The goal of this project is to establish that use of the macrolide azithromycin (AZM) during severe RSV bronchiolitis is an effective, simple, inexpensive, and safe intervention that substantially reduces the occurrence of post-RSV recurrent wheezing and potentially represents the first successful strategy for the prevention of asthma following RSV bronchiolitis. Asthma is the most common chronic disease of childhood, resulting in significant long-term morbidity. As asthma is not curable, investigation of asthma prevention strategies is highly desirable. Early life RSV bronchiolitis is a major risk factor for recurrent wheezing and asthma. The highest risk is among infants with severe bronchiolitis requiring hospitalization: up to 75% of hospitalized infants experience recurrent (?3) wheezing episodes and almost 50% are diagnosed with asthma by the age of 7 yrs. Therefore, prevention of recurrent wheeze following hospitalization for RSV bronchiolitis may reduce the subsequent diagnosis of asthma. Conventional asthma therapies are ineffective in attenuating post-RSV recurrent wheezing. Therefore, we have begun to investigate an innovative approach for the prevention of post-RSV wheeze: the utilization of the antibiotic AZM, which has beneficial effects in other inflammatory airway diseases. Our previous proof-of-concept trial in 40 infants hospitalized with RSV bronchiolitis has shown that AZM reduced the occurrence of recurrent wheeze during the subsequent year by approximately 50% and decreased markers of airway inflammation. Moreover, our preliminary studies have suggested that AZM's beneficial effects may also be related to its anti-bacterial effect on the airway microbiome. Based on our previous observations we propose to investigate the 2 following domains: 1. to perform a clinical trial evaluating if the addition of AZM, compared to placebo, to routine bronchiolitis care in 188 infants hospitalized with RSV bronchiolitis reduces the occurrence of recurrent (?3) wheezing episodes during the preschool years. 2. To examine how AZM changes the upper airway microbiome community structure over time; and to determine if these changes are related to the reduction in the occurrence of post-RSV recurrent wheeze. This trial may identify the first effective intervention to apply during severe RSV bronchiolitis wth the goal of preventing post-RSV recurrent wheeze, and ultimately asthma. If successful, this would have significant impact on society and the health system through reductions in morbidity and health care utilization associated with recurrent wheeze and asthma. The microbiome studies in this project should inform us how the AZM modifies the microbiome, and how these changes relate to the development of recurrent wheeze. Moreover, these findings may inform the development of microbiome-directed therapies for asthma prevention.