Usually associated with atopy (e.g., eczema, rhinitis)
  • Responds well to ICS-containing treatment
• Nonallergic asthma
  • Less common than allergic asthma
  • Triggered by, e.g., viral upper respiratory tract infections, cold air, GERD
  • Not associated with atopy
  • Responds poorly to ICS-containing treatment
• Adult-onset asthma:
  • An uncommon phenotype in which symptoms first manifest in adulthood
  • Typically nonallergic
  • Responds poorly to ICS-containing treatment
• Cough variant asthma: a type of asthma characterized by chronic dry cough without other typical symptoms of asthma (see also “Cough”)
• Aspirin-exacerbated respiratory disease
• Asthma-COPD overlap
• Occupational asthma

Asthma-COPD overlap ^[6]

Definition ^[6][7][8]

Asthma-COPD overlap is the concurrent presence of features of asthma and COPD. ^[6][7][8]

Clinical features ^[6]

• Chronic presentation, most commonly with intermittent or episodic symptoms
• Common symptoms include cough, SOB, chest tightness, and wheezing.
• Symptoms may:
  • Worsen after exposure to common triggers for asthma, e.g., pollen
  • Improve after use of antiasthmatic medications
• May develop in patients with a known history of asthma or COPD

Individuals with asthma-COPD overlap experience more symptoms, more frequent exacerbations, and higher mortality than individuals with either asthma or COPD alone. ^[6]

Diagnostics ^[6][7]

• Take a comprehensive history, including smoking history and toxin exposure.
• All patients require spirometry and diagnostic studies for asthma and diagnostic studies for COPD, if not already performed.
• The diagnosis of asthma-COPD overlap can be made when all of the following criteria are met: ^[7][9][10]
  • Persistent airflow limitation (FEV₁/FVC < 0.7) on PFTs (consistent with a diagnosis of COPD)
  • History of asthma and/or some clinical features of asthma ^[9]
  • Episodic nature of symptoms

Do not wait for diagnostic confirmation before initiating treatment for asthma in patients with suspected asthma-COPD overlap; untreated patients are at risk of life-threatening acute asthma attacks. ^[6]

Asthma and COPD both cause an obstructive pattern on PFTs. A positive response to post-bronchodilator testing is more common in asthma, but reversibility of bronchoconstriction is not a reliable factor for differentiating between COPD and asthma. ^[8]

Management ^[6]

• Refer to a pulmonologist for any of the following:
  • Presence of symptoms atypical of asthma or COPD
  • Suspected chronic airway disease but minimal symptoms of asthma or COPD
  • Uncertain diagnosis or suspicion of an alternative diagnosis
  • Comorbidities causing difficulty with work-up or management
• All other patients
  • Initiate asthma treatment with low-dose or medium-dose ICS, even if the diagnosis is not yet confirmed. ^[6]
  • Add LABA and/or LAMA as needed for the treatment of COPD according to the GOLD group classification system.
  • Optimize management of both underlying conditions with:
    • Adjunctive therapy for asthma (e.g., reduce trigger exposure, have an asthma action plan)
    • Supportive measures for COPD (e.g., smoking cessation, immunizations, pulmonary rehabilitation)
  • If no improvement after 2–3 months, refer to a pulmonologist.

Patients with concurrent asthma and COPD symptoms should never be treated with a LABA or long-acting muscarinic antagonist (LAMA) alone; these must always be given in combination with an ICS. ^[6]

Occupational asthma

Background

• Definition ^[11]
  • Occupational asthma: asthma that is induced by specific workplace allergens and/or irritants
  • Work-exacerbated asthma: preexisting asthma that is worsened by specific workplace allergens and/or irritants
• Epidemiology
  • The most commonly affected occupations include farmers, grain workers, and bakery workers.
  • Up to 25% of adult-onset asthma is attributable to occupational asthma. ^[6][12]
• Subtypes
  • Sensitizer-induced (i.e., IgE-mediated, allergic): caused by exposure to high-molecular-weight (e.g., flour, animal proteins) and low-molecular-weight (e.g., diisocyanates) agents ^[12][13]
  • Irritant-induced: caused by acute inhalation injury or repeated exposure to the irritant agent (e.g., vapors, gas, fumes)
  • Reactive airways dysfunction syndrome: a type of irritant-induced occupational asthma characterized by the sudden onset of symptoms within 24 hours of exposure to a high concentration of corrosive gas, vapors, or fumes ^[14]

Clinical features

• Asthma symptoms develop in a working environment with sensitizers and/or irritants and improve when outside of the workplace. ^[6]
• Rhinitis and conjunctivitis often precede asthma symptoms. ^[6][13]
• Exacerbations after repeat exposures can be severe. ^[6]

Diagnostics ^[6][13][15]

Refer to a specialist for diagnostic confirmation.

• Obtain a comprehensive work exposure history.
• Confirm diagnosis of asthma with PFTs.
• Perform serial peak expiratory flow (PEF) monitoring: A decrease in PEF with exposure to the offending agent supports the diagnosis.
• Obtain skin prick test or allergy-specific serum IgE testing to identify the causative agent.

Treatment ^[6]

• Most important: Eliminate or reduce exposure to the offending agent (e.g., use of respiratory PPE or stop the exposure through work reassignment or removal of the agent). ^[6]
• Provide stepwise asthma treatment with ICS-containing therapy. ^[6]

Complications

• Persistent bronchial hyperresponsiveness

Prevention

• Primary prevention: reducing or avoiding exposure by removing, replacing, or isolating the hazard
• Screening: medical surveillance programs in the workplace (e.g., regular spirometry) for early detection of occupational asthma

Approach ^[6]

• Perform PFTs with bronchial reversibility tests to confirm the diagnosis.
• For symptomatic patients with normal PFT results:
  • Advise self-monitoring at home with peak flow measurements 2 ×/day.
  • If an ICS is already prescribed, consider tapering off the ICS and repeating PFTs after 2–4 weeks (if feasible).
• Consider additional studies to rule out differential diagnoses of asthma and/or assess for comorbidities.
• Consult an asthma specialist if there is difficulty in confirming the diagnosis.
• “Diagnosis of acute asthma exacerbation” is covered separately.

Spirometry is the gold standard test for diagnosing asthma.

Diagnostic confirmation ^[6]

The presence of all of the following confirms the diagnosis: ^[6]

• Typical symptoms of asthma that vary in severity
• Expiratory airflow limitation (obstructive pattern) on PFTs
• Excessive variability of lung function parameters (FEV₁, PEF)

More variation or frequent instances of excessive variation in PFTs increase diagnostic certainty. ^[6]

In settings with limited or no access to spirometry, use a peak flow meter to assess for an expiratory flow limitation. ^[6]

Spirometry ^[6]

Spirometry can be paired with specialized tests in obstructive lung diseases, e.g., bronchodilator responsiveness testing, or bronchial challenge tests.

• Indication: first-line test
• Supportive findings
  • Expiratory airway limitation: i.e., ↓ FEV₁ and ↓ FEV₁/FVC ratio
  • Excessive variability in lung function, defined as ≥ 1 of the following:
    • ↑ FEV₁ of ≥ 12% and ≥ 200 mL (reversibility of airflow obstruction), in response to either: ^[16][17];
      • Bronchodilator responsiveness testing
      • 4 weeks of ICS-containing therapy
    • Variation in FEV₁ of ≥ 12% and ≥ 200 mL from one appointment to the next
    • Response during bronchial challenge testing (may be ordered if initial PFTs are inconclusive)
      • ↓ FEV₁ ≥ 20% from baseline with methacholine challenge test
      • ↓ FEV₁ ≥ 15% from baseline with hypertonic saline, hyperventilation, or inhaled mannitol
      • ↓ FEV₁ > 10% and > 200 mL from baseline with standardized exercise challenge

A bronchial challenge test is sensitive but not specific for asthma. This test is most useful for ruling out asthma in patients with inconclusive spirometry results or in those with atypical symptoms and/or response to therapy. ^[18]

Peak flow meter (PFM) ^[6]

• Indication: Spirometry is normal or not available. ^[6]
• Technique: Use the same meter each time. ^[6]
  • Stand up, inhale deeply, close mouth around the PFM mouthpiece, and blow out as forcefully as possible.
  • Note the level recorded on the meter.
  • Repeat three times in succession.
  • Record the highest reading every morning and evening.
• Supportive findings: excessive variability in lung function
  • Daily diurnal variability of PEF of > 10% (averaged over 1–2 weeks)
  • An increase in PEF by ≥ 20% after any of the following:
    • 4 weeks of ICS-containing therapy
    • Bronchodilator responsiveness testing
  • ↓ PEF from baseline while symptomatic

Additional studies ^[6]

• Allergy workup: Obtain if allergens are suspected to play a significant role in exacerbations. ^[6]
  • CBC: possible eosinophilia
  • Antibody testing: ↑ total IgE, ↑ allergen-specific IgE ^[6]
  • Skin allergy tests: skin prick testing or intradermal skin testing ^[3]
• Serum alpha-1 antitrypsin level: Obtain in individuals with adult-onset asthma or asthma that is unresponsive to treatment. ^[19]
• Single-breath diffusion capacity: : normal or ↑ DL_CO
• Fractional exhaled nitric oxide (FE_NO): the concentration of nitric oxide in exhaled air ^[20]
  • Not universally recommended ^[6][20][21]
  • May be elevated in response to airway inflammation (e.g., allergic asthma, atopy, eosinophilic bronchitis) ^[20]
• Sputum analysis (not routinely recommended)
  • Curschmann spiral: a spiral mucus plug in sputum that is formed from shed bronchial epithelium
  • Charcot-Leyden crystals: histopathologic finding in patients with eosinophilic inflammation and/or proliferation
  • Creola bodies: aggregate of desquamated epithelial cells ^[22]
• Imaging studies (e.g., HRCT)
  • Not routinely recommended; useful for differential diagnosis
  • Usually normal; may reveal air trapping and bronchial thickness

For more information on the differential diagnoses below, see “Differential diagnosis of chronic cough,” “Differential diagnosis of dyspnea,” “Differential diagnosis of acute asthma,” and “Wheezing in children.”

• Pulmonary
  • COPD or asthma-COPD overlap
  • Exercise-induced bronchoconstriction
  • Allergic bronchopulmonary aspergillosis
  • Cystic fibrosis
  • Bronchiectasis
  • α1-antitrypsin deficiency
  • Interstitial lung disease
  • Central airway obstruction
  • Infection, e.g., tuberculosis, pertussis
  • Reactive airway disease
• Cardiac
  • Heart failure
  • Congenital heart disease
• Upper respiratory
  • Upper airway cough syndrome
  • Laryngeal obstruction
  • Vocal cord dysfunction
• Gastrointestinal: GERD
• Other
  • Adverse effect of medication, e.g., cough due to ACE inhibitors
  • Hyperventilation

Consider allergic bronchopulmonary aspergillosis if respiratory symptoms worsen and/or features of bronchiectasis develop despite asthma treatment.

Comparison of asthma and COPD

Reactive airway disease ^[23]

• Description
  • A nonspecific term used to describe symptoms and findings that are similar to those of asthma (e.g., wheezing, coughing, airway sensitivity)
  • Underlying conditions include asthma, pneumonia, COPD, and/or bronchitis
  • Most commonly used in pediatric settings when asthma is suspected, but not yet confirmed
• Clinical features: wheezing, coughing, dyspnea, and/or sputum production

Ascription of the label “Reactive airway disease” may prevent a thorough workup of the actual underlying condition and/or lead to the prescription of ineffective medication.

The differential diagnoses listed here are not exhaustive.

The National Asthma Education and Prevention Program (NAEPP) guideline classifies asthma severity as intermittent or persistent in individuals who are not receiving asthma maintenance therapy. ^[3][6]

In individuals who are not receiving asthma maintenance therapy, severity is classified based on impairment over the previous 4 weeks, lung function (e.g., spirometry), and number of exacerbations in the past year. ^[3]

General principles ^[6][21]

Treatment of patients ≥ 12 years is detailed here.

• Follow a step-wise approach to management.
• Manage comorbidities; reduce exposure to asthma triggers (see “Adjunctive therapy”).
• Schedule frequent follow-ups, e.g.:
  • Appointments: 1–3 months after initiating treatment, every 3–12 months thereafter
  • PFTs: 3–6 months after initiating treatment, every 1–2 years once stable
• Management of acute asthma exacerbation and management of exercise-induced bronchoconstriction are discussed separately.
• See “Tips and links” for guidance on the management of asthma in individuals < 12 years of age.

Long-term management of asthma involves a continuous cycle of clinical assessment and adjustment of stepwise asthma treatment.

Stepwise asthma treatment ^[6][21]

Prescribe asthma relievers and maintenance bronchodilators depending on the severity and previous response to treatment.

• Before initiating treatment
  • Document supporting evidence for asthma diagnosis, asthma severity, and risk factors for asthma.
  • Provide education on proper inhaler technique.
• Before stepping up treatment
  • Assess adherence and review proper inhaler technique.
  • Identify any persistent exposures to asthma triggers.
  • Consider alternative causes for new or persistent symptoms.
• After stepping up treatment
  • Reassess symptoms at 2–6 weeks.
  • Consider stepping down treatment in patients who achieve well-controlled symptoms and stable lung function for at least 2 months.

Advise patients to seek medical care if they require > 12 inhalations from their ICS/LABA inhaler in a single day. ^[6]

Indications for referral

Refer to an asthma specialist if a patient has risk factors for asthma-related death or experiences any of the following:

• Frequent exacerbations
• Treatment side effects
• Persistent or severe symptoms despite correct use of inhaler and adherence to ICS/LABA
• Need for advanced therapies, e.g., asthma biologics

Overview of pharmacotherapy ^[3][6][21]

The goal of antiasthmatic pharmacotherapy is to counteract bronchoconstriction by reducing bronchial inflammation and parasympathetic tone.

• Asthma relievers
  • Medications that are effective in acute asthma exacerbation
  • Examples: ICS/formoterol, SABAs, SAMAs, systemic glucocorticoids
• Asthma maintenance therapy
  • Medications that are effective in the long-term management of asthma
  • Examples: ICS/formoterol, ICS, LAMA, leukotriene receptor antagonists

Patients with asthma should not be on LABAs or LAMAs without an ICS. ^[6]

PRN low-dose ICS/formoterol results in fewer severe exacerbations and ED visits than PRN SABA regimens regardless of baseline severity. ^[6]

Commonly used asthma medication

• See “Side effects of glucocorticoid therapy” for details.
• See “Contraindications for glucocorticoid therapy” for details.
• See “Antimuscarinic side effects” for details.

Adverse effects of LABA therapy can include arrhythmias, tachycardia, tremor, hyperglycemia, and hypokalemia.

Inhaled corticosteroids do not take full effect until they have been used for approx. 1 week.

Additional medications

These medications are typically reserved for patients under the care of a specialist.

Theophylline is no longer routinely prescribed because of the risk of toxicity. It is used solely as an adjunctive or alternative therapy.

The following drugs are not effective during an acute asthma attack: LABAs without ICS, leukotriene pathway modifiers, theophylline, mast-cell stabilizers, and biologics.

Implementing tertiary prevention measures improves symptom control and decreases the frequency of acute asthma exacerbations. ^[6][21]

• Reduce exposure to triggers or allergens.
  • Indoor/outdoor allergens (e.g., dust, pollen, dust mites)
  • Occupational exposure
  • Medications
  • Consider allergen immunotherapy in allergic asthma.
• Manage comorbidities.
  • Obesity
  • Rhinosinusitis and nasal polyps
  • Anxiety and depression
  • PPI if GERD is suspected
• Reduce the risk of infection-induced exacerbations.
  • Early treatment of infections in infection-triggered asthma
  • Immunizations (influenza, COVID-19, pneumococcal vaccines)
• Lifestyle recommendations
  • Provide information and tools for self-monitoring and self-management (e.g., written action plan, peak flow meter).
  • Encourage physical activity.
  • Encourage a diet rich in fruits and vegetables, e.g., Mediterranean diet, DASH diet
  • Smoking cessation
  • Promote strategies to reduce stress
• Social interventions ^[28][29][30]
  • Screen for systemic barriers to care and socioeconomic/environmental risk factors contributing to poor outcomes.
  • Provide support to enhance access to care, treatment adherence, and sustainable functional improvement.

• Asthma in pregnancy
  • Asthma symptoms may be worse, better, or unchanged during pregnancy.
  • Same stepwise management as with other patients
  • Inhalation treatments preferred
  • Poorly managed asthma can increase the risk of pregnancy complications (e.g., preeclampsia, premature birth, congenital abnormalities).
  • Monthly monitoring of asthma is recommended.
• Children under 5 years of age
  • Asthma in patients under 5 years of age is challenging to diagnose and is often underdiagnosed, as children in this age group are not typically able to adequately perform the spirometric maneuvers.
  • Regimens containing glucocorticoids are preferred as initial therapy in infants and young children; see “Tips and links” for details on treatment regimens and dosages. ^[21]
  • Young children (< 5 years) may require nebulizers because of difficulty using inhalers. ^[3]

• One-Minute Telegram 99-2024-1/3: Specialized care of newly diagnosed asthma and COPD leads to better outcomes
• One-Minute Telegram 49-2022-1/3: Improving asthma care in Black and Hispanic patients

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