Microbial dynamics and pulmonary immune responses in COVID-19 secondary bacterial pneumonia
Natasha Spottiswoode, Alexandra Tsitsiklis, Victoria Chu, Hoang Van Phan, Catherine DeVoe, Christina Love, Rajani Ghale, Joshua Bloomstein, Beth Shoshana Zha, Cole Maguire, Abigail Glascock, Aartik Sarma, Peter M. Mourani, Katrina Kalantar, Angela M. Detweiler, Norma Neff, Sidney C. Haller, Saharai Caldera, Sarah B. Doernberg, Eran Mick, Hoang Van Phan, Paula Hayakawa Serpa, Deanna Lee, Maíra Phelps, Carolyn S. Calfee, Suzanna Chak, Stephanie A. Christenson, Walter L. Eckalbar, David J. Erle, Alejandra Jáuregui, Chayse Jones, Carolyn Leroux, Michael A. Matthay, Lucile Neyton, Viet Thanh Nguyen, Austin Sigman, Andrew Willmore, Prescott G. Woodruff, Michael Adkisson, Saurabh Asthana, Zachary Collins, Gabriela K. Fragiadakis, Lenka Maliskova, Ravi K. Patel, Arjun A. Rao, Bushra Samad, Andrew Schroeder, Cole Shaw, Kirsten N. Kangelaris, Divya Kushnoor, Tasha Lea, Kenneth H. Hu, Alan Shen, Jessica Tsui, Raymund Bueno, David Lee, Yang Sun, Erden Tumurbaatar, Alyssa Ward, Monique G.P. van der Wijst, Chun Ye, K. Mark Ansel, Vincent Chan, Kamir J. Hiam-Galvez, Elizabeth McCarthy, Priscila Muñoz-Sandoval, Anton Ogorodnikov, Matthew H. Spitzer, Wandi S. Zhu, M. Grace Gordon, George C. Hartoularos, Sadeed Rashid, Nicklaus Rodriguez, Kevin Tang, Luz Torres Altamirano, Alexander Whatley, Yun S. Song, Aleksandra Leligdowicz, Michael R. Wilson, Nayvin W. Chew, Alexis J. Combes, Tristan Courau, Norman L. Jones, Jeff Milush, Nitasha Kumar, Billy Huang, Salman Mahboob, Randy Parada, Gabriella C. Reeder, Joseph L. DeRisi, David J. Erle, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Matthew F. Krummel, Michael A. Matthay, Prescott G. Woodruff, Carolyn S. Calfee, Charles Langelier
Abstract
Secondary bacterial pneumonia (2°BP) is associated with significant morbidity following respiratory viral infection, yet remains incompletely understood. In a prospective cohort of 112 critically ill adults intubated for COVID-19, we comparatively assess longitudinal airway microbiome dynamics and the pulmonary transcriptome of patients who developed 2°BP versus controls who did not. We find that 2°BP is significantly associated with both mortality and corticosteroid treatment. The pulmonary microbiome in 2°BP is characterized by increased bacterial RNA mass and dominance of culture-confirmed pathogens, detectable days prior to 2°BP clinical diagnosis, and frequently also present in nasal swabs. Assessment of the pulmonary transcriptome reveals suppressed TNFα signaling in patients with 2°BP, and sensitivity analyses suggest this finding is mediated by corticosteroid treatment. Further, we find that increased bacterial RNA mass correlates with reduced expression of innate and adaptive immunity genes in both 2°BP patients and controls. Taken together, our findings provide fresh insights into the microbial dynamics and host immune features of COVID-19-associated 2°BP, and suggest that suppressed immune signaling, potentially mediated by corticosteroid treatment, permits expansion of opportunistic bacterial pathogens.