Asthma

Asthma is a chronic inflammatory disease of the respiratory system characterized by bronchial hyperresponsiveness, episodic acute asthma exacerbations, and reversible airflow obstruction. Allergic (extrinsic) asthma usually develops in childhood and is triggered by allergens such as pollen, dust mites, and certain foods. Nonallergic (environmental or intrinsic) asthma usually develops in patients over the age of forty and can have various triggers, such as cold air, medications (e.g., aspirin), exercise, and viral infections. The cardinal symptoms of asthma are intermittent dyspnea, cough, and high-pitched expiratory wheeze. Symptoms remit in response to antiasthmatic medications or resolve spontaneously upon removal of the trigger. In a patient with typical clinical features of asthma, diagnosis is confirmed by demonstrating reversible bronchial obstruction on pulmonary function tests. Additional tests may be required to evaluate for asthma triggers and comorbidities that increase the risk of acute exacerbations. Treatment regimens differ based on the severity of asthma but primarily consist of different combinations of beta-2 agonists and inhaled corticosteroids (ICS). Systemic corticosteroids are usually reserved for patients with severe persistent asthma. To achieve symptomatic control and minimize the risk of exacerbations, comorbidities should be managed and exposure to asthma triggers minimized. Follow-ups are essential to monitor the response to therapy and to adjust treatment regimens in a stepwise manner.

“Acute asthma exacerbations” and “Exercise-induced bronchoconstriction” are discussed in their own articles.

• Asthma: a chronic inflammatory disease of the respiratory system characterized by bronchial hyperresponsiveness, episodic exacerbation (asthma attacks), and reversible airflow obstruction; manifests with reversible cough, wheezing, and dyspnea
• 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; may be the first manifestation of asthma in some patients
• Allergic asthma: the most common type of asthma; begins with intermittent symptoms in childhood and is usually associated with atopy (e.g., eczema, rhinitis) and a good response to treatment
• Nonallergic asthma: an uncommon type of asthma that is not related to atopy and is typically associated with a poor response to standard treatment (e.g., ICS)
• See also “Subtypes and variants.”

• Prevalence
  • 5–10% of the US population
  • More common in black than white patients
  • 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:
  • Family history of asthma
  • Past history of allergies
  • Atopic dermatitis
  • Low socioeconomic status
• See also risk factors for fatal asthma exacerbations.
• Several factors can trigger an initial asthma attack or cause acute asthma exacerbation.

Childhood exposure to second-hand 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-induced asthma (NSAID-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 intermittent 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 exacerbation is covered in detail separately.

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

• Adult-onset asthma: an uncommon phenotype in which patients present with symptoms for the first time in adulthood; more likely to be nonallergic and involves a poor response to standard treatment
• Cough variant asthma: : a form of asthma in which the predominant symptom is chronic dry cough, without other characteristic symptoms of asthma, e.g., wheeze, congestion, dyspnea (see also “Cough”)
• Exercise-induced bronchoconstriction: covered separately in its own article

Asthma-COPD overlap

Asthma-COPD overlap is the presence of features of both asthma and COPD in an individual. ^[6][7][8]

Asthma-COPD overlap is not a distinct disease entity, but a term used to describe a heterogeneous category of patients with features of both diseases. ^[7][9]

Clinical features ^[7]

• 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
• See also “Comparison of asthma and COPD.”

Patients with asthma-COPD overlap experience more symptoms, more frequent exacerbations, and higher mortality than patients with either asthma or COPD alone. ^[7]

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: ^[6][7][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 ^[7]
  • 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. ^[7]

Management ^[7]

• 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. ^[7]
  • 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 LAMA alone; these must always be given in conjunction with an ICS. ^[7]

General principles ^[3][11][12]

• Asthma can be diagnosed in patients ≥ 5 years of age, based on a combination of: ^[13]
  • Typical clinical features of asthma
  • Demonstration of reversible bronchial obstruction
    • First-line: PFTs
    • Second-line (if initial PFTs are inconclusive): bronchial provocation tests
• Consider adjunctive studies as needed:
  • To identify common comorbidities
  • To exclude differential diagnoses of asthma
• Diagnostics for acute asthma are covered separately.

Pulmonary function testing ^[3][11][12]

• Characteristic findings (observable using any of the PFT modalities described below)
  • An obstructive pattern of airflow limitation (see “Obstructive lung diseases”)
  • Reversibility of airflow obstruction on bronchodilator administration
  • Excessive variability of lung function parameters (FEV₁, PEFR) on repeat testing

A normal FEV₁ in a patient who is symptomatic at the time of testing makes a diagnosis of asthma less likely.

Asthma and COPD both cause an obstructive pattern on PFTs. Complete reversibility of bronchial obstruction after bronchodilator administration rules out COPD.

Adjunctive studies

• Allergy workup: Consider if allergens are suspected to play a significant role in exacerbations.
  • Skin allergy tests: skin prick testing (SPT) or intradermal skin testing
  • CBC: possible eosinophilia
  • Antibody testing, total IgE (increased), allergen-specific IgE (increased)
• Evaluation for additional asthma triggers: e.g., see “Rhinitis”, “Sinusitis”, “GERD” ^[3]
• Additional diagnostic studies (not routinely recommended)
  • Sputum analysis revealing one or more of the following:
    • Curschmann spirals: whorled mucous plug in sputum that is formed by shed bronchial epithelium
    • Charcot-Leyden crystals: histopathologic finding in patients with eosinophilic inflammation and/or proliferation
    • Creola bodies: aggregate of desquamated epithelial cells ^[14]
  • Single-breath diffusion capacity: normal or ↑ DL_CO
  • Fractional exhaled nitric oxide (FeNO)
    • The concentration of nitric oxide in exhaled air.
    • Usually elevated in response to airway inflammation (e.g., allergic/eosinophilic asthma, atopy, eosinophilic bronchitis)
    • Although not routinely recommended, FeNO measurement may be useful for distinguishing between inflammatory and noninflammatory asthma and guiding allergic asthma treatment; higher FeNO levels indicate more inflammation and the potential need to escalate therapy.
    • May be elevated in allergic asthma ^[11][12]

The main alternate obstructive lung disease to consider is COPD. The main differentiating features are detailed below. See also “Differential diagnosis of chronic cough,” “Differential diagnosis of dyspnea,” “Differential diagnosis of acute asthma”, and “Wheezing in children” for other conditions that can mimic asthma.

Asthma vs. COPD

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

Reactive airway disease ^[15]

• 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.

General principles ^[3][11][12]

• Long-term management of asthma involves a combination of treatment, close follow-up, and patient education.
• Goals for managing asthma
  • Symptom control with antiasthmatic medications and adjunctive therapy
  • Reducing the risk of exacerbations (e.g., allergen mitigation; treatment of modifiable risk factors such as obesity or smoking)
• Specific asthma variants and phenotypes (e.g., exercise-induced asthma) require tailored treatment.
• For the management of exacerbations, see “Acute asthma exacerbation.”

The key to long-term asthma management is a continuous cycle of clinical assessment and treatment adjustment.

Approach ^[3][11][12]

1. Confirm diagnosis of asthma.
2. Assess severity (see “Classification of asthma severity”).
3. Initiate antiasthmatic medication based on severity.
4. Manage comorbidities; reduce exposure to asthma triggers (see “Adjunctive therapy”).
5. Monitor response to therapy.
6. Adjust treatment (step up or step down) based on response to therapy.
7. Schedule frequent follow-ups.

Long-term follow-up and reassessment of asthma symptom control are recommended every 1–6 months.

• The National Asthma Education and Prevention Program (NAEPP) guidelines classify asthma severity as intermittent or persistent in individuals who have not yet been initiated on long-term therapy based on the following: ^[3][11]
  • Symptom severity
  • Degree of impairment in lung function
  • Frequency and risk of exacerbations
• The 2020 Global Initiative for Asthma (GINA) guidelines classify severity into well-controlled, partly-controlled, and uncontrolled based on the minimum level of long-term treatment required to achieve symptom control (not detailed here). ^[3][12]

• Different combinations of daily and rescue therapies are given in a stepwise fashion until symptoms are controlled. ^[3][11]
• In treatment-naive patients, the initial treatment regimen should be guided by the severity class of asthma, clinical judgment, and patient preference.
• Consult asthma specialists for treatment of step 4 and higher; consider specialist consultation for step 3 treatment. ^[11]
• The recommendations here are consistent with the 2020 NAEPP guidelines; in areas in which they differ, the 2020 GINA guideline recommendations are also discussed.
• Treatment of patients ≥ 12 years is detailed here; regimens differ according to the patient's age (see “Tips & links” for guidance on management of asthma in infants and children < 12 years of age).

Any change in treatment regimen should be monitored closely with regular follow-ups.

General principles ^[3][11][12]

• The goal of antiasthmatic pharmacotherapy is to counteract bronchoconstriction by reducing bronchial inflammation and parasympathetic tone.
• Asthma relievers: drugs effective in acute asthma exacerbation: SABAs, SAMAs, and systemic corticosteroids ^[3]
• Asthma controllers: drugs effective in the long-term management of asthma (i.e., not for acute management) ^[3]
  • Commonly used: LABAs, LAMAs, LTRAs, and systemic steroids
  • Not routinely used: monoclonal antibodies, mast cell stabilizers, leukotriene pathway modifiers, and methylxanthines

Commonly used medications ^[3][11][12]

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

Additional medications

These medications are not commonly used in clinical practice. They are typically reserved for special cases under the guidance of a specialist.

Theophylline is no longer routinely prescribed due to 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, leukotriene pathway modifiers, theophylline, mast-cell stabilizers, biological agents!

These measures should be optimized in all patients to reduce antiasthmatic medication requirements and decrease the frequency of acute asthma exacerbations. ^[3][11][12]

• Reducing exposure to triggers or allergens
  • Indoor/outdoor allergens (e.g., dust, pollen, dust mites)
  • Occupational exposure
  • Medications
  • Consider allergen immunotherapy in allergic asthma.
• Managing comorbidities
  • Obesity
  • Rhinosinusitis and nasal polyps
  • Anxiety and depression
  • PPI if GERD is suspected
• Reducing the risk of infection-induced exacerbations
  • Early treatment of infections in infection-triggered asthma
  • Immunizations (influenza, 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, especially in younger patients.
  • Smoking cessation
• Social interventions ^[23][24][25]
  • 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.

Controlling modifiable risk factors (e.g., smoking cessation) and comorbidities (e.g., GERD, sinusitis) can lead to better symptom control, often allowing for a step down in treatment.

• 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 corticosteroids are preferred as initial therapy in infants and young children; see “Tips & links” for details on treatment regimens and dosages. ^[11]
  • Young children (< 5 years) may require nebulizers because of difficulty using inhalers. ^[3]

• One-Minute Telegram 49-2022-1/3: Improving asthma care in Black and Hispanic patients

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