Advanced lecture notes : Asthma management

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Overview

Asthma is a heterogeneous chronic inflammatory airway disease characterized by recurrent episodes of wheezing, breathlessness, chest tightness, and cough, predominantly nocturnal or early morning. It involves variable expiratory airflow limitation due to bronchospasm, mucosal edema, mucus hypersecretion, and, in advanced cases, airway remodeling. Per GINA 2025, emphasis is on personalized management to address phenotypic heterogeneity and prevent exacerbations.

Core Features (GINA 2025)

  • Inflammation Phenotype: Predominantly type 2 (eosinophilic) but includes non-type 2 variants.
  • Airway Dynamics: Reversible obstruction; chronic remodeling risks fixed limitation.
  • Symptom Profile: Episodic, trigger-dependent; diurnal variation.
  • Global Burden: Impacts quality of life; preventable via early intervention.

Epidemiology

Globally, asthma affects ~400 million individuals (updated 2025 estimate), with surging prevalence in low- and middle-income countries due to urbanization and climate change. In the US, 8.5% prevalence (CDC 2025), higher in urban minorities (e.g., 12% in African American children). Mortality remains ~0.15/100,000, but exacerbations drive 1.8 million ER visits annually.

Demographic Trends Key Statistics (2025)
Global Prevalence ~400 million; 20% rise in LMICs
US Incidence 8.5% overall; 11% pediatrics
Mortality Rate 0.15/100,000; climate-linked increases
High-Risk Groups Urban youth; post-pubertal females; obese adults

Pathophysiology

Asthma's hallmark is chronic type 2 airway inflammation mediated by Th2 cells, ILC2s, eosinophils, and IgE, releasing histamine, leukotrienes (LTC4/D4/E4), prostaglandins, and cytokines (IL-4/5/13). Triggers induce mast cell degranulation and epithelial barrier dysfunction, culminating in bronchoconstriction, vascular leakage, and goblet cell metaplasia. Advanced: subepithelial fibrosis via TGF-β, smooth muscle hypertrophy, and angiogenesis perpetuate irreversible changes. Genetic-epigenetic interplay (e.g., ORMDL3, ADAM33) modulates susceptibility; non-type 2 phenotypes involve neutrophils/IL-17.

Pathophysiology Cascade (Advanced Schema)
Trigger (Allergen/Pollutant) → Epithelial Alarmins (TSLP/IL-33/25) → Type 2 Activation (Th2/ILC2) → Mediator Cascade
↓
Acute Phase: Mast Cell Degranulation + Eosinophil Recruitment → Bronchospasm + Edema + Mucus Plugs
↓ (Persistent)
Remodeling: TGF-β Fibrosis + VEGF Angiogenesis + ASM Hypertrophy → Fixed Obstruction
GINA 2025: Integrate climate triggers (e.g., extreme heat/pollution exacerbating non-type 2 inflammation)

Risk Factors and Triggers

Intrinsic Risks: Atopy (e.g., AR, AD), genetic load (polygenic risk scores), obesity (adipokines promote Th2 skewing), sex hormones (estrogen post-puberty). Extrinsic Triggers: Aeroallergens, viral URIs (RV/RSV), pollutants (PM2.5/NO2), occupational sensitizers. GINA 2025 highlights climate risks: extreme weather, wildfire smoke increasing severe exacerbations by 15-20%.

Category Advanced Examples Protective/Modifiable
Host (Intrinsic) Viral predisposition (TLR3 variants); low vitamin D Microbiome diversity; allergen avoidance
Environmental Climate extremes (heat waves); secondhand smoke Farmyard exposure; air purifiers

Clinical Presentation

Presentations span classic tetrad to variants: obstructive pattern (prolonged I:E ratio >1:3), tachypnea >30/min, accessory muscle recruitment. Advanced signs: pulsus paradoxus >12 mmHg, cyanosis in severe attacks. Phenotype-specific: eosinophilic (nocturnal wheeze), paucigranulocytic (exercise-dominant).

Phenotypic Variants

  • Eosinophilic: High FeNO, steroid-responsive.
  • Neutrophilic: Infection-triggered, biologic-resistant.
  • Paucigranulocytic: Remodeling-dominant, poor response to ICS.

Diagnosis

GINA 2025 introduces updated diagnostic flowchart emphasizing early spirometry and biomarkers. Confirm reversibility: ΔFEV1 ≥12%/200mL post-BD; assess hyperresponsiveness (methacholine PD20 <4mg fixed="" hrct="" if="" mimics="" obstruction="" out="" p="" rule="" suspected.="" via="">

Tool Advanced Indicator Threshold (GINA 2025)
Spirometry Pre/post-BD comparison ΔFEV1 ≥12% & 200mL
FeNO Type 2 biomarker ≥50 ppb (high); 25-50 (intermediate)
Blood Eosinophils Exacerbation predictor ≥300/μL

Classification and Severity Assessment

GINA 2025 refines control-based classification (well/partly/uncontrolled) with integrated risk assessment via ORACLE2 tool (biomarkers + comorbidities). Severity tiers guide initial therapy; track via ACT ≥20 or m-AQLQ.

GINA 2025 Control Matrix

  • Well-Controlled: Daytime Sx ≤2/wk; no night awakenings; ACT ≥20; FEV1 >80%.
  • Uncontrolled: Frequent Sx; ≥1 exacerbation/yr; biomarkers elevated.

Management Principles

GINA 2025 stepwise: Track 1 (preferred): ICS-formoterol as reliever + controller from step 2. Personalized escalation: Biomarker-guided (e.g., anti-IL5 for eosinophils ≥300). Non-pharma: self-management plans, adherence via apps, climate adaptation counseling.

Updated Stepwise Therapy (GINA 2025)
Step 1: Low-dose ICS-formoterol PRN
↓ Step 2: Daily low ICS + PRN formoterol
↓ Step 3: Medium ICS-LABA; consider LAMA add-on
↓ Step 4: High ICS-LABA + LTRA/tiotropium
↓ Step 5: Biologics (dupilumab for mixed type 2) + oral CS taper

Acute Exacerbations

GINA 2025 action plans emphasize early intervention based on PEF zones. Severe: PEF <50 predicted="" strong="">, respiratory acidosis (pH <7 .35="" management:="" strong="">high-flow O2, continuous nebulized SABA/anticholinergic, IV MgSO4 (2g), early systemic CS (prednisone 1mg/kg).

Severity PEF % / Signs Advanced Management
Moderate 50-75%; talks in phrases Ipratropium + CS burst; home Mg trial
Severe <50 chest="" silent="" strong=""> NIV/BiPAP; heliox; ICU if pCO2 >45 mmHg

Special Populations and Prognosis

Tailored approaches: Pediatrics (<5yo strong="">MDI-spacer preferred

; Elderly: beta-blocker caution; Pregnancy: biologics safe (e.g., omalizumab). Prognosis: 30% adult persistence; poor factors include smoking, SHS, low adherence (OR 2.5 for exacerbations).

Prognostic Predictors

  • Favorable: Early remission (50% by age 18).
  • Adverse: Female sex, obesity (BMI >30), frequent ED visits.

Advanced Topics: Biomarkers & Personalized Medicine

GINA 2025 prioritizes type 2 biomarkers for phenotyping: FeNO ≥50 ppb or eosinophils ≥150/μL predict ICS response. Biologics: Omalizumab (IgE >700 IU/mL), mepolizumab (eosinophils ≥300), tezepelumab (non-type 2). Precision: Cluster analysis (e.g., T2-high vs. low) guides therapy; ORACLE2 risk score integrates biomarkers for exacerbation prediction (AUC 0.78).

Biomarker Interpretation Table
FeNO: High → Anti-IL4/13 (dupilumab); Low + Eos high → Anti-IL5.
Periostin/FENO discordance: Suggests mixed inflammation; trial biologics.
Climate Integration: Monitor pollution via apps; adjust therapy during high-risk periods.

Key Takeaways and Self-Assessment

Master GINA 2025 for biomarker-driven, patient-centered care. Annual review mandatory.

Advanced Quiz

  1. Diagnostic Hallmark? FEV1 reversibility ≥12% + biomarker confirmation.
  2. Remodeling Mechanism? TGF-β induced fibrosis vs. acute cytokine storm.
  3. Step 5 Choice? Tezepelumab for T2-low severe asthma.
  4. New GINA 2025 Focus? Climate risks & ORACLE2 scoring.
Mnemonic: Advanced Asthma ABCDE
A: Assess biomarkers
B: Biomarker-guided biologics
C: Climate & comorbidity control
D: De-escalate stepwise
E: Educate & empower patients

References

Global Initiative for Asthma (GINA). 2025 GINA Strategy Report (Minor Update, Nov 2025). Available at: ginasthma.org.
UpToDate: Asthma (accessed Dec 2025).
ORACLE2 Study: Risk Stratification in Asthma (NEJM 2025).
BTS/SIGN Guidelines 2024 (for regional adaptations).

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