Lung disease caused by Respiratory Syncytial Virus (RSV) is associated with substantial short and long-term morbidity for infants and children. Despite this far-reaching disease burden, current management is limited. Developing an effective intervention for acute infection with RSV would have an enormous impact on the public health of children. Matrix metalloproteinase (MMP)-9 is a protease that has been implicated in RSV pathogenesis. Azithromycin (AZM) is a commonly used macrolide antibiotic with a well-known safety profile that has immunomodulatory effects that have been beneficial against other inflammatory airway diseases and may work through an MMP-9-based mechanism of action. We completed a Phase II, randomized controlled trial (RCT) of high-dose AZM [20 mg/kg (IV) x 3 days], and demonstrated that the treatment was safe and associated with decreased hospital length of stay and decreased endotracheal MMP-9 concentrations in mechanically-ventilated children. Taken together, these data provide compelling evidence that justifies a multi-centered Phase III RCT to determine the effectiveness of AZM. The overarching hypothesis of the ARRC Trial (AZM treatment for RSV-induced Respiratory Failure in Children) is administration of AZM during acute, RSV-induced respiratory failure will be beneficial, mediated through an MMP-9 pathway. To test this overall hypothesis, we have developed a research network of pediatric critical care physicians to enroll 370 children in a double-masked placebo-controlled RCT of high-dose AZM. Inclusion criteria will be age less than 2 years and acute respiratory failure secondary to RSV infection requiring ICU admission with intensive respiratory support [defined as mechanical ventilation, non-invasive bi-level positive airway pressure (BiPAP), continuous positive end-expiratory pressure (CPAP) or high-flow nasal cannula (HFNC) therapy of > 1L/kg/min of flow]. Exclusion criteria includes previous use of AZM within 7 days, cardiac arrhythmias, chronic home ventilation/oxygenation and immunosuppressive conditions. We will test the following aims: 1: High-dose AZM administration will result in decreased length of hospital stay, decreased duration of oxygen therapy and decreased ICU length of stay. Enrolled patients will be administered high-dose AZM or placebo, receive all other therapies based on standard American Academy of Pediatrics guidelines for RSV infection, and outcomes will be assessed; 2: Administration of high-dose AZM will result in reduced number of wheezing episodes over 12 months after primary infection and the time to the first wheezing episode and 3: Nasal markers of MMP-9 driven lung inflammation will be decreased in patients receiving AZM, and predictive of outcome. Successful completion of this impactful grant application will determine the effectiveness of AZM on the recovery of children with severe RSV infection. A positive result from this trial will represent a paradigm shift in the management of se...