Consideration of host nutritional status as a mitigating factor against current and future pandemics: a review of nutrient studies and experiences with infectious diseases including Covid-19

Main Article Content

Richard Z Cheng, MD, PhD Michael Passwater Tievi Yang, MD

Abstract

For over 3 years, the Covid-19 pandemic felt like a world war and has taken close to 7 million lives, disabled many more people, and caused innumerable economic losses around the globe. What can we learn from this tragedy? Are we ready for another Covid-19-like pandemic? Studies show that the majority of people with SARS-Cov-2 infection either show no symptoms or only mild to moderate clinical manifestations; only a small percentage develop severe Covid-19 disease, indicating that the clinical severity of Covid-19 disease is not determined only by the SARS-Cov-2 virus, but more importantly by how the host responds to the viral infection, what is known as natural immunity. Research of what enhances or weakens the natural immunity against viral infections and the practical application thereof is an important lesson one can learn from the pandemic. Research of natural immunity enhancing factors is summarized in this paper. One key characteristic of natural immunity against viral diseases is its non-specificity. The importance of this non-specificity helping to prevent and treat other infections of known or unknown viruses is also discussed. Calls for the clinical application of safe and inexpensive nutrients such as vitamin C in the prevention and treatment of Covid-19 have met significant resistance and objection from the medical authorities and the media since the pandemic outbreak. The main objection is the perceived lack of research and the absence of regulatory approvals. This raises a fundamental philosophical question: what is the primary goal of the medical profession? Facing a new viral pandemic like Covid-19 with no prior research, let alone any approved treatments, why is there opposition to known safe, inexpensive, widely available and often effective nutrients like vitamin C? Why are case reports and case series discounted or ignored rather than explored further to try to help more people? Is such objection protecting consumers or harming the public? Statistics show that viral epidemics and pandemics are occurring more frequently, with a recent review of epidemics and pandemics since 1600 concluding “ the yearly probability of occurrence of extreme epidemics can increase up to threefold in the coming decades.”1. When the next Covid-19-like pandemic of a new virus hits us, are we going to repeat the Covid-19 tragedy? Can improved emphasis on nutritional interventions to prepare for and respond to disease outbreaks mitigate future pandemics?

Keywords: infectious diseases, Covid-19, review of nutrient studies

Article Details

How to Cite
CHENG, Richard Z; PASSWATER, Michael; YANG, Tievi. Consideration of host nutritional status as a mitigating factor against current and future pandemics: a review of nutrient studies and experiences with infectious diseases including Covid-19. Medical Research Archives, [S.l.], v. 11, n. 9, sep. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4419>. Date accessed: 15 may 2024. doi: https://doi.org/10.18103/mra.v11i9.4419.
Section
Review Articles

References

1. Marani M, Katul GG, Pan WK, Parolari AJ. (2021) Intensity and frequency of extreme novel epidemics. PNAS. August 23, 2021. 118 (35) e2105482118 https://doi.org/10.1073/pnas.2105482118 https://www.pnas.org/doi/10.1073/pnas.2105482118

2. Pezzullo, A. M., Axfors, C., Contopoulos-Ioannidis, D. G., Apostolatos, A. & Ioannidis, J. P. A. Age-stratified infection fatality rate of COVID-19 in the non-elderly informed from pre-vaccination national seroprevalence studies. 2022.10.11.22280963 Preprint at https://doi.org/10.1101/2022.10.11.22280963 (2022)

3. Wong, J. Y. et al. Case fatality risk of influenza A(H1N1pdm09): a systematic review. Epidemiology 24, 10.1097/EDE. 0b013e3182a67448 (2013).

4. Cheng, R. Z. COVID-19 Highlights the Shortcomings of Evidence-Based Medicine. ISOM https://isom.ca/article/covid-19-highlights the-shortcomings-of-evidence-based-medicine/.

5. Richard Z. Cheng. Protected Population Immunity, Not A Vaccine, Is The Way To Stop Covid-19 Pandemic. J Clin Immunol Immunother 6, 1–4 (2020).

6. Curran, J. The Yellow Emperor’s Classic of Internal Medicine. BMJ 336, 777 (2008).

7. Demeda, P. COVID-19 and Nutrition: An Orthomolecular Perspective. ISOM https://isom.ca/covid19-info/.

8. Gombart, A. F., Pierre, A. & Maggini, S. A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection. Nutrients 12, 236 (2020).

9. Calder, P. C. Nutrition, immunity and COVID-19. BMJ Nutr Prev Health 3, 74–92 (2020).

10. Gröber, U. & Holick, M. F. The coronavirus disease (COVID-19) - A supportive approach with selected micronutrients. Int J Vitam Nutr Res 92, 13–34 (2022).

11. Galmés, S., Serra, F. & Palou, A. Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework. Nutrients 12, E2738 (2020).

12. de Faria Coelho-Ravagnani, C. et al. Dietary recommendations during the COVID-19 pandemic. Nutr Rev 79, 382–393 (2021).

13. Hogarth, M. et al. Clinical characteristics and comorbidities associated with SARS-CoV-2 breakthrough infection in the University of California Healthcare Systems. Am J Med Sci 366, 102–113 (2023).

14. Chiodini, I. et al. Vitamin D Status and SARS-CoV-2 Infection and COVID-19 Clinical Outcomes. Front Public Health 9, 736665 (2021).

15. Reider, C. A., Chung, R.-Y., Devarshi, P. P., Grant, R. W. & Hazels Mitmesser, S. Inadequacy of Immune Health Nutrients: Intakes in US Adults, the 2005-2016 NHANES. Nutrients 12, E1735 (2020).

16. Gibbons, J. B. et al. Association between vitamin D supplementation and COVID-19 infection and mortality. Sci Rep 12, 19397 (2022).

17. Ohaegbulam, K. C., Swalih, M., Patel, P., Smith, M. A. & Perrin, R. Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series. Am J Ther 27, e485–e490 (2020).

18. Entrenas Castillo, M. et al. 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. J Steroid Biochem Mol Biol 203, 105751 (2020).

19. Healing Factor: Stone, Irwin: 9780399507649: Amazon.com: Books. https://www.amazon.com/Healing-Factor-GD-Perigee-book/dp/0399507647.

20. Klenner FR. Observations on the dose and administration of ascorbic acid when employed beyond the range of a vitamin in human pathology. The Journal of Applied Nutrition, Winter 1971, Volume 23, Number 3 & 4, pp. 61-88

21. Khan, H. M. & et al. Unusual Early Recovery of a Critical COVID-19 Patient After Administration of Intravenous Vitamin C. https://www.amjcaserep.com/download/index/idArt/925521.

22. Mj, G. et al. High Dose Intravenous Vitamin C Treatment for Zika Fever. Journal of orthomolecular medicine : official journal of the Academy of Orthomolecular Medicine 31, (2016).

23. Gonzalez, M. J. et al. High Dose Intraveneous Vitamin C and Chikungunya Fever: A Case Report. J Orthomol Med 29, 154–156 (2014).

24. Fowler III, A. A. et al. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med 6, 85–90 (2017).

25. Klenner, F. The treatment of poliomyelitis and other virus diseases with vitamin C. Southern Medicine & Surgery 111, 209–214 (1949).

26. Yr, L. et al. Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C. Critical care medicine 49, (2021).

27. Ichim, T. E. et al. Intravenous ascorbic acid to prevent and treat cancer-associated sepsis? J Transl Med 9, 25 (2011).

28. Hunt, C., Chakravorty, N. K., Annan, G., Habibzadeh, N. & Schorah, C. J. The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. Int J Vitam Nutr Res 64, 212–219 (1994).

29. The Treatment of Infectious Disease Using Vitamin C and other Nutrients. http://orthomolecular.org/resources/omns/v17n04.shtml.

30. McCORMICK, W. J. Vitamin C in the prophylaxis and therapy of infectious diseases. Arch Pediatr (N Y) 68, 1–9 (1951).

31. Riordan, H. D. et al. Intravenous ascorbic acid: protocol for its application and use. P R Health Sci J 22, 287–290 (2003).

32. Marik, P. E., Khangoora, V., Rivera, R., Hooper, M. H. & Catravas, J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest 151, 1229–1238 (2017).

33. Bharara, A. et al. Intravenous Vitamin C Administered as Adjunctive Therapy for Recurrent Acute Respiratory Distress Syndrome. Case Rep Crit Care 2016, 8560871 (2016).

34. Borrelli, E. et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit. Care Med. 24, 392–397 (1996).

35. Xu, C. et al. Association of Oral or Intravenous Vitamin C Supplementation with Mortality: A Systematic Review and Meta-Analysis. Nutrients 15, 1848 (2023).

36. Taylor, E. W. (2020) RNA viruses vs. DNA synthesis: a general viral strategy that may contribute to the protective antiviral effects of selenium.Preprints 2020, 2020060069.

37. Wang Y, Huang J, Sun Y, Stubbs D, He J, Li W, Wang F, Liu Z, Ruzicka JA, Taylor EW, Rayman MP, Wan X, Zhang J. SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, ER stress and DNA synthesis.Food Chem Toxicol153 (2021) 112286.

38. Gallardo IA, Todd DA, Lima ST, Chekan JR, Chiu NH and Taylor EW (2023) SARS-CoV-2 main protease targets host selenoproteins and glutathione biosynthesis for knockdown via proteolysis, potentially disrupting the thioredoxin and glutaredoxin redox cycles.Antioxidants, 2023,12(3), 559.

39. Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition. 2020 Jun;12:100190. doi: 10.1016/j.phanu.2020. 100190. Epub 2020 Apr 21. PMID: 32322486; PMCID: PMC7172861.

40. Lei XG, Cheng WH, McClung JP. Metabolic regulation and function of glutathione peroxidase-1. Annu Rev Nutr. 2007;27:41-61

41. Brigelius-Flohé R. Glutathione peroxidases and redox-regulated transcription factors. Biol Chem. 2006;387:1329-35

42. Go YM, Jones DP. Redox compartmentalization in eukaryotic cells. Biochim Biophys Acta. 2008;1780:1273-90

43. Flaring UB, Rooyackers OE, Wernerman J, Hammarqvist F. Temporal changes inmuscle glutathione in ICU patients Intensive Care Med 2003; 29:2193–98.

44. Beck MA, Nelson HK, Shi Q, Van Dael P, Schiffrin EJ, Blum S, Barclay D,Levander OA. Selenium deficiency increases the pathology of an influenza virusinfection. FASEB J 2001; 15:1481-1483

45. Vunta H, Davis F, Palempalli UD, Bhat D, Arner RJ, Thompson JT, Peterson DG,Reddy CC, Prabhu KS. The anti-inflammatory effects of selenium are mediatedthrough 15-deoxy-Delta12,14-prostaglandin J2 in macrophages. J Biol Chem.2007;282:17964-73

46. Hollenbach B, Morgenthaler NG, Struck J, Alonso C, Bergmann A, Köhrle J,Schomburg L. New assay for the measurement of selenoprotein P as a sepsisbiomarker from serum. J Trace Elem Med Biol. 2008;22:24-32

47. Burk RF, Hill KE. Selenoprotein P: an extracellular protein with unique physicalcharacteristics and a role in selenium homeostasis. Annu Rev Nutr 2005; 25:215-235

48. Forceville X, Vitoux D, Gauzit R, Combes A, Lahilaire P, Chappuis P. Selenium,systemic immune response syndrome, sepsis, and outcome in critically ill patients.Crit Care Med 1998; 26:1536-1544

49. Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P,Strauss R, Meier-Hellmann A, Insel R, Radke J, Schüttler J, Gärtner R. Seleniumin Intensive Care (SIC): results of a prospective randomized, placebo-controlled,multiple-center study in patients with severe systemic inflammatory responsesyndrome, sepsis, and septic shock. Crit Care Med. 2007;35:118-26

50. Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: asystematic review of trace elements and vitamins in the critically ill patient.Intensive Care Med. 2005; 31: 327-337

51. Vincent JL, Forceville X. Critically elucidating the role of selenium. Curr Opin Anaesthesiol. 2008;21:148-54.]

52. Taylor, E.W. (2009) The oxidative stress-induced niacin sink (OSINS) model for HIV pathogenesis. Toxicology 278: 124-130.

53. Laforge M, Elbim C, Frère C, Hémadi M, Massaad C, Nuss P, Benoliel JJ, Becker C. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat Rev Immunol. 2020 Sep Nat Rev Immunol. PMID: 32728221.

54. Johnston et al. (2015) Cytokine modulation correlates with severity of monkeypox disease in humans. J Clin PMID: 25600603

55. Martín-Fernández M, Aller R, Heredia-Rodríguez M, Gómez-Sánchez E, Martínez-Paz P, Gonzalo-Benito H, Sánchez-de Prada L, Gorgojo Ó, Carnicero-Frutos I, Tamayo E, Tamayo-Velasco Á. Lipid peroxidation as a hallmark of severity in COVID-19 patients. Redox Biol. 2021 Nov 6;48:102181. doi: 10.1016/j.redox.2021.102181. Epub ahead of print. PMID: 34768063; PMCID: PMC8572041.

56. Cheng, R. Jan. 22, 2022. http://orthomolecular.org/resources/omns/v18n03.shtml

57. Tsermpini EE, Glamočlija U, Ulucan-Karnak F, Redenšek Trampuž S, Dolžan V. Molecular Mechanisms Related to Responses to Oxidative Stress and Antioxidative Therapies in COVID-19: A Systematic Review. Antioxidants (Basel). 2022 Aug 19; PMID: 36009328;

58. Ebrahimi et al. Int J Biol Macromol. 2021 Oct. PMID: 34418419.Tsermpini). Antioxidants (Basel). 2022 Aug. PMID: 36009328;

59. Martín-Fernández et al. Redox Biol. 2021 Nov. PMID: 34768063.

60. Avila-Nava et al. Oxid Med Cell Longev. 2022 Jun. PMID: 35746958.]

61. Fowler, A. A. et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 12, 32 (2014).

62. Zhao, B. et al. Vitamin C treatment attenuates hemorrhagic shock related multi-organ injuries through the induction of heme oxygenase-1. BMC Complement Altern Med 14, 442 (2014).

63. Ladurner, A. et al. Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status. Free Radic Biol Med 52, 2082–2090 (2012).

64. Heller, R., Münscher-Paulig, F., Gräbner, R. & Till, U. L-Ascorbic acid potentiates nitric oxide synthesis in endothelial cells. J Biol Chem 274, 8254–8260 (1999).

65. Dingchao, H., Zhiduan, Q., Liye, H. & Xiaodong, F. The protective effects of high-dose ascorbic acid on myocardium against reperfusion injury during and after cardiopulmonary bypass. Thorac Cardiovasc Surg 42, 276–278 (1994).

66. Chambers, R. & Pollack, H. MICRURGICAL STUDIES IN CELL PHYSIOLOGY : IV. COLORIMETRIC DETERMINATION OF THE NUCLEAR AND CYTOPLASMIC pH IN THE STARFISH EGG. J Gen Physiol 10, 739–755 (1927).

67. Clark, E. J. & Rossiter, R. J. Carbohydrate Metabolism After Burning. Quarterly Journal of Experimental Physiology and Cognate Medical Sciences 32, 279–300 (1944).

68. Fe, H. & Jm, M. Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free radical biology & medicine 46, (2009).

69. Lee, R. E. Ascorbic acid and the peripheral vascular system. Ann N Y Acad Sci 92, 295–301 (1961).

70. Barabutis, N., Khangoora, V., Marik, P. E. & Catravas, J. D. Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest 152, 954–962 (2017).

71. Carr, A. C. & Rowe, S. The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19. Nutrients 12, 3286 (2020).

72. Oudemans-van Straaten, H. M., Spoelstra-de Man, A. M. & de Waard, M. C. Vitamin C revisited. Crit Care 18, 460 (2014).

73. Holford, P. et al. Vitamin C-An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19. Nutrients 12, E3760 (2020).

74. (PDF) COVID-19: Up to 87% Critically Ill Patients Had Low Vitamin C Values. https://www.researchgate.net/publication/346221436_COVID19_Up_to_87_Critically_Ill_Patients_Had_Low_Vitamin_C_Values.

75. Arvinte, C., Singh, M. & Marik, P. E. Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study. Med Drug Discov 8, 100064 (2020).

76. Chiscano-Camón, L., Ruiz-Rodriguez, J. C., Ruiz-Sanmartin, A., Roca, O. & Ferrer, R. Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome. Crit Care 24, 522 (2020).

77. Sinnberg, T. et al. Vitamin C Deficiency in Blood Samples of COVID-19 Patients. Antioxidants (Basel) 11, 1580 (2022).

78. Wang, Y., Lin, H., Lin, B.-W. & Lin, J.-D. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann Intensive Care 9, 58 (2019).

79. Xing, Y. et al. Vitamin C supplementation is necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandem mass spectrometry finding. J Pharm Biomed Anal 196, 113927 (2021).

80. Angstwurm, M. W. A. et al. Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med 35, 118–126 (2007).

81. Fang, L.-Q. et al. The Association between Hantavirus Infection and Selenium Deficiency in Mainland China. Viruses 7, 333–351 (2015).

82. Abd-ElMoemen, N. et al. Ebola Outbreak in West Africa; Is Selenium Involved? Int J Pept Res Ther 22, 135–141 (2016).

83. Guillin, O. M., Vindry, C., Ohlmann, T. & Chavatte, L. Selenium, Selenoproteins and Viral Infection. Nutrients 11, 2101 (2019).

84. Research, I. of M. (US) C. on M. N. Trace Minerals, Immune Function, and Viral Evolution. in Military Strategies for Sustainment of Nutrition and Immune Function in the Field (National Academies Press (US), 1999).

85. Harthill, M. Review: micronutrient selenium deficiency influences evolution of some viral infectious diseases. Biol Trace Elem Res 143, 1325–1336 (2011).

86. Beck, M. A. et al. Benign human enterovirus becomes virulent in selenium-deficient mice. J Med Virol 43, 166–170 (1994).

87. Nelson, H. K. et al. Host nutritional selenium status as a driving force for influenza virus mutations. FASEB J 15, 1727–1738 (2001).

88. Beck, M. A. et al. Selenium deficiency increases the pathology of an influenza virus infection. FASEB J 15, 1481–1483 (2001).

89. Beck, M. A. & Levander, O. A. Dietary oxidative stress and the potentiation of viral infection. Annu Rev Nutr 18, 93–116 (1998).

90. Akaike, T. et al. Viral mutation accelerated by nitric oxide production during infection in vivo. FASEB J 14, 1447–1454 (2000).

91. Miller, R., Wentzel, A. R. & Richards, G. A. COVID-19: NAD+ deficiency may predispose the aged, obese and type2 diabetics to mortality through its effect on SIRT1 activity. Med Hypotheses 144, 110044 (2020).

92. Marik, P. E., Kory, P., Varon, J., Iglesias, J. & Meduri, G. U. MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale. Expert Rev Anti Infect Ther 19, 129–135 (2021).

93. Colunga Biancatelli, R. M. L., Berrill, M., Catravas, J. D. & Marik, P. E. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol 11, 1451 (2020).

94. Hoang, B. X., Shaw, G., Fang, W. & Han, B. Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection. J Glob Antimicrob Resist 23, 256–262 (2020).

95. Kumari, P. et al. The Role of Vitamin C as Adjuvant Therapy in COVID-19. Cureus 12, e11779 (2020).

96. Liu, F., Zhu, Y., Zhang, J., Li, Y. & Peng, Z. Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial. BMJ Open 10, e039519 (2020).

97. Zhao, B. et al. Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study. Ann Palliat Med 10, 1599–1609 (2021).

98. Cheng, R. Z. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discov 5, 100028 (2020).

99. Hess, A. L. et al. High-dose intravenous vitamin C decreases rates of mechanical ventilation and cardiac arrest in severe COVID-19. Intern Emerg Med 17, 1759–1768 (2022).

100. Horowitz, R. I., Freeman, P. R. & Bruzzese, J. Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respir Med Case Rep 30, 101063 (2020).

101. Polonikov, A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis 6, 1558–1562 (2020).

102. Vavougios, G. D., Ntoskas, K. T. & Doskas, T. K. Impairment in selenocysteine synthesis as a candidate mechanism of inducible coagulopathy in COVID-19 patients. Med Hypotheses 147, 110475 (2021).

103. Moghaddam, A. et al. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 12, 2098 (2020).

104. Mal’tseva, V. N., Goltyaev, M. V., Turovsky, E. A. & Varlamova, E. G. Immunomodulatory and Anti-Inflammatory Properties of Selenium-Containing Agents: Their Role in the Regulation of Defense Mechanisms against COVID-19. Int J Mol Sci 23, 2360 (2022).

105. Larvie, D. Y., Perrin, M. T., Donati, G. L. & Armah, S. M. COVID-19 Severity Is Associated with Selenium Intake among Young Adults with Low Selenium and Zinc Intake in North Carolina. Curr Dev Nutr 7, 100044 (2023).

106. Zhang, H.-Y. et al. Association between fatality rate of COVID-19 and selenium deficiency in China. BMC Infect Dis 21, 452 (2021).

107. Zhang, J., Taylor, E. W., Bennett, K., Saad, R. & Rayman, M. P. Association between regional selenium status and reported outcome of COVID-19 cases in China. Am J Clin Nutr 111, 1297–1299 (2020).

108. Heller, R. A. et al. Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker. Redox Biol 38, 101764 (2021).

109. Gallardo, I. A. et al. SARS-CoV-2 Main Protease Targets Host Selenoproteins and Glutathione Biosynthesis for Knockdown via Proteolysis, Potentially Disrupting the Thioredoxin and Glutaredoxin Redox Cycles. Antioxidants (Basel) 12, 559 (2023).

110. Argano, C. et al. Protective Effect of Vitamin D Supplementation on COVID-19-Related Intensive Care Hospitalization and Mortality: Definitive Evidence from Meta-Analysis and Trial Sequential Analysis. Pharmaceuticals (Basel) 16, 130 (2023).

111. Beck, M. A., Handy, J. & Levander, O. A. Host nutritional status: the neglected virulence factor. Trends Microbiol 12, 417–423 (2004).

112. Colunga Biancatelli, R. M. L., Berrill, M., Catravas, J. D. & Marik, P. E. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol 11, 1451 (2020).

113. Cheng, R. A Hallmark of Covid-19: Cytokine Storm/Oxidative Stress and its Integrative Mechanism. http://orthomolecular.org/resources/omns/v18n03.shtml (2022)