Diet and COVID-19

Diet is an important influencing factor in COVID-19 susceptibility and symptom severity (Butler & Barrientos, 2020).

Immune function and diet

• An adequate and balanced diet is foundational for an optimally functioning immune system (Iddir et al., 2020).
• Inadequate nutrition has been shown to weaken the immune response (Caccialanza et al., 2020).
• Poor nutrition is associated with oxidative stress and inflammation – both of which negatively affect immune function (Iddir et al., 2020).
• People who regularly eat vegetables and fruit have lower markers of inflammation and coagulation-related factors (Iddir et al., 2020).

Diet, blood-sugar levels, and inflammation

• Excess consumption of refined carbohydrates, including white flour and sugar, results in free radical production and inflammation, while consumption of vegetables, fruit, nuts, seeds, and whole grains does not (Iddir et al., 2020).
• Insulin resistance, decreased glucose tolerance, and obesity are known inflammation-promoting conditions resulting from overconsumption of sugar and starches (Sestili & Fimognari, 2020).
• Hyperglycemia (excess blood sugar) and advanced glycation end products (AGEs) are common results of the typical Western diet which result in systemic inflammation and chronic disease (Zabetakis et al., 2020).

Protein and immunity

• High-quality protein in a meal slows down the rate of food movement through the digestive tract, which decreases the rate of glucose absorption and associated inflammation (Iddir et al., 2020).
• Protein is required to make components of the immune system, especially antibodies.
• Low protein intake is known to increase the risk of infection (Iddir et al., 2020).

Pro-inflammatory food components

• Foods that contain added sugars, trans-fats, damaged fats, and chemical additives are inherently pro-inflammatory (Sestili & Fimognari, 2020).
• Processed foods that contain trans-fats, for example potato chips and fries, are known to increase inflammation (Iddir et al., 2020).

Diet and COVID-19

• Healthy diets, like the Mediterranean diet, support appropriate immune system function and are known to prevent viral infections, systemic inflammation, and thrombosis (Detopoulou et al., 2021).
• The Mediterranean diet may also be protective against COVID-19-induced thrombosis (Detopoulou et al., 2021).

The Mediterranean diet includes foods that are beneficial, and also reduces or eliminates foods that promote inflammation and reduced immune function. Whole food diets, like the Mediterranean Diet, also contain the key vitamins and minerals required to support healthy immune function.

General components of the Mediterranean diet include:

• plenty of vegetables and fruit
• healthy fats including olive oil
• regular consumption of seafood
• poultry, beans, and small amounts of red meat
• small amounts of dairy as yogurt and cheeses
• whole grains instead of refined grains

Vitamin A and immunity

Vitamin A supports (Gröber & Holick, 2022; Calder, 2020; Tepasse et al., 2021; Junaid et al., 2020):

• antibody production
• cytokine expression
• formation of lymphocytes (a type of white blood cell)
• immune cell proliferation, maturation and function
• both the innate and adaptive immune responses
• TH1 and TH2 cell balance
• barrier function – integral part of the mucous layer in the respiratory, gastrointestinal, urogenital tracts, and skin

Carotenoids support (Gröber & Holick, 2022):

• defence against viral, bacterial and protozoal diseases (Gröber & Holick, 2022)
• free radical reduction
• reduction of pro-inflammatory cytokines
• reproduction and maintenance of epithelial cells (skin cells)

Vitamin A deficiency is common

• 75% of adults in the US do not achieve the 3,000 IU/day recommendation for vitamin A intake (Gröber & Holick, 2022).
• 34% of adults in the US consume less than the EAR (Estimated Average Requirement) for vitamin A (Sestili & Fimognari, 2020).
• Hospitalized patients have been shown to have significantly lower levels of vitamin A when compared to convalescent persons (Tepasse et al., 2021).
• Vitamin A deficiency is one of the top micronutrient deficiencies, especially in countries with low protein and meat consumption (Iddir et al., 2020).

Dietary beta carotene needs to be converted to vitamin A (retinol)

• Conversion has been shown to be impaired in 24–57% of people with associated genetic variations (Sestili & Fimognari, 2020).
• Decreased conversion of beta carotene to retinol may have clinical consequences, especially for vegans (Sestili & Fimognari, 2020).
• Vitamin A levels decrease during various infections due to decreased absorption and urinary losses ((Sestili & Fimognari, 2020; Iddir et al., 2020).

Vitamin A deficiency and immunity

• Low levels of vitamin A are shown to result in (Sestili & Fimognari, 2020):
  • impaired antibody response
  • decreased T-helper cells
  • altered B and T-cell function (Gröber & Holick, 2022)
  • decreased integrity of mucosal linings in the respiratory and digestive tracts
  • more susceptibility to respiratory conditions and infectious diseases
  • increased mortality rates (Detopoulou et al., 2021)
• Vitamin A deficiency has been long-associated with an increased risk of infection and is an indicator of overall immune status (Iddir et al., 2020; Sf, n.d.).

Key actions of vitamin A in COVID-19

• antioxidant effects (Gröber & Holick, 2022)
• anti-inflammatory effects (Tepasse et al., 2021)
• immune modulation (Gröber & Holick, 2022)

Vitamin A deficiency and COVID-19

• Vitamin A deficiency has been significantly correlated with reduced lymphocytes; a key predictor of worse outcomes in patients with COVID-19 (Tepasse et al., 2021.)
• Significantly reduced plasma vitamin A levels have been found in the acute COVID-19 phase compared to convalescent patients (Tepasse et al., 2021).
• “Immune imbalance and disruption of antiviral T-cell responses in cases of severe and critical COVID-19 may, in part, be driven by decreased vitamin A plasma levels during the acute phase” (Tepasse et al., 2021).

Vitamin A and COVID-19 symptoms and illness

Vitamin A, inflammation, and COVID-19

Reduced vitamin A plasma levels correlate significantly with increased levels of inflammatory markers (CRP, ferritin), and with markers of acute SARS-CoV-2 infection (reduced lymphocyte count, LDH (lactate dehydrogenase))  (Tepasse et al., 2021).

Vitamin A and lung injury

• People with low vitamin A levels have increased risk of lung dysfunction and respiratory disease (Iddir et al., 2020).
• Roles of vitamin A in lung health:
  • support for healthy mucous layers – especially in the respiratory tract (Iddir et al., 2020)
  • development of normal lung tissue (Tepasse et al., 2021)
  • lung tissue repair after injury from infection (Tepasse et al., 2021)
  • restoration of lung surfactant (Gröber & Holick, 2022)

Vitamin A and ARDS

Severely deficient plasma vitamin A levels (below 0.2 mg/L) have been shown to be significantly correlated with ARDS development (Tepasse et al., 2021).

Vitamin A can help modulate the progression of ARDS (Jovic et al., 2020).

Causes of vitamin A deficiency

• conditions that affect the digestion and absorption of fats and fat-soluble nutrients (Vitamin A Deficiency – Nutritional Disorders, n.d.)
• Crohn’s disease and ulcerative colitis (Office of Dietary Supplements – Vitamin A and Carotenoids, n.d.)

Signs of vitamin A deficiency (Office of Dietary Supplements – Vitamin A and Carotenoids, n.d.)

• dry eyes
• night blindness

Vitamin C and immunity

Vitamin C is an essential part of immune function and vital for both innate and adaptive immunity.

Key roles of vitamin C roles in immunity

• Modulates oxidative stress
• Regulates inflammation (Milani et al., 2021)
• Supports epithelial barrier function (e.g. alveolar membrane), and endothelial barrier protection (Gröber & Holick, 2022)
• Supports differentiation and maturation of T-cells and NK cells (Iddir et al., 2020)
• Influences microbial killing and antibody production (Gröber & Holick, 2022)
• Enhances migration of immune cells (neutrophils and macrophages) toward infection sites (Cerullo et al., 2020; Iddir et al., 2020). Impaired chemotaxis (movement of immune cells in response to chemical stimulus) has been observed in patients with severe infection (Milani et al., 2021)
• Protects immune cells from oxidative burst (rapid release of ROS) (Milani et al., 2021)
• Promotes programmed apoptosis (cell death) (Milani et al., 2021)

In controlled trials vitamin C has (Hemilä & Chalker, 2019):

• improved endothelial barrier function
• lowered blood pressure
• decreased bronchoconstriction
• shortened the duration of colds
• prevented pain

Vitamin C deficiency is common

• Vitamin C deficiency is common in Western populations and verified by epidemiological studies (Gröber & Holick, 2022).
• Over 50–75% of American adults do not meet the RDA for vitamin C intake (90 mg/day) (Gröber & Holick, 2022).
• Over 50–75% of Dutch and Germans do not meet the RDIs for vitamin C (Gröber & Holick, 2022).
• Approximately 25% of men and 16% of women in the UK who are low-income or materially deprived are deficient in vitamin C (defined as less than > 11 μmol/L 103] (Holford et al., 2020).

Greater need for vitamin C when under physiologic stress

Vitamin C levels can rapidly decline with physiological stressors including (Holford et al., 2020; Abobaker et al., 2020):

• respiratory and other infections
• surgery
• trauma
• sepsis
• COVID-19

Vitamin C levels in critical illness and hospital setting:

• Vitamin C levels can be very low in critically ill patients (Hemilä & Chalker, 2020), due to increased metabolic needs (Holford et al., 2020).
• Studies show that despite receiving standard nutrition, a high amount of critically ill patients are vitamin C deficient (Hoang et al., 2020).
• 35% of Scottish patients with acute respiratory infections had very low plasma vitamin C levels (less than 11 μmol/L) (Hemilä & Chalker, 2019).
• 19% of patients in a Canadian hospital had levels less than 11 μmol/L (Hemilä & Chalker, 2019).
• 21% of surgical patients in an Australian study had plasma levels less than 11 μmol/L (Hemilä & Chalker, 2019).
• Abnormally low levels of vitamin C were found in 75% of critically ill patients in an observational study (Hoang et al., 2020).
• The use of high-dose vitamin C can reduce needs for medications including corticosteroids, anti-bacterials, and anti-virals (Hoang et al., 2020).
• Vitamin C may shorten the length of disease and prevent disease complications  (Hoang et al., 2020).

Vitamin C deficiency in COVID-19

• Mean plasma concentration has been shown to be five times lower in COVID-19 patients than in healthy volunteers (Xing et al., 2021).
• Vitamin C levels were undetectable in more than 90% of patients with COVID-19-associated ARDS (Chiscano-Camón et al., 2020).
• Vitamin C intakes of 2–3 g/day may be needed to maintain normal plasma vitamin C levels with viral infections (Holford et al., 2020).

Vitamin C and COVID-19 symptoms and illness

Vitamin C and viral infection and replication

• Vitamin C has been shown beneficial against the common cold in clinical trials (Bae & Kim, 2020).
• Vitamin C decreases viral infectivity in both RNA and DNA viruses and supports the body’s detoxification of inflammation and pain-inducing viral products (Hoang et al., 2020).
• High-dose vitamin C has been demonstrated to be virucidal in many studies (Boretti & Banik, 2020).
• Vitamin C counters downregulation of the primary anti-viral defence mechanism – type-1 interferons – that occurs as a result of COVID-19 (Holford et al., 2020).

Vitamin C and ACE2 receptors

• Vitamin C was shown to stop ACE2 receptor upregulation during COVID-19 (Holford et al., 2020).

Vitamin C and the cytokine storm

• High-dose vitamin C was shown effective at reducing the risk of cytokine storm development in late-stage COVID-19 infection (Abobaker et al., 2020).
• Vitamin C helps downregulate cytokine activity in the critical phase of COVID-19 (Holford et al., 2020) and protects against COVID-19-induced cytokine storms (Keflie & Biesalski, 2021).

Vitamin C and oxidative stress

• Vitamin C decreases oxidative stress by decreasing NF-kB activation (Holford et al., 2020).
• It protects the lungs from oxidative stress caused by inflammation and infection (Abobaker et al., 2020).
• It helps to protect neutrophils when they produce ROS to destroy antigens, and supports apoptosis (programmed cell death) instead of necrosis (uncontrolled cell death) of exhausted neutrophils, resulting in a less inflammatory response (Cerullo et al., 2020).

Vitamin C and inflammation

• Vitamin C decreases pro-inflammatory cytokines (Cerullo et al., 2020), increases anti-inflammatory cytokines (Shakoor et al., 2021), and enhances cortisol production (Holford et al., 2020).
• IV vitamin C was shown in a small COVID-19 trial to significantly reduce levels of pro-inflammatory cytokine IL-6 by the seventh day of infusion (Carr & Rowe, 2020).
• Intake of 1 g/day of vitamin C in clinical studies increased the anti-inflammatory cytokine IL-10 (Shakoor et al., 2021).
• An RCT study showed that 1 g/day of vitamin C significantly reduced the markers of inflammation – CRP and IL-6 – in 64 obese, hypertensive, and/or diabetic patients who had existing high levels of CRP (Cerullo et al., 2020).

Vitamin C and ARDS

• Decreased levels of vitamin C have been found in patients with viral infections, sepsis, and sepsis-related ARDS (Colunga Biancatelli et al., 2020).
• High-dose vitamin C can help severely ill COVID-19 patients with viral pneumonia and ARDS by (Kumari et al., 2020):
  • decreasing inflammation
  • decreasing viral infectiveness and virulence
  • improving immune defence
  • reducing tissue and organ injuries
• In the context of ARDS vitamin C:
  • provides mucosal protection (Hoang et al., 2020)
  • supports collagen synthesis to support epithelial integrity (Im et al., 2020)
  • supports alveolar fluid clearance (Liu et al., 2020)
• Patients with pneumonia and sepsis have been shown to have low vitamin C levels and high oxidative stress (Carr & Rowe, 2020; Abobaker et al., 2020).
• Vitamin C helps suppress inflammation and regulate immunity in pneumonia (Milani et al., 2021).
• Vitamin C administration, along with other antioxidants, to patients with septic shock and ARDS was shown to decrease markers of oxidative stress, improve cardiovascular health, and increase survival (Carr & Rowe, 2020).
• Administration of vitamin C to critically ill patients can decrease the duration of mechanical ventilation and stay in ICU (Carr & Rowe, 2020).

Vitamin C and coagulation abnormalities

Vitamin C has been shown to:

• play a significant role in the prevention of sepsis-associated coagulation abnormalities  (Hoang et al., 2020)
• decrease markers of thrombosis in high-risk cardiovascular and diabetes patients (Detopoulou et al., 2021)
• prevent microthrombi formation and capillary plugging (Carr & Rowe, 2020)

Vitamin C and mitochondrial dysfunction

Vitamin C has been shown to protect against (Corrao et al., 2021):

• mitochondrial membrane depolarization (shift in electric charge distribution)
• mitochondrial DNA oxidative stress
• cell toxicity

Vitamin C and sepsis

• Vitamin C deficiency is common in patients with sepsis (Abobaker et al., 2020).
• Patients with sepsis and multiple organ failure are known to have very low vitamin C levels (Carr & Rowe, 2020).
• Vitamin C anti-sepsis actions include (Abobaker et al., 2020):
  • reducing oxidative stress
  • reducing inflammation
  • suppressing inappropriate immune activity
• A trial of IVC (intravenous vitamin C) in patients with severe sepsis showed significantly reduced multiorgan failure scores. The effect was greater in the high-dose vitamin C group (200 mg/kg) compared to the low-dose group (50 mg/kg) (Liu et al., 2020).
• In an RCT trial of septic patients with ARDS, IV vitamin C administration (200 mg/kg) decreased 28-day mortality and increased ICU-free and hospital-free days (Carr & Rowe, 2020).
• Vitamin C is also required for the synthesis of catecholamines and adrenal steroid hormones – which help mitigate the circulatory system effects of septic shock (Abobaker et al., 2020).

› Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: A retrospective case series study. Annals of Palliative Medicine (Zhao et al., 2021)

• high-dose IV vitamin C was used to treat moderate to severe COVID-19 patients
• benefits were seen in inflammatory response as well as improvement in immune and organ function

› Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. Journal of Translational Medicine (Fowler et al., 2014)

• intravenous vitamin C infusions of 3.5 and 14 g/day for four days significantly decreased multi-organ failure scores
• the decrease in failure scores with the higher dose was twice that of the lower dose

› Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. Journal of Research in Pharmacy  (Zabet et al., 2016)

• patients with septic shock requiring norepinephrine treatment to maintain blood pressure were given either 25 mg/kg IV vitamin C every 6 hours for 72 hours or a placebo
• average dose and duration of norepinephrine were significantly lower in the vitamin C-treated patients
• 28-day mortality was significantly lower in the IV vitamin C-treated group (14.28% vs 64.28%)

Some additional studies that support the use of vitamin C in the context of respiratory distress and sepsis include:

› Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients (Hemilä & Chalker, 2019)

› Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: A meta-regression analysis. Journal of Intensive Care (Hemilä & Chalker, 2020)

› Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. Journal of Translational Medicine (Fowler et al., 2014)

› Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA (Fowler et al., 2019)

› Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World Journal of Critical Care Medicine (Fowler Iii et al., 2017)

Causes of vitamin C deficiency

• restrictive diets
• a diet lacking in sources of vitamin C especially fresh fruit and vegetables
• digestive tract disorders, e.g. diarrhea, Crohn’s disease, and colitis
• smoking
• alcoholism
• chronic inflammatory conditions

Signs of vitamin C deficiency

• bleeding or swollen gums
• frequent nosebleeds
• dry hair, split ends
• easy bruising
• slow wound healing
• fatigue
• moodiness
• depression and cognitive impairment (Plevin & Galletly, 2020)

Vitamin D and immunity

• Supports transcription of antimicrobial peptides (Vyas et al., 2021) that have activities against various bacteria, viruses, and fungi (Bae & Kim, 2020; Mitchell, 2020).
• Induces autophagy (cleaning out of damaged or unnecessary cellular components) thereby enhancing clearance of viruses and viral constituents (Malaguarnera, 2020).
• Modulates innate and adaptive immune activity (Radujkovic et al., 2020).
• Regulates growth and differentiation of several types of immune cells (Sulli et al., 2021).
• Suppresses over-expression of pro-inflammatory cytokines (Sulli et al., 2021).
• Supports gut integrity and gut microbial balance (Charoenngam & Holick, 2020).
• Helps maintain the integrity of epithelial tight junctions which decreases risk of infection and pulmonary edema (Shakoor et al., 2021).
• Helps maintain TH1:TH2 immune balance (Malaguarnera, 2020) by reducing TH1 and inducing TH2 immune responses (Bae & Kim, 2020).

Vitamin D deficiency is common:

• Vitamin D deficiency is common in the winter months in countries north of the 42^nd parallel (Biesalski, 2020).
• In Germany, France, and Italy more than 25% of the population is vitamin D deficient, especially the elderly (Biesalski, 2020).
• In Scandinavia only around 5% of the population is low in vitamin D – likely due to regular consumption of cod liver oil (sources of vitamin D and A) (Biesalski, 2020).
• Almost 50% of the world’s population is deficient in vitamin D (Getachew & Tizabi, 2021; DiNicolantonio & O’Keefe, 2021).
• COVID-19 patients have been found to have lower levels of 25(OH)D compared to healthy people without COVID-19.
• The rate of vitamin D deficiency was highest in severe or critical cases of COVID-19 (Ye et al., 2021).

› Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic? Nutrients (Brenner et al., 2020)

• The majority of those 50–75 years of age at baseline had insufficient or deficient vitamin D levels.
• Low levels were associated with increased mortality – especially from respiratory diseases.
• Some key risk factors for vitamin D deficiency are age, obesity, diabetes, hypertension, and smoking (Bae & Kim, 2020).

Vitamin D deficiency is common in COVID-19

› The role of vitamin D in the age of COVID-19: A systematic review and meta-analysis. International Journal of Clinical Practice (Ghasemian et al., 2021)

• This meta-analysis of 11 studies that included 360,972 COVID-19 patients.
  • 37.7% had vitamin D deficiency
  • 32.2 had vitamin D insufficiency
• Most confirmed COVID-19 patients had deficient or insufficient vitamin D levels.
• They were nearly three times more likely to become infected and about five times more likely to progress to severe COVID-19 symptoms.

› 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients (D’Avolio et al., 2020)

• Adults who were vitamin D-deficient were at increased risk of being infected with the COVID-19 virus.
• Those with COVID-19 had lower 25(OH)D levels than those without COVID-19.

Vitamin D deficiency and COVID-19 susceptibility and severity

Vitamin D deficiency:

• has been shown to be associated with increased susceptibility to COVID-19  (Mukherjee et al., 2022).
• was correlated with increased hospitalization and ICU admission due to COVID-19  (Bae & Kim, 2020).
• was inversely correlated to COVID-19 virus positivity (SARS-CoV-2 RNA Nucleic Acid Amplification Test) (Herrera-Quintana et al., 2021).
• is associated with increased inflammation and decreased immune function, which increases risk of severe infection (Vyas et al., 2021).

› Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients (Radujkovic et al., 2020)

Vitamin D-deficient patients:

• had a higher hospitalization rate
• required more oxygen therapy
• needed more invasive mechanical ventilation

Vitamin D deficiency was associated with:

• 6-times greater risk of a severe course of COVID-19
• approximately 15-times greater risk of death

Vitamin D deficiency was shown to be:

• significantly higher in COVID-19 patients and associated with increased COVID-19 severity (Mukherjee et al., 2022)
• correlated with increased severe lung involvement, longer duration of illness, and increased risk of death in elderly patients (Sulli et al., 2021)

› Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS One (Maghbooli et al., 2020)

• People who were deficient in vitamin D were more likely to experience severe COVID-19 disease.

› Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. Journal of Medical Virology (Munshi et al., 2021)

• Low vitamin D status significantly correlated to worse prognosis in a meta-analysis of 1368 COVID-19 patients.

Vitamin D deficiency and COVID-19 mortality

• Fatality rates from COVID-19 parallel vitamin D deficiency rates (Herrera-Quintana et al., 2021).
• Below-average vitamin D levels are associated with increased susceptibility to COVID-19 mortality (Vyas et al., 2021; Annweiler et al., 2020).
• Vitamin D levels were significantly lower in people who died during hospitalization compared to survivors (Sulli et al., 2021).

› Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS One (Maghbooli et al., 2020)

› Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. Journal of Endocrinological Investigation (Carpagnano et al., 2021)

• Mortality and morbidity were shown to be higher in patients with vitamin D deficiency.

› Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality. American Journal of Clinical Pathology (De Smet et al., 2021)

› Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: An Israeli population-based study. The FEBS Journal (Merzon et al., 2020)

• Vitamin D deficiency is considered to be an independent risk factor for COVID-19 infection, hospitalization, and death.

Vitamin D deficiency has been associated with increased mortality compared with vitamin D-sufficient patients in many studies. Some are listed here:

› Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgraduate Medical Journal (Baktash et al., 2021).

› Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. Journal of Endocrinological Investigation (Carpagnano et al., 2021).

› Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital. Clinical Nutrition (Edinburgh, Scotland) (Cereda et al., 2021).

› Sex-specific association between vitamin D deficiency and COVID-19 mortality in older patients. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA (Hars et al., 2020).

› Interaction between age and vitamin D deficiency in severe COVID-19 infection. Nutricion Hospitalaria (Macaya et al., 2020).

› Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients (Radujkovic et al., 2020).

› Vitamin D and Lung Outcomes in Elderly COVID-19 Patients. Nutrients (Sulli et al., 2021).

“…results imply that 87% of COVID-19 deaths may be statistically attributed to vitamin D insufficiency and could potentially be avoided by eliminating vitamin D insufficiency” (Brenner & Schöttker, 2020).

› Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS One (Maghbooli et al., 2020).

• Mortality rate dropped to almost to 0% when the serum 25(OH) D concentrations were higher than 34 ng/mL (retrospective study).

Vitamin D and COVID-19 symptoms and illness

Vitamin D and viral infection

Low vitamin D levels:

• are significantly associated with an increased likelihood of COVID-19 infection (Pizzini et al., 2020).
• increase the likelihood of COVID-19  infection by 3.3 times, and the risk of severe COVID-19 by around five times (Ghasemian et al., 2021).

A study of 191,779 COVID-19 patients from all 50 US states showed (Gröber & Holick, 2022):

• circulating 25(OH)D levels were inversely associated with the rate of COVID-19 infection. This relationship persisted across latitudes, races and ethnicities, sexes, and ages.

Vitamin D protects from COVID-19 infection by (Bae & Kim, 2020):

• enhancing physical barriers in the body
• increasing production of antimicrobial peptides

Vitamin D has antiviral properties  (Vyas et al., 2021) and has been shown to promote viral clearance in COVID-19 patients who were asymptomatic or mildly symptomatic (Gröber & Holick, 2022).

Vitamin D and ACE2 receptors

• The COVID-19 virus uses ACE2 to access cells, which results in decreased ACE2 function.
• ACE2 helps convert ANG II to the protective ANG 1-7.
• ANG II causes problems when not in balance with ANG 1-7.
• Decreased ACE2 function results in less ANG 1-7 which promotes COVID-19 pathology.
• In the context of COVID-19, decreased ACE2 promotes runaway inflammation and progression to cytokine storm (Annweiler et al., 2020).
• High amounts of ANG II can promote ARDS or cardiopulmonary damage (Mercola et al., 2020).

Vitamin D, ACE2 and renin

Vitamin D:

• upregulates expression of ACE 2 receptors, increasing the conversion of ANG II to ANG 1-7 (Brenner et al., 2020; Mitchell, 2020).
• lowers ANG II levels (Grant et al., 2020).
• suppresses renin, which in turn reduces ANG expression, resulting in decreased ANG II expression (Sulli et al., 2021).
• has been shown to inhibit renin and ANG II expression, while supporting ACE2 levels in LPS-induced respiratory distress (Vyas et al., 2021).
• has been shown effective against acute lung injury by modulating renin, ACE2, (Ebadi & Montano-Loza, 2020), and ANG 1-7 (Singh & Singh, n.d.).

Vitamin D and the cytokine storm

Vitamin D can inhibit cytokine storm by:

• boosting innate immunity while decreasing over-expression of adaptive immunity, and suppressing excessive immune reactions to pathogens (Vyas et al., 2021)
• decreasing pro-inflammatory cytokines while increasing anti-inflammatory cytokines (Lakkireddy et al., 2021).
• maintaining tight junctions and killing enveloped viruses (Singh & Singh, n.d.)
• increasing serum vitamin D levels to 80 ng/ml has been shown to decrease the severity of cytokine storms (Lakkireddy et al., 2021)

Sufficient levels of vitamin D can help prevent and control cytokine storms (Brenner et al., 2020; Junaid et al., 2020).

Vitamin D and oxidative stress

Roles of vitamin D in managing oxidative stress include:

• activating several antioxidant pathways and inhibiting oxidative stress-activating pathways (Abdrabbo et al., 2021)
• inducing antioxidant defenses including catalase, superoxide dismutase, and glutathione to reduce oxidative stress (Gröber & Holick, 2022)
• inhibition of inflammatory mediator inducible nitric oxide synthase (Malaguarnera, 2020)

Vitamin D and inflammation

Vitamin D can balance inflammation by:

• regulating the inflammatory response by decreasing the production of pro-inflammatory cytokines and increasing the production of anti-inflammatory cytokines (Shakoor et al., 2021; Lakkireddy et al., 2021)
• inhibiting pro-inflammatory Th1 activity and upregulating anti-inflammatory Th2 and T regulatory cells (Abdrabbo et al., 2021)
• suppressing over-expression of inflammatory cytokines (Sulli et al., 2021)
• helping to reduce the inflammatory response to COVID-19  infection (Mitchell, 2020)

Vitamin D deficiency was shown to be correlated to C-reactive protein (CRP):

• CRP, a marker of inflammation and surrogate marker of the cytokine storm, was highly elevated in severe COVID-19 patients and correlated with vitamin D deficiency (Shakoor et al., 2021).

Vitamin D and ARDS

Vitamin D offers protection against ARDS by:

• mediating innate and adaptive immune activity (Brenner et al., 2020)
• decreasing production of pro-inflammatory cytokines (Annweiler et al., 2020)
• increasing production of anti-inflammatory cytokines (Annweiler et al., 2020)
• stabilizing physical barriers (maintaining tight junctions) (Annweiler et al., 2020) and maintaining the integrity of epithelial barriers (Vyas et al., 2021), in conjunction with vitamin A (Biesalski, 2020)
• inactivating some viruses by stimulating antiviral mechanisms such as antimicrobial peptides (Srivastava et al., 2021)
• increasing ACE2 concentrations (Srivastava et al., 2021)
• reducing the risk of bradykinin storm (Srivastava et al., 2021) (Bradykinin is a compound formed in injured tissue that has bronchodilation, vasodilation, and pro-inflammatory properties)
• reducing MMP concentrations (Srivastava et al., 2021) (MMP is involved in the degradation of extracellular matrix during inflammatory episodes (Ben Moftah & Eswayah, 2022)
• increasing proliferation of alveolar type-II cells (lung cells) and stimulating their production of surfactant (Ebadi & Montano-Loza, 2020). Decreased surfactant increases the risk of developing ARDS (Xu et al., 2020)
• reducing apoptosis of pneumocytes preventing severe lung injury (Xu et al., 2020)
• attenuating LPS-induced lung damage (Biesalski, 2020)

Vitamin D deficiency and upper respiratory tract infection:

• Low vitamin D status has been shown to increase susceptibility to acute respiratory infections (Martineau et al., 2017; Mitchell, 2020).
• The US Third National Health and Nutrition Examination Survey of 18,883 adults showed an inverse relationship between vitamin D levels and upper respiratory tract infections (Calder et al., 2020).
• Vitamin D insufficiency and deficiency resulted in strongly increased respiratory mortality when compared to those with sufficient vitamin D (Brenner et al., 2020).
• Levels lower than 15 ng/mL (37.5 nmol/L) are known to significantly increase risk of acute respiratory infections (Lordan, 2021).
• Serum 25(OH)D levels below 75 nmol/L were shown in a retrospective study of 2000 critically ill patients to increase the risk of severe respiratory tract infection and ARDS (Annweiler et al., 2020).
• Supplementation of vitamin D has been shown to result in decreased risk of respiratory tract infection, especially in those with vitamin D deficiency (Martineau et al., 2017; (Annweiler et al., 2020; Brenner et al., 2020).

› Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ (Clinical Research Ed).(Martineau et al., 2017)

• Vitamin D supplementation was shown to be protective against acute respiratory tract infections in a meta-analysis of 25 randomized controlled trials (RCTs) with 11,321 people.

Vitamin D deficiency was shown to:

• increase the risk of pneumonia in a systematic review and meta-analysis involving 20,966 subjects (Shakoor et al., 2021)
• increase the risk of intensive care admission and mortality in those with severe pneumonia (Dramé et al., 2021)

Vitamin D deficiency and sepsis

• Sepsis, a systematic inflammatory response by the body to a microbial pathogen, is a major cause of death in hospitalized patients (Charoenngam & Holick, 2020).
• In regard to sepsis, vitamin D deficiency has been shown in multiple observational studies to be linked to (Charoenngam & Holick, 2020):
  • increased occurrence
  • increased morbidity and mortality
  • prolonged length of stay in the ICU

Vitamin D protects against sepsis by (Charoenngam & Holick, 2020):

• preventing vascular leakage
• decreasing over-expression of inflammatory cytokines
• promoting anti-bacterial immune responses

Vitamin D and coagulation abnormalities

COVID-19-associated coagulopathy is strongly associated with the rate of survival after COVID-19 (Vyas et al., 2021)

Vitamin D has roles in:

• regulation of blood-clotting pathways (Sulli et al., 2021)
• upregulating anticoagulant activity and downregulating pro-coagulation activity (Lau et al., 2020).

Vitamin D deficiency:

• can worsen COVID-19 severity by increasing blood clotting action leading to both arterial and venous thrombosis (Abou-Ismail et al., 2020)
• has been shown in clinical studies to be correlated with increased thrombosis (Vyas et al., 2021), and is associated with an increased risk of thrombotic events (Sulli et al., 2021)

Causes of vitamin D deficiency

• limited sun exposure
• strict vegan diet (most sources of vitamin D are animal-based)
• darker skin (the pigment melanin reduces the vitamin D production by the skin)
• digestive tract and kidney issues
• obesity (vitamin D is sequestered by fat cells)

Some drugs that affect vitamin D absorption or metabolism include (Vitamin D, 2014):

• cholestyramine
• colestipol
• orlistat
• mineral oil
• phenytoin
• fosphenytoin
• phenobarbital
• carbamazepine
• rifampin
• cimetidine
• ketoconazole
• glucocorticoids
• HIV treatment drugs

Measuring vitamin D

The best indicator of vitamin D status is serum 25(OH)D, also known as 25-hydroxyvitamin D. 25(OH)D reflects the amount of vitamin D in the body that is produced by the skin and obtained from food and supplements.

Serum 25(OH)D levels (Ghasemian et al., 2021):

Sufficiency – greater than 30ng/mL (75 nmol/L)

Insufficiency – 20-30 ng/mL (50–75 nmol/L)

Deficiency: – less than 20 ng/mL (50 nmol/L)

Vitamin E and immunity

Vitamin E:

• is an important antioxidant that protects cell membranes from oxidative damage (including immune cell membranes) (Detopoulou et al., 2021; Kumar et al., 2021.)
• improves T-cell production and overall immune system functioning (Iddir et al., 2020.)
• has been shown to improve cell-mediated immune activity and decreases the risk of infections in 60-year-old adults (Calder, 2020)
• prevents coagulation issues by supporting dilation of blood vessels and inhibits platelet aggregation (Kumar et al., 2021.)

.

Causes of vitamin E deficiency:

• conditions that affect the digestion and absorption of fats and fat-soluble nutrients (Office of Dietary Supplements – Vitamin E, n.d.)

Magnesium and immunity

Magnesium has roles in:

• both innate and acquired immune activity (Dominguez et al., 2021)
• signaling pathways tied to immune cell development, homeostasis, and activation (Dominguez et al., 2021)
• antibody synthesis and antibody-dependent cell destruction (Srivastava et al., 2021)
• regulating functions of natural killer cells (DiNicolantonio & O’Keefe, 2021)

Magnesium deficiency interferes with programmed cell death (DiNicolantonio & O’Keefe, 2021).

Magnesium deficiency

• Up to 30% of a given population may have subclinical serum magnesium deficiency (DiNicolantonio & O’Keefe, 2021).
• Magnesium deficiency is relatively common and often unrecognized in clinical settings, as magnesium is rarely tested (Wallace, 2020).
• Magnesium deficiency is associated with (Dominguez et al., 2021):
  • increased inflammation
  • increased oxidative stress
  • decreased glutathione levels (DiNicolantonio & O’Keefe, 2021)
  • increased risk of infectious diseases
• Magnesium supplementation has been recommended for COVID-19 patients with hypertension, kidney injury, diabetes, or pregnancy complications (Srivastava et al., 2021).
• Proton-pump inhibitor medications decrease intestinal magnesium absorption and have been linked to poorer outcomes in COVID-19 patients (van Kempen & Deixler, 2021).

Magnesium and COVID-19 symptoms and illness

Magnesium and oxidative stress

• Magnesium deficiency increases tissue susceptibility to oxidative stress and risk of lung tissue damage from cytokine storms (DiNicolantonio & O’Keefe, 2021).

Magnesium and inflammation

Magnesium:

• decreases inflammatory cytokine production (DiNicolantonio & O’Keefe, 2021)
• has calcium-channel-blocking effect that limits systemic inflammation (Wallace, 2020)
• regulates proliferation and development of lymphocytes (Dominguez et al., 2021)

Serum magnesium levels inversely affect markers of inflammation (Nielsen 2018; Iotti et al. 2020; Srivastava et al., 2021; Dominguez et al., 2021).

Magnesium deficiency can promote inflammation via (Dominguez et al., 2021):

• activation of phagocytic immune cells
• opening calcium channels
• activating N-methyl-d-aspartate (NMDA) receptors
• increasing oxidative stress

Magnesium deficiency is known to:

• increase the production of pro-inflammatory cytokines (Srivastava et al., 2021)
• increase thymus cell apoptosis (programmed cell death) (Srivastava et al., 2021)
• be associated with low-grade systemic inflammation (Dominguez et al., 2021).

Magnesium and lung injury

Magnesium:

• prevents collagen deposition and lung fibrosis( COVID-19 survivors often develop lung fibrosis (Wang, Dong, et al. 2020; Srivastava et al., 2021))
• promotes bronchodilation and improved lung function (Dominguez et al., 2021).

Magnesium and coagulation abnormalities

• Magnesium has vasodilation, bronchodilation, anti-thrombotic, and anti-platelet activity Srivastava et al., 2021).
• Serum magnesium deficiency is associated with (DiNicolantonio & O’Keefe, 2021):
  • increased risk of thrombosis
  • decreased fibrin breakdown
  • endothelial dysfunction and loss of vascular integrity (Dominguez et al., 2021)
• Magnesium has been shown to reduce mortality in in-vivo (within a living organism) experiments of induced pulmonary thromboembolism (DiNicolantonio & O’Keefe, 2021).

Magnesium and mitochondrial dysfunction

Magnesium has roles in ATP (energy) production in mitochondria.

Magnesium deficiency promotes decreased ATP production and destruction of mitochondria by:

• increasing mitochondrial ROS production (oxidative stress)
• suppressing antioxidant defences
• promoting calcium overload
• depolarization (loss of electrical charge distribution) of mitochondrial membrane potential

Reasons for magnesium deficiencies

• Increased stress (causes magnesium depletion)
• Low dietary protein (needed for magnesium absorption)
• Gastrointestinal disorders (e.g. Crohn’s disease, malabsorption syndromes, and prolonged diarrhea)
• High doses of supplemental zinc (competes for absorption)
• Certain diuretic medications
• Alcoholism

Elderly adults tend to have lower dietary intake, absorption, and increased loss of magnesium.

Selenium and immunity

Selenoproteins

• Selenium acts in the body mainly as a component of proteins called selenoproteins.
• Selenoproteins have roles in the activation, proliferation, and differentiation of immune cells (Hoang et al., 2020).
• One of the main selenoproteins is glutathione peroxidase which helps prevent cellular oxidative stress (Erol et al., 2021).

Roles of selenium in immunity include supporting:

• innate and adaptive immune function (Srivastava et al., 2021)
• T-cell maturation and function (Bae & Kim, 2020; Hoang et al., 2020)
• antibody production (Bae & Kim, 2020; Hoang et al., 2020)
• natural killer cell function (Bae & Kim, 2020)
• regulation of excessive immune responses (Hoang et al., 2020)
• regulation of oxidative burst by immune cells, which is required for destruction of microbes and immune cell signalling (Hoang et al., 2020)

Selenium deficiency and COVID-19

• Inadequate intake of selenium is widespread in many parts of the world (Gröber & Holick, 2022), including in Western countries (Iddir et al., 2020).
• A study by Im et al. (2020) found 42% of 50 hospitalized COVID-19 patients to be deficient in selenium. 100% of those with very severe symptoms were deficient (Im et al., 2020).
• Low selenium levels are more prevalent in patients with severe COVID-19 (Khatiwada & Subedi, 2021).
• An observational study by Notz et al.(2021) found that 50% of COVID-19 patients admitted to ICU had considerable selenium deficiency (Notz et al., 2021).
• Issues with liver function can contribute to decreased production of selenoproteins (Erol et al., 2021).
• Selenium levels are known to be lower in people with obesity (Bermano et al., 2021).

Selenium deficiency and immunity

• Selenium deficiency is known to result in:
  • decreased production of selenoproteins (Gröber & Holick, 2022)
  • increased prevalence and severity of viral infections, including influenza (Iddir et al., 2020)
  • decreased antibody production, killing ability of natural killer and other immune cells, and decreased response to vaccination (Galmés et al., 2020)
• Selenium deficiency can be worsened by inflammation and disease states, and the inflammatory and hypoxic (low oxygen) state of a prolonged ICU stay can deplete selenium even further (Kieliszek & Lipinski, 2020).
• Immune cells lose selenium more rapidly than other tissue cells during deficiency (Hoang et al., 2020; (Khatiwada & Subedi, 2021).

Selenium deficiency in COVID-19

• A cross-sectional observational study by Moghaddam et al. ( 2020) found selenium deficiency resulted in increased risk of mortality due to COVID-19.
• A study of Chinese COVID-19 patients demonstrated that rates of recovery were significantly associated with selenium levels (Bae & Kim, 2020).
• Sufficient levels of selenium, as assessed by hair selenium content, were shown to result in higher COVID-19 recovery rates (Detopoulou et al., 2021).

Selenium and COVID-19 symptoms and illness

Selenium and viral infection and replication

• Selenium deficiency:
  • is a known risk factor for viral infections (Kieliszek & Lipinski, 2020)
  • intensifies the virulence and progression of some viral infections, including influenza (Bae & Kim, 2020; Zhang et al., 2020)
  • can increase virus mutation rates in patients identified as selenium-deficient (Kieliszek & Lipinski, 2020)
• The selenium-containing enzyme glutathione peroxidase protects epithelial barriers, which block virus entry, from oxidative damage (Bermano et al., 2021).

Selenium and oxidative stress

• Selenium has antioxidant properties when incorporated into selenoproteins (Hoffmann & Berry, 2008).
• Selenium and vitamin E work together to prevent oxidative damage to cells and tissues (Keflie & Biesalski, 2021).
• Selenium helps prevent oxidative stress caused by viral infections, including corona and influenza viruses (Gröber & Holick, 2022).
• Consumption of 100 micrograms a day of selenium is required for optimal function of the most important selenoproteins (Alexander et al., 2020).
• Selenium recycles coenzyme Q10 which also has a role in addressing cellular oxidative stress (Srivastava et al., 2021).

Selenium and inflammation

Selenium:

• modulates the production and actions of the proinflammatory molecules called eicosanoids (Hoang et al., 2020)
• shifts the action of macrophage cells from pro-inflammatory to anti-inflammatory in response to COVID-19 infection (Srivastava et al., 2021)
• may be beneficial in COVID-19 as it modulates the endothelial damage and inflammation caused by the body’s response to viral infections (Bermano et al., 2021)

Selenium and ARDS and lungs

Selenium has roles in:

• supporting integrity of the respiratory tract epithelial barrier, which in turn reduces viral entry into respiratory cells (Khatiwada & Subedi, 2021; Alexander et al., 2020)
• synthesizing antioxidant enzymes and defensive proteins on mucosal surfaces of the respiratory tract (Khatiwada & Subedi, 2021)
• modulating several immune pathways that can over-respond to viral infection (Khatiwada & Subedi, 2021)

Sepsis

• Mortality risk from sepsis is decreased when selenium levels increase (Kieliszek & Lipinski, 2020).
• Selenium, administered as sodium selenite, has been shown to reduce death from septic shock (Khatiwada & Subedi, 2021).   

Selenium and coagulation abnormalities

• Formation of clots in blood vessels are a significant contributor to COVID-19-patient deaths (Kieliszek & Lipinski, 2020).
• Selenium deficiency increases platelet activating factor (PAF), which activates platelets to increase clot formation (Detopoulou et al., 2021).

Zinc and immunity

Functions of zinc in immunity

• Supports the innate and adaptive immune systems (Carlucci et al., n.d).
• Has immunoregulatory and anti-viral properties (Shakeri et al., 2022).
• Required for normal development and function of some immune cell types (Shankar & Prasad, 1998).
• Required for the production of some types of antibodies (Shankar & Prasad, 1998).
• Intracellular killing, cytokine production, and phagocytosis (Shankar & Prasad, 1998) (Pal et al., 2021).
• Anti-inflammatory agent (Pal et al., 2021).
• Antioxidant (Pal et al., 2021).
• Prevention of thymus and lymphoid tissue atrophy (Pal et al., 2021).
• Maintaining epithelial barrier structure and function (Gröber & Holick, 2022; Gammoh & Rink, 2017) which is very important in the lungs and digestive tract.
• Required for the production of the active form of thymulin which stimulates the development of T cells in the thymus (Shankar & Prasad, 1998; Costagliola et al., 2021)
• Can block viral replication inside cells (Read et al. 2019; Rahman et al. 2020; Joachimiak 2021; Srivastava et al., 2021).
• Helps prevent an imbalance of TH1 and TH2 immune cells (Gammoh & Rink, 2017; Pal et al., 2021).

Zinc deficiency is common

• Zinc deficiency:
  • is common in the elderly (Gröber & Holick, 2022) with almost half of older populations having inadequate intake (Sestili & Fimognari, 2020)
  • is increased in those avoiding red meat, vegans, and people in developing countries who consume a mainly plant-based diet (Gammoh & Rink, 2017)
  • ranges from 15% to 31% in developed countries (Vogel-González et al., 2021)
  • accounts for around 16% of lower respiratory tract infections (Gammoh & Rink, 2017)

• Zinc requirements are increased:
  • during or severe infections, stress, and trauma (Gammoh & Rink, 2017)
  • in the elderly, infants, and alcoholics (Pal et al., 2021)
• Zinc deficiency increases susceptibility to a variety of infections (Sestili & Fimognari, 2020); Iddir et al., 2020).

Zinc deficiency is known to affect immunity by:

• impairing the activity of various immune cells (Gröber & Holick, 2022)
• causing atrophy of the thymus which negatively affects, T cells, B cells, and antibody production (Gammoh & Rink, 2017; Shankar & Prasad, 1998)
• damaging linings of the pulmonary and digestive tracts (Shankar & Prasad, 1998)

Loss of sense of smell and distorted sense of taste are classic symptoms of zinc deficiency, and are commonly reported by COVID-19 patients (Sestili & Fimognari, 2020).

Zinc deficiency in COVID-19

• The majority of COVID-19 patients had acute zinc deficiency upon admission to hospital (Gröber & Holick, 2022).
• Serum zinc levels in people admitted to hospital or ICU and died were shown to be significantly lower than in those who survived (Shakeri et al., 2022).
• More COVID-19 patients who were zinc-deficient had prolonged hospital stays compared to patients with normal zinc levels (Jothimani et al., 2020).

› COVID-19: Poor outcomes in patients with zinc deficiency. International Journal of Infectious Diseases (Jothimani et al., 2020)

• COVID-19 patients had significantly lower zinc levels compared to healthy controls.
• 54% of the COVID-19 patients were zinc deficient.
• Zinc-deficient patients had higher rates of complications including ARDS, longer hospital stays, and increased mortality.
• Zinc-deficient patients were 5.54 times more likely to develop complications.

Zinc and COVID-19 symptoms and illness

Zinc and viral infection and replication

• Zinc has been shown to inhibit the synthesis, replication, and transcription of coronaviruses (Shakoor et al., 2021; Junaid et al., 2020), including COVID-19 (Rahman & Idid, 2021).
• Zinc also prevents viral attachment to host cells (Srivastava et al., 202).
• Zinc inhibits replication by:
  • directly interfering with viral replication and protein synthesis (Shakoor et al., 2021)
  • inhibiting elements required for viral replication including RNA synthesis, DNA polymerase, reverse transcriptase, and viral proteases (Gröber & Holick, 2022; Calder, 2020; Keflie & Biesalski, 2021)

Zinc and the cytokine storm

Zinc helps prevent cytokine storms by:

• modulating the immune response (Gammoh & Rink, 2017)
• counteracting interferon interference by COVID-19 viral proteins (Pal et al., 2021)
• inhibiting pro-inflammatory cytokines and C-reactive protein, and regulating T cell activity (Keflie & Biesalski, 2021)

Zinc and oxidative stress

Antioxidant effects of zinc include (Gammoh & Rink, 2017):

• acting as a cofactor of the antioxidant enzyme CuZn-SOD
• inhibiting ROS-forming NADPH oxidase enzymes
• increasing production of proteins called metallothioneins, which have roles in cellular antioxidant defence (Shankar & Prasad, 1998)

Zinc and inflammation

• Zinc modulates pro-inflammatory responses, (Gammoh & Rink, 2017) while deficiency causes overproduction of pro-inflammatory mediators (Gröber & Holick, 2022).
• Long-term zinc deficiency increases inflammation and inflammation biomarkers (Alexander et al., 2020).

Zinc and lung issues/ARDS

Deficiency of zinc:

• has been shown in infectious lung diseases including tuberculosis and pneumonia (Gammoh & Rink, 2017)
• is associated with pneumonia in the elderly (Alexander et al., 2020)
• causes a decreased immune response toward bacterial infections and sepsis (Gammoh & Rink, 2017)

Zinc sufficiency decreases the prevalence of upper respiratory tract infections (Elham et al., 2021).

Essential Fatty Acids (EFAs) and immunity

EFAs influence immune system function by shaping the composition of cell membranes and modulating cell signaling in a positive way (Phelan et al., 2020).

EFA deficiency/imbalance

• Imbalances in fatty acids can promote metabolic, allergic, and autoimmune conditions.
• Key imbalances that have implications for proper immune function include:
  • saturated to unsaturated fatty acids
  • omega 6 to omega 3 fatty acids
• An elevated omega 6 fatty acid concentration:
  • interferes with omega-3 fatty acid metabolism and its positive effects (Iddir et al., 2020)
  • is associated with a pro-inflammatory context
• The dietary intake ratio of omega 6 to omega 3 in Westernized diets can be as high as 10:1  (Iddir et al., 2020).

EFAs and COVID-19 symptoms and illness

EFAs and viral entry and replication

• EFAs inhibit viral replication (Shakoor et al., 2021) and may interfere with viral entry into cells (Detopoulou et al., 2021).

EFAs and cytokine storm

• EFAs in combination with antioxidants may be used favourably to treat COVID-19-associated cytokine storm due to their anti-inflammatory actions (Calder, 2020).

EFAs and inflammation

• EPA and DHA (omega-3 FAs) decrease the production of inflammatory eicosanoids and cytokines, and inhibit the upregulation of pro-inflammatory genes (Calder, 2020).
• EPA is the precursor for the E series resolvins, and DHA is the precursor for the D series resolvins, neuroprotectins, and maresins. These lipid mediators play a key role in the resolution phase of the inflammatory process (Sestili & Fimognari, 2020).
• The intake of omega-3 FAs from fish and seafood has been shown to trigger anti-inflammatory reactions via oxygenated metabolites (oxylipins), including resolvins and protectins (Iddir et al., 2020).

EFAs and coagulation abnormalities

• Omega 3 fatty acids have anti-thrombotic effects including decreasing the pro-inflammatory omega 6 metabolite thromboxane, and platelet activating factor (Detopoulou et al., 2021).

Reasons for EFA deficiencies

• inadequate dietary intake
• poor absorption
• deficiencies of nutrients required for EFA metabolism
• issues with metabolism that cause decreased incorporation of, or increased removal of, fatty acids from cell membranes

Melatonin and immunity

Roles of melatonin in immunity include:

• immunomodulation (Carlberg, 2000)
• “resetting” immune cells at night (Bahrampour Juybari et al., 2020)
• promoting cell-mediated and humoral immunity (Garcia-Mauriño et al., 1997)
• assisting in the proliferation and maturation of natural killer cells, B and T cells (Bahrampour Juybari et al., 2020)
• suppressing excessive innate immunity (Brown et al., 2021)
• facilitating antibody production (Brown et al., 2021)
• inducing of apoptosis (programmed cell death) (Carlberg, 2000)
• anti-viral activity (Silvestri and Rossi, 2013; Bahrampour Juybari et al., 2020)

In addition, melatonin is known to:

• promote sleep initiation
• provide cardiovascular protection (Bahrampour Juybari et al., 2020)

Melatonin and COVID-19 symptoms and illness

Melatonin and viral infection and replication

› A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19. PLoS Biology (Zhou et al., 2020)

• A study of 26,779 COVID-19 subjects showed that higher melatonin levels were associated with a 28% decreased likelihood of infection in the general population, and a 52% decrease in the African American population.

Melatonin and oxidative stress

• Is a potent scavenger of free radicals (Reiter et al., 2016)
• Induces glutathione synthesis and increases production of antioxidant enzymes (DiNicolantonio et al., 2021)

Melatonin and inflammation

• Has anti-inflammatory actions (Brown et al., 2021).
• Reduces airway inflammation (Simko & Reiter, 2020).
• Inhibits pro-inflammatory cytokine activation (Brown et al., 2021).
• Modulates both innate and adaptive pro-inflammatory reactions that are excessively activated in COVID-19 patients (Corrao et al., 2021).

Melatonin and ARDS

• The anti-inflammatory and anti-oxidative actions of melatonin counter the acute lung injury seen in ARDS, as induced by viral and bacterial infections (Bahrampour Juybari et al., 2020).

Melatonin and mitochondrial dysfunction

• Is essential for maintaining effective mitochondrial function (Juybari et al., n.d.).
• Protects mitochondria from free radical damage (Bahrampour Juybari et al., 2020).

Melatonin and cardiac health

• Reduces vessel permeability. (Bahrampour Juybari et al., 2020).
• Has protective properties in the context of myocarditis (Ouyang et al., 2019).
• Improves heart function (Bahrampour Juybari et al., 2020).
• Represses virally-induced heart cell apoptosis (Bahrampour Juybari et al., 2020).
• Has been associated with decreased myocardial fibrosis and progression of hypertension (Simko et al., 2013; Bahrampour Juybari et al., 2020).

N-acetyl cysteine (NAC) and immunity

• NAC is converted in the liver to cysteine.
• The majority of cysteine is incorporated into glutathione, a major antioxidant and detoxification molecule.
• The availability of cysteine is the rate-limiting factor in glutathione synthesis (Sestili & Fimognari, 2020).

NAC and COVID-19 symptoms and illness

NAC and viral infection and replication

NAC and ACE2 receptors

• NAC may interfere with the binding of the COVID-19 virus to ACE2 receptors (Khatiwada & Subedi, 2021), thereby providing protection from the negative effects of ANGII (angiotensin 2) imbalance (Khatiwada & Subedi, 2021).

NAC and the cytokine storm

NAC can help:

• address the oxidative stress and ROS caused by cytokine storms (Jorge-Aarón & Rosa-Ester, 2020)
• attenuate immune overactivation and prevent cytokine release (Mohanty et al., n.d.)

NAC and oxidative stress

• NAC provides antioxidant support by:
  • direct antioxidant activity
  • acting as a precursor for the synthesis of glutathione (Mohanty et al., n.d.)
  • restoring redox-regulating thiol pools (Jorge-Aarón & Rosa-Ester, 2020)
• NAC increases glutathione levels at sites of inflammation (Mohanty et al., n.d.)
• Both NAC and glutathione have important roles in providing antioxidant support in COVID-19 (Sestili & Fimognari, 2020).

NAC and inflammation

• NAC has anti-inflammatory action (Mohanty et al., n.d.).

NAC and ARDS

NAC treatment has been shown to:

• lower the viscosity of mucous in the airways by breaking disulfide bonds (Bourgonje et al., 2021; Jorge-Aarón & Rosa-Ester, 2020).
• prevent and treat lung cell injury in ARDS by restoring glutathione levels (Polonikov, 2020).
• decrease the length of stay in intensive care units (Poe & Corn, 2020).

NAC and coagulation abnormalities

• NAC has been shown to have anti-thrombotic effects, increase platelet glutathione levels, and decrease platelet ROS (Sestili & Fimognari, 2020).

Glutathione and immunity

Glutathione is a molecule made by the body and is important for (Polonikov, 2020):

• detoxification
• regeneration of vitamin C and E
• anti-inflammatory responses (Sestili & Fimognari, 2020)
• maintenance of mitochondrial function
• protection from viruses
• innate and adaptive immune responses
• protein folding
• regulation of cellular proliferation and apoptosis

Glutathione deficiency is common

• Glutathione production by the body progressively declines with age (Polonikov, 2020).
• Some risk factors associated with glutathione depletion include smoking, aging, and male sex (Polonikov, 2020).
• Glutathione deficiency is common in people with chronic diseases (Polonikov, 2020).
• Consumption of fresh fruits and vegetables contributes to over 50% of dietary glutathione intake, and can decrease in the winter and spring seasons, contributing to glutathione deficiency (Polonikov, 2020).

Glutathione deficiency in COVID-19

• Glutathione deficiency is known to imbalance immune function by promoting TH2 immune dominance (Sestili & Fimognari, 2020).
• Glutathione deficiency in COVID-19 promotes increased oxidative stress, inflammation, progression to ARDS, multi-organ failure, and death (Polonikov, 2020).
• COVID-19 patients with moderate and severe illness are known to have lower glutathione levels (Karkhanei et al., 2021), and higher ROS levels (Polonikov, 2020), than those with mild illness.

› Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Frontiers in Pharmacology (Sestili & Fimognari, 2020)

• Glutathione levels were significantly lower in hospitalized COVID-19 patients compared to controls.
• Glutathione levels were directly related to oxygen saturation and indirectly related to fever and length of hospitalization.

Glutathione and COVID-19 symptoms and illness

Glutathione and viral infection and replication

• Inhibits viral replication of various viruses at several stages of the virus life cycle (Polonikov, 2020).
• The anti-viral effect of glutathione is non-specific; therefore it may be effective at inhibiting COVID-19 viral replication (Polonikov, 2020).

Glutathione and ARDS

• Glutathione reduces lung inflammation and oxidative stress and mitigates the risk of fibrotic damage to the lungs and other organs (Sestili & Fimognari, 2020).

Vitamin B1:

• has anti-inflammatory and oxidative-stress-reducing properties (Spinas et al. 2015; Kumar et al., 2021.)
• has been shown to promote humoral and cell-mediated immunity in COVID-19 patients (Shakoor et al. 2020b.)

Vitamin B2 (Jovic et al., 2020):

• promotes modulation of immune response.
• deficiency results in pro-inflammatory gene expression.

Vitamin B6

• Vitamin B6 affects proliferation and function of innate and adaptive immune cells (Kumar et al., 2021), and improves immune function (Keflie & Biesalski, 2021).
• Low levels of pyridoxal 5′phosphate, the active form of vitamin B6, are associated with decreased immunity (Iddir et al., 2020).
• Vitamin B6 addresses COVID-19 symptoms by decreasing inflammation, preventing coagulation, and supporting endothelial barriers (Kumar et al., 2021).

Vitamin B12

• Vitamin B12 (Shakoor et al., 2021):
  • suppresses viral replication in infected cells.
  • has anti-viral and anti-inflammatory properties.
  • deficiency is associated with decreased numbers of immune cells and suppression of natural killer cell activity.
• Serum vitamin B12 levels in patients who died due to COVID-19 were found to be lower than ICU and non-ICU admitted patients (Shakoor et al., 2021).

Folate

• Folate is required for proper antibody production and TH-1 immune response (Galmés et al., 2020).
• Folate and its derivatives support immune activity against the COVID-19 virus (Kumar and Jena 2020; Kumar et al., 2021).

Nutrient synergy in COVID-19

Nutrients function synergistically in the body to create health benefits that are greater than any nutrient could produce alone.

Some nutrient synergies relevant to the context of COVID-19 are listed here.

Vitamin D and magnesium

• Magnesium is required for the synthesis, transport, and activation of vitamin D (Dominguez et al., 2021).
• Supplementation of magnesium is recommended when taking vitamin D (Mercola et al., 2020).

Vitamin D, B12, and magnesium

• 17 patients with COVID-19 were supplemented with:
  • 1000 IU vitamin D
  • 500 mcg vitamin B12
  • 150 mg magnesium
• Compared to those who did not, those who received the nutrients had (DiNicolantonio & O’Keefe, 2021):
  • 87% decreased risk of needing oxygen therapy
  • 85% lower risk of needing intensive care support

Vitamin D, B12, C, and iron

• An ecological study by Galmés et al. (2020) showed that inadequate intake of vitamin D, vitamin C, vitamin B12, and iron is associated with increased COVID-19 incidence or mortality.

Vitamin D, C, E, Zn, and omega 3 fatty acids

• A review of immune-boosting nutrients in the context of COVID-19 by Shakoor et al. (2021) concluded that higher than recommended supplementation of vitamins D, C, E; zinc; and omega 3 fatty acids, could reduce COVID-19 viral load and duration of hospitalization.

Vitamin D and glutathione

• Glutathione deficiency can suppress vitamin D synthesis and metabolism (Vyas et al., 2021).
• Glutathione deficiency may be the main driver of vitamin D deficiency in COVID-19 complications and mortality (Polonikov, 2020).

Vitamin C and quercetin

• Together, vitamin C and quercetin have synergistic anti-viral and immunomodulatory properties.
• Vitamin C recycles quercetin, increasing its protective effect (Colunga Biancatelli et al., 2020).