Abstract
Despite a high disease burden, there is no effective treatment for respiratory syncytial virus (RSV) infection. To determine whether administration of azithromycin (AZM) to children with RSV-induced respiratory failure is safe and to define the effect of AZM therapy on nasal matrix metalloproteinase 9 (MMP-9) levels. This randomized, double-blind, placebo-controlled phase 2 trial was conducted at a single tertiary pediatric intensive care unit from February 2016 to February 2019. The study included children with RSV infection who were admitted to the pediatric intensive care unit and required respiratory support via positive pressure ventilation (invasive and noninvasive). A total of 147 children were screened; 90 were excluded for not meeting inclusion criteria, having an absent legal guardian, lacking pharmacy support, or having a language barrier and 9 declined participation, resulting in 48 patients enrolled in the study. Receipt of standard dose AZM (10 mg/kg/d), high-dose AZM (20 mg/kg/d), or a matching placebo of normal saline intravenously for 3 days. Nasal and endotracheal samples were collected at baseline as well as at 24 hours and 48 hours after start of treatment. The secondary outcome was to determine treatment effect on clinical outcome measures, including days of positive pressure ventilation and length of hospital stay. A total of 48 patients were enrolled in the trial, with a median (range) age at randomization of 12 (1 to 125) months; 36 participants (75.0%) were younger than 2 years. Overall, 26 participants (54.2%) were boys, and 29 (60.4%) had a comorbidity. A total of 16 patients were randomized into each trial group (ie, placebo, standard-dose AZM, and high-dose AZM). Baseline demographic characteristics were comparable among the 3 groups. Both doses of AZM were safe, with no adverse events observed. No difference in nasal MMP-9 levels were observed between treatment groups. Among those who required mechanical ventilation and received high-dose AZM, endotracheal active and total MMP-9 levels were lower on day 3. Compared with baseline, active and total MMP-9 levels in endotracheal aspirates were 1.0 log lower in the high-dose AZM group (active MMP-9: 99.8% CI, -1.28 to -0.64; P < .001; total MMP-9: 99.8% CI, -1.37 to -0.57; P < .001). Patients who received high-dose AZM had fewer median (interquartile range) hospital days compared with those receiving the placebo (8 [6-14] days vs 11 [8-20] days; mean ratio estimate, 0.57; 95% CI, 0.38-0.87; P = .01). In this phase 2 randomized clinical trial, both doses of AZM were safe. While nasal MMP-9 levels were unchanged among treatment groups, endotracheal MMP-9 levels were lower among those who received high-dose AZM. The positive secondary clinical outcome, while exploratory, provides insight for end points in a multicenter randomized trial. ClinicalTrials.gov Identifier: NCT02707523.
Highlights
IntroductionRespiratory syncytial virus (RSV) infection has a substantial global disease burden.[1,2,3,4] Matrix metalloproteinases (MMPs) are proteases implicated in the pathogenesis of both acute and chronic lung disease.[5,6,7,8,9,10,11] In 2015, we reported[12] that early elevation of endotracheal matrix metalloproteinase 9 (MMP-9) levels was positively associated with RSV disease severity and that MMP-9 inhibition decreased RSV replication in a murine model, suggesting that MMP-9 might be a potential marker of disease severity and a therapeutic target in RSV disease.Macrolides are a class of antibiotics that are known to penetrate cells, making them active against intracellular pathogens; azithromycin (AZM) is reported to have a long intracellular half-life.[13]
No difference in nasal matrix metalloproteinase 9 (MMP-9) levels were observed between treatment groups
While nasal Matrix metalloproteinases (MMPs)-9 levels were unchanged among treatment groups, endotracheal MMP-9 levels were lower among those who received high-dose AZM
Summary
Respiratory syncytial virus (RSV) infection has a substantial global disease burden.[1,2,3,4] Matrix metalloproteinases (MMPs) are proteases implicated in the pathogenesis of both acute and chronic lung disease.[5,6,7,8,9,10,11] In 2015, we reported[12] that early elevation of endotracheal MMP-9 levels was positively associated with RSV disease severity and that MMP-9 inhibition decreased RSV replication in a murine model, suggesting that MMP-9 might be a potential marker of disease severity and a therapeutic target in RSV disease.Macrolides are a class of antibiotics that are known to penetrate cells, making them active against intracellular pathogens; azithromycin (AZM) is reported to have a long intracellular half-life.[13]. AZM is an immune modulator that has been reported to provide clinical benefit in inflammatory airway diseases.[14,15] we performed a randomized, placebo-controlled phase 2 trial to test the hypothesis that AZM therapy during RSV-induced respiratory failure was safe and would reduce nasal and lung MMP-9 levels as well as to explore preliminary effects on the disease course for planning a subsequent definitive trial
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