Cockcroft DW, et al. - Given more sensitivity and less specificity of direct inhalation challenges (eg, methacholine) vs indirect challenges (eg, exercise, non-isotonic aerosols, mannitol, etc.) for diagnosing asthma, and existing conflicting data surrounding comparative sensitivity and specificity for methacholine vs mannitol challenges, and in view of the fact that relative to tidal breathing inhalation methods, when methacholine is inhaled by deep total lung capacity (TLC) inhalations, deep inhalation inhibition of bronchoconstriction results in a marked loss of diagnostic sensitivity, researchers investigated whether conflicting sensitivity/specificity data may be explained by deep inhalation methacholine methods with resulting bronchoprotection. They analyzed 27 studies in a review. Methacholine and mannitol challenges were performed in mostly the same people in the included studies. Findings lend support to the hypothesis that the method of methacholine inhalation is responsible for the conflicting data comparing methacholine and mannitol sensitivity and specificity. Compared with either TLC dosimeter methacholine challenge methods or mannitol challenge, tidal breathing methacholine methods yielded a substantially greater sensitivity for asthma diagnosis. The recent guideline has recommended performing methacholine challenges by tidal breathing. Therefore, methacholine (more sensitive) and mannitol (more specific) will have complementary diagnostic characteristics.