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The coronavirus disease 2019 (COVID-19) pandemic has created new and unpredictable challenges for healthcare systems. Healthcare professionals are heavily affected by this rapidly changing situation, especially frontline healthcare professionals who are directly engaged in the diagnosis, treatment, and care of patients with COVID-19 and may experience psychological burdens. The objective of this study is to explore the evolution of psychosocial, cardiovascular, and immune markers in healthcare professionals with different levels of exposure to the COVID-19 pandemic.   Methods and Analysis:  This is a STROBE compliant, blended, exploratory study involving online and onsite approaches that use wearable monitoring. A planned random probability sample of residents, staff physicians, nurses, and auxiliary healthcare professionals will be recruited. The study sample will be stratified by exposure to the COVID-19 pandemic. As a first step, recruitment will be conducted online, with e-consent and using e-surveys with Maslach Burnout Inventory, Fuster-BEWAT score, and sociodemographic characteristics. Onsite visits will be planned for the second step where participants will receive a wearable setup that will measure heart rate, actimetry, and sleep quality monitoring, which will be used together with blood sampling for immune biomarkers. Steps 1 and 2 will then be repeated at 2–3 months, and 6 months. Power BI and Tableau will be used for data visualization, while front-end data capture will be used for data collection using specific survey/questionnaires, which will enable data linkage between e-surveys, internet of things wearable devices, and clinical laboratory data.   Clinical Trial Registration:   ClinicalTrials.gov ; Identifier: NCT04422418

Impact of COVID-19 Pandemic Burnout on Cardiovascular Risk in Healthcare Professionals Study Protocol: A Multicenter Exploratory Longitudinal Study