Patients with asthma experience circadian variations in their symptoms. However it remains unclear how specific aspects of this common airway disease relate to clock genes, which are critical to the generation of circadian rhythms in mammals. Here, we used a viral model of acute and chronic airway disease to examine how circadian clock disruption affects asthmatic lung phenotypes. Deletion of the core clock gene bmal1 or environmental disruption of circadian function by jet-lag exacerbated acute viral bronchiolitis caused by Sendai virus (SeV) and influenza A virus (IAV) in mice. Post-natal deletion of bmal1 was sufficient to trigger increased SeV susceptibility and correlated with impaired control of viral replication. Importantly, bmal1−/− mice developed much more extensive asthma-like airway changes post-infection, including mucus production and increased airway resistance. In human airway samples from two asthma cohorts, we observed altered expression patterns of multiple clock genes. Our results suggest a role for bmal1 in the development of asthmatic airway disease via the regulation of lung antiviral responses to common viral triggers of asthma.

Background Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. As azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in humans may provide a strategy for the prevention of post-bronchiolitis recurrent wheezing. Objectives To investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of post-bronchiolitis recurrent wheezing. Method A randomized, double-masked, placebo-controlled, proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks. Results Compared to placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (p=0.6), but resulted in a greater decline in nasal lavage IL-8 by day 15 (p=0.03). 22% of azithromycin-treated participants experienced at least 3 wheezing episodes compared to 50% of participants in the placebo group (p=0.07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (p=0.048), and in fewer days with respiratory symptoms over the subsequent year in comparison to placebo (36.7 vs. 70.1 days; p=0.01). Conclusion In this proof-of-concept study, azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to a third wheezing episode, and reduced overall respiratory morbidity over the subsequent year.

Among this cohort of infants that were hospitalized for RSV bronchiolitis, vitamin D status at the time of bronchiolitis was not associated with indicators of acute bronchiolitis severity.

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