Respiratory Viral Infection, COVID19, & Ketone Bodies?
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Thank you for visiting impactmetabolism.com. We believe that open communication and intellectual collaboration are the surest route to advancing the research into metabolic therapies. This is particularly true for research into the role of immunometabolic countermeasures for SARS CoV 2 and other respiratory viral infections, where rapid progress is of vital importance and the outstanding questions cannot be answered by one or two groups working alone. We hope that our recent manuscript, manuscript, and list of key experimental questions are of utility to the community. If you would like to discuss with us, please feel free to reach out via email.
Full Text Article: https://www.cell.com/med/fulltext/S2666-6340(20)30013-1
Despite huge advances in medical sciences, viral infection remains a scourge on globalized society, with seasonal influenza infecting millions and killing many thousands annually, and deadly viral pandemics recurring every 11.2 and 3.2 year since 1918 and 2003, respectively, leaving social and economic destruction in its wake. Older adults and adults with cardiovascular disease or metabolic disease such as diabetes mellitus are at increased risk of severe disease and death from these viral infections. Additionally, there is no universally efficacious vaccine for IAV or SARS-CoV-2, nor effective and/or approved therapy currently available for COVID19; Consequently, novel, immediately deployable, multifaceted therapeutic approaches which improve disease resilience, augment emergent therapeutic efficacy, and mitigate immediate and chronic health impact of respiratory viral illness are vital for the treatment of widespread diseases Thus, immuno-metabolic therapies targeted towards the aging or diabetic population may be important tools to reduce the burden of death and long-term disability caused by pandemic viruses. Because of their pleiotropic effects, such immuno-metabolic interventions might not only target the virus itself, but also enhance existing best-practice supportive care to reduce cardiopulmonary complications, improve cognitive resilience, and facilitate physical recovery after serious illness. Ketone bodies are endogenous metabolic molecules which have relevant molecular and systems-based mechanisms in respiratory viral infection, that have core roles in maintaining cellular energy supplies but also feature drug-like signaling activities that affect immune activity, metabolism, and epigenetics.
Through these actions, ketone bodies are thought to target mechanisms of aging and have so far been best studied clinically in age-related diseases including diabetes, metabolic syndrome, heart failure, and neurodegeneration. Several of these pleiotropic mechanisms have evidence to suggest that they may be therapeutically relevant to populations at highest risk of infection and related complications, but have not been tested in this specific context. We would like to stress that there is as yet NO direct evidence that supports that either exogenous ketones or the ketogenic diet either prevents or treats respiratory viral infection and that some mechanisms of ketone action may even be harmful. Our team is working to address these knowledge gaps by exploring these questions at various levels and by providing a list of experimental questions which we believe will help advance our understanding on respiratory viral infection, SARS-CoV-2 and ketone bodies. We hope this will expedite understanding, translation, and potential impact to the general population, but particularly the most vulnerable of our society. We realize the immediacy of this problem illuminated by SARS-CoV-2, but also appreciate that what is learned here can help mitigate and inform future respiratory viral pandemics.
If you are interested in additional information, have questions, or are interested in supporting any efforts related to this, please reach out via impactmetabolism@gmail.com and/or via the message box available here https://www.impactmetabolism.org/donate.
Key Clinical Questions:
1. Can exogenous ketones decrease viral replication and progression to disease in ambulatory IAV or SARS-CoV-2 positive patients?
a. Mechanistic target: Viral replication
i. Goal: Reduce progression to symptomatic disease
ii. Primary outcome: Quantitative viral load
iiii. Secondary outcomes: Blood BHB and glucose levels, respiratory symptom scale, pulse oximetry, body temperature, time to ED or hospital admissions
iv. Other safety outcomes: GI symptom scale, liver transaminases
v. Inclusion criteria: New positive SARS-CoV-2 test or documented high-risk exposure requiring isolation
vi. Exclusion criteria: Peripheral oxygen saturation <94% or hospital admission at time of enrollment, goals of care precluding hospitalization, pre-existing hospice-appropriate diagnosis, T1DM, pregnancy cirrhosis or other diagnosed liver pathology.
vii. Intervention: Exogenous ketones oral administration; four times daily; sustained R-BHB ≥0.5 mM, ideally >1 mM; two weeks. Control group would receive taste & volume matched placebo drinks.
viii. Hypothesized mechanisms: Inhibition of K+ efflux through viral E protein cationic pore formation to restrict SARS-CoV-2 replication/fitness, reduced ROS production, and/or reduced glycolytic throughput in infected cells.
2. Can exogenous ketones decrease systemic and local lung inflammation in ambulatory patients?
a. Mechanistic target: Progression of lung and systemic inflammation.
i. Goal: Reduce progression to hypoxia, hospitalization, and ARDS
ii. Primary outcome: Inflammatory blood biomarkers (hsCRP, IL-1β, IL-6, TNF-α, Lactate Dehydrogenase).
iii. Secondary outcomes: Metabolites (ketones, glucose, lactate), respiratory symptom scale, pulse oximetry, body temperature, time to emergency department and/or hospital admissions.
iv. Safety outcomes, inclusion criteria, exclusion criteria, intervention as above.
v. Hypothesized mechanisms: Reduction in exaggerated innate immune activation. and inflammation-induced tissue dysfunction via inhibition of NLRP3 inflammasome activation, reduced ROS, microbiome modulation
3. In hospitalized patients, can exogenous ketones reduce innate immune activation in ARDS?
a. Mechanistic target: Innate immune activation in ARDS
i. Goal: Reduce severity of ARDS
ii. Primary outcome: Hypoxemia
iii. Secondary outcomes: Blood BHB, respiratory symptom scale (if not intubated), FiO2/PEEP, time to intubation, time to extubation, survival, inflammatory blood biomarkers (CRP, IL-1β, IL-6, TNFα, LDH), lactate, maximal inspiratory pressure, diaphragm muscle thickness.
iv. Safety outcomes: Blood pressure, glucose, bicarbonate/pH, potassium, liver transaminases, GI symptom scale (non-intubated)
v. Inclusion criteria: Hospitalized for COVID-19-related respiratory symptoms (could restrict to ICU-only or ward-only)
vi. Exclusion criteria: T1DM, cirrhosis, goals of care exclude intubation or ICU care
vii. Intervention: Oral provision of exogenous ketones as for ambulatory patients (non-intubated), or provision of exogenous ketones via tube feeds supplementing standard nutrition dosed approximately 1 g/kg over the feeding cycle to maintain R-BHB ≥0.5 mM, ideally >1 mM (intubated). Control groups would be fed a taste & volume matched placebo (non-intubated) or standard tube feed diet (intubated).
viii. Hypothesized mechanisms: Reduction in exaggerated innate immune activation and inflammation-induced tissue dysfunction via inhibition of NLRP3 inflammasome activation, reduced neutrophilia, reduced ROS, microbiome modulation. Attenuation in maximal inspiratory pressure decline and diaphragm atrophy via altered inflammatory and ubiquitin pathways.
4. In intubated patients, can exogenous ketones improve systemic tolerance to hypoxemia?
a. Mechanistic target 1: Improved systemic tolerance to hypoxemia
i. Goal: Prevent or resolve end-organ dysfunction caused by hypoxemia
ii. Primary outcome: Blood lactate
iiii. Secondary outcomes: Blood troponin, liver transaminases, creatinine/GFR (to assess end-organ function)
iv. Inclusion criteria: COVID-19-related ICU admission for hypoxemic respiratory failure
v. Other secondary outcomes, safety outcomes, exclusion criteria, intervention as above
vi. Hypothesized mechanisms: Oxidation of BHB to provide oxygen-efficient ATP to support metabolic functions of hypoxic tissues
b. Mechanistic target 2: Hypoxia-induced inflammation and oxidative stress
i. Goal: Attenuate hypoxia-induced systemic inflammation and oxidative stress
ii. Primary outcomes: Pulse oxygenations, systemic cytokines (TNF-a, IL-6, IL-1b), CBC, urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), serum MDA, Capillary ketone, glucose, and lactate.
iii. Secondary outcomes: Cognition task evaluation, dynamometer grip strength, altitude symptom score.
iv. Other safety outcomes: As above for ward and ICU patients.
v. Inclusion criteria: Healthy, Type-2 Diabetic, and/or >65 years of age
vi. Exclusion criteria: T1DM, patients current on low carbohydrate diet,
vii. Intervention: Two oral provisions of exogenous ketones supplementing standard nutrition dosed approximately to maintain nutritional ketosis >0.5-1 mM during reduced oxygen breathing derive hypoxia exposure. Control groups would be fed a taste-and calorie-matched placebo.
viii. Hypothesized mechanisms: Reduced systemic inflammatory and oxidative stress activation via 1) increased energetic efficiency under hypoxic conditions, 2) reduced systemic inflammatory cytokine and oxidative stress via attenuation of HIF-1a activation.
5. In severely ill patients, can exogenous ketones protect cardiac, skeletal muscle, and cognitive function? Separately address younger patients and gereatric patients, who are at a relatively greater risk of muscle function loss and delirium.
a. Mechanistic target 1: Reduced cardiac ischemic and arrhythmic complications
i. Goal: Prevent cardiac dysfunction through metabolic support
ii. Primary outcome: Blood troponin
iii. Secondary outcomes: Occurence of pathological arrhythmias, requirement for cardioversion, use of antiarrhythmic drugs, vasopressor requirement, major cardiac ischemic events, sudden cardiac death, echocardiographic morphological change, hemodynamic alterations
iv. Inclusion criteria: COVID-19-related ICU admission for hypoxemic respiratory failure
v. Other secondary outcomes, safety outcomes, exclusion criteria, intervention as above
vi.Hypothesized mechanisms: Oxidation of BHB to provide ATP to support cardiomyocyte function
b. Mechanistic target 2: Preserved muscle mass & function
i. Goal: Prevent immobility- and inflammation-associated loss of muscle mass and function
ii. Primary outcome: Dynamometer grip strength, fat-free mass, diaphragm (thickness) and lower limb (quadricep; CSA)
iii. Secondary outcomes: Blood BHB, respiratory symptom scale (if not intubated), FiO2/PEEP, time to intubation, time to extubation, discharge setting, ADL/IADL function at discharge and at 1 month follow-up, survival, inflammatory blood biomarkers (CRP, IL-1β, IL-6, TNFα, LDH)
iv. Other safety outcomes: As above for ward and ICU patients.
v. Inclusion criteria: Hospitalized for COVID-19-related respiratory symptoms
vi. Exclusion criteria: T1DM, cirrhosis, goals of care exclude intubation or ICU care, unable to participate in PT/OT (e.g. advanced dementia).
vii. Intervention: As above for ward and ICU patients.
viii. Hypothesized mechanisms: Anticatabolic effects of BHB via preserved cytoplasmic NADPH pool, reduced oxidative stress, reduced inflammatory activation, altered ubiquitination.
c. Mechanistic target 3: Delirium associated with inflammatory activation and metabolic dysfunction
i. Goal: Reduce incidence and duration of acute illness-associated delirium
ii. Primary outcome: Delirium incidence via 3D-CAM and CAM-ICU
iii. Secondary outcomes: Delirium duration/days, delirium severity via 3D-CAM-S, blood BHB, respiratory symptom scale (if not intubated), FiO2/PEEP, time to intubation, time to extubation, discharge setting, ADL/IADL function at discharge and at 1 month follow-up, survival, inflammatory blood biomarkers (CRP, IL-1β, IL-6, TNFα, LDH)
iv. Other safety outcomes: As above for ward and ICU patients.
v. Inclusion criteria: Hospitalized for COVID-19-related respiratory symptoms
vi. Exclusion criteria: T1DM, cirrhosis, goals of care exclude intubation or ICU care.
vii. Intervention: As above for ward and ICU patients.
viii. Hypothesized mechanisms: Reduced systemic inflammatory activation, oxidation of BHB in neurons to generate ATP and support neuronal function
Key Preclinical Questions
What is the role/fate of ketone bodies in the lung?
How do ketone bodies affect replication of key respiratory viruses?
How does treatment with ketones affect inflammation, cellular metabolism, redox state, oxidative stress and mitochondrial energetics in lung immune and non-immune cells in health and during viral infection?
How do ketone bodies affect cellular immunity in the lung following IAV or SARS-CoV-2 challenge? What is the role of NLRP3, HCAR2, adenosine 1a receptor?
How do ketone bodies affect cardiomyocyte, skeletal muscle and/or cognitive dysfunction caused by IAV or SARS-CoV-2?
While the urgent nature of SARS-CoV-2 has placed clinical evaluation at the forefront (and highlighted above). Our team is currently working diligently to address some of the critical knowledge gaps related to RVI, SAR-CoV-2 and Ketone Bodies also from a basic science and preclinical level to better inform the above clinical research questions. If you are interested in additional details or helping to support this work please reach out via impactmetabolism@gmail.com and/or via the message box available here https://www.impactmetabolism.org/donate.