Asthma¶

Part 7 | Disorders of the Respiratory System · Part 7 – Respiratory Disorders · Chapter 298

Key Clinical Points¶

Asthma is characterized by episodic airway obstruction, airway hyperresponsiveness (AHR), and airway inflammation, which is usually reversible but potentially irreversible in a subset.
Airway hyperresponsiveness is a hallmark defined as an acute narrowing response to agents that do not elicit responses in nonaffected individuals or an excess narrowing response to inhaled agents compared to those in nonaffected individuals.
Type 2 inflammation (IL-4, IL-5, IL-13) is the most common mechanism; Non-type 2 (neutrophilic) inflammation occurs in severe or steroid-resistant asthma.
FeNO elevation increases the odds of asthma in children >5 years and adults, but tailoring therapy based on FeNO has not been shown to improve outcomes.
Sweat testing (chloride concentration) is the gold standard for Cystic Fibrosis (≥60 mmol/L), but is not a primary diagnostic tool for asthma.
Occupational asthma accounts for 10–25% of adult-onset asthma, involving immunologic (high-molecular-weight) and irritative stimuli (RADS).
Allergic bronchopulmonary aspergillosis (ABPA) is characterized by IgE >1000 IU/mL, eosinophils >500/μL, and positive skin test to Aspergillus.
Obese adults with asthma have more severe symptoms and are 2–4 times more likely to be hospitalized with an exacerbation.
Beta-blockers may trigger bronchospasm even in ophthalmic preparations; ACE inhibitors may cause cough attributed to poorly controlled asthma.
Asthma mortality declined globally from 0.44 per 100,000 in 1993 to 0.19 in 2006, attributed to increased use of inhaled corticosteroids.

DEFINITION & OVERVIEW¶

• Definition: Asthma is a disease characterized by episodic airway obstruction and airway hyperresponsiveness (AHR) usually accompanied by airway inflammation. • Reversibility: In most cases, the airway obstruction is reversible, but in a subset of asthmatics, a component of the obstruction may become irreversible. • Inflammation Profile: Inflammation is predominantly eosinophilic in many patients, but some present with different types (e.g., neutrophilic) or no obvious evidence of inflammation. • Developmental Pathway: Result of interaction between genetic susceptibility, environmental exposure, and endogenous developmental factors (e.g., aging and menopause). • Clinical Definition: Characterized by AHR with varying degrees of airway inflammation and airway structural changes accompanied by varying degrees of symptoms influenced by triggers causing acute deterioration or chronic symptoms.

• Classification & Nosology: ◦ Old Paradigm: Atopic (allergen sensitivity, IgE production) vs. Nonatopic (intrinsic, often eosinophilic). ◦ Current Paradigm: Based on immune profile—Type 2 vs. Non-type 2 inflammation. ◦ Rationale: Driven by understanding of underlying immune processes and development of therapies targeting Type 2 inflammation.

EPIDEMIOLOGY¶

• Global Prevalence: ~262 million people affected globally; approximately 4.3% prevalence worldwide (7.9% in the United States). • Demographics: ◦ Higher prevalence in children (8.4%) than adults (7.7%). ◦ Children: 2:1 male-to-female ratio. ◦ Adults: Trend toward greater prevalence in women. • Risk Factors (Table 298-1): ◦ 1. Allergen exposure (atopy predisposition) ◦ 2. Occupational exposure ◦ 3. Air pollution ◦ 4. Infections (viral and Mycoplasma) ◦ 5. Tobacco ◦ 6. Obesity ◦ 7. Diet ◦ 8. Fungi in allergic airway mycoses ◦ 9. Acute irritants and reactive airway dysfunction syndrome (RADS) ◦ 10. High-intensity exercise in elite athletes • Genetic Factors: ◦ 25–80% degree of heritability. ◦ Complex polygenic inheritance with environmental interaction. ◦ Key genes: ORMDL3/GSDMB, ADAM33, DPP-10, TSLP, IL-12, IL-33, ST2 (IL-33 receptor), HLA-DQB1, HLA-DQB2, TLR1, IL-13, and IL6R. ◦ Only 7.2% of asthma risk explained by known single nucleotide polymorphisms. • Mortality Trends: ◦ Global decline from 0.44 per 100,000 (1993) to 0.19 in 2006; further reduction has not occurred since that time. ◦ Decline attributed to increased use of inhaled corticosteroids.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Airway Inflammation: ◦ Type 2 Inflammation: → Driven by Th2 cells, ILC2s, Mast cells, and Eosinophils. → Key Cytokines: IL-4 (B-cell switching to IgE), IL-5 (eosinophil regulation/survival), IL-13 (AHR, mucus hypersecretion, goblet cell metaplasia). ◦ Non-Type 2 Inflammation: → Driven by Th17 and Th1 cells; involves Neutrophils. → Associated with severe asthma, steroid resistance, chronic infection (e.g., Mycoplasma), and RADS.

• Airway Remodeling & Structural Changes: ◦ Smooth Muscle: Hyperresponsive; hypertrophy and hyperplasia lead to airway wall thickening; cells produce chemokines/cytokines promoting inflammation. ◦ Subepithelial Collagen: Deposition of repair-type collagens (tenascin, periostin, fibronectin, osteopontin) by myofibroblasts → stiffens airway → exaggerated response to tension; reduces ability to relax. ◦ Airway Epithelium: Disruption leads to formation of trophic units with mesenchyme; source of alarmins and cytokines. ◦ Vascular Proliferation: Angiogenesis and leakage from postcapillary venules causing acute/chronic edema. ◦ Mucus Hypersecretion: Goblet cell metaplasia → mucus plugs → persistent airway obstruction. ◦ Neuronal Proliferation: Neurotrophins from smooth muscle, epithelial cells, and inflammatory cells regulate tone and mucus production.

• Mediators: ◦ Cytokines: IL-4, IL-5, IL-13 (Type 2); TSLP, IL-25, IL-33; IL-9. ◦ Non-type 2 markers: IL-6, IL-17, TNF-α, IL-1β, IL-8. ◦ Fatty Acid Mediators: → Cysteinyl leukotrienes (C, D, E): Produced by eosinophils/mast cells → potent smooth-muscle constrictors, mucus secretion, and recruitment of inflammatory cells. → LTB4: Produced by neutrophils; potent chemoattractant. → Prostaglandins: PGD2 produced by mast cells; CRTH2 receptors on T2 cells/eosinophils upregulate Type 2 inflammation. ◦ Other factors: Nitric Oxide (NO) promotes mucus production and smooth-muscle proliferation; Reactive Oxygen Species (ROS), Myeloperoxidase (MPO), and Elastase are involved in tissue damage in non-type 2 pathways.

CLINICAL FEATURES¶

• Symptoms & Signs: ◦ Episodic airway obstruction. ◦ Symptoms influenced by triggers causing acute deterioration or chronic issues. • Exacerbations: ◦ Defined as episodes of acute bronchospasm. ◦ May require systemic corticosteroids; severe exacerbations may accelerate lung function decline.

DIFFERENTIAL DIAGNOSIS¶

• Overlap Syndromes: ◦ Asthma/COPD overlap syndrome. ◦ Note: Sputum eosinophils may help tailor therapy; FeNO does not improve outcomes in this context.

• Diseases with Overlang Symptoms (Table 298-3): 1. Heart failure 2. Chronic obstructive pulmonary disease (COPD) 3. α Antitrypsin deficiency 4. Airway obstruction from mass or foreign body 5. Inducible laryngeal dysfunction (vocal cord dysfunction) 6. Bronchiolitis obliterans 7. Bronchiectasis 8. Tracheobronchomalacia

• Comorbidities Affecting Control (Table 298-3): 1. Chronic rhinosinusitis ± nasal polyposis 2. Obesity 3. Gastroesophageal reflux disease (GERD) 4. Inducible laryngeal obstruction (vocal cord dysfunction) 5. COPD 6. Anxiety/depression 7. Obstructive sleep apnea.

DIAGNOSTIC APPROACH¶

Clinical Assessment: Identify symptoms and specific triggers (Table 298-2).
Allergy Testing: • Purpose: Identify exposure to allergens and determine reactivity. • Methods: → Patch testing (more cost-effective for Type I reactions). → Delayed intradermal testing (higher sensitivity for Type IV reactions; results must be interpreted with pretest probability).
Sweat Testing: • Method: Pilocarpine iontophoresis to measure chloride concentration. • Interpretation: → geq60 mmol/L → High likelihood of Cystic Fibrosis. → 30–59 mmol/L → Intermediate (requires clinical/genetic correlation). → <40 mmol/L → Low likelihood of Cystic Fibrosis. • Note: Not a primary diagnostic tool for asthma.

MANAGEMENT & TREATMENT¶

Initial Management: • Address exposures and comorbidities (Table 298-2, Table 298-3). • Confirm inhaler technique and optimize adherence.
Step Therapy (Table 298-5): Determine step based on control (Table 298-3). • Step 1: Preferred: None; Alternative: None or low-dose ICS. • Step 2: Preferred: None; Alternative: LTRA. • Step 3: Preferred: Low-dose ICS/formoterol; Alternative: Medium-dose ICS. • Step 4: Preferred: Medium-dose ICS/formoterol; Alternative: High-dose ICS. • Step 5: Preferred: High-dose ICS/LABA + add-on LAMA; Adjunctive: LTM, azithromycin, OCS.
Goals of Therapy (Table 298-4): • Reduction in symptom frequency to ≤2 times/week. • Reduction of nighttime awakenings to ≤2 times/month. • Reduction of reliever use to ≤2 times a week (except before exercise). • No more than 1 exacerbation/year. • Optimization of lung function. • Maintenance of normal daily activities. • Satisfaction with asthma care with minimal or no side effects of treatment.

PROGNOSIS & COMPLICATIONS¶

• Mortality Risk Factors (Table 298-6): → History of intensive care unit admission for asthma. → History of intubation for asthma. → Illicit drug use. → Depression. → New diagnosis within past year. → ≥2 emergency unit visits in past 6 months. → Severe psychosocial problems. → Lower socioeconomic status. → On daily prednisone prior to admission.

SPECIAL CONSIDERATIONS¶

• Obesity: → More severe symptoms. → 2–4 times more likely to be hospitalized with exacerbation. • Occupational Asthma: → 10–25% of adult-onset asthma. → Includes immunologic (high-molecular-weight) and irritative (RADS) stimuli. • Pregnancy & Hormonal: → Identified as specific triggers for airway narrowing.

KEY PEARLS & CLINICAL TRAPS¶

• FeNO Utility: Increases odds of asthma in children >5 years and adults; however, it does not improve outcomes when used to tailor therapy. • Sweat Test Thresholds: ≥60 (High), 30–59 (Intermediate), <40 (Low) for CF diagnosis. • Type 2 vs. Non-type 2: Type 2 is the standard inflammatory pathway; Non-type 2 (neutrophilic) is associated with severity and steroid resistance. • Remodeling Components: Includes smooth muscle hypertrophy, collagen deposition, and goblet cell metaplasia.

Reference Tables¶

Harrison's 22e, p.2216

1. Allergen exposure in those with a predisposition to atopy
  2. Occupational exposure
  3. Air pollution
  4. Infections (viral and Mycoplasma)
  5. Tobacco
  6. Obesity
  7. Diet
  8. Fungi in allergic airway mycoses
  9. Acute irritants and reactive airway dysfunction syndrome (RADS)
  10. High-intensity exercise in elite athletes

TABLE 298-2 Triggers of Airway Narrowing 1. Allergens 2. Irritants 3. Viral infections 4. Exercise and cold, dry air 5.…¶

Harrison's 22e, p.2217

1. Allergens
  2. Irritants
  3. Viral infections
  4. Exercise and cold, dry air
  5. Air pollution
  6. Drugs
  7. Occupational exposures
  8. Hormonal changes
  9. Pregnancy

TABLE 298-3 Differential Diagnosis and Comorbidities That May Make Asthma Difficult to Control Differential Diagnosis…¶

Harrison's 22e, p.2222

Differential Diagnosis of Diseases with Overlapping Symptoms That
Can Present with Obstructive Pulmonary Function Tests
1. Heart failure
  2. Chronic obstructive pulmonary disease (COPD)
  3. α Antitrypsin deficiency
  1
  4. Airway obstruction from mass or foreign body
  5. Inducible laryngeal dysfunction (vocal cord dysfunction)
  6. Bronchiolitis obliterans
  7. Bronchiectasis
  8. Tracheobronchomalacia
Comorbidities That Can Make Asthma Difficult to Control
1. Chronic rhinosinusitis +/– nasal polyposis
  2. Obesity
  3. Gastroesophageal reflux disease
  4. Inducible laryngeal obstruction (vocal cord dysfunction)
  5. COPD
  6. Anxiety/depression
  7. Obstructive sleep apnea

TABLE 298-4 Goals of Asthma Therapy 1. Reduction in symptom frequency to ≤2 times/week 2. Reduction of nighttime…¶

Harrison's 22e, p.2223

1. Reduction in symptom frequency to ≤2 times/week
  2. Reduction of nighttime awakenings to ≤2 times/month
  3. Reduction of reliever use to ≤2 times a week (except before exercise)
  4. No more than 1 exacerbation/year
  5. Optimization of lung function
  6. Maintenance of normal daily activities
  7. Satisfaction with asthma care with minimal or no side effects of treatment

TABLE 298-5 Step Therapy for the Treatment of Asthma Ages 12+ (Modified from GINA and NAEPP) Preferred regular therapy…¶

Harrison's 22e, p.2225

	Address exposures and comorbidities (see Tables 298-2 and 298-3)
	Confirm inhaler technique and optimize adherence
	Move up or down steps based on control (see Table 298-3)
	STEP 1	STEP 2	STEP 3	STEP 4	STEP 5
Preferred regular therapy	None	Nonea or low-dose ICSb	Low-dose ICS/formoterol	Medium-dose ICS/formoterol	High-dose ICS/LABA + add-on LAMA
	None	LTRA	Medium-dose ICS	High-dose ICS
Adjunctive therapy					LTM, azithromycin, OCSc
	ICS/formoterol (low dose) or SABAb or ICS/SABAf	ICS/formoterol (low dose)a, or PRN concomitant ICS and SABAa,b or SABAe,b or ICS/SABAf

TABLE 298-6 Patients at Greater Risk for Asthma Mortality 1. History of intensive care unit admission for asthma 2.…¶

Harrison's 22e, p.2227

1. History of intensive care unit admission for asthma
  2. History of intubation for asthma
  3. Illicit drug use
  4. Depression
  5. New diagnosis within past year
  6. ≥2 emergency unit visits in past 6 months
  7. Severe psychosocial problems
  8. Lower socioeconomic status
  9. On daily prednisone prior to admission