The present growth analyses in the PEAK preschool aged cohort with recurrent wheezing at high risk of developing asthma demonstrated that two years of treatment with fluticasone (176 mcg/day) is associated with less linear growth that dissipates over time after treatment discontinuation when the cohort as a whole is evaluated. The ICS treated group, as a whole, demonstrated catch-up linear growth during the two years after treatment discontinuation. However, post-hoc analysis identified a subgroup of younger children of lesser weight (two years of age and <17 kg at enrollment) that did not demonstrate catch-up linear growth. We confirm the findings of Murray et al.(9
), who showed that ICS compared to placebo had a greater effect on linear growth in younger (age 2 years) versus older children (age 3 years). Similar to the PEAK study, school-aged children with persistent asthma treated with budesonide (400 mcg/day) for an average of 4.3 years in the Childhood Asthma Management Program (CAMP) Study had gained 1.1 cm less in height at the end of the study period compared to the placebo group(2
). The difference in mean height in the budesonide group relative to the placebo group at the end of the trial diminished but remained statistically significant (0.9 cm; P = 0.01) after an additional 4.8 years (10
) after the study medication was stopped. Participants in all CAMP treatment groups used inhaled corticosteroids during 30% of the post-trial period similar to the 40% observed in the PEAK study. In this study, the ICS treated groups had less linear growth than the placebo treated group; however, the effect diminished with time even while these children continued to receive ICS treatment and even more so once ICS treatment was discontinued. The PEAK study identified a group of younger children of lesser weight (relative to the cohort) for whom the growth suppressive effects of ICS were pronounced and this effect did not diminish with time or after the ICS treatment was discontinued. This is in contrast to the effects observed in the younger, heavier children (relative to the cohort) or the older children of any weight after adjusting for open-label ICS and oral corticosteroid use during both the treatment and follow-up periods.
The effect of ICS exposure on linear growth may be more profound in younger children of lesser weight (two years of age and <17 kg at enrollment) who may be predisposed to growth rates in the low-mid end of the normal range in early childhood(11
). In addition, the weight gain was not significantly different between treatment groups at baseline, during treatment, or after treatment was discontinued. Indeed, these children with an enrollment weight of < 17 kg remained lighter relative to their peers at the end of the study. The younger children of lesser weight likely received a higher relative exposure (mcg/kg) of fluticasone than the older children. However, this does not appear to be solely a weight effect as the older children of lesser weight (three years of age and <17 kg at enrollment) did not show the same growth effect and demonstrated significant catch-up growth once the ICS treatment was discontinued. Thus, the inhaled corticosteroid exposure may have occurred during a key period of rapid growth in these children who were two years of age and <17 kg at enrollment and they were unable to accelerate their growth rate to the degree needed to catch up to their peers. Furthermore, no consistent, greater clinical benefit with respect to episode-free days or oral corticosteroid courses were seen in the younger children of lesser weight with a higher fluticasone exposure compared to those with a lower exposure (data not shown), and a previous analysis of this cohort demonstrated that two year old children did not have more favorable responses to fluticasone than placebo compared to three year olds(12
). Thus, a higher relative ICS exposure resulted in an increased risk of less linear growth in the younger children of lesser weight without a correspondingly greater clinical benefit in symptom control or exacerbations.
In studies of this age group of children with recurrent wheezing(9
) and in other studies of older children with persistent wheezing(2
), the inhibitory effect of inhaled corticosteroids on growth appears “front-loaded”, or occurs during the first year of ICS treatment and the effect diminishes over time. However, in this study, the younger, lesser weight children (relative to the cohort) had a different pattern where they did not demonstrate catch-up growth over time. Unlike the CAMP study in older children with persistent asthma, we did not find that girls in the PEAK study were more likely to have less linear growth(10
). In addition, these observations differ from the normal growth velocities reported in a study of fluticasone treatment for one year(15
) in pre-school children with recurrent wheezing. A larger volume spacer(15
), which may have led to a different ICS deposition pattern, less adherence, or the higher dropout rate in that study(15
), may explain these differences in findings.
Based on the observed effects of ICS on growth in the younger children of lesser weight (relative to the cohort),, an estimate for a cut-off for per-kg fluticasone dose that would be expected to have the largest growth effect was determined. In this analysis, we saw a growth effect in the children two years of age and <17 kg at enrollment ( and E-Figure 3
) that persisted two years after treatment was discontinued. Based on the fluticasone CFC dose of 176 mcg/day used in PEAK, we estimate that 10 mcg/kg/day is the upper limit of fluticasone dose to use to avoid the potential effects of long-term daily ICS use on growth in children 2–3 years of age. This dose range is speculative and would need to be studied prospectively.
Several limitations should be noted. The subgroup analyses described here are post-hoc as the original study was not designed or powered to examine the linear growth effects of ICS on smaller subgroups of children with particular baseline characteristics. The results presented herein can serve to generate hypotheses for future studies. The PEAK study was not initially designed to follow these children for an additional year of observation; thus, only 72% of the population had growth outcomes measured two years after the ICS treatment was stopped. However, these observations did not change when children who were lost to follow-up by the second observation period were added to the analysis. These results also did not change when the analyses were adjusted for parent-reported adherence. It should be noted that the sample size is smaller for the age by weight analyses. Height measurements in very young children can vary in their accuracy; however, we used a similar technique of repeated stadiometry measurements similar to that adopted in the CAMP trials and endocrinology literature(2
). It is also possible that the height difference in the 2 year olds in this group may resolve with time and be attributable to a younger cohort effect.
The PEAK study used a small volume valved spacer [AeroChamber™
(Monaghan Medical Corporation, Plattsburgh, NY) with mask] and a CFC-based fluticasone inhaler and we do not know how other types of spacer devices, other types of ICS, or HFA-based or dry powder inhalers would alter these findings. Furthermore, Z-score analyses were used similar to other growth studies(17
) to standardize the study population to a larger, reference population(8
). The average height percentile range of the younger children of lesser weight at enrollment using this reference population was 43.2%. Our placebo population did not perfectly mirror the growth of this reference population, but children with recurrent wheezing may not demonstrate the same growth as a healthier population nor have the same racial or ethnic composition, stressing the importance of a placebo group. An additional finding that may limit the generalizability of these results is that 33% of the 2–3 year old children enrolled in the PEAK study cohort were > 75th
percentile for weight compared to a reference population [CDC], which may reflect recent observations of increased obesity rates in older children with asthma(19
ICS continue to be recommended as the most effective therapy for children with persistent asthma(24
) based on studies clearly demonstrating significantly decreased disease impairment and risk(2
). In preschool children at high risk for subsequent asthma, we have also demonstrated that ICS treatment significantly reduces disease burden(3
). Previous studies have shown that, on average, the growth suppressive effects of ICS are small(2
) and may improve with time(1
), but subgroups with variations in this response are potentially unrecognized when averaging the population. This study has identified a group of children in which ICS therapy was associated with an increased risk of adverse growth effects without apparent increase in benefit. Therefore, in this subgroup, these effects need to be balanced with prospective regular assessments of asthma control and possible appropriate ICS dose reductions, discontinuation of medication, use of alternative controller medications, or formulation adjustment to maximize the benefit risk ratios of inhaled corticosteroids.