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 severe RSV infection, as the first successful treatment for acute and post-RSV
related respiratory exacerbation and has the potential to identify novel biomarkers of disease outcome.