FeNO Non-Suppression Identifies Corticosteroid-Resistant Type-2 Signaling in Severe Asthma

Recently, two post-hoc analyses of clinical trials in moderate to severe asthma showed that fractional exhaled nitric oxide (FeNO) and the blood eosinophil (Eos) count provide additive prognostic information on the occurrence of severe asthma attacks (1, 2). The effect is large, with a three-fold increased risk in attacks seen in patients with FeNO ≥50 ppb and blood Eos ≥0.3×109/L compared to those with a FeNO <25 ppb and blood Eos <0.15×109/L (2). Importantly, this risk can be reduced with type-2 cytokine and alarm in directed biologic agents (3–6). The additive, independent and differentially modifiable risk associated with these biomarkers suggests that they identify different yet complementary aspects of type-2 airway inflammation.

Although raised FeNO classically identifies corticosteroid responsiveness, the advent of FeNOsuppression testing for uncontrolled type-2 high asthma has proven that a third of patients have corticosteroid-resistant elevations in FeNO – and disease burden – despite objective evidence of treatment adherence (7, 8). FeNO non-suppression provides a convenient model to control for nonadherence and independently study corticosteroid resistance in severe asthma.

We tested the hypothesis that FeNO and blood Eos relate differently to inflammation observed in the sputum (reflecting airway) and blood (reflecting systemic) compartments. An important feature of our approach was to study patients in whom we had a high degree of confidence in treatment adherence to high-dose inhaled corticosteroids (ICS) and/or systemic corticosteroids.