Image by sym from Pixabay

January 16th, 2023

A massive 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, sedentary behavior, 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 or at least some pathogenic inflammation induced damage? 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 1,000,000+ 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, hypertension, 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 24+ 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 responses. 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)

Control what you can control!

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