Direct bronchoprovocation test methods: history 1945–2018

ABSTRACT Introduction: Bronchoprovocation inhalation challenge tests with direct acting stimuli (e.g. methacholine) are widely used clinically to aid in the diagnosis of asthma. Areas covered: The history of direct challenges with histamine and muscarinic agonists is reviewed. This began with parenteral administration of stimuli with responses monitored clinically and by VC, progressing to inhalation dose-response challenges monitored by FEV1 and FEV1/VC ratio, both (the challenge method and the technology to measure FEV1) developed by Robert Tiffeneau in the mid-1940s. Careful standardization of methods has become appreciated albeit after-the-fact. Recent guidelines recommend standardizing the methacholine PD20 at 400 μg above which a methacholine challenge is considered negative. Conclusions: The methacholine inhalation test is highly sensitive for a diagnosis of current asthma when symptoms under evaluation are clinically current and when methacholine is inhaled without deep inhalations. Under these circumstances, a methacholine PD20 > 400 μg excludes current asthma with reasonable certainty. PD20 values >25 μg and ≤400 μg will have a variable specificity and positive predictive value for asthma which increases the lower the PD20 and the higher the pre-test probability for a diagnosis of asthma. A PD20 ≤25 μg has high specificity and low sensitivity for asthma.