VITAMIN D AND MORE: THE FUNCTIONAL MEDICINE APPROACH TO Covid AND VIRUSES

This document discusses the mechanisms of action of a number of different botanical and nutraceutical agents. These agents can be considered as immunoadjuvants, defined as substances that act to accelerate, prolong, or enhance antigen-specific immune responses by potentiating or modulating the immune response.[1]

A coronavirus such as SARS-CoV-2 can be deadly because of its ability to stimulate a part of the innate immune response called the inflammasome, which can cause uncontrolled release of pro-inflammatory cytokines, leading to cytokine storm and severe, sometimes irreversible, damage to respiratory epithelium.[2] The SARS-CoV-2 virus has been shown to activate the NLRP3 inflammasome.[3,4] 

A 2016 review article[5] entitled “Natural compounds as regulators of NLRP3 inflammasome-mediated IL-beta production” notes that “resveratrol, curcumin, EGCG [epigallocatechin gallate], and quercetin are potent inhibitors of NLRP3 inflammasome-mediated IL-1beta production, typically acting at more than one element of the involved pathways. However, it should be noted that these polyphenols have an even much broader biological effect, as they influence a variety of pathways.” For example, these polyphenols modulate NF-kB upregulation, which is useful to counteract the COVID-19 ’hyper-inflammation.[6]

A preprint released on March 23, 2020, identified the ability of plant bioactive compounds to inhibit the COVID-19 main protease (Mpro),[7] which is necessary for viral replication. There is much excitement surrounding the recent identification of Mpro, and it is a current potential pharmaceutical drug target. Kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate were the natural compounds that appeared to have the best potential to act as COVID-19 Mpro inhibitors. Though further research is necessary to prove their efficacy, this study provides the biologic plausibility and mechanistic support (SARS-CoV-2 protease inhibition) to justify their use.

For these reasons, we recommend the following compounds, at standard dosages, to prevent activation of the NLRP3 inflammasome, to decrease NF-kB activation, and to potentially inhibit SARS-CoV-2 replication. There is no literature to support a regimen of a single vs. multiple agents. Our recommendation is to use higher dosing and/or multiple agents when patient contextual factors (e.g., patient desire, pre-existing inflammation, multiple co-morbidities, higher risk, etc.) and/or therapeutic decision-making warrant such use.

Recommended Interventions

QUERCETIN

Quercetin has been shown to have antiviral effects against both RNA (e.g., influenza and coronavirus) and DNA viruses (e.g., herpesvirus). Quercetin has a pleiotropic role as an antioxidant and anti-inflammatory, modulating signaling pathways that are associated with post-transcriptional modulators affecting post-viral healing.[8]

Mechanism(s) of action against non-COVID-19 viruses
Promote viral eradication or inactivation:[9],[10],[11],[12],[13]
•Inhibition of viral replication
Favorably modulate viral-induced pathological cellular processes:
Modulation of NLRP3 inflammasome activation[5],[14],[15]
Mechanistically promote resolution of collateral damage and restoration of function:
Modulation of mast cell stabilization (anti-fibrotic)

CURCUMIN

Curcumin has been shown to modulate the NLRP3 inflammasome,5 and a preprint suggests that curcumin can target the SARS-CoV-2 main protease to reduce viral replication.18

Mechanism(s) of action against non-COVID-19 viruses
Favorably modulate viral-induced pathological cellular processes:
Modulation of NLRP3 inflammasome activation[5],[19],[20],[21]

EPIGALLOCATECHIN GALLATE (EGCG)

Green tea, in addition to modulating the NLRP3 inflammasome and, based on a preprint, potentially targeting the SARS-CoV-2 main protease (Mpro)7 to reduce viral replication, has also been shown to prevent influenza in healthcare workers.28

Mechanism(s) of action against non-COVID-19 viruses
Favorably modulate viral-induced pathological cellular processes:
Modulation of NLRP3 inflammasome activation[5],[28],[29]

N-ACETYLCYSTEINE (NAC)

N-acetylcysteine promotes glutathione production, which has been shown to be protective in rodents infected with influenza. In a little-noticed six-month controlled clinical study enrolling 262 primarily elderly subjects, those receiving 600 mg NAC twice daily, as opposed to those receiving placebo, experienced significantly fewer influenza-like episodes and days of bed confinement.[36]
Mechanism(s) of action against non-COVID-19 viruses:[36]Favorably modulate cellular defense and repair mechanisms:
Hypothetical: repletion of glutathione and cysteine
Outcomes data supporting their mitigating effects on illness from other viral strains
Reduce progression from colonization to illness
Reduce the severity and duration of acute symptoms

RESVERATROL

Resveratrol, a naturally occurring polyphenol, shows many beneficial health effects. It has been shown to modulate the NLRP3 inflammasome.[5] In addition, resveratrol was shown to have in vitro activity against MERS-CoV.[43]

Mechanism(s) of action against non-COVID-19 viruses
Favorably modulate viral-induced pathological cellular processes
Modulation of NLRP3 inflammasome activation[5]
Outcomes data supporting their mitigating effects on illness from other viral strainsMERS-CoV[43]
Influenza[44],[45]

VITAMIN D

Activated vitamin D,1,25(OH) D, a steroid hormone, is an immune system modulator that reduces the expression of inflammatory cytokines and increases macrophage function. Vitamin D also stimulates the expression of potent antimicrobial peptides (AMPs), which exist in neutrophils, monocytes, natural killer cells, and epithelial cells of the respiratory tract.[54] Vitamin D increases anti-pathogen peptides through defensins and has a dual effect due to suppressing superinfection. Evidence suggests vitamin D supplementation may prevent upper respiratory infections.[55] However, there is some controversy as to whether it should be used and the laboratory value that should be achieved. Research suggests that concerns about vitamin D (increased IL-1beta in cell culture) are not seen clinically. The guidance we suggest is that a laboratory range of >50 and < 80ng/mL serum 25-hydroxy vitamin D may help to mitigate morbidity from COVID-19 infection.

Mechanism(s) of action against non-COVID-19 viruses[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78]

Favorably modulate cellular defense and repair mechanisms:
Activation of macrophages
Stimulation of anti-microbial peptides
Modulation of defensins
Modulation of TH17 cells
Favorably modulate viral-induced pathological cellular processes:
Reduction in cytokine expression
Modulation of TGF beta
Outcomes data supporting their mitigating effects on illness from other viral strains
Reduce progression from colonization to illness Reduce the severity and duration of acute symptoms and complications

VITAMIN A
Vitamin A is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. Vitamin A is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. Vitamin A is involved in the development of the immune system and plays regulatory roles in cellular immune responses and humoral immune processes through the modulation of T helper cells, sIgA, and cytokine production. Vitamin A has demonstrated a therapeutic effect in the treatment of various infectious diseases.[95]

Mechanism(s) of action against non-COVID-19 viruses [95],[96]Favorably modulate cellular defense and repair mechanisms:
Modulation of T helper cells
Modulation of sIgA
Favorably modulate viral-induced pathological cellular processes:
Modulation of cytokine production
Outcomes data supporting their mitigating effects on illness from other viral strainsNo data available

ELDERBERRY

Elderberry (Sambucus nigra) is seen in many medicinal preparations and has widespread historical use as an anti-viral herb.[103] Based on animal research, elderberry is likely most effective in the prevention of and early infection with respiratory viruses.[104] One in-vitro study reported an increase in TNF-alpha levels related to a specific commercial preparation of elderberry[105] leading some to caution that its use could initiate a “cytokine storm.” However, these data were not confirmed when the same group performed similar studies, which were published in 2002.[106] Therefore, these data suggest it is highly implausible that consumption of properly prepared elderberry products (from berries or flowers) would contribute to an adverse outcome related to overproduction of cytokines or lead to an adverse response in someone infected with COVID-19.

Mechanism(s) of action against non-COVID-19 viruses[103],[107],[108],[109],[110],[111],[112]
Favorably modulate cellular defense and repair mechanisms
Favorably modulate viral-induced pathological cellular processes
Outcomes data supporting their mitigating effects on illness from other viral strainsNo data available

PALMITOYLETHANOLAMIDE (PEA)

PEA is a naturally occurring anti-inflammatory palmitic acid derivative that interfaces with the endocannabinoid system. There was a significantly favorable outcome in five of six double blind placebo-controlled trials looking at acute respiratory disease due to influenza.[115] Dosing was generally 600 mg three times daily for up to three weeks. There are multiple mechanisms of action associated with PEA, from inhibition of TNF-alpha and NF-kB to mast cell stabilization. In influenza, it is thought that PEA works by attenuating the potentially fatal cytokine storm.

Mechanism(s) of action against non-COVID-19 viruses[115]
Favorably modulate cellular defense and repair mechanisms
Favorably modulate viral-induced pathological cellular processes

VITAMIN C

Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. Supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections.[120] Vitamin C has been used in hospital ICUs to treat COVID-19 infection.

Mechanism(s) of action against non-COVID-19 viruses [120]
Favorably modulate cellular defense and repair mechanisms
Favorably modulate viral-induced pathological cellular processes

ZINC
Zinc contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. There is also evidence that it suppresses viral attachment and replication. Zinc deficiency is common, especially in those populations most at risk for severe COVID-19 infections, and it is challenging to accurately diagnosis with laboratory measures. Supplementation with zinc is supported by evidence that it both prevents viral infections and reduces their severity and duration. Moreover, it has been shown to reduce the risk of lower respiratory infection, which may be of particular significance in the context of COVID-19.

Mechanism(s) of action against non-COVID-19 viruses120,121,122,123,124,125,126,127
​Favorably modulate innate and adaptive immune system
Favorably modulate viral-induced pathological cellular processes, attachment, and replication

www.ifm.org/news-insights/the-functional-medicine-approach-to-covid-19-virus-specific-nutraceutical-and-botanical-agents/

This resource is only intended to identify nutraceutical and botanical agents that may boost your immune system. It is not meant to recommend any treatments, nor have any of these been proven effective against COVID-19. None of these practices are intended to be used in lieu of other recommended treatments. Always consult your physician or healthcare provider prior to initiation. For up-to-date information on COVID-19, please consult the Centers for Disease Control and Prevention at www.cdc.gov.