Asthma¶
Chapter 298 | Part 7: Disorders of the Respiratory System
KEY CLINICAL POINTS¶
- Asthma is characterized by episodic airway obstruction, airway hyperresponsiveness, and reversible inflammation.
- Type 2 inflammation (IL-4, IL-5, IL-13) drives eosinophilic airway inflammation and is central to pathophysiology.
- Key triggers include allergens, viral infections, exercise, cold air, and occupational exposures.
- Inhaled corticosteroids (ICS) and LABA combinations are cornerstone therapies for persistent asthma.
- Biologics (anti-IgE, anti-IL-5, anti-IL-4/13) target specific endotypes in severe or refractory asthma.
1. DEFINITION & OVERVIEW¶
Asthma is a chronic inflammatory disease of the airways characterized by episodic bronchoconstriction, airway hyperresponsiveness, and reversible airflow obstruction. It is associated with airway inflammation, mucus hypersecretion, and structural changes. Symptoms include wheezing, dyspnea, chest tightness, and cough, often triggered by allergens or irritants.
Table 298-1: Exposures and Risk Factors Related to the Development of Asthma¶
| Risk Factor | Description |
|---|---|
| Allergen exposure | Predisposition to atopy increases risk |
| Occupational exposure | Common in nursing, cleaning, and manufacturing |
| Air pollution | Associates with increased asthma prevalence |
| Infections | Viral and Mycoplasma infections linked to exacerbations |
| Tobacco use | Smoking increases risk and severity |
| Obesity | Linked to increased asthma severity and exacerbations |
| Diet | Vitamin D deficiency may increase risk |
| Fungi | Allergic fungal sinusitis may contribute to asthma |
1.1 Pathophysiology¶
Asthma involves type 2 inflammation mediated by IL-4, IL-5, and IL-13, leading to eosinophilic infiltration, mucus overproduction, and airway remodeling. Airway hyperresponsiveness to non-specific stimuli (e.g., cold air, exercise) is a hallmark. Non-type 2 mechanisms (neutrophilic inflammation) may also occur in severe cases.
1.2 Clinical Features¶
Symptoms include episodic wheezing, shortness of breath, chest tightness, and cough. Exacerbations may be triggered by allergens, viral infections, or environmental irritants. Chronic symptoms may include nocturnal awakenings and exercise-induced bronchoconstriction.
2. EPIDEMIOLOGY¶
Asthma affects ~262 million globally, with prevalence increasing from 7.3% in 2001 to 8.4% in the U.S. Children have higher prevalence (8.4%) than adults (7.7%). Risk factors include genetic predisposition, atopy, and environmental exposures. Mortality declined globally from 0.44 to 0.19 per 100,000 between 1993–2006.
Table 298-2: Triggers of Airway Narrowing¶
| Trigger | Mechanism |
|---|---|
| Allergens | IgE-mediated mast cell activation |
| Irritants | Direct smooth muscle contraction |
| Viral infections | Neutrophilic inflammation |
| Exercise | Cold air-induced bronchoconstriction |
| Air pollution | Oxidative stress and inflammation |
| Drugs | Beta-blockers, NSAIDs, aspirin |
| Occupational exposures | Irritants like isocyanates |
| Hormonal changes | Menstrual cycle, pregnancy |
2.1 Demographics¶
Higher prevalence in boys (2:1 male-to-female ratio) in childhood, with a trend toward female predominance in adulthood. Black populations have higher prevalence and morbidity in the U.S.
2.2 Global Trends¶
Urbanization and environmental changes correlate with rising prevalence. Mortality has decreased due to corticosteroid use, but remains higher in low-income regions.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Asthma results from a complex interplay of genetic and environmental factors. Type 2 inflammation (IL-4/IL-13) drives eosinophilic inflammation, mucus hypersecretion, and airway remodeling. Non-type 2 mechanisms (e.g., neutrophilic inflammation) may occur in severe cases. Environmental triggers (allergens, pollutants) activate innate and adaptive immune responses.
Table 298-3: Differential Diagnosis and Comorbidities That May Make Asthma Difficult to Control¶
| Condition | Clinical Features |
|---|---|
| Chronic rhinosinusitis | Nasal polyps, nasal congestion |
| Obesity | Increased severity and exacerbations |
| GERD | Nighttime symptoms, postnasal drip |
| COPD | Overlap syndrome with chronic bronchitis |
| Anxiety/depression | Worsening symptoms, poor adherence |
| Condition | Clinical Features |
|---|---|
| Obstructive sleep apnea | Nocturnal symptoms, fatigue |
3.1 Mediators¶
Cytokines (IL-4, IL-5, IL-13), chemokines (eotaxin, RANTES), and leukotrienes (CysLTs) mediate inflammation. Nitric oxide (NO) and reactive oxygen species (ROS) contribute to airway hyperresponsiveness and oxidative stress.
3.2 Genetic Factors¶
Genes like ORMDL3, ADAM33, and IL-13 are associated with asthma susceptibility. Epigenetic modifications and gene-environment interactions influence disease expression.
4. CLINICAL FEATURES¶
Symptoms include episodic wheezing, dyspnea, chest tightness, and cough. Exacerbations may be triggered by allergens, viral infections, or environmental irritants. Chronic symptoms include nocturnal awakenings, exercise-induced bronchoconstriction, and reduced quality of life. Severe asthma may present with irreversible airway obstruction.
Table 298-4: Goals of Asthma Therapy¶
| Goal | Target |
|---|---|
| Symptom frequency | £2 times/week |
| Nighttime awakenings | £2 times/month |
| Reliever use | £2 times/week |
| Exacerbations | £1/year |
| Lung function | Optimized |
| Daily activities | Maintained |
| Treatment satisfaction | Minimal side effects |
4.1 Complications¶
Severe exacerbations may lead to respiratory failure, ICU admission, or death. Chronic complications include airway remodeling, fixed airflow obstruction, and increased risk of cardiovascular disease.
4.2 Special Populations¶
Pregnancy may worsen or improve asthma. Aspirin-exacerbated respiratory disease (AERD) involves severe eosinophilic inflammation, nasal polyposis, and anaphylaxis to NSAIDs.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include COPD, heart failure, vocal cord dysfunction, and bronchiectasis. Comorbidities like GERD, rhinosinusitis, and anxiety may mimic or complicate asthma.
Table 298-5: Step Therapy for the Treatment of Asthma Ages 12+¶
| Step | Preferred Therapy | Add-on Therapy |
|---|---|---|
| Step 1 | None or low-dose ICS | LTRA, leukotriene modifiers |
| Step | Preferred Therapy | Add-on Therapy |
|---|---|---|
| Step 2 | Low-dose ICS/formoterol | ICS/SABA |
| Step 3 | Medium-dose ICS/formoter, LTRA | ICS/SABA |
| Step 4 | High-dose ICS/LABA + LAMA | ICS/SABA |
| Step 5 | ICS/LABA + biologics | ICS/SABA |
5.1 Overlapping Conditions¶
COPD (overlap syndrome), heart failure (fluid overload), and vocal cord dysfunction (laryngeal obstruction) must be distinguished by clinical features and pulmonary function tests.
5.2 Red Flags¶
Persistent nocturnal symptoms, fixed airflow obstruction, or failure to respond to ICS suggest alternative diagnoses like bronchiectasis or COPD.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis involves clinical evaluation, spirometry (FEV1/FVC <0.7), and reversibility testing ( ≥ 12% improvement with bronchodilators). FeNO and sputum eosinophils help assess type 2 inflammation. Allergy testing (RAST, skin prick) identifies sensitization.
Table 298-6: Patients at Greater Risk for Asthma Mortality¶
| Risk Factor | Clinical Significance |
|---|---|
| Intensive care admission | High mortality risk |
| Intubation history | Severe disease progression |
| Illicit drug use | Increased exacerbation risk |
| Depression | Poor adherence and outcomes |
| New diagnosis | Higher mortality risk |
| Multiple ED visits | Poor asthma control |
| Psychosocial stress | Worsening outcomes |
| Low socioeconomic status | Limited access to care |
| Daily prednisone | Severe disease burden |
6.1 Diagnostic Criteria¶
Reversible airflow obstruction (FEV1 improvement >15% after bronchodilators), history of episodic symptoms, and response to ICS confirm asthma.
6.2 Biomarkers¶
FeNO ( ≥ 25 ppb) and sputum eosinophils (>300/ µ L) indicate type 2 inflammation. Blood eosinophils and IgE correlate with disease severity.
7. MANAGEMENT & TREATMENT¶
Management includes trigger avoidance, ICS as first-line therapy, and LABA for persistent symptoms. Biologics (anti-IgE, anti-IL-5) target specific endotypes. Severe asthma may require OCS, bronchial thermoplasty, or surgical interventions.
Table 298-7: Medications for Asthma Management¶
| Drug Class | Examples | Mechanism |
|---|---|---|
| ICS | Beclomethasone, Budesonide | Anti-inflammatory |
| LABA | Salmeterol, Formoterol | Bronchodilator |
| Leukotriene modifiers | Montelukast, Zafirlukast | Inhibit leukotriene action |
| Biologics | Omalizumab, Mepolizumab | Target specific cytokines |
| SABA | Albuterol, Levalbuterol | Beta-2 agonist |
7.1 Controller Therapies¶
ICS (beclomethasone, budesonide) reduce inflammation. LABA (salmeterol, formoterol) enhance bronchodilation. ICS/LABA combinations (fluticasone/salmeterol) are preferred for persistent asthma.
7.2 Biologics¶
Anti-IgE (omalizumab), anti-IL-5 (mepolizumab), and anti-IL-4/13 (dupilumab) target eosinophilic or type 2 inflammation. Used in severe, refractory asthma with biomarker evidence.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis varies by severity and control. Poorly controlled asthma increases risk of exacerbations, ICU admission, and mortality. Long-term complications include airway remodeling, fixed airflow obstruction, and increased cardiovascular risk.
Table 298-8: Asthma Exacerbation Risk Factors¶
| Factor | Impact |
|---|---|
| Poor adherence | Increased exacerbation frequency |
| Non-adherence to ICS | Higher risk of severe attacks |
| Allergen exposure | Trigger for acute episodes |
| Infections | Viral exacerbations common |
| Environmental pollutants | Worsen airway hyperresponsiveness |
8.1 Long-term Outcomes¶
Early-onset asthma may resolve in adulthood, but persistent symptoms increase risk of chronic obstructive lung disease. Severe asthma is associated with reduced quality of life and higher healthcare costs.
8.2 Mortality¶
Annual mortality in the U.S. is ~3,000. Risk factors include ICU admission, intubation history, and poor adherence. Severe exacerbations with respiratory failure carry the highest mortality risk.
9. SPECIAL CONSIDERATIONS¶
Special populations include pregnant women, athletes, and patients with AERD. Asthma management during pregnancy requires careful OCS use and avoidance of triggers. Exercise-induced symptoms may require pre-exercise bronchodilators.
Table 298-9: Asthma Management in Special Populations¶
| Population | Considerations |
|---|---|
| Pregnancy | Avoid smoking, use ICS/LABA, monitor fetal growth |
| Athletes | Pre-exercise SABA, avoid cold air exposure |
| AERD | Biologics over NSAIDs, avoid triggers |
| Children | Monitor growth, use low-dose ICS |
| Elderly | Minimize OCS, use LABA cautiously |
9.1 Pregnancy¶
Asthma may improve, worsen, or remain stable. OCS use is minimized, but acute exacerbations require corticosteroids. Avoidance of smoking and allergens is critical for fetal outcomes.
9.2 Aspirin-Exacerbated Respiratory Disease¶
Patients with AERD have severe eosinophilic inflammation, nasal polyposis, and anaphylaxis to NSAIDs. Biologics (dupilumab, mepolizumab) are preferred over aspirin desensitization.
10. KEY POINTS & CLINICAL PEARLS¶
- Asthma is a heterogeneous disease with type 2 and non-type 2 mechanisms.
- ICS remain the cornerstone of therapy, with LABA as add-on for persistent symptoms.
- FeNO and sputum eosinophils guide biologic therapy.
- Poor adherence and trigger exposure are major contributors to poor control.
- Severe asthma requires multidisciplinary management, including biologics and bronchial thermoplasty.