Articles
Long-term azithromycin for Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study): a multicentre, double-blind, randomised controlled trial

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Summary

Background

Indigenous children in high-income countries have a heavy burden of bronchiectasis unrelated to cystic fibrosis. We aimed to establish whether long-term azithromycin reduced pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease.

Methods

Between Nov 12, 2008, and Dec 23, 2010, we enrolled Indigenous Australian, Maori, and Pacific Island children aged 1–8 years with either bronchiectasis or chronic suppurative lung disease into a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial. Eligible children had had at least one pulmonary exacerbation in the previous 12 months. Children were randomised (1:1 ratio, by computer-generated sequence with permuted block design, stratified by study site and exacerbation frequency [1–2 vs ≥3 episodes in the preceding 12 months]) to receive either azithromycin (30 mg/kg) or placebo once a week for up to 24 months. Allocation concealment was achieved by double-sealed, opaque envelopes; participants, caregivers, and study personnel were masked to assignment until after data analysis. The primary outcome was exacerbation (respiratory episodes treated with antibiotics) rate. Analysis of the primary endpoint was by intention to treat. At enrolment and at their final clinic visits, children had deep nasal swabs collected, which we analysed for antibiotic-resistant bacteria. This study is registered with the Australian New Zealand Clinical Trials Registry; ACTRN12610000383066.

Findings

45 children were assigned to azithromycin and 44 to placebo. The study was stopped early for feasibility reasons on Dec 31, 2011, thus children received the intervention for 12–24 months. The mean treatment duration was 20·7 months (SD 5·7), with a total of 902 child-months in the azithromycin group and 875 child-months in the placebo group. Compared with the placebo group, children receiving azithromycin had significantly lower exacerbation rates (incidence rate ratio 0·50; 95% CI 0·35–0·71; p<0·0001). However, children in the azithromycin group developed significantly higher carriage of azithromycin-resistant bacteria (19 of 41, 46%) than those receiving placebo (four of 37, 11%; p=0·002). The most common adverse events were non-pulmonary infections (71 of 112 events in the azithromycin group vs 132 of 209 events in the placebo group) and bronchiectasis-related events (episodes or investigations; 22 of 112 events in the azithromycin group vs 48 of 209 events in the placebo group); however, study drugs were well tolerated with no serious adverse events being attributed to the intervention.

Interpretation

Once-weekly azithromycin for up to 24 months decreased pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease. However, this strategy was also accompanied by increased carriage of azithromycin-resistant bacteria, the clinical consequences of which are uncertain, and will need careful monitoring and further study.

Funding

National Health and Medical Research Council (Australia) and Health Research Council (New Zealand).

Introduction

Bronchiectasis and chronic suppurative lung disease, which we collectively term bronchiectasis, unrelated to cystic fibrosis, is characterised by recurrent bacterial infection and airway inflammation.1, 2 Its prevalence is especially high in Indigenous children from high-income countries such as Australia, New Zealand, and the USA, ranging from 63 to 1600 per 100 000 children.2 Treatment of bronchiectasis aims to resolve acute infection and control infection and inflammation. Treatment improves symptoms (persistent or recurrent wet cough and breathlessness), reduces frequency of acute pulmonary exacerbations, preserves lung function, and improves quality of life.1 Pulmonary exacerbations (especially those needing admission to hospital) are the only known independent risk factor for long-term pulmonary decline in children with bronchiectasis.3 The public health importance of bronchiectasis is shown by Indigenous Australians dying from bronchiectasis in the third and fourth decades of life.4 This poor outcome might be the result of scarce access to medical care and delayed or inadequate treatment early in life, since lung function is stable when children are managed optimally.4

Because bacteria have a central role in pathogenesis,5 antibiotics are used to reduce bacterial load and accompanying airway inflammation.1, 6 Antibiotics are administered regularly for treatment of exacerbations;1, 6 however, their use as maintenance therapy over prolonged periods is controversial. Although long-term antibiotics might reduce exacerbations, the absence of high-quality evidence in children (and concerns about antibiotic resistance) means they are not recommended as routine treatment.1 Moreover, evidence is also scarce for Indigenous populations, who are among the most disadvantaged groups in affluent countries and for whom optimum management of disease is often most difficult to achieve.

In children with cystic fibrosis, 6 months of treatment with azithromycin leads to modest improvement in lung function, reduced pulmonary exacerbation rates, and improved weight gain.7 Its antimicrobial effects, anti-inflammatory actions, and prolonged half-life (allowing once-weekly oral dosing)8 make azithromycin an attractive option for maintenance treatment. Randomised controlled trials in adults with bronchiectasis showed that 6 months and 12 months of azithromycin reduced rates of pulmonary exacerbation and respiratory symptoms.9, 10 By contrast, there are no reported randomised controlled trials of long-term antibiotics in children with bronchiectasis, even though infective exacerbations in developing lungs could lead to substantial impairment of lung function in adulthood.11

Our study (the Bronchiectasis Intervention Study) aimed to establish whether long-term (24 months) antibiotic treatment with azithromycin would reduce the rate of pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis. We also monitored for serious adverse events associated with azithromycin and examined its effect on nasopharyngeal carriage of bacterial pathogens.12

Section snippets

Study design and participants

We did this multicentre, double-blind, randomised, parallel-group, placebo-controlled trial in Australia and New Zealand. Details of this study were described previously.13 Briefly, between Nov 12, 2008, and Dec 23, 2010, we enrolled Indigenous children from community clinics in central and northern Australia, and urban Maori and Pacific Island children from a tertiary paediatric hospital in Auckland (New Zealand) who were aged 1–8 years, lived within the study area, had either bronchiectasis

Results

Of 92 eligible children, 89 were enrolled, 45 were randomised to receive azithromycin and 44 placebo (figure 1). Of children enrolled, 75 (84%) received the intervention for 12 months or more (52 children [58%] received the intervention for 23–24 months [26 in each group] and 11 children [12%] for 18–22 months [four in the placebo group and seven in the azithromycin group]). Table 115 shows baseline characteristics. The most substantial difference was mechanical ventilation with more children

Discussion

We showed that once-weekly azithromycin administered for 12–24 months to Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease significantly reduced pulmonary exacerbations and improved weight-for-age Z-scores. Additionally, post-hoc analysis showed that children given azithromycin had significantly fewer non-pulmonary illnesses treated acutely with non-macrolide antibiotics. The study drug was well tolerated with no trial-medication-related differences

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