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J Appl Physiol 105: 393, 2008; doi:10.1152/japplphysiol.90623.2008
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LETTER TO THE EDITOR

Reply to Macklem and Irvin

TO THE EDITOR: We thank Drs. Macklem and Irvin (3) for their comments, and for their insights regarding the 1996 paper coauthored by Dr. Macklem (2). As noted in our paper (4), the study by Gibbons et al. (2) was the first to introduce the concept of partitioning the forced expiratory volume in 1 s (FEV1) in the context of a response to aerosolized histamine, and the first to report an association between a histamine-induced reduction in forced vital capacity (FVC) and a history of asthma instability. These were important findings that, as noted in our paper (4), were concepts on which we based our analyses of baseline obstruction in severe asthma. Our study developed further the concept of partitioning the FEV1, demonstrating mathematically that this may be applied to an analysis of baseline obstruction, and we employed this approach to compare patterns of air trapping relative to airflow limitation in severe vs. nonsevere asthma in a large cohort that was fortified with subjects meeting the American Thoracic Society (ATS) Workshop classification for "Severe Asthma" (1). In their letter, Drs. Macklem and Irvin (3) challenge the originality of our results, suggesting that our conclusions had already been established by the paper of Gibbons et al. (2); however, there are several original aspects of our paper that were not recognized by Drs. Macklem and Irvin.

Most importantly, the Severe Asthma Research Program (SARP) data set is unique. The cohort used for our study included 669 nonsmoking adults with asthma, 43% of whom met the ATS Workshop criteria for Severe Asthma. These numbers provided an unprecedented opportunity to explore the characteristics of predefined populations of severe and nonsevere asthma with adequate power to discern distinct patterns within these broadly defined classifications. In contrast, it is unlikely that there was a substantial number of subjects in the Gibbons cohort that would have been classified as "Severe" by the ATS Workshop criteria, in that baseline airway obstruction and air trapping, prevalent in the SARP Severe Asthma group, was largely absent from the Gibbons cohort, which had minimal baseline obstruction [FEV1 99 ± 14 (SD) %predicted], and no apparent baseline air trapping [FVC 106 ± 14 (SD) %predicted, similar to that of the non-asthma group in SARP, 103 ± 12 (SD) %predicted]. About one-half of the subjects in the Gibbons cohort were current smokers, which may have introduced an additional variable that was absent in the SARP cohort. Baseline airway obstruction in predefined severe vs. nonsevere asthma was the primary focus of our analysis of the SARP cohort, in contrast to the Gibbons focus on histamine responsiveness in a cohort of asthmatic subjects without baseline obstruction. Thus the two studies addressed different questions in different populations.

Although Gibbons et al. (2) presented the idea that a change in FEV1 might be partitioned into the accompanying changes in FVC and FEV1/FVC, the quantitative aspect of their analysis was limited to the percent decrease in FVC associated with a 20% decrease in FEV1. They did not do a mathematical confirmation of their idea, and their implication that the concomitant percent decrease in FEV1/FVC would be equal to 20 minus the FVC percent decrease is approximately, but not mathematically, accurate. We developed the idea further, deriving equations that provide a mathematical foundation for the partitioning of FEV1, not only in the context of a change during bronchoprovocation, but also for patterns of baseline obstruction. We believe this to be original. Our results showing differences in the patterns of baseline air trapping relative to baseline airflow limitation in the two defined asthma populations also are original. Our paper complements and extends the ideas and results presented by Gibbons et al. (2) in 1996; we hope that it refreshes interest in exploring patterns of airway obstruction and asthma phenotypes.

FOOTNOTES


Address for reprint requests and other correspondence: R. L. Sorkness, 777 Highland Ave., Madison, WI 53705 (e-mail: rlsorkne{at}wisc.edu)

REFERENCES

  1. American Thoracic Society. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 162: 2341–2351, 2000.[Free Full Text]
  2. Gibbons WJ, Sharma A, Lougheed D, Macklem PT. Detection of excessive bronchoconstriction in asthma. Am J Respir Crit Care Med 153: 582–589, 1996.[Abstract]
  3. Macklem PT, Irvin CG. Dividing the FEV1 into its component parts. J Appl Physiol; doi:10.1152/japplphysiol.90489.2008.[Free Full Text]
  4. Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, Curran-Everett D, Erzurum SC, Gaston BM, Israel E, Jarjour NN, Moore WC, Peters SP, Teague WG, Wenzel SE, for the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. J Appl Physiol 104: 394–403, 2008.[Abstract/Free Full Text]

Ronald L. Sorkness
 School of Pharmacy and Departments of Medicine and Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin





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