The Impact of Fear and Anxiety on the Human Immune System: Part I

“The enemy is fear. We think it is hate, but it is really fear”.
‍Gandhi (1)

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We live in the age of anxiety. We who see, see clearly this is a pandemic of fear. One of the central emotional responses during a pandemic is fear. Fear comprises both an emotional and physical response to stress. Functional fear helps people develop coping strategies, and the ‘right’ amount of anxiety can help us perform better and stimulate action. However, the fear created during this pandemic is completely disproportionate and irrational (2). The coronavirus disease 2019 (COVID-19) pandemonium is associated with highly significant levels of anxiety, depression, post-traumatic stress disorder and psychological distress (3). The ruling class say functional fear predicts our compliance in the COVID-19 pandemic (4). The more anxious we are, the more we comply. Eastern religion philosopher Alan Watts wrote, “If we look deeply into such ways of life as Buddhism, we do not find either philosophy or religion as these are understood in the West. We find something more nearly resembling psychotherapy” (3) . Psychotherapy, or talk therapy, helps eliminate or alleviate disturbing symptoms to enable one to encourage personal well-being and encourage healing. Our controllers know this hence they apply behavioural science techniques on us that discourage well-being and healing; the intention to increase compliance (5).
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‘Project Fear’ is a 21 st century term used in British politics that entered British politics in the 2014 Scottish independence referendum and again during the 2016 United Kingdom (UK) Brexit referendum (6). Our elected representatives call it the “fear appeal”. Fear appeal is a means of persuasion that threatens us with a negative, physical, psychological, and/or social consequence that will likely happen if we behave a certain way or engage in certain behaviour (7). In the case of the COVID-19 pandemonium, policymakers are supposedly guided by ‘the science’, however the science is, in many cases, preliminary and very often conflicting. It is apparent our policymakers are being guided by a perceived public clamour for draconian measures to tackle the pandemic, or at the very least it makes them appear as if they’re doing something. What our policy makers may ‘perceive’ is often filtered by a media skewed toward hyping the fear factor.

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Public health’s seven-step recipe for project fear

“As long as not everybody is vaccinated, nobody will be safe”. Klaus Schwab

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The recipe is entitled the ‘Seven-Step Recipe for Generating Interest in, and Demand for, Flu (or any other) Vaccination’. The recipe aimed to foster public interest and high vaccine demand was discussed at the National Influenza Vaccine Summit 2004, sponsored by the Centres for Disease Control and Prevention (CDC) and the American Medical Association (AMA) and devised by Glen Nowak Acting Director of Media Relations, CDC. The recipe includes:

• Statements of alarm in the media by medical experts and public health authorities.
• Prediction of dire outcomes from influenza (or other infectious disease).
• Continued reports by the media of influenza (or other infectious disease) causing severe illness affecting lots of people.
• Repeated urging of influenza (or other infectious disease) vaccination.
• Roll out the celebrity or past president to get the ‘vaccine’ on national media (8).

As an example, a lot of needless panic and fear was spread WORLDWIDE during the 2014-2016 Ebola outbreak in West Africa although only infectious upon direct contact (9). There as well, the World Health Organisation (WHO) and Global Health authorities immediately engaged with Big Pharmaceutical Research and Manufacturers of America (PhRMA) to expedite clinical trials and deploy the vaccine in the field based on highly suspicious data (10). The Ebola vaccine has been massively stockpiled and Healthcare workers (HCWs) in West-Africa were coerced to take the vaccine. But sure enough, Ebola burned out spontaneously, not due to a safe and effective vaccine, however due to improved hygiene, disinfection and precautions taken to avoid direct contact with infected people, corpses and potential animal reservoirs.

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Social engineering and newly documented COVID-19 psychoses

Social engineering is taking advantage of a potential victim’s natural tendencies and emotional reactions. Fear is a powerful social-engineering technique. One study sampled a large international community to evaluate factors associated with compliance, including self-perceived risk, fear of the virus, moral and ethical principles, political orientation, and behaviour changes in response to the pandemic and found that the only predictor of positive behaviour change (compliance) was fear of COVID-19 (11). Three billion people globally were living under lockdown during the spring of 2020. The World Economic Forum (WEF) themselves admit that this is the largest psychological experiment ever and will result in a secondary epidemic of burnouts and stress-related absenteeism in the latter half of 2020. How hypocritical that the authors of the ‘Great Reset’ purport to care about our mental health and are calling on a two-tier approach; one for the wounded and one to treat the invisible, psychological wounds of trauma (12). A Lancet review of 245 studies exploring the psychological effects of COVID-19 lockdowns concluded that those quarantined experienced psychological stress disorders such as depression, insomnia, stress, anxiety, anger, irritability, emotional exhaustion and post-traumatic stress symptoms (13). Public health lockdowns, and the associated sequelae of mandates, have driven anxiety, fear and phobias and exacerbated feelings of social isolation. The severe stress caused by a combination of COVID-19 restrictions to our liberties has resulted in three newly documented COVID-19 related neuropsychiatric disorders; COVID-19-associated brief psychotic disorder, COVID-19-induced psychosis and suicidal behaviour and COVID-19 psychosis (14-16).

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Social exclusion and discrimination

The model used to exclude advocates of natural immunity is known as the ‘spiral of silence’ theory, which had its origins in mass communication. The spiral of silence theory states that a social group or society as a whole might isolate or exclude members due to the members’ opinions. This theory stipulates that individuals have a fear of isolation. The spiral of silence stops people from expressing their opinions on controversial public issues as they believe they may be unpopular and lead to social exclusion. The spiral of silence theory results in populations tending to support majority views, resulting in a homogenisation of public opinion (17). This model makes me, a Complementary and Alternative Medicine (CAM) consultant, a social pariah. To discriminate against someone because of their gender, marital status, family status, age, disability, sexual orientation, race, religion, or membership of a minority community is not acceptable, however mentioning that you don’t vaccinate provides free rein to discriminate.

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Name-calling, intimidation and bullying

Even before COVID (BC), calls were being made by the Royal College of Physicians Ireland for mandatory vaccines for HCWs working in certain settings (18). Anyone who did not comply experiences name-calling, intimidation, bullying, discrimination and ultimately segregation. Names used include ‘anti-vaxxers’, ‘fascists’, ‘threat to all patients’, ‘danger to society’, ‘blood on their hands’, ‘unable to reason’, ‘neglectful’, ‘vaccine dodgers’, ‘deplorables’ etc. In 2019, the WHO name-called vaccine refusers by describing them as one of “the ten greatest threats to Global Health” (19).

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Stress is a risk factor for severe COVID-19 disease.

I call ‘innate immunity’, ‘natural immunity’, which is essentially ‘naturally acquired immunity’ (i.e., acquired upon recovery from disease). The relationship between both acute and chronic stress and immune dysfunction has been known for decades. A meta-analysis of more than 300 articles describing a relationship between psychological stress and the immune system published in 2004 by Suzanne Segerstrom, found that acute stressors (lasting minutes) are associated with potentially adaptive upregulation of certain innate immunity parameters (primary response) and downregulation of certain functions of adaptive immunity (secondary response). Brief stressors, such as exams, tended to suppress cellular immunity while preserving humoral immunity (antibodies production by B lymphocytes). Stress is not only a consequence of the pandemic, but is also a potential promoter of respiratory viral infections, and is implicated in increased susceptibility to SARS-CoV-2 infection, and a risk factor for severe COVID-19 disease (20).

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The neurobiology of stress-related to COVID-19

Neurobiology relates to biological mechanisms of mediation by the nervous system. The neurobiology of stress related to COVID-19 is complex. An article by Eva M. J. Peters et al., published in Neurobiology of Stress entitled, ‘To stress or not to stress: Brain-behaviour-immune interaction may weaken or promote the immune response to SARS-CoV-2’, describes the mechanisms as to how stress suppresses innate immunity. The authors describe how stress research accumulating over the past decades suggests that acute versus more chronic stress produces differing responses and that neuroendocrine-immune activation provoked by either physical or emotional stress interacts with biomolecular effects of stress. Psychoneuroimmunology is the study of neural, endocrine and immune system mutual interdependence. The authors state that historical psychoneuroimmune experiments demonstrated that stress lowers the threshold for viral infections, and hypothesise that chronic stress mechanisms compromise the immune system's defence against viral infections (21).

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The effects of fear on the human body

Stressors are both emotional and physical and, as previously mentioned, fear is an emotional and physical response to stress. COVID-19 links have been made between stress-associated health issues such as chronic, non-infectious, non-communicable diseases (NCD) in industrial countries and socioeconomic factors. In an article entitled, The Effects of Chronic Fear on a Person's Health, published in the American Journal of Managed Care Article in 2017, Moller outlines the potential consequences of fear on physical, emotional, environmental and spiritual health. The potential effects of chronic fear on overall health include, immune system dysfunction, endocrine system dysfunction, autonomic nervous system alterations, sleep/wake cycle disruptions, eating disorders and alterations in hypothalamus-pituitary-adrenal (HPA) axis (22).

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Fear and the impact on innate defences

Stress affects both innate and adaptive immunity. The innate immune system is the one we are born with. The adaptive immune system develops when the body is exposed to infectious disease. Stress affects both primary and secondary line of immune defences. The respiratory tract mucosa, intestinal mucosa, and skin provide the first line of defence against viruses. These act as a mechanical and biochemical barrier. In the first instance, stress negatively impacts the cohesion of the cells that form the barrier-providing mucosa and the skin’s epidermis. Stress impairs proliferation and repair and induces apoptosis (programmed cell death). The stress mediators that affect barrier function include hormones, neurotransmitters and neuropeptides. The modulation of the HPA axis is via the (nor)adrenergic and cholinergic (Adrenergic; sympathetic nervous system receptors / Cholinergic; parasympathetic nervous system receptors) stress axis to neuropeptides (chemical messengers) and neurotrophins (regulate development, maintenance and function of the nervous system) released in response to stress. These stress-response systems enhance barrier permeability. Innate immune cells, such as mast cells that reside in the skin, can be activated by stress to release histamine and proinflammatory cytokines such as interleukin-1β (IL-1β) IL-6 and tumour necrosis factor-
alpha (TNF-α), that further compromise barrier function (21).

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Fear and the impact on adaptive defences

Investigations in chronic stress and resultant neuroendocrine mediators have found that infectious microbes are able to enter unhindered to exacerbate disease. Moreover, inflammation in the form of neuroendocrine mediators and immune cells can permeate from the initial infection site to reach the brain and affect the blood-brain barrier (21). Chronic stress exposure increases noradrenergic (involving noradrenalin in nerve transmission) innervation of lymphatic system organs which reduces the activity of the innate type I interferon system. I describe interferons (IFN) as the ‘General of our natural immunity army’. IFNs are named for their ability to ‘interfere’ with viral replication by protecting cells from virus infections and triggering an increase in natural immune response such as Natural Killer cells (NK cells), macrophages, phagocytes and other immune cells to target pathogens, not only viruses, but also bacteria, fungus, parasites and tumour (23).

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Hans Selye’s Three General Adaption Syndrome

Moller continues to explain Hans Selye’s three predictable stages that the body uses to respond to stressors called the General Adaption Syndrome (GAS). It was as far back as1936 in fact, that the founder of the stress theory, Hans Selye’s first described his GAS. This theory is a fundamental principle in naturopathic teaching. The three stages of the GAS are the Alarm Phase, Resistance Phase and Exhaustion Stage. The exhaustion stage is also described as adrenal exhaustion or 21 st century syndrome. People experience this as ‘burnout’.

1. Alarm: The first reaction is called the fight or flight stress response whereby the body recognises there is imminent danger and prepares to fight and/or take flight. Selye's research showed that the HPA axis and autonomic nervous system are activated and the primary stress hormones, cortisol, adrenaline, and nonadrenaline are released.
2. Resistance: Homeostasis, our self-regulatory mechanism, begins restoring balance, and a period of recovery for repair and renewal takes place. If the stress subsides, stress hormones may return to normal, but there may be reduced defences. Prolonged stress will further deplete adrenal stores and reduce the ability of the body to adapt.
3. Exhaustion: During the exhaustive phase, the prolonged stress has caused the body to lose its ability to adapt, as adrenal hormone stores become depleted. Naturopaths term this ‘adrenal exhaustion’ (22).

Another adrenal steroid, dehydroepiandrosterone (DHEA) is increasingly documented to be released during these phases. DHEA is a sex hormone precursor (24).

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The stress response is paradoxical, and cortisol is a two-edged sword

The HPA axis plays an important role in immune suppression through its glucocorticoid stress hormone end product, cortisol. Cortisol is released by the adrenal glands. Cortisol is a glucocorticoid with anti-inflammatory and immunosuppressive properties (25). Glucocorticoids promote gluconeogenesis (formation of glucose from non-carbohydrate substrates) in the liver, whereas in skeletal muscle and white adipose tissue, they decrease glucose uptake and utilisation by antagonising insulin response. Therefore, excess glucocorticoid exposure causes hyperglycaemia and insulin resistance (26). Adrenalin and noradrenalin increase heart rate and vasoconstriction respectively (27) . Cortisol however, is a two-edged sword. On the one hand, endogenously produced (nor)adrenaline and cortisol production suppresses natural killer (NK) cell activity and represses the transcription of the proinflammatory cytokines IL-1β, IL-6 and TNF-α via direct interaction of the glucocorticoid receptor with the transcription factor nuclear factor-kappa B (NF-κB). NF-κB is a transcription factor involved in inflammatory and immune response is associated with
higher susceptibility to viral infections of the respiratory tract (28). Proinflammatory cytokines up-regulate inflammatory reactions which initially stimulate immunity. On the other hand, chronic stress-induced HPA activation, as with treatment using high doses of cortisol-based medications, inhibits host defence by downregulating innate and cellular immune defence mechanisms. This process is associated with CD8 + (cytotoxic) T-cell senescence (aging) which mediates adaptive immunity. Excess cortisol production results in negative feedback and down-regulation of glucocorticoid receptors and can lead to glucocorticoid resistance, which results in an increased production of inflammatory cytokines, and it is thought that this could promote the cytokine storm seen in critically ill COVID-19 patients (21) . Chronic stress can also lead to depression. Cortisol has been shown to induce an increase in the expression of the gene coding for the serotonin transporter, which subsequently elevates uptake of serotonin (29). Patients with major depression exhibit decreased brain serotonin (5-hydroxytryptamine, 5-HT) function and elevated cortisol  (30)
Sleep disorders are a core symptom of depression (31).

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The endocrine system works independently

As we recognise in holistic medicine, the endocrine system works independently. These mechanisms are highly complex. HPA dysfunction affects the hypothalamic–pituitary–thyroid (HPT) axis. The interdependence between thyroid
hormones (THs), namely thyroxine and triiodothyronine, and the immune system is today well-recognised  (32) . Cortisol inhibits down-regulation by both thyroid hormones (THs), 3,3′,5,5′ tetraiodo-L-thyroxine (T4) and 3,3′,5-triiodo-L-thyronine (T3), which play essential roles in both innate and adaptive immune responses (33, 34). In healthy individuals, cortisol displays the opposite circadian pattern to melatonin our sleep hormone; peaking early in the morning and lowest at night. Circulating cortisol exerts a negative-feedback effect at multiple levels within the HPA axis, which has been hypothesised as one of the key mechanisms associated with immune dysfunction, and in neuroinflammation and mood disorders (35).

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Brain-gut-microbiome-immune axis

There has been a lot said about the gut-immune connection. The gut microbiota regulate immune homeostasis to boost host immunity (36). A more accurate description of this is the brain-gut-microbiome-immune axis. Brain-gut-microbiome-immune communication interacts with channels involving nervous, endocrine, and immune signalling mechanisms. Many major neuronal molecules play important roles in both the nervous system and the immune system. These molecules were originally discovered in the immune system, however later found to have functions in the nervous system. Innate immunity-related molecules, such as cytokines, and acquired immunity-related molecules, such as the major histocompatibility complex (MHC) and antibody receptors, are also expressed in the brain (37). MHC genes are expressed to produce surface antigens on the cell membrane which allows the immune system to recognise and eliminate foreign pathogens. Two types of MHC classes exist; MHC class 1 (MHC I) and MHC class 2 (MHC II). MHC I molecules present antigens to cytotoxic T cells with CD8+ receptors, whereas MHC class 2 molecules present antigens to helper T cells with CD4+ receptors (38).

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Angiotensin-converting enzyme 2 and SARS-CoV-2

Angiotensin-converting enzyme 2 can tilt the balance between pro- and anti-inflammatory immune responses to stress. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) to overcome the barrier and bind to host cells in the alveoli (39). Whilst ACE2 binds angiotensin II is normally known for its role in regulating blood pressure, it has recently been identified as a key player in the conventional renin-angiotensin system (RAS) that promotes inflammation, oxidative stress and apoptosis, and these prolonged immunological effects may weaken innate and adaptive immunity (21, 40). ACE is a new immunologic target for SARS-CoV-2 as it regulates cellular immune responses through a calcineurin-dependent pathway, which is involved in the activation of T cells. Changes in tissue ACE II levels are associated with many diseases and hyperinflammatory states, and it is assumed that elevated levels of ACE II could aggravate the course of COVID-19 infection (41, 42).

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Stress and associated lifestyle factors that contribute to immune suppression

Oxidative stress can cause chronic inflammation. Oxidative stress results both from the exogenous environment (UV light, heavy metals, persistent organic pollutants (POPs) cigarette smoke, air pollution) and from endogenous processes, such as the enzymatic production of reactive oxygen species (ROS) by mitochondria or by neutrophil activated by danger-associated molecular patterns (DAMPs) released during inflammation. Antioxidants can decrease oxidative stress-induced carcinogenesis (the transformation of healthy cells into cancer cells) by directly scavenging f ROS and/or by inhibiting cell proliferation secondary to protein phosphorylation (modification of proteins) (43).

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Obesity as a risk factor for stress and severe COVID-19 disease

Increased long-term cortisol levels are strongly related to abdominal obesity and to specific mental disorders (44). Patients with comorbidities such as diabetes, hypertension, or obesity have a higher risk of getting seriously ill and dying from COVID-19, and a higher risk of dying in general (45). A higher body mass index (BMI) is a predictor of lower stress resilience (46). Higher BMI is also a predictor of inflammation and immune suppression. In response to chronic stress, obese individuals overproduce the inflammatory marker IL-6 which is strongly associated with negative health outcomes including severe COVID-19 disease outcomes. High levels of IL-6 counteract NK cells and CD8 + T cell responses thus suppressing immunity and increasing susceptibility to SARS-CoV-2 infection. A combination of both obesity and a lower number of CD8 + T cells are predictive of a more severe course of the disease (21). Elevated levels of IL-6 among other factors of innate immune hyperactivation are considered to be responsible for the hyperinflammation seen in patients with COVID-19 disease. Innate immune cells, monocytes and macrophages, and increased production of cytokines such as IL-6, IL-7 and tumour necrosis factor (TNF), and inflammatory chemokines play a role in the pathological inflammation in patients with COVID-19 (47).

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Conclusion

We are living under duress. In additon to lockdowns, we face the continuing threat of mandatory vaccines, mandatory masking of our children, mandatory quarantine, and forced removals from our homes. These techniques of coercive control used by public health authorities are an abuse of power and are in fact, coercive abuse. Fear and anxiety have a profound impact on several different biological systems and the interaction and stability thereof. Prolonged stress conditions in particular, can negatively impact the homeostasis of the entire organism with deep ramifications into the neurological, immunological and endocrine system, thereby resulting in imbalanced physiological and behavioral responses and flawing of our natural immune defences against all pathogens, including SARS-CoV-2.

As much of the fear is caused by public health authorities, it becomes difficult to believe that they care about our health. From a naturopathic perspective, there are many dietary, lifestyle, herbal medicine and nutritional supplement recommendations that can address the biomedical causes associated with fear, stress and anxiety. These natural approaches combine traditional knowledge with cutting edge science. By adopting dietary, lifestyle and herbal medicine and nutritional supplement recommendations, we have the ability to reprogramme the cells in the innate immune system to create ‘memory’ of a pathogen, an ability normally only associated with the secondary immune defences of the adaptive immune system. I discuss naturopathic treatment principles and naturopathic treatments in ‘The Impact of Fear and Anxiety on the Human Immune System: Part II'. Let us all keep our eye on the goal, which is to get healthy and liberate ourselves from public health’s grip. In these dark days, the future in fact, looks bright.

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Abbreviations

- Angiotensin-converting enzyme 2 (ACE2)
- Glycaemic-index (GI)
- Healthcare workers (HCWs)
- Hypothalamus-pituitary-adrenal (HPA)
- Interferons (IFNs)
- Interleukin-1β (IL-1β)
- Major histocompatibility complex (MHC)
- MHC class 1 (MHC I) and MHC class 2 (MHC II)
- Natural Killer (NK) cell
- Nuclear factor-kappa B (NF-κB)
- Omega-3 fatty acids (ω−3 fatty acids/ n−3 fatty acids)
- Progressive muscle relaxation (PMR)
- Reactive oxygen species (ROS)
- Severe acute respiratory syndrome CoV 2 (SARS-CoV-2)
- Tumour necrosis factor-alpha (TNF-α)

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