• Direct (methacholine, histamine) – agent binds to specific receptor on the bronchial smooth muscle causing it to contract
  • Indirect (mannitol, AMP, hypertonic saline, etc.) – agent triggers release of mediators in airways (from mast cells/eosinophils) leading to bronchial smooth muscle contraction
    • In EIB, exercise itself is considered an indirect challenge

  • 5 breath dosimeter method of methacholine challenge may be less sensitive than tidal breathing method, because the 5 breath dosimeter method requires inhalation to TLC that may provide bronchoprotection
    • Cockroft: methacholine should be inhaled by submaximal inhalations to preserve diagnostic sensitivity

Common Indications

  • To diagnose or exclude asthma in someone with asthma-like symptoms and normal lung function
    • Borish: arguably all patients with seemingly severe, steroid-resistant asthma and with an FEV1 >70% with inconsistencies in their presentation should undergo a methacholine challenge
  • To determine whether asthma treatment can be weaned (ICS)
  • Document effects of exposure to an occupational irritant or allergen that is suspected of causing asthma symptoms

Significance of Positive Mannitol Challenge

  • Confirms the presence of a sufficient number of cells with a sufficient concentration of mediators and a responsive bronchial smooth muscle to those endogenously released mediators at the time of testing
  • Correlates well with physician diagnosis of asthma
  • More likely to have:
    • Positive methacholine challenge and lower PC20
    • EIB
    • Higher FENo and more likely to have eosinophilic (steroid-responsive) asthma
      • Negative mannitol challenge may be observed in asthmatics well-controlled on medications

Significance of Positive Methacholine Challenge

  • The major value of methacholine challenge is the high diagnostic sensitivity and high negative predictive value providing that symptoms are clinically current (ie, within the past day or two)
    • Increased responsiveness to methacholine occurs in almost all (98-100%) of patients with symptomatic asthma
    • Sensitivity is decreased in Caucasians (vs. African Americans), non-atopics (vs. atopics)
  • Positive methacholine challenge without asthma may be due to:
    • Allergic rhinitis
    • Viral URI
    • COPD
    • CF
    • Inhalation of irritants
      • Cigarette smokers
      • Swimmers
      • Occupational exposures
    • Airway injury from breathing large volumes of unconditioned air (e.g. in elite cross country skiers)
    • Family history of atopy (e.g. siblings of asthmatics)
    • Remodeling of the airways in response to childhood asthma
  • ATS guideline: if the prior probability of asthma is 30-70% and the PC20 is >16 mg/mL, it may be stated with a high degree of confidence that the patient does not currently have asthma


Note: In a study of methacholine challenge safety on 88 patients with FEV1 < 60%, only 4.5% and 0% failed to return to baseline with 1 and 2 albuterol treatments