The present study found that while adjunctive macrolide therapy did not affect FEV1 in children without oral corticosteroid-dependent asthma, FEV1 improved in children with oral corticosteroid-dependent asthma. Moreover, among children requiring daily oral corticosteroids for control of asthma, addition of a macrolide agent decreased daily oral corticosteroid dosage requirements, and the degree of this reduction was directly proportional to duration of macrolide therapy.
While the utility of macrolide therapy in asthma has been well studied in the general population, it has been poorly studied in childhood asthma. Richeldi et al18
reviewed randomized controlled trials of macrolide administration in patients with asthma, and identified a sample size of 398 adults from six studies, and 18 children from one study. This meta-analysis found insufficient evidence to recommend macrolide therapy in patients with chronic asthma. In particular, the authors failed to find that macrolide therapy had a significant impact on daily oral corticosteroid dosage. This last conclusion was based on two studies. Nelson et al19
studied 75 adults and did not find a difference in daily oral corticosteroid dosage between their treatment and placebo groups. Kamada et al14
studied 11 children, and found a statistically significant reduction in daily oral corticosteroid dosage for children receiving macrolide therapy when compared with a placebo group. The present study, which found an effect of macrolide therapy on daily oral corticosteroid dosage, included parallel and crossover clinical trials involving only children. These observations suggest that macrolide therapy may have a steroid-sparing effect in children but not in adults. Further studies are needed to resolve this issue.
Potential mechanisms of macrolide effects are likely related to modulation of inflammatory cytokines, such as interleukin (IL)-5, IL-8, and vascular endothelial growth factor (VEGF). In a prospective cohort study from 2010, Korematsu et al20
showed a correlation between children with severe asthma and high levels of IL-8 and VEGF. Furthermore, that study showed that low-dose erythromycin significantly improved clinical symptoms and decreased levels of both IL8 and VEGF in children with severe asthma, but not in children with mild to moderate asthma.20
In a cross-sectional controlled study performed in 2011, Lin et al21
showed that children with asthma produced significantly higher levels of IL-5 compared with children without asthma, and addition of azithromycin significantly decreased IL-5 levels in a dose-dependent fashion. In the present study, the most severely affected children, ie, those who were dependent on oral corticosteroids, saw the most benefit from macrolide therapy, a result that is likely related to the pathophysiology observed in the Korematsu et al20
study. It is unclear why children but not adults (as determined by a Cochrane review18
) show significant steroid-sparing effects from adjunctive macrolide therapy. The common saying may be appropriate here, ie, that “children are not simply young adults”.
The present study has several limitations. First, troleandomycin and methylprednisolone were used in all studies where a steroid-sparing effect was observed. Prior studies have suggested a pharmacokinetic interaction between these two agents that directly increases steroid concentrations.13
It is not known whether this same effect exists between other members of the macrolide and corticosteroid classes. Another significant limitation is sample size: our aggregate data analyzed a total of 69 patients from six studies, and four of these (n = 28) were analyzed for steroid-sparing effect. Nevertheless, to the authors’ knowledge, this is the largest sample size to date to have evaluated the effect of macrolides in children with corticosteroid-dependent asthma. Further, the studies were performed many years earlier, in some cases 30 years ago, when definitions and standard of care protocols were different from those used today. Furthermore, although the improvement in FEV1
was statistically significant, it may not necessarily be clinically significant, and future studies should include outcomes, such as responses to an asthma symptom questionnaire and numbers of acute care visits.
In summary, this study demonstrates that macrolides have a steroid-sparing effect in children with steroid-dependent asthma. In addition, we found a direct association between duration of macrolide therapy and magnitude of change in oral corticosteroid dosage before and after therapy. The present study supports the need for a large, randomized, placebo-controlled, crossover trial of a modern macrolide in children with steroid-dependent asthma.