Abstract
BackgroundViral bronchiolitis is the leading cause of hospitalization in young infants. It is associated with the development of childhood asthma and contributes to morbidity and mortality in the elderly. Currently no therapies effectively attenuate inflammation during the acute viral infection, or prevent the risk of post-viral asthma. We hypothesized that early treatment of a paramyxoviral bronchiolitis with azithromycin would attenuate acute and chronic airway inflammation.MethodsMice were inoculated with parainfluenza type 1, Sendai Virus (SeV), and treated daily with PBS or azithromycin for 7 days post-inoculation. On day 8 and 21 we assessed airway inflammation in lung tissue, and quantified immune cells and inflammatory mediators in bronchoalveolar lavage (BAL).ResultsCompared to treatment with PBS, azithromycin significantly attenuated post-viral weight loss. During the peak of acute inflammation (day 8), azithromycin decreased total leukocyte accumulation in the lung tissue and BAL, with the largest fold-reduction in BAL neutrophils. This decreased inflammation was independent of changes in viral load. Azithromycin significantly attenuated the concentration of BAL inflammatory mediators and enhanced resolution of chronic airway inflammation evident by decreased BAL inflammatory mediators on day 21.ConclusionsIn this mouse model of paramyxoviral bronchiolitis, azithromycin attenuated acute and chronic airway inflammation. These findings demonstrate anti-inflammatory effects of azithromycin that are not related to anti-viral activity. Our findings support the rationale for future prospective randomized clinical trials that will evaluate the effects of macrolides on acute viral bronchiolitis and their long-term consequences.
Highlights
Viral bronchiolitis is the leading cause of hospitalization in young infants
Azithromycin attenuated viral-dependent weight loss To determine if azithromycin could confer anti-inflammatory properties in a mouse model of viral bronchiolitis, we inoculated mice on day 0 with Sendai Virus (SeV) (5,000 egg infectious dose 50%, 5 K) and treated the mice daily with azithromycin or PBS from day 0 to day 7 (Figure 1A)
To assess whether azithromycin treatment would be beneficial using a higher infectious dose, we performed an experiment using a lethal infectious dose of virus (50,000 egg infectious dose 50%, 50 K). Treatment of this lethal infection with azithromycin did not significantly alter weight loss, overall survival or delay the time of death compared to treatment with PBS (N = 5 in each cohort). These results demonstrated that azithromycin treatment, in the 5 K infectious dose, attenuated some clinical features of the severity of the acute viral bronchiolitis
Summary
Viral bronchiolitis is the leading cause of hospitalization in young infants. It is associated with the development of childhood asthma and contributes to morbidity and mortality in the elderly. No therapies effectively attenuate inflammation during the acute viral infection, or prevent the risk of post-viral asthma. The rate of admissions has doubled in the past 2 decades [3]; as a result, severe RSV bronchiolitis is the leading cause of hospitalization in infants younger the age of 1 year [4]. Chronic respiratory symptoms are common after severe RSV bronchiolitis, with about 40% of hospitalized children eventually developing asthma [5,6,7,8]. Definitive conclusions regarding the usefulness of macrolides as a treatment of viral-bronchiolitis cannot be made at this time
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