Asthma

Asthma is a chronic inflammatory disease of the respiratory system characterized by bronchial hyperresponsiveness, episodic exacerbations (asthma attacks), 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, medication (e.g., aspirin), exercise, and viral infection. The cardinal symptoms of asthma are intermittent dyspnea, coughing, and high-pitched expiratory wheezing. Symptoms remit in response to antiasthmatic medication or resolve spontaneously upon removal of the trigger. Confirmation of the diagnosis involves pulmonary function tests, allergy tests, and chest x-ray. First-line treatment consists of inhaled bronchodilators (e.g., short-acting beta-2 agonists) for acute exacerbations and inhaled corticosteroids (e.g., budesonide) for long-term asthma control. Patients should be taught the correct usage of inhalers for self-medication and measurement of peak expiratory flow (PEF) to self-monitor disease progression and severity. Severe asthma exacerbation can be life-threatening and may require emergency treatment and/or hospitalization.

• 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 at onset
  • ♂ > ♀ in patients < 18 years
  • ♀ > ♂ in patients > 18 years
• Age of onset
  • Allergic asthma: typically in childhood
  • Nonallergic asthma: typically > 40 years

References:^[2][3]

Epidemiological data refers to the US, unless otherwise specified.

The exact etiology of asthma remains unknown. Known risk factors for asthma include the following:

• Family history of asthma
• Past history of allergies
• Atopic dermatitis
• Low socioeconomic status

Childhood exposure to second-hand smoke increases the risk of developing asthma!

The following factors can also act as initial triggers of asthma or exacerbate an existing condition:

• Allergic asthma (extrinsic asthma)
  • Cardinal risk factor: atopy
  • Environmental allergens: pollen (seasonal), dust mites, domestic animals; , mold spores
  • Allergic occupational asthma: from exposure to allergens in the workplace (e.g., flour dust)
• Nonallergic asthma (intrinsic asthma)
  • Viral respiratory tract infections (one of the most common stimuli, especially in children) ^[4]
  • Cold air
  • Physical exertion (exercise-induced asthma)
  • Gastroesophageal reflux disease (GERD): often exists concurrently with asthma
  • Chronic sinusitis or rhinitis
  • Medication: aspirin/NSAIDS (aspirin-induced asthma); , beta-blockers
  • Stress
  • Irritant-induced asthma; (e.g., from exposure to solvents, ozone, tobacco or wood smoke, cleaning agents)

References:^[5][2]

Asthma is generally characterized as an inflammatory disease driven by T-helper type 2 (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 ^[6][7]
3. Endobronchial obstruction caused by:
   • Bronchospasm
   • Mucosal edema
   • Hypertrophy of smooth muscle cells
   • Increased mucus production

Some forms of asthma have specific pathophysiologies:

• 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 inhibition of COX-1 → ↓ PGE₂ → ↑ leukotrienes and inflammation → submucosal edema → airway obstruction

References: ^[2]

Chronic/persistent signs and symptoms

• Mild to moderate signs and symptoms
  • 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
  • Chest tightness
  • Chronic allergic rhinitis with nasal congestion
• Severe signs and symptoms
  • Severe dyspnea
  • Pulsus paradoxus
  • Hypoxemia
  • Accessory muscle use
  • Increased risk of pulmonary infection (in chronic asthma)
• Cough variant asthma
  • A form of asthma in which the predominant symptom is chronic, dry cough
  • Other characteristic symptoms of asthma (e.g., wheezes, congestion, dyspnea) are absent.

Acute asthma attack

• Definition: acute, reversible episode of lower airway obstruction that may be life-threatening

Clinical features	Mild	Moderate	Severe
Symptoms
Breathlessness	While walking	While at rest	At rest
Position	Can lie down	Prefers sitting	Hunched over
Ability to speak	Sentences	Phrases	Individual words
Alertness	May be agitated	Usually agitated	Agitated
Signs
Respiratory rate	Increased	Increased	Often > 30/minute
Wheezing	Moderate, often only end-expiratory	Loud; throughout exhalation	Throughout inhalation and exhalation; can also be absent
Use of accessory muscles	Rarely	Commonly	Usually
Pulse/minute	< 100	100–120	> 120
Pulsus paradoxus	Absent	May be present	Often present
PCO2	< 42 mm Hg	> 42 mm Hg	≥ 42 mm Hg
SaO2	> 95%	90–95%	< 90%

Clinical examination

• Auscultation (characteristic findings are usually only present during acute attacks)
  • Prolonged expiratory phase with wheezing (dry crackles)
  • Decreased breath sounds; possibly “silent chest”
  • Tachypnea
• Percussion
  • Hyperresonant sound
  • Inferior displacement and poor movement of the diaphragm
• In severe attacks
  • Altered level of consciousness
  • Cyanosis

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

References: ^[5][8][2][9]

• The differential diagnosis of chronic cough and the causes of dyspnea are both addressed in other articles.
• The other main obstructive lung disease is COPD, which is compared with asthma in the table below.

Comparison of asthma and COPD
	Asthma	COPD
Age at diagnosis	Often childhood or adolescence, although nonallergic asthma can manifest after the age of 40	Typically > 40 years old
Etiology	Allergic and nonallergic (see “Etiology” above)	Cigarette consumption (90% of cases)
Clinical presentation	Episodic: symptom-free phases, sudden attacks	Insidious onset and chronic progression over years
Obstruction	Reversible	Persistent airflow limitation
Medication	Good response to treatment with long-term inhaled corticosteroids	Good response to parasympatholytics (e.g., ipratropium bromide)

References:^[2]

The differential diagnoses listed here are not exhaustive.

A combination of clinical findings ; and objective measurement of pulmonary function (for adults and children ≥ 5 years of age) is needed to confirm the diagnosis and assess the severity of asthma.

Evaluation of pulmonary function

• Pulmonary function testing (spirometry)
  • First-line diagnostic test for confirmation of the diagnosis in patients ≥ 5 years of age.
    • Shows signs of obstructive lung disease with increased airway resistance → ↓ FEV₁, ↓ Tiffeneau index (FEV1/FVC ratio)
    • Obstruction is reversible with bronchodilators → diagnostic confirmation via post-bronchodilator test
• Methacholine challenge test (bronchoprovocation test)
  • Second-line diagnostic test if pulmonary function testing is nondiagnostic
  • Evidence of bronchial hyperresponsiveness after inhalation of methacholine
  • Positive if FEV1 reduced ≥ 20%
• Chest x-ray
  • Usually only indicated in patients with severe asthma to exclude differential diagnoses (e.g., pneumonia, pneumothorax)
  • Normal in mild cases
  • Signs of pulmonary hyperinflation in cases of severe asthma
    • Low, flattened diaphragm
    • Wide intercostal spaces
    • Barrel chest

Laboratory studies and further workup

• Pulse oximetry and blood gas analysis (ABG)
  • Blood gas analysis should be performed if oxygen saturation (SpO₂) is < 94%.
  • Findings on ABG
    • Initially: ↓ pCO₂, ↑ pH, ↓ pO₂ leading to type 1 respiratory failure
    • Ultimately: severe respiratory distress: ↑ pCO₂, ↓ pH, and ↓↓ pO₂ leading to type 2 respiratory failure

Patients with acute asthma exacerbations initially have ↓ PCO₂ and respiratory alkalosis (↑ pH) due to tachypnea. Rising PCO₂ is a sign of respiratory fatigue and impending respiratory failure! ICU admission and intubation should be considered.

• In allergic asthma
  • Antibody testing, total IgE (increased), allergen-specific IgE (increased)
  • CBC: possibly eosinophilia
  • Skin allergy tests: skin prick testing (SPT) or intradermal skin testing
• In asthma triggered by infection: elevated inflammatory markers
• Sputum sample
  • 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)
  • and/or Creola bodies (aggregate of desquamated epithelial cells) ^[10]

Classification of asthma severity at initial assessment for children ≥ 12 years and adults

The following table allows for classification of asthma severity in the initial assessment of patients who are not yet taking asthma control medication.

Classification of asthma severity
	Mild intermittent asthma	Mild persistent	Moderate persistent	Severe persistent
Symptoms (e.g., dyspnea, wheezing, cough)	≤ 2 days/week	> 2 days/week	Daily	Throughout the day
Nighttime symptoms (e.g., difficulty falling asleep because of symptoms, nighttime awakenings)	Rare	3–4 times/month	1–2 times/week	Often (most nights)
FEV1	> 80%	> 80%	60–80%	< 60%

References: ^[2][4][11]

Causal

• Avoid triggers (see “Etiology” above).
• Allergen immunotherapy in allergic asthma
• Early treatment of infections in infection-triggered asthma
• If GERD is suspected: proton pump inhibitors

Symptomatic

Overview of asthma medication
Class	Examples	Mechanism		Primary use
Beta-2 agonists	Short-acting beta-2 agonists (SABA) Albuterol Terbutaline Long-acting beta-2 agonists (LABA) Salmeterol Formoterol	Dilate bronchial smooth muscles (see beta-2 agonists).		SABA: acute exacerbations LABA: long-term maintenance treatment
Inhaled corticosteroids (ICS)	Beclomethasone Fluticasone Budesonide Ciclesonide Mometasone Triamcinolone	Inhibit transcription factors (e.g., NF-κB) → ↓ expression of pro-inflammatory genes Also see “Effects” in glucocorticoids.		Long-term maintenance treatment (first-line)
Leukotriene pathway modifiers	Montelukast Zafirlukast	Leukotriene receptor antagonists (LTRAs): prevent leukotrienes from binding to their receptors	↓ Bronchoconstriction and inflammation	Long-term maintenance treatment (particularly in children) Exercise-induced and aspirin-induced asthma
	Zileuton	Inhibits 5-lipoxygenase → ↓ production of leukotrienes
Muscarinic antagonists	Short-acting muscarinic antagonists (SAMA): ipratropium bromide Long-acting muscarinic antagonists (LAMA): tiotropium bromide	Competitively inhibit postganglionic muscarinic receptors in bronchial smooth muscle → bronchodilation See muscarinic antagonists.		Option for long-term maintenance treatment
Biological agents	Omalizumab	Anti-IgE antibody that binds to serum IgE Reduced serum levels of IgE prevent binding of IgE to high affinity IgE receptor (FcεRI) on mast cells and basophils → The inflammatory cascade triggering asthma is inhibited. Long-term reduction in serum IgE levels will reduce surface expression of IgE receptor on mast cells and basophils.		Allergic asthma
	Mepolizumab [12]	Monoclonal antibody against IL-5: potent chemoattractant for eosinophils		Additional medication for severe eosinophilic asthma that is not sufficiently controlled with other measures
Methylxanthines	Theophylline	Inhibits phosphodiesterase (PDE) → ↑ cAMP levels → anti-inflammatory and mild bronchodilatory effect See “Treatment” in chronic obstructive pulmonary disease.		Limited use (cardiotoxic, neurotoxic)
Mast cell stabilizers	Cromolyn sodium Nedocromil sodium	Prevents release of inflammatory mediators from mast cells.		Preventive treatment prior to exercise or unavoidable exposure to known allergens in patients ≥ 5 years old
Oral corticosteroids	Methylprednisolone Prednisone	Similar to inhaled corticosteroids		Used in severe and refractory cases

Acute management

• For mild symptoms: short-acting beta-2 agonist
• For exercise-induced asthma: short-acting beta-2 agonist prior to exercise
• For severe asthma exacerbations, see “Treatment” in status asthmaticus.

The following drugs are not effective during an acute asthma attack: LABA, leukotriene pathway modifiers, theophylline, mast-cell stabilizers, biological agents!

To remember the meds for asthma exacerbations, think ASTHMA: Albuterol, Steroids, Theophylline (rare), Humidified O₂, Magnesium (severe exacerbations), Anticholinergics.

Long-term management

• General principles
  • Reduce number of asthma attacks → Medical therapy is escalated or de-escalated depending on the patient's individual needs.
  • Self-monitoring for patients: peak flow meter to measure peak expiratory flow rate (PEFR)
    • Patients can avoid exacerbations with frequent PEFR measurements: PEFR decreases before symptoms appear → indicates insufficient medication regimen
  • Influenza and pneumococcal vaccines are administered in all patients.
• Pharmaceutical management
  • Reliever medications: provide relief of asthma symptoms and are taken as needed when symptoms are present
  • Controller medications: control underlying inflammation of asthma
  • Shift in treatment paradigm as of 2019 ^[13]
    • Previously: As-needed SABA reliever inhaler was the mainstay of intermittent asthma treatment.
    • New recommendation: ICS-containing controller inhaler for every adult and adolescent with asthma (no more SABA-only treatment)
    • Reasoning: ICS addresses the underlying problem of airway inflammation → reduces both frequency of symptoms and risk of severe asthma exacerbations (SABAs only address symptoms)
    • Note that many resources still list as-needed SABA reliever treatment as the only therapy necessary in intermittent asthma.

Pharmaceutical management of chronic asthma (adults and adolescents)
Severity
Treatment	Mild intermittent	Mild persistent	Moderate persistent	Severe persistent
Preferred reliever	As-needed low-dose ICS-formoterol or SABA
Preferred controller	As-needed low-dose ICS-formoterol	Daily low-dose ICS OR as-needed low dose ICS-formoterol	Daily low-dose ICS-LABA	Daily medium/high-dose ICS-LABA
Alternative and add-on controllers	OR low-dose ICS whenever SABA is taken	OR LTRA OR low-dose ICS whenever SABA is taken	OR low-dose ICS + LTRA OR medium dose ICS	OR high-dose ICS ± LAMA ± LTRA ± Low-dose OCS ± Omalizumab or mepolizumab in refractory cases

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

• Monitoring
  • Routine follow-up every 1–6 months, depending on severity
  • Purpose of follow-up: assessment of asthma symptom control

Asthma symptom control
Control questions	Well controlled	Partly controlled	Uncontrolled
Limitation of activities due to asthma symptoms?	Patient answers “No” to all questions	Patient answers “Yes” to 1–2 questions	Patient answers “Yes” to 3–4 questions
Reliever inhaler use more than twice weekly?
Daytime asthma symptoms more than twice weekly?
Awakening at night due to asthma symptoms?

References: ^{[5][8][4][14][13]}

Status asthmaticus

• Definition: extreme asthma exacerbation that does not respond to initial treatment with bronchodilators
• Clinical features
  • Initially: orthopnea, tachypnea, tachycardia, and cyanosis
  • Signs of imminent respiratory arrest
    • Drowsiness/confusion
    • Paradoxical thoracoabdominal movement
    • Bradycardia
    • Absent wheezing
    • Pulsus paradoxus
• Diagnosis
  • The following diagnostic workups should be done in patients with status asthmaticus attacks:
    • ABG (i.e., to identify hypercapnia and hypoxemia)
    • CBC
    • BMP
    • Peak expiratory flow measurement
    • Chest x-ray
    • ECG (in older patients)
• Management
  • Hospitalization
    • PEF or FEV₁: 50–70% of the predicted value
    • PEF or FEV₁ < 50% of the predicted value → admitted in the ICU
  • Medications
    • Short-acting beta-2 agonist (SABA)
    • Short-acting muscarinic antagonists (SAMA) like ipratropium bromide
    • Oral corticosteroid
    • Intravenous magnesium sulfate
  • Oxygenation and ventilation
    • Supplemental oxygen and/or helium-oxygen mixture (heliox)
    • Noninvasive ventilation (NIV)
      • Bilevel positive airway pressure (BiPAP) provides greater support.
        • Maintains airways open → decreases airways resistance → reduces auto-PEEP → reduces work of breathing
      • Use for 1–2 hours in cooperative patients not responding to medical therapy.
      • Do not delay intubation when it is indicated.
    • Indications for intubation
      • Use of accessory muscles
      • Decreased oxygen saturation
      • Inability to speak in full sentences
      • Inadequate response to initial therapy
      • Normalizing PCO₂ or pH (see “Laboratory Studies” under “Diagnostics” above)

Status asthmaticus is a medical emergency, as it can be a life-threatening!

References: ^[16][17]

We list the most important complications. The selection is not exhaustive.