Inhaled corticosteroids in children with persistent asthma: effects of different drugs and delivery devices on growth
Inhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. Although treatment with ICS is generally considered to be safe in children, the potential adverse effects of these drugs on growth remains a matter of concern for parents and physicians.
To assess the impact of different inhaled corticosteroid drugs and delivery devices on the linear growth of children with persistent asthma.
We searched the Cochrane Airways Trials Register, which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, Embase, CINAHL, AMED and PsycINFO. We handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases, or contacted the manufacturer, to search for potential relevant unpublished studies. The literature search was initially conducted in September 2014, and updated in November 2015, September 2018, and April 2019.
We selected parallel‐group randomized controlled trials of at least three months' duration. To be included, trials had to compare linear growth between different inhaled corticosteroid molecules at equivalent doses, delivered by the same type of device, or between different devices used to deliver the same inhaled corticosteroid molecule at the same dose, in children up to 18 years of age with persistent asthma.
Data collection and analysis
At least two review authors independently selected studies and assessed risk of bias in included studies. The data were extracted by one author and checked by another. The primary outcome was linear growth velocity. We conducted meta‐analyses using Review Manager 5.3 software. We used mean differences (MDs) and 95% confidence intervals (CIs ) as the metrics for treatment effects, and the random‐effects model for meta‐analyses. We did not perform planned subgroup analyses due to there being too few included trials.
We included six randomized trials involving 1199 children aged from 4 to 12 years (per‐protocol population: 1008), with mild‐to‐moderate persistent asthma. Two trials were from single hospitals, and the remaining four trials were multicentre studies. The duration of trials varied from six to 20 months.
One trial with 23 participants compared fluticasone with beclomethasone, and showed that fluticasone given at an equivalent dose was associated with a significant greater linear growth velocity (MD 0.81 cm/year, 95% CI 0.46 to 1.16, low certainty evidence). Three trials compared fluticasone with budesonide. Fluticasone given at an equivalent dose had a less suppressive effect than budesonide on growth, as measured by change in height over a period from 20 weeks to 12 months (MD 0.97 cm, 95% CI 0.62 to 1.32; 2 trials, 359 participants; moderate certainty evidence). However, we observed no significant difference in linear growth velocity between fluticasone and budesonide at equivalent doses (MD 0.39 cm/year, 95% CI ‐0.94 to 1.73; 2 trials, 236 participants; very low certainty evidence).
Two trials compared inhalation devices. One trial with 212 participants revealed a comparable linear growth velocity between beclomethasone administered via hydrofluoroalkane‐metered dose inhaler (HFA‐MDI) and beclomethasone administered via chlorofluorocarbon‐metered dose inhaler (CFC‐MDI) at an equivalent dose (MD ‐0.44 cm/year, 95% CI ‐1.00 to 0.12; low certainty evidence). Another trial with 229 participants showed a small but statistically significant greater increase in height over a period of six months in favour of budesonide via Easyhaler, compared to budesonide given at the same dose via Turbuhaler (MD 0.37 cm, 95% CI 0.12 to 0.62; low certainty evidence).
This review suggests that the drug molecule and delivery device may impact the effect size of ICS on growth in children with persistent asthma. Fluticasone at an equivalent dose seems to inhibit growth less than beclomethasone and budesonide. Easyhaler is likely to have less adverse effect on growth than Turbuhaler when used for delivery of budesonide. However, the evidence from this systematic review of head‐to‐head trials is not certain enough to inform the selection of inhaled corticosteroid or inhalation device for the treatment of children with persistent asthma. Further studies are needed, and pragmatic trials and real‐life observational studies seem more attractive and feasible.
Inge Axelsson, Estelle Naumburg, Sílvio OM Prietsch, Linjie Zhang
Plain language summary
Which inhaled corticosteroid and inhalation device has least impact on growth in children with asthma?
We reviewed the evidence about which inhaled corticosteroid and inhalation device has least impact on growth in children with asthma.
Inhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. Persistent asthma is a more severe asthma that requires daily use of medications for controlling symptoms. Although treatment with ICS is generally considered safe in children, daily use of these drugs over a long period of time may cause reduction of growth. The effect on growth may depend on type of steroid and delivery device.
In this review, we included trials that compared either different inhaled corticosteroid drugs or inhalation devices, for at least three months in children aged from 4 to 12 years with mild‐to‐moderate persistent asthma. We found six trials involving 1199 people, and we included information from 1008 people in our analysis. Four trials compared the drug fluticasone with either beclomethasone or budesonide. Two trials compared different inhalation devices. Four trials were conducted in more than two different centres (multicentre studies). The multicentre studies were financially supported by industry companies that manufacture the drugs or devices.
This systematic review did not include children with persistent asthma treated with other ICS besides beclomethasone, budesonide and fluticasone, or ICS combined with medications called long acting beta2‐agonists (LABA). Thus, evidence derived from this review does not apply for these people.
One trial with 23 people showed that fluticasone had less negative effects on children's growth compared to beclomethasone (low certainty evidence). Three trials compared fluticasone and budesonide, and showed some different results. The combined results of two trials with 359 people suggested that fluticasone had less negative effects on children's height compared to budesonide (moderate certainty evidence), while the combined results of another two trials with 236 people revealed similar growth velocity (average increase in height per year) between fluticasone and budesonide (very low certainty evidence).
Two trials compared inhalation devices. One trial with 212 people showed a similar growth velocity between beclomethasone delivered by hydrofluoroalkane‐metered dose inhaler (HFA‐MDI) at half the dose, and beclomethasone delivered by chlorofluorocarbon‐metered dose inhaler (CFC‐MDI) (low certainty evidence). Another trial with 229 people showed that budesonide delivered by Easyhaler had less negative effects on children's height over a period of six months, compared to budesonide given at the same dose through Turbuhaler (low certainty evidence).
Certainty of the evidence
We judged the certainty of the evidence in this review to range from very low to moderate, mainly because of small numbers of trials and people, low quality of some included trials, and the possible influence of industry funding on reporting of trial results. 'Very low certainty' means that we are very uncertain about the results, while 'moderate certainty' means that further research is likely to have an important impact on the results and may change the current conclusions.
The type of drug and inhalation device may affect the size of negative effects of ICS on growth in children with persistent asthma. Fluticasone seems to inhibit growth less than beclomethasone and budesonide. Easyhaler is likely to have less a negative effect on growth than Turbuhaler when used for delivery of budesonide. However, the evidence from this review is not certain enough to help people select which inhaled corticosteroid or inhalation device to use for the treatment of children with asthma. Further studies are needed.
The well‐established benefits of ICS in controlling asthma outweigh the potential risk of a relatively small suppression in growth. Fear of drug side effects means some children do not take their steroid inhalers as prescribed, leading to poor asthma control. Uncontrolled asthma can also impair children's growth, and can cause significant morbidity and mortality. Good communication between healthcare professionals and parents is essential to reduce people's concerns about using steroids and to improve treatment adherence.
This review is current to April 2019.
Inge Axelsson, Estelle Naumburg, Sílvio OM Prietsch, Linjie Zhang
Implications for practice
This review suggests that drug molecule and delivery device may impact the effect size of inhaled corticosteroids (ICS) on growth in children with persistent asthma. Fluticasone at an equivalent dose seems to inhibit growth less than beclomethasone and budesonide. Easyhaler is likely to have less adverse effect on growth than Turbuhaler when used for delivery of budesonide. However, the evidence from this systematic review of head‐to‐head trials is not certain enough to definitively inform the selection of inhaled corticosteroid or inhalation device for the treatment of these patients. The selection of inhaled corticosteroid and delivery device should be based on the efficacy, overall safety profile, ease of use, availability, cost of treatment, and preference of the child. No matter the type of drug and inhalation device, use of the lowest effective dose of ICS along with regular monitoring of growth are recommended for all asthmatic children who receive long‐term treatment with ICS.
Implications for research
There is a limited number of head‐to‐head randomized trials that compare different inhaled corticosteroid molecules and delivery devices regarding the effects on growth in children with asthma. Both patient factors (age, asthma severity, and adherence to treatment) and drug factors (inhaled corticosteroid molecules, doses, formulation, and delivery devices) can affect the effect size of ICS on growth. These factors should be taken into account in study design, and this is one of the main methodological challenges of such head‐to‐head trials. We did not find any ongoing trials by searching the database ClinicalTrials.gov. There is probably little impetus for both pharmaceutical industries and researchers to conduct further head‐to‐head randomized trials to compare inhaled corticosteroid molecules and devices because of complexities in study design, limited clinical relevance, and concerns for conflict of interests. Pragmatic randomized trials have the same methodological challenges as mentioned above. However, such a study design enables the inclusion of a broader spectrum of patients and interventions, as seen in real‐life practice, and therefore the results from pragmatic trials have greater applicability. Real‐life observational studies are another feasible option to assess the effects of ICS on growth in children with asthma. Confounding is one of the main shortcomings of observational studies, and should be identified and addressed appropriately.