Annual variability in methacholine responsiveness in nonasthmatic working adults

Abstract

Change in airway responsiveness is used frequently as a clinical as well as an epidemiological tool. Changes in airway responsiveness can be superior to other measures of lung function in that they are more sensitive indicators of an environmental effect. However, normal variation in test results must be defined before change can be interpreted.To characterize annual variability in airways responsiveness, we administered a high-dose methacholine challenge at 1 yr intervals for up to 4 yrs to 105 healthy, nonasthmatic working subjects. Using this high-dose protocol, the majority of tests (83%) produced at least a 20% fall in forced expiratory volume in one second (FEV1), allowing standard calculation of the provocative dose of methacholine causing a 20% fall in FEV1 (PD20).An annual change in methacholine responsiveness by one or more doubling doses was seen in at least 30% of subjects each year. The components of variance of airways responsiveness measures were estimated to allow direct comparison of within-subject and between-subject variability. The within-subject variability in PD20, was markedly greater than the comparable within-subject variability in FEV1. Level of FEV1 and age were both significant determinants of methacholine responsiveness. Comparison of two methods of expressing methacholine responsiveness (PD20 using the full challenge up to 250 mg·mL -1 methacholine, and the dose-response slope using data up to 32 mg·mL -1 methacholine as the maximum dose) had similar annual variability in censored data and mixed-effects models. We then developed an approach to statistical analysis of "right-censored" methacholine challenge data using a maximum likelihood estimation under a censored Gaussian model. These studies of methacholine responsiveness provide normative data on annual test variability in healthy, nonasthmatic working adults, and show that a shorter low-dose challenge has comparable annual variability to a lengthier high-dose challenge.

Reproducibility of non-specific bronchial challenge in adults: implications for design, analysis and interpretation of clinical and epidemiological studies

“…4 New results including an extra follow up survey gave an overall ICC of 0.37, with a within person standard deviation of 1.0 doubling concentrations that was comparable to other studies, but lower between person variation. An ICC of 0.45 for PD 20 was obtained by Beckett et al, 30 with the largest within person standard deviation of any study. The third study, carried out in general practice, found an ICC of 0.48 for 27 subjects with complete data and measurable PD 20 on six occasions, but higher ICCs (0.56 and 0.68) when all first year and all second year pairs were analysed.…”

“…The one population study of short term repeatability had a within person standard deviation in line with short term studies of asthmatic patients 13 23 but also with the long term Vlagtwedden/ Vlaardingen study (table 4), while the long term population study of Beckett et al had greater within person variation. 30 Hence, the effect of selection of subjects on between person variation and the effect of length of follow up on within person variation both influence the ICC. However, restriction of data to participants with two measurable PD 20 values decreases between person variation and hence the ICC.…”

Diagnosing Exercise-Induced Bronchoconstriction With Eucapnic Voluntary Hyperpnea: Is One Test Enough?

“…The reason for the poor reproducibility is not clear however environmental factors and/or physiological variation impacts significantly on variability (37). Airway calibre fluctuates throughout the day and over short-term periods (38).…”

Interpretation of the “positive” methacholine challenge

“…Beckett et al [1997] examined methacholine responses among a group of 105 nonasthmatic adults at 1 year intervals for up to 4 years. At least 30% of the participants had an annual change in methacholine responsiveness of one or more doubling doses.…”