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
- Genetics
- 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
- Decreased risk of asthma:
- 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).
- Respiratory infections early in life:
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
- Allergic (atopic) or extrinsic asthma
- 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.
A: Lung and airway anatomy
Image: “Asthma attack-illustration” by United States-National Institute of Health. License: Public Domain
B: Cross-section of a normal airway
C: Cross-section of an airway during asthma symptoms: constriction of airway muscles, airway inflammation, and increased mucus contribute to the limited airflow
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
Component | Classification | |||
---|---|---|---|---|
Intermittent | Persistent: mild | Persistent: moderate | Persistent: severe | |
Symptoms | ≤ 2 days/week | > 2 but < 7 days/week | Daily | Throughout the day |
Short-acting bronchodilator use | ≤ 2 days/week | > 2 days/week | Daily | Several times/day |
Nighttime awakenings | ≤ 2/month | 3–4/month | ≥ 1/week | Nightly |
Activity limitation | None | Minor | Some | Extreme |
Lung function | FEV1 > 80% | FEV1 > 80% | FEV1 60%–80% | FEV1 < 60% |
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)
Flow-volume loop (blue line) showing an obstructive pattern of expiration, reduced peak expiratory flow (approximately 4 L/sec), and lung hyperinflation (approximately 4 L at residual volume and > 8 L after full inspiration). A normal pattern (green line) and restrictive pattern (red line) are shown for comparison.
Image by Lecturio.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
- IV corticosteroids:
- 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
Related videos
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
Intermittent | Persistent: mild | Persistent: moderate | Persistent: severe | |
---|---|---|---|---|
Controller | Preferred: daily low-dose ICS | Daily low-dose ICS-LABA | Daily medium-dose ICS-LABA +/- LTRA, zileuton | |
Alternative controllers and additional therapies | Daily LTRA | Daily medium-dose ICS or daily low-dose ICS + LTRA | More severe symptoms: daily high-dose ICS-LABA +/- omalizumab +/- oral CS | |
Reliever | SABA, as needed | SABA, as needed | SABA, as needed |
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)
Step 1 (< 2x a month) | Step 2 (< 2x a month, not daily) | Step 3 (most days) | Step 4 (uncontrolled asthma) | |
---|---|---|---|---|
Controller | See preferred reliever | Low-dose ICS-formoterol as needed or daily low-dose ICS | Daily low-dose ICS-LABA |
|
Alternative controller | See alternative reliever | Low-dose ICS, if SABA is taken, or daily LTRA | Daily medium-dose ICS or daily low-dose ICS with LTRA |
|
Preferred reliever | Low-dose ICS-formoterol, as needed | Low-dose ICS-formoterol, as needed | Low-dose ICS-formoterol, as needed | Low-dose ICS-formoterol, as needed |
Alternative reliever | SABA, as needed | SABA, as needed | SABA, as needed | SABA, as needed |
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).
References
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