Coronavirus Disease 2019 Temperature Trajectories Correlate With Hyperinflammatory and Hypercoagulable Subphenotypes

• Type of Material: Article
• Authors: Sivasubramanium Bhavani, Emory University; Philip A. Verhoef, University of Hawaii; Cheryl Maier, Emory University; Chad Robichaux, Emory University; William F. Parker, University of Chicago; Andre Holder, Emory University; Rishikesan Kamaleswaran, Emory University; Dongmei Wang, Emory University; Matthew M. Churpek, University of Wisconsin; Craig Coopersmith, Emory University
• Language: English
• Date: 2022-02-01
• Publisher: Lippincott Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1097/CCM.0000000000005397
• Title of Journal or Parent Work: Critical Care Medicine
• Volume: 50
• Issue: 2
• Start Page: 212
• End Page: 223
• Grant/Funding Information: Dr. Maier is supported by NIH/National Center for Advancing Translational Sciences UL1TR002378. Dr. Churpek is supported by NIGMS (R01GM123193), Department of Defense (W81XWH-21-1-0009), National Institute on Aging (R21 AG068720), and National Institute on Alcohol Abuse and Alcoholism (R01 DA051464-01); he has a patent pending (ARCD. P0535US.P2) for risk stratification algorithms for hospitalized patients and has received research support from EarlySense (Tel Aviv, Israel).; Dr. Coopersmith is supported by funding from the NIH (GM072808, GM104323, AA027396). Drs. Bhavani, Parker, Holder, Kamaleswaran, Churpek, and Coopersmith received support for article research from the NIH. Drs. Parker’s, Kamaleswaran’s, Wang’s, Churpek’s, and Coopersmith’s institutions received funding from the NIH. Dr. Holder received funding from Baxter International.; Dr. Bhavani is supported by the American Thoracic Society and GlaxoSmithKline research grant in coronavirus disease 2019 and by National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) K23GM144867.; Dr. Wang’s institution received funding from The Petit Institute Faculty Fellow Fund, the Amazon Faculty Research Fellowship, The Wallace H. Coulter Distinguished Faculty Fellow Award, the Georgia Institution of Technology, and the National Science Foundation;; she received support for article research from The Petit Institute Faculty Fellow, The Wallace H. Coulter Distinguished Faculty Fellow, and The Amazon Faculty Research Fellowship.
• Keywords: Critical Care Medicine; Life Sciences & Biomedicine; coronavirus disease 2019; General & Internal Medicine; venous thromboembolic event; Critically ill patients; Science & Technology; Mortality; group-based trajectory modeling; inflammation; COVID-19; Clinical phenotypes; temperature
• Research Categories: Health Sciences, Health Care Management; Health Sciences, Public Health; Biology, Bioinformatics; Health Sciences, Epidemiology

Abstract

OBJECTIVES: Body temperature trajectories of infected patients are associated with specific immune profiles and survival. We determined the association between temperature trajectories and distinct manifestations of coronavirus disease 2019. DESIGN: Retrospective observational study. SETTING: Four hospitals within an academic healthcare system from March 2020 to February 2021. PATIENTS: All adult patients hospitalized with coronavirus disease 2019. INTERVENTIONS: Using a validated group-based trajectory model, we classified patients into four previously defined temperature trajectory subphenotypes using oral temperature measurements from the first 72 hours of hospitalization. Clinical characteristics, biomarkers, and outcomes were compared between subphenotypes. MEASUREMENTS AND MAIN RESULTS: The 5,903 hospitalized coronavirus disease 2019 patients were classified into four subphenotypes: hyperthermic slow resolvers (n = 1,452, 25%), hyperthermic fast resolvers (1,469, 25%), normothermics (2,126, 36%), and hypothermics (856, 15%). Hypothermics had abnormal coagulation markers, with the highest d-dimer and fibrin monomers (p < 0.001) and the highest prevalence of cerebrovascular accidents (10%, p = 0.001). The prevalence of venous thromboembolism was significantly different between subphenotypes (p = 0.005), with the highest rate in hypothermics (8.5%) and lowest in hyperthermic slow resolvers (5.1%). Hyperthermic slow resolvers had abnormal inflammatory markers, with the highest C-reactive protein, ferritin, and interleukin-6 (p < 0.001). Hyperthermic slow resolvers had increased odds of mechanical ventilation, vasopressors, and 30-day inpatient mortality (odds ratio, 1.58; 95% CI, 1.13–2.19) compared with hyperthermic fast resolvers. Over the course of the pandemic, we observed a drastic decrease in the prevalence of hyperthermic slow resolvers, from representing 53% of admissions in March 2020 to less than 15% by 2021. We found that dexamethasone use was associated with significant reduction in probability of hyperthermic slow resolvers membership (27% reduction; 95% CI, 23–31%; p < 0.001). CONCLUSIONS: Hypothermics had abnormal coagulation markers, suggesting a hypercoagulable subphenotype. Hyperthermic slow resolvers had elevated inflammatory markers and the highest odds of mortality, suggesting a hyperinflammatory subphenotype. Future work should investigate whether temperature subphenotypes benefit from targeted antithrombotic and anti-inflammatory strategies.