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ASTHMA - Brief Harrison's 22E, Tintinalli's & GINA 2025

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DEFINITION

• Harrison's Principles of Internal Medicine 22E, 2025
• Tintinalli's Emergency Medicine, Ch. 69

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PATHOPHYSIOLOGY

Harrison's 22E

• Airway hyperresponsiveness - hallmark; airways narrow excessively to stimuli that don't affect normal individuals
• Three overlapping processes:
  1. Bronchoconstriction - smooth muscle contraction (early phase)
  2. Airway wall edema and inflammation - eosinophils, lymphocytes, mast cells, macrophages, dendritic cells; mediated by IgE, Th2 cytokines (IL-4, IL-5, IL-13), and innate lymphoid cells (ILC2)
  3. Airway remodeling - subepithelial fibrosis, smooth muscle hypertrophy, mucous gland hyperplasia; leads to fixed airflow limitation over time
• Inflammation affects all bronchial structures but not the parenchyma
• Two endotypes: Type 2 (T2-high) - eosinophilic, IgE-mediated; non-Type 2 - neutrophilic, obesity-related

Tintinalli's

• Hallmark: reduction in airway diameter from smooth muscle contraction + vascular congestion + wall edema + thick secretions
• Acute allergic bronchoconstriction = IgE-dependent mast cell mediator release (histamine, leukotrienes, tryptase, prostaglandins)
• Asthma is a continuum: acute bronchospasm → airway inflammation → permanent airway remodeling
• Viral infections most common acute trigger (40-80% in adults, 80% in children)

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RISK FACTORS & TRIGGERS

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DIAGNOSIS

Clinical Features

• Recurrent wheeze, dyspnea, chest tightness, cough (especially nocturnal/morning)
• Symptoms variable, episodic, often triggered

Spirometry (Objective Confirmation)

• Bronchodilator response: post-BD FEV1 or FVC increase ≥200 mL AND ≥12% (GINA 2025)
• FEV1/FVC ratio reduced (<0.70 or below LLN)
• PEF variability >10% (or >20% with BDR test)

GINA 2025 - New Diagnostic Flowchart

• 4 typical symptoms + evidence of variable expiratory airflow limitation = asthma
• If spirometry negative but typical symptoms: FeNO >50 ppb (adults/adolescents) or blood eosinophils above reference range can support diagnosis
• FeNO and blood eosinophils do not rule out asthma if normal

Asthma Mimickers (Tintinalli's - must exclude)

• Acute heart failure ("cardiac asthma")
• Upper airway obstruction / vocal cord dysfunction
• Pulmonary embolism
• Foreign body aspiration
• Endobronchial tumors
• Interstitial lung disease

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SEVERITY CLASSIFICATION (Harrison's 22E)

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CHRONIC MANAGEMENT - Harrison's 22E

Medications

• Short-acting β2-agonists (SABA) - albuterol/salbutamol: activate β2-receptors → cAMP → smooth muscle relaxation; onset 5-15 min; primary rescue agent
• Regular SABA use alone risks tachyphylaxis and increased airway reactivity

• Inhaled corticosteroids (ICS): most effective anti-inflammatory; reduce eosinophil infiltration, cytokine production; first-line controller. Systemic effects rare at low-to-medium doses.
• Long-acting β2-agonists (LABA): salmeterol, formoterol; NEVER use as monotherapy - always with ICS (risk of fatal outcomes when used alone)
• Leukotriene receptor antagonists (LTRA): montelukast; useful add-on, especially aspirin-exacerbated asthma and allergic rhinitis comorbidity
• Long-acting muscarinic antagonists (LAMA): tiotropium; add-on at Step 4-5
• Anti-IgE (omalizumab): for allergic, severe, uncontrolled asthma with elevated IgE
• Anti-IL-5/IL-4Rα biologics: mepolizumab, benralizumab (anti-IL-5), dupilumab (anti-IL-4Rα) - for severe eosinophilic/T2-high asthma
• Theophylline: weak bronchodilator + mild anti-inflammatory; narrow therapeutic window; now third-line

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CHRONIC MANAGEMENT - GINA 2025 STEPWISE APPROACH

TRACK 1 (PREFERRED) - ICS-formoterol as both controller and reliever

TRACK 2 (Alternative) - ICS controller + SABA reliever

Key GINA 2025 Updates

• ICS-formoterol as reliever (Track 1) reduces exacerbation risk vs. SABA reliever
• FeNO + blood eosinophil assessment now incorporated into treatment decisions as Type 2 biomarkers
• New figure on population-level vs. patient-level treatment decisions
• Risk factors for severe exacerbation: updated data
• Step down when well-controlled for 2-3 months; choose appropriate time (no infection, not pregnant, not travelling)
• LAMA add-on at Step 5 before biologics

Step 5 - Severe Asthma (GINA 2025)

• Refer for expert assessment + phenotype evaluation
• Add LAMA to ICS-LABA
• If sputum or blood eosinophilia - consider:
  • Anti-IL-5: mepolizumab, benralizumab
  • Anti-IL-4Rα: dupilumab
  • Anti-IgE: omalizumab (if allergic)
  • Anti-TSLP: tezepelumab (broad; works across phenotypes)
• High-dose ICS adds risk of adrenal suppression

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ACUTE EXACERBATION MANAGEMENT - TINTINALLI'S (ED)

Goal: Rapid reversal of airflow obstruction via repeated/continuous inhaled β2-agonists, oxygen, and systemic anti-inflammation

Severity Assessment (ED)

ED Drug Dosages (Tintinalli's Table 69-5)

• Albuterol nebulizer: 2.5-5 mg q20 min × 3 doses, then as needed (or continuous 10-15 mg/hr)
• Albuterol MDI: 4-8 puffs q20 min × 3 doses via spacer
• Levalbuterol: half the dose of albuterol

• Ipratropium bromide nebulizer: 0.5 mg q20 min × 3 doses (add to SABA in severe)

• Prednisone/methylprednisolone: 40-80 mg/day orally or IV
• Dexamethasone: 8-10 mg single dose (evidence supports as alternative)

ED Treatment Algorithm

Discharge Criteria (Good Response)

• FEV1 or PEFR ≥70%
• Response sustained 60 min after last treatment
• No distress; physical exam normal
• Discharge with: SABA + oral corticosteroid course + initiate/continue ICS + written action plan + follow-up in 1-4 weeks

Admit to ICU if:

• FEV1/PEFR <40% after treatment
• PCO2 ≥42 mmHg (impending respiratory failure - CO2 should be low in early asthma)
• Severe symptoms, drowsiness, confusion
• Possible intubation + mechanical ventilation

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STATUS ASTHMATICUS / NEAR-FATAL ASTHMA

• Defined as acute severe asthma not responding to initial aggressive bronchodilator therapy
• IV methylprednisolone + continuous nebulization
• IV magnesium sulfate 2 g
• IV ketamine (1-2 mg/kg) for intubation - provides bronchodilation (preferred induction agent)
• Heliox, IV β2-agonists (terbutaline)
• If intubated: permissive hypercapnia, low respiratory rate (10-14/min), long expiratory time to avoid dynamic hyperinflation (auto-PEEP); avoid barotrauma

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HIGH-RISK ASTHMA PATIENTS (Harrison's 22E)

• Prior intubation or ICU admission for asthma
• ≥2 hospitalizations or ≥3 ED visits/year
• Using >2 canisters SABA/month
• Low socioeconomic status, illicit drug use
• Difficult-to-perceive symptoms

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ASTHMA-COPD OVERLAP (ACO) - Harrison's 22E

• Features of both asthma and COPD; older patients, smokers with asthma or asthmatics who develop fixed obstruction
• Treat underlying component; LABA/LAMA combinations useful
• ICS should be included when eosinophilia present

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KEY COMORBIDITIES TO TREAT

• Allergic rhinitis - treat with intranasal corticosteroids; improves asthma control
• GERD - treat aggressively
• Obesity - weight loss improves asthma control
• Obstructive sleep apnea - CPAP beneficial
• Anxiety/depression - screen and manage

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GINA 2025 - KEY NEW CHANGES SUMMARY

• GINA 2025 Full Summary Guide
• Harrison's Principles of Internal Medicine 22E (2025), Chapter 298
• Tintinalli's Emergency Medicine, Chapter 69