Risk factors for severe COVID-19 symptoms include 65+ years of age, obesity, metabolic syndrome (i.e., diabetes, heart disease, stroke), and weakened immune systems (i.e., recovery from chemotherapy, HIV).1 Having previously considered SARS-CoV-2 viral entry and its ability to induce strong oxidation, inflammation, thrombotic events, and cellular damage, it is imperative to consider all interventions which support the immune system. As such, the following sections will explore the same in greater detail.

VITAMIN D3

In previous articles, I covered the effects of D3 and its relationship to rhinovirus (i.e., the common cold). D3 has immune-modulating effects and directs the activity of both the innate and adaptive immune systems.2 D3, when at optimal levels, supports mucosal defensives (i.e., surfaces of the nose and throat where SARS-CoV-2 enters) while dampening excessive inflammation; a defining hallmark of COVID-19.2(1) Considering that vitamin D deficiency is associated with increased risks of respiratory infections such as influenza, tuberculosis, such may also be likely for COVID-19.2(1) Marik et al2(1) indicated that in the United States, case fatality rates for COVID-19 tended to elevate with increasing latitude (less sun exposure). Furthermore, individuals with risk factors for COVID-19, stated in the introduction, also tended to have low vitamin D3 levels.3 Research cited an optimal dose as high as 4000 IU/day.3(1)

ZINC


Populations at risk of zinc deficiency include those with chronic diseases, to include populations outlined in the introductory section of this article.4 Zinc has been used and prescribed for other respiratory tract infections and is known to play a central role in immune function, wound healing, and gene expression.4(253) Specifically, in-vitro (cell) studies indicated that zinc can inhibit SARS-CoV-2  RNA polymerase; an enzyme critical for the production of “offspring” and infectivity (transmission to others).4(254) Furthermore, zinc also plays a role in anti-coagulation; COVID-19 has been known to induce thrombotic (blood clotting) events.4(254) As such, and due to the relative safety and accessibility of zinc, Arentz et al4(259) suggested it might be reasonable to prescribe the same, especially for populations with zinc deficiency and poorer outcomes from SARS-CoV2-2. Doses of up to 50 mg/day may be helpful while symptomatic.4(259)

VITAMIN C

Vitamin C is both an antioxidant and an anti-inflammatory.5 Generally, individuals who suffer from acute respiratory distress syndrome (ARDS) also have low levels of vitamin C.5(1) Furthermore, those experiencing COVID-19 also experienced ARDS.5(1) To confirm said tendency, Chiscano-Camon et al5(1) measured vitamin C levels in 18 patients (small sample size) hospitalized with COVID-19 and ARDS; 94.4% of patients had undetectable levels of vitamin C. Such might be due to increased metabolic use from the inflammatory cascade associated with COVID-19, decreased absorption, or decreased recycling of dehydroascorbate to ascorbic acid (usable form).5(1) Considering there is strong evidence that vitamin C can shorten the duration of respiratory infections in general, use of vitamin C during COVID-19 is plausible.6 Although 100 mg/day maintains ordinary levels of vitamin C, critically ill patients may require 2000-3000 mg/day to regain normal levels.6(2)

QUERCETIN

SARS-CoV-2 contributes to oxidative stress and inflammation of the host cell, upon entry.7 Such processes eventually trigger the immune system to generate excessive oxidative stress and deeper inflammation. Left uncontrolled, local and systemic tissue damage can occur, eventually leading to multiple organ collapse.7(3) Quercetin has been shown to control the expression of pro-inflammatory cell signalling molecules (cytokines) which can induce excessive/uncontrolled inflammation to include IL-1, IL-6, IL-18, TNF-alpha, iNOS, and PGE2.8(7) Quercetin also down regulates excessive activity of NLRP3; an inflammasome (proteins found on innate immune cells which trigger inflammation) residing in macrophages.8(7) Furthermore, quercetin may have a synergistic effect with vitamin C; quercetin can spontaneously oxidize, hampering its utility. Co-administration with vitamin C can help stabilize quercetin (vitamin C donates electrons to quercetin).9 Up to 600 mg/day of quercetin has been used in small studies exploring its use for managing COVID-19 symptoms.10

OMEGA-3 FATTY ACIDS

As mentioned previously, virulence (severity) of COVID-19 is driven by rapid and aggressive elevations in inflammatory cytokines (messengers) to include TNF-alpha, IL-1B, and IL-6.11 Interestingly, omega-3 fatty acids (O3FAS) are well-documented to modulate the inflammatory process, cytokine expression, as well as the resolution (ending) of inflammation.11(1) Furthermore, O3FAS are precursors to inflammation-resolving mediators (i.e., protectins, maresins, resolvins) directly involved in down-regulating inflammatory cytokines.11(1)

Such inflammatory resolution can be supported by a small pilot study, which demonstrated a correlation between COVID-19 deaths and O3FAS blood levels; individuals who had an omega-3 index (a way of measuring O3FAS levels) of 5.7% or higher has a 75% lower risk of death, compared to lower omega-3 indexes.11(3) Another double-blind, randomized clinical trial demonstrated that 600 mg of O3FAS/day for 14 days in the intervention group (all critically ill patients with COVID-19) improved respiratory function and renal function, when compared to the control group (no O3FAS).12 The researchers noted that higher doses of O3FAS could provide greater benefit, though their findings did suggest the beneficial influence of modest doses.12(7)

MELATONIN

Melatonin is most prominently known for its ability to support sleep. However, said substance has also demonstrated antiviral properties.13 Melatonin has the potential to reduce virulence (disease severity) and infectivity (replication/transmission) of COVID-19 through multiple pathways by modulating: viral entry, viral replication, oxidative, and inflammatory cascades.13(850) Melatonin can inhibit viral entry by down-regulating calmodulin synthesis, which regulates ACE-2 receptor expression; such is relevant since SARS-COV-2 interfaces with said receptors for host cell entry.14  If the virion does gain entry, melatonin can reduce the virus’ ability to replicate; a key step in its propagation and survival.13(853) Replication requires 3-chymotrypsin-like protease (an enzyme); melatonin has been shown to inhibit the effects of said enzyme, thereby interfering with replication.13(851),15

SARS-CoV-2 drives oxidative stress, ultimately damaging cells and tissues. Melatonin, according to Cardinali,16 is an antioxidant considered equal to or superior to other antioxidants, in part because of its ability to stimulate glutathione; the “master” antioxidant in the body.13(850)17 SARS-CoV-2 is also known to deplete tryptophan (precursor to melatonin) and suppress enzymes required to synthesize melatonin; events justifying support of melatonin supplementation.18,19Furthermore, melatonin suppresses angiotensin 2 pathways (pro-inflammatory) while up-regulating angiotensin 1 pathways (anti-inflammatory).13(852) For more information on receptor pathways, please see my article below. Finally, research has suggested up to 10 mg of melatonin at night during SARS-CoV-2 infection.13(853)

LINK: Understanding SARS-CoV-2

BLACK CUMIN SEED OIL

Black cumin seed (BCS), formally known as Nigella sativa, is a well-known supplement and medicinal plant that has been used in multiple cultures for centuries.20 Interestingly, BCS possesses analgesic (pain relief), antipyretic (fever reducing), antitussive (cough reducing), antihistaminic, bronchodilatory (improves breathing), anticoagulant, anti-inflammatory, antioxidant, and antiviral properties; all of which have been supported by randomized controlled trials, pilot studies, in vitro/vivo studies and case reports.21  Eight in silico (molecular docking) studies, according to Koshak et al.,20(2) indicated that a compound of BCS (thymoquinone) had a strong binding affinity to ACE-2 receptors, while another compound of BCS (Nigelledine) tended to complex with proteases (necessary for viral replication) of SARS-CoV-2.20(2) As an aggregate, studies suggested that BCS compounds could inhibit viral entry and replication, respectively.

Preprint research by Ashraf et al.22 implemented a multicenter, placebo-controlled, randomized clinical trial enrolling 313 participants with COVID-19 (210 with moderate, 103 severe). 107 moderate subjects were assigned to the experimental group (using BCS oil at 80 mg/kg/day and honey at 1000 mg/kg/day) while 103 moderate participants were assigned to the placebo group.22(8) 50 severe cases were also assigned to the experimental group while 53 severe cases were assigned to the placebo group.22(8) Results indicated that the experimental group experienced a 50% reduction (moderate and severe group) in time taken to alleviate symptoms compared to the placebo group (moderate and severe).22(8) Furthermore, the experimental group (moderate and severe) cleared the virus 4 days earlier when compared to the placebo group (moderate and severe).22(8) Dosing of 500 mg of BCS oil twice daily has been used in other studies treating COVID-19 participants, as well as clinical trials on asthmatic patients.23

CURCUMIN

Curcumin, also known as diferuloylmethane, is the primary polyphenol residing in the rhizome of Curcuma longa (turmeric).24 Its medicinal benefits have been known for thousands of years to include modern day uses which address pain, metabolic syndrome, and inflammatory conditions.24(1) Curcumin has recently gained attention as a viable intervention to address multiple stages of SARS-CoV-2 viral pathophysiology to include viral entry, replication, inflammation, shedding, and thrombosis.25 Clinical studies using curcumin on mild and severe COVID-19 patients, when compared to placebo groups, noted significant reductions in fever, cough, dyspnea, and mortality rates.26 In silico studies have shown curcumin to have a high binding affinity to the spike protein as well as ACE-2 receptors; even greater than that of hydroxychloroquine25(3) Such suggests a possible mechanism for inhibiting viral entry into host cells.

If virions successfully gain access into host cells, in silico studies have also suggested that curcumin has a high binding affinity (which blocks activity) to the main protease (MPRO); an enzyme considered critical for viral replication, and release.26(4) SARS-CoV-2 also requires host cells to increase in acidity as part of its replication process, similar to cancer cells. Rattis et al25(4) noted that curcumin blocks the expression of V-ATPase; an enzyme/pump necessary to increase cell acidity in tumor cells. Such suggests utility in addressing SARS-CoV-2 virions and their requirement for acidic environments.

Curcumin controls excessive inflammation from COVID-19; a hallmark, and driver of organ failure and death, otherwise known as the cytokine storm.25(5) Clinical studies suggested high levels of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-18) and inflammatory mediators (NF-kB) in COVID-19 patients.25(5) However, treatment with curcumin indicated significant reductions in IL-1β, IL-6, and NF-kB thereby reducing inflammation and cell death.25(5) Finally, curcumin helps reduce thrombotic (blood clotting) events by inhibiting thrombin (an enzyme necessary in the formation of clots) and FXa (an enzyme which facilitates production of thrombin). Dosing of 500 mg of curcumin twice daily have been used in studies managing inflammatory and thrombolytic cascades.27 However, adding 2.5 mg of black pepper (piperine) to curcumin improved absorption significantly.27(2)

SUMMARY OF SUPPLEMENTS

  • Vitamin D3
  • Zinc
  • Vitamin C
  • Quercetin
  • Omega-3
  • Melatonin
  • Black Cumin Seed Oil
  • Curcumin (with pepper)

POSSIBLE SUPPLEMENT REGIMEN (BASED ON ABOVE FINDINGS)

6 AM:
500-1000 mg omega-3 fatty acids
4000 IU D3
500 mg curcumin + black pepper
*Oral and nasal cleanse*

12 PM
250 mg quercetin
25 mg zinc
1000 mg vitamin C
500 mg black cumin seed oil
*Oral and nasal cleanse*

6 PM
250 mg quercetin
25 mg zinc
1000 mg vitamin C
500 mg black cumin seed oil
*Oral and nasal cleanse*

10 PM
Up to 10 mg melatonin
500 mg curcumin + black pepper
*Oral and nasal cleanse*

*Though oral/nasal cleanses are not micronutrient interventions, evidence does support their utility for inactivating SARS-CoV-2 virions at point of entry, thereby reducing viral titers within the body. Please see the below link for greater detail on said cleanses:

LINK: Oral and Nasal Cleanses, SARS-CoV-2, and Early Interventions

In conclusion, risk factors for severe COVID-19 symptoms include 65+ years of age, obesity, metabolic syndrome, and weakened immune systems. Having previously considered SARS-CoV-2 viral entry and its ability to induce strong oxidation, inflammation, thrombotic events, and cellular damage, it is imperative to explore all interventions which support the immune system against such a disease. It is possible that implementation of the above micronutrients could serve as a complementary intervention in managing COVID-19; a discussion that I encourage between individuals and their family physicians, beforehand.

References

1. COVID-19: Who’s at Higher Risk of Serious Symptoms? Mayo Clinic. Updated October 30, 2021. Accessed October 31, 2021. https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-who-is-at-risk/art-20483301.
2. Marik PE, Kory P, Varon J. Does vitamin D status impact mortality from SARS-CoV-2. Med Drug Discov. 2020;6:1-3. doi:https://doi.org/10.1016/j.medidd.2020.100041.
3. Hernandez JL, Nan D, Fernandez-Ayala M, et al. Vitamin D status in hospitalized patients with SARS-CoV-2 infection. J Clin Endocrinol Metab. 2021;106(3):e1343-e1353. doi: 10.1210/clinem/dgaa733.
4. Arentz S, Hunter J, Yang G, et al. Zinc for the prevention and treatment of SARS-CoV-2 and other acute respiratory infections: A rapid review. Adv Integr Med. 2020; 7(4): 252-260. doi: 10.1016/j.aimed.2020.07.009.
5. Chiscano-Camon L, Ruiz-Rodriguez JC, Ruiz-Sanmartin A, et al. Vitamin C levels in patients with SARS-CoV-2 associated acute respiratory distress syndrome. Crit Care. 2020;24(1):1-3. doi: https://doi.org/10.1186/s13054-020-03249-y.
6. Hemila H, Carr A, Chalker E. Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2 infection by 70%: Reanalysis of the COVID A to Z randomized clinical trial. Front Immunol. 2021;12:1-4. doi:10.3389/fimmu.2021.674681.
7. Cecchini R, Cecchini AL. SARS-Cov-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypothesis. 2020;143:1-6. doi:10.1016/j.mehy.2020.110102.
8. Saeedi-Boroujrni A, Mahmoudian-Sani MR. Anti-inflammatory potential of quercetin in COVID-19 treatment. J Inflamm. 2021;18(3):1-9. doi: https://doi.org/10.1186/s12950-021-00268-6.
9. Biancatelli R, Berrill M, Catravas JD, et al. Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol. 2020:1-11. doi:10.3389/fimmu.2020.01451.
10. Pierro FD, Iqtadar S, Khan A, et al. Potential benefits of quercetin in the early stage if COVID-19: Results of a second, pilot, controlled and open label clinical trial. Int J Gen Med. 2021;14:2807-2816. doi:10.2147/IJGM.S318949.
11. Asher A, Tintle NL, Myers M, et al. Blood omega-3 fatty acids and death from COVID-19: A pilot study. PLEFA. 2021;166:1-5. doi:https://doi.org/10.1016/j.plefa.2021.102250.
12. Doaei S, Gholami S, Rastgoo S, et al. The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: A randomized clinical trial. J Transl Med. 2021;19(1):1-9. doi:10.1186/s12967-021-02795-5.
13. Cross KM, Landis DM, Sehgal L, et al. Melatonin for the early treatment of COVID-19: A narritive review of current evidence and possible efficacy. Endocr Pract. 2021;27(8):850-855. doi:10.1016/j.eprac.2021.06.001.
14. Cardinali DP. High doses of melatonin as a potential therapeutic tool for the neurologic sequels of covid-19 infection. Melatonin Res. 2020;3:311-317. doi: https://doi.org/10.32794/mr11250064.
15. Gyebi GA, Ogunro OB, Adegunloye AP, et al. Potential inhibitors of coronavirus 3-chymotrypsin-like proteoase (3CLpro): an in silico screening of alkaloids and terpenoids from African medicinal plants. J Biomol Struct Dyn. 2021;39(9):1-13. doi: 10.1080/07391102.2020.1764868.
16. Cardinali DP. High doses of melatonin as a potential therapeutic tool for the neurologic sequels of covid-19 infection. Melatonin Res. 2020;3(2020):311-317. doi:10.32794/11250064.
17. Bains VK, Bains R. The antioxidant master glutathione and periodontal health. Dent Res J. 2015;12(5):389-405. doi:10.4103/1735-3327.166169.
18. Tan DX, Hardeland R. Targeting host defense system and rescuing compromised mitochondria to increase tolerance against pathogens by melatonin may impact outcome of deadly virus infection pertinent to COVID-19. Molecules. 2020;25(19):1-26. doi: https://doi.org/10.3390/molecules25194410.
19. Eroglu IE, Eroglu BC, Guven GS. Altered tryprophan absorption and metabolism could underlie long-term symptoms in survivors of coronavirus disease 2019 (COVID-19). Nutrition. 2021; 90:1-3. doi:10.1016/j.nut.2021.111308.
20. Koshak AE, Koshak EA. Nigela sativa L as a potential phytotherapy for coronavirus disease 2019: A mini review of in silico studies. Curr Res Ther Clin Exp. 2020;93:1-3. doi: 10.1016/j.curtheres.2020.100602.
21. Maideen NMP. Prophetic medicine-Nigella sativa (black cumin seeds)-potential herb for covid-19? J Pharmacopuncture. 2020; 23(2):62-70. doi:10.3831/KPI.2020.23.010.
22. Ashraf S, Ashraf S, Ashraf M, et al. Honey and Nigella sativa against COVID-19 in Pakistan (HNS-COVID-PK): A multi-center placebo-controlled randomized clinical trial. MedRxiv. Preprint posted online November 30, 2020. doi:https://doi.org/10.1101/2020.10.30.20217364.
23. Koshak AE, Koshak EA, Mobeireek AF, et al. Nigella sativa for the treatment of COVID-19: An open-label randomized controlled trial. Compliment Ther Med. 2021;61:1-6. doi:10.1016/j.ctim.2021.102769.
24. Hewlings SJ, Kalman DS. Curcumin; A review of its effects on human health. Foods. 2017;6(10):1-11. doi:10.3390/foods6100092.
25. Rattis BAC, Ramos SG, Seles MRN. Curcumin as a potential treatment for COVID-19. Front Pharmacol. 2021;12:1-14. doi:10.3389/fphar.2021.675287.
26. Tahmasebi , El-Esaw MA., Mahmoud ZH et al. Immunomodulatory effects of nanocurcumin on Th17 cell responses in mild and severe COVID-19 patients. J. Cell Physiol. 2020;236(7):5325–5338. doi:10.1002/jcp.30233.
27. Pawar KS, Matstud RN, Pawar AK, et al. COVID-19: A randomized clinical trial. Front Pharmacol. 2021;12:1-7. doi:10.3389/fphar.2021.669362.

 

-Michael McIsaac