Asthma

Definition and Epidemiology

Definition

Asthma is a chronic inflammatory disorder of the airways:

• Involving many cells and cellular elements (mast cells, eosinophils, neutrophils, T lymphocytes, macrophages, and epithelial cells) 
• Characterized by recurrent episodes of coughing, wheezing, breathlessness, and chest tightness 
• Associated with episodic airflow obstruction, which is often reversible (spontaneously or with treatment)

Epidemiology

• Affects approximately 8% of the population in the United States
• Most common chronic disease of childhood with peak presentation at 3 years of age
• Male-to-female ratio is 2:1 in childhood but this reverses in late adulthood.
• Some cases of childhood asthma resolve in adolescence, but in those with severe asthma, the condition returns by adulthood.

Etiology

Predisposing factors for asthma

• Host risk factors:
  • Genetics
    • Studies of families show heritability of asthma.
    • Multiple genes and environmental influence complicate genetic studies.
  • Atopy
    • Genetic predisposition to produce immunoglobulin E (IgE) antibodies on allergen exposure
    • Strong risk factor for asthma
  • Perinatal factors (increased asthma risk)
    • Prematurity at birth
    • Neonatal or early abnormality of lung function
  • Sex
    • Asthma is more common in boys before puberty. 
    • 1:1 ratio in adulthood, with women affected more by age 40
    • Unclear if sex hormones are linked to development of asthma
  • Obesity: ↑ risk of asthma 
• Maternal factors
  • Decreased risk of asthma:
    • Increasing maternal age at delivery (> 30 years)
    • Breastfeeding: ↓ wheezing in the first 2 years of life
  • Increased risk of asthma:
    • Maternal diet: low in vitamin D and omega-3 polyunsaturated fatty acid
    • Poorly controlled maternal asthma
    • Prenatal exposure to maternal smoking
• Environmental factors
  • Respiratory infections early in life: 
    • 40% have asthma/wheezing later in life.
    • Commonly from respiratory syncytial virus, human rhinovirus
  • Pollution: living close to a major road and ↑ nitrogen dioxide → ↑ asthma 
  • Smoking (including secondhand smoke)
  • Occupational exposure (fires, pesticides, industrial agents) 
  • Allergens (fungi, dust mite, cockroach allergen)
  • Early exposure to pet allergens: 
    • Varied results
    • Protects by decreasing sensitization to pet allergens
    • In some, asthma develops, possibly influenced by other exposures (tobacco, pollution).

Asthma triggers

In established asthma, different triggers may exacerbate the symptoms. These include the following:

• Environmental and drug-induced:
  • Allergens
  • Cold air
  • Paints and fumes
  • Irritant gasses
  • Air pollution
  • Drugs (beta blockers and aspirin)
• Endocrine:
  • Premenstrual hormones
  • Thyrotoxicosis
  • Hypothyroidism
• Behavioral and psychological:
  • Exercise
  • Hyperventilation
  • Stress
• Other triggers:
  • Upper respiratory tract infections
  • Gastroesophageal reflux

Pathophysiology

Predominant inflammatory response

• Initial exposure to antigen:
  • Prompts naive T-cell differentiation to T helper (Th) 2 cells
  • Followed by production of IgE antibodies, which bind to mast cells and basophils (ready to respond on antigen rechallenge)
• Early phase: inhaled antigen (presented by dendritic cells): IgE-bound mast cells and basophils degranulate (early-phase reaction) → release of mediators (prostaglandin D₂, histamine, leukotrienes) → airway smooth muscle contraction → airway tightening
• Late phase: recruitment of inflammatory cells: Th2 cells → production of mediators and cytokines
  • IL-5: ↑ differentiation of eosinophils (which migrate to the lungs) 
  • IL-3, IL-4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) prolong eosinophil survival.
  • IL-4 also helps with T-cell differentiation and IgE production.
  • IL-13 increases mucus glands, airway fibrosis, and remodeling.
  • Eosinophils (the most prominent cells) increase the release of inflammatory mediators.
• Effects:
  • Cellular response → airway inflammation
  • Airway smooth muscle contraction and edema, with mucus plug formation → airway obstruction
  • Increased histamine, airway smooth muscle mass, sensitivity of neural pathways with exaggerated airway constriction → airway hyperresponsiveness
  • Structural changes (smooth muscle hyperplasia and hypertrophy, increased extracellular matrix) affect reversibility of obstruction → airway remodeling

Other mechanism

• Non-eosinophilic 
• Does not involve Th2 cells
• Environmental factors (pollution, smoking, infections, allergens) → involve Th1 and Th17 cell responses → neutrophilic inflammation and airway hyperresponsiveness
• Neutrophilic inflammation: 
  • High sputum neutrophil counts
  • Associated with severe asthma exacerbations
  • Often difficult to treat and less responsive to corticosteroids

Heterogeneity of asthma

• Asthma types based on triggers and etiology:
  • Allergic (atopic) or extrinsic asthma
    • Typically prevalent in childhood
    • Triggered by environmental allergens
  • Non-allergic or intrinsic asthma
    • Onset in adulthood
    • Various triggers: infection, exercise, aspirin 
• Asthma is now believed to have more phenotypes, with a classification based on underlying pathophysiologic mechanism:
  • Th2–mediated (T2 high) inflammation: associated with eosinophilia and steroid responsiveness
  • Non-Th2 (non-T2): no eosinophilia, with sputum neutrophils (or normal eosinophils and neutrophils) and non-response to steroids
• Implication: Treatment options are available and under development based on pathophysiology.

Clinical Presentation

Symptoms

• Recurrent wheezing
• Dyspnea: chest tightness/heavy weight on the chest
• Cough: 
  • Can be dry or productive of sputum
  • Worse at night and in the early morning hours
• Episodic, can resolve spontaneously or with treatment
• Symptoms occur with characteristic triggers (i.e., allergens, cold air).

Signs

• Asymptomatic when under control
• When symptomatic:
  • Tachypnea, tachycardia
  • Expiratory ± inspiratory wheezing and rhonchi
  • Prolonged expiratory phase of respiration

Classification of asthma based on severity

Diagnosis

Clinical findings

• Recurrent episodes of airflow obstruction or airway hyperresponsiveness are present.
• Airflow obstruction is at least partially reversible. 
• Alternative diagnoses are excluded.

Pulmonary function tests

• Spirometry:
  • Maximal inhalation followed by rapid forceful exhalation (at least 6 seconds)
  • Measures: 
    • FEV1 (forced expiratory volume in 1 second)
    • FVC (forced vital capacity or the maximal volume exhaled with maximally forced effort)
  • ↓ FEV1 and FEV1/FVC ratio < 0.70 (suggests airway obstruction)
• Bronchodilator response:
  • Nebulized or 2–4 puffs of bronchodilator (e.g., albuterol) given, then spirometry rechecked after 15 minutes
  • Increase in FEV1 by > 12% or 200 mL (bronchodilator responsiveness)
• Peak expiratory flow (PEF):
  • Maximal inhalation, then fast forceful exhalation (< 2 seconds) into peak flowmeter
  • A single peak flow is obtained during symptoms.
  • Results compared with average normal values (based on height and age)
  • Post-bronchodilator administration, improvement of > 20% suggests airway obstruction (favors diagnosis of asthma)
  • Used more for monitoring than for diagnosis
• Bronchoprovocation testing:
  • A stimulus (methacholine, exercise, histamine, inhaled mannitol) is tried, to trigger bronchoconstriction.
  • ≥ 20% reduction in FEV1 with challenge/testing (airway hyperresponsiveness)
• Impulse oscillometry (IOS):
  • For children < 5 years old or those who cannot perform spirometry
  • Passive measurement of lung mechanics
  • Requires minimal patient cooperation, but not available to many clinicians

Exhaled nitric oxide

• Nitric oxide measured in patient’s exhaled breath
• Basis of test: eosinophilic airway inflammation upregulates nitric oxide synthase → ↑ amount of fraction of exhaled nitric oxide (FENO)
• FENO > 50 parts per billion: 
  • Indicates eosinophilic airway inflammation 
  • Improves with inhaled corticosteroid (ICS)
• Limitations:
  • Asthma is not always due to eosinophilic airway inflammation.
  • Lower FENO: cannot exclude use of ICS (as it provides benefit even for mild asthma)
  • Affected by smoking, atopy, age, and sex

Chest X-ray

• Excludes other diagnosis (pneumothorax or pneumonia in exacerbations)
• Normal in mild asthma
• May show hyperinflation in severe asthma (flattened diaphragm, wide intercostal spaces)
• Indicated for atypical presentation of asthma (fever, crackles, hypoxemia)

Additional tests

• No blood test can confirm diagnosis of asthma.
• Complete blood count: may show eosinophilia (which suggests atopic asthma)
• IgE level: 
  • Moderate-to-severe asthma
  • When anti-IgE monoclonal antibody treatment is considered
• Allergy tests: may determine allergic triggers and help provide allergen avoidance measures
• Alpha-1 antitrypsin level: detects alpha-1 antitrypsin deficiency (for patients with persistent airway obstruction)
• Biomarkers:
  • Sputum eosinophils: can be used as biomarker for T2-high asthma
  • Periostin: biomarker for eosinophilic inflammation despite use of corticosteroids
• Sweat chloride test:
  • In children with persistent respiratory symptoms, to rule out cystic fibrosis
  • Low threshold in performing test due to lifelong implications of disease
• Arterial blood gas (in severe asthma exacerbation):
  • Obtain when oxygen saturation of < 94%, no bronchodilator response, mental status change(s)
  • Initial finding(s): hypoxia (reduced oxygen), hypocarbia (due to hyperventilation), ↑ pH
  • Respiratory failure: hypoxia, hypercarbia, ↓ pH (respiratory acidosis)

Management

Non-pharmacologic management

• Patient education: 
  • Asthma symptoms
  • Indications for and proper technique of bronchodilator and corticosteroid inhaler use
  • Discuss asthma action plan (PEF monitoring and corresponding action)
• Goals: 
  • Control of symptoms and triggers
  • Reduce future risks and complications
• Smoking cessation
• Update influenza and pneumococcal vaccinations.

Pharmacologic and invasive management

• For rescue treatment of acute exacerbation:
  • Short-acting beta2-agonists (SABA): for exercise-induced asthma or asthma exacerbation
  • Long-acting beta2-agonists (LABA): low-dose inhaled corticosteroids; formoterol can be used as acute symptom reliever (Global Initiative for Asthma guidelines)
• Controllers:
  • Inhaled corticosteroids (ICS): most effective anti-inflammatory medications for asthma
  • Systemic corticosteroids:
    • Short-term treatment (< 7 days) recommended
    • Tapering required if > 2 weeks 
  • Leukotriene receptor antagonists (LTRA) and 5-lipoxygenase inhibitor:
    • Exercised-induced bronchospasm
    • Mild persistent asthma + allergic rhinitis
    • Asthma + aspirin-exacerbated respiratory disease
• Monoclonal antibodies for severe asthma:
  • Anti-IgE or IgE antibody: omalizumab
  • IL-5 antagonist: mepolizumab, reslizumab 
  • IL-5 receptor antagonist: benralizumab
  • Anti-IL-4 receptor antagonist: dupilumab 
• Bronchial thermoplasty: 
  • Ablates bronchial smooth muscles through the application of heat during bronchoscopy 
  • Carries procedure-related risks; only modest improvement of asthma
  • Strict criteria for selection (including patients who are unresponsive to maximum pharmacologic therapy)

Emergency management

Emergency management is for severe asthma exacerbation, not for responding to initial outpatient management.

• Oxygen therapy goal: 93%–95% oxygen saturation (adults)
• Inhaled therapy:
  • High dose of SABA via nebulizer or spacer
  • Nebulized ipratropium if no response to beta2-agonists
  • High-dose ICS given in 1st hour
• Intravenous medication(s):
  • IV corticosteroids:
    • If asthma does not improve consistently after SABA treatment
    • If exacerbation occurs despite ongoing daily oral steroid therapy 
    • If exacerbation is recurrent after recent discontinuation of systemic steroids
  • Consider IV magnesium sulfate (1 dose):
    • Found to reduce hospital admissions in some patients
    • Not for routine use in asthma exacerbations
    • Contraindicated in renal insufficiency
• Endotracheal intubation and mechanical ventilation in case of impending respiratory failure: 
  • Mental status changes (confused, agitated, or drowsy)
  • Silent chest on auscultation
  • Respiratory fatigue (respiratory rate > 30/min, heart rate > 120/min, use of accessory muscles)
  • Respiratory acidosis with increasing hypercapnia
  • Low oxygen saturation (< 92%) despite high-flow oxygen
• Improved PEF > 80% and resolution of symptoms: discharge

Management Guidelines

National Asthma Education and Prevention Program (NAEPP)

• Basis of disease severity: 
  • Symptoms, activity limitation, SABA use, lung function
  • Includes spirometric values in determining severity (intermittent to persistent asthma)
  • Stepwise approach in initiation and continuation of medication(s) based on severity 
• SABA: 1st-line therapy for acute exacerbation
• Corticosteroids: 
  • Initiated in persistent asthma symptoms
  • Dose increased depending on severity

Global Initiative for Asthma (GINA)

• Updated 2020
• Basis of severity: level of treatment (steps) needed to control symptoms and exacerbations
• All patients given ICS either daily or as needed
• ICS-formoterol:
  • 1st-line therapy (reliever) for adults and adolescents > 12 years of age
  • Preferred over SABAs for as-needed relief (except for age < 5 years)

Differential Diagnosis

• Upper airway obstruction by tumor or laryngeal edema: causes stridor rather than wheezing. Flow-volume loop shows a limitation in flow in both inspiratory and expiratory curves. Bronchoscopy confirms diagnosis.
• Foreign-body aspiration: shows localized or generalized wheezing. Chest X-ray can be normal or with unilateral hyperinflation or infiltrate. Bronchoscopy is diagnostic and therapeutic (foreign body retrieval).
• Left ventricular failure: wheezing is accompanied by crackles. History, physical examination with chest X-ray, echocardiogram, and ECG help distinguish congestive heart failure.
• Vocal cord dysfunction: presents with wheezing, cough, and dyspnea. Spirometry would show flattened inspiratory flow loop suggestive of variable extrathoracic obstruction. Laryngoscopy (gold standard) is recommended for diagnosis.
• Eosinophilic granulomatosis with polyangiitis: may present with cough and wheezing. The condition is refractory to usual asthma treatment and has peripheral manifestations of vasculitis.
• Chronic obstructive pulmonary disease (COPD): manifests with dyspnea, cough, and wheezing. The condition has a strong association with smoking history. Pulmonary function test will show obstructive pattern without significant reversibility. Emphysema, a form of COPD, also has reduced diffusing capacity of the lung for carbon monoxide (DLCO).