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Tsitsiklis A, Zha BS, Byrne A, et al. Impaired antibacterial immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19. medRxiv. 2021;doi: 10.1101/2021.03.23.21253487.
Tsitsiklis, A., Zha, B. S., Byrne, A., Devoe, C., Levan, S., Rackaityte, E., Sunshine, S., Mick, E., Ghale, R., Jauregui, A., Sarma, A., Neff, N., Serpa, P. H., Deiss, T. J., Kistler, A., Carrillo, S., Ansel, K. M., Leligdowicz, A., Christenson, S., Jones, N., Wu, B., Darmanis, S., Matthay, M. A., Lynch, S. V., DeRisi, J. L., Hendrickson, C. M., Kangelaris, K. N., Krummel, M. F., Woodruff, P. G., Erle, D. J., Rosenberg, O., Calfee, C. S., & Langelier, C. R. (2021). Impaired antibacterial immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19. medRxiv : the preprint server for health sciences, . https://doi.org/10.1101/2021.03.23.21253487
Tsitsiklis, Alexandra, et al. "Impaired antibacterial immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19." medRxiv : the preprint server for health sciences vol. (2021). doi: https://doi.org/10.1101/2021.03.23.21253487
Tsitsiklis A, Zha BS, Byrne A, Devoe C, Levan S, Rackaityte E, Sunshine S, Mick E, Ghale R, Jauregui A, Sarma A, Neff N, Serpa PH, Deiss TJ, Kistler A, Carrillo S, Ansel KM, Leligdowicz A, Christenson S, Jones N, Wu B, Darmanis S, Matthay MA, Lynch SV, DeRisi JL, Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Erle DJ, Rosenberg O, Calfee CS, Langelier CR. Impaired antibacterial immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19. medRxiv. 2021 Mar 26; doi: 10.1101/2021.03.23.21253487. PMID: 33791731; PMCID: PMC8010763.
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medRxiv. 2021 Mar 26; doi: 10.1101/2021.03.23.21253487.

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

medRxiv : the preprint server for health sciences

Alexandra Tsitsiklis, Beth Shoshana Zha, Ashley Byrne, Catherine Devoe, Sophia Levan, Elze Rackaityte, Sara Sunshine, Eran Mick, Rajani Ghale, Alejandra Jauregui, Aartik Sarma, Norma Neff, Paula Hayakawa Serpa, Thomas J Deiss, Amy Kistler, Sidney Carrillo, K Mark Ansel, Aleksandra Leligdowicz, Stephanie Christenson, Norman Jones, Bing Wu, Spyros Darmanis, Michael A Matthay, Susan V Lynch, Joseph L DeRisi, Carolyn M Hendrickson, Kirsten N Kangelaris, Matthew F Krummel, Prescott G Woodruff, David J Erle, Oren Rosenberg, Carolyn S Calfee, Charles R Langelier

PMID: 33791731 PMCID: PMC8010763 DOI: 10.1101/2021.03.23.21253487

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.

ONE SENTENCE SUMMARY: COVID-19 patients with secondary bacterial pneumonia have impaired immune signaling and lung microbiome changes weeks before onset.

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