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Re: The authors’ response to Dr Quanjer

Dear Editor,

We appreciate the comments made by Prof. Quanjer concerning our manuscript (1) and fully agree with his comments. In his letter to the editor Prof. Quanjer gives valuable background information to the reasons why pulmonary function tests are relatively insensitive to track pulmonary changes in the longitudinal follow up of cystic fibrosis (CF) lung disease (2). We agree with his arguments that this is in part related to the use of cross-sectional reference equations which do not adequately describe longitudinal lung growth of individuals. For the clinical management of our patients we routinely track for each patient the longitudinal pattern of the lung function expressed in percent predicted. The patterns of the individual curves are most often highly variable. This in part related to the arguments given by Prof. Quanjer and in part this is disease related. Unfortunately, these two important influences can not be untangled.

The data acquired in the cohort study were collected not as part of a prospective study but as routine follow up of the patients (1). Hence, no healthy control group was included in this study. We agree that ideally in clinical intervention studies a healthy control group should be included. Clearly such approach is likely to reduce the noise related to the use of lung function parameters. However, we think that the use of such a control group will only partially solve the problems discussed by Prof. Quanjer. A good example of such a study is the Pulmozyme Early Intervention Study of two years duration (3). In this study only children of ten years or younger were included. Lung function behavior was heretic for both the intervention as for the placebo group and could not be fitted into a statistical model. Whether the inclusion of a third healthy control group would have resolved these statistical problems is questionable.

The arguments given by Prof. Quanjer underline the difficulty of using lung function as the key parameter to monitor lung disease in CF and strengthens our view that computed tomography (CT) is a more suitable tool to monitor the progression of lung disease of CF patients. The most important structural changes observed on CT in the CF cohort were bronchiectasis and mucus plugging both of which are not present in the healthy population independent of age.

Sincerely,
Pim A de Jong MD PhD
Harm AWM Tiddens MD PhD

References

1. de Jong PA, Lindblad A, Rubin L, Hop WC, de Jongste JC, Brink M, et al. Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis. Thorax 2006;61(1):80-5.

2. Brody AS, Tiddens HA, Castile RG, Coxson HO, de Jong PA, Goldin J, et al. Computed tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med 2005;172(10):1246-52.

Send letter to journal:
Re: Pulmonary function tests in following up cystic fibrosis

I read with great interest the paper by de Jong et al. [1]. The authors conclude from a carefully conducted study that scores derived from CT scans are more sensitive in detecting progression of cystic fibrosis in children and adults than pulmonary function tests. I have no difficulty in accepting any such outcome. However, it seems that undue reliance was placed on predicted pulmonary indices, and that the value of a control group was not fully appreciated. The interpretation of longitudinal data on lung function is bedeviled by the fact that lung volumes and ventilatory flows increase due to growth up to age 30+ years, and decline thereafter [2]. Since in the type of study carried out by de Jong a matched control group is usually too costly to be feasible, it is often replaced with predicted values, as was done in this study. This approach has potential problems which I will illustrate in children and adolescents.

The authors selected prediction equations for their youngest subjects that have been shown to fit a cross-section of healthy European children and adolescents well [3]. In using them they implicitly assumed that healthy individuals will track along the cross-sectional predicted values. Improvement or decline in these indices in sick children then indicates either improvement or deterioration in their condition. However, cross-sectional prediction equations do not describe the longitudinal trajectory of individuals. The top panel in figure 1 shows the mean FEV1 and its 95% confidence interval, expressed as either Z-score or per cent predicted, in over 350 healthy non-smoking boys followed up at half year intervals for up to 7 years; their cross-sectional data contributed to the prediction equations [3] used by de Jong et al. In this study the variability of FEV1 within subjects tested on 5 consecutive days was 2.7% [4], relatively small compared to 11.6% between individuals [3]. Whilst the overall mean FEV1 is very nearly 100% predicted, there is a clear trend with a minimum at about age 13-14 yr. The lower panel illustrates the pattern in 6 boys. Five show a steady rise after age 13-14 yr, in three of them preceded by a decline of up to one unit Z-score (11% predicted); one boy seems to be tracking at about a constant level. Although the selected reference equation has gone a long way in accommodating the changing relationship between body and lung dimensions at these ages [3] and the above pattern would be more pronounced with older prediction equations, this equation nor any other one available does not describe individual growth curves. In de Jong's study Z-scores were recorded at three year intervals. Note how even in a healthy individual in this age range such scores might have easily gone up or down by as much as one unit, a fall in the youngest subjects being compensated by a rise in the older ones. Similar reasoning holds for girls and for adults.

These observations underline the fact that cross-sectional spirometric reference values, apart from being imperfect, do not describe the growth and decline of pulmonary function within individuals. It follows that it might be useful to analyse separately longitudinal changes in those under 13 year, and in older adolescents possibly up to 30 yr. Even then spirometric findings need to be compared to findings in a matched control group. Given the difficulties in interpreting longitudinal spirometric data, obviously the CT technique provides an apparently reliable and reproducible as well as practical alternative for assessing the progression of lung disease in cystic fibrosis, albeit a costly one.