Airway refractoriness to inhaled mannitol after repeated challenge

Abstract

Exercise and inhaled mannitol are thought to cause bronchoconstriction through a similar mechanism in asthma. The response to exercise becomes refractory with repeated challenges. This study aimed to investigate whether repeated challenge with mannitol induces refractoriness, as with exercise. Forty-one children with asthma underwent two consecutive dose-response mannitol challenges (Phase 1); the second challenge proceeded after recovery (FEV(1) : 95% or more of baseline value) from the first. The response to mannitol was expressed as a provocative dose causing a 15% fall in FEV(1) (PD(15) ) and the response-dose ratio (RDR) (% fall in FEV(1) /cumulative dose). In 18 subjects who were deemed to have mannitol refractoriness in Phase 1, a mannitol challenge was performed before and after a methacholine challenge (Phase 2). In Phase 1, the time taken for the FEV(1) to recover after the first mannitol challenge ranged from 20 to 100 min with a median of 50 min. In the 23 subjects with a measurable mannitol PD(15) in both challenges, the geometric mean (95%CI) PD(15) in the second challenge (163 mg [114-232]) was significantly higher than that in the first challenge (66 mg [50-88], P < 0.001). The geometric mean (95%CI) RDR decreased from the value of 0.083%/mg (0.055-0.125) in the first challenge to 0.029%/mg (0.017-0.048) in the second challenge (P < 0.001). In Phase 2, prior challenge with methacholine or mannitol did not significantly alter subsequent bronchoconstriction to the opposite challenge. Repeated challenge with mannitol resulted in less bronchoconstriction when compared with the initial challenge. This refractoriness seems not to be attributable to functional loss of responsiveness or non-specific effect of prior bronchoconstriction.

Airway responsiveness to mannitol 24 h after allergen challenge in atopic asthmatics

“…The decrease in airway responsiveness to mannitol at 24 h post–allergen challenge is likely not explained by a refractory or cross‐refractory mechanism as the reported duration of refractory periods ranges from 1 to 2 h for exercise‐induced bronchoconstriction , 2–8 h for adenosine‐5′‐monophosphate (AMP) , and up to 2 h for mannitol . We are unaware of a refractory state with respect to repeat allergen exposure.…”

Allergen inhalation challenge, refractoriness and the effects of ibuprofen

“…We observed that the early asthmatic response to a second allergen challenge was unchanged compared to that of the first challenge indicating a refractory state does not develop when allergen challenges are performed 24 h apart. Refractoriness is common with non-allergic indirect acting stimuli including exercise [ 6 ], adenosine monophosphate [ 7 ] and mannitol [ 8 ]. Cross refractoriness has also been shown between exercise and metabisulphate [ 9 ], exercise and AMP [ 11 ] and allergen and mannitol [ 5 , 12 ].…”

“…By definition, the bronchoconstriction caused by allergic stimuli occurs through an indirect mechanism. A phenomenon commonly seen with indirect acting stimuli is refractoriness [ 5 – 8 ]. Refractoriness refers to a diminished airway response to a given stimuli when a subsequent challenge is performed within a relatively short time frame (e.g.…”