Azithromycin therapy feasible for paediatric cystic fibrosis management

In a newborn-screened cohort of children with cystic fibrosis (CF), azithromycin treatment from infancy to 36 months did not reduce the extent of structural lung disease (SLD). However, it did decrease airway inflammation and morbidity and improved some clinical outcomes associated with CF lung disease, the phase III COMBAT CF study has shown.

“Treatment with azithromycin did not affect the two primary outcomes for SLD,” said the researchers. At 36 months, there was no significant difference between the azithromycin and placebo arms in terms of the extent of radiologically defined bronchiectasis (median difference, 0.18 percent; p=0.46) and total airway disease (median difference, –0.02 percent; p=0.96). [Lancet Respir Med 2022;doi:10.1016/S2213-2600(22)00165-5]

The researchers said that this might have been due to the insensitivity of the PRAGMA-CF* algorithm to quantify small differences in the lung structure of young children owing to several factors. “These include the low number of airways captured due to their small size in relation to the resolution of the CT scans, low resolution for imaging the peripheral airways where early disease is most evident, and the diffuse and heterogenous lung disease in very young children.”

Favourable clinical, exploratory outcomes

The secondary endpoints however appeared to favour azithromycin over placebo, as indicated by the reductions in hospital days for pulmonary exacerbations in the former vs the latter arm (mean difference, –6.3 days; p=0.0037), as well as in the days of IV antibiotics each year (median difference, –6.7 days; p=0.018) and courses of inhaled or oral antibiotics (incidence rate ratio, 0.88; p=0.0088).

The exploratory analysis also showed a direct anti-inflammatory effect of azithromycin in the lower airways. Concentrations of airway inflammation were substantially lower in the azithromycin vs the placebo arm at age 36 months (median differences, –1.2 pg/mL; p=0.0012 [interleukin-8] and –0.6 μg/mL; p=0.0087 [neutrophil elastase activity]).

By age 3 months, most infants with CF have neutrophilic airway inflammation, which is tied to progressive airway disease and bronchiectasis. [Am J Respir Crit Care Med 2009;180:146-152; Thorax 2012;67:509-516; Eur Respir J 2019;54:1801771] Therefore, the treatment effect of azithromycin on airway inflammation is a clinically relevant observation, the researchers stressed.

“Given the strong association between neutrophilic inflammation and lung disease in all age groups and the particular role of neutrophil elastase in the progression of lung damage in early life, [our findings suggest that] azithromycin could be used as a safe and effective anti-inflammatory agent for continuous use in young children,” they said.

Innovative approach for early intervention

Early intervention with cost-effective and safe treatments that rehydrate the airways, reduce neutrophilic inflammation, and prevent release of destructive biochemical mediators is warranted for children with CF, especially for those who do not have access to transformative but expensive CFTR** modulator therapies.

High-dose ibuprofen is the only recommended anti-inflammatory agent for CF that reduces lung function decline in paediatric patients. [Ann Am Thorac Soc 2018;15:485-493; Am J Respir Crit Care Med 2007;176:1084-1089] “However, it is not generally recommended for use in young children … [A]zithromycin was a strong candidate as a useful anti-inflammatory agent in [this cohort],” the researchers noted.

The researchers therefore randomized 130 infants with CF from paediatric clinics in Australia and New Zealand (mean age 3.6 months) 1:1 to receive either azithromycin 10 mg/kg body weight orally TIW or matched placebo until age 36 months.

“[Overall, our findings show that azithromycin treatment is an] innovative approach to address the prevention of progressive lung disease that develops even before diagnosis after newborn screening,” said the researchers. “Therefore ... thrice-weekly azithromycin is a strategy that could be considered for the routine early management of paediatric patients with CF.”

The effect of early azithromycin intervention on SLD and lung function in later childhood shall be explored in a follow-up analysis.