Low levels of fractional exhaled nitric oxide and deep inhalation bronchoprotection are associated with mannitol non-responsiveness in asthma

Respir Med. 2014 Jun;108(6):859-64. doi: 10.1016/j.rmed.2014.03.005. Epub 2014 Mar 20.


Background: Airway hyperresponsiveness (AHR) to indirect agents like mannitol is thought to be dependent on concurrent airway inflammation as these stimuli exert their effects via the release of bronchoconstricting mediators from inflammatory cells. Airway inflammation correlates negatively with deep inhalation bronchoprotection against direct stimuli like methacholine. We hypothesised that deep inhalation bronchoprotection to methacholine would be absent and airway inflammation would be present in individuals with AHR to inhaled mannitol.

Methods: Twenty asthmatic, otherwise healthy individuals, either gender, aged 18-65 years, with a Visit 1 (screening) methacholine two-minute tidal breathing PC20 of 16 mg/mL or less completed the study. Visits 2 and 3 consisted of either mannitol or deep inhalation methacholine challenge in random order, at least 24 h apart. All visits were completed within a period of two weeks.

Results: Eleven of the twenty participants had AHR to mannitol (PD15 ≤ 635 mg, the "responders") and nine did not (the "non-responders"). Responders did not bronchoprotect to methacholine via deep inhalation (doubling dose shift = 0.7; p = 0.13) and had high levels of exhaled nitric oxide (geometric mean 49 ppb; range 16-109 ppb). Conversely, significant deep inhalation bronchoprotection to methacholine occurred in the non-responder group (doubling dose shift = 1.6; p = 0.013). This group also had significantly lower levels of exhaled nitric oxide (geometric mean 23 ppb (range 16-45 ppb; p = 0.015).

Conclusions: Deep inhalation bronchoprotection to methacholine and low levels of exhaled nitric oxide coincide with mannitol non-responsiveness in an asthmatic population. Clinical Trials Registration #NCT01642745 (clinicaltrials.gov).

Keywords: Airway hyperresponsiveness; Asthma; Deep; Inhalation; Mannitol; Methacholine.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Asthma / physiopathology*
  • Biomarkers / analysis
  • Bronchial Hyperreactivity / diagnosis
  • Bronchial Hyperreactivity / physiopathology
  • Bronchoconstrictor Agents
  • Female
  • Forced Expiratory Volume / physiology
  • Humans
  • Inhalation / physiology
  • Male
  • Mannitol*
  • Methacholine Chloride
  • Middle Aged
  • Nitric Oxide / analysis*
  • Powders
  • Young Adult


  • Biomarkers
  • Bronchoconstrictor Agents
  • Powders
  • Methacholine Chloride
  • Nitric Oxide
  • Mannitol

Associated data

  • ClinicalTrials.gov/NCT01642745