In order to fully understand the current “pandemic” coronavirus (COVID-19) infection, it is essential that one understands some basics about the immune system. Second, we will look at how a poor understanding of the immune system has duped many about how the body actually responds to this virus.
Normal functions of the immune system include defense against infections and detection and destruction of malignant or abnormal cells. As our immune system ages and these capabilities decline, there is increased susceptibility to infections and cancer and an increased incidence of autoimmune disorders. The study of age-related changes in immune function is a relatively new area of investigation, which is limited by incomplete understanding of the complexities of immune mechanisms in general. These age related changes make it clear why COVID-19 is mild in some and severe in others.
The coronavirus tends to be more problematic in those over age 55. In fact, 87% of all deaths in Arizona due to COVID-19 are in those over age 55. The clinical presentation of infections in older patients may be different from that in younger patients. Older adults with severe infections tend to have fewer symptoms, and fever is absent or blunted in 20 to 30% of those over age 55 years old. This suggests a decreased ability to mount inflammatory cytokine responses (small proteins used as signaling molecules between cell) in the face of infection. Signs of infection in older adults can be nonspecific and include falls, delirium (confusion), anorexia (loss of appetite), or generalized weakness (Norman DC, Clin Infect Dis. 2000;31(1):148).
Immune System & Aging
All immune cells originate from stem cells in the bone marrow, and there is a general decline in the total bone marrow cellular tissue as we age (Geiger H, Rudolph KL. Trends Immunol. 2009;30(7):360). Production of pro-B cells is significantly decreased with aging, resulting in a smaller number of B cells leaving the bone marrow, while T cell precursors seem to be less affected (Cancro MP, Hao Y, Scholz JL, Riley RL, Frasca D, Dunn-Walters DK, Blomberg BB., Trends Immunol. 2009;30(7):313. e-pub 2009 Jun 18).
The immune system is divided into innate and adaptive immunity. The innate immunity refers to immune responses that are present from birth and not learned, not adapted, and not refined as a result of exposure to micro-organisms/antigens. In contrast, adaptive immunity, which consists of the responses of T and B lymphocytes, is generated and then refined over the lifetime of a person as a result of repeated exposure to antigens from bacteria, viruses or fungi. Aging affects both innate and adaptive immunity, although innate immune mechanisms are better preserved overall (Weiskopf D, Weinberger B, Grubeck-Loebenstein B, Transpl Int. 2009; 22(11):1041).
Innate Immunity
The innate immune system consists of epithelial barriers (skin, gastrointestinal and respiratory protective lining), macrophages, neutrophils, natural killer (NK) cells, natural killer T (NKT) cells, dendritic cells (DCs), and complement proteins. Additional normal defenses include production of mucus in the proper quantity and viscosity, local antimicrobial proteins, and normal sweeping function ciliary cells.
Though some innate immune mechanisms are decreased in the adult over 55 years old, other mechanisms appear to be more active.. The result of these changes is a propensity to develop chronic inflammation. The result of aging of the innate immune system may be most accurately characterized as a state of immune dysregulation characterized by low-grade, chronic inflammatory changes (Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM, Curr Opin Immunol. 2010;22(4):507). This is why many of my patients feel that the “Golden Years” are full of lead.
Adaptive Immunity
Adaptive immunity consists of the functioning of two types of white blood cells: T and B lymphocytes. T and B lymphocytes mediate control cellular and humoral immune responses, respectively.
Cellular Immune Response and the T Cells
There are several key changes that occur to T cells during aging.
Thymus – The thymus gland is most active early in life, reaches maximum size within the first year of life, and then undergoes a steady decline with age. By age 7, the part of the thymus and it’s activity decrease to less than 10 percent of the total thymic space. The functional thymic cortex and medulla are progressively replaced by fatty tissue. These changes become almost complete some time between the ages of 40 to 50 (Flores KG, Li J, Sempowski GD, Haynes BF, Hale LP. J Clin Invest. 1999;104(8):1031). As a result, the number of T cells exiting the thymus is significantly decreased and gets progressively lower between the age groups of 40 to 54, 55 to 69, and 70 to 90 (Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ. J Immunol. 2005; 174(11):7446).
T Cells Change Over Time – T cell receptors become less divers after age 65. The production of new T cells is dramatically reduced in the very old. T cell populations are largely composed of persistent long-lived lymphocytes. Age-related defects in the signaling pathways of CD4 T cells have been identified due to changes in T cell receptors (Li G, Yu M, Lee WW, Tsang M, Krishnan E, Weyand CM, Goronzy JJ. Nat Med., 2012 Sep;18(10):1518-24. e-pub 2012 Sep 30).
T Cell Numbers Decrease – There is a decrease in the numbers of (helper) CD4 T cells, an increase in CD8 T cells, and a decrease in CD28 with aging. Reduction in CD28 results in an impaired ability of T cells to proliferate and secrete IL-2, an essential cytokine in promoting growth of T cells (Kaltoft K, Exp Clin Immunogenet., 1998;15(2):84). Because (helper) CD4 T cells are important in stimulating B cells, the ability of T cells to help B cells grow, expand and produce antibodies diminishes with aging (Haynes L, Maue AC., Curr Opin Immunol, 2009;21(4):414. E-pub 2009 Jun 6).
Decreased Cytokine Signaling – T cells respond specifically to cytokines like IL-2, IL-6, TNF-alpha. With aging over 50 years, production and signaling of these cytokines diminishes and has been found to be directly correlated with degree of frailty in older adults (Marcos-Pérez D, et al., Front Immunol. 2018;9:1056. Epub 2018 May 16).
Humoral Immunity
B Cells – B cells produce their own surface membrane immunoglobulin and differentiate into plasma cells, which then make immunoglobulin for the blood or secretions. These immunoglobulins are the mediators of humoral immunity. B cells respond to antigen exposure (protein markers or flags on the surface of bacteria or viruses) by producing antibodies, which then bind to antigens to fight concurrent infections or prevent future infections. B cells produce primarily the immunoglobulin IgM. Upon stimulation with and antigen, B cells switch to the production of IgG, IgA, or IgE. The ability of B cells to respond to antigens and produce antibodies is their main job.
The numbers of B cells precursor in the bone marrow (pre-B cells), as well as peripheral B cells, decrease with age. Immunoglobulin levels (IgM), on the other hand, do not change with aging, and may actually increase (Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R, Riley RL, Blomberg BB. J Immunol. 2008;180(8):5283). However, quantities of specific antibodies (ie, those generated by encounters with antigens through infection or vaccination) decline with age (Lazuardi L, Jenewein B, Wolf AM, Pfister G, Tzankov A, Grubeck-Loebenstein B, Immunology. 2005;114(1):37).
Antibody production from vaccination is also noted to be lower in those over age 55. This is why booster vaccinations are required (Weinberger B, et al, Front Immunol. 2018;9:1035. Epub 2018 May 15).
Memory B & T Cells – The generation of long-lasting protective immune memory is one of the most unique and important characteristics of the adaptive immune system. Memory is essential for individual defense from infections to which you have previously been exposed. As the thymic output declines, individuals rely more on re-expansion of experienced memory cells for defense against infections.
Memory responses from immunoglobulins to previous infections appear to be relatively well-preserved as we get older, compared with new responses of B and T cells. Data suggest that memory B and T cells, once elicited by antigen during youth, are quite resilient to the impact of age (Stacy S, et al, Mech Ageing Dev, 2002;123(8):975; Kovaiou RD, et al, Int Immunol, 2005;17(10):1359. Epub 2005 Sep 1).
An example of this was seen during the 2009 H1N1 influenza pandemic, in which older adults were better protected from H1N1 infection than middle-aged adults, probably because of the persistence of memory lymphocytes producing antibodies generated in response to an H1N1 virus that circulated prior to 1957 (Hancock K, Veguilla V, Lu X, Zhong W, Butler EN, Sun H, Liu F, Dong L, DeVos JR, Gargiullo PM, Brammer TL, Cox NJ, Tumpey TM, Katz JM. N Engl J Med. 2009;361(20):1945). The antibody avidity for 2009 H1 was higher in older adults than in middle-aged adults (Monsalvo AC, Batalle JP, Lopez MF, Krause JC, et al. Nat Med. 2011;17(2):195. E-pub 2010 Dec 5).
Ketogenic Diets Improve T Cell Function
T Cells were found to function more efficiently on fatty acid oxidation, instead of glucose metabolism. Ketogenic diets have been found to have a protective effect on preservation of T cell immune responses (Goldberg EL, et al, Sci Immunol Nov 2019 4(41): eaav2026). The ketogenic diet was found to expand the presence of T cells and improve the inflammatory changes common with aging and diminished immune function (Goldberg EL, Shchukina I, Asher JL, et al. Nat Metab 2020: 2, 50–61).
COVID-19 and the Immune System
Information about the coronavirus has dramatically changed in the last six months since it was discovered. Initially, it was suspected that humoral related antibodies were essential to mount an effective attack against COVID-19. This is why the focus has been directed at screening for active infection, quarantine and measurement of antibodies.
What we now know is that most individuals with asymptomatic or mild symptoms generate a highly functional T cell response. In fact, 50% of those who have been exposed to coronavirus formed a T cell (cellular immunity) response without activation of B cell response (humoral immunity) and had no antibody formation (Li X, Geng M, Peng Y, Meng L, Lu S. J Pharm Anal. Apr 2020; 10(2): 102-108).
A large Swedish study demonstrated that twice as many exposed family members and healthy individuals who donated blood during the pandemic of COVID-19 generated memory T cell responses (cellular immunity) versus those generating antibody responses (humoral immunity). This imply’s that the seroprevaleance (presence of antibodies like IgG & IgM found on B-cells) as an indicator has grossly underestimated the extent of population level immunity against SARS-CoV-2 (COVID-19). And none of these patients with this type of immune response have experience further episodes of COVID-19 to date (Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. bioRxiv (Biology) Jun 2020; e-pub: 174888).
What this all means is that 50% of people get exposed and form immunity with T cells, instead of B cells an may never even know they’ve had the virus.
Increased Susceptibility to COVID-19
As you can see above, age over 55 places one at greater risk for severe COVID-19 infection and complications. This is due to the effect age has on the immune system.
Three additional maladies (hypertension, diabetes, elevated cholesterol & coronary artery disease) are also significant risk factors for severe COVID-19 infections. These are also are the four most common medical problems that I see in my clinic, and they affect 85% of the people in my practice. All four are caused and driven by hyperinsulinemia.
Hyperinsulinemia is defined as an elevated insulin production (2-30 times normal) when ingesting any form of carbohydrate or starch. It starts 15-20 years before the onset of diabetes and is the cause of hypoglycemia, elevated fasting blood sugar, pre-diabetes, metabolic syndrome, chronic kidney disease, idiopathic neuropathy, hypertension and coronary artery disease.
Elevated insulin, even small elevations, puts a load on the immune system. The higher your insulin response to starches or sugars, the more likely you are to have hypertension, diabetes and heart disease. We found that those with elevated insulin levels and those over 45 years old with stressed immune systems are the most susceptible to severe COVID-19 infection.
We know that just four or more hours of elevated blood sugar and insulin increases the cytokine IL-6 significantly. This has a suppressive effect on T cell immunity. The body raises insulin chronically to protect itself from the damage caused by chronic elevation in blood sugar. Chronic elevated blood sugars can lead to severe inflammation and clotting disorders. The body attempts to raise insulin to protect angainst these issues, however, the chronic elevation in insulin leads to chronic elevation in the cytokines IL-2, IL-6, TNF-alpha, PAI-1, NF-kB, ROS and eventually IL-33.
Should We Be Waiting For A Vaccine?
As a preface to this section, please be aware that I am a very strong proponent of safe and effective vaccine use. Because the RNA vaccines are so new, long-term efficacy, safety and adverse reaction studies are essential before these vaccines can be recommended across the board. It takes at least 4-5 years to 1) bring a vaccine to market and 2) complete adequate safety studies.
Let’s start by looking at the effectiveness of current RNA viral vaccines. The most common RNA vaccine currently in use is the influenza vaccine, quadravalent (four flu strains) and high dose (five flu strains) versions. Over the last 20 years, the percentage of seniors getting flu shots increased sharply from 15% to 65%. It stands to reason that flu deaths among the elderly should have taken a dramatic dip due to increased flu vaccination each year.
Instead, as you can see above, influenza deaths among the elderly continued to climb. It was hard to believe, so researchers at the National Institutes of Health set out to do a study adjusting for all kinds of factors that could be masking the true benefits of the shots. But no matter how they crunched the numbers, they got the same disappointing result: flu shots had not reduced deaths among the elderly.
It’s not what health officials hoped to find. I was shocked when I read these studies. Two studies, here and here, demonstrate that yearly flu vaccine for those over age 65 does nothing to decrease influenza related death. These studies funded by the government in 2005 and 2006 were suppressed and I never heard about them. Yet the CDC still emphasizes to the elderly, “Get your flu shot.”
One reason these vaccines are ineffective is that viruses like influenza and corona-viruses are highly antigenic. That means that there are hundreds of strains and the virus is changing rapidly. Influenza has over 600 strains. Our current high dose vaccine only covers five of these strains.
SARs-CoV-2 (COVID-19) is known to have over 160 strains. “There are too many rapid mutations to neatly trace a COVID-19 family tree.” Said Peter Forster, geneticist at the University of Cambridge. “We used a mathematical network algorithm to visualize all the plausible trees simultaneously.” (Proceedings of the National Academy of Sciences, 2020). Dr. Forster’s research identifies 160 genomes within the hundreds of additional variants of the three central COVID-19 strain variants.
A second reason, as stated above, is that 50% of people who are exposed to COVID-19 mount a T cell immune response without ever forming antibodies through B cell immunity. And, the antibodies that do form only give 3-4 months of protective effect.
Another other very fascinating concern found when making RNA virus vaccines is the potential to increase susceptibility to other viruses. In a Department of Defense study, looking at 6000 military personal vaccinated in the 2017-2018 season, those who got the influenza vaccine demonstrated an increases susceptibility to corona-viruses by 36%. Those who were vaccinated with the flu vaccine had additional increased susceptibility to non-influenza viruses by 15%, and increased susceptibility to human metapneumovirus by 59%.
A second influenza study demonstrated an increased risk of para-influenza virus in adults (increased by 4.6% of vaccinated adults and only 2.6% of un-vaccinated adults.) Though the researchers dismissed it as calculation error, the p value reflects that the vaccine played some roll (P=0.04) in the increased susceptibility.
Herd Immunity?
As with any other infection, there are two ways to achieve herd immunity: A large proportion of the population either gets infected or gets a protective vaccine. Based on early estimates of this virus’s infectiousness, we will likely need at least 70% of the population to be immune to have herd protection.
If the Penn State study is correct, the up to 50% of the U.S. population may have already been exposed as of the first week in March 2020, and by today, we may already be at Herd Immunity levels. This may be why we are now seeing continued drop in death rates across the country, despite increase infection counts (due to increased testing frequency).
Should we push for a vaccine? Do the math on a vaccine that covers only four out of 600+ strains like the quadravalent influenza vaccine. For a vaccine to create “herd immunity,” currently being touted across the airwaves as the way to return to normal, it would require the average human to be vaccinated every year for 100 years, and would take 200-400 years to create any semblance of herd immunity. And, that’s after 4-5 years studying the safety of a vaccine in large populations.
Influenza and HPV, the two most widely used RNA vaccines, still have a number of post-market adverse reactions including: Guillain-Barré syndrome (GBS), convulsions, febrile convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell’s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), dizziness, and paresthesia (tingling of the extremities) (Package-Insert—Gardasil.pdf; Package-Insert—Fluzone High Dose.pdf). Though these adverse events occur more rarely, it is essential you and I understand the risks of these newer RNA vaccines. Because it is an RNA virus, any coronavirus vaccine will come with similar risks.
What Can You & I Do?
First, our focus should be continued protection of our elderly and immune-compromised. Our focus should be placed on improving the immune systems of those at risk through diet, hand washing & quarantine of the ill. The evidence does not support quarantine of the healthy. Evidence does not support general public mask wearing. And there is no evidence that continued business closure is beneficial.
- Reduce your risk of hyperinsulinemia. Follow a carbohydrate restricted diet, exercise, control blood sugar, blood pressure, cholesterol and limit risk factors that suppress your immune system. Quit smoking, vaping, etc.
- For my patients with insulin resistant/hyperinsulinemia, I recommend Berberine 500mg twice daily with meals. (Talk to your doctor before you add any supplements or medications.)
- Use over-the-counter Zinc 10-30mg once daily – this has been shown to improve T cell control of viral replication.
- Use over-the-counter Melatonin 5-10mg nightly – this helps in sleep recovery and strengthening the T and B cell immune response.
- If you have been diagnosed with COVID-19, using Vitamin B3 (Niacin) has been show to be protective on the lungs. Niacin is found in meat, fish and eggs (there’s reason for that ketogenic diet, again!)
- Ensure your loved ones, especially the elderly and immune suppressed, understand the truth about their risk of infection.
- Make a list of the things this pandemic has taught you. What can you do to better protect yourself in the future?
- We live in a society with a limited supply chain.
- We have become excessively dependent upon foreign business and supply
- We have become dependent upon “just-in-time” and over-night delivery systems
- We have a number of local and Federal deficiencies in our health care system
- How important to your health, personal liberty and constitutional rights is defense of the borders?
- How has freedom of speech, freedom of religion and freedom of assembly affected your family and your physical, emotional or spiritual health?
Consider the following poem in all of this:
Don’t be afraid to go outside and be a human being again. And, pass the bacon.
