Cystic fibrosis

Purpose: To evaluate quantitative air trapping measurements in children with mild cystic fibrosis (CF) lung disease during a 1-year, double-blind, placebo-controlled, recombinant human deoxyribonuclease (rhDNase) [dornase alfa] intervention trial and compare results from quantitative air trapping with those from spirometry or visually scored high-resolution CT (HRCT) scans of the chest.

Materials and methods: Twenty-five children with CF randomized to either daily rhDNase or placebo aerosol were evaluated at baseline, and at 3 months and 12 months by spirometer-triggered HRCT and spirometry. Outcome variables were percentage of predicted FVC, [FEV.sub.1], and forced expiratory flow, midexpiratory phase ([FEF.sub.25-75%]); total and subcomponent visual HRCT scores; and quantitative air trapping measurements derived from chest HRCT images. Results: At baseline, there were no statistical differences between groups in any of the variables used as an outcome. After 3 months of treatment, both groups had improvements in percentage of predicted [FEV.sub.1] and [FEF.sub.25-75%], and total HRCT visual scores. In contrast, the rhDNase group had a 13% decrease in quantitative air trapping from baseline (severe air trapping [[A.sub.3]]), compared to an increase of 48% in the placebo group (p = 0.023). After 12 months, both groups had declines in percentage of predicted FVC and [FEV.sub.1], but the rhDNase group retained improvements in percentage of predicted [FEF.sub.25-75%] and quantitative air trapping. The mucus plugging and total HRCT visual scores were also improved in the rhDNase group after 12 months of treatment, with and without significant differences between groups (p = 0.026 and p = 0.676). Quantitative air trapping ([A.sub.3]) remained improved in the rhDNase group (-15.4%) and worsened in the placebo group (+61.3%) with nearly significant differences noted between groups (p = 0.053) after 12 months of treatment.

Conclusions: Quantitative air trapping is a more consistent sensitive outcome measure than either spirometry or total HRCT scores, and can discriminate differences in treatment effects in children with minimal CF lung disease.

Key words: cystic fibrosis; dornase alfa; high-resolution CT; mucus plugging; quantitative air trapping

Abbreviations: [A.sub.1] = mild, moderate, and severe air trapping. [A.sub.2] = moderate and severe air trapping; [A.sub.3] = severe air trapping; CF = cystic fibrosis; [FEF.sub.25-75%] = forced expiratory flow, midexpiratory phase; HRCT = high-resolution CT; HU = Hounsfield unit; PFT = pulmonary function test; rhDNase = recombinant human deoxyribonuclease (dornase alfa)

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The predominant cause of morbidity and mortality in cystic fibrosis (CF) lung disease is progressive obstructive lung disease resulting from reduced mucociliary clearance, airway obstruction, recurrent endobronchial infections, and persistent inflammation and destruction of the airways. Early manifestations of CF lung disease include submucosal gland hypertrophy, inspissated airway mucus, inflammatory infiltrates, and bronchiectasis. (1,2) High-resolution CT (HRCT) in infants and children with early and/or mild CF lung disease has demonstrated evidence of peripheral regional air trapping, bronchial/bronchiolar wall thickening, and bronchial/bronchiolar airway dilatation. (3-14) Using spirometer-triggered HRCT imaging and an automated approach for quantifying air trapping defects, we previously demonstrated increased quantitative air trapping in children with mild CF lung disease compared to age-matched normal children. (9) Unlike percentage of predicted [FEV.sub.1] and forced expiratory flow, midexpiratory phase ([FEF.sub.25-75%]), which did not discriminate statistical differences between these groups, the quantitative air trapping measures clearly showed robust differences between groups with p values < 0.001. This suggests that quantitative air trapping obtained by HRCT imaging is a more sensitive outcome measure than pulmonary function measurements in discriminating early obstructive lung disease. (9) The sensitivity of HRCT measures being more sensitive than PFT measures is further supported by de Jong et al (10) and Brody et al (11) who have recently demonstrated that visual HRCT scores, including HRCT air trapping scores, were more sensitive than pulmonary function tests (PFTs) in detecting early and progressive CF lung disease. The purpose of the present study was to evaluate quantitative air trapping, spirometric measurements, and chest HRCT scores as outcome measures in therapeutic response to recombinant human deoxyribonuclease (rhDNase) [dornase alfa] in 25 children with mild CF lung disease over a 1-year, controlled intervention trial.

MATERIALS AND METHODS

Study Design

We conducted a randomized, double-blind, placebo-controlled, 1-year trial of dornase alfa in 25 children and adolescents with mild CF lung disease. All children had a confirmed diagnosis of CF by pilocarpine iontophoresis sweat chloride test and/or CF gene mutation analysis. Inclusion criteria included routine medical care in a CF clinic, age 6 to 18 years, percentage of predicted FVC [greater than or equal to] 85% and a percentage of predicted [FEV.sub.1] approximately [greater than or equal to] 70%, and the ability to perform reproducible PFTs. Exclusion criteria were inability to perform reproducible upright and supine spirometry; inability to take the trial medication; acute asthma attack; recent lower respiratory tract infection prior to enrollment requiring a change in antibiotic, bronchodilator, or anti-inflammatory therapy (inhaled or oral steroids; ibuprofen); or use of dornase alfa within a previous 3-week period prior to enrollment and testing. The patient cohort was described and evaluated in a previous article (12) with a different visual scoring system that emphasized an outcome equation combining elements of HRCT scores and PFT measures. Before enrollment into the study, informed assent and consent were obtained from the patients and their parents respectively. The study protocol was approved by the Stanford University Administrative Panel in Human Subjects. Patients were studied at randomization, and at approximately 3 months and 12 months afterwards.

Eligibility was assessed at the initial pretreatment visit. Subjects already receiving dornase alfa prior to the study discontinued their treatment 3 weeks before screening and enrollment. At the second visit, baseline testing was completed for all groups, and CF patients were randomized to receive either 2.5 mg dornase alfa or placebo aerosol once daily with a jet nebulizer (Pari LC Plus; Pari; Richmond, VA) and compressor (PulmoAide; DeVilbiss; Somerset, PA; or Pari Pro Neb; Pari). Randomized treatment assignment was conducted by the Division of Biostatistics, Department of Health Research and Policy, of Stanford University in conjunction with the Lucile Packard Children's Hospital pharmacy department. All patients, investigators, and study participants were blinded to the treatment assignment until the study was completed.

The outcome variables for the study included spirometry (FVC, [FEV.sub.1], [FEF.sub.25-75%]), global and subcomponent HRCT scores, (15) and quantitative expiratory air trapping measurements (mild, moderate, and severe air trapping [[A.sub.1]; moderate and severe air trapping [[A.sub.2]]; severe air trapping [[A.sub.3]]). During each testing session, a brief medical history and physical examination were performed, height and weight were measured, and spirometry and spirometer-triggered inspiratory and expiratory CT imaging were performed. Further details of the testing equipment and protocols utilized have been described. (12) Pulmonary function measurements were expressed as percentages of predicted based on normal prediction equations derived from the data of the Harvard Six Cities Study. (16) Chest HRCT images were obtained using a previously described protocol. (12) Contiguous 1.5-mm images were obtained at [greater than or equal to] 95% slow vital capacity. To allow for consistent matching of images from serial studies, inspiratory scans were acquired volumetrically during a single breath-hold from 1.5 cm above the aortic arch to 1 cm above the right hemidiaphragm. Six thin-slice expiratory (1.5 mm per slice) images that were equally spaced between 1.0 cm above the aortic arch to 1 cm above the right hemidiaphragm were obtained at near residual volume to evaluate the extent of air trapping. The calculated total radiation exposure for the inspiratory and expiratory CT scans for each testing session was 75 to 135 millirem for children 6 to 18 years old, which is below the estimated average annual radiation exposure in communities at high elevations such as Denver, CO, and is also below the average radon exposure per year. (17,18)

HRCT Scoring and HRCT Image Analysis

Total (global) and component HRCT scores were determined for each CT scan utilizing a scoring system similar to that of Brody et al, (6) with different scoring components and different rating criteria. (15) A total (global) score was calculated as the sum of the seven component scores of extent and severity of bronchiectasis, extent and severity of bronchial wall thickening, and extent of mucus plugging, atelectasis/consolidation, and air trapping. Each component feature was scored individually from 1 to 4 in each lobe (with the lingula considered as a separate lobe) at each of the six image levels. A score of 4 for each component would field a total possible score of 168. The HRCT scans were independently assessed by three radiologists, and the average of the three readers was utilized for analysis. To evaluate regional air trapping, chest HRCT images were postprocessed utilizing an automated approach for lung segmentation and subsequent air trapping defect determination as described. (9) In short, air trapping was based on the density distribution of individual voxel densities (in Hounsfield units [HUs]) within the segmented lung in the expiratory and inspiratory images, with a range defined by the median HUs in the inspiratory vs expiratory images. Within this defined range of HU densities, three thresholds were set. Voxels with densities below the given thresholds were considered to have air trapping. The threshold with the lowest density (in HUs) defines those regions of segmented lung with [A.sub.3], while the threshold with the highest density corresponds to those regions of segmented lung that include [A.sub.1]. An additional threshold was also arbitrarily chosen midway between the lowest and highest density threshold to represent those regions of segmented lung on CT that represent [A.sub.2]. Global air trapping was therefore expressed as a fraction of the number of involved voxels in the individual and summated expiratory slices that corresponded to [A.sub.1], [A.sub.2], and [A.sub.3] (Fig 1). (9)

[FIGURE 1 OMITTED]

Statistical Analysis

Group averages were compared at baseline using two-sample t tests adjusted for unequal variances as well as the Fisher Exact Test. Over the active treatment period, changes in air trapping, spirometric measurements, and HRCT scores including the HRCT score for the extent of air trapping were evaluated using paired t tests for within-group comparisons and unpaired t tests for between-group differences for percentage change from baseline to 3 months: ([3-month value - baseline value]/baseline value x 100) and baseline to 12 months ([12-month value - baseline value]/baseline value x 100). Data met normality assumption required for t tests. Results were considered statistically significant for p < 0.05.

RESULTS

Twenty-five CF subjects were enrolled and randomized, and 21 subjects completed the 1-year trial with follow-up testing. All four noncompleters withdrew for nonstudy drug-related reasons. For the quantitative air trapping analysis, 25 subjects could be evaluated at baseline and 3 months; however, only 19 subjects (3 fewer subjects from each group) could be evaluated at baseline and 12 months due to noncompleters and the unavailability of stored electronic imaging for post-processed CT image analysis in two subjects for which the expiratory scan digital data were not saved. Adherence (average proportion of medication taken based on returned used and unused vials and diary sheets) over 12 months was 86.9% for the placebo group and 85.6% for the dornase alfa group.

Baseline Assessment

The baseline characteristics for study subjects are presented in Table 1. Between-reader reliability for total HRCT scores and air trapping component at test 1 for the three radiologists who scored the HRCT scans were 0.83 and 0.62, respectively. This interreader reliability for the total HRCT score was comparable to the interreader reliability for two readers (0.78) in our previous study (15) in CF patients with more severe disease using the same HRCT scoring system. Although there were no statistically significant differences in mean age, weight, height, pulmonary function measurements, HRCT scores, and quantitative air trapping indices between the groups at baseline testing, the dornase alfa group were older and had greater quantitative air trapping values. Only 1 of 25 subjects (randomized to the dornase alfa group) received rhDNase aerosol prior to the study, but this subject did not receive rhDNase for 3 weeks prior to enrollment in the study: On morphologic analyses of segmented expiratory chest HRCT scans in the majority of subjects in both groups, there was a heterogeneous distribution of air trapping defects as demonstrated in Figure 1. Utilizing previous data defining normal standards (mean + 2 SD) for no air trapping in age-matched normal subjects, (9) 73%, 64%, and 55% of the dornase alfa subjects had air trapping at baseline, compared to 57%, 50%, and 43% of placebo subjects for [A.sub.1], [A.sub.2], and [A.sub.3] thresholds, respectively. Despite the higher incidence of air trapping in the dornase alfa group, there were no statistical differences between groups for the number of subjects with air trapping at baseline utilizing the two-tailed Fisher Exact Test (p = 0.691, p = 0.689, and p = 0.677 for [A.sub.1], [A.sub.2], and [A.sub.3] thresholds, respectively).

Treatment Results

After 3 months of treatment, both groups had improvements in percentage of predicted [FEV.sub.1] and [FEF.sub.25-75%] as well as total visual HRCT and mucus plugging scores. The dornase alfa group, however, had an increase (ie, worsening) in the visual air trapping CT score, whereas the placebo group had a decline (ie, improvement) in the visual air trapping CT score (Table 2). For the visual air trapping score, the interreader reliability for the three radiologists was 0.65. At 3 months, the dornase alfa group had a fourfold larger increase in mean percentage of predicted [FEV.sub.1] and [FEF.sub.25-75%] than the placebo group, resulting in a nearly statistical difference for improvement in percentage of predicted [FEF.sub.25-75%] (baseline, 91 [+ or -] 33.8%; 3 months, 112 [+ or -] 26.7% [p = 0.07]) when paired t tests were utilized within groups. Additional improvements for the dornase alfa group were also noted in the visual extent of bronchiectasis and bronchial wall thickness scores. No statistical differences, however, were noted between groups for changes after 3 months. Unlike the visual HRCT air trapping score at 3 months, the quantitative air trapping measurements in the dornase alfa group had mean reductions in air trapping of 2 to 13% for [A.sub.1] to [A.sub.3], compared to mean increases of 34 to 48% for [A.sub.1] to [A.sub.3] in the placebo group (Table 2). Figure 2 demonstrates changes in quantitative HRCT air trapping from a subject in the placebo group compared to a subject in the dornase alfa group after 3 months of treatment. These differences between groups for percentage change from baseline for [A.sub.2] and [A.sub.3] after 3 months of treatment were statistically significant.

[FIGURE 2 OMITTED]

After 12 months of treatment, the placebo group declined in all spirometric measurements but showed continued improvement in the visual total HRCT score and minimal improvement in the mean visual air trapping score (Table 2). The dornase alfa group had a similar decline in the percentage of predicted [FEV.sub.1], a greater decline in percentage of predicted FVC, but continued improvement in percentage of predicted [FEF.sub.25-75%] and all visual HRCT scoring components except for the mean air trapping score. When paired t tests were utilized for within-group analysis, only percentage of predicted FVC and [FEV.sub.1] showed significant declines in both groups (placebo group [n = 11]: baseline FVC, 116 [+ or -] 31.2%; 12 months, 102 [+ or -] 8.9% [p=0.034]; baseline [FEV.sub.1], 104 [+ or -] 19.6%; 12 months, 92 [+ or -] 11.8% [p = 0.051]; and dornase alfa group [n = 8]: baseline FVC, 122 [+ or -] 15.2%; 12 months, 102 [+ or -] 15.2% [p = 0.003]; baseline [FEV.sub.1], 107 [+ or -] 21.8%; 12 months, 97 [+ or -] 17.9% [p = 0.046]). At 12 months, the dornase alfa group had a significant increase in the visual air trapping HRCT score compared to the mean baseline score in the eight dornase alfa subjects evaluated (baseline air trapping score, 12.3 [+ or -] 3.66%; 12 months, 13.7 [+ or -] 3.59% [p = 0.036]). However, the inter-reader reliability for the three-reader visual air trapping score at 12 months was only 0.49. Despite worsening visual air trapping HRCT scores, there was no significant difference between groups for changes in visual air trapping scores after 12 months of the intervention. When other changes in visual HRCT scores were compared between groups after 12 months of treatment, the dornase alfa group had a 6% decline in the mean total mucus plugging score, while the placebo group had a 12% increase (p = 0.026). When quantitative air trapping measurements were evaluated after 12 months of treatment, the dornase alfa group continued to show reduction in mean air trapping ([A.sub.1] to [A.sub.3], 14 to 16%), while the placebo group had a 38 to 61% increase in mean air trapping ([A.sub.1], [A.sub.2], and [A.sub.3]: p = 0.091, p = 0.061, and p = 0.053, respectively; Table 2).

DISCUSSION

In this 1-year intervention study evaluating the effect of dornase alfa in children with mild CF lung disease, only the visual mucus plugging CT score at 1 year demonstrated significant differences between groups, with a continued decline in the dornase alfa group compared to an increase in the placebo group. However, this discrimination only occurred at 1 year and not at 3 months. Overall, much more consistent differences between groups at 3 months and 12 months were demonstrated in the quantitative air trapping measurements compared to spirometry or visual HRCT scores. This was especially true for the quantitative [A.sub.2] and [A.sub.3], which demonstrated significant differences between groups after 3 months of treatment and nearly statistical differences between groups after 12 months of intervention. It is suspected that if there had been comparable subject numbers evaluated at 12 months similar to 3-month testing, the quantitative air trapping measures would have demonstrated significant differences between groups after 12 months of treatment as well. This suggests that quantitative CT air trapping measurements better discriminate differences in treatment effects in children with minimal CF lung disease (baseline [FEV.sub.1] [greater than or equal to] 70%).

In this study, there was a marked difference between the results of the visual HRCT air trapping scores and the quantitative air trapping measures ([A.sub.1] to [A.sub.3]). In contrast to all HRCT scoring components in Table 2 and quantitative air trapping measures that improved in the dornase alfa group with treatment, the visual air trapping scores worsened after 3 months and 12 months of therapy. In a similar manner, the visual air trapping scores in the placebo group improved after 3 months and 12 months compared to a worsening in quantitative air trapping scores. This surprising and counterintuitive discrepancy between the visual HRCT air trapping score and quantitative air trapping measurements may be explained by three factors. First, subjective differences among the CT readers contributed since the interreader reliability at baseline, 3 months, and 12 months were only 0.62, 0.65, and 0.49, respectively. This illustrates the intrinsic weakness of reader-dependent intersubjectivity in visual CT scoring systems. Second, the visual HRCT air trapping scoring system (scaled from 6 to 24 for the total of six lung zones) reaches an asymptote at the higher end of the scale (corresponding to scores [greater than or equal to] 17) compared to the quantitative air trapping measures. When regression analysis was done to evaluate the relationship between visual CT air trapping scores and quantitative air trapping measures, the relationship was linear only for visual scores between 6 and 12 (r = 0.84, slope = 0.69, with visual scores as independent variable for scores 6 to 12), becoming alinear for scores > 12 (r = 0.72, slope = 3.2, with visual scores as independent variable for scores 13 to 24). This demonstrates that for visual scores > 12, a small increase in the visual HRCT score corresponds to a larger increase in [A.sub.3] measurements. Per happenstance, the saline solution placebo group started with higher visual HRCT air trapping scores (median, 15.67 vs 12.50 in the rhDNase group), and higher scores were more likely to decrease since they were at the higher (asymptotic) values. In contrast, the range of quantitative air trapping measures ([A.sub.2] and [A.sub.3]) were from 2.5 to 46.1% and 0.9 to 24.9% (median, 15.9% and 6.4%) in the rhDNase group, and 0.7 to 44.6% and 0.4 to 21.1% (median, 13.2% and 5.1%) in the saline solution placebo group, respectively. Finally, the visual HRCT air trapping score (1 = absent; 2 = < 25% of lobar surface area; 3 = 25 to 50% of lobar surface area; 4 = > 50% of lobar service area) did not have enough gradations in scoring (ie, an additional numeric score to account for milder air trapping corresponding to 7 to 20% of the lobar surface area) to pick up the milder extent of regional air trapping seen in CF patients with mild lung disease. (9)

After 3 months of treatment, both groups demonstrated improvements in percentage of predicted [FEV.sub.1] and [FEF.sub.25-75%] as well as total HRCT scores. Improvements seen at 3 months in the placebo group as well as the dornase alfa group may have occurred due to the well-known finding that subjects participating in research studies often have better follow-up and adherence with medications during the initial phases of a clinical study. At 12 months of treatment, despite continued therapy, both groups demonstrated declines in percentage of predicted FVC and [FEV.sub.1] but continued improvements in the total visual HRCT score. In part, this may have been due to the smaller sample sizes in each group tested at 1 year, who had initial higher PFT values at baseline in each of the groups compared to the larger groups comprising the 25 subjects, or the observed greater decline in lung function that occurs in CF children with mild obstructive lung disease, (19-21) given that our subjects had essentially normal spirometric measurements at initial enrollment with mean percentage of predicted values for FVC and [FEV.sub.1] > 100%. In this study, the dornase alfa group had 38% and 17% mean increases in percentage of predicted [FEF.sub.25-75%] at 3 months and 12 months, respectively, compared to a mean increase of 9% at 3 months and a mean decline of 5% at 12 months in the placebo group. Despite the large differences in group mean results, there was no significant differences noted between groups probably due to large among-subject variances in [FEF.sub.25-75%] measurements (Table 2), which have also been observed by others, (19,21-23) Although there was a decline in lung function at 1 year, continued improvement was seen in the average visual total HRCT scores in each group with no significant difference in means between the groups (Table 2). These results suggest that changes in spirometric airflow measurements are not tracking changes in structural differences noted by HRCT scoring in children with mild CF lung disease. This has also been recently confirmed by de Jong et al (10) and Brody et al. (11) When individual component HRCT scores were evaluated at 3 months and 12 months, only the average total mucus plugging score at 12 months was significantly different between groups, with the dornase alfa group having an improvement of 6% compared to worsening of 12% in the placebo group (p = 0.026). This suggests that dornase alfa therapy may effect mucus clearance in children with mild CF lung disease.

Quantitative CT air trapping measurements are one of several new CT post-processing techniques that appear to be promising new methods for providing standardized quantitative CT measures similar to quantitative PFT measurements. (9,13,14,24-27) After 3 months of treatment, there were significant differences noted between treatment groups for percentage change in quantitative air trapping determined using [A.sub.2] or [A.sub.3] thresholds (Table 2). After 12 months of treatment, there were nearly significant differences noted between the dornase alfa and placebo groups for these outcome measures, despite a smaller sample size. In each treatment period, the dornase alfa group had improvement in quantitative HRCT air trapping measures, while the placebo group demonstrated worsening results, suggesting that dornase alfa improved global HRCT air trapping measures. In addition, after 12 months of dornase alfa therapy, there was continued decreases in total visual mucus plugging HRCT scores as well as continued improvement from baseline in percentage of predicted [FEF.sub.25-75%], suggesting enhanced mucus clearance and improvement and perhaps prevention of further small airway obstruction with dornase alfa therapy in children with mild CF lung disease. These findings also suggest a possible association between decreased mucus plugging and improvements in air trapping and small airway flow rates ([FEF.sub.25-75%]) in children with mild CF lung disease.

We have previously demonstrated improvements in the composite CT/PFT score after dornase alfa therapy in this same subject population. (12) This score incorporates aspects of visual CT scores and pulmonary function measurements to evaluate changes in CF lung disease with treatment. The findings presented here corroborate the beneficial effects of dornase alfa therapy in this group. Since these results were obtained in a small sample (n = 25), they should not be generalized without further studies in larger groups of patients. However, in our view, this study demonstrates the potential utility of quantitative CT measures during therapeutic interventions in subjects with early or mild obstructive airways disease.

In conclusion, we found that quantitative air trapping measurements were more consistent sensitive outcome measures at 3 months and 12 months of treatment than spirometric pulmonary function measurements or visual HRCT scores, discriminating differences in treatment effects in children with minimal CF lung disease. These findings suggest a potential advantage of using quantitative air trapping measurements for understanding the pathogenesis of CF lung disease and as outcome measures in clinical trials in subjects with mild CF lung disease.

ACKNOWLEDGMENT: The authors thank Tyson Holmes from the Division of Biostatistics, Health Research and Policy, Stanford University Medical Center, for statistical analysis; Malayattil Vijayalakshmi, Anne S. Bonnel, Krishnaveni and Kesavaraju for technical support; and Glenn Hodge (Pediatric Pulmonary Function Laboratory) and Lisa McClennan and Diane Holmes (Pediatric Radiology Section- Ultrafast CT imaging) for their participation in the study.

This study was funded by the Cystic Fibrosis Foundation and Genentech, Inc.

Manuscript received November 26, 2004; revision accepted April 29, 2005.

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Terry E. Robinson, MD; Michael L. Goris, MD; Hongyun J. Zhu, MD; Xiaorong Chen, MS; Prache Bhise, MD; Farzana Sheikh, MD; and Richard B. Moss, MD, FCCP

* From the Departments of Pediatrics (Pulmonary) [Drs. Robinson, Bhise, Sheikh, and Moss], and Radiology (Nuclear Medicine) [Drs. Goris and Zhu], Stanford University Medical Center Palo Alto; and Department of Statistics (Ms. Chen), Stanford University, Stanford, CA.

Dr. Robinson received a research grant from Genentech, Inc. of $3,700.00 representing the cost of pharmacist set-up and inventory activities associated with Pulmozyme and placebo medication for this study.

Dr. Moss has received research grants from Genentech, Inc. for studies related to Pulmozyme since 1993.

Correspondence to: Terry E. Robinson, MD, Pediatric Pulmonary Division, Stanford University Medical Center 701 Welch Rd, Whelan Building, #3328, Palo Alto, CA 94305-5786; e-mail: ter@stanford.edu

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