This meta-analysis shows that long-term macrolide treatment over 3–24 months in cases of pediatric non-cystic fibrosis BE reduces the frequency of exacerbation with a decrease in the mean number of exacerbations per patient during the macrolide treatment period. In addition, we found that long-term macrolide treatment improved the sputum purulence score; however, it did not affect the pulmonary function index and cytokine levels, including IL-8 and TNF-α, in the sputum and BAL. As an adverse effect of long-term macrolide treatment, the rate of azithromycin-resistant bacteria significantly increased (azithromycin-resistant Streptococcus pneumoniae, OR, 13.2; azithromycin-resistant Staphylococcus aureus, OR: 4.1; azithromycin-resistant any bacteria, OR: 7.13), although no other serious adverse reactions were identified. Our meta-analysis provides an assessment of the advantages and disadvantages of long-term macrolide treatment focused on pediatric non-cystic fibrosis BE.
We meta-analyzed the effects of macrolides for acute exacerbation in pediatric BE with three RCTs, that were performed with roxithromycin for 12 weeks,11 erythromycin for 52 weeks,12 and azithromycin for up to 24 months.13 They showed consistent results on reduction of the number of exacerbation, although the RCTs were performed for different study durations in different study populations, including immunocompromised children due to HIV infection in one RCT.12 One study on the effects of clarithromycin did not investigate the effect of long-term macrolide on the frequency of exacerbation of bronchiectasis in children but pulmonary functions and sputum cytokines.14 One study showed a significant decrease in sputum purulence score in group with roxithromycin compared to control group.11 Although there was heterogeneity in the protocols of the RCTs for macrolides, dosage of macrolides, study duration, age, and characteristics of the study population, we concluded that long-term macrolide treatment has beneficial effects on the reduction of exacerbation and sputum score in children with non-cystic fibrosis BE.
Despite the beneficial effects, it is important to consider the safety of long-term macrolide treatment in children. Among the four RCTs included in the meta-analysis, only one study investigated the adverse reactions.13 The critical adverse reactions in the long-term macrolide treatment group significantly increased azithromycin–resistant bacteria, including S. pneumonia and S. aureus, when 30 mg/kg of azithromycin were administered once a week for up to 24 months.13 In the era of increasing macrolide resistance,15,16 the increased risk of macrolide resistance in the long-term macrolide treatment in pediatric non-cystic fibrosis BE arouse attention to the widespread use of long-term macrolide treatment in children. The benefits of long-term macrolide treatment and the risks of bacterial resistance must be weighed.
Although a previous study reported that administering azithromycin for 5 days can increase the risk of cardiovascular diseases in adults17 and long-term macrolide treatment in adults with non-cystic fibrosis BE showed gastrointestinal complications, including diarrhea, nausea, vomiting or abdominal discomfort,18 no adverse events were reported in long-term macrolide treatment in cases of pediatric non-cystic fibrosis bronchiectasis compared to the control group.13 In addition, there was no reported severe adverse events of long-term macrolide treatment in children with non-cystic fibrosis BE. To identify and prevent the adverse reactions of long-term macrolide treatment, regular monitoring on the possible complications, such as cardiovascular diseases, are warranted in future studies. Despite these adverse reactions, long-term macrolide treatment can be one of the options that can decrease the exacerbation of non-cystic fibrosis BE in children, if other treatment strategies are insufficient.
There are some limitations in the present study. The RCTs in the present meta-analysis are differ in terms of characteristics of the study population (age, sex, and severity of bronchiectasis, and immune-state), study duration, and the classes of macrolide. Despite protocols' heterogenicity, this meta-analysis is a study that analyzes limited results so far, and it is clear that long-term macrolide treatment helps prevent pediatric BE from deteriorating. The question is which one to choose between the benefits of preventing deterioration and the risk of increased antibiotic resistance. The findings of this meta-analysis can be one of the alternatives for the long-term management of pediatric non-cystic fibrosis BE in the absence of a definite treatment other than the administration of antibiotics in exacerbation.1
In conclusion, long term macrolide treatment prevents exacerbation of BE in children, but increases antibiotic resistance. Long-term macrolide treatment cannot be claimed uniformly in all pediatric BE patients because there are clear risks coexisting with benefits. However, long-term macrolide therapy would be one treatment option, given that there are no other special treatments for BE exacerbation prevention and the poor quality of life for pediatric patients. The decision shall be made in consideration of various factors, such as the condition of individual patients, duration of disease, quality of life, etc. Valuable studies on the treatment of the area of pediatric BE are needed in the future.