Azithromycin failed to reduce structural lung damage in infants with cystic fibrosis (CF) but could still form part of early management strategies given its impact on airway inflammation, exacerbations and hospitalisations, an Australian-led trial suggests.
In the phase 3 COMBAT CF study infants aged aged 3-6 months with newly diagnosed CF seen at eight paediatric CF centres in Australia and New Zealand were randomised to receive either azithromycin (n=68) or placebo (n=62) until three years of age.
The team, co-led by Professor Stephen Stick, Director the Wal-yan Respiratory Research Centre, Perth and Professor Peter Sly, of The University of Queensland aimed to determine whether early treatment with azithromycin could reduce lung damage using structural airway disease on CT imaging as the primary outcome measure.
Results, published in The Lancet Respiratory Medicine, showed that at 36 months “there were no differences between treatment groups with regards to the prevalence of structural lung abnormalities or measures of disease extent”.
This was most likely down to the relative insensitivity of the algorithm “to quantify small differences between individuals in lung structure due to a combination of factors in very young children”, including the low number of airways captured because of their small size in relation to the results of the CT scans.
However, the trial cohort will continue to be followed to determine whether early management of the disease with azithromycin might have an effect on structural lung disease and function later on in childhood.
While the trial failed to meet its primary endpoint, it did demonstrate that thrice weekly azithromycin reduced airway inflammation, morbidity including pulmonary exacerbations in the first year of life and hospitalisations, and improved some clinical outcomes associated with CF lung disease, the authors noted.
According to the data, in the treatment arm there were fewer days in hospital for pulmonary exacerbations (p=0·0037) and fewer courses of inhaled or oral antibiotics (p=0·0088), while concentrations of airway inflammation were also lower, including interleukin-8 (p=0·0012) and neutrophil elastase activity (p=0·0087).
“Whether the antimicrobial, anti-inflammatory, immunomodulatory, or other effects of azithromycin such as, gut prokinesis or epithelial sodium channel inhibition, are responsible for the effects on exacerbations and quality of life that we observed, is unclear”, the authors said.
Nevertheless, they suggested the combination of azithromycin with hypertonic saline in young children “might address cardinal factors in the early genesis and progression of lung damage in cystic fibrosis” and could potentially “improve and stabilise the early airway microenvironment until CFTR modulator therapies can be accessed”.
Professor Stick said azithromycin could be an early intervention to help change the trajectory of the disease in a group of children who are not yet able to access CF medications such as CFTR modulator therapies.
“Most modulators are approved for school-aged kids but not for those under four years old. So now we have a medication that is safe to use in early life that could slow the progression of the disease, until they are old enough for modulator therapies,” he said.
“Based on our study, treatment with azithromycin could significantly reduce the hospital cost for treating a young child with CF, which is about $12,000 a year,” he added.
However a commentary in the journal said that while study had provided proof of principal that inflammation can be modified with azithromycin in infancy, “more evidence will be needed to recommend its routine use in this age group.”
Professor Margaret Rosenfeld, Seattle Children’s Research Institute, and Dr Felix Ratjen, University of Toronto Hospital for Sick Children, said it was not clear whether the study did not meet its primary endpoint due to a true lack of effect, the few visible airways on low-dose CTs at age 36 months, or lack of power.
Nevertheless, “the effect on pulmonary exacerbations is noteworthy in that the trials of hypertonic saline in infants and preschool children have consistently found no treatment effect on exacerbations,” they acknowledged.
The authors observed that the treatment landscape for early CF was changing rapidly and it was likely infants with CF would get soon access to CFTR modulator therapies, and “the evidence for the efficacy of hypertonic saline as an early intervention strategy is now rather strong.”