Etiology of lower respiratory tract infections in children requiring mechanical ventilation: a multicenter prospective surveillance study incorporating airway metagenomics

Background: Lower respiratory tract infections (LRTI) are a leading cause of critical illness and mortality in invasive mechanically ventilated children. Despite this, the pathogenic microbes in this vulnerable demographic frequently remain unknown. Metagenomic next generation sequencing (mNGS) can complement traditional diagnostics in epidemiologic surveillance studies by providing broad-range pathogen detection.Methods: We conducted a prospective, multicenter cohort study of critically ill children ages 31 days to 17 years with respiratory failure requiring prolonged mechanical ventilation in the United States from February 2015 to December 2017. Using a combination of clinically-ordered testing and tracheal aspirate mNGS we determined the prevalence, seasonal variation, and genetic relatedness of respiratory pathogens in children with clinically adjudicated LRTI (n=276) or no LRTI (n=121).Findings: A presumptive microbiologic etiology was identified in 92% of children, with RSV (46%), Haemophilus influenzae (25%) and Moraxella catarrhalis (24%) being most common. mNGS identified uncommon pathogens including Ureaplasma parvum (Interpretation: The combination of clinical diagnostics and mNGS enabled comprehensive pathogen surveillance in critically ill children with LRTI. RSV, H. influenzae, and M. catarrhalis were disproportionately represented. Carriage of potentially pathogenic microbes was common in children without LRTI.