Different response to doubling and fourfold dose increases in methacholine provocation tests in healthy subjects.

RATIONALE In a modified methacholine provocation test that was used to study changes in airway responsiveness to occupational irritants or sensitizers in healthy subjects, two protocols were used: a long protocol (doubling methacholine concentrations between dose steps) or a short protocol (fourfold increases in concentration). This modified methacholine provocation allows measurements of the provocative dose causing 20% decrease in FEV(1) (PD(20)) in a high proportion of a normal population. METHODS The distribution of PD(20) was investigated in healthy nonatopic men without history of allergy or asthma symptoms using the long protocol (n = 101) or the short protocol (n = 309). In addition, 30 healthy subjects underwent methacholine provocation tests using both protocols. RESULTS PD(20) was defined in 79% of subjects with the long protocol and in 48% of subjects with the short protocol. The provocative concentration of methacholine causing a 20% decline in FEV(1) (PC(20)) and PD(20) were significantly lower using the long protocol: long-protocol PC(20) (median [25th to 75th percentile]), 19.9 mg/mL (3.9 to > 32 mg/mL) compared with short-protocol PC(20), > 32 mg/mL (8.7 to >32 mg/mL; p < 0.0001); long-protocol PD(20), 4.2 mg (1.6 to 20 mg) compared with short-protocol PD(20), > 13.7 (2.6 to > 13.7 mg; p = 0. 006). The differences in PD(20) using short and long protocols were confirmed in a randomized trial of 30 healthy subjects tested with both protocols. CONCLUSION Using doubling concentrations, PC(20) and PD(20) could be defined in a higher proportion of healthy subjects than a protocol using fourfold dose increases. Furthermore, the doubling protocol results in a PD(20) estimate that is less than half the value obtained when using a protocol with fourfold concentrations between dose steps. The difference remains, whether the methacholine effect is regarded as cumulative or noncumulative. The explanation for the difference between the protocols is unclear.