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September 21st, 2020

Warning - very technical piece. I am attempting to put together a coherent hypothesis as to the pathophysiology of this fascinating disease. However, it explains a lot about risk and lifestyle choices mechanistically. We are learning a lot rapidly. There is no time to waste to reduce your risk and be a part of the 99%.

What do we know or better yet, what do we THINK that we know. This reminds me of the Donald Rumsfeld comment on the known knowns and the known unknowns and so on.

He was quoted as saying: "Reports that say that something hasn't happened are always interesting to me, because as we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know." I digress.

 SARS2 is a 120 nanometer RNA virus that enters the body primarily as an aerosol droplet via the oral and nasal passages and minimally by the ocular or fecal route. It primarily travels to the lungs and attaches to the type 2 pneumocyte via an angiotensin converting enzyme receptor. This virus uses our protease enzymes, that are upregulated in metabolic diseases like diabetes and cardiovascular disease, to cleave a portion of it's spike protein off allowing it to fuse with the cell surface thereby injecting its RNA into our cells for replication and further spread throughout the body via the blood stream or what is called viremia.

The RNA or ribonucleic acid is the virus's genetic code to make more of itself. Replicating rapidly in these cells, the virus ultimately destroys many of these type 2 pneumocytes. These cells are found in the alveolus which is an air sac in the terminal lung tissue, like the very tips of a leaf on a tree, that expands with respiration to exchange oxygen and carbon dioxide with our blood. The type 2 pneumocyte sits inside of the alveolus and releases a chemical phospholipid called surfactant that holds the alveolus open like a balloon by reducing surface tension avoiding collapse. Early in the pandemic, the lung alveoli's capabilities were thought to be reduced by the lack of production of surfactant by these dying type 2 pneumocytes leading to lung failure. This turns out not to be the whole story.

As discussed, the SARS2 virus grabs the ACE receptor fusing with the pneumocyte cell and taking it over. These same cells would normally produce angiotensin converting enzyme 2, ACE2, that is normally lung cell protective and anti-inflammatory. Thus, less type 2 pneumocyte function causes a reduction in ACE2 with this infection serving as a double whammy at the lung tissue site by increasing inflammation and lung collapse. This is the beginning process of what we normally call ARDS or acute respiratory distress syndrome which was seen in SARS1 and MERS. We presumed that this was occurring again with SARS2. When enough of these small air sacs collapse, air exchange becomes impossible and patients respond by increasing the rate of breathing and using accessory muscles to draw deeper and deeper breaths until this is not enough to maintain oxygen levels. Essentially, your lungs collapse to the point that effective oxygen exchange is lost and life is not sustainable without mechanical ventilation. If the inflammation and organ damage worsens, then that may not be enough and death ensues. However, this is not what we are really seeing in the Intensive care units nationwide and at autopsy analysis post mortem.

Enter the new bradykinin theory recently proposed by the group led by Michael Garvin at Oak Ridge Laboratories.

 The renin angiotensin system is the vasopressor controller that is involved in raising and lowering blood pressure. Angiotensin converting enzyme or ACE elevates blood pressure while the counter enzyme angiotensin converting enzyme 2 or ACE2 reduces blood pressure. Bradykinin, produced by ACE2, is a chemical that naturally induces blood vessel dilation and permeability leading to local leakage of fluid into tissue spaces during a healing process that requires clotting or inflammation. This allows immune and inflammatory mediators of healing to be mobilized to areas of infection or injury. Under normal circumstances, the dilation and leakage are all self limited and result in an inflammatory response, resolution and complete recovery.

According to the new complementary hypothesis, the SARS2 virus induces excessive volumes of bradykinin all over the body by up regulating ACE2 by a factor of 199X and down regulating the counter enzyme ACE by 8X leading to leakage of increased amounts of fluid into healthy tissue areas. Inflammatory cytokines follow this event leading to a circular event with ever more inflammatory cytokines infiltrating the tissue and compounding the fluid based inflammatory response that essentially drowns a sick patient. Thus, what we previously thought was an alveolar collapse is now really a hyaluronic based jelly like inflammatory fluid infiltration which reduces our oxygen exchange capacity and feels like drowning.

Recap: The tricky SARS2 virus has the ability to hijack our proteins to gain access to receptors, fuse with cells, impregnate them, replicate massively, cause a viremia and then alter the vascular permeability and ultimately dump a boat load of inflammatory cells into the system to really damage healthy tissue. This is the crux of the cytokine/bradykinin storm theory. But there are still missing pieces.

Somewhere along the way in a subset of very sick patients, the inflammatory cytokine storm, pathophysiology not completely worked out yet, is triggering a hypercoagulable state that we see as deep venous clotting, strokes and organ damage. It is thought that the clotting cascade begins to cause trouble in the lung tissue before becoming systemic and causing massive damage. The markers of disease are elevated D-dimers and fibrinogen.

Here is the latest pathophysiologic understanding of the hypercoagulable State in COVID-19. The current understanding of the pathophysiology of COVID-19 induced coagulopathy centers around the bidirectional cross-talk between inflammation and thrombosis. COVID-19 leads to a severe inflammatory response that originates in the alveoli. Release of inflammatory cytokines leads to activation of epithelial cells, monocytes and macrophages. Direct infection of the endothelial cells through the ACE2 receptor also leads to endothelial activation and dysfunction, expression of tissue factor, and platelet activation and increased levels of Von Willebrand factor and factor VIII, all of which contribute to thrombin generation and fibrin clot formation. Thrombin, in turn, causes inflammation through its effect on platelets which promote neutrophil extracellular trap formation in neutrophils. It also activates endothelium through the protease activated receptor, which leads to release of complement component C5A that further activates monocytes. (Abou-Ismail et. al. 2020)

The other big known problem in this infection is that the SARS2 virus has the ability to infect or enter circulating or stationary immune cells causing a rapid decline in white blood cell function and number. This leads to less viral surveillance and killing ability leaving the virus free to replicate at will. This is a major reason for the corresponding extraordinary release of proteins called cytokines that inflame all local tissues worsening the disease in multiple organs.

The massive volume of circulating viral particles then travel far and wide attacking and targeting organs that express ACE2 receptors, such as the lungs, heart, kidneys, and gastrointestinal tract. The average time to illness is 7 days after exposure. This essentially is the time that it takes for the virus to go through these phases of replication and spread. During the initial stages of the illness most individuals have normal immune responses with robust white blood cell mobilization and viral killing leading to the mild or asymptomatic disease that happens in most individuals. However, we now know that individuals that develop moderate to severe disease have reduced white blood cell responses and reduced T and B cell activity. Whether this is genetic or lifestyle related or both is patient dependent. We also now know from studies to date that inherent genetic defects in immune pattern recognition receptors puts even healthy individuals at risk because of the lost viral surveillance and killing ability. This is albeit a very rare event.

The other clear reality is that poor lifestyle choices as the standard American diet, sloth, toxin exposure, eating excessive calories, inadequate sleep, mental stress and other issues all drive dysfunctional shifts in T helper cell activity, antibody production and systemic inflammation. These changes are present in the host prior to infectious viral exposure setting the stage for poor viral surveillance and killing capacity.

I think that this is the KEY piece of the entire narrative. What can we control in order to surveil, recognize and then kill the SARS2 virus before it has the opportunity to cause a bradykinin/cytokine storm? We can control our lifestyle choices that enhance immune function and prevent exposure. It is that simple - The rest is relatively out of your control.

After having a dysfunctional discussion with one of my ICU colleagues about the efficacy of lifestyle modification and the lack of need to push it, I am even more determined to push this message. The message that modern medicine is here to save you is not lost on the 190,000+ deceased Americans. Could they have reduced their risk had they known and chosen to change the antecedent physiology that put them at risk in the first place? I, resoundingly, think so for many.

Understanding the pathogenesis of the virus has taken some time but is the key to making educated choices to support immune responses. The bottom line according to the excellent work by Dr. Sam Yanuck and colleagues is two fold with regard to prevention of SARS2. First, support immune surveillance by making sure that the immune system is fine tuned to recognize and destroy the virus early on so that it has minimal opportunity to replicate and hijack our immune system.

Secondly, support survival if you get ill and the virus has had the ability to replicate. This means that we want adequate and functional responses from natural killer cells and T helper type 1 cells. Then you need a low starting inflammation point so that when your immune system begins to inflame and attack the virus, you are not pushed into a place of over inflammation and death.

Now, we know that obesity, cardiovascular disease and type 2 diabetes are risk factors for a negative COVID outcome. We also know that these diseases are associated with significant flares in innate immune inflammasome activity. Therefore, the leap of faith seems to be that if we reduce the triggers of baseline inflammasome activity, then we could mitigate some of the downstream risk if we contract SARS2. For example, reducing high fructose corn syrup consumption would reduce the metabolite uric acid, a known trigger of inflammasome formation and activity. Refined foods are loaded with poor quality fatty acids and huge glucose loads that drive inflammasome responses and suppress Th 1 and NK cell activity. Corn fed animal meats are loaded with pro-inflammatory omega 6 fatty acids that are potentially driving the excessive arachidonic acid and cytokine response. These events conspire to reduce viral surveillance and killing while paradoxically increasing inflammation through inflammasome formation and cytokine release. This is the perfect storm for a bad outcome. This is only a small representation of the many changes that lifestyle modification could have on immune function and COVID risk as discussed over the last 6 months.

I truly think that this virus is a wake up call for all of us to eat whole foods that are minimally processed, mostly vegetables, fruits, legumes, seeds and nuts spiked with wild caught naturally raised meat, fish and eggs. Sleep more, stress less, exercise and move often, laugh, live and prepare for the future. That is a dramatic recipe for inflammation reduction and protection.

Thank you for bearing with me through that deep dive into immunology. I hope that it helps explain the WHY we need to be proactive with lifestyle medicine and nutritional therapy.


Dr. M

Garvin eLifesciences
Lancet Editorial
Tartof Annals of Internal Medicine
Hamer PNAS
Martines Emerging Infectious Diseases
Abou-Ismail Thrombosis Research