Abstract
Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.
Competing Interest Statement
The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines which list Florian Krammer as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Florian Krammer has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures, Merck and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. Viviana Simon is a co-inventor on a patent filed relating to SARS-CoV-2 serological assays (the "Serology Assays"). Ofer Levy is a named inventor on patents held by Boston Childrens Hospital relating to vaccine adjuvants and human in vitro platforms that model vaccine action. His laboratory has received research support from GlaxoSmithKline (GSK). Charles Cairns serves as a consultant to bioMerieux and is funded for a grant from Bill & Melinda Gates Foundation. James A Overton is a consultant at Knocean Inc. Jessica Lasky-Su serves as a scientific advisor of Precion Inc. Scott R. Hutton, Greg Michelloti and Kari Wong are employees of Metabolon Inc. Vicki Seyfer- Margolis is a current employee of MyOwnMed. Nadine Rouphael reports contracts with Lilly and Sanofi for COVID-19 clinical trials and serves as a consultant for ICON EMMES for consulting on safety for COVID19 clinical trials. Adeeb Rahman is a current employee of Immunai Inc. Steven Kleinstein is a consultant related to ImmPort data repository for Peraton. Nathan Grabaugh is a consultant for Tempus Labs and the National Basketball Association. Akiko Iwasaki is a consultant for 4BIO, Blue Willow Biologics, Revelar Biotherapeutics, RIGImmune, Xanadu Bio, Paratus Sciences. Monika Kraft receives research funds paid to her institution from NIH, ALA; Sanofi, Astra-Zeneca for work in asthma, serves as a consultant for Astra-Zeneca, Sanofi, Chiesi, GSK for severe asthma; is a co-founder and CMO for RaeSedo, Inc, a company created to develop peptidomimetics for treatment of inflammatory lung disease. Esther Melamed received research funding from Babson Diagnostics, honorarium from Multiple Sclerosis Association of America and has served on advisory boards of Genentech, Horizon, Teva and Viela Bio. Carolyn Calfee receives research funding from NIH, FDA, DOD, Roche-Genentech and Quantum Leap Healthcare Collaborative as well as consulting services for Janssen, Vasomune, Gen1e Life Sciences, NGMBio, and Cellenkos. Wade Schulz was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to Hugo Health, a personal health information platform; cofounder of Refactor Health, an AI-augmented data management platform for health care; and has received grants from Merck and Regeneron Pharmaceutical for research related to COVID-19.
Footnotes
↵# The IMPACC Network
National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD 20814, USA: Patrice M. Becker, Alison D. Augustine, Steven M. Holland, Lindsey B. Rosen, Serena Lee, Tatyana Vaysman
Clinical and Data Coordinating Center (CDCC) Precision Vaccines Program, Boston Children’s Hospital, Boston, MA 02115, USA: Al Ozonoff, Joann Diray-Arce, Jing Chen, Alvin Kho, Carly E. Milliren, Annmarie Hoch, Ana C. Chang, Kerry McEnaney, Brenda Barton, Claudia Lentucci, Maimouna D. Murphy, Mehmet Saluvan, Tanzia Shaheen, Shanshan Liu, Caitlin Syphurs, Marisa Albert, Arash Nemati Hayati, Robert Bryant, James Abraham, Sanya Thomas, Mitchell Cooney
Benaroya Research Institute, University of Washington, Seattle, WA 98101, USA: Matthew C. Altman, Naresh Doni Jayavelu, Scott Presnell, Bernard Kohr, Tomasz Jancsyk, Azlann Arnett La Jolla Institute for Immunology, La Jolla, CA 92037, USA: Bjoern Peters, James A. Overton, Randi Vita, Kerstin Westendorf
Knocean Inc. Toronto, ON M6P 2T3, Canada: James A. Overton
Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA: Ofer Levy, Hanno Steen, Patrick van Zalm, Benoit Fatou, Kinga Smolen, Arthur Viode, Simon van Haren, Meenakshi Jha
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA: Lindsey R. Baden, Kevin Mendez, Jessica Lasky-Su, Alexandra Tong, Rebecca Rooks, Michael Desjardins, Amy C. Sherman, Stephen R. Walsh, Xhoi Mitre, Jessica Cauley, Xiofang Li, Bethany Evans, Christina Montesano, Jose Humberto Licona, Jonathan Krauss, Nicholas C. Issa, Jun Bai Park Chang, Natalie Izaguirre
Metabolon Inc, Morrisville, NC 27560, USA: Scott R. Hutton, Greg Michelotti, Kari Wong Prevention of Organ Failure (PROOF) Centre of Excellence, University of British Columbia, Vancouver, BC V6T 1Z3, Canada: Scott J. Tebbutt, Casey P. Shannon
Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA: Rafick-Pierre Sekaly, Slim Fourati, Grace A. McComsey, Paul Harris, Scott Sieg, Susan Pereira Ribeiro
Drexel University, Tower Health Hospital, Philadelphia, PA 19104, USA: Charles B. Cairns, Elias K. Haddad, Michele A. Kutzler, Mariana Bernui, Gina Cusimano, Jennifer Connors, Kyra Woloszczuk, David Joyner, Carolyn Edwards, Edward Lee, Edward Lin, Nataliya Melnyk, Debra L. Powell, James N. Kim, I. Michael Goonewardene, Brent Simmons, Cecilia M. Smith, Mark Martens, Brett Croen, Nicholas C. Semenza, Mathew R. Bell, Sara Furukawa, Renee McLin, George P. Tegos, Brandon Rogowski, Nathan Mege, Kristen Ulring, Pam Schearer, Judie Sheidy, Crystal Nagle
MyOwnMed Inc., Bethesda, MD 20817, USA: Vicki Seyfert-Margolis
Emory School of Medicine, Atlanta, GA 30322, USA: Nadine Rouphael, Steven E. Bosinger, Arun K. Boddapati, Greg K. Tharp, Kathryn L. Pellegrini, Brandi Johnson, Bernadine Panganiban, Christopher Huerta, Evan J. Anderson, Hady Samaha, Jonathan E. Sevransky, Laurel Bristow, Elizabeth Beagle, David Cowan, Sydney Hamilton, Thomas Hodder, Amer Bechnak, Andrew Cheng, Aneesh Mehta, Caroline R. Ciric, Christine Spainhour, Erin Carter, Erin M. Scherer, Jacob Usher, Kieffer Hellmeister, Laila Hussaini, Lauren Hewitt, Nina Mcnair, Susan Pereira Ribeiro
Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA: Ana Fernandez-Sesma, Viviana Simon, Florian Krammer, Harm Van Bakel, Seunghee Kim-Schulze, Ana Silvia Gonzalez-Reiche, Jingjing Qi, Brian Lee, Juan Manuel Carreño, Gagandeep Singh, Ariel Raskin, Johnstone Tcheou, Zain Khalil, Adriana van de Guchte, Keith Farrugia, Zenab Khan, Geoffrey Kelly, Komal Srivastava, Lily Q. Eaker, Maria C. Bermúdez-González, Lubbertus C.F. Mulder,
Katherine F. Beach, Miti Saksena, Deena Altman, Erna Kojic, Levy A. Sominsky, Arman Azad, Dominika Bielak, Hisaaki Kawabata, Temima Yellin, Miriam Fried, Leeba Sullivan, Sara Morris, Gliulio Kleiner, Daniel Stadlbauer, Jayeeta Dutta, Hui Xie, Manishkumar Patel, Kai Nie Immunai Inc. New York, NY 10016, USA: Adeeb Rahman
Oregon Health Sciences University, Portland, OR 97239, USA: William B. Messer, Catherine L. Hough, Sarah A.R. Siegel, Peter E. Sullivan, Zhengchun Lu, Amanda E. Brunton, Matthew Strnad, Zoe L. Lyski, Felicity J. Coulter, Courtney Micheleti
Stanford University School of Medicine, Palo Alto, CA 94305, USA: Holden Maecker, Bali Pulendran, R. Kari C. Nadeau, Yael Rosenberg-Hasson, Michael Leipold, Natalia Sigal, Angela Rogers, Andrea Fernandes, Monali Manohar, Evan Do, Iris Chang, Alexandra S. Lee, Catherine Blish, Henna Naz Din, Jonasel Roque, Linda Geng, Maja Artandi, Mark M. Davis, Neera Ahuja, Samuel S. Yang, Sharon Chinthrajah, Thomas Hagan
David Geffen School of Medicine at the University of California Los Angeles, Los Angeles CA 90095, USA: Elaine F. Reed, Joanna Schaenman, Ramin Salehi-Rad, Adreanne M. Rivera, Harry C. Pickering, Subha Sen, David Elashoff, Dawn C. Ward, Jenny Brook, Estefania Ramires-Sanchez, Megan Llamas, Claudia Perdomo, Clara E. Magyar, Jennifer Fulcher University of California San Francisco, San Francisco, CA 94115, USA: David J. Erle, Carolyn S. Calfee, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Viet Nguyen, Deanna Lee, Suzanna Chak, Rajani Ghale, Ana Gonzalez, Alejandra Jauregui, Carolyn Leroux, Luz Torres Altamirano, Ahmad Sadeed Rashid, Andrew Willmore, Prescott G. Woodruff, Matthew F. Krummel, Sidney Carrillo, Alyssa Ward, Charles R. Langelier, Ravi Patel, Michael Wilson, Ravi Dandekar, Bonny Alvarenga, Jayant Rajan, Walter Eckalbar, Andrew W. Schroeder, Gabriela K. Fragiadakis, Alexandra Tsitsiklis, Eran Mick, Yanedth Sanchez Guerrero, Christina Love, Lenka Maliskova, Michael Adkisson, Aleksandra Leligdowicz, Alexander Beagle, Arjun Rao, Austin Sigman, Bushra Samad, Cindy Curiel, Cole Shaw, Gayelan Tietje-Ulrich, Jeff Milush, Jonathan Singer, Joshua J. Vasquez, Kevin Tang, Legna Betancourt, Lekshmi Santhosh, Logan Pierce, Maria Tecero Paz, Michael Matthay, Neeta Thakur, Nicklaus Rodriguez, Nicole Sutter, Norman Jones, Pratik Sinha, Priya Prasad, Raphael Lota, Sadeed Rashid, Saurabh Asthana, Sharvari Bhide, Tasha Lea, Yumiko Abe-Jones
Yale School of Medicine, New Haven, CT 06510, USA: David A. Hafler, Ruth R. Montgomery, Albert C. Shaw, Steven H. Kleinstein, Jeremy P. Gygi, Shrikant Pawar, Anna Konstorum, Ernie Chen, Chris Cotsapas, Xiaomei Wang, Leqi Xu, Charles Dela Cruz, Akiko Iwasaki, Subhasis Mohanty, Allison Nelson, Yujiao Zhao, Shelli Farhadian, Hiromitsu Asashima, Omkar Chaudhary, Andreas Coppi, John Fournier, M. Catherine Muenker, Allison Nelson, Khadir Raddassi, Michael Rainone, William Ruff, Syim Salahuddin, Wade L. Shulz, Pavithra Vijayakumar, Haowei Wang, Esio Wunder Jr., H. Patrick Young, Albert I. Ko, Xiomei Wang
Yale School of Public Health, New Haven, CT 06510, USA: Denise Esserman, Leying Guan, Anderson Brito, Jessica Rothman, Nathan D. Grubaugh
Baylor College of Medicine and the Center for Translational Research on Inflammatory Diseases, Houston, TX 77030, USA: David B. Corry, Farrah Kheradmand, Li-Zhen Song, Ebony Nelson
Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA: Jordan P. Metcalf, Nelson I. Agudelo Higuita, Lauren A. Sinko, J. Leland Booth, Douglas A. Drevets, Brent R. Brown
University of Arizona, Tucson AZ 85721, USA: Monica Kraft, Chris Bime, Jarrod Mosier, Heidi Erickson, Ron Schunk, Hiroki Kimura, Michelle Conway, Dave Francisco, Allyson Molzahn, Connie Cathleen Wilson, Ron Schunk, Trina Hughes, Bianca Sierra
University of Florida, Gainesville, FL 32611, USA: Mark A. Atkinson, Scott C. Brakenridge, Ricardo F. Ungaro, Brittany Roth Manning, Lyle Moldawer
University of Florida, Jacksonville, FL 32218, USA: Jordan Oberhaus, Faheem W. Guirgis University of South Florida, Tampa FL 33620, USA: Brittney Borresen, Matthew L. Anderson
University of Texas, Austin, TX 78712, USA: Lauren I. R. Ehrlich, Esther Melamed, Cole Maguire, Dennis Wylie, Justin F. Rousseau, Kerin C. Hurley, Janelle N. Geltman, Nadia Siles, Jacob E. Rogers.
