Abstract
Pulmonary function tests are seldom performed in preschool children with asthma. The aim of this multicenter study was to compare pulmonary function in 74 preschool children with asthma (height of 90–130 cm) and 84 healthy control subjects. Functional residual capacity (helium dilution technique) and expiratory interrupter resistance (interrupter technique) were measured. As compared with control children, children with asthma had a significantly higher resistance (0.77 ± 0.20 vs. 0.92 ± 0.22 kPa · L−1 · second, p < 0.001) and significantly lower specific expiratory interrupter conductance (p < 0.005) values. Resistance values were significantly higher in children with asthma with than without symptoms on exertion (p < 0.05). The effect of bronchodilator administration, expressed as the percentage of baseline and predicted resistance values, was significantly greater in children with asthma than in control subjects (−18.6 ± 13.6% vs. −11.2 ± 15.2%, p ⩽ 0.001, and −23.2 ± 19.2% vs. −12.6 ± 17.8%, p < 0.001), respectively. A 35% decrease in resistance after bronchodilation expressed as the percentage of predicted values had a likelihood ratio of 3 for separating the bronchodilator response in children with asthma from that in healthy control subjects. Pulmonary function tests that do not require active cooperation may help in the management and follow-up of preschool children with asthma who are unable to perform forced expiratory maneuvers.
The incidence of pediatric asthma is increasing in most countries (1). Pulmonary function tests (PFTs) are used to determine asthma severity, along with clinical symptoms and medication requirements (2). Normal lung function is one of the goals of asthma management in international guidelines (3, 4). Furthermore, long-term cohort studies have established that PFT results in children with asthma are correlated with asthma severity and with pulmonary function impairment in adulthood (5).
Forced expiratory maneuvers are used in school children and in adults. However, preschool children may be too young to perform acceptable and reproducible forced expiratory maneuvers (6). As a result, PFTs are seldom performed in clinical practice in preschool children with asthma.
In recent years, PFTs that do not require active cooperation, such as the interrupter technique or the forced oscillation technique, have been evaluated for estimating airflow resistance in healthy (7–10) and in preschool children who have asthma or who are wheezing (9, 11–14). We recently reported prebronchodilator and postbronchodilator expiratory interrupter resistance (Rintexp) values in healthy preschool children (15) and then used these normative data to study preschool children with respiratory disorders (16).
The aim of this multicenter study in preschool children with asthma was to evaluate pulmonary function using tests that do not require active cooperation. We measured FRC using the helium dilution technique and Rintexp before and after administration of a short-acting bronchodilator. We determined whether PFT data were correlated with the clinical characteristics of asthma. Furthermore, we evaluated the bronchodilator response threshold that may separate children with asthma from healthy control children.
The study was part of a multicenter investigation whose design has been described elsewhere (15) (additional detail is provided in the online supplement). The control subjects were 91 healthy white preschool children in the 90- to 130-cm height range included in a previously reported French multicenter study (15). The patients were 77 white preschool outpatients with a medical diagnosis of asthma. The diagnosis was based on typical asthma symptoms such as recurrent wheeze and breathlessness resolving spontaneously or with an inhaled bronchodilator. The only exclusion criterion was the presence of an acute exacerbation, defined as asthma symptoms requiring oral corticosteroids, an emergency visit, or hospitalization during the last 4 weeks. Physical examination, including height and weight measurements, was performed on the day of the study. In the children with asthma, we recorded age at onset of symptoms, history of atopy and of hospitalization, frequency and circumstances of symptoms, asthma-related absences from school, and antiasthma treatments in the last year. Exposure to environmental tobacco smoke was recorded in all participants. None of the study children with asthma had had PFTs previously. The study was approved by the local ethical committees, and written informed consent was obtained from both parents of each child.
Short-acting bronchodilator therapy was withheld for at least 8 hours and long-acting bronchodilator therapy for at least 24 hours. Pulse oximetry was recorded (Nellcor N-200, Hayward, CA) in the children with asthma. FRC was measured using the helium dilution method as the mean of two measurements differing by less than 10%, as previously described (16). The conditions and validation of Rintexp measurements have been described previously (15). Briefly, the flow signal used to calculate Rint was obtained just before the interruption. Linear–back extrapolation of mouth pressure was used to estimate alveolar pressure for Rintexp calculation. Seven Rintexp measurements with an intrasubject coefficient of variation that was smaller than 20% were validated. The 20% limit for acceptance was chosen because it was equal to the mean baseline Rintexp coefficient of variation plus 2 SDs (15). Specific expiratory interrupter conductance was the ratio of expiratory interrupter conductance over FRC (sGintexp). Data collection was performed as previously reported (15).
The 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). The effects of the bronchodilator were presented in three ways: (1) as raw data, (2) as the percentage of the baseline Rintexp values (prebronchodilator values), and (3) as the percentage of the predicted Rintexp values.
Data were expressed as frequencies (percentages) for categorical variables and as means ± SD or medians (interquartile range) for normally and nonnormally 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's exact test, as appropriate, for categorical variables and the Student's or Wilcoxon test, as appropriate, for continuous variables. Correlations between quantitative variables were studied by the Spearman correlation coefficient. Receiver-operating characteristic (ROC) curves for the bronchodilator effect expressed as the percentages of baseline and predicted values were generated to assess diagnostic performance. The comparison between ROC curves was performed with the Mann-Whitney U–statistic (17). The likelihood ratios (sensitivity/1− specificity) were calculated (18).
Eighty-four of the 91 healthy children completed the baseline and postbronchodilator Rintexp measurements. Among the 77 children with asthma, 2 were excluded by the coordinating center because they had fewer than seven validated Rint measurements at baseline, and another was excluded because the coefficient of variation was more than 20% at baseline. The 74 other children with asthma performed the baseline and postbronchodilator Rintexp measurements. Table 1
Healthy Subjects (n = 84) | Patients with Asthma (n = 74) | |
|---|---|---|
| Girls/boys | 42/42 | 24/50* |
| Age, yr | 5.3 ± 1.4 (2.9–7.9) | 5.2 ± 1.2 (3.2–7.8) |
| Height, cm | 111.7 ± 9.1 (92–129) | 110.7 ± 8.6 (92–130) |
| Weight, kg | 19.3 ± 3.6 (12–29) | 19.5 ± 3.8 (13–28) |
| BMI, kg/m2 | 15.4 ± 1.3 (11.6–18.8) | 15.7 ± 1.5 (12.6–19.4) |
| Passive smoke, n
(%) | 28 (33) | 30 (40.5) |
Children with Asthma (n = 74) | |
|---|---|
| Median (range) or n (%) | |
| Asthma | |
| Age at onset, yr | 1.9 (0.2–6) |
| Disease duration, yr | 3.05 (0.3–6.8) |
| Previous hospitalization | 30 (40.5) |
| Atopy* | 48 (64.9) |
| In the last year | |
| Attack(s) of asthma | |
| ⩾ 1 in the last yr | 63 (85.1) |
| ⩾ 1 in the last wk | 2 (2.7) |
| Hospitalization for an attack | 11 (14.8) |
| Frequency of symptoms (excluding symptoms on exertion) | |
| ⩾ 1/d | 0 |
| ⩾ 1/wk | 5 (6.7) |
| ⩾ 1/mo | 18 (24) |
| < 1/mo | 49 (66.2) |
| At night | 41 (55.4) |
| Symptoms on exertion | 32 (43.2) |
| Preschool missed | 40 (54) |
| Number of days | 11.6 ± 9.3 |
| Daily antiasthmatic treatment | 70 (95) |
| Inhaled bronchodilator | 30 (40.5) |
| Inhaled steroids | 63 (85.1) |
SaO2 (mean ± SD) was 98 ± 1% (range, 95–100%) at baseline in the children with asthma.
Mean ± SD baseline FRC values in the healthy control subjects and children with asthma are shown in Table 3
Healthy | With Asthma | |
|---|---|---|
| (n = 84) | (n = 74) | |
| FRC, L | 0.82 ± 0.20 | 0.80 ± 0.26 |
| FRC, % predicted | 99 ± 19 | 98 ± 24 |
| Rintexp, kPa · L−1 · s | 0.77 ± 0.20 | 0.92 ± 0.22* |
| Rintexp, % predicted | 101 ± 22 | 118 ± 23† |
| sGintexp | 1.74 ± 0.55 | 1.50 ± 0.46‡ |
Mean ± SD Rintexp and sGintexp values in the healthy children are reported in Table 3. There was no effect of center or sex on these PFT data in healthy children. Figure 1
Figure 1. Individual expiratory interrupter resistance (Rintexp) measurements in children with asthma (closed circle, boys; open circle, girls) related to regression lines (solid lines) and 95% confidence limits (dotted lines) for healthy children.
[More] [Minimize]The children with asthma had significantly higher Rintexp (Figure 1 and Table 3) values than did the healthy children (p < 0.001), with 15% having values greater than the 95% confidence interval. The intrasubject coefficient of variation of Rintexp was not significantly different between the healthy control subjects and children with asthma (Table 4)
Rintexp BD (kPa · L−1 · s) | Rintexp BD%P | BD-B (kPa · L−1 · s) | BD-B%B | BD-B%P | CV%B | CV%BD | |
|---|---|---|---|---|---|---|---|
| Healthy | |||||||
| Mean ± SD | 0.68 ± 0.18* | 88.4 ± 19.6 | −0.10 ± 0.14 | −11.2 ± 15.2 | −12.6 ± 17.8 | 12.2 ± 3.4 | 14.0 ± 4.9§ |
| Asthma | |||||||
| Mean ± SD | 0.74 ± 0.18*,† | 94.8 ± 19† | −0.18 ± 0.15‡ | −18.6 ± 13.6‡ | −23.2 ± 19.2‡ | 11.7 ± 3.9 | 12.2 ± 3.4 |
Rintexp decreased significantly after bronchodilator inhalation in both the children with asthma and the healthy control subjects (p < 0.03; Table 4). The effect of the bronchodilator was greater in the group with asthma whether the response was expressed as the percentage of baseline Rintexp values or as the percentage of predicted Rintexp values (p ⩽ 0.001) (Table 4). These differences persisted after exclusion of the 15% of children with asthma with significantly abnormal baseline Rintexp values (p < 0.03). The postbronchodilator Rintexp values were significantly higher in the group with asthma than in the control group (Table 4). Furthermore, children with asthma with abnormal baseline Rintexp had higher postbronchodilator values expressed as the percentage of predicted than those with baseline Rintexp values in the normal range (median [interquartile range] 103% [90%−137%] vs. 90% [78–103%], p < 0.03). In both the control group and the group with asthma, the bronchodilator response expressed as the percentage of baseline Rintexp values was significantly correlated with absolute baseline Rintexp (r = −0.24, p < 0.04, and r = −0.24, p < 0.05, respectively) and with baseline Rintexp expressed as the percentage of predicted Rintexp (r = −0.29, p < 0.008, and r = −0.37, p < 0.002, respectively); in addition, the bronchodilator response expressed as the percentage of predicted Rintexp was significantly correlated with baseline Rintexp values expressed as the percentage of predicted Rintexp (r = −0.37, p < 0.001, and r = −0.55, p < 0.001, respectively). In the control group and group with asthma, the distribution of bronchodilator responses was unimodal, and marked overlap occurred between the two populations (Figure 2)
Figure 2. Relative frequency distribution of bronchodilator response expressed as the percentage of predicted Rintexp values in children with asthma and healthy control children (open bars, children with asthma; slashed bars, healthy children).
[More] [Minimize]Effect of BD, % predicted | −20 | −25 | −30 | −35 | −40 | −50 |
|---|---|---|---|---|---|---|
| Specificity | 69 | 76 | 86 | 92 | 93 | 96 |
| Sensitivity | 54 | 38 | 34 | 24 | 19 | 9 |
Children with asthma with symptoms on exertion had significantly higher Rintexp values at baseline (Rintexp 1.00 ± 0.23 kPa · L−1 · s vs. 0.86 ± 0.18 kPa · L−1 · s, p < 0.005; corresponding to median values [interquartile range] 123% [107–140%] vs. 110% [96–120%] of predicted; p < 0.02) and significantly higher postbronchodilator Rintexp values (Rintexp 0.79 ± 0.17 kPa · L−1 · s vs. 0.70 ± 0.18 kPa · L−1 · s; p < 0.03; corresponding to median values [interquartile range] of 96% [87–104%] vs. 87% [77–106%] of predicted, p < 0.05) than did the children with asthma without symptoms on exertion (Table 2).
The aim of this multicenter study was to compare PFT data in preschool children with asthma and healthy control subjects using methods that do not require active cooperation of the child. Children with asthma had significantly higher Rintexp and lower sGintexp values than did the healthy control children. Baseline Rintexp and postbronchodilator Rintexp values were significantly higher in the children with asthma with than without symptoms on exertion. The effect of short-acting bronchodilator inhalation, expressed as the percentages of baseline and predicted Rintexp values, was significantly greater in the children with asthma than in the control children. A 35% decrease in Rintexp expressed as the percentage of the predicted values had a likelihood ratio of 3 for separating the bronchodilator response in children with asthma from that in healthy control subjects.
All of the centers used the same standardized procedure for PFT measurements and data collection (15). Of the 91 healthy preschool children in our previous study (15), we included the 84 in whom both pre- and post-Rintexp measurements were obtained. To calculate the predicted FRC and Rintexp values, we used the equations of FRC and Rintexp according to height that we had established previously in healthy preschool children (15, 16). Rintexp was not measured after placebo administration in the healthy preschool children. Previous studies have reported little or no change after placebo in either resistance at 5 Hz measured using the oscillation technique (Rrs5) or Rint in healthy preschool children (9, 10, 13). Our study is in line with previous studies in healthy subjects showing a reduction in bronchial tone after bronchodilator administration in healthy infants (19), preschool children (9, 10, 13), school-age children (20–22), and adults (23). The distribution of the bronchodilator effect on Rintexp was continuous and unimodal (Figure 2) in the healthy children in our study, as was FEV1 in a large group of healthy subjects (23). The wide variability of the bronchodilator response in healthy subjects (9, 15, 23) may be due to differences in environmental conditions and/or in genetic make-up (24).
All of the children with asthma had baseline SaO2 values that were more than 95%, and their FRC values were within the range of those in the control children. The baseline coefficient of variation of Rintexp in the children with asthma was not significantly different from that in the healthy control children. The children with asthma had higher Rintexp and lower sGintexp values than did the control subjects. However, only 15% of the children with asthma had baseline Rintexp values above the 95% confidence interval of Rintexp in the healthy control subjects. Rintexp values were significantly higher in the children with asthma with than without symptoms on exertion.
Few comparisons of PFT data in children with asthma and control preschool children are available. Hellinckx and coworkers found that Rrs5 was within the normal range in 34 preschool children with asthma, half of whom were on asthma medications (9). Nielsen and Bisgaard collected PFT data in 55 preschool children with asthma, including 73% on inhaled steroid therapy (13), and found higher specific airway resistance, Rrs5, and Rint in the children with asthma than in the control children. However, they performed Rint measurements using the opening interrupter method, in which the pressure used for Rint calculation was measured at the end of an 80-ms occlusion and the flow shortly after airway reopening. Rint measured by this method is thought to represent flow resistance plus the resistance of the tissue viscoelastic component of the respiratory system (25, 26). Therefore, Rint values measured by the opening interrupter method are higher than those obtained in this study. Consequently, our Rint data cannot be compared with those reported by Nielsen and Bisgaard (13) in children with asthma.
We found that the effect of bronchodilator inhalation was significantly greater in the children with asthma than in the control children. Nielsen and Bisgaard (13) found a similar difference, whereas Hellinckx and colleagues (9) did not. Differences in asthma severity and asthma treatment may explain these differences in the magnitude of bronchodilator effects in children with asthma. The slightly but significantly higher postbronchodilator values in the group with asthma than in the control group suggest that relaxation of bronchial smooth muscle was less marked in the children with asthma. The bronchodilator was less effective in the children with asthma with abnormal baseline Rintexp who had higher postbronchodilator Rintexp values expressed as the percentage of predicted values than in the children with asthma with normal baseline Rintexp values. Residual obstruction in the children with asthma who were less responsive to the bronchodilator would perhaps have been lifted by a higher bronchodilator dose than used in this study.
There is no consensus on the best way to express the bronchodilator response in children (27). Waalkens and colleagues recommended the percentage of predicted values rather than the percentage of baseline values in a group of children with asthma with relatively severe obstruction as assessed by FEV1 measurements (27). They based this recommendation on their finding that the bronchodilator response as the percentage of baseline was significantly dependent on baseline FEV1, whereas the bronchodilator response as the percentage of predicted was not (27). We studied preschool children with moderately severe asthma, in whom the bronchodilator responses were related to baseline obstruction whether they were expressed as percentage of baseline or as percentage of predicted. Further investigations are needed in preschool children with asthma with more severe obstruction to determine whether the bronchodilator response remains dependent on baseline obstruction when expressed as the percentage of predicted values.
Previous reports in healthy and adults with asthma and school children have shown that reversibility of airway obstruction in response to a bronchodilator is a continuous rather than a dichotomous trait (27, 28). In keeping with these data, we found a marked overlap in bronchodilator responses between the control and the children with asthma groups (Figure 2). This overlap complicates the determination of a cutoff for defining a positive bronchodilator response in patients with respiratory disorders. Various approaches have been proposed for defining a cutoff separating bronchodilator responses in healthy subjects from those in patients (28). One possibility is to consider that bronchodilator responses outside the 95% confidence interval in healthy subjects are abnormal. This definition would identify only seven (9%) of the children with asthma in our study (Table 4). Another approach is to take into account the intrinsic variability of Rintexp measurements, defining a bronchodilator response as abnormal if it exceeds the 95th percentile of the distribution of Rintexp variability (Table 4). In this study, this definition results in overclassification of bronchodilator responses as positive (Figure 2 and Table 5). A third possibility is to calculate the cutoffs from ROC curves. Using the ROC curve for bronchodilator response expressed as the percentage of predicted values, we found that a 35% decrease in Rintexp had high specificity (92%) (Table 5) and a likelihood ratio of 3 for separating bronchodilator responses in children with asthma from those in healthy control subjects. Because only 15% of the children with asthma had abnormal baseline Rintexp values, sensitivity of the 35% cutoff was low. Further studies are needed to evaluate the clinical usefulness of the proposed cutoff.
In summary, PFTs that do not require active cooperation of the child are well accepted by preschool children. They can be used to evaluate baseline pulmonary function and the effect of bronchodilator inhalation. This study provided a snapshot of the use of Rintexp measurements in preschool children with asthma. Longitudinal studies are needed to determine how variables such as baseline Rintexp, postbronchodilator Rintexp, and bronchodilator response correlate with clinical symptoms and disease severity. Furthermore, PFT follow-up would show whether early PFTs improve the management of young children with asthma who are unable to perform reproducible expiratory forced maneuvers.
The authors are grateful to the physicians who participated in the study: H. Trang, A. Bernard, (Robert Debré Teaching Hospital, Paris), M. Voisin, F. Couwil (Arnaud de Villeneuve Teaching Hospital, Montpellier), Y. Grossi, 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), 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, 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, 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). They also thank P. Le Corre (Dyn'R Ltd., Toulouse) for assistance with the computer program and 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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