American Journal of Respiratory and Critical Care Medicine

To the Editor:

Dr. Hansen's argument (in his letter that appears in this issue [1]) that a response to a medical intervention in a patient should be considered as positive only if the functional parameter exceeds intra-individual variability is interesting and needs serious consideration. His statement is based on studies documenting more discriminative responses after acute inhalation of a β2-agonist (2) or a rehabilitation program (3), when individual rather than group variability was considered. Our comments are intended to bring further contribution to the topic.

Most of the problems in biology arise not only from how the data are analyzed but also from the choice of the parameters that best identify the outcome. As an example, when using volitional tests such as the FEV1 or 6-minute-walk test, the pros of the statistical approach might well be overweighed by the cons of functional parameters whose variability is largely determined by the patient's cooperation and, specifically for FEV1, by the variable effect of the inspiratory maneuver preceding forced expiration on bronchial tone (4) and thoracic gas compression (5). Based on an average measurement variability within 8% and 150 ml, the European Respiratory Society/American Thoracic Society guidelines suggested that changes in the FEV1 larger than 12% and 200 ml are required to define bronchoreversibility (6). Although we do agree with Dr. Hansen that smaller changes may be significant in subjects able to give highly repeatable measurements, there are some requirements for short-term natural variability of a given test to be used as a diagnostic tool or an outcome in clinical practice. These include the knowledge of short-term variability in healthy subjects, long-term variability in patients (7), and minimum clinically important difference. Therefore, threshold values need to be set even if a statistical approach is used, as suggested by Dr. Hansen.

Besides the above considerations, we believe that the most promising application of short-term intra-individual variability may be in the prediction of clinically relevant events, such as asthma attacks or deterioration of lung function (8). To this aim we report that the choice of lung function tests requiring minimal or no patient cooperation, such as the forced oscillation technique, has been revealing a very promising and encouraging tool for assessment of home variability of airway caliber (9).

1. Hansen JE. Has my patient responded? [letter]. Am J Respir Crit Care Med 2012;185:895.
2. Hansen JE, Casaburi R, Goldberg AS. A statistical approach for assessment of bronchodilator responsiveness in pulmonary function testing. Chest 1993;104:11191126.
3. Dolmage TE, Hill K, Evans RA, Goldstein RS. Has my patient responded? Interpreting clinical measurements such as the 6-minute-walk test. Am J Respir Crit Care Med 2011;184:642646.
4. Pellegrino R, Sterk P, Sont JK, Brusasco V. Assessing the effect of deep inhalation on airway calibre: a novel approach to lung function in bronchial asthma and COPD. Eur Respir J 1998;12:12191227.
5. Sharafkhaneh A, Babb TG, Officer TM, Hanania NA, Sharafkhaneh H, Boriek AM. The confounding effects of thoracic gas compression on measurement of acute bronchodilator response. Am J Respir Crit Care Med 2007;175:330335.
6. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CPM, Gustafsson P, Hankinson J, et al.. Interpretative strategies for lung function tests. Official statement of the American Thoracic Society and the European Respiratory Society. Eur Respir J 2005;26:948968.
7. Herpel LB, Kanner RE, Lee SM, Fessler HE, Sciurba FC, Connett JE, Scott RA; Lung Health Study Research Group and the National Emphysema Treatment Trial Research Group. Variability of spirometry in chronic obstructive pulmonary disease: results from two clinical trials. Am J Respir Crit Care Med 2006;173:11061113.
8. Frey U, Brodbeck T, Majumdar A, Taylor DR, Town GI, Silverman M, Suki B. Risk of severe asthma episodes predicted from fluctuation analysis of airway function. Nature 2005;438:667670.
9. Gobbi A, Gulotta C, Gasparini P, Pellegrino R, Majumdar A, Pedotti A, Brusasco V, Suki B, Dellaca R. Short and long-term variability of oscillatory mechanics parameters in asthma [abstract]. Eur Respir J 2011;38:P928.

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