Recent research on inhaled corticosteroids and growth

Abstract

Purpose of review

Description of recent studies evaluating growth and inhaled corticosteroids.

Recent findings

Corticosteroids are the gold standard of asthma maintenance treatment, but effects on growth remain controversial. This is a review of recent research in this area, which has focused on medications causing less adrenal suppression as well as alternative regimens for chronic illness such as asthma.

Summary

The use of newer corticosteroids and regimens shows short-term evidence of minimal growth effects without worsening of asthma control.

INTRODUCTION AND BACKGROUND: PREVIOUS WORK EXAMINING THE EFFECTS OF INHALED CORTICOSTEROIDS ON GROWTH

Glucocorticoids are widely used medications to decrease activation of the immune system in diverse diseases. Recent work studying glucocorticoids centers on inhaled corticosteroids (ICS) and their effects on growth.

Inhaled corticosteroids are the standard of care for maintenance or control of asthma, the most common chronic disease of childhood [1], as well as other chronic respiratory conditions such as allergies and cystic fibrosis. These medications are the most consistently effective way to prevent morbidity due to asthma. However, many practitioners hesitate to use these medications due to concerns of decreased growth. This has led to studies examining the effects of ICS on growth [2]. These investigations have primarily focused on short-term growth effects rather than on final adult height. Furthermore, in order to avoid the confounding effects of the pubertal growth spurt, the vast majority of these studies examine prepubertal children. In spite of these methodological limitations, work examining the effects of ICS on growth has yielded significant knowledge. Broadly considered, previous work in this area revealed that ICS cause a short-term decrease in growth rate in the first 1–2 years of treatment. This growth decrement appears to correlate with adrenal suppression from ICS and improves after the first 2 years, even with continuation of the ICS. Additionally, this work reveals ICS do not appear to have an adverse effect on final adult height [3].

Recent research in this area has focused on new medications or newer formulations of older agents as well as alternative regimens to conventional daily inhaled steroid treatment. These studies offer exciting new treatment options with fewer short-term side-effects.

NEW DRUGS AND FORMULATIONS

The body of work on new drugs such as ciclesonide is much smaller than that examining other ICS. Ciclesonide is a prodrug converted to its active form by the lung and, when absorbed into the circulation, is highly protein-bound. Because of its unique activation and low degree of systemic availability, ciclesonide is thought to cause less adrenal suppression and decreased short-term effects on growth than older ICS [4■]. Ciclesonide is FDA approved for ages 12 years and up in the USA.

Recently two interesting studies have investigated the growth effects of ciclesonide when used as an asthma controller. In the first study, Pedersen et al. [5■■] performed a 12-week, double-blind, randomized, controlled study of asthma control using one of three doses (40, 80, and 160 μg) of ciclesonide compared to placebo in Europe and South Africa in over 1000 children aged 6–11 years with persistent asthma. They used stadiometry to measure growth rate and 24-h urine cortisol to assess adrenal suppression. They found each of the three doses improved pulmonary function tests and other indices of asthma control without causing any statistically significant decrease in growth rate between any of the treatment groups and placebo [5■■]. Three months is a small interval for growth measurement using a stadiometer but there is corroborative evidence from another study [6■]. Interestingly there was not a difference in asthma improvements between the three doses of ciclesonide.

In a second study examining the growth effects of ciclesonide, Agertoft and Pedersen [6■] used a double-blind, placebo-controlled, three-period crossover study to compare the adrenal and growth effects of ciclesonide, fluticasone and placebo in children with mild asthma. This study used knemometry, highly accurate measurement of the lower leg, as a proxy for growth rate and overnight 12-h urine cortisol as a measure for adrenal function. In this study, 28 children aged 6–12 years sequentially received daily doses of either ciclesonide (320 mcg) or fluticasone (375 mcg) and placebo via a spacer in a randomized order. Notably, this is a higher dose of ciclesonide than has been used in any study prior to this one. Each treatment was given for 2 weeks followed by a 2-week washout. There were no statistically significant differences in lower-leg growth rates between ciclesonide (0.30 mm/week) and placebo (0.43 mm/week) treatments. However, fluticasone significantly decreased lower-leg growth rate (0.08 mm/week) relative to either placebo or ciclesonide. Neither fluticasone nor ciclesonide were different from placebo in terms of their effects on 12-h urine cortisol; however, fluticasone treatment led to a statistically significant decrement in 12-h urine cortisol relative to ciclesonide treatment. The clinical significance of this alteration is unclear. Two drawbacks in this study were its lack of comparison of treatment efficacy for improving asthma control and that ICS dosing equivalency was unclear. Together, these studies demonstrate that ciclesonide appears to have decreased impact on adrenal function and short-term growth compared to fluticasone. Additionally, that each of the three doses used in the first study by Pedersen et al. have equivalent benefits in treating asthma suggest that the lowest dose of ciclesonide may be an adequate controller dose.

In addition to studies on newer medications, there was also a recent study on a new formulation, the dry powder form, of an older medication, budesonide. This study was a small, randomized, open-label study on 52 prepubertal children [7■] that had the novel goal of correlating short-term (2 weeks) knemometric data with 1-year height and growth data. The treatment group received 200 mcg of budesonide and the control group received 5 mg of montelukast. Both lower leg and height growth rates were decreased in the budesonide group relative to the montelukast group, with mean 2 weeks lower-leg growth rate of 0.17 mm/week in the budesonide group and 0.39 mm/week in the montelukast group (P = 0.02). Mean 1-year growth velocity was 5.51 cm/year in the budesonide group and 6.51 cm/year in the montelukast group. Interestingly these values showed a high degree of correlation between 2-week knemometry and yearly growth velocity, with r_s or rho (a nonparametric measure of statistical dependence between two variables, where closeness to 1 is proportional to correlation) values greater than 0.95 in both treatment groups. Whereas no final differences in FEV1 were found between groups, the similarity in pulmonary function changes between groups may reflect a lack of power for this variable given the small sample size. This study appears to confirm the early effects of budesonide on acute growth velocity, and in addition, opens the door for using 2-week knemometric data in research on growth effects of ICS as a proxy for yearly decline in growth velocity.

ALTERNATIVE APPROACHES TO USING INHALED CORTICOSTEROIDS

Another consideration is the use of alternative approaches to the current standards of care in controlling asthma. Specifically, one study evaluated asthma treatment by using controller medication as a rescue medication. Another study attempted to escalate control regimens by adding a long-acting beta-agonist instead of increasing the steroid dose.

The first study by Martinez et al. [8■■] assessed asthma control using ICS as a rescue treatment for exacerbations rather than as a daily controller. One of the rationales for this controversial [9] study is that many patients with mild asthma on inhaled steroids are noncompliant, and many of these patients might be well managed on ICS treatment for exacerbations alone. This investigation was done over 44 weeks in 5 centers in the US and was structured as a randomized, double-blind, placebo-controlled trial occurring in 200 children aged 5–18 with mild persistent asthma. There were four treatment groups: a combined daily and rescue group, a daily beclomethasone group, a rescue beclomethasone group and a placebo group. As expected, the placebo group had more exacerbations as well as a greater frequency of treatment failure than each of the other three groups. There were no statistically significant differences in either exacerbations or treatment failures between the conventionally treated (daily beclomethasone groups) and the rescue beclomethasone group. However, the percentage of treatment failure is likely to be thought of as clinically significant: 2.8% in the daily beclomethasone group versus 8.5% in the rescue beclomethasone group; the failure rate in the placebo group was 23%. Interestingly, whereas the combined and daily beclomethasone arms had a statistically significant decrement in linear growth (1 cm difference in 44 weeks or 0.3 SD) relative to the placebo group, no such difference was observed between the placebo and rescue beclomethasone groups (P = 0.26). This study offers the possibility of maintenance of growth rate with a 3–4-fold instead of a 7–8-fold increase in exacerbation risk. Although such an exchange is tantalizing, we would recommend continuing daily ICS use until further studies confirm the safety of using ICS as a rescue treatment.

Another study using an alternative approach to asthma control by Vaessen-Verberne et al. [10■] examined the addition of a long-acting beta agonist to ICS therapy compared with doubling the ICS dose, as is currently recommended in conventional asthma control regimens. This study compared salmeterol/fluticasone (50/100 mcg twice a day) with monotherapy fluticasone (200 mcg twice a day). This study was structured as a 26-week long randomized, double-blind parallel group study involving 158 children between the ages of 5 and 16 who were symptomatic on their regimen of fluticasone 100 mcg twice a day. These children had been on ICS for an average of 4 years at the start. Both groups had improvements of approximately 25% in their symptom-free days. There were no statistically significant differences in pulmonary function measurements, symptom-free days, or growth. The lack of a growth difference between the group escalating with a beta-agonist versus the group increasing their ICS dose is consistent with the understanding that most of the growth decrement in treatment with ICS occurs in the first year of treatment. The significance of this study is two-fold: adding a long-acting beta-agonist may be a viable option prior to moving to higher doses of ICS and increasing ICS dosing after the first year may not alter growth at that point.

CONCLUSION: RECENT WORK ON INHALED CORTICOSTEROIDS AND GROWTH

Inhaled corticosteroids have been the backbone of asthma control or maintenance treatment for more than two decades and are widely used in other chronic respiratory diseases of childhood. Despite data to the contrary, persistent concerns about their effects on growth have necessitated studies to determine the effects of ICS on growth.

The work in this field is challenged by difficulty in identifying appropriate controls and in following growth to final adult height. Although further work in this area is necessary, the current data show that ICS therapy at doses commonly used in mild and moderate asthma causes a temporary reduction in growth rate over the first year, but likely does not cause any decrease in final adult height. Recent work has revealed that new drugs such as ciclesonide may have fewer short-term growth effects than traditional ICS. In addition, there is evidence that 2-week knemometry may be a useful research tool as a proxy for yearly decline in growth velocity. Finally, there is some evidence to suggest that mild forms of asthma may be treated with ICS for exacerbations rather than as a daily controller with decreased effects on short-term growth.

In summary, from the point of minimizing adrenal and growth side-effects of ICS therapy, we recommend that when initiating ICS treatment, consider medications that may have less adrenal suppression as well as less of a negative effect on 1–2-year growth rates. In addition, use of a long-acting beta agonist in the first 1–2 years may be helpful. Until more data confirm the safety of these medications for rescue, continue to use ICS as daily controller medications.

KEY POINTS.

• ICS therapy at doses commonly used in mild and moderate asthma causes a temporary reduction in growth rate over the first year, but likely does not cause any decrease in final adult height.

• When initiating ICS treatment, consider medications such as ciclesonide that may have less adrenal suppression as well as less of a negative effect on growth rate.

• Until more data confirm the safety of using these medications for rescue, continue the practice of using ICS as daily controller medications.