January 17th, 2022
The massive update to this theory is finished for now: it is long, complex and interesting!
SARS2, the virus that causes Covid – 19, is now known to be an infectious disease with features of a human disease that span the spectrum from asymptomatic to profoundly dysregulated immune system responses leading to both aggressive inflammation and autoimmunity in the moderately to severely affected persons. It is now very clear that the vast majority of these significantly affected
individuals have a high burden of antecedent systemic inflammation in the form of chronic diseases of aging and poor lifestyle choices that predispose the immune system to poor pathogen killing and upregulated inflammation and autoreactive features. The poor early innate immune based pathogen killing allows for increased viral loads leading to time based systemic viral immune reactions that we see as hyperinflammation and cellular damage at a macrolevel. The second category of poor Covid related outcomes comes from genetic single nucleotide mutations of immune viral pathogen recognition and killing. These two realities can co exist leading to massive disease burdens. In this piece, we will explore the current scientific evidence behind this disease and how it so tragically tore through the United States with such a high death burden.
Warning – this is a very technical piece. After 2 years of science research and data mining, I am attempting to put together a coherent hypothesis as to the pathophysiology of this novel and fascinating infectious disease. The origins of this disease may never be known as the natural origins theory has not turned up a causative organism and the lab leak theory has significant data behind it but is unprovable at the present time. They are both hotly debated in the scientific community. I see more fire in the lab leak side, but that is what it is and little more.
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.
What do we really know today?
In normal times, a human will balance the need for inflammation as a right of pathogen killing against self-preservation from excessive damage from said inflammation. When all goes according to plan, the immune system revs up robustly at first sign of a novel viral pathogen causing immediate action of viral killing through the innate immune system primarily driven by local white blood cells, inflammation based mechanisms like inflammasomes as well as other systems like complement. Then, once the pathogen is adequately controlled, the immune system returns to baseline activity and cleans up all inflammatory debris through the lymphatic system and rebuilds any damaged cellular systems. It is a beautiful and dynamic system full of flux and resolution leading to health long term.
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 ciliated epithelial cells as well as the type 2 pneumocyte via an angiotensin converting enzyme 2 receptor, ACE2R that decreases in number as you go farther into the smaller lung tubes toward the alveoli, air sacs. This virus uses our protease enzymes to cleave a portion of it's spike protein off allowing it to fuse with the attacked cell’s 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.
As the SARS2 virus grabs the ACE2 receptor fusing with the cell and taking it over, it takes approximately 10min to enter susceptible cells and about 10 hours to reproduce inside the infected cell. It can release 100 plus virions per infected cell. (Bar-On et. al. 2021 doi: 10.7554/eLife.57309) And the process repeats itself until the immune system catches up to the virus. If the type 2 pneumocyte cells are damaged within the alveoli, distal air sacs, then the normally produced angiotensin converting enzyme 2, ACE2, that is normally lung cell protective and anti-inflammatory becomes less available for protection of the lung tissue as the receptors are bound and the cells die. Thus, damaged epithelial cells proximally cause local inflammation and the damaged distal type 2 pneumocytes lose function causing some 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 ventilation 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.
Part of the difference was originally shown by the group led by Michael Garvin at Oak Ridge Laboratories as they discovered the new bradykinin theory.
The renin angiotensin system is the vasopressor controller that is involved in raising and lowering blood pressure. ACE2 converts angiotensin II to angiotensin I. Thus, if ACE2 activity is reduced angiotensin II levels rise and they in turn signal through AT1 receptor the actions: vasoconstriction, interstitial fibrosis, macrophage activation and the production of inflammatory cytokines which induce more endothelial dysfunction and increases in pulmonary permeability leading to pulmonary edema. Reduced expression of ACE2 from damaged type 2 pneumocytes reduces the breakdown of bradykinin, 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. Under normal conditions, this process allows immune and inflammatory mediators of healing to be mobilized to areas of infection or injury where the dilation and leakage are all self-limited and result in an inflammatory response, resolution and complete recovery. However, in this case the excess bradykinin is counterproductive and leads to more edema, inflammation and fibrosis. More 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. Autopsy results showed these changes confirming the different airway pathology in SARS2 vs SARS1.
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/ACE2/bradykinin storm theory. But there are still missing pieces.
Somewhere along the way in a subset of very sick patients, the inflammatory cytokine reaction 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 lung epithelial cells and pneumocytes. The subsequent release of inflammatory cytokines leads to activation of epithelial cells, monocytes and macrophages. Direct infection of the endothelial cells 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 another 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 relatively rare event.
Let us look at this event from the perspective of the innate immune system. The innate immune system is the first line of defense against any invading pathogen. The innate immune system is comprised of pattern recognition receptors that detect fragments of viruses, bacteria and parasites and then signal cells to come in for a killing party. The PRR’s are divided into PAMP and DAMP types. PAMP’s or pathogen associated molecular patterns are specifically set up to recognize protein fragments of a pathogen’s structure. DAMP’s or damage associated molecular patterns recognize damaged human cell parts as a serious danger signal to self. This DAMP response signal is a high-level warning that your cells are being attacked and elicits a big response. TLR’s or toll-like receptors are a type of PRR that bind to their pathogen target when visualized in the body which in turn leads to the production of interferons (IFN), cytokines (CTK) and chemokines (CMK) which are signaling molecules to enhance local immune killing via white blood cells. In the case of SARS2, the TLR recognizes the virus and sends out interferons to recruit killer white blood cells to the area, block viral replication and activate the dendritic cells and adaptive immune activity which we know of as the circulating antibodies that develop over time. When infected cells die and release more virus in high number, the cellular debris and viral particles are recognized by DAMPs and PAMPs inducing a robust local immune response that has a recurrent autocrine effect.
Type I and III IFNs activate and upregulate the function of innate immune system’s tissue resident cells including dendritic cells, alveolar and interstitial tissue resident macrophages and Natural Killer cells (NK-cells). For example, monocytes/macrophages phagocytose the infected cells and induce type I IFN responses and pro-inflammatory molecules. NK cells recognize peptides expressed on the surface of infected cells and destroy them via direct cytotoxicity, through perforins and granzyme B. All immune cells release cytokines and chemokines, such as among others, TNF-a, IL1β, IL6 and IL8, that amplify and propagate the immune response by recruiting more cells in the following time order: Neutrophils are recruited first within 24 hours post-infection peaking by day 3. They are followed by dendritic cells and monocytes. T- and B-cells appear later around day 5 which begins the adaptive phase of immunity. It takes 6 to 10 days to build a functional adaptive response through priming. This delay for education is critical for developing a clone specific T and B cell repertoire which are targeted directly to the pathogen’s proteins. (Kaklamanos et. al. 2021)
SARS2 in certain individuals has the ability to delay the interferon response which appears to be worse with advancing age. The mechanisms utilized by the coronaviruses to evade the initial immune recognition and response via IFNs can be divided into three categories: avoidance of the recognition by the pattern recognition receptors, suppression of the generation of type I-III interferons, and the reduction of IFN signaling. Other individuals, mostly men, have autoantibodies against interferons making the viral response weak and allowing for a permissive viral environment. Furthermore, the reduced IFN signaling reduces the interferon stimulated genes (ISG) which directly messes with the antigen presenting cells like macrophages ability to recognize, engulf and kill the virus. It also reduces the activity of the major histocompatibility complex I and II’s ability to adequately present the viral proteins for adaptive recognition leading to worsened antibody responses.
Pause: So we now see a picture where the clever virus has developed methods for reducing our ability to recognize it, kill it and then develop memory against it for the future. In the long term, these evasion methods are not functional for a healthy person as they eventually overwhelm the virus and revert to normalcy. The kicker is the already inflamed individual with autoantibodies against self-derived innate immune mechanisms like the IFNs. They are less likely to catch up to the virus and survive as the initial immune response is so weak that the viral particle number gets so large that the immune system goes into micro wars all over the body leading to an exhausted state. This has been shown by the lower number of white blood cells and the weak function of those present seen in the very sick. Thus, it is imperative that we have a very robust initial innate immune response right out of the gate like the infants and young children do.
As the process progresses, more cellular contents are spilled into the local tissue space releasing far more DAMPs, self-tissue proteins, which in turn signals the formation of neutrophil extracellular traps (NETs) and inflammasomes. NETs form when a group of actively recruited neutrophils, early attendees to the process, form a net like trap. Neutrophils are the first line of defense in the fight against pathogens. During an infection, these cells’ protective duty is performed through phagocytosis, degranulation of antibacterial proteins, generation of reactive oxygen species (ROS), and the recruitment and activation of other immunocompetent cells. These powerful neutrophils have the ability to generate extracellular neutrophil traps (NETs). The structure of NETs is made up of thin, smooth strands of DNA, yes your DNA, trapping the SARS2 virus within this net of DNA fibers preventing their spread. It also allows the concentration of antimicrobial factors in the neutrophils at the site of the infection to grow. This is a very powerful way to control an infection early on. It becomes problematical when it persists for a long time based on the viral load and autocrine feedback loop of DAMP’s from cellular damage. This persistence of NET’s inflammation causes significant systemic damage leading to increased SARS2 morbidity and mortality. (Janiuk et. al. 2021)
In this same line of thinking, our innate immune systems have a fire-based system called pyrins. Chief among them is the inflammasome. By its name, we see that it is a robust source of inflammation at a local tissue site where a PRR called NLRP3 gets activated by the presence of the virus, ATP, cellular debris and more. The inflammasome then assembles and releases cell wall pore forming materials which are used to insert gasdermin, IL1B and IL18 into the cell. The downstream effect is cellular apoptosis or death as well as the further formation of NETs and activation of the complement clotting system leading to thrombosis and cardiovascular compromise that is the hallmark of COVID disease and is vastly different from other SARS/MERS infections.(Vora et. al. 2021)
Ok, so let us assume that the innate immune process goes according to plan and is not overactivated. What happens next? The adaptive immune system gets activated and begins the process of developing antibodies as well as memory cells for future recognition. For this process to occur correctly, a certain cell type is critical, the T cell. The T cell is responsible for ushering viral and other information back and forth between the antigen presenting cells like monocytes and macrophages of the innate immune system and the B cells of the adaptive immune system that eventually allow for the long lived plasma and memory B cells to form, get educated and persist for years. This is the process by which we are able to see the same virus again in the future and little to no issue this time around. The memory B and T cells are prepped to pump out immune fighting antibodies targeted to the virus in question. The resolution of the circulating antibodies after a few months as with SARS2 is due to the fact that in the absence of active disease the immune system does not want to carry large loads of antibodies against the millions of pathogens and proteins in the world. This is energetically taxing and would cause problems with excess proteins in the blood leading possibly to coagulation.
T cells are divided into two types, CD4 or helper and CD8 which are cytotoxic. The CD4+ cells receive viral information from the antigen presenting cell educating it on the specific type of pathogen. That information is then swapped with a B cell leading to antibody producing plasma cells or memory B cells specific for SARS2. The CD8+ T cell takes the same information and targets the SARS2 infected cells directly for destruction. These T cells release interferons and cytokines to enhance the local pathogen killing by recruiting neutrophils and other monocytes. Simultaneously, the amazing key to our long-lived immunity occurs in the local lymph nodes. The initially programmed B cells get further education in the germinal centers of local and systemic lymph nodes whereby they progress through layers of learning like rings on a tree heading to the center. A slight shift in the protein structure in either direction mimics nature’s viral mutagenesis in lock step unless the virus has a whole sale large sequence amino acid protein change as was seen with the Omicron variant. This activity further expands the ability of the antibodies to recognize viral particles that may have slightly mutated which occurs with most viral diseases. The end result of this intricate process is the production of a wide array of B cells that are capable of recognizing a pathogen and it’s mutant cousins rapidly leading to rapid killing and survival via antibody production. The first antibodies produced are of the IgA class, during the first week of infection, followed by IgM over week 2 and finally IgG after the 3 weeks. (Sterlin et. al. 2020) In the case of SARS2, the antibodies are primarily directed against the spike protein’s receptor binding site and the nucleocapsid. The antibody against the spike protein prevents the virus from attaching to the ACE2 receptor and replicating. In babies and infants, the antibody response is primarily only against the spike protein as the infection is cleared rapidly in this age group.
This is the normal adaptive immune response. What happens in the abnormal state?
In an aggressive disease state, we need to further subdivide the CD4+ T cells as they are the main player in the process as they migrate to the sites of infection to begin this education and mobilization process. The CD4+ T cell is divided into many types, but for the purposes of this paper we will stick to the T regulator, T helper 1, T helper 2 and T helper 17. The T regulator cell is involved primarily in immune dampening and tolerance to non-pathogenic proteins. TH1 is involved in intracellular pathogen killing of organisms like herpes viruses and SARS2. TH2 is involved in macrobe killing like larger organisms in the parasite family. TH17 is involved in extracellular pathogens like bacteria. The balance of these cells can dictate the effective response to a pathogen. The dysfunctional side of each TH cell polarity response is as follows: TH1 excess leads to uncontrolled inflammation, TH2 excess leads to allergies and atopic diseases like asthma, TH17 excess leads to autoimmunity and finally Treg dysfunction leads to immune tolerance breaks.
In COVID disease, these innate and adaptive processes are rendered dysfunctional by the precursor lifestyle inflammatory abnormalities, host genetic single nucleotide polymorphisms of pattern recognition receptors and interferons, viral induced lymphocyte and cytokine changes. Chronic hyperglycemia, hypoxia, toxic exposures and much more lead to alterations in immune activity that are counter to effective killing of pathogens. When investigators have looked at mild, moderate, and severe COVID19 cases, they noted change occurring between mild and moderate disease. They found unusual cell types, including exhausted CD4+ T-cells, cytotoxic CD4+ T-cells and proliferative exhausted CD8+ T-cells. (Su et. al. 2021) The presence of exhausted T cells is a marker of poor outcome and portends immune dysregulation in general. To me, this is a marker of baseline over activity of immune surveillance and killing as Patrice Cani calls low level endotoxemia from microbial intestinal dysbiosis.
These same exhausted cells initially, pre exhaustion, secrete interferons and cytokines like IL2 and tumor necrosis factor further increasing local pathogen destruction and polarizing the T helper cells towards a T CD4+ helper 2 type pattern which is reserved normally for attacks on parasites and is involved with histamine release a hallmark of poor covid outcome. The polarity switch that occurs post and pre-infection are believed to be the main drivers of adaptive immune dysregulation that we see playing out clinically. There is also evidence that increased IL-17 production by Th17 cells in COVID-19 patients has broad pro-inflammatory effects through the upregulation of pro-inflammatory cytokines like G-CSF, IL-1β, IL-6, TNFα, as well as chemokines like MIP2A, IL-8, IP10, MIP3A, and matrix metalloproteinases all of which lead to uncontrolled immune cell recruitment and signaling which we see as profound systemic inflammation, organ damage and finally death by coagulation, vascular leakage and pulmonary failure. The TH17 polarity change is also associated with COVID autoimmunity.
Thus, we see that humans immunologically polarized to TH2 and TH17 pre infection are likely to have a worse outcome overall due to poor viral surveillance and killing capacity coupled to an over indulgent immune reactivity after the virus has had a period of time to robustly replicate and seed the whole human corpus. The resultant inflammatory response overwhelms the entire immune system leading to exhaustion and tissue damage throughout the organ systems ultimately leading to severe illness and death.
The last piece of the pathophysiology story resides in precursor risk factors for poor pathogen clearance and worsened inflammatory responses. Epidemiologically, it is very clear that 95% or more of the COVID related deaths were in groups that had either advanced age and/or comorbid diseases related to 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, autoantibody production and systemic inflammation. These changes are present in the host prior to infectious viral exposure setting the stage for poor viral surveillance, killing capacity and later hyper inflammation.
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 840,000+ deceased Americans and counting. 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 is twofold 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, one 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 fructose and high fructose corn syrup consumption would reduce the metabolite uric acid, a known trigger of inflammasome formation and activity system wide. This occurs notoriously in the mitochondria of the liver, muscles and kidneys inducing adipose deposition, insulin resistance, high blood pressure and nephron damage. Inflammasomes also worsen cardiac coronary artery damage which is seen with many COVID deaths. Panoptosis is a term used to describe cell death globally in a human body via the simultaneous activation of pyroptosis, apoptosis and necroptosis in the same cell, leading to its inflammatory death. This appears to happen in a subset of severe COVID19 patients who have severe obesity and inflammation.
The greatest risk for all cause human mortality appears to be the overconsumption of refined foods that are loaded with poor quality fatty acids and huge glucose loads that drive insulin resistance via diacylglycerol inhibition of the transcription of the muscle’s GLUT4 receptor as well as fat deposition of the secondary hyperglycemia/insulinemia response. Large volume fructose ingestion in these same refined foods drives fat deposition via the metabolite uric acid through historically beneficial survival pathways in the mitochondria and liver. These processes lead to obesity which is notorious for having immunologically activated fat cells that slant toward dysfunctional inflammatory macrophages, T cells that are activated and notorious for presenting antigen to the immune system for reaction leading to autoimmunity. These same fat cells also drive inflammasome responses and suppress NK cell activity as is well noted in diabetics, the poster humans for hyperglycemia in general. There are many other nutrition based issues to discuss but for the sake of this piece I will only add this, corn and grain fed animal meats are loaded with pro-inflammatory omega 6 fatty acids that are potentially driving excessive arachidonic acid production and cytokine responses. These and many other nutrition based 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 20 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.
For more on the to do here, I will read from an excellent paper by Dr. Yancuk and colleagues: Eliminating factors that can drive non-purposeful inflammation and related dysregulatory impacts on immune function. The patient’s inflammatory baseline status is influenced by pre-existing inflammatory conditions. An opportunity presents itself in the non-infected patient (and potentially in the infected patient early in the course of the disease) to reduce non-purposeful contributions to their level of inflammation, to mitigate the risk of the patient entering the Escalating Inflammation Phase, should they become infected. Several potential areas of interest should be included in the clinical inventory:
1) Sleep - Healthy sleep is anti-inflammatory and promotes appropriate Th1 response. Disordered sleep is characterized by reduced sleep efficiency, less slow wave sleep, and more REM sleep. Disordered sleep yields increased inflammation and increases Th2 response at the expense of Th1 response. Sound sleep hygiene practices are fundamental for promoting healthy sleep. In addition, substances such as melatonin may be added to enhance sleep promotion. Not only is melatonin a useful sleep aid, it also inhibits NLRP3 inflammasome activation, and reduces airway inflammation.
2) Stress – Stress chemistry is inherently inflammatory. Many patients will have been enduring significant chronic stress by the time they become infected. Though it is not part of the main protocol, for patients with significantly elevated stress levels, it may be useful to give adaptogens like ginseng or ashwagandha. The immune suppressive effects of cortisol are well known. Research has suggested that lung inflammation driven by the NLRP3 inflammasome mechanism is steroid resistant and the resultant Interleukin-1β (IL-1β) production is driven by NLRP3 inflammasome activation which drives autocrine loop activation in macrophages and other cells in which NLRP3 activation is taking place reinforcing the inflammasome assembly sequence. Non-steroidal treatments targeting inflammasome activation, specifically the IL-1R antagonist anakinra, has been shown to block LPS-induced neutrophil influx in healthy subjects. Stress chemistry can and should also be addressed by a number of other techniques that have proven useful for decreasing the stress response. Patient ability and personal preferences will guide the appropriate choices. Techniques include mindfulness-based stress reduction exercise, relaxing music, creative pursuits, biofeedback, and many others. Whatever works for you.
3) Glycemic Control - Addressing glycemic control is a critical part of controlling baseline inflammation. As stated earlier, insulin resistance, and impaired glucose tolerance are associated with inflammation, and may be a contributing factor that puts diabetics at a higher risk for severe COVID-19 outcomes. Most of the work of achieving optimal glycemic control involves subtracting foods from the diet that contribute to an increased post-prandial glycemic response. This avoids adding to the burden of polypharmacy involved in implementing other tactics. While there is individual variation in what foods cause a higher glycemic response in specific individuals, the general advice of reducing foods with a high glycemic load is a good place to start. Food combining in order to reduce glycemic burden should also be considered. By monitoring blood sugars using a continuous glucose monitor or intermittent glucometers one can get a good sense of what types of foods increase postprandial glycemic response.
4) Other Dietary Factors - Dietary factors in addition to those contributing to disrupted glycemic control should also be addressed. A high quality nutrient dense diet that focuses on eating whole plant-based foods that are rich in healthy fats and phytonutrients (multicolored fruits and vegetables) is foundational to decreasing overall inflammation. Reducing or eliminating inflammation promoting foods is also important. Foods that are highly processed and/or contain chemical additives, trans-fats, oxidized fats and added sugars are inherently inflammatory.
5) Microbiome Balance – Both the lung and the GI tract have a normal microbiome and the complex relationship between the microbiota of the lung and GI tract, and its bidirectional influence with the immune system has been reviewed in the past in many newsletters. Dysregulation of the balance of GI microbiome bacteria has been shown to be a source of systemic inflammation. Intestinal metabolism of dietary fiber and the resulting increase in short chain fatty acids (SCFAs), specifically propionate, has been shown to enhance hematopoietic generation of macrophages and DC’s seeding the lungs. The DC’s had increased phagocytic capacity and decreased capacity to induce Th2-bias in lung T cells, an effect that reduced Th2 inflammation. Exacerbations of chronic lung diseases have been proposed to be episodes of lung microbial dysbiosis. The status of the lung microbiome may be especially important in situations requiring the use of ventilators, as depletion of the lung microbiota by broad-spectrum antibiotics prior to high tidal volume ventilation was shown to render mice more susceptible to developing ventilator-induced lung injury.
6) Exercise – Physical activity has long been known to be critical for proper function of virtually all physiological systems. However, to decrease inflammation the right intensity is critical with moderate levels effective at lowering inflammatory markers while intense exercise does not. IL-6 drives significant inflammatory pathology in COVID-19, as discussed here. Skeletal muscle has been shown to produce and releases significant levels of IL-6 after prolonged exercise, so caution should be used when considering the form and duration of exercise.
7) Supporting levels of vitamins and minerals with known immunological roles. (see details and references in the paper in the links section) (Yanuck et. al. 2020)
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
Yanuck Integr Medicine
Garvin eLifesciences
Lancet Editorial
Tartof Annals of Internal Medicine
Hamer PNAS
Martines Emerging Infectious Diseases
Abou-Ismail Thrombosis Research
Kaklamanos Frontiers in Immunology
Janiuk Cells
Vora Nature Reviews Immunology
Sterlin Science Translat Medicine
Su Cell
Trougakos J Biomedical Sciences
Osuchowksi Lancet Resp Medicine
For the Unifying Theory of SARS2/COVID19 pathology that was published in September, please follow this link. In this piece, I lay out what appears to be the pathway to infection and subsequent significant illness. It will be updated in the coming months.
