Table 1.

Key Outstanding Research Questions

Key Questions
Preclinical
How do ketone bodies affect replication of influenza A or SARS-CoV-2?
What is the fate of ketone bodies in the lung?
How does treatment with ketones affect cellular metabolism, redox state, and mitochondrial energetics in lung immune and non-immune cells in health and during viral infection?
How do ketone bodies affect innate immunity in the lung following influenza or SARS-CoV-2 challenge? What is the role of NLRP3, HCAR2, and adenosine A1 receptor?
What are the mechanisms by which ketone bodies affect cardiomyocyte, skeletal muscle, and/or cognitive dysfunction caused by influenza or SARS-CoV-2?
Clinical
How might exogenous ketones affect viral replication and progression to disease in ambulatory influenza- or SARS-CoV-2-positive patients?
Do exogenous ketones affect systemic and local lung inflammation, innate immune activation, and progression to ARDS following viral infection?
In severely ill patients, can exogenous ketones support cardiac, skeletal muscle, and cognitive function through reduced oxidative stress and increased tolerance of hypoxemia?
How will exogenous ketones affect glycemia and hemodynamics in critically ill patients?
In older adults, can exogenous ketones help preserve muscle function in acute illness and/or affect the incidence or severity of delirium associated with inflammatory activation and metabolic dysfunction?