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Division of Respiratory Medicine, Department of Pediatrics
Department of Epidemiology and Biostatistics, Erasmus University Medical Center/Sophia Children's Hospital
Department of Pediatrics, Medical Center Rijnmond-Zuid, Rotterdam
Department of Pediatrics, Amphia Hospital, Breda
Department of Pediatrics, Groene Hart Hospital, Gouda, The Netherlands
ABSTRACT
The role of inhaled corticosteroids in the treatment of recurrent or persistent wheeze in infancy remains unclear. We evaluated the effect of 3 months of treatment with inhaled fluticasone propionate, 200 e daily (FP200), on lung function and symptom scores in wheezy infants. Moreover, we evaluated whether infants with atopy and/or eczema respond better to FP200 as compared with non-atopic infants. Forced expiratory flow (maxFRC) was measured at baseline and after treatment. Sixty-five infants were randomized to receive FP200 or placebo, and 62 infants (mean age, 11.3 months) completed the study. Mean maxFRC, expressed as a Z score, was significantly below normal at baseline and after treatment in both groups. The change from baseline of maxFRC was not different between the two treatment arms. After 6 weeks of treatment, and not after 13 weeks, the FP200 group had a significantly higher percentage of symptom-free days and a significant reduction in mean daily cough score compared with placebo. Separate analysis of treatment effect in infants with atopy or eczema showed no effect modification. We conclude that in wheezy infants, after 3 months of treatment with fluticasone, there was no improvement in lung function and no reduction in respiratory symptoms compared with placebo.
Key Words: fluticasone propionate infant lung function testing inhaled corticosteroids recurrent wheeze wheezy infants
Recurrent episodes of wheezing are a common problem of early childhood, affecting about 30% of all children aged 0 to 3 years (1eC3). Numerous infants with wheeze are treated with inhaled corticosteroids (ICS), as it is thought that ICS reduce or reverse airway inflammation (4, 5). Moreover, it has been suggested that early introduction of ICS may have a disease-modifying effect and may prevent the development of irreversible airway obstruction (5, 6). However, data from studies determining the effectiveness of inhaled steroids in infants with recurrent wheezing are equivocal (7eC16). Three studies evaluated the effect of fluticasone propionate (FP) on symptom scores in wheezy infants (13, 14, 16). To our knowledge, no study has evaluated the effect of FP in a large group of wheezy infants, using objective end points. As it is known that only a minority of all wheezing infants has asthma (17), it has been suggested that atopic infants are more likely to respond to ICS treatment as compared with nonatopic infants (14, 18).
We aimed to evaluate the effect of FP on lung function and symptom scores in infants with recurrent or persistent wheeze. A secondary aim was to evaluate the treatment effect in subgroups of infants with atopy or eczema.
METHODS
See the online supplement for additional details about the methods used in this study.
Patients
Inclusion criteria were as follows: age, 4eC24 months; and three or more reported wheezing episodes, or at least one period of persistent wheezing longer than 2 months (but not continuously present from birth on). Exclusion criteria included lung disease other than asthma, gastroesophageal reflux, premature birth, and corticosteroid treatment in the month before the start of study. The study was approved by the medical ethics committees of all participating hospitals. All parents gave informed consent.
Study Design
We performed a randomized, double-blind, placebo-controlled study, with a treatment period of 3 months (Figure 1). During the first visit a physical examination was performed and a modified ISAAC (International Study of Asthma and Allergies in Childhood) questionnaire (19) was completed. At the second visit a lung function test was performed. Infants were then stratified for baseline lung function and randomized to receive fluticasone propionate (200 e daily; FP200) or placebo, at an FP200-to-placebo ratio of 2:1. To minimize seasonal influences, infants were randomized in blocks of three (2 FP200:1 placebo). Subjects were allowed to use salbutamol as needed (Ventolin, 100 e). At the fourth visit, lung function measurements were repeated and study medication was stopped.
Lung Function Measurements
Infants were sedated with chloral hydrate. We measured airway resistance by the interrupter technique (Rint), functional residual capacity by means of a whole body plethysmograph (FRCp), and forced expiratory flow at FRC (maxFRC), using the end-tidal rapid thoracoabdominal compression technique. Equipment and procedures were in accordance with previously published guidelines (20eC22). Mean maxFRC and mean FRCp were expressed as Z scores (21, 23).
Symptom Scores
Parents recorded symptoms in the 2 weeks before Visits 2, 3, and 4. The diary card asked for daytime and nocturnal symptoms of dyspnea, cough, and wheeze on a scale from 0 (no symptoms) to 3 (severe symptoms), the number of salbutamol puffs, and cooperation of the child while giving the medication.
Blood Samples
Capillary blood was obtained for determination of total IgE and specific IgE (mixes of house dust mite, cat, and dog; grass and birch pollen; and cow's milk and hen's egg).
Statistics
Power calculations for the primary end point, maxFRC, expressed as a Z score, led to a study size of 60 infants. Secondary end points were the mean percentage of symptom-free days per diary card period; the mean daily total scores of wheeze, dyspnea, and cough; and the mean daily number of salbutamol doses taken. Diary cards with less than 50% of days scored properly were excluded. Other secondary end points were FRCp and Rint. Changes from baseline of lung function parameters were compared by analysis of covariance with adjustment for baseline values. Within-group changes from baseline were evaluated by paired t test. Evaluation of the various diary card data for the two diary card periods during treatment was done by repeated measurements analysis of variance, with adjustment for the outcome at the baseline run-in period. Separate analysis of treatment effect was performed in subgroups of infants with atopy (personal or parental history of asthma, eczema, or hay fever), or infants with eczema. In addition, exploration of baseline patient characteristics regarding the change in maxFRC was performed by univariate analyses. A p value of 0.05 or less was considered significant.
RESULTS
Seventy-five infants were enrolled in the trial. Sixty-five infants were randomized and 62 infants completed the study (Figure 2). Anthropometric data of the total group, and of the two subgroups, are shown in Table 1. The mean (SD) treatment duration for the whole group was 13.2 (1.3) weeks and did not differ between the two study arms. The results of the lung function measurements are shown in Table 2. For the whole group, and for the two treatment groups separately, mean (SD) maxFRC expressed as a Z score was significantly below the mean normal level (Z score = 0) both at baseline and after the treatment period (p < 0.001) (Table 2 and Figure 3). The change from baseline of maxFRC (Z score) did not significantly differ between the FP200 and placebo groups (mean [95% confidence interval, 95% CI] adjusted difference, 0.2 [eC0.3 to 0.6]; p = 0.46). During the treatment period, both groups showed no significant change in mean maxFRC expressed as a Z score (mean [95% CI] change, 0.1 [eC0.2 to 0.4] and 0.1 [eC0.3 to 0.5] for the FP200 group and the placebo group, respectively). Four of 57 diary cards (7%) were not returned in the placebo group, and 7 of 120 diary cards (6%) were not returned in the FP200 group. All returned diary cards were suitable for analysis.
At baseline, the mean percentage of symptom-free days was similar for both the placebo group and the FP200 group (Figure 4). In both treatment groups, there was a significant increase in percentage of symptom-free days from baseline after 6 and 13 weeks of treatment. After 6 weeks of treatment, the mean percentage of symptom-free days adjusted for baseline was significantly higher in the FP200 group as compared with the placebo group (mean [95% CI] difference, 23% [3 to 43%]; p = 0.02). After 13 weeks of treatment, the mean percentage of symptom-free days was similar in both groups (mean [95% CI] adjusted difference, 12% [eC11 to 34%]; p = 0.30). At baseline, the mean daily use of salbutamol was similar for both groups and the changes from baseline were not significantly different within or between groups.
When the mean daily total scores of wheeze, dyspnea, and cough were analyzed separately, there was a significant reduction from baseline during the complete treatment period for all three parameters in the FP200 group (Table 3). In the placebo group there was a significant reduction from baseline only in mean daily cough score at 13 weeks. However, when these reductions from baseline were compared between the two treatment groups, only after 6 weeks of treatment was the mean daily cough score significantly lower in the FP200 group as compared with the placebo group (mean [95% CI] adjusted difference, 0.7 [0.1 to 1.4]; p = 0.03). At baseline, the mean score for nocturnal disturbance due to respiratory symptoms and the degree of infant's cooperation while administering the drug were similar for both groups and the changes from baseline were not significantly different within or between groups. For both treatment groups the reported degree of cooperation was good (mean score, 1; indicating quiet breathing of between 10 and 20 seconds per puff).
When the change from baseline of FRCp and Rint was compared between treatment groups, the adjusted differences of means were not significant (p = 0.65 and 0.38, respectively). In the placebo group Rint showed a significant decrease, whereas in the FP200 group the decrease was not significant. For the whole group there was a significant decrease in Rint during the study (p = 0.01). This is probably the result of increasing age as Rint correlated significantly with age (r = eC0.34, p = 0.007). After adjustment for age, there was no longer any significant difference in Rint before and after treatment in both groups. Tidal breathing parameters (tidal volume, breathing frequency, and minute ventilation per kilogram body weight) were similar for both treatment groups at baseline, and the changes from baseline were not significantly different within or between groups.
Separate analysis of treatment effect on maxFRC (Z score) was performed in subgroups of infants with atopy (defined as personal or parental history of asthma, eczema, or hay fever), and in infants with eczema. In these subgroups there was no evidence of a significant treatment effect (p = 0.77 and p = 0.79, respectively). In further analyses it was found that the presence of elevated total IgE, specific IgE, smoking during pregnancy and/or postnatal environmental tobacco smoke exposure did not affect the results. This conclusion was based on nonsignificant interaction tests.
During treatment, infants in both study arms showed a significant increase in height (mean [95% CI] increase of 3.4 cm [2.9 to 3.9 cm] and 4.1 cm [3.4 to 4.7 cm] in the placebo group and FP200 group, respectively). Canisters were weighed to check compliance and there was no difference in weight reduction between the first 6 weeks and last 7 weeks in either study arm, nor did we find a difference between groups. Nonserious adverse events were not different between groups, with no oral candidiasis. Three infants experienced a serious adverse event, of which none was judged to be related to study medication. Delayed psychomotor development was diagnosed in one infant (in the FP200 group) during the study, and two infants experienced a febrile seizure requiring hospitalization (one in the FP200 group and one in the placebo group).
DISCUSSION
Infants with recurrent or chronic wheeze did not show improved lung function from a 3 months treatment with fluticasone 200 e daily, inhaled via a Babyhaler (GlaxoSmithKline, Brentford, UK). We therefore reject the hypothesis that FP improves lung function in infants with recurrent or persistent wheezing. However, after 6 weeks of treatment, the infants treated with FP200 had a significant improvement in symptom-free days and a significant reduction in mean daily cough score, as compared with placebo. After 13 weeks of treatment, these findings were not different between the study arms. Treatment effect was not modified by the presence of atopy or eczema.
Several studies have evaluated the role of inhaled steroids in the treatment of wheezy infants (7eC16, 24). Only three studies used lung function as an objective end point (11, 12, 24). Kraemer and coworkers (12) studied the combined effect of 300 e of beclomethasone dipropionate (BDP) and 600 e of salbutamol daily (BDP/S) in nine infants with recurrent wheeze. Thoracic gas volume and airway conductance improved after 6 weeks of treatment as compared with the placebo group (n = 6). The small patient numbers and the combined drug make it difficult to estimate the benefit from steroid treatment alone. In a cross-over trial, Maayan and coworkers (24) studied the efficacy of 2 weeks of treatment with 300 e of nebulized BDP in nine infants with persistent wheeze. After treatment with BDP, maxFRC increased, but the difference did not reach significance. From this study duration and small sample size, no conclusions can be drawn. Stick and coworkers (11) evaluated the efficacy of 8 weeks of treatment with 400 e of BDP administered daily via a Volumatic spacer (GlaxoSmithKline) in 38 infants with recurrent wheezing. They found that symptoms improved for both the placebo group and the ICS group, whereas maxFRC improved significantly in the placebo group, but not in the ICS group (11). There are several differences between our study and the study by Stick and coworkers (11). First, we studied a larger number of infants (62 versus 38). Second, the longer treatment period in our study must have been sufficient to show an effect, as a treatment period of 12 weeks showed a reduction in symptom scores (13, 14). Third, we studied FP at half the dose of BDP. A large systematic review (25) concluded that when compared at an FP-to-BDP dose ratio of 1:2, FP treatment produced a greater improvement in lung function as compared with BDP treatment. This applied to all drug doses, age groups (children and adults), and delivery devices. This study suggests that FP is a more potent ICS as compared with BDP (25). If this is also true for infants remains to be elucidated. Nonetheless, this makes our study the first large randomized controlled trial investigating the effect of FP on objective outcome measures in infants.
Three studies evaluated the effect of fluticasone propionate in wheezy infants on the basis of subjective outcome measures (13, 14, 16). They found a significant improvement from baseline in symptom scores, and a lower number of patients with at least one exacerbation during treatment in the FP group as compared with placebo. We found an improvement in symptom scores only after 6 weeks of treatment. An explanation could be that the children in the study by Bisgaard and coworkers were slightly older, with a mean age of 28 months (13). One could speculate that a larger proportion of children above 2 years of age has wheezing related to asthma. Consequently, treatment with ICS could be more effective. In the studies by Chavasse and coworkers (14) and Teper and coworkers (16) only wheezy infants with a history of atopy were included. These infants are known to be at high risk for developing asthma, and therefore inhaled steroids may be more effective. In our study, all infants with recurrent or persistent wheeze were included, irrespective of atopy. After 6 weeks of treatment, but not after 13 weeks, there was a significant improvement in percentage of symptom-free days in the FP200 group. An explanation could be that the reduction in symptoms at 6 weeks in the FP200 group led to a decrease in compliance. However, canisters were weighed to check compliance and we found no difference in weight reduction between the first 6 weeks and last 7 weeks of treatment in the FP200 group, nor did we find a difference between groups. Therefore, differences in compliance cannot explain our results.
Separate analysis of treatment effect in subgroups of infants with atopy or eczema in our study showed no effect modification. This is in contrast to a study by Chavasse and coworkers, showing improvement of clinical symptoms in response to FP in a group of atopic wheezy infants (14). In addition, Roorda and coworkers showed that preschool children (aged 12eC47 months) with recurrent asthma symptoms showed the greatest response to FP treatment if they had frequent symptoms, a family history of asthma, or both (18). Our study does not confirm that atopic infants are more likely to respond to ICS treatment than nonatopic infants.
There are several possible explanations for the lack of a clear effect of FP200 treatment on lung function in our study. First, the majority of infants with wheezing have transient conditions associated with diminished airway function at birth and do not have increased risks of asthma or allergies later in life (17). Infants who have respiratory illnesses with wheezing in the first year of life have lower levels of lung function before any lower respiratory illness develops, compared with infants who do not have illnesses with wheezing (26). This suggests that small airways predispose many infants to wheezing in association with common viral infections (17). The effect of ICS in nonasthmatic viral wheeze is uncertain.
Another explanation could be that our lung function measurements were insensitive to detect ICS effects. Although infant lung function tests have their limitations—especially when airway obstruction is severe—infant lung function test results have been shown to be quite sensitive markers that demonstrate acceptable reproducibility and enough sensitivity to be a useful research tool (20).
Some studies suggest that forced expirations produced by the raised volume rapid thoracoabdominal compression (RVRTC) technique can detect alterations that are missed by forced expirations performed in the tidal volume range (27, 28). Assessing airway patency by means of the RVRTC technique is promising but has not yet proved to be beneficial relative to the RTC technique (29). Furthermore, the RVRTC technique is not standardized because it lacks consensus (20, 30). Although the RTC technique is well accepted and standardized, a disadvantage is that measurement of maxFRC relies on the FRC not changing between forced expirations (31). A decrease in FRC could have masked a response in maxFRC because airway resistance is higher at lower lung volumes (27). We think that the lack of response of maxFRC after ICS treatment cannot be explained by this as FRCp and resistance (Rint) did not change during the study. In addition, maxFRC has proven to be a sensitive parameter for peripheral airway patency in several physiologic, clinical, and epidemiologic investigations (23, 32eC35). On the other hand, lung function measurements are known to correlate poorly with wheezy infant symptoms as scored by the parent (36). It can be argued that a larger effect might be seen in infants with more severe respiratory symptoms. We believe that this is unlikely as the baseline values for maxFRC were significantly below zero for both groups, and at baseline the percentage of symptom-free days was only about 20% for the whole group, suggesting that there was room for improvement. Another possible explanation for the lack of response in maxFRC to FP200 could be an inadequate steroid dose. We consider this unlikely as Bisgaard and coworkers showed that even 100 e of FP daily was effective in reducing asthma symptoms in a large group of young children (13). One might argue that in infants, inadequate drug delivery to the airways explains a lack of response to inhaled medication. However, two studies showed a reduction in symptoms after FP treatment in infants (13) (14), suggesting that the Babyhaler with metered dose inhaler is able to deliver a clinically effective dose of aerosol in infants. Moreover, urinary cortisol measurements indicate that about 8% of the nominal steroid dose is inhaled from the Babyhaler (37). Finally, in our study the inhalation technique was taught according to Janssens and coworkers (38) and was checked regularly. In both study arms the reported cooperation was good. Because there was an effect on symptom scores in the FP200 group after 6 weeks, we believe that inadequate delivery is not a likely explanation for the lack of response in lung function to FP200 in our study.
In summary, although FP200 gave a significant reduction in respiratory symptoms after 6 weeks of treatment compared with placebo, there was no difference in lung function or respiratory symptoms after 13 weeks of treatment between the study arms. We therefore conclude that a 3-month treatment with fluticasone propionate (200 e daily) is not effective in infants with recurrent or chronic wheeze. Further studies are needed to optimally characterize those wheezy infants who will respond to antiinflammatory treatment.
Acknowledgments
The authors thank the parents and the children, Wim Holland (Department of Experimental Medical Instrumentation, Erasmus MC, Rotterdam), and all participating pediatricians of the AIR-study group: Medical Center Rijnmond Zuid, Rotterdam: Dr. F. J. Smit. Amphia Hospital, Breda: Dr. A. A. P. H. Vaessen-Verberne. A. Schweitzer Hospital, Dordrecht: Dr. R. Schornagel. R. de Graaf Gasthuis, Delft: Dr. P. J. van der Straaten. Groene Hart Hospital, Gouda: Dr. F. G. A. Versteegh. Beatrix Hospital, Gorinchem: Dr. R. M. Colombijn. Sint Franciscus Gasthuis: Dr. M. C. W. Jacobs. Sophia Children's Hospital: Dr. M. J. Affourtit and Dr. W. W. Abels.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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