© 2005 American Thoracic Society
Ventilation Inhomogeneities in Patients with Cystic FibrosisInappropriate Reference Data and Errors?From the Authors:We thank Drs. Ranganathan and Robertson for their thoughtful comments regarding lung clearance index (LCI) in the longitudinal assessment of patients with cystic fibrosis (1). We would like to take the opportunity to complete the information about the Bernese Cystic Fibrosis Database, and to elucidate the data processing of the LCI. Set up in 1976, the database recruits CF patients from a population of 800,000 people of mainly Central European origin, including patients reviewed as inpatients and/or outpatients in our clinic. Initially, the database provided clinical findings, survival data (2), and interrelationships to pulmonary function (3). However, more recently, the database has been prospectively developed to focus on genotype–phenotype associations (1, 4, 5). Currently, it contains survival data of 208 patients, complete follow-up data from infancy to adolescence of 186 patients, including whole-body plethysmographic data of 58 infants with CF (6). For the present study, 142 patients with CF presenting with a follow-up of at least three lung function measurements per year were selected. The median number of tests per year was 92, with 29 as minimum at age 20 years and 131 as maximum at age 8 years. The median (range) number of tests per child was 8 (3–15), documenting a follow-up over at least 10 years in 58 (40.8%) CF patients. From those documented less than 10 years, 22 (15.4%) were older than 6 years at entry of the study, and 61 (42.9%) have not yet reached the age of 20 years at closure of data collection. There was a slight downward trend in the median (range) ages from 12.6 years (4.6–20.5) in the late 1970s to 10.8 years (4.3 – 20.5) in the test period (1994–1998). The reference data, especially those of the LCI, were obtained according international standards (7), and are in line with those from other studies. It may help to explain that (1) the range of normal values for LCI is extremely narrow, and that (2) the degree of ventilation inhomogeneity is particularly marked in the presence of CF lung disease in comparison to the variability between healthy subjects. Therefore, z-scores for this technique tend to be much higher than for many other lung function tests. The intriguing methodological question is how such data should be z-transformed, if not on the basis of equations of values predicted, as usually done. Z-transformation can alternatively be performed by using log-transformed gender-specific patient values on the basis of logarithms of corresponding reference data. We checked this option and became aware that the z-scores are lower, but that there is still a gender difference (p < 0.05), and LCI and maximal flow at 50% vital capacity are the earliest predictors of progression. The comments of Drs. Ranganathan and Robertson highlight the difficulty in explaining the gender difference of the LCI. One explanation was given in the paper: as cumulative expired volume was smaller and functional residual capacity greater in females than males, LCI must in fact be greater (and not smaller) in females with CF. Other explanations may relate to differences in gender-specific nutritional status. Our female patients presented with higher z-scores for weight, height, and body mass index (unpublished data), which may in part explain that the washouts in females were more efficiently performed (shorter washout time, smaller cumulative expired volume, greater functional residual capacity). Finally, better well-being in girls with CF may also influence some endocrinological factors such as pubertal delay, menarcheal age, fibrosis-related diabetes mellitus, impaired glucose tolerance, or even the insulin-like growth factor. Unfortunately, we have no long-term data in this respect. Notwithstanding the fact that some functional features of the LCI are not yet entirely understood, we remain convinced that the data provide important new insights into the pathophysiologic mechanism of lung progression in CF, and that there is sufficient evidence for including the LCI into the set of lung function parameters for individual long-term evaluation.
University of Berne, Berne, Switzerland FOOTNOTES Conflict of Interest Statement: R.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; R.A.A does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; S.G does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
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