COVID-19 and Nutrition: An Orthomolecular Perspective

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

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References

Butler, M. J., & Barrientos, R. M. (2020). The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain, Behavior, and Immunity, 87, 53–54. https://doi.org/10.1016/j.bbi.2020.04.040

Caccialanza, R., Laviano, A., Lobascio, F., Montagna, E., Bruno, R., Ludovisi, S., Corsico, A. G., Di Sabatino, A., Belliato, M., Calvi, M., Iacona, I., Grugnetti, G., Bonadeo, E., Muzzi, A., & Cereda, E. (2020). Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol. Nutrition, 74, 110835. https://doi.org/10.1016/j.nut.2020.110835

Detopoulou, P., Demopoulos, C. A., & Antonopoulou, S. (2021). Micronutrients, Phytochemicals and Mediterranean Diet: A Potential Protective Role against COVID-19 through Modulation of PAF Actions and Metabolism. Nutrients, 13(2), 462. https://doi.org/10.3390/nu13020462

Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Sestili, P., & Fimognari, C. (2020). Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Frontiers in Pharmacology, 11, 579944. https://doi.org/10.3389/fphar.2020.579944

Zabetakis, I., Lordan, R., Norton, C., & Tsoupras, A. (2020). COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation. Nutrients, 12(5), 1466. https://doi.org/10.3390/nu12051466

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 A food sources and supplementation

Top sources of preformed vitamin A based on serving size (Vitamin A, 2014)

• beef liver
• cod liver oil
• eggs
• butter
• whole milk

Top sources of provitamin A carotenoids based on serving size (Vitamin A, 2014)

• sweet potato
• pumpkin
• carrot
• cantaloupe
• mango
• spinach

Comprehensive food list: Table 3. Some Food Sources of Vitamin A
https://lpi.oregonstate.edu/mic/vitamins/vitamin-A

Referenced Dietary Intakes

RDAs for Vitamin A as preformed vitamin A (mcg/day) (measured as Retinol Activity Equivalents (RAE))
Adolescents (14-18 years): 900 (M) 700 (F)
Adults (19 years and older): 900 (M) 700 (F)

Vitamin A supplementation

Amounts of vitamin A used in practice and research range from 50–7,500 mcg RAE a day in divided doses (Office of Dietary Supplements – Vitamin A and Carotenoids, n.d.).

Vitamin A dosing and recommendations for all patients presenting with COVID-19 (Gröber & Holick, 2022):

• Prevention of respiratory tract viral infection
  • Adults, adolescents, and the elderly – 2,000–4,000 IU vitamin A (retinol) per day.
• With severe COVID-19
  • initial oral dose between 50,000 IU and 200,000 IU of retinol
  • then, 10,000 IU/day for 1 month
  • then, 5,000 IU/day

SAFETY, SIDE EFFECTS

• Vitamin A toxicity is rare. 
• Symptoms of long-term high-dose preformed vitamin A intake may include (Vitamin A, 2014):
  • nausea, headache, fatigue, loss of appetite, dizziness, dry skin, desquamation, and cerebral edema
• Symptoms of lower-dose long-term supplementation of preformed vitamin A intake may include (Vitamin A, 2014):
  • dry itchy skin, anorexia, weight loss, headache, anemia, and bone and joint pain.
• “Vitamin A, especially when in balance with vitamin D, has low toxicity except at high dosages. For adults, toxicity is typically seen after 100,000 IU/d for 6 months” (Sestili & Fimognari, 2020).

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References

Calder, P. C. (2020). Nutrition, immunity and COVID-19. BMJ Nutrition, Prevention & Health, 3(1). https://doi.org/10.1136/bmjnph-2020-000085

Detopoulou, P., Demopoulos, C. A., & Antonopoulou, S. (2021). Micronutrients, Phytochemicals and Mediterranean Diet: A Potential Protective Role against COVID-19 through Modulation of PAF Actions and Metabolism. Nutrients, 13(2), 462. https://doi.org/10.3390/nu13020462

Gröber, U., & Holick, M. F. (2022). The coronavirus disease (COVID-19) – A supportive approach      with selected micronutrients. International Journal for Vitamin and Nutrition Research, 92(1), 13–34. https://doi.org/10.1024/0300-9831/a000693

Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Jovic, T. H., Ali, S. R., Ibrahim, N., Jessop, Z. M., Tarassoli, S. P., Dobbs, T. D., Holford, P., Thornton, C. A., & Whitaker, I. S. (2020). Could Vitamins Help in the Fight Against COVID-19? Nutrients, 12(9), 2550. https://doi.org/10.3390/nu12092550

Junaid, K., Ejaz, H., Abdalla, A. E., Abosalif, K. O. A., Ullah, M. I., Yasmeen, H., Younas, S., Hamam, S. S. M., & Rehman, A. (2020). Effective Immune Functions of Micronutrients against SARS-CoV-2. Nutrients, 12(10), 2992. https://doi.org/10.3390/nu12102992

Office of Dietary Supplements—Vitamin A and Carotenoids. (n.d.). Retrieved September 3, 2022, from https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/

Sestili, P., & Fimognari, C. (2020). Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Frontiers in Pharmacology, 11, 579944. https://doi.org/10.3389/fphar.2020.579944

Tepasse, P.-R., Vollenberg, R., Fobker, M., Kabar, I., Schmidt, H., Meier, J. A., Nowacki, T., & Hüsing-Kabar, A. (2021). Vitamin A Plasma Levels in COVID-19 Patients: A Prospective Multicenter Study and Hypothesis. Nutrients, 13(7), 2173. https://doi.org/10.3390/nu13072173

Vitamin A. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-A

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).

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References

Galmés, S., Serra, F., & Palou, A. (2020). Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework. Nutrients, 12(9), 2738. https://doi.org/10.3390/nu12092738

Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Jovic, T. H., Ali, S. R., Ibrahim, N., Jessop, Z. M., Tarassoli, S. P., Dobbs, T. D., Holford, P., Thornton, C. A., & Whitaker, I. S. (2020). Could Vitamins Help in the Fight Against COVID-19? Nutrients, 12(9), 2550. https://doi.org/10.3390/nu12092550

Keflie, T. S., & Biesalski, H. K. (2021). Micronutrients and bioactive substances: Their potential roles in combating COVID-19. Nutrition, 84, 111103. https://doi.org/10.1016/j.nut.2020.111103

Kumar, P., Kumar, M., Bedi, O., Gupta, M., Kumar, S., Jaiswal, G., Rahi, V., Yedke, N. G., Bijalwan, A., Sharma, S., & Jamwal, S. (2021). Role of vitamins and minerals as immunity boosters in COVID-19. Inflammopharmacology, 29(4), 1001–1016. https://doi.org/10.1007/s10787-021-00826-7

Kumar, V., Kancharla, S., & Jena, M. K. (2021). In silico virtual screening-based study of nutraceuticals predicts the therapeutic potentials of folic acid and its derivatives against COVID-19. Virusdisease, 32(1), 29–37. https://doi.org/10.1007/s13337-020-00643-6

Shakoor, H., Feehan, J., Mikkelsen, K., Al Dhaheri, A. S., Ali, H. I., Platat, C., Ismail, L. C., Stojanovska, L., & Apostolopoulos, V. (2021). Be well: A potential role for vitamin B in COVID-19. Maturitas, 144, 108–111. https://doi.org/10.1016/j.maturitas.2020.08.007

Spinas, E., Saggini, A., Kritas, S. K., Cerulli, G., Caraffa, A., Antinolfi, P., Pantalone, A., Frydas, A., Tei, M., Speziali, A., Saggini, R., Pandolfi, F., & Conti, P. (2015). CROSSTALK BETWEEN VITAMIN B AND IMMUNITY. Journal of Biological Regulators and Homeostatic Agents, 29(2), 283–288.

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 C food sources and supplementation

Top sources of vitamin C based on serving size

• grapefruit and orange juice
• strawberries
• kiwifruit
• orange
• sweet pepper
• broccoli

Comprehensive food list:
Table 3. Some Food Sources of vitamin C (Vitamin C, 2014)
https://lpi.oregonstate.edu/mic/vitamins/vitamin-C

Referenced Dietary Intakes

RDAs for vitamin C (mg/day)
Adolescents (14-18 years): 75 (M) 65 (F)
Adults (19-50 years): 90 (M) 75 (F)
Smokers: 125 (M) 110 (F)

Tolerable Upper Intake: 2000 mg /day
(Office of Dietary Supplements – Vitamin C, n.d.)

Vitamin C supplementation

• Amounts of vitamin C used in practice and research range from 500–6000 mg/day in divided doses.

“High-dose IV vitamin C has been proven to be safe and therapeutic in critical care medicine, primarily as an adjunct to the treatment of septic shock and multiple organ failure, where it has been shown to improve outcomes and reduce mortality.” (Liu et al., 2020).

Oral vitamin C and COVID-19

›The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Fur Vitamin- Und Ernahrungsforschung. Journal International De Vitaminologie Et De Nutrition (Hunt et al., 1994)

• In this RCT trial, 200 mg/day of oral vitamin C for 4 weeks was given to hospitalized elderly patients with acute respiratory infections.
• Vitamin C administration was shown to reduce severity of illness and decreased mortality rate.
• 6–24 g/day of oral vitamin C has potential benefits for COVID-19 patients (Holford et al., 2020):
  • addressing COVID-19-induced vitamin C deficiency
  • reducing inflammation
  • treating acute respiratory tract infections
  • supporting glucocorticosteroid action
• Oral dosing of vitamin C up to 6–8 g/day can be utilized with viral infections, active cold symptoms, those with positive PCR tests, and hospitalized COVID-19 patients (Holford et al., 2020).
• 1000–3000 mg of vitamin C with quercetin per day taken in divided doses is recommended for COVID-19 prevention (Gröber & Holick, 2022).

IV vitamin C and COVID-19

• 2–3 g/day of IV vitamin C have been shown to raise plasma vitamin C to normal levels in critically ill patients, however higher doses (10–16 g/day) are needed to achieve therapeutic levels (Hoang et al., 2020).

› The Role of Vitamin C as Adjuvant Therapy in COVID-19. Cureus (Kumari et al., 2020)

• 50 patients with severe COVID-19 were given IV vitamin C (50 mg/kg/day) in conjunction with standard of care treatment versus the control group who received standard of care alone.
• The vitamin C group became symptom-free sooner and had decreased hospital stay duration.

› The use of IV vitamin C for patients with COVID-19: A case series. Expert Review of Anti-Infective Therapy (Hiedra et al., 2020)

• 17 patients with COVID-19 received 1 gram every 8 hours for 3 days of IV vitamin C.
• Treatment resulted in decreased inflammatory markers and decreased oxygen requirements.

› Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Medicine in Drug Discovery (Cheng, 2020)

• 10–20 g/day of IV vitamin C was given to COVID-19 patients with moderate to severe symptoms.
• Treatment improved patient oxygenation index and all patients eventually recovered. 

When used adjunctively with steroids and anticoagulants, 3g of IV vitamin C every 6 hours, has resulted in clinical benefits in severe COVID-19 patients (Marik et al., 2021).

SAFETY, SIDE EFFECTS

• Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes (Office of Dietary Supplements – Vitamin C, n.d.).
• Vitamin C at higher doses can, in some people, cause side effects such as nausea, abdominal cramps, and other digestive tract disturbances

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References

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Bae, M., & Kim, H. (2020). The Role of Vitamin C, Vitamin D, and Selenium in Immune System against COVID-19. Molecules, 25(22), 5346. https://doi.org/10.3390/molecules25225346

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Cerullo, G., Negro, M., Parimbelli, M., Pecoraro, M., Perna, S., Liguori, G., Rondanelli, M., Cena, H., & D’Antona, G. (2020). The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19. Frontiers in Immunology, 11. https://www.frontiersin.org/article/10.3389/fimmu.2020.574029

Cheng, R. Z. (2020a). Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Medicine in Drug Discovery, 5, 100028. https://doi.org/10.1016/j.medidd.2020.100028

Chiscano-Camón, L., Ruiz-Rodriguez, J. C., Ruiz-Sanmartin, A., Roca, O., & Ferrer, R. (2020). Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome. Critical Care, 24(1), 522. https://doi.org/10.1186/s13054-020-03249-y

Colunga Biancatelli, R. M. L., Berrill, M., Catravas, J. D., & Marik, P. E. (2020a). Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Frontiers in Immunology, 11. https://www.frontiersin.org/article/10.3389/fimmu.2020.01451

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Fowler, A. A., Truwit, J. D., Hite, R. D., Morris, P. E., DeWilde, C., Priday, A., Fisher, B., Thacker, L. R., Natarajan, R., Brophy, D. F., Sculthorpe, R., Nanchal, R., Syed, A., Sturgill, J., Martin, G. S., Sevransky, J., Kashiouris, M., Hamman, S., Egan, K. F., … Halquist, M. (2019). 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, 322(13), 1261–1270. https://doi.org/10.1001/jama.2019.11825

Fowler Iii, A. A., Kim, C., Lepler, L., Malhotra, R., Debesa, O., Natarajan, R., Fisher, B. J., Syed, A., DeWilde, C., Priday, A., & Kasirajan, V. (2017). Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World Journal of Critical Care Medicine, 6(1), 85–90. https://doi.org/10.5492/wjccm.v6.i1.85

Gröber, U., & Holick, M. F. (2022). The coronavirus disease (COVID-19) – A supportive approach      with selected micronutrients. International Journal for Vitamin and Nutrition Research, 92(1), 13–34. https://doi.org/10.1024/0300-9831/a000693

Hemilä, H., & Chalker, E. (2019). Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients, 11(4), E708. https://doi.org/10.3390/nu11040708

Hiedra, R., Lo, K. B., Elbashabsheh, M., Gul, F., Wright, R. M., Albano, J., Azmaiparashvili, Z., & Patarroyo Aponte, G. (2020a). The use of IV vitamin C for patients with COVID-19: A case series. Expert Review of Anti-Infective Therapy, 18(12), 1259–1261. https://doi.org/10.1080/14787210.2020.1794819

Hoang, B. X., Shaw, G., Fang, W., & Han, B. (2020). Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection. Journal of Global Antimicrobial Resistance, 23, 256–262. https://doi.org/10.1016/j.jgar.2020.09.025

Holford, P., Carr, A. C., Jovic, T. H., Ali, S. R., Whitaker, I. S., Marik, P. E., & Smith, A. D. (2020). Vitamin C—An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19. Nutrients, 12(12), 3760. https://doi.org/10.3390/nu12123760

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Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Im, J. H., Je, Y. S., Baek, J., Chung, M.-H., Kwon, H. Y., & Lee, J.-S. (2020). Nutritional status of patients with COVID-19. International Journal of Infectious Diseases, 100, 390–393. https://doi.org/10.1016/j.ijid.2020.08.018

Keflie, T. S., & Biesalski, H. K. (2021). Micronutrients and bioactive substances: Their potential roles in combating COVID-19. Nutrition, 84, 111103. https://doi.org/10.1016/j.nut.2020.111103

Kumari, P., Dembra, S., Dembra, P., Bhawna, F., Gul, A., Ali, B., Sohail, H., Kumar, B., Memon, M. K., & Rizwan, A. (2020). The Role of Vitamin C as Adjuvant Therapy in COVID-19. Cureus, 12(11). https://doi.org/10.7759/cureus.11779

Liu, F., Zhu, Y., Zhang, J., Li, Y., & Peng, Z. (2020). Intravenous high-dose vitamin C for the treatment of severe COVID-19: Study protocol for a multicentre randomised controlled trial. BMJ Open, 10(7), e039519. https://doi.org/10.1136/bmjopen-2020-039519

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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 D food sources and supplementation

Top sources of vitamin D based on serving size (Office of Dietary Supplements – Vitamin D, 2020)

• cod liver oil
• trout
• pink salmon
• sardines
• fortified cereal, milk, and orange juice
• fortified almond, soy, and oat milks
• egg yolk

Comprehensive food list
Table 3: Vitamin D Content of Selected Foods
https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

Referenced Dietary Intakes

RDAs for vitamin D (IU/day)
Adolescents (14-18 years): 600 (M) 600 (F)
Adults (19-50 years): 600 (M) 600 (F)
Adults (51 years and older): 800 (M) 800 (F)

Tolerable Upper Intake: 4000 IU/day
(Office of dietary supplements, 2020)

Vitamin D supplementation

• Amounts of vitamin D used in practice and research range from 400-14 000 IU/day. (Vitamin D, 2014)

Supplementing vitamin D in COVID-19 patients has been shown to :

• positively affect immune response (Xu et al., 2020)
• suppress pathogen activity (Xu et al., 2020).
• induce apoptosis of infected epithelial cells to promote clearance of respiratory pathogens (Xu et al., 2020).
• decrease oxygen requirements (Sulli et al., 2021).
• decrease severity of COVID-19 symptoms (Annweiler et al., 2020).
• decrease length of hospitalization (Sulli et al., 2021).
• increase survival rate in hospitalized frail elderly patients (Annweiler et al., 2020).

› Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series. American Journal of Therapeutics. (Ohaegbulam et al., 2020)

• 50,000 IU/day for 5 days in COVID-19 patients resulted in decreased inflammation and decreased recovery time compared to those receiving 1000 IU/day.

› Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. The Journal of Steroid Biochemistry and Molecular Biology (Entrenas Castillo et al., 2020)

• In combination with standard of care treatment, early high-dose vitamin D treatment prevented COVID-19-patient need for ICU admission.

Vitamin D dosing

“The aim of a therapy with vitamin D should be a normalization of the vitamin D status, preferably > 75 nmol/L” (Biesalski, 2020).

It is important to consider that vitamin D works synergistically with vitamin A in the body (Biesalski, 2020), and this is especially relevant in the context of respiratory tract health and COVID-19. Therefore it is recommended that vitamins A and D be supplemented together.

Vitamin D dosing to PREVENT deficiency

• 1500–2000 IU/day of vitamin D3 for adults of any age who are at high risk for vitamin D deficiency (Brenner et al., 2020).
• At least 400 IU/day of vitamin D for infants and children (Wong et al., 2021).

Vitamin D dosing to ADDRESS deficiency

With the goal of achieving sufficiency (25(OH)D level above 30 ng/ml) (Holick et al., 2011):

Institute of Medicine:

• Adults 19 years and older –10,000 IU/day

Endocrine Society:

• 50,000 IU once a week for 8 weeks
• Followed by maintenance therapy of 1500–2000 IU/day

In obese patients, patients with malabsorption syndromes, and patients on medications affecting vitamin D metabolism 

• 6000–10,000 IU/day to maintain above 30 ng/ml
• Followed by maintenance therapy of 3000–6000 IU/day

Vitamin D dosing in research

• 10,000 IU for a few weeks to increase levels above 40–60 ng/mL, followed by 5000 IU/day to decrease COVID-19 risk (Vyas et al., 2021).
• 200,000–300,000 IU/week to decrease the risk and severity of COVID-19 (Vyas et al., 2021).
• In the context of minimal sunlight exposure, 4000–6000 IU/day would be required to maintain serum 25(OH)D levels in the range of 40–60 ng/mL (50–100 nmol/L) (Charoenngam & Holick, 2020).

Vitamin D dosing in COVID-19 research

• 800 to 1000 IU daily is recommended for all SARS-CoV-2-positive patients upon diagnosis (Lordan, 2021).
• Up to 2,000 IU/day of oral vitamin D was safe and protective against acute respiratory tract infection and COVID-19 (Getachew & Tizabi, 2021).
• At least one single dose of 50,000 IU of vitamin D to all COVID-19 patients as soon as possible after being hospitalized (Charoenngam & Holick, 2020).
• 50,000 IU twice in the first week following diagnosis for patients with vitamin D below 50 nmol/L (Ebadi & Montano-Loza, 2020)
• 60,000 IU for 7 days resulted in a larger proportion of vitamin D-deficient COVID-19 patients becoming SARS-CoV-2 RNA negative (Lordan, 2021).

“Vitamin D supplementation could be especially important for older people as they are at high risk of poor outcome from COVID-19 and of vitamin D deficiency” (Mitchell, 2020).

SAFETY, SIDE EFFECTS (Vitamin D, 2014)

• “Research suggests that vitamin D toxicity is very unlikely in healthy people at intake levels lower than 10,000 IU/day”
• Vitamin D can increase the risk of hypercalcemia with calcium-related medical conditions – including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma
• Certain medical conditions can increase the risk of hypercalcemia in response to vitamin D, including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma

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References

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Maghbooli, Z., Sahraian, M. A., Ebrahimi, M., Pazoki, M., Kafan, S., Tabriz, H. M., Hadadi, A., Montazeri, M., Nasiri, M., Shirvani, A., & Holick, M. F. (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, 15(9), e0239799. https://doi.org/10.1371/journal.pone.0239799

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Martineau, A. R., Jolliffe, D. A., Hooper, R. L., Greenberg, L., Aloia, J. F., Bergman, P., Dubnov-Raz, G., Esposito, S., Ganmaa, D., Ginde, A. A., Goodall, E. C., Grant, C. C., Griffiths, C. J., Janssens, W., Laaksi, I., Manaseki-Holland, S., Mauger, D., Murdoch, D. R., Neale, R., … Camargo, C. A. (2017a). Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ, 356, i6583. https://doi.org/10.1136/bmj.i6583

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Merzon, E., Tworowski, D., Gorohovski, A., Vinker, S., Golan Cohen, A., Green, I., & Frenkel-Morgenstern, M. (2020). Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: An Israeli population-based study. The FEBS Journal, 287(17), 3693–3702. https://doi.org/10.1111/febs.15495

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Vitamin D. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-D

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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.)

Vitamin E food sources and supplementation

Top sources of vitamin E based on serving size:

• sunflower seeds
• almonds
• sunflower oil
• safflower oil
• hazelnuts
• grapeseed oil

Comprehensive food list: Table 2. Some Food Sources of Vitamin E
https://lpi.oregonstate.edu/mic/vitamins/vitamin-E

Referenced Dietary Intakes (IU/day)

Adolescents (14-18 years): 22.5 (M) 22.5 (F)
Adults (19 years and older): 22.5 (M) 22.5 (F)

Vitamin E supplementation

• Amounts of vitamin E used in practice and research range from 400–2,000 IU a day in divided doses (Office of Dietary Supplements – Vitamin E, n.d.)

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References

Calder, P. C. (2020). Nutrition, immunity and COVID-19. BMJ Nutrition, Prevention & Health, 3(1). https://doi.org/10.1136/bmjnph-2020-000085

Detopoulou, P., Demopoulos, C. A., & Antonopoulou, S. (2021). Micronutrients, Phytochemicals and Mediterranean Diet: A Potential Protective Role against COVID-19 through Modulation of PAF Actions and Metabolism. Nutrients, 13(2), 462. https://doi.org/10.3390/nu13020462

Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Kumar, P., Kumar, M., Bedi, O., Gupta, M., Kumar, S., Jaiswal, G., Rahi, V., Yedke, N. G., Bijalwan, A., Sharma, S., & Jamwal, S. (2021). Role of vitamins and minerals as immunity boosters in COVID-19. Inflammopharmacology, 29(4), 1001–1016. https://doi.org/10.1007/s10787-021-00826-7

Office of Dietary Supplements—Vitamin E. (n.d.). Retrieved September 3, 2022, from https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/

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.

Magnesium food sources and supplementation

Top food sources of magnesium by serving size

• Brazil nuts
• oat bran
• brown rice (whole grain)
• mackerel

Comprehensive list: Table 2. Some Food Sources of Magnesium
(Magnesium, 2014)
https://lpi.oregonstate.edu/mic/minerals/magnesium

Referenced Dietary Intakes

RDAs for magnesium (mg/day)

Adolescents (14-18 years): 410 (M) 360 (F)
Adults (19-30 years): 400 (M) 310 (F)
Adults (31 years and older): 420 (M) 320 (F)

Supplementing magnesium

• Amounts of magnesium used in practice and research range from 100–750 mg/day in divided doses (elemental magnesium dose).
• Magnesium supplementation has been shown to reduce inflammatory markers including CRP and IL-6 (Wallace, 2020; Srivastava et al., 2021).

SAFETY, SIDE EFFECTS

• Side effects of magnesium supplementation are rare but can include a laxative effect, dizziness or faintness, sluggishness, cognitive impairment, and depression.

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References

DiNicolantonio, J. J., & O’Keefe, J. H. (2021). Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients. Missouri Medicine, 118(1), 68–73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861592/

Dominguez, L. J., Veronese, N., Guerrero-Romero, F., & Barbagallo, M. (2021). Magnesium in Infectious Diseases in Older People. Nutrients, 13(1), 180. https://doi.org/10.3390/nu13010180

Iotti, S., Wolf, F., Mazur, A., & Maier, J. A. (2020). The COVID-19 pandemic: Is there a role for magnesium? Hypotheses and perspectives. Magnesium Research, 33(2), 21–27. https://doi.org/10.1684/mrh.2020.0465

Magnesium. (2014, April 23). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/minerals/magnesium

Nielsen, F. H. (2018). Magnesium deficiency and increased inflammation: Current perspectives. Journal of Inflammation Research, 11, 25–34. https://doi.org/10.2147/JIR.S136742

Srivastava, A., Gupta, R. C., Doss, R. B., & Lall, R. (2021). Trace Minerals, Vitamins and Nutraceuticals in Prevention and Treatment of COVID-19. Journal of Dietary Supplements, 1–35. https://doi.org/10.1080/19390211.2021.1890662

van Kempen, T. A. T. G., & Deixler, E. (2021). SARS-CoV-2: Influence of phosphate and magnesium, moderated by vitamin D, on energy (ATP) metabolism and on severity of COVID-19. American Journal of Physiology-Endocrinology and Metabolism, 320(1), E2–E6. https://doi.org/10.1152/ajpendo.00474.2020

Wallace, T. C. (2020). Combating COVID-19 and Building Immune Resilience: A Potential Role for Magnesium Nutrition? Journal of the American College of Nutrition, 39(8), 685–693. https://doi.org/10.1080/07315724.2020.1785971

Wang, Y., Dong, C., Hu, Y., Li, C., Ren, Q., Zhang, X., Shi, H., & Zhou, M. (2020). Temporal Changes of CT Findings in 90 Patients with COVID-19 Pneumonia: A Longitudinal Study. Radiology, 296(2), E55–E64. https://doi.org/10.1148/radiol.2020200843

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).

Selenium food sources and supplementation

Top sources of vitamin selenium based on serving size

• Brazil nuts
• tuna, halibut, salmon
• oysters, clams, shrimp
• pork, beef, chicken

Comprehensive food list: Table 2. Some Common Food Sources of Selenium
https://lpi.oregonstate.edu/mic/minerals/selenium

The amount of selenium in foods is dependent on the amount of selenium in the soil in which they are grown (Khatiwada & Subedi, 2021; Bermano et al., 2021).

Referenced Dietary Intakes

RDAs for selenium (mcg/day)

Adolescents (14-18 years): 55 (M) 55 (F)
Adults (19 years and older): 55 (M) 55 (F)

Selenium supplementation

• Amounts of selenium used in practice and research range from 100–300 mcg a day in divided doses (Office of Dietary Supplements – Selenium, n.d.).

Selenium supplementation in the context of COVID-19

• Selenium supplementation is known to prevent viral genetic adaptations that lead to increased virus virulence (Hoffmann & Berry, 2008).
• Selenium in the form of sodium selenite can block the entry of viruses into cells (Detopoulou et al., 2021).
• Selenium supplementation has been shown to increase proliferation of T-cells and activity of natural killer cells (Bermano et al., 2021).
• Supplementation between 100 and 300 mcg/day has been shown to enhance immune functions (Calder, 2020).
• 100–200 mcg/day can quickly normalize selenoprotein status in people with low plasma selenium levels (Alexander et al., 2020).
• Studies have shown selenium supplementation protects against COVID-19 complications – especially in elderly patients (Fakhrolmobasheri et al. 2020; Hiffler and Rakotoambinina 2020; Kieliszek and Lipinski 2020; Srivastava et al., 2021).

Selenium supplementation amounts used (Gröber & Holick, 2022):

• for prevention of respiratory tract infections
  – adolescents, adults, and the elderly
  100–200 mcg sodium selenite or selenomethionine (Gröber & Holick, 2022)
• with hospital admission and severe COVID-19 symptoms – first 7 days 1000 mcg/day of sodium selenite, then 300-500 mcg/day

SAFETY, SIDE EFFECTS

• Indicators of excess selenium intake include (Office of Dietary Supplements – Selenium, n.d.) garlic odour in the breath and a metallic taste in the mouth, brittleness or loss of hair or nails.
• Although normally safe, high-dose selenium supplementation may have negative effects for people who already have sufficient dietary selenium intake  (Gröber & Holick, 2022).
• Long-term intakes of selenium in excess of 300 mcg/day from food and supplements may be associated with toxicity (Alexander et al., 2020).
• Monitoring of selenium blood levels is recommended with prolonged high-dose supplementation (Khatiwada & Subedi, 2021).

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References

Alexander, J., Tinkov, A., Strand, T. A., Alehagen, U., Skalny, A., & Aaseth, J. (2020). Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19. Nutrients, 12(8), 2358. https://doi.org/10.3390/nu12082358

Bae, M., & Kim, H. (2020). The Role of Vitamin C, Vitamin D, and Selenium in Immune System against COVID-19. Molecules, 25(22), 5346. https://doi.org/10.3390/molecules25225346

Bermano, G., Méplan, C., Mercer, D. K., & Hesketh, J. E. (2021). Selenium and viral infection: Are there lessons for COVID-19? British Journal of Nutrition, 125(6), 618–627. https://doi.org/10.1017/S0007114520003128

Calder, P. C. (2020). Nutrition, immunity and COVID-19. BMJ Nutrition, Prevention & Health, 3(1). https://doi.org/10.1136/bmjnph-2020-000085

Detopoulou, P., Demopoulos, C. A., & Antonopoulou, S. (2021). Micronutrients, Phytochemicals and Mediterranean Diet: A Potential Protective Role against COVID-19 through Modulation of PAF Actions and Metabolism. Nutrients, 13(2), 462. https://doi.org/10.3390/nu13020462

Erol, S. A., Polat, N., Akdas, S., Aribal Ayral, P., Anuk, A. T., Ozden Tokalioglu, E., Goncu Ayhan, Ş., Kesikli, B., Ceylan, M. N., Tanacan, A., Moraloglu Tekin, Ö., Yazihan, N., & Sahin, D. (2021). Maternal selenium status plays a crucial role on clinical outcomes of pregnant women with COVID-19 infection. Journal of Medical Virology, 93(9), 5438–5445. https://doi.org/10.1002/jmv.27064

Fakhrolmobasheri, M., Nasr-Esfahany, Z., Khanahmad, H., & Zeinalian, M. (2020). Selenium supplementation can relieve the clinical complications of COVID-19 and other similar viral infections. International Journal for Vitamin and Nutrition Research. https://econtent.hogrefe.com/doi/abs/10.1024/0300-9831/a000663

Galmés, S., Serra, F., & Palou, A. (2020). Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework. Nutrients, 12(9), 2738. https://doi.org/10.3390/nu12092738

Gröber, U., & Holick, M. F. (2022). The coronavirus disease (COVID-19) – A supportive approach      with selected micronutrients. International Journal for Vitamin and Nutrition Research, 92(1), 13–34. https://doi.org/10.1024/0300-9831/a000693

Hiffler, L., & Rakotoambinina, B. (2020). Selenium and RNA Virus Interactions: Potential Implications for SARS-CoV-2 Infection (COVID-19). Frontiers in Nutrition, 7. https://www.frontiersin.org/articles/10.3389/fnut.2020.00164

Hoang, B. X., Shaw, G., Fang, W., & Han, B. (2020). Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection. Journal of Global Antimicrobial Resistance, 23, 256–262. https://doi.org/10.1016/j.jgar.2020.09.025

Hoffmann, P. R., & Berry, M. J. (2008). The influence of selenium on immune responses. Molecular Nutrition & Food Research, 52(11), 1273–1280. https://doi.org/10.1002/mnfr.200700330

Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Im, J. H., Je, Y. S., Baek, J., Chung, M.-H., Kwon, H. Y., & Lee, J.-S. (2020). Nutritional status of patients with COVID-19. International Journal of Infectious Diseases, 100, 390–393. https://doi.org/10.1016/j.ijid.2020.08.018

Keflie, T. S., & Biesalski, H. K. (2021). Micronutrients and bioactive substances: Their potential roles in combating COVID-19. Nutrition, 84, 111103. https://doi.org/10.1016/j.nut.2020.111103

Kieliszek, M., & Lipinski, B. (2020). Selenium supplementation in the prevention of coronavirus infections (COVID-19). Medical Hypotheses, 143, 109878. https://doi.org/10.1016/j.mehy.2020.109878

Khatiwada, S., & Subedi, A. (2021). A Mechanistic Link Between Selenium and Coronavirus Disease 2019 (COVID-19). Current Nutrition Reports, 10(2), 125–136. https://doi.org/10.1007/s13668-021-00354-4

Moghaddam, A., Heller, R. A., Sun, Q., Seelig, J., Cherkezov, A., Seibert, L., Hackler, J., Seemann, P., Diegmann, J., Pilz, M., Bachmann, M., Minich, W. B., & Schomburg, L. (2020). Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients, 12(7), 2098. https://doi.org/10.3390/nu12072098

Notz, Q., Herrmann, J., Schlesinger, T., Helmer, P., Sudowe, S., Sun, Q., Hackler, J., Roeder, D., Lotz, C., Meybohm, P., Kranke, P., Schomburg, L., & Stoppe, C. (2021). Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS. Nutrients, 13(6), 2113. https://doi.org/10.3390/nu13062113

Office of Dietary Supplements—Selenium. (n.d.). Retrieved September 3, 2022, from https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/

Srivastava, A., Gupta, R. C., Doss, R. B., & Lall, R. (2021). Trace Minerals, Vitamins and Nutraceuticals in Prevention and Treatment of COVID-19. Journal of Dietary Supplements, 1–35. https://doi.org/10.1080/19390211.2021.1890662

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).

Zinc food sources and supplementation

Top sources of zinc based on serving size

• oyster, cooked
• beef, chuck, blade roast, cooked
• beef, ground, 90% lean meat, cooked 
• crab, Dungeness, cooked
• fortified, whole-grain toasted oat cereal

Comprehensive food list:
Table 2. Some Food Sources of Zinc
https://lpi.oregonstate.edu/mic/minerals/zinc

Referenced Dietary Intakes

RDAs for zinc (mg/day)

Adolescents (14-18 years): 11 (M) 9 (F)
Adults (19 years and older): 11 (M) 8 (F)

Supplementing zinc

• Amounts of zinc used in practice and research range from 10–200 mg/day in divided doses (Zinc, 2014).

Supplementing zinc in the context of COVID-19

“Zinc has potent immunomodulatory and antiviral properties, and can be utilized in the treatment of COVID-19” Gröber & Holick, 2022)..

• Studies have shown that zinc supplementation can help decrease COVID-19 symptom severity and shorten its course (Mossink 2020; Skalny et al. 2020; Joachimiak, 2021; Srivastava et al., 2021).

› Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients. International. Journal of Infectious Diseases: IJID: Official Publication of the International Society for Infectious Diseases (Finzi, 2020)

• High-dose zinc supplementation led to a decrease in symptoms within 24 hours in four COVID-19 patients.
• Achieving sufficient cellular uptake of zinc for viral inhibition can be increased by combining zinc supplementation with zinc ionophores such as quercetin or hydroxychloroquine. 

Zinc dosing in the context of COVID-19

• The Recommended Daily Intake (RDI) for zinc is between 12–15 mg.
• 50–150 mg of elemental zinc/day has been suggested for inhibiting coronaviruses, and has been proven safe for short periods of time (Carlucci et al., n.d.).
• 200 mg has been used adjunctively with other anti-infective medications (e.g. hydroxychloroquine, ivermectin, etc). (Butters & Whitehouse, 2021).
• 220 mg zinc sulfate (containing 50 mg of elemental zinc) has been used in clinical trials (Rahman and Idid 2020; Srivastava et al., 2021)

SAFETY, SIDE EFFECTS

• High zinc intakes can inhibit copper absorption, sometimes producing copper deficiency and associated anemia (Office of Dietary Supplements, 2014).
• Intakes of zinc should not exceed the UL (40 mg/day for adults) in order to limit the risk of copper deficiency in particular
• Milder gastrointestinal distress has been reported at doses of 50 to 150 mg/day of supplemental zinc (Zinc, 2014).

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References

Butters, D., & Whitehouse, M. (2021). COVID-19 and nutriceutical therapies, especially using zinc to supplement antimicrobials. Inflammopharmacology, 29(1), 101–105. https://doi.org/10.1007/s10787-020-00774-8

Calder, P. C. (2020). Nutrition, immunity and COVID-19. BMJ Nutrition, Prevention & Health, 3(1). https://doi.org/10.1136/bmjnph-2020-000085

Carlucci, P. M., Ahuja, T., Petrilli, C., Rajagopalan, H., Jones, S., & Rahimian, J. 2020. (n.d.). Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients. Journal of Medical Microbiology, 69(10), 1228–1234. https://doi.org/10.1099/jmm.0.001250

Costagliola, G., Spada, E., Comberiati, P., & Peroni, D. G. (2021). Could nutritional supplements act as therapeutic adjuvants in COVID-19? Italian Journal of Pediatrics, 47(1), 32. https://doi.org/10.1186/s13052-021-00990-0

Elham, A. S., Azam, K., Azam, J., Mostafa, L., Nasrin, B., & Marzieh, N. (2021). Serum vitamin D, calcium, and zinc levels in patients with COVID-19. Clinical Nutrition ESPEN, 43, 276–282. https://doi.org/10.1016/j.clnesp.2021.03.040

Finzi, E. (2020). Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients. International Journal of Infectious Diseases: IJID: Official Publication of the International Society for Infectious Diseases, 99, 307–309. https://doi.org/10.1016/j.ijid.2020.06.006

Gammoh, N. Z., & Rink, L. (2017). Zinc in Infection and Inflammation. Nutrients, 9(6), 624. https://doi.org/10.3390/nu9060624

Gröber, U., & Holick, M. F. (2022). The coronavirus disease (COVID-19) – A supportive approach      with selected micronutrients. International Journal for Vitamin and Nutrition Research, 92(1), 13–34. https://doi.org/10.1024/0300-9831/a000693

Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Joachimiak, M. P. (2021). Zinc against COVID-19? Symptom surveillance and deficiency risk groups. PLoS Neglected Tropical Diseases, 15(1), e0008895. https://doi.org/10.1371/journal.pntd.0008895

Jothimani, D., Kailasam, E., Danielraj, S., Nallathambi, B., Ramachandran, H., Sekar, P., Manoharan, S., Ramani, V., Narasimhan, G., Kaliamoorthy, I., & Rela, M. (2020). COVID-19: Poor outcomes in patients with zinc deficiency. International Journal of Infectious Diseases, 100, 343–349. https://doi.org/10.1016/j.ijid.2020.09.014

Junaid, K., Ejaz, H., Abdalla, A. E., Abosalif, K. O. A., Ullah, M. I., Yasmeen, H., Younas, S., Hamam, S. S. M., & Rehman, A. (2020). Effective Immune Functions of Micronutrients against SARS-CoV-2. Nutrients, 12(10), 2992. https://doi.org/10.3390/nu12102992

Keflie, T. S., & Biesalski, H. K. (2021). Micronutrients and bioactive substances: Their potential roles in combating COVID-19. Nutrition, 84, 111103. https://doi.org/10.1016/j.nut.2020.111103

Mossink, J. P. (2020). Zinc as nutritional intervention and prevention measure for COVID–19 disease. BMJ Nutrition, Prevention & Health, bmjnph. https://doi.org/10.1136/bmjnph-2020-000095

Office of Dietary Supplements—Zinc. (n.d.). Retrieved October 29, 2020, from https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Pal, A., Squitti, R., Picozza, M., Pawar, A., Rongioletti, M., Dutta, A. K., Sahoo, S., Goswami, K., Sharma, P., & Prasad, R. (2021). Zinc and COVID-19: Basis of Current Clinical Trials. Biological Trace Element Research, 199(8), 2882–2892. https://doi.org/10.1007/s12011-020-02437-9

Rahman, N., Basharat, Z., Yousuf, M., Castaldo, G., Rastrelli, L., & Khan, H. (2020). Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2). Molecules, 25(10), 2271. https://doi.org/10.3390/molecules25102271

Rahman, M. T., & Idid, S. Z. (2021b). Can Zn Be a Critical Element in COVID-19 Treatment? Biological Trace Element Research, 199(2), 550–558. https://doi.org/10.1007/s12011-020-02194-9

Read, S. A., Obeid, S., Ahlenstiel, C., & Ahlenstiel, G. (2019). The Role of Zinc in Antiviral Immunity. Advances in Nutrition, 10(4), 696–710. https://doi.org/10.1093/advances/nmz013

Skalny, A. V., Rink, L., Ajsuvakova, O. P., Aschner, M., Gritsenko, V. A., Alekseenko, S. I., Svistunov, A. A., Petrakis, D., Spandidos, D. A., Aaseth, J., Tsatsakis, A., & Tinkov, A. A. (2020). Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review). International Journal of Molecular Medicine, 46(1), 17–26. https://doi.org/10.3892/ijmm.2020.4575

Sestili, P., & Fimognari, C. (2020). Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Frontiers in Pharmacology, 11, 579944. https://doi.org/10.3389/fphar.2020.579944

Shakeri, H., Azimian, A., Ghasemzadeh-Moghaddam, H., Safdari, M., Haresabadi, M., Daneshmand, T., & Namdar Ahmadabad, H. (2022). Evaluation of the relationship between serum levels of zinc, vitamin B12, vitamin D, and clinical outcomes in patients with COVID-19. Journal of Medical Virology, 94(1), 141–146. https://doi.org/10.1002/jmv.27277

Shakoor, H., Feehan, J., Dhaheri, A. S. A., Ali, H. I., Platat, C., Ismail, L. C., Apostolopoulos, V., & Stojanovska, L. (2021). Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19? Maturitas, 143, 1–9. https://doi.org/10.1016/j.maturitas.2020.08.003

Shankar, A. H., & Prasad, A. S. (1998). Zinc and immune function: The biological basis of altered resistance to infection. The American Journal of Clinical Nutrition, 68(2), 447S-463S. https://doi.org/10.1093/ajcn/68.2.447S

Srivastava, A., Gupta, R. C., Doss, R. B., & Lall, R. (2021). Trace Minerals, Vitamins and Nutraceuticals in Prevention and Treatment of COVID-19. Journal of Dietary Supplements, 1–35. https://doi.org/10.1080/19390211.2021.1890662

Vogel-González, M., Talló-Parra, M., Herrera-Fernández, V., Pérez-Vilaró, G., Chillón, M., Nogués, X., Gómez-Zorrilla, S., López-Montesinos, I., Arnau-Barrés, I., Sorli-Redó, M. L., Horcajada, J. P., García-Giralt, N., Pascual, J., Díez, J., Vicente, R., & Güerri-Fernández, R. (2021). Low Zinc Levels at Admission Associates with Poor Clinical Outcomes in SARS-CoV-2 Infection. Nutrients, 13(2), 562. https://doi.org/10.3390/nu13020562

Zinc. (2014, April 23). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/minerals/zinc

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

EFA food sources and supplementation

Top EPA and DHA (omega 3) food sources by serving size

• herring, Pacific
• salmon, chinook
• sardines, Pacific
• salmon, Atlantic
• oysters, Pacific

Comprehensive food list:
Table 4. Food Sources of EPA (20:5n-3) and DHA (22:6n-3) (Office of Dietary Supplements, n.d.)
https://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

Commonly suggested amounts for dietary fatty acid consumption:

• cold water fish – 2 to 3 times a week, or
• flaxseed oil – 2 to 6 tbsp daily, or
• ground flax seed –  2 tbsp daily
• Flaxseed oil may have negative effects in about 3% of people, including hypomania, mania, behaviour changes. (Prousky, 2015)

Referenced Dietary Intakes

Adequate Intakes for Alpha linolenic acid (Omega 3) (g/day) (Essential Fatty Acids, 2014)
Adolescents (14–18 years): 1.6 (M) 1.1 (F)
Adults (≥ 19 years): 1.6 (M) 1.1 (F)

Recommendations for long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (mg/day) (European Food Safety Authority, 2009)
Adults:  250 (M+F)

Supplementing omega 3 fatty acids

• Amounts of omega-3 fatty acids used in practice and research range from 1–4 g a day of combined EPA and DHA, in divided doses.

SAFETY, SIDE EFFECTS

• Common side effects of high dose EPA and DHA supplementation include heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat
• The European Food Safety Authority considers long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day to be safe.
• The FDA recommends not exceeding 3 g/day EPA and DHA combined, with up to 2 g/day from dietary supplements (Office of Dietary Supplements, n.d.).

OMEGA 3 FATTY ACIDS AND MEDICATIONS

• Use caution when supplementing omega-3 fatty acids while taking blood-thinning medications, or blood-sugar issues (Essential fatty acids, 2014).

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References

Calder, P. C. (2020). Nutrition, immunity and COVID-19. BMJ Nutrition, Prevention & Health, 3(1). https://doi.org/10.1136/bmjnph-2020-000085

Detopoulou, P., Demopoulos, C. A., & Antonopoulou, S. (2021). Micronutrients, Phytochemicals and Mediterranean Diet: A Potential Protective Role against COVID-19 through Modulation of PAF Actions and Metabolism. Nutrients, 13(2), 462. https://doi.org/10.3390/nu13020462

Essential Fatty Acids. (2014, April 28). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

European Food Safety Authority. Labelling reference intake values for n-3 and n-6 polyunsaturated fatty acids. (2009, July 10). https://www.efsa.europa.eu/en/efsajournal/pub/1176

Iddir, M., Brito, A., Dingeo, G., Fernandez Del Campo, S. S., Samouda, H., La Frano, M. R., & Bohn, T. (2020a). Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients, 12(6). https://doi.org/10.3390/nu12061562

Office of Dietary Supplements—Omega-3 Fatty Acids. (n.d.). Retrieved October 29, 2020, from https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/

Phelan, A. L., Katz, R., & Gostin, L. O. (2020). The Novel Coronavirus Originating in Wuhan, China: Challenges for Global Health Governance. JAMA, 323(8), 709. https://doi.org/10.1001/jama.2020.1097

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment, Kindle Edition. CCNM Press.

Sestili, P., & Fimognari, C. (2020). Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Frontiers in Pharmacology, 11, 579944. https://doi.org/10.3389/fphar.2020.579944

Shakoor, H., Feehan, J., Dhaheri, A. S. A., Ali, H. I., Platat, C., Ismail, L. C., Apostolopoulos, V., & Stojanovska, L. (2021). Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19? Maturitas, 143, 1–9. https://doi.org/10.1016/j.maturitas.2020.08.003

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).

Melatonin food sources and supplementation

Top food sources of melatonin (Meng et al., 2017)

• salmon
• chicken, pork
• milk
• strawberries, cherries, cranberries
• tomatoes

Comprehensive food list: Table 1 Concentration of melatonin in food.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409706/

Melatonin supplementation

• Amounts of melatonin used in practice and research range from 2–20 mg a day in divided doses (Malhotra et al., 2004)

Supplementing melatonin in the context of COVID-19

• 50 mg a day for 7 days was used as part of the Iranian Ministry of Health and Medical Education standard regimen (Simko & Reiter, 2020). 
• Multiple doses taken throughout the day may be required in the context of virally-induced cytokine storm (DiNicolantonio et al., 2021).
• When used as a preventative measure, melatonin should be taken at bedtime in order to prevent disruption of the circadian rhythm (DiNicolantonio et al., 2021).
• An analysis of 791 intubated COVID-19 patients showed that those treated with melatonin had a lower risk for mortality (DiNicolantonio et al., 2021).

› Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial. Archives of Medical Research (Farnoosh et al., 2022)

• 3 mg of melatonin was given three times a day to 24 COVID-19 patients, and 20 patients were not given melatonin.
• Those receiving the melatonin had significantly fewer symptoms and were released from the hospital earlier.

› Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): A case series. Melatonin Research (Castillo et al., 2020)

• Ten COVID-19 pneumonia patients were supplemented with 36–72 mg of melatonin in four divided doses.
• Supplementation was associated with decreased duration of hospital stay, need for mechanical ventilation, and decreased mortality.

SAFETY, SIDE EFFECTS

Indicators of excess melatonin intake include (Melatonin, n.d.):

• headache
• dizziness
• nausea
• sleepiness

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References

Bahrampour Juybari, K., Pourhanifeh, M. H., Hosseinzadeh, A., Hemati, K., & Mehrzadi, S. (2020). Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Research, 287, 198108. https://doi.org/10.1016/j.virusres.2020.198108

Brown, G. M., Karthikeyan, R., Pandi-Perumal, S. R., & Cardinali, D. P. (2021). Autism Spectrum Disorder patients may be susceptible to COVID-19 disease due to deficiency in melatonin. Medical Hypotheses, 149, 110544. https://doi.org/10.1016/j.mehy.2021.110544

Carlberg, C. (2000). Gene regulation by melatonin. Annals of the New York Academy of Sciences, 917, 387–396. https://doi.org/10.1111/j.1749-6632.2000.tb05403.x

Castillo, R. R., Quizon, G. R. A., Juco, M. J. M., Roman, A. D. E., Leon, D. G. de, Punzalan, F. E. R., Guingon, R. B. L., Morales, D. D., Tan, D.-X., & Reiter, R. J. (2020). Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): A case series. Melatonin Research, 3(3), 297–310. https://doi.org/10.32794/mr11250063

Corrao, S., Mallaci Bocchio, R., Lo Monaco, M., Natoli, G., Cavezzi, A., Troiani, E., & Argano, C. (2021). Does Evidence Exist to Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc. Nutrients, 13(4), 1261. https://doi.org/10.3390/nu13041261

DiNicolantonio, J. J., McCarty, M., & Barroso-Aranda, J. (2021). Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections. Open Heart, 8(1), e001568. https://doi.org/10.1136/openhrt-2020-001568

Farnoosh, G., Akbariqomi, M., Badri, T., Bagheri, M., Izadi, M., Saeedi-Boroujeni, A., Rezaie, E., Ghaleh, H. E. G., Aghamollaei, H., Fasihi-Ramandi, M., Hassanpour, K., & Alishiri, G. (2022). Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial. Archives of Medical Research, 53(1), 79–85. https://doi.org/10.1016/j.arcmed.2021.06.006

Garcia-Mauriño, S., Gonzalez-Haba, M. G., Calvo, J. R., Rafii-El-Idrissi, M., Sanchez-Margalet, V., Goberna, R., & Guerrero, J. M. (1997). Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: A possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. Journal of Immunology (Baltimore, Md.: 1950), 159(2), 574–581.

Juybari, K. B., Hosseinzadeh, A., Ghaznavi, H., Kamali, M., Sedaghat, A., Mehrzadi, S., & Naseripour, M. (n.d.). Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells. Current Pharmaceutical Design, 25(28), 3057–3073. Retrieved August 22, 2022, from https://www.eurekaselect.com/article/100521

Malhotra, S., Sawhney, G., & Pandhi, P. (2004). The Therapeutic Potential of Melatonin: A Review of the Science. Medscape General Medicine, 6(2), 46. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1395802/

Melatonin: What You Need To Know. (n.d.). NCCIH. Retrieved September 3, 2022, from https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know

Meng, X., Li, Y., Li, S., Zhou, Y., Gan, R.-Y., Xu, D.-P., & Li, H.-B. (2017). Dietary Sources and Bioactivities of Melatonin. Nutrients, 9(4), 367. https://doi.org/10.3390/nu9040367

Ouyang, H., Zhong, J., Lu, J., Zhong, Y., Hu, Y., & Tan, Y. (2019). Inhibitory effect of melatonin on Mst1 ameliorates myocarditis through attenuating ER stress and mitochondrial dysfunction. Journal of Molecular Histology, 50(5), 405–415. https://doi.org/10.1007/s10735-019-09836-w

Reiter, R. J., Mayo, J. C., Tan, D.-X., Sainz, R. M., Alatorre-Jimenez, M., & Qin, L. (2016). Melatonin as an antioxidant: Under promises but over delivers. Journal of Pineal Research, 61(3), 253–278. https://doi.org/10.1111/jpi.12360

Silvestri, M., & Rossi, G. A. (2013). Melatonin: Its possible role in the management of viral infections–a brief review. Italian Journal of Pediatrics, 39, 61. https://doi.org/10.1186/1824-7288-39-61

Simko, F., & Reiter, R. J. (2020). Is melatonin deficiency a unifying pathomechanism of high risk patients with COVID-19? Life Sciences, 256, 117902. https://doi.org/10.1016/j.lfs.2020.117902

Zhou, Y., Hou, Y., Shen, J., Mehra, R., Kallianpur, A., Culver, D. A., Gack, M. U., Farha, S., Zein, J., Comhair, S., Fiocchi, C., Stappenbeck, T., Chan, T., Eng, C., Jung, J. U., Jehi, L., Erzurum, S., & Cheng, F. (2020). A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19. PLoS Biology, 18(11), e3000970. https://doi.org/10.1371/journal.pbio.3000970

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).

NAC food sources and supplementation

Food sources of NAC

NAC is not found in food but can be made by the body from the amino acid cysteine.

Food sources high in cysteine include (Foods Highest in Cystine, n.d.):

• beef, lamb, pork
• poultry
• fish

Supplementing NAC

• Amounts of NAC used in practice and research range from 600 to 3600 mg a day in divided doses.
• NAC needs to be taken away from food for maximum therapeutic effect.
• NAC supplementation has been shown to increase blood glutathione levels (Lavoie et al., 2007), and regulate the metabolism of glutamate and GABA (Dean, Giorlando, & Berk, 2011).

NAC Supplementation in the context of COVID-19

• Adjunctive treatment with NAC is known to reduce the severity of many acute respiratory conditions, including influenza, pneumonia, ARDS, and ventilator-associated pneumonia. Oral doses of 1200 mg/day are well tolerated (Mohanty et al., n.d.).
• 1200 mg/day of oral NAC in patients with COVID-19 pneumonia was shown to reduce the risk of mechanical ventilation and death (Assimakopoulos et al., 2021).
• Glutathione synthesis is known to decline with age, resulting in decreased tissue glutathione levels. This can be corrected with NAC supplementation (Bourgonje et al., 2021).

› Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. Clinical Immunology (Ibrahim et al., 2020)

• 10 patients with severe COVID-19 showed clinical improvement with a considerable reduction of inflammation with IV NAC.
• NAC actions may have involved blocking viral infection and reducing cytokine storm progression.

SAFETY, SIDE EFFECTS

Side effects of NAC can include:

• mild nausea
• upset stomach and indigestion
• diarrhea
• tiredness or weakness
• sweating
• skin rash

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References

Assimakopoulos, S. F., Aretha, D., Komninos, D., Dimitropoulou, D., Lagadinou, M., Leonidou, L., Oikonomou, I., Mouzaki, A., & Marangos, M. (2021). N-acetyl-cysteine reduces the risk for mechanical ventilation and mortality in patients with COVID-19 pneumonia: A two-center retrospective cohort study. Infectious Diseases, 53(11), 847–854. https://doi.org/10.1080/23744235.2021.1945675

Bourgonje, A. R., Offringa, A. K., van Eijk, L. E., Abdulle, A. E., Hillebrands, J.-L., van der Voort, P. H. J., van Goor, H., & van Hezik, E. J. (2021). N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019. Antioxidants & Redox Signaling, 35(14), 1207–1225. https://doi.org/10.1089/ars.2020.8247

Dean, O., Giorlando, F., & Berk, M. (2011). N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. Journal of Psychiatry and Neuroscience, 36(2), 78.

Foods highest in Cystine. (n.d.). Retrieved December 8, 2020, from https://nutritiondata.self.com/foods-000085000000000000000-10.html?

Ibrahim, H., Perl, A., Smith, D., Lewis, T., Kon, Z., Goldenberg, R., Yarta, K., Staniloae, C., & Williams, M. (2020). Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. Clinical Immunology, 219, 108544. https://doi.org/10.1016/j.clim.2020.108544

Jorge-Aarón, R.-M., & Rosa-Ester, M.-P. (2020). N-acetylcysteine as a potential treatment for COVID-19. Future Microbiology, 15(11), 959–962. https://doi.org/10.2217/fmb-2020-0074

Khatiwada, S., & Subedi, A. (2021). A Mechanistic Link Between Selenium and Coronavirus Disease 2019 (COVID-19). Current Nutrition Reports, 10(2), 125–136. https://doi.org/10.1007/s13668-021-00354-4

Mohanty, R. R., Padhy, B. M., Das, S., & Meher, B. R. (n.d.). Therapeutic potential of N-acetyl cysteine (NAC) in preventing cytokine storm in COVID-19: Review of current evidence. 6.

Poe, F. L., & Corn, J. (2020). N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Medical Hypotheses, 143, 109862. https://doi.org/10.1016/j.mehy.2020.109862

Polonikov, A. (2020). Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infectious Diseases, 6(7), 1558–1562. https://doi.org/10.1021/acsinfecdis.0c00288

Sestili, P., & Fimognari, C. (2020). Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Frontiers in Pharmacology, 11, 579944. https://doi.org/10.3389/fphar.2020.579944

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).

Glutathione Supplementation

Supplements and foods to support boosting glutathione levels (Glutathione Benefits, Plus Foods and Supplements to Boost It, n.d).:

• vitamin C
• NAC
• alpha lipoic acid
• selenium
• vitamin E
• methylation supporting vitamins (B6, B12, folate, biotin) choline
• sulfur-containing foods
• whey protein 
• milk thistle herb

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References

Glutathione Benefits, Plus Foods and Supplements to Boost It. (n.d.). Dr. Axe. Retrieved August 13, 2022, from https://draxe.com/nutrition/glutathione/

Karkhanei, B., Talebi Ghane, E., & Mehri, F. (2021). Evaluation of oxidative stress level: Total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID-19. New Microbes and New Infections, 42, 100897. https://doi.org/10.1016/j.nmni.2021.100897

Polonikov, A. (2020). Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infectious Diseases, 6(7), 1558–1562. https://doi.org/10.1021/acsinfecdis.0c00288

Sestili, P., & Fimognari, C. (2020). Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness? Frontiers in Pharmacology, 11, 579944. https://doi.org/10.3389/fphar.2020.579944

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).

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References

Colunga Biancatelli, R. M. L., Berrill, M., Catravas, J. D., & Marik, P. E. (2020a). Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Frontiers in Immunology, 11. https://www.frontiersin.org/article/10.3389/fimmu.2020.01451

Dominguez, L. J., Veronese, N., Guerrero-Romero, F., & Barbagallo, M. (2021). Magnesium in Infectious Diseases in Older People. Nutrients, 13(1), 180. https://doi.org/10.3390/nu13010180

DiNicolantonio, J. J., & O’Keefe, J. H. (2021). Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients. Missouri Medicine, 118(1), 68–73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861592/

Galmés, S., Serra, F., & Palou, A. (2020). Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework. Nutrients, 12(9), 2738. https://doi.org/10.3390/nu12092738

Mercola, J., Grant, W. B., & Wagner, C. L. (2020). Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients, 12(11), 3361. https://doi.org/10.3390/nu12113361

Polonikov, A. (2020). Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infectious Diseases, 6(7), 1558–1562. https://doi.org/10.1021/acsinfecdis.0c00288

Shakoor, H., Feehan, J., Dhaheri, A. S. A., Ali, H. I., Platat, C., Ismail, L. C., Apostolopoulos, V., & Stojanovska, L. (2021). Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19? Maturitas, 143, 1–9. https://doi.org/10.1016/j.maturitas.2020.08.003

Vyas, N., Kurian, S. J., Bagchi, D., Manu, M. K., Saravu, K., Unnikrishnan, M. K., Mukhopadhyay, C., Rao, M., & Miraj, S. S. (2021). Vitamin D in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects. Journal of the American College of Nutrition, 40(7), 632–645. https://doi.org/10.1080/07315724.2020.1806758