Identification of Distinct Clinical Subphenotypes in Critically Ill Patients With COVID-19
Charles R. Vasquez, Shruti Gupta, Todd A. Miano, Meaghan S. Roche, Jesse Y. Hsu, Wei Yang, Daniel N. Holena, John P. Reilly, Sarah J. Schrauben, David E. Leaf, M.G.S. Shashaty, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, Thuy-Duyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Megan L. Krajewski, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoé A. Kibbelaar, Ambarish M. Athavale, Peter C. Hart, Shristi Upadhyay, Ishaan Vohra, Oyintayo Ajiboye, Adam Green, Jean-Sébastien Rachoin, Christa Schorr, Lisa Shea, Daniel Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick‐Santoyo, Gabriela Bambrick-Santoyo, Bijal Mehta, Aquino Williams, Samantha K. Brenner, Patricia Walters, Ronaldo C. Go, Keith Rose, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Pattharawin Pattharanitima, Emily J. Gallagher, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Katherine J. Kelly, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona‐Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, C. Elena Cervantes, Samir C. Gautam, Mary C. Mallappallil, Jie Ouyang, Sabu John, Ernie Yap, Yohannes Adama Melaku, Ibrahim Mohamed, Siddhartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John E. Wagner, Leon Boudourakis, H. Bryant Nguyen, Afshin Ahoubim, Kianoush Kashani, Shahrzad Tehranian, Leslie F. Thomas, Dheeraj Reddy Sirganagari, Pramod Guru, Yan Zhou, Paul A. Bergl, Jesús Rodríguez, Jatan A. Shah, Mrigank S. Gupta, Princy Kumar, Deepa G. Lazarous
Abstract
BACKGROUND: Subphenotypes have been identified in patients with sepsis and ARDS and are associated with different outcomes and responses to therapies. RESEARCH QUESTION: Can unique subphenotypes be identified among critically ill patients with COVID-19? STUDY DESIGN AND METHODS: Using data from a multicenter cohort study that enrolled critically ill patients with COVID-19 from 67 hospitals across the United States, we randomly divided centers into discovery and replication cohorts. We used latent class analysis independently in each cohort to identify subphenotypes based on clinical and laboratory variables. We then analyzed the associations of subphenotypes with 28-day mortality. RESULTS: Latent class analysis identified four subphenotypes (SP) with consistent characteristics across the discovery (45 centers; n = 2,188) and replication (22 centers; n = 1,112) cohorts. SP1 was characterized by shock, acidemia, and multiorgan dysfunction, including acute kidney injury treated with renal replacement therapy. SP2 was characterized by high C-reactive protein, early need for mechanical ventilation, and the highest rate of ARDS. SP3 showed the highest burden of chronic diseases, whereas SP4 demonstrated limited chronic disease burden and mild physiologic abnormalities. Twenty-eight-day mortality in the discovery cohort ranged from 20.6% (SP4) to 52.9% (SP1). Mortality across subphenotypes remained different after adjustment for demographics, comorbidities, organ dysfunction and illness severity, regional and hospital factors. Compared with SP4, the relative risks were as follows: SP1, 1.67 (95% CI, 1.36-2.03); SP2, 1.39 (95% CI, 1.17-1.65); and SP3, 1.39 (95% CI, 1.15-1.67). Findings were similar in the replication cohort. INTERPRETATION: We identified four subphenotypes of COVID-19 critical illness with distinct patterns of clinical and laboratory characteristics, comorbidity burden, and mortality.