COVID-19 symptoms and illness can be tied to these factors:

1. Virus entry and replication

2. ACE2 receptor inactivation

3. COVID-19-associated cytokine storm

4. Oxidative stress/Reactive oxygen species (ROS)

5. Inflammation

6. Lung  injury + Acute Respiratory Distress Syndrome (ARDS)

7. Coagulation abnormalities/thrombosis

ALL of these factors are modifiable with nutrition.

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1. Virus entry and replication

Virus life-cycle in the body

• COVID-19 virus enters the body primarily through inhalation, with initial infection occurring in the lungs (Malaguarnera, 2020).
• Once in the body, the virus gains entry into lung cells by attaching its spike protein to Angiotensin Converting Enzyme- 2 (ACE2) receptors.
• Inside the cell, the virus releases its RNA which is subsequently replicated by hijacking the cell’s protein-creating “machinery”.
• The copies of the virus are packaged by the cell and released into the body where they infect other cells, repeating the cycle.
• Viral replication causes cell death which also releases virus copies to further infect nearby cells (Khatiwada & Subedi, 2021).

Roles of the immune system in addressing COVID-19 entry and replication:

• prevent viral entry into the tissues and cells
• prevent viral replication once the virus has accessed the cells

2. ACE2 receptor inactivation

• The ACE2 receptor is an enzyme on the surface of many cells – especially lung alveolar cells, but also other tissues including the nervous system, heart, mouth, intestines, blood vessels, kidneys, adrenal glands, and pancreas. (Srivastava et al., 2021; Malaguarnera, 2020).
• ACE2 has roles in cytokine release, immune response, as well as regulation of infection and viral replication (Srivastava et al., 2021).
• An important function of ACE2 is to convert angiotensin 2 to angiotensin 1–7.
• Angiotensin 2 is an endocrine hormone that has roles in regulating blood pressure, inflammation, angiogenesis, and vascular aging. (Wong, 2016).

ACE2 and COVID-19

• COVID-19 spike proteins bind to ACE2 receptors, which enables the virus to enter cells (Vyas et al., 2021;Janssen et al., 2021). This causes a depletion of ACE2 receptors on the surface of lung cells, as the receptor is brought into the cell with the virus.
• As a result of this functional depletion of ACE2 receptors in the lungs, the conversion of angiotensin 2 to angiotensin 1–7 is reduced (Abdrabbo et al., 2021.)
• The resulting accumulation of angiotensin 2 leads to (Bouillon & Quesada-Gomez, 2021; Wong, 2016; Malaguarnera, 2020; Biesalski, 2020; Abdrabbo et al., 2021):
  • increased oxidative stress
  • increased inflammation
  • vascular permeability
  • acute lung damage and pneumonia
  • progression to severe ARDS
  • hypertension
  • liver and kidney failure
  • cardiac fibrosis
• It has been shown that ACE2 concentrations are inversely correlated with damage to heart and lung tissues (Grant et al., 2020).

3. COVID-19–associated cytokine storm

• Cytokines are messenger molecules released by immune cells.
• The cytokine storm is an abnormally strong release of inflammatory cytokines and chemical mediators by a dysregulated immune system (Iddir et al., 2020) (Lordan, 2021).
• The main effects of the cytokine storm are increased oxidative stress, systemic inflammation, decreased vascular nitric oxide production, and inappropriate vascular coagulation (Malaguarnera, 2020).
• Cytokine storm-associated lung damage can result in pneumonia, ARDS, and sepsis (Grant et al., 2020).
• Heart damage due to the cytokine storm includes myocarditis, heart failure, arrhythmias, and venous blood clots (Grant et al., 2020).

4. Oxidative stress

• Oxidative Stress is a biological condition that results in excess accumulation of reactive oxygen species (ROS) as a result of (Moghadas et al, 2019):
  • production of excessive amounts of oxidants
  • a decreased level of antioxidants
  • a combination of the above
• ROS are unstable oxygen-containing molecules that react with other molecules. Immune cells generate large amounts of ROS to destroy pathogens (Hoang et al., 2020).

Environmental contributors to oxidative stress include (Gammoh & Rink, 2017):

• air pollution
• tobacco smoke
• ionizing radiation
• drugs
• heavy metals (lead, arsenic, mercury, chromium, cadmium)
• organic solvents
• pesticides
• stress, lack of exercise, lack of sleep (Gombart et al., 2020)

Oxidative stress and COVID-19:

• promotes virus entry into cells by facilitating binding of the virus to ACE2 receptors (Abdrabbo et al., 2021)
• increases immune system over-activation, release of pro-inflammatory cytokines, and promotion of the cytokine storm (Mohanty et al., n.d.)
• causes inappropriate cell death by apoptosis (Mohanty et al., n.d.)

Key promoters of excessive oxidative stress in COVID-19 are (Mohanty et al., n.d.):

• prolonged excessive inflammation
• excessive ROS generation
• decreased amounts of the antioxidant glutathione

5. Inflammation

• Inflammation is a normal part of the body’s defence to injury or infection. However, when it occurs in healthy tissues, or lasts too long (months or years), inflammation is damaging to the body.
• Causes of chronic inflammation include (Inflammation, n.d.):
  • poor nutrition
  • environmental chemicals
  • an imbalanced microbiome
  • sleep issues
  • stress
  • personal environment

Inflammation and COVID-19

• Excessive inflammation in COVID-19 is caused by immune system over-activation due to viral infection (Janssen et al., 2021) and the propagating effects of the cytokine storm.
• High levels of circulating pro-inflammatory cytokines have been found in patients admitted to intensive care units with severe COVID-19 symptoms and pneumonia (Shakoor et al., 2021).

6. ARDS/Lung issues

Acute respiratory distress syndrome (ARDS) is a serious lung condition in which fluid accumulates in the tiny air sacs (alveoli) of the lungs, and production of surfactant required to keep the alveoli open is disrupted. ARDS results in dangerously low blood oxygen levels (Acute Respiratory Distress Syndrome – What Is Acute Respiratory Distress Syndrome? | NHLBI, NIH, n.d.).

Factors involved with COVID-19 ARDS include:

• viral infection
• excessive immune cell infiltration and over-activation in the lungs (cytokine storm)
• excessive oxidative stress and inflammation
• alveolar damage and increased permeability
• thick mucous secretions in the airways
• edema
• extensive lung damage
• microthrombosis (micro blood clots)

Surfactant

Type-II alveolar epithelial cells are the main target of the COVID-19 virus. Impairment of these cells by the virus decreases their production of the surfactant required to keep the alveoli open, resulting in reduced oxygen transfer into the body (Xu et al., 2020).

Sepsis

ARDS can result in sepsis – a life-threatening dysfunction of multiple organs, caused by widespread inflammation and blood clotting resulting in reduced blood flow. Sepsis is the primary cause of death from infection (Cerullo et al., 2020), including COVID-19 infection.

7. Coagulation abnormalities/ thrombosis

The cells lining blood vessels (endothelial cells) normally prevent clot formation. However, increased clot formation in COVID-19 can be caused by:

• inflammation resulting from viral infection of the cells of the vessel lining (endothelial cells) (Srivastava et al., 2021; Bouillon & Quesada-Gomez, 2021)
• direct destruction of endothelial cells by the virus (Mercola et al., 2020)

Thromboembolisms are blockages in arteries and veins caused by particles that have broken away from blood clots. These blockages have been frequently observed in patients with severe COVID-19 (Bouillon & Quesada-Gomez, 2021).

Comorbidities as COVID-19 risk factors

• Comorbidity is the condition of having two or more diseases or health conditions at the same time.
• Comorbidities are acknowledged factors for increasing the risk of contracting COVID-19 and having a poorer outcome.
• The presence of several comorbidities further increases the risk for poor COVID-19 outcomes (Hiedra et al., 2020).
• The presence of diabetes, cardiovascular disease, hypertension, and respiratory diseases is more common in critical or lethal COVID-19 patients than in non-critical patients (Khatiwada & Subedi, 2021).

The main comorbidities that increase the risk of unfavourable outcomes in COVID-19 are:

• diabetes
• obesity
• cardiovascular disease
• hypertension
• respiratory disease
• advanced age
• chronic illness
• malnutrition

What ALL these comorbidities have in common:

• overall malnutrition
• vitamin D deficiency
• increased baseline inflammation
• increased baseline oxidative stress

Diabetes and COVID-19

• A meta-analysis that included 16,003 diabetic patients showed diabetics have double the rate of death from COVID-19 compared to non-diabetic COVID-19 patients (Cerullo et al., 2020).

Diabetes factors that worsen COVID-19 outcomes:

• inflammation (Cerullo et al., 2020)
• insulin resistance, which is associated with increased inflammation (Sestili & Fimognari, 2020)
• low evening melatonin production (Simko & Reiter, 2020)

Obesity and COVID-19

• Obesity significantly increases the risks of COVID-19 (Skalny et al., 2021).
• A study of 383 COVID-19 patients showed an 86% increased risk of developing pneumonia in overweight people and a 142% increased risk in those who were obese, when compared to healthy weight people (Biesalski, 2020).

Obesity factors that worsen COVID-19 outcomes:

• inflammation (de Faria Coelho-Ravagnani et al., 2021; Feyaerts & Luyten, 2020)
• low magnesium intake (Dominguez et al., 2021)
• low vitamin D levels (Biesalski, 2020)
• vascular damage (Corrao et al., 2021)
• loss of immune competence (Calder, 2020)
• increased susceptibility to infection (Calder, 2020)
• an elevated amount of adipose tissue, which may be a repository for the COVID-19 virus (Bermano et al., 2021)
• restricted respiration (de Faria Coelho-Ravagnani et al., 2021)

Cardiovascular disease and COVID-19

• Cardiovascular disease can be considered to be an independent risk factor for mortality in COVID-19 patients (Biesalski, 2020).
• A meta-analysis of over 3,000 patients showed that those with cardiovascular disease are five times more likely to develop critical stage COVID-19 (Cerullo et al., 2020).
• Low levels of vitamin C which are common (Gröber & Holick, 2022), increase the risk of worsening COVID-19 cardiovascular pathology (Morelli et al., 2020)

Advanced age and COVID-19

• Mortality is less than 1.1% in COVID-19 patients under 50 years of age. In those over 50, the rate is around 30% with frail elderly patients contributing most significantly to severe cases and mortality (Annweiler et al., 2020).
• Advanced age is considered a principal risk factor for COVID-19 complications and fatalities (Bourgonje et al., 2021; Getachew & Tizabi, 2021).
• Mortality from acute infections was shown to be more than 50 times higher in people over 65 years old compared with people 30–50 years of age (Dominguez et al., 2021).
• COVID-19 hospital admission rates increase with age, with most hospitalized patients having underlying conditions (Sestili & Fimognari, 2020).

Factors associated with age that worsen COVID-19 outcomes

• Malnourishment – impairs immune function and increases susceptibility to infection (Zabetakis et al., 2020; Cerullo et al., 2020)

• Vitamin A deficiency (Gröber & Holick, 2022) – associated with decreased immune action against infections (Gröber & Holick, 2022)
• Zinc deficiency – common in the elderly and those with chronic diseases (Vogel-González et al., 2021)
• Decreased glutathione (Poe & Corn, 2020) – makes cells more vulnerable to oxidative damage (Dominguez et al., 2021,) and prone to lung inflammation progressing to ARDS (Polonikov, 2020)
• Decreased night-time melatonin levels – melatonin is a factor in “resetting” and retaining immune function (Bahrampour Juybari et al., 2020; Simko & Reiter, 2020)

• Polypharmacy (taking multiple medications) – contributes to immunosenescence (Dominguez et al., 2021)

• Oxidative damage – which in many people accumulates over their lifetime (Huang et al., 2012), and also increases COVID-19 virus binding to ACE2 receptors (Abdrabbo et al., 2021)
• Inflammation – aging is associated with increased levels of many inflammatory markers in the body (Calder, 2020)

• Immunosenescence (a loss of immune competence) (Getachew & Tizabi, 2021; Calder, 2020)
• Decreased innate immunity and unfavourably amplified adaptive immunity (Vyas et al., 2021)

• Hypertension – which is more common in the elderly and a known risk factor for severe COVID-19 symptoms (Poe & Corn, 2020)
• Decreased estrogen – which is associated with increased levels of pro-inflammatory cytokines (Brenner et al., 2020)
• Downregulation of ACE2 receptors – promotes increased inflammation (Getachew & Tizabi, 2021)

Systemic inflammation and comorbidities

• Chronic disease conditions can exacerbate the inflammatory response to COVID-19, which increases risk of severe symptoms and mortality (Corrao et al., 2021).
• Diabetes, obesity, and cardiovascular disease have inflammation as a key causal component (Sestili & Fimognari, 2020).
• Low-grade systemic inflammation is common in diabetes, obesity, and cardiovascular disease (Iddir et al., 2020).
• Poor diet is a common contributor to low-grade chronic inflammation seen in obesity, diabetes, cardiovascular diseases, and autoimmune diseases (Iddir et al., 2020).

Other factors that worsen COVID-19 outcomes

• Smoking – increases oxidative stress and depletes nutrients including glutathione and other antioxidants (Bazzini et al., 2013).
• Environmental pollution – elevates oxidative stress and inflammation, and is also associated with increased pulmonary and cardiovascular morbidity and death (Lodovici & Bigagli, 2011).

Malnutrition and comorbidities

• Malnutrition increases susceptibility to COVID-19 infection and more severe symptoms and outcomes, especially in the elderly and disadvantaged populations (Rodriguez-Leyva & Pierce, 2021).
• Malnutrition is common in COVID-19 patients and seen in:
  • 42% of hospitalized COVID-19 patients (Bedock et al., 2020)
  • 39% of COVID-19-infected patients (Allard et al., 2020)
  • 67% of COVID-19 patients admitted to the intensive care unit (Bedock et al., 2020)
• A Canadian study of university students showed that during the time of pandemic preventative procedures, nutrient and calorie intake from food decreased, while consumption of alcohol increased (Bertrand et al., 2021). Alcohol is known to deplete many nutrients.

Vitamin D deficiency and comorbidities

• Vitamin D deficiency is common in diabetes, cardiovascular disease, hypertension, and respiratory diseases (Annweiler et al., 2020).
• Vitamin D deficiency is a risk factor for diabetes, cardiovascular disease, and hypertension (Lordan, 2021).

Magnesium deficiency and comorbidities

• Magnesium deficiency is associated with increased severity of COVID-19 outcomes, and is also a known factor in chronic inflammation, diabetes, hypertension, and old age (Dominguez et al., 2021).