Allergen-induced change in airway responsiveness to direct and indirect stimuli in mild atopic asthmatics

Abstract

Methacholine (MCh) and mannitol challenges are tests used to assess airway responsiveness. It has been shown that airway responsiveness to direct bronchoconstrictors like MCh tends to increase following exposure to allergen but the response to mannitol an indirect stimuli, is not known. Furthermore, the provocative concentration causing a 20% decrease in Forced Expiratory Volume in one second (FEV1) for adenosine 5’ monophosphate (AMP) correlates better to sputum eosinophilia than MCh PC 20. Hence, we hypothesized that airway responsiveness will be greater when measured with mannitol than MCh. We studied airway responsiveness to MCh and mannitol first at 3 hours and then later at 24 hours after allergen challenge. The 3-hour study yielded results contrary to our hypothesis therefore a twenty-four hour study was undertaken. Ten mild atopic asthmatics who had a positive MCh challenge and an allergic response to allergen extracts such as cat, horse, and house dust mite completed the 3-hour study. Eleven mild atopic asthmatics with the criteria above completed the 24-hour study. Both studies were non-blinded, randomized clinical trials. Airway responsiveness to MCh was quantitated by changes in PC20. Airway responsiveness to mannitol was quantitated as PD15 in the 3-hour study and dose response ratio (DRR) in the 24-hour study. In both studies, the allergen challenges were separated by 14 days. Fractional exhaled nitric oxide measurements (FENO) were collected in both studies at varying time points to track airway inflammation. In the 3-hour study, the geometric mean MCh PC20 decreased significantly after allergen exposure from 0.88 mg/ml to 0.50 mg/ml (p = 0.02) indicating airway responsiveness to MCh increased. Conversely, the geometric mean mannitol PD15 increased significantly from 174 mg to 284 mg (p =0.02) indicating a decrease in airway responsiveness to mannitol. In the 24-hour study, the geometric mean MCh PC20 again decreased significantly from 5.9 mg/ml to 2.2 mg/ml (p= 0.01) after allergen exposure. The mannitol DRR increased significantly from 63 mg/∆%FEV1 to 158 mg/∆%FEV1 (p = 0.03). FENO levels increased significantly in MCh arm but not mannitol arm. That is pre allergen challenge versus 24 hours after allergen challenge (for MCh arm: 26 ppb pre to 55 ppb post; for mannitol arm: 31 ppb pre to 39 ppb post). In conclusion, at three and twenty-four hours after allergen challenge, a time when the airways are more responsive to MCh, there is a significant decrease in airway responsiveness to mannitol.