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

Tsitsiklis, Alexandra; Zha, Beth; Byrne, Ashley; DeVoe, Catherine; Levan, Sophia; Rackaityte, Elze; Sunshine, Sara; Mick, Eran; Ghale, Rajani; Jauregui, Alejandra; Neff, Norma; Sarma, Aartik; Serpa, Paula; Deiss, Thomas; Kistler, Amy; Carrillo, Sidney; Ansel, K. Mark; Leligdowicz, Aleksandra; Christenson, Stephanie; Jones, Norman; Wu, Bing; Darmanis, Spyros; Matthay, Michael; Lynch, Susan; DeRisi, Joseph; Consortium, COMET; Hendrickson, Carolyn; Kangelaris, Kirsten; Krummel, Matthew; Woodruff, Prescott; Erle, David; Rosenberg, Oren; Calfee, Carolyn; Langelier, Charles

Secondary bacterial infections, including ventilator-associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections including in patients with coronavirus disease 2019 (COVID-19). Using a combination of tracheal aspirate bulk and single-cell RNA sequencing (scRNA-seq) we assessed lower respiratory tract immune responses and microbiome dynamics in 28 COVID-19 patients, 15 of whom developed VAP, and eight critically ill uninfected controls. Two days before VAP onset we observed a transcriptional signature of bacterial infection. Two weeks prior to VAP onset, following intubation, we observed a striking impairment in immune signaling in COVID-19 patients who developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients with VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. These findings suggest that COVID-19 patients who develop VAP have impaired antibacterial immune defense detectable weeks before secondary infection onset.