Coronavirus Disease 2019 Temperature Trajectories Correlate With Hyperinflammatory and Hypercoagulable Subphenotypes

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.

Development and validation of novel sepsis subphenotypes using trajectories of vital signs

“…The full 8-h training model was then applied to the validation data: The sub-phenotypes are defined by a set of five unique polynomial functions describing each vital sign as a function of time from presentation to the hospital (i.e., Temperature = β 0 + β 1 *Time + β 2 *Time 2 ). As done in prior work, patients in the validation cohort were classified to the sub-phenotype trajectory that resulted in the lowest mean squared error [ 22 , 23 ].…”

“…The vitals used for sub-phenotype classification were restricted to vitals measured prior to administration of study fluid (given that fluid itself could alter the trajectory of vital signs). Vital signs were standardized to the mean and standard deviation of the original training data and the study patients were classified to the sub-phenotype trajectory that resulted in the lowest mean squared error [ 22 , 23 ]. Clinical characteristics and outcomes were compared between the sub-phenotypes.…”

Simulation of COVID-19 symptoms in a genetically engineered mouse model: implications for the long haulers

“…2 A). Future work should focus whether temperature variation could potentially determine the disease outcome in models but in COVID-19 infected humans hypothermia displayed abnormal markers of coagulopathy thus clearly suggesting a hypercoagulable phenotype; however, hyperthermic slow resolvers did exhibit elevated inflammatory markers and the highest odds of mortality [ 66 ]. It is worth mentioning that COVID-19 is associated with clinically significant weight loss and risk of hospitalization in human subjects since the disease negatively impacts body weight and the nutritional status [ 67 ].…”

Insights into COVID-19-associated critical illness: a narrative review

“…Recently, they also classified patients with COVID-19 into the four previously defined subphenotypes using the validated group-based trajectory model, and these subphenotypes were found to be correlated with different inflammatory and coagulation abnormalities. Specifically, hypothermics were correlated with hypercoagulable state, while hyperthermic slow resolvers were correlated with hyperinflammatory state and had the highest odds of mortality ( 104 , 105 ). These results suggest that patients with specific temperature subphenotypes of COVID-19 could benefit from targeted antithrombotic and anti-inflammatory strategies, but this proposition requires further investigation and validation.…”

“…Subphenotypes or endotypes of COVID-19 Fewer ventilator-free days, more venous thrombotic events, and upward trajectories of ventilatory ratio and mechanical power over the first 4 days of invasive mechanical ventilation(104,105) Hyperthermic slow resolvers Highest C-reactive protein, ferritin, and IL-6 levels; highest odds of mechanical ventilation and vasopressor requirement, and mortality Fewer chronic medical conditions, milder physiologic abnormalities, and lowest mortality COVID-19, 2019 novel coronavirus disease; IL, interleukin; HDHC, high D-dimers and high compliance; HDLC, high D-dimers and low compliance; LDHC, low D-dimers and high compliance; LDLC, low D-dimers and low compliance; Th1, T helper type 1; Th2, T helper type 2; NK, natural killer; ARDS, acute respiratory distress syndrome.…”