Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19
Lucile Neyton, Ravi K. Patel, Aartik Sarma, K. Mark Ansel, Stephanie A. Christenson, Michael Adkisson, Walter L. Eckalbar, Lenka Maliskova, Andrew Schroeder, Raymund Bueno, M. Grace Gordon, George C. Hartoularos, Divya Kushnoor, David Lee, Elizabeth McCarthy, Anton Ogorodnikov, Matthew H. Spitzer, Kamir Hiam, Yun S. Song, Yang Sun, Erden Tumurbaatar, Monique G.P. van der Wijst, Alexander Whatley, Chayse Jones, Saharai Caldera, Catherine DeVoe, Paula Hayakawa Serpa, Christina Love, Eran Mick, Maíra Phelps, Alexandra Tsitsiklis, Carolyn Leroux, Sadeed Rashid, Nicklaus Rodriguez, Kevin Tang, Luz Torres Altamirano, Aleksandra Leligdowicz, Michael A. Matthay, Michael R. Wilson, Chun Ye, Suzanna Chak, Rajani Ghale, Alejandra Jáuregui, Deanna Lee, Nguyễn Hoàng Việt, Austin Sigman, Kirsten N. Kangelaris, Saurabh Asthana, Zachary Collins, Ravi K. Patel, Arjun A. Rao, Bushra Samad, Cole Shaw, Tasha Lea, Alyssa Ward, Norman L. Jones, Jeff Milush, Vincent Chan, Nayvin W. Chew, Alexis J. Combes, Tristan Courau, Kenneth H. Hu, Billy Huang, Nitasha Kumar, Salman Mahboob, Priscila Muñoz-Sandoval, Randy Parada, Gabriella C. Reeder, Alan Shen, Jessica Tsui, Beth Shoshana Zha, Wandi S. Zhu, Andrew Willmore, Sidney C. Haller, Kirsten N. Kangelaris, Walter L. Eckalbar, David J. Erle, Matthew F. Krummel, Carolyn M. Hendrickson, Prescott G. Woodruff, Charles Langelier, Carolyn S. Calfee, Gabriela K. Fragiadakis
Abstract
Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.