DIRECT AIRWAY CHALLENGES
Methacholine and Histamine Challenges
Histamine is a pro-inflammatory mediator released by activated mast cells and basophils in the airways. Histamine exerts its actions by binding to histamine receptors. Of the four G protein-coupled histamine receptors that have been discovered in humans, designated H1 through H4, the binding of histamine to H1 receptors on airway smooth muscle and endothelium causes bronchoconstriction and vasodilation (Figure 10.2).
Methacholine is a synthetic derivative of acetylcholine delivered as a wet aerosol. Methacholine acts as a nonselective muscarinic receptor agonist in the parasympathetic nervous system and is highly active at all of the muscarinic receptors. Methacholine induces bronchoconstriction primarily through a direct binding to muscarinic receptors on smooth muscle within the airways (Figure 10.2). Acetyl-p- methylcholine chloride (Provocholine) is available as a dry crystalline powder and approved by the U.S. Food and Drug Administration for testing in humans (Juniper et al. 1978; Fowler et al. 2000).
During inhalation challenges, increasing concentrations of methacholine (or histamine) from 0.031 to 16 mg/mL are administered in an aerosolized form by tidal breathing or by dosimeter in doubling concentrations (i.e., 2, 4, 8 mg/mL). The forced expiratory volume in 1 s (FEVj) is measured at 30, 90, and 180 s after each concentration and the test is terminated when there is a 20% reduction in FEVj. The methacholine (or histamine) provocative concentration causing a 20% fall in the FEV1 (PC20) is calculated by linear interpolation. Responses to histamine and methacholine are highly reproducible (coefficients of determination [r2] = 0.994 and 0.990, respectively) (Juniper et al. 1978). A positive test is commonly considered as a PC20 of less than 8 mg/mL. A test >16 mg/mL is considered to be negative, while tests of 4-16 mg/mL should be interpreted with caution.