Isaiah Tekalign
PA Portfolio III – Spring 2023
Mini-CAT
Clinical Scenario:
You are a PA specializing in pulmonology in a pediatric clinic and are tending to a returning 7-year-old patient who has been diagnosed with asthma and is not well controlled with a SABA. Being the astute PA you are, you are recommending that the child move to step 2 as per the GINA guidelines and take an inhaled corticosteroid daily. The mother however, recently heard in her parent group at the park that inhaled corticosteroids can have negative effects on children’s growth.
Search Question:
In pediatric patients with asthma does the use of inhaled corticosteroids negatively affect growth compared to not using an inhaled corticosteroid?
PICO Table:
| P | I | C | O |
| Pediatric asthma | Inhaled corticosteroids | placebo | Growth rate |
| Child asthma | Inhaled glucocorticoids | High dose steroids | Decreased body weight |
| Wheezing | Low dose steroids | Decreased body height | |
Search Strategy and Databases Used:
Pub Med:
(Asthma) AND (inhaled corticosteroids) AND (Growth rate) : 86 results
- Filters: last 10 years, full text: 16 results
- Filters: last 10 years, full text, RCT, meta-analysis, systematic review: 8 results
(Pediatric Asthma) AND (inhaled steroids) AND (Growth) : 175 results
- Filters: last 10 years, full text: 40 results
- Filters: last 10 years, full text, RCT, meta-analysis, systematic review: 10 results
(Children Asthma) AND (steroids) AND (decreased growth) : 103 results
- Filters: last 10 years, full text: 25 results
- Filters: last 10 years, full text, RCT, meta-analysis, systematic review: 4 results
Cochrane:
Population “Asthma” Intervention “inhaled corticosteroids” Outcome “growth”: 5 results
Children asthma inhaled steroids growth in Title Abstract Keyword: 8 results
Trip Medical Database:
Population “Asthma” Intervention “inhaled corticosteroids” Comparison “placebo” Outcome “growth”: 12 results
Population “Pediatric Asthma” Intervention “inhaled steroids” Comparison “placebo” Outcome “growth”: 24 results
Explanation: At first, I just searched asthma, inhaled corticosteroids, and growth rate on PubMed and encountered many different articles, this then led to me apply the filter of “within the last 10 years” and free text. After doing this I still encountered 16 different articles and wanted to limit this, so I added another filter of RCT, meta-analysis, and systematic review which brought the results down to 8. When doing my search on Cochrane I put in asthma for population, inhaled corticosteroids for intervention, and growth for outcome which led to a surprisingly 5 articles. For the Trip database I searched Population “asthma” Intervention “inhaled corticosteroids” Comparison “placebo” Outcome “growth”, and it showed 12 results. However, these results were of no benefit to my question because many of them were outdated or had nothing to do with inhaled corticosteroids effect on growth rate.
Research Used:
| Citation | Axelsson I, Naumburg E, Prietsch SOM, Zhang L. Inhaled corticosteroids in children with persistent asthma: effects of different drugs and delivery devices on growth. Cochrane Database of Systematic Reviews 2019, Issue 6. Art. No.: CD010126. DOI: 10.1002/14651858.CD010126.pub2 |
| Abstract | Background 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. Objectives To assess the impact of different inhaled corticosteroid drugs and delivery devices on the linear growth of children with persistent asthma. Search methods 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 hand searched 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. Selection criteria 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. Main results 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 multicenter 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 favor 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). Authors’ conclusions 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. |
| Link: | https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010126.pub2/full |
| Citation | Zhang L, Prietsch SOM, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: effects on growth. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD009471. DOI: 10.1002/14651858.CD009471.pub2. |
| Abstract | Background Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first‐line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. Objectives To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). Search methods We searched the Cochrane Airways Group Specialized Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we hand searched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers’ clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014. Selection criteria Parallel‐group randomized controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non‐steroidal drugs in children up to 18 years of age with persistent asthma. Data collection and analysis Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta‐analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random‐effects model for meta‐analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. Main results We included 25 trials involving 8471 (5128 ICS‐treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had dropout rates of over 20%. Compared with placebo or non‐steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD ‐0.48 cm/y, 95% CI ‐0.65 to ‐0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD ‐0.61 cm/y, 95% CI ‐0.83 to ‐0.38, moderate quality evidence) during a one‐year treatment period. Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one‐year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)‐beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS‐induced suppression of linear growth velocity during a one‐year treatment period. However, head‐to‐head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD ‐0.19 cm/y, 95% CI ‐0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD ‐0.33 cm/y, 95% CI ‐0.52 to ‐0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch‐up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three‐year trial. One trial with follow‐up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI ‐1.90 to ‐0.50) in adult height compared with those treated with placebo. Authors’ conclusions Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61‐cm change from baseline in height during a one‐year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS‐induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterize the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma. |
| Link: | https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009471.pub2/full |
| Citation | Pruteanu AI, Chauhan BF, Zhang L, Prietsch SOM, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: dose‐response effects on growth. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD009878. DOI: 10.1002/14651858.CD009878. |
| Abstract | Background Inhaled corticosteroids (ICS) are the first‐line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. Objectives To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. Search methods We searched the Cochrane Airways Group Specialized Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. Selection criteria Studies were eligible if they were parallel group randomized trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. Data collection and analysis Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. Main results Among 22 eligible trials, 17 pairs of groups comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta‐analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long‐acting beta2‐agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)‐beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower‐dose ICS (N = 728 school‐aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high‐quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X2 = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non‐steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI ‐0.28 to ‐0.02; moderate‐quality evidence) in favor of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, body mass index and skeletal maturation reported with low quality of evidence due to imprecision. Authors’ conclusions In prepubescent school‐aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA‐beclomethasone equivalent, favoring the use of low‐dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one‐year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents’ and physicians’ concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future pediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma. |
| Link: | https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009878.pub2/full |
| Citation | Loke YK, Blanco P, Thavarajah M, Wilson AM. Impact of inhaled corticosteroids on growth in children with asthma: Systematic Review and meta-analysis. PLOS ONE. https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0133428. Accessed April 23, 2023. |
| Abstract | Background Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth. Methods We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic. Results We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65). Conclusion Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users. |
| Link: | https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133428 |
Summary of Evidence:
Conclusion
The first article suggests that the specific choice of which inhaled corticosteroid and delivery device can possibly have an impact on growth in pediatric patients with persistent asthma. The study showed that when comparing fluticasone and beclomethasone at equivalent doses fluticasone inhibited growth less. When it came to delivery devices the study suggests that easyhaler is less likely to have adverse effects on growth rate than turbuhaler.
The second article displayed that the regular usage of inhaled corticosteroids at a low or medium daily dose is correlated with a reduction in linear growth velocity in height during a one-year treatment period in children with persistent asthma. Unlike the pervious article this study suggests that the effect of inhaled corticosteroids on growth are mostly associated with the molecule rather than the device or dose. The study concluded that inhaled corticosteroid suppression on growth is maximal during the first year of therapy and less pronounced during subsequent years.
The third article concluded that over 12 months children with mild to moderate persistent asthma showed a significant difference in linear growth over 12 months. It was also shown that lower inhaled corticosteroid doses of fluticasone, mometasone, and ciclesonide showed to have less of an effect on growth velocity than HFA-beclomethasone.
The fourth article suggests that long term use of inhaled corticosteroids is associated with a reduction in growth velocity and final height in pediatric patients with asthma. However, this study identified dose responsiveness and reported that low doses had less of an effect on growth than higher doses. It was also found that adverse effects on growth were more prominent in younger children than older children. As the other studies this study also concluded that the reduction in growth velocity was most prominent with in the first year of treatment and was decreased in magnitude over the following years.
All four of the articles clearly display a correlation between the use of inhaled corticosteroids and decreased growth velocity. One aspect that is inconsistent across the articles is whether this impact on growth is possibly dose or delivery dependent. A key finding across all the studies is that the specific molecule of inhaled corticosteroid seems to play a role in the severity of impact on growth velocity. Another common finding across the four studies is that the decrease in growth velocity appears to be most impacted during the first year of treatment.
Clinical Bottom Line:
Overall, all the articles have weaknesses through various biases which factor into the overall weight of evidence for each article. In the first article the number of included trials was too little to evaluate the possibility of publication bias. There was also a risk of reporting bias in three trials since the study conclusion was favorable to the sponsor’s product. In the second article seven trials did not report standard deviations or other metrics of uncertainty for growth measurements, therefore the credibility of those seven trials can be argued. The third article has a clear limitation and questionable credibility seeing that each trial compared many different doses using the same device, therefore it was not tested if the device is a factor on the outcome of decreased growth rate. Like the first article the last study’s trials were sponsored predominantly by the pharmaceutical industry, and the study itself may have been aimed at obtaining favorable results for the sponsored drug. The last study is also limited in that it does not compare the different inhaled corticosteroids and have enough evidence to conclude which one is safer and has less adverse effects on growth velocity. The clinical bottom line as outlined in all the articles is that studies have shown that inhaled corticosteroids have been shown to have a suppressive effect on growth rate in asthmatic pediatric patients. The risks need to be discussed with both the patient and their parents to decide what treatment option is best. For example, based on the first article a parent and patient may want to decide to opt for fluticasone instead of budesonide since it showed to have fewer negative effects on overall growth. Another example is seen in the last article where it was shown that low dose steroids have less effect on growth than high dose so a parent may factor this into decision making. Of course, other alternatives to inhaled corticosteroids need to be discussed with the patients and their parents like a leukotriene receptor antagonist such as montelukast. Even though the articles presented here seem to show a correlation between suppressed growth rate and the use of inhaled corticosteroids more research and studies need to be done before this is accepted as completely factual. Therefore, it is our job as clinicians to be transparent with patients and their parents regarding the possible suppression of growth and alternative options when it comes to decision making for asthma management/treatment
