Particle size matters: diagnostics and treatment of small airways involvement in asthma.

Small airways are an important site of inflammation and obstruction in asthma, which contributes to the severity of airway hyperresponsiveness (AHR) that is usually measured by nebulisation of large-particle stimuli. We investigated whether small and large particle sizes of aerosolised adenosine monophospate (AMP) provoke similar severity of AHR. Additionally, effects of the small-particle inhaled corticosteroid (ICS) ciclesonide and large-particle ICS fluticasone on AHR to large-and small-particle size AMP were assessed. After a 4-week run-in period using open-label fluticasone (100 mu g b.i.d.), 37 mild-to-moderate asthmatics underwent provocations with standard-size (3.7 mu m), large-particle (9.9 mu m) and small-particle (1.06 mu m) AMP. Subjects received 4-week ciclesonide (160 mu g s.i.d.) or fluticasone (100 mu g b.i.d.) treatment (double-blind and double-dummy) followed by large- and small-particle AMP provocation. Small-particle AMP induced a 20% decrease in forced expiratory volume in 1 s (FEV1) at a significantly higher dose than large-particle AMP. Ciclesonide and fluticasone had comparable effects on AMP provocations. Not all subjects reached the provocative concentration causing a 20% fall in FEV1 (PC20) at the highest AMP dose. In those who did, ciclesonide improved small-particle AMP PC20 by 1.74 doubling doses (DD) (p=0.03), whereas fluticasone did not. Conversely, fluticasone improved large-particle AMP PC20 significantly (1.32 DD; p=0.03), whereas ciclesonide did not. Small-particle AMP provocation appears to be a promising tool to assess changes in small airway inflammation. Future adjustments are necessary taking into account the very small particle size used, with large exhaled fractions. In asthmatics reaching a PC20 with small- and large-particle AMP provocations, ciclesonide improves hyperresponsiveness to small particle size AMP, and fluticasone to large particle size. This warrants further research to target provocations and treatment to specific airway sizes.