American Journal of Respiratory and Critical Care Medicine

Pulmonary function tests have rarely been assessed in preschool children with cystic fibrosis (CF). The objective of this multicenter study was to compare pulmonary function in 39 preschool children with CF (height, 90–130 cm; 16 homozygous ΔF508) and in 79 healthy control children. Functional residual capacity (helium dilution technique) and expiratory interrupter resistance (Rintexp) (interrupter technique) were measured. As compared with control children, children with CF had significantly higher Rintexp, expressed as absolute values and as Z-scores (1.05 ± 0.36 versus 0.80 ± 0.20 kPa·L−1 · second, p < 0.0001; and 1.31 ± 1.72 versus 0.19 ± 0.97, p < 0.0001), and significantly lower specific expiratory interrupter conductance (1.29 ± 0.34 versus 1.63 ± 0.43 kPa−1 · second, p < 0.0001). The effect of the bronchodilator salbutamol on Rintexp was not significantly different between children with CF and control children. Rintexp Z-scores were significantly higher in children with CF who were exposed to passive smoke (n = 8) (p < 0.03). Children with CF and with a history of respiratory symptoms (n = 31) had significantly higher functional residual capacity Z-scores (p < 0.02) and lower specific expiratory interrupter conductance Z-scores (p < 0.04). Genotype did not influence the data. We conclude that Rintexp and functional residual capacity measurements may help to follow young children with CF who are unable to perform reproducible forced expiratory maneuvers.

Pulmonary function tests (PFTs) play a central role in the management of school children, adolescents, and adults with cystic fibrosis (CF) (1). FEV1 has been shown to reflect disease progression (1, 2). However, the role of PFTs in very young patients with CF has been less well documented. Available data show that airway obstruction and/or hyperinflation can be present not only in infants with CF-related respiratory symptoms but also in asymptomatic infants with CF (315). That the ΔF508/ΔF508 mutation may have a deleterious effect on early lung function has been suggested by a study in which infants with CF who had the ΔF508/ΔF508 mutant had significantly higher airflow resistance than did infants with CF who had other mutations (6).

There is a paucity of PFT data from preschool children with CF (9, 16, 17). Preschool children are too old to be sedated and may be too young to perform acceptable FEV1 maneuvers (18). In many centers, preschool children with CF do not receive PFT follow-up until they are able to perform reproducible forced expiratory maneuvers. In recent years, however, PFTs that do not require active cooperation, such as the interrupter technique, have been evaluated for estimating airflow resistance in preschool children. We recently reported expiratory interrupter resistance (Rintexp) values in healthy white preschool children (19).

The aim of the present multicenter study was to perform PFTs that do not require active cooperation in preschool children with CF and in healthy control children. We measured functional residual capacity (FRC), using the helium dilution method, and Rintexp in children with CF and in control children. The effect of a short-acting bronchodilator on Rintexp was compared in both groups. In addition, we examined whether PFT data were correlated with factors that may affect the severity of PFT alterations, such as a history of meconium ileus (20), exposure to passive smoke (21, 22), and genotype (1, 6, 10, 23).

Subjects

The control group was comprised of 79 healthy, white preschool children in the 90- to 130-cm height range who were included in a previously reported French multicenter study (19). The study design has been described elsewhere (19), and additional detail is provided in the online data supplement. The patients were 40 white preschool outpatients recruited at CF clinics, with freedom from acute respiratory symptoms during the previous 4 weeks as the only exclusion criterion. Passive smoking was not an exclusion criterion. Physical examination, including height and weight measurements, was performed on the day of the study. In children with CF, we recorded CF transmembrane conductance regulator gene mutations, circumstances of the diagnosis, pancreatic insufficiency, CF-related respiratory symptoms and, if present, the history of respiratory infections, intravenous antibiotics used, and antiasthma treatments. Exposure to passive smoke was recorded in all participants. The study was approved by the local ethics committees, and written informed consent was obtained from both the parents of each child.

Procedures

All children with CF had a chest physiotherapy session 1 to 2 hours before PFT, and the short-acting bronchodilator therapy was withheld for at least 8 hours. Pulse oximetry was recorded (Nellcor N-200, Hayward, CA) in children with CF. FRC was measured using the helium dilution method as the mean of two measurements differing by less than 10%.

The conditions and validation of Rintexp measurements have been described previously (19). All centers used the same apparatus (Spiroteq apparatus; Dyn'R Ltd, Toulouse, France). Linear-back extrapolation of mouth pressure was used to estimate alveolar pressure for Rintexp calculation. Seven Rintexp measurements with an intrasubject coefficient of variation (CV) smaller than 20% were validated. The 20% limit for acceptance was chosen because it was equal to the mean baseline Rintexp CV plus two SD values (19). Mean Rintexp was calculated at baseline and 10 minutes after bronchodilator administration (200 μg of salbutamol, administered using a metered-dose inhaler and a spacer; Volumatic, Glaxo, Badoldesloe, Germany). Specific expiratory interrupter conductance (sGintexp) was the ratio of expiratory interrupter conductance over FRC. Data collection was performed as previously reported (19).

Statistical Analysis

Data were expressed as frequencies (percentages) for categorical variables and as mean (± SD) or as median (interquartile range [IQR]) values for normally and non-normally distributed continuous variables, respectively. Normality plots were constructed to check that assumptions of normality were met. Comparisons between groups used the chi-square or Fisher exact test, as appropriate, for categorical variables and the Student's t test or Wilcoxon test, as appropriate, for continuous variables. Z-scores of height, weight, and body mass index adjusted for age and sex were computed using Sempe tables (24). Stepwise, multiple linear regression was performed to identify significant correlations linking standing height, weight, age, sex, and exposure to passive smoking to FRC in control children. The residual SD (RSD) of the best equation was calculated and used to compute Z-scores ([measured value − fitted mean]/[fitted SD]) in children with CF (12). Z-scores for Rintexp were computed using a previously published equation (19).

Additional details on the methods are provided in the online data supplement.

Subjects

Among the 40 children with CF, 1 was unable to perform a satisfactory second FRC maneuver and was excluded. The other 39 children with CF performed the baseline Rintexp measurement, and 38 performed the postbronchodilator Rintexp measurement. Table 1

TABLE 1. Description of the study population




Healthy (n = 79)

Cystic Fibrosis (n = 39)
Girls/Boys39/4015/24
Age, yr 5.3 ± 1.4 (3–7.9) 5.2 ± 1.4 (3–8.2)
Height, cm112 ± 9.2 (92–129)107 ± 8.7* (90–127)
Height Z-score1.41 ± 1.16 (−0.93–3.85)0.47 ± 1.40 (−1.84–4.61)
Weight, kg19.7 ± 3.6 (12–29)18.2 ± 4* (12–34)
Weight Z-score0.95 ± 1.17 (−1.75–3.19)0.34 ± 1.45* (−1.73–4.20)
BMI15.5 ± 1.2 (12.8–18.8)15.6 ± 1.5 (13.4–21.1)
BMI Z-score
−0.11 ± 1.08 to (−2.79–2.65)
−0.06 ± 1.22 (−2.15–3.82)

*p < 0.02.

p < 0.001.

Definition of abbreviations: BMI = body mass index.

Results are shown as means ± SD and (range). Values were significantly lower in children with cystic fibrosis than in healthy control children.

reports anthropometric data in children with CF and in healthy control children. Height, height Z-score, weight, and weight Z-score (Table 1) were significantly lower in children with CF than in control children (p < 0.02). Z-scores for weight and body mass index were not significantly different between children with CF, with or without CF-related respiratory symptoms (Table 2)

TABLE 2. Clinical characteristics of the cystic fibrosis population




Homozygous ΔF508
 (n = 16)

Heterozygous ΔF508
 (n = 14)

No ΔF508
 (n = 8)
Circumstances of diagnosis
Neonatal screening612
Familial history021
Respiratory symptoms864
Digestive symptoms (except meconium ileus)310
Meconium ileus133
Failure to thrive353
Clinical status at the time of the study
Respiratory symptoms*14116
Age of onset, yr0.5 (0.3–0.9)0.2 (0.2–0.4)0.4 (0.3–0.4)
Pancreatic insufficiency16146
Chronic Pseudomonas aeruginosa colonization 451
Passive smoking
5
2
1

*History of cystic fibrosis–related respiratory symptoms.

Age at onset of respiratory symptoms, median (interquartile range).

Number of children with cystic fibrosis who had chronic P. aeruginosa colonization among the children with CF and with respiratory symptoms.

Information on molecular biology not available for one patient.

. Table 2 reports the clinical data of children with CF, including CF transmembrane conductance regulator gene mutations, the circumstances of diagnosis, and the clinical status at the time of the study. Among these children, 41% were homozygous and 36% compound heterozygous for the ΔF508 mutation. Ninety-five percent of children with CF had pancreatic insufficiency. Thirty-one children had CF-related respiratory symptoms that had started at a median age of 0.4 years (IQR, 0.2–0.5). Among them, 14 had a history of intravenous antibiotic therapy, 10 had chronic Pseudomonas aeruginosa colonization, 9 used inhaled short-acting bronchodilator therapy, and 7 of these 9 also used inhaled corticosteroid therapy.

PFT Data

Pulse oximetry. Arterial oxygen saturation (mean ± SD) was 97 ± 2% (range, 94–100%) at baseline in children with CF. Three children with CF had an oxyhemoglobin saturation of 94%.

FRC measurements.

The regression equation for FRC versus height (H) in healthy children was − 0.517 (SE = 0.208) + 0.012 (SE = 0.002) × H (cm) (RSD = 0.151). There was no effect of center or sex on FRC values in healthy children. Figure 1

shows the relationship between FRC and patient height. Mean (± SD) baseline FRC and FRC Z-score values in healthy control children and in children with CF are shown in Table 3

TABLE 3. Comparison of pulmonary function test results at baseline between healthy control children and children with cystic fibrosis




Healthy
 (n = 79)

Cystic Fibrosis
 (n = 39)
FRC (l)0.84 ± 0.190.83 ± 0.25
Z-score FRC0.00 ± 1.000.34 ± 1.27
Rintexp, (kPa · L−1 · s)0.80 ± 0.201.05 ± 0.36*
Z-score Rintexp0.19 ± 0.971.31 ± 1.72*
Gintexp, (L · kPa−1 · s−1)1.33 ± 0.341.04 ± 0.27*
sGintexp, (kPa−1 · s−1)
1.63 ± 0.43
1.29 ± 0.34*

*Children with cystic fibrosis were significantly different from healthy control children, p < 0.0001.

Definition of abbreviations: FRC = functional residual capacity; Gintexp = expiratory interrupter conductance; Rintexp = expiratory interrupter resistance; sGintexp = specific expiratory interrupter conductance.

Results are shown as mean ± SD.

. FRC and FRC Z-score values were not different between healthy control children and children with CF.

Baseline Rintexp values.

Figure 2

shows the relationship between Rintexp and height in patients with CF. Mean (± SD) Rintexp, Rintexp Z-score, expiratory interrupter conductance, and sGintexp values in healthy children are reported in Table 3. There was no effect of center or sex on these PFT data in healthy children. Neither absolute Rintexp values nor Rintexp Z-scores were significantly different between healthy control children who were (n = 26) and were not (n = 53) exposed to passive smoke.

Children with CF had significantly higher Rintexp (Figure 2 and Table 3) and Rintexp Z-score values (Table 3) than did healthy children (p < 0.0001). Nine (23%) children with CF had a baseline Rintexp Z-score greater than 2. The intrasubject CV of Rintexp was not significantly different between healthy control children and children with CF. As shown in Table 3, expiratory interrupter conductance and sGintexp were significantly decreased in children with CF when compared with healthy control children (p < 0.0001). No effect of sex was observed for Rintexp, expiratory interrupter conductance, or sGintexp in children with CF.

Postbronchodilator Rintexp values.

In control children, the Rintexp CV was significantly higher after bronchodilator inhalation than before inhalation (Table 4)

TABLE 4. Pre- and postbronchodilator expiratory interrupter resistance measurements



Rintexp (kPa · L−1 · s)

Rintexp Z-score

CV (%)

B
BD
BD − B
BD − B%
B
BD
BD − B
B
BD
Healthy children
Mean ± SD0.80 ± 0.200.70* ± 0.19−0.09 ± 0.14−12.4 ± 18.60.19 ± 0.97−0.36 ± 0.91−0.52 ± 0.7812 ± 3.514.2 ± 4.8
Children with CF
Mean ± SD
1.05 ± 0.36
0.91* ± 0.31
−0.14 ± 0.22
−16.5 ± 25.6
1.31 ± 1.72
0.53* ± 1.47
−0.77 ± 1.22
11.9 ± 3.6
12.1 ± 3.5

*p < 0.001.

p < 0.0001.

BD CV greater than B CV in healthy control children; p < 0.02.

Definition of abbreviations: B = baseline; BD = values after bronchodilator administration; BD − B% = effect of BD as a percentage of the predicted value; CF = cystic fibrosis; CV = intrasubject coefficient of variation; Rintexp = expiratory interrupter ressistance.

BD values were different from B values.

. Rintexp decreased significantly after bronchodilator inhalation in both children with CF and in healthy control children (Table 4). The effect of the bronchodilator was not significantly different between the CF and control groups. In three children with CF, the postbronchodilator Rintexp increase was more than twice the mean baseline CV for Rintexp (Table 4).

Relationships between PFT Data and Clinical Characteristics in Children with CF

Patients with a history of CF-related respiratory symptoms (n = 31) had significantly higher FRC Z-score and lower sGintexp values than did children with CF and without respiratory symptoms (n = 8) (median [IQR] FRC Z-score, 0.3 [−0.3 to 1.2] versus −0.5 [−1.1 to −0.2]; p < 0.02; sGintexp, 1.18 [1–1.52] versus 1.50 [1.35–1.62]; p < 0.04, respectively).

The eight children with CF who were exposed to passive smoke had higher baseline Rintexp Z-score values when compared with the other 31 children with CF (median [IQR] Rintexp Z-score, 2.4 [0.8–3.5] versus 0.6 [0–1.7]; p < 0.03). No significant relationships were found between PFT data and genotype in children with CF. There was a trend toward higher Rintexp Z-score values in children with CF who were homozygous for ΔF508 when compared with the other children with CF (median [IQR] Rintexp Z-score, 1.5 [0.4–2.7] versus 0.5 [0–1.5]; p = 0.08). However, an analysis of the influence of genotype and passive smoking on Rintexp Z-score values showed that passive smoking was the main risk factor for having a Rintexp Z-score value greater than 2 (odds ratio, 9.5; p < 0.03 by the Mantel–Haenzel test). The seven children with CF with a history of meconium ileus had lower Rintexp Z-score values than did the other children with CF (median [IQR] Rintexp Z-score, 0 [−0.2 to 0.3] versus 1.3 [0.4–2.1]; p < 0.01).

PFT data were not significantly different between children with CF, with (n = 10) and without (n = 29) chronic P. aeroginosa colonization. PFT results in children with CF were not related to the history of intravenous antibiotic therapy or inhaled antiasthma medications. Finally, genotype, clinical characteristics at the time of the study (Table 2), and treatments had no influence on the effect of bronchodilator inhalation on Rintexp in children with CF.

The aim of the present multicenter study was to obtain PFT data in preschool children with CF and in healthy control children using methods that do not require active cooperation of the child. Among the 39 children with CF who were tested, 21% had never had respiratory symptoms related to the disease. Children with CF had significantly higher Rintexp and Rintexp Z-score values and significantly lower sGintexp values than did control children. Significant relationships were found between some of the clinical characteristics and the PFT data. Thus, children with CF and with CF-related respiratory symptoms had significantly higher FRC Z-score values and lower sGint values than did children with CF and without respiratory symptoms. Exposure to passive smoke was significantly associated with higher Rintexp Z-scores. Genotype did not influence PFT data. The effect of a bronchodilator was neither significantly different between children with CF and control children nor significantly related to the clinical characteristics in CF.

Measurement Methods and PFT Data in Healthy Control Children

All the centers used the same standardized procedure for PFT measurements and data collection (19). We included 79 of the 90 healthy preschool children from our previous study (19) as the control group because these 79 control children performed both FRC and Rintexp at baseline. The preschool children who comprised the control group had positive Z-scores for height and weight, presumably because the nutritional status of French children has improved over the two decades that have elapsed since the normative data were published (24). The equation linking FRC to height that we established in the present study was not significantly different from previously reported equations in healthy control children within the same age range (Student's t test on regression coefficients) (25, 26). To calculate the predicted Rintexp values, we used the equation of Rintexp according to the height that we previously established in the 90 preschool children. (19). PFT data were expressed as Z-scores (12, 27) because stature was smaller in children with CF than in control children. Nevertheless, the choice of the reference population, and consequently, of the reference equation may have an effect on lung function assessment in patients with CF (28).

PFT Data in Children with CF

The present study provides a snapshot of pulmonary function in a group of 39 preschool children with CF who are undergoing PFTs for the first time. Most of the children with CF were able to complete the PFTs. Interestingly, the baseline CV for Rintexp in children with CF was not significantly different from that in healthy control children. Studies of expiratory flows measured using forced expiratory maneuvers have shown greater variability in older children with CF than in control children (29, 30). Methods not requiring active cooperation may result in less variability data in patients with CF.

We found significantly higher Rintexp and lower sGintexp values in the CF group than in the control group. Little PFT data regarding preschool children with CF are available. Godfrey and coworkers (16) found abnormalities in radioisotopic lung function tests in five children with CF studied at 5 years of age. Beardsmore (9) compared PFT data expressed as Z-scores in 29 patients with CF tested twice, at 6 months and at 5 years 10 months of age. Lung function worsened significantly between the two time points (9). Finally, Waters and coworkers (17) followed patients with CF from birth. By 5 years of age, mean FEV1, expressed as the percent of predicted values in patients who could perform forced expiratory maneuvers, was greater than 90%. Taken together, our data and those published by others suggest that lung function may be abnormal by preschool age in children with CF. We found that airflow resistance, as assessed by Rintexp measurement, was significantly increased in preschool children with CF when compared with that in control children. However, airway obstruction was assessed by Rintexp, which depends on the proximal airways. It would have been useful to explore the peripheral airways by measuring expiratory flows at low volume on a partial expiratory flow–volume curve (31). Furthermore, the multiple breath washout of inert gases technique appears to have great potential for the detection of early CF lung function abnormalities. School-age children with CF and with normal FEV1 values have been reported to have elevations in the mixing ratio and lung clearance index (32). Such data have not been reported in young children with CF.

We previously reported the effect of bronchodilator administration on Rintexp in healthy preschool children (19). No studies have evaluated the effect of a bronchodilator in preschool children with CF. In our study, a short-acting bronchodilator had an effect of similar magnitude both in preschool children with CF and in control children. A total of 3 of 38 patients had an Rintexp increase that was greater than twice the CV of the baseline Rintexp value, suggesting a paradoxical response to bronchodilator inhalation. Paradoxical expiratory flow responses to bronchodilator inhalation have been reported in school children with CF and probably indicate increased airway collapsibility after bronchodilator administration (33, 34).

Relationship between Clinical and PFT Data in Preschool Children with CF

Seventy-nine percent of our children with CF had respiratory symptoms that started during the first year of life. This subgroup had significantly higher FRC Z-score and lower sGintexp values than children with CF and without CF-related respiratory symptoms. These findings are in agreement with other studies in which lung function impairment was more severe in infants with than without CF-related respiratory symptoms (4, 7).

The effect of exposure to passive smoke has been examined previously in school children with CF (21, 22). In the present study, the Rintexp Z-score was significantly higher in children with CF who were exposed to passive smoke than in other children with CF, whereas no difference in Rintexp Z-score was found between exposed and nonexposed control children. Thus, our data indicate an association between exposure to passive smoke and airway obstruction in preschool children with CF.

Few studies have examined relationships between genotype and lung function impairment in infants (6, 10, 14) or school children (1, 23) with CF. The subgroup of ΔF508 homozygotes showed a trend toward a higher Rintexp Z-score when compared with that in other patients with CF in our study. However, when we analyzed the influence of genotype and passive smoking on Rintexp Z-score values, we found that passive smoking was the main risk factor for having a Rintexp Z-score greater than 2. Nevertheless, the sample size of children with CF and with Rintexp Z-scores greater than 2 was too small to allow multivariable regression analysis. Previous studies found either positive or negative relationships between genotype and PFT impairment. Respiratory resistance was significantly higher in infants with ΔF508 deletion than in those with other genotypic variants (6). Infants with CF and with the heterozygote 3905insT mutation had more severe hyperinflation than did other infants with CF (10). A recent study found no significant correlations between genotype and PFT abnormalities in infants with CF (14). Two studies found opposite results on the relationship between genotype and lung function deterioration in late childhood and adolescence (1, 23).

More severe pulmonary function alterations in patients with a history of meconium ileus have been found in 9-year-old children with CF (20) but not in infants with CF (4). In our study, Rintexp Z-score values were lower in the seven children with a history of meconium ileus than in the other children with CF. PFTs in the preschool children with CF were not influenced by any of the other clinical characteristics.

In summary, given that many centers do not use PFT follow-up in preschool children with CF who are not yet able to perform reproducible forced expiratory maneuvers, earlier follow-up during the transition period from infancy to school age could be achieved by using PFTs that do not require active cooperation. Further studies are needed to determine whether this can improve the management of preschool patients with CF and provide useful data for therapeutic trials.

The authors are grateful to the physicians who participated in the study: H. Trang, A. Bernard, A. Munck, and M. Gérardin (Robert Debré Teaching Hospital, Paris), M. Voisin and F. Couwil (Arnaud de Villeneuve Teaching Hospital, Montpellier), Y. Grossi and D. Sarni (Morvan Teaching Hospital, Brest), J.L. Iniguez (Saint-Vincent-de-Paul Teaching Hospital, Paris), V. Diaz (Poitiers Teaching Hospital, Poitiers), E. Cixous (Calmette Teaching Hospital, Lille), and B. Wuyam, C. Pilenko-Mc Guigan, and H. Bensaïdane (Grenoble Teaching Hospital, Grenoble). For their technical assistance, the authors thank S. Benjamaa, M. Pisica, F. Dubois, and J. C. Sismeiro (Robert Debré Teaching Hospital, Paris), V. Alibert (Arnaud de Villeneuve Teaching Hospital, Montpellier), M. N. Guiffaut (Morvan Teaching Hospital, Brest), C. Lebeau and A. Roche (Saint-Vincent-de-Paul Teaching Hospital, Paris), M. C. Mathlin (Calmette Teaching Hospital, Lille), M. Guyard, B. Julien, and M. Trochu (Grenoble Teaching Hospital, Grenoble, France). The authors are also thankful to P. Le Corre (Dyn'R Ltd, Toulouse) for assistance with the computer program, and to F. Zerah and A. Harf (Henri Mondor Teaching Hospital, Créteil) for their advice during the preparation of the grant application. The authors are especially indebted to the parents and children who participated in the study.

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Correspondence and requests for reprints should be addressed to Claude Gaultier, Service de Physiologie, Hopital Robert Debré, 48 Bd Serurier, 75019, Paris, France. E-mail:

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