Impaired immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19

Abstract

Secondary bacterial infections, including ventilator associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections. Critically ill patients with coronavirus disease 2019 (COVID-19) face an elevated risk of VAP, although susceptibility varies widely. Because mechanisms underlying VAP predisposition remained unknown, we assessed lower respiratory tract host immune responses and microbiome dynamics in 36 patients, including 28 COVID-19 patients, 15 of whom developed VAP, 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 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 patients who did not develop VAP. 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 clearance and persistent interferon signaling characterized the patients who later developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients who developed VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. Together, these findings demonstrate that COVID-19 patients who develop VAP have impaired antibacterial immune defense weeks before secondary infection onset.

Relationship between corticosteroid use and incidence of ventilator-associated pneumonia in COVID-19 patients: a retrospective multicenter study

“…Previous studies demonstrated a significantly higher incidence of VA-LRTI and notably VAP in SARS-CoV-2 pneumonia patients versus non-SARS-CoV-2 pneumonia patients [ 5 , 8 – 10 ]. High rates of ARDS, alveolar inflammation, prolonged IMV, lung microbiota alteration, COVID-19-related specific lesions, neuromuscular blocking and immunosuppressive agent use could explain this high rate of VAP in SARS-CoV-2 pneumonia patients [ 11 , 12 ].…”

Prophylactic application of antibiotics selects extended‐spectrum β‐lactamase and carbapenemases producing Gram‐negative bacteria in the oral cavity

“…Disruption of the lung microbiota community was found to be due to the overgrowth of the opportunistic pathogens in patients developing VAP compared to the critically ill patients without VAP (Tsitklis et al . 2021).…”

Phage therapy for secondary bacterial infections with COVID-19

“…Patients with BSIs had significantly longer hospitalizations, higher ICU admission and mortality rates compared to those without BSIs [ 13 • ]. Moreover, COVID-19-induced pathological processes such as accumulation of mucus, diffuse alveolar damage, impairment of immune signaling, and immune cell depletion may have facilitated the onset of SBIs and reduced the efficacy of drug treatment [ 7 , 19 , 20 ].…”