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Literature Review for COVID-19

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The following article is a summary of some of the current literature detailing the potential for natural substances to have an impact on COVID-19. This is just for information purposes and not for diagnosis or treatment. Recommendation for prevention and treatment for COVID-19 come from Public Health agency in Canada in conjunction with standard COVID-19 therapy as directed by hospital or country of origin.

Summarized will be glutathione, vitamin D, melatonin, quercetin and intravenous vitamin C.

Glutathione

Glutathione is plentiful antioxidant found in most cells in the body, but it is abundant in the airway epithelial lining fluid in the lungs and helps to decrease pro-inflammatory processes1.

There is evidence that glutathione inhibits replication of various viruses at different stages of the viral life cycle and this antiviral property of glutathione seems to prevent increased viral loads and the subsequent massive release of inflammatory cells into the lung also called a cytokine storm2.

The role of glutathione in COVID-19

  • Acts like a potent antioxidant that cleans up oxidative damage3
  • Is necessary is detoxification of foreign and endogenous compounds3
  • Maintains mitochondrial function3
  • Higher levels of glutathione help to improve an individual’s response to viral infection3
  • Regulation of cellular function3

In particular, glutathione is known to protect host immune cells through its antioxidant mechanism and is also responsible for optimal functioning of a variety of cells that are part of the immune system by inhibiting TNF-?-induced NF-kappaB activation4.

Oral and IV glutathione as well as glutathione precursors such as NAC (N-acetyl-cysteine), represent an approach for blocking NFK-KappaB and addressing cytokine storm syndrome and respiratory distress in patients suffering with COVID 19 pneumonia4,5,6,7.

COVID-19 and ARDS

ARDS has been reported to be the main cause of death in COVID-19, resulting from an uncontrolled systemic inflammatory response releasing large amounts of pro-inflammatory cytokines as well as chemokines by immune effector cells7,8.

Predicting severity of COVID-19 through glutathione status

One group of scientists generated a model for determining the severity of those infected with COVID-19. There were over 220 clinical and laboratory observations/records collected to generate a modelused to estimate how severe the patient would be effected with COVID-19. Four strong predictive model which could effectively estimate severe/critical patients. The four key makers that corresponded to a patient developing severe/critical symptoms were age, GSH, total protein and CD3 percentage9.

Vitamin D

Vitamin D is an important anti-inflammatory function in immune effectors through decreasing pro-inflammatory cytokine generation and increasing anti-inflammatory cytokines in immune cells12.

The role of vitamin D in the immune system:

  • Vitamin D regulates calcium and phosphorus metabolism, therefore important in bone-formation.
  • Vitamin D an immunomodulator targeting various immune cells, including monocytes, macrophages, dendritic cells as well as T-lymphocytes and B-lymphocytes, hence modulating both innate and adaptive immune responses.
  • Vitamin D plays a role in maintenance of immune homeostasis. Several epidemiological studies have linked inadequate vitamin D levels to a higher susceptibility of immune-mediated disorders, including chronic infections.
  • Vitamin D supplementation can increase gene expression related to stimulate glutathione reductase modifier subunit and therefore increased production of glutathione12,13,14.

Low vitamin D and COVID-19 increase risk

Low vitamin D promotes the renin angiotensin system, which may lead to chronic cardiovascular disease and decreased lung function. Patients with this comorbidity account for a higher proportion of critically ill cases in COVID?1916. Several studies have found a negative correlation to vitamin D levels and severity of COVID-19 infection16,17. It has been observed between mean vitamin D levels and COVID-19 cases per one million population in European countries17.There is a significant correlation between vitamin D levels and COVID-19 cases and severity.,18,19,20.

Melatonin

Melatonin is a chronobiotic hormone21which is present in all forms of life with aerobic respiration and whose primary function seems to be cytoprotection. Melatonin has indirect antiviral actions as an anti-inflammatory, antioxidant and immunostimulant. And is has and a very effective neuroprotective activity22.

Role of Melatonin in COVID-19:

  • Melatonin downregulates NF-?B activation in T cells and lung tissue and has an anti-inflammatory effect by suppressing of NF-?B activation in ARDS.
  • The anti-oxidative effect of melatonin cooperates with its anti-inflammatory actions by up-regulating anti-oxidative enzymes such as superoxide dismutase, and down-regulating pro-oxidative enzymes such as nitric oxide synthase.
  • Melatonin induces the up-regulation of Nrf2 with therapeutic effects in hepatoprotection and cardioprotection
  • Melatonin causes a reduction in the pro-inflammatory cytokines such as TNF-?, IL-1?, IL-6, and IL-8, and an elevation in the level of anti-inflammatory cytokine IL-10
  • Melatonin exerts regulatory actions on the immune system and directly enhances the immune response by improving proliferation and maturation of natural killing cells, T and B lymphocytes, granulocytes and monocytes in both bone marrow and other tissues
  • Melatonin mediates the suppression of VEGF in vascular endothelial cells
  • Melatonin exerts neurological protection by reducing the cerebral inflammatory response, cerebral edema and brain-blood barrier permeability under a number of experimental conditions
  • Melatonin reduced the infiltration of macrophages and neutrophils into the lung in acute lung injury due to the inhibition of NLRP3 inflammasome 23,24,25,26.

Cytokine storm from COVID-19 and Melatonin

The pathogenesis of a COVID-19 respiratory infection is called a cytokine storm thought to be caused by pro inflammatory cytokines such as TNF-? IL-1?, and others. In severe cases, the cytokine storm is responsible for the most obvious signs of a COVID-19 infection including fever, lung injury which causes cough and shortness of breath and the long-term complication, such as lung fibrosis and in death26,27.

It is theorized that melatonin may mitigate some the damage done by COVID-19 by stabilizing endothelial-dependent nitric oxide production to prevent multiple organ damage21, 22, 23, 24, 25,.

Quercetin

Quercetin a flavonoid polyphenol derived from plants, has a wide range of biological actions including anti-carcinogenic, anti-inflammatory and antiviral activities; as well as attenuating lipid peroxidation, platelet aggregation and capillary permeability28.

Role of Quercetin in COVID-19

  • Quercetin is an antioxidant that can protect against free radicals
  • Quercetin inhibits inflammatory enzymes cyclooxygenase (COX) and lipooxygenase thereby decreasing inflammatory mediators such as prostaglandins and leukotrienes
  • Quercetin inhibits the platelet aggregation and improves the health of the endothelium.
  • Flavonoids exert multiple beneficial effects on the vascular system leading to changes in cerebrovascular blood flow which are capable of changing neuronal morphology causing neurogenesis and angiogenesis.
  • Quercetin has potent anticarcinogenic properties and known to contribute as apoptosis inductor whereby it decreases the growth of tumor in and brain, liver, colon, and other tissues and inhibits the spread of malignant cells
  • Quercetin is known to exhibit antibacterial and antiviral effects by polymerases, proteases, reverse transcriptase, suppressing DNA gyrase, and binding viral capsid proteins.
  • Quercetin exerts anti-allergy effects by inhibiting the release of histamine from mast cells and other allergic substance thus acting as a natural antihistamine28,29,30,31.

Quercetin and COVID-19

In China, Traditional Chinese Medicine (TCM) was used to treat patients with COVID-19. The National Health and Commission of PRC has recommended some TCM in the guideline, such as HuoxiangZhengqi, LianhuaQingwen ShufengJiedu and XueBijing, and actually displayed a remarkable effect in clinical strategic for COVID-1932. These herbal combinations contained high levels of quercetin 32.

Quercetin dose with COVID-19 Prevention/Treatment

Oral supplementation with quercetin up to 1 g/day for 3 months has not resulted in significant adverse effects. Renal toxicty was reached when quercetin was administered intravenously at doses up to 51.3 mg/kg administered33.

IV Vitamin C in clinical trials of COVID-19

Due to the use of IV vitamin C for sepsis, the treatment was tried for COVID-19 patients 35,36. Septic patients receiving high dose intravenous vitamin C exhibit significant reduction in multiple organ injury and reduced inflammatory biomarker levels36. Vitamin C down-regulates pro-inflammatory genes that are driven by transcription factorNF-?B ,37.

IV vitamin C significantly increases alveolar fluid clearance in septic lung-injured animals38. Finally, infused vitamin C’s capability to down-regulate liberated reactive oxygen and nitrogen species appears to be critical for attenuating lung injury 38.

In trials in which the control groups were ventilated for 24?h or more, vitamin C shortened the duration of mechanical ventilation by 18% to 25%39.

Acute respiratory distress syndrome (ARDS) is a key factor of fatality. Significantly increased oxidative stress due to rapid release of free radicals and cytokines is the hallmark of ARDS which leads to cellular injury, organ failure and death.

References:

Glutathione

  1. Gaucher C, Boudier A, Bonetti J, Clarot I, Leroy P, Parent M. Glutathione: Antioxidant Properties Dedicated to Nanotechnologies. Antioxidants (Basel). 2018;7(5):62. Published 2018 Apr 27. doi:10.3390/antiox7050062
  2. Saadat M. An evidence for correlation between the glutathione S-transferase T1 (GSTT1) polymorphism and outcome of COVID-19. Clin Chim Acta. 2020;508:213-216. doi:10.1016/j.cca.2020.05.041
  3. Pizzorno J. Glutathione!. Integr Med (Encinitas). 2014;13(1):8-12.
  4. Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. 2020;6(7):1558-1562. doi:10.1021/acsinfecdis.0c00288
  5. Horowitz RI, Freeman PR. Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials [published online ahead of print, 2020 May 22]. Med Hypotheses. 2020;143:109851. doi:10.1016/j.mehy.2020.109851
  6. Horowitz RI, Freeman PR, Bruzzese J. Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases [published online ahead of print, 2020 Apr 21]. Respir Med Case Rep. 2020;30:101063. doi:10.1016/j.rmcr.2020.101063
  7. Poe FL, Corn J. N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2 [published online ahead of print, 2020 May 30]. Med Hypotheses. 2020;143:109862. doi:10.1016/j.mehy.2020.109862
  8. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0
  9. Sun L, Song F, Shi N, et al. Combination of four clinical indicators predicts the severe/critical symptom of patients infected COVID-19. J Clin Virol. 2020;128:104431. doi:10.1016/j.jcv.2020.104431
  10. Sies H, Parnham MJ. Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections [published online ahead of print, 2020 Jun 26]. Free Radic Biol Med. 2020;156:107-112. doi:10.1016/j.freeradbiomed.2020.06.032
  11. Saadat M. An evidence for correlation between the glutathione S-transferase T1 (GSTT1) polymorphism and outcome of COVID-19.Clin Chim Acta. 2020;508:213-216. doi:10.1016/j.cca.2020.05.041

Vitamin D

  1. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system.Curr Opin Pharmacol. 2010;10(4):482-496. doi:10.1016/j.coph.2010.04.001
  2. Meftahi GH, Jangravi Z, Sahraei H, Bahari Z. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging” [published online ahead of print, 2020 Jun 11]. Inflamm Res. 2020;1-15. doi:10.1007/s00011-020-01372-8
  3. Jolliffe, D.A.; Griffiths, C.J.; Martineau, A.R. Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies. Steroid Biochem. Mol. Biol. 2013, 136, 321–329.
  4. Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020;12(4):988. Published 2020 Apr 2. doi:10.3390/nu12040988
  5. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients. 2020;12(4):1181. Published 2020 Apr 23. doi:10.3390/nu12041181
  6. Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity [published online ahead of print, 2020 Jun 20]. J Infect Public Health. 2020;S1876-0341(20)30531-1. doi:10.1016/j.jiph.2020.06.021
  7. Fabbri A., Infante M., Ricordi C. Editorial-Vitamin D status: a key modulator of innate immunity and natural defense from acute viral respiratory infections.Eur Rev Med Pharmacol Sci. 2020;24:4038–4042
  8. Glicio EJ. Vitamin D level of mild and severe elderly cases of COVID-19: a preliminary report. Available at SSRN:https://ssrn.com/abstract=3593258; 2020.
  9. Tan C.W., Ho L.P., Kalimuddin S., Cherng B.P.Z., Teh Y.E., Thien S.Y. A cohort study to evaluate the effect of combination Vitamin D. Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients [preprint]Infect Dis (except HIV/AIDS) 2020 doi: 10.1101/2020.06.01.20112334.

Melatonin

  1. NaveenKumar SK, Hemshekhar M, Jagadish S, et al. Melatonin Restores Neutrophil Functions and Prevents Apoptosis amid Dysfunctional Glutathione Redox System [published online ahead of print, 2020 Jun 29]. J Pineal Res. 2020;e12676. doi:10.1111/jpi.12676
  2. García IG, Rodriguez-Rubio M, Mariblanca AR, et al. A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):466. Published 2020 Jun 3. doi:10.1186/s13063-020-04436-6
  3. Zhang R, Wang X, Ni L, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020;250:117583. doi:10.1016/j.lfs.2020.117583
  4. Anderson G, Reiter RJ. Melatonin: Roles in influenza, Covid-19, and other viral infections. Rev Med Virol. 2020;30(3):e2109. doi:10.1002/rmv.2109
  5. Loh, D. 2020. The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding. Melatonin Research. 3, 3 (Jun. 2020), 380-416. DOI:https://doi.org/https://doi.org/10.32794/mr11250069.
  6. Cardinali, D.P. 2020. High doses of melatonin as a potential therapeutic tool for the neurologic sequels of covid-19 infection. Melatonin Research. 3, 3 (Jun. 2020), 311-317. DOI:https://doi.org/https://doi.org/10.32794/mr11250064.
  7. Reiter, R.J., Sharma, R., Ma, Q., Liu, C., Manucha, W., Abreu-Gonzalez, P. and Dominguez-Rodriguez, A. 2020. Plasticity of glucose metabolism in activated immune cells: advantages for melatonin inhibition of COVID-19 disease. Melatonin Research. 3, 3 (Jun. 2020), 362-379. DOI:https://doi.org/https://doi.org/10.32794/mr11250068.

Quercetin

  1. Li Y, Yao J, Han C, et al. Quercetin, Inflammation and Immunity.Nutrients. 2016;8(3):167. Published 2016 Mar 15. doi:10.3390/nu8030167
  2. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol. 2020;11:1451. Published 2020 Jun 19. doi:10.3389/fimmu.2020.01451
  3. Yi L, Li Z, Yuan K, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78(20):11334-11339. doi:10.1128/JVI.78.20.11334-11339.2004
  4. Glinsky GV. Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells. Biomedicines. 2020;8(5):129. Published 2020 May 21. doi:10.3390/biomedicines8050129
  5. Tong T, Wu YQ, Ni WJ, Shen AZ, Liu S. The potential insights of Traditional Chinese Medicine on treatment of COVID-19. Chin Med. 2020;15:51. Published 2020 May 24. doi:10.1186/s13020-020-00326-w
  6. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties.Food Chem Toxicol. 2007;45(11):2179-2205.

Vitamin CCOVID-19 photo

  1. https://lpi.oregonstate.edu/COVID19/IV-VitaminC-virus
  2. Shanghai 2019 comprehensive treatment of coronavirus disease expert consensus: Expert Group on Clinical Treatment of New Coronary Virus Disease in Shanghai.China Journal of Infectious Diseases, 2020,38: Online Prepublish. DOI: 10.3760/cma.j.issn.1000-6680.2020.0016
  3. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Richard Z Cheng. https://doi.org/10.1016/j.medidd.2020.100028
  4. Three U.S. hospitals use IVs of Vitamin C and other low-cost, readily available drugs to cut the death-rate of COVID-19 — without ventilators! https://isom.ca/wp-content/uploads/2020/03/Treating-Covid-19-in-ER-2-March-30-1.pdf
  5. Hemilä, H., Chalker, E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. j intensive care8, 15 (2020). https://doi.org/10.1186/s40560-020-0432-y
  6. Boretti A, Banik BK. Intravenous Vitamin C for reduction of cytokines storm in Acute Respiratory Distress Syndrome [published online ahead of print, 2020 Apr 21]. PharmaNutrition. 2020;12:100190. doi:10.1016/j.phanu.2020.100190
  7. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China [published online ahead of print, 2020 Feb 7]. JAMA. 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585
  8. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?. Med Drug Discov. 2020;5:100028. doi:10.1016/j.medidd.2020.100028
  9. Fowler Iii AA, Kim C, Lepler L, et al. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med. 2017;6(1):85-90. Published 2017 Feb 4. doi:10.5492/wjccm.v6.i1.85
  10. Patel V, Dial K, Wu J, et al. Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1. Int J Mol Sci. 2020;21(3):977. Published 2020 Feb 1. doi:10.3390/ijms21030977
  11. Kashiouris, M.G.; L’Heureux, M.; Cable, C.A.; Fisher, B.J.; Leichtle, S.W.; Fowler, A.A. The Emerging Role of Vitamin C as a Treatment for Sepsis. Nutrients2020, 12, 292.
  12. https://cdn.ymaws.com/naturopathic.org/resource/resmgr/documents/covid19/clinical_resources/ivaa-covid19-hospital-anders.pdf

 

 

 

 

 

 

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