Secondary
bacterial infections MESHD, including ventilator associated
pneumonia MESHD (VAP), lead to worse clinical outcomes and increased mortality following viral
respiratory infections MESHD.
Critically ill MESHD patients with
coronavirus disease 2019 MESHD (
COVID-19 MESHD) face an elevated risk of VAP, although susceptibility varies widely. Because mechanisms underlying
VAP MESHD predisposition remained unknown, we assessed lower respiratory tract host immune responses and microbiome dynamics in 36 patients, including 28
COVID-19 MESHD patients, 15 of whom developed
VAP MESHD, and eight critically ill controls. We employed a combination of tracheal aspirate bulk and single cell RNA sequencing (scRNA-seq). Two days before VAP onset, a lower respiratory transcriptional signature of
bacterial infection MESHD was observed, characterized by increased expression of neutrophil degranulation, toll-like receptor and cytokine signaling pathways. When assessed at an earlier time point following endotracheal intubation, more than two weeks prior to VAP onset, we observed a striking early impairment in antibacterial innate and adaptive immune signaling that markedly differed from
COVID-19 MESHD patients who did not develop
VAP MESHD. scRNA-seq further demonstrated suppressed immune signaling across monocytes/macrophages, neutrophils and T cells. While viral load did not differ at an early post-intubation timepoint,
impaired SARS-CoV-2 MESHD clearance and persistent interferon signaling characterized the patients who later developed
VAP MESHD. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients who developed
VAP MESHD, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. Together, these findings demonstrate that
COVID-19 MESHD patients who develop
VAP MESHD have impaired antibacterial immune defense weeks before secondary infection onset.