A 22-year-old male athlete presents with a 6-month history of exertional dyspnea and cough during competitive running. Spirometry at rest shows normal FEV1 (92% predicted). Methacholine challenge is not available at your centre. A mannitol bronchial challenge test is performed using escalating dry-powder doses. The patient's FEV1 remains unchanged at 5 mg mannitol (point B), drops 8% at cumulative dose 155 mg (point C), and falls 16% from baseline at cumulative dose 315 mg (point **D**), at which point the test is stopped and salbutamol is administered. The finding at point **D** (PD15 reached at 315 mg cumulative dose with ≥15% FEV1 fall) in this athlete is most consistent with which of the following?

Explanation

## Why option 1 is correct A positive mannitol bronchial challenge (PD15 < 635 mg, specifically 315 mg in this case with ≥15% FEV1 fall) is an **indirect bronchoprovocation test** that detects **active Type-2 airway inflammation**. Unlike direct challenges (methacholine), mannitol acts via **osmotic dehydration of airway surface liquid**, triggering **mast cell and eosinophil degranulation** with release of histamine, leukotrienes (LTC4/D4/E4), and prostaglandin D2. This mechanism makes mannitol **highly specific (≈95%) for asthma with active eosinophilic inflammation**, particularly **exercise-induced bronchoconstriction (EIB)** in athletes. The positive mannitol test at point **D** (PD15 = 315 mg, mild hyperresponsiveness range 155–635 mg) confirms the presence of inflammatory substrate and predicts **ICS responsiveness**. This athlete is eligible for sport participation with appropriate inhaled corticosteroid controller therapy (ATS Bronchoprovocation Guidelines 2017; GINA 2024). ## Why each distractor is wrong - **Option 2**: COPD does not typically present with exertional symptoms alone in a young athlete with normal resting FEV1, and COPD is **negative on indirect challenges** (mannitol) because it lacks the mast cell/eosinophil inflammatory substrate. Direct challenges (methacholine) may be positive in COPD, but mannitol is specific for asthma inflammation. - **Option 3**: Allergic rhinitis alone does not produce a positive mannitol challenge. While allergic rhinitis may coexist with asthma, a positive mannitol test indicates **active airway inflammation with mast cells and eosinophils**, not merely rhinitis. The specificity of mannitol (95%) rules out non-specific hyperresponsiveness. - **Option 4**: Vocal cord dysfunction is a functional disorder that does not trigger mast cell/eosinophil degranulation. Vocal cord dysfunction would be **negative on both mannitol and methacholine tests** because there is no inflammatory substrate. A positive mannitol test excludes this diagnosis. **High-Yield:** Mannitol PD15 < 635 mg = **positive indirect challenge** = **asthma with active Type-2 inflammation** (high specificity, correlates with sputum eosinophils and FeNO); methacholine PC20 < 8 mg/mL = **positive direct challenge** = **airway hyperresponsiveness** (lower specificity, seen in COPD, rhinitis, smokers). [cite: ATS Bronchoprovocation Guidelines 2017; GINA 2024]