COVID | Anti-Viral Glossary

"As we know, new research and data about SarsCoV-2 and COVID-19 is coming out daily. It's important to get information from trusted sources.

The Institute for Functional Medicine (IFM) has put together a 'COVID Task Team' of top doctors to track and comment on existing and new research.

The intention is to give accurate recommendations about ways you can strengthen your immune system and, hopefully, lessen symptom intensity and duration if you are exposed to the virus.

The information below is copied directly from the IFM's site. 

I will keep updating this page as the IFM releases new info so that you can stay abreast of new developments.

The info below if aimed at healthcare practitioners but I have included it on my site because I believe informed, educated patients can make the best decisions about their health.

If it all seems a little complicated, just download the Immune Checklist | Expanded here.

Please email me know if you have any questions." Dr Heidi

liveheidi@liveheidi.com

Download COVID-19: Nutraceutical and Botanical Recommendations for Patients

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Virus-Specific Nutraceutical and Botanical Agents

Background and Introduction

Health professionals and the public must be well informed about the COVID-19 virus, the disease it causes, and how it spreads. This information is readily available and not within the scope of this document.

At this time, there are no specific vaccines or uniformly successful treatments for COVID-19. In this context of insufficient evidence, the scope of this document will be to assess the scientific plausibility of promising prevention approaches and therapeutic (nutraceutical and botanical) interventions and then to offer clinical recommendations.

With respect to interventions, the practice of Functional Medicine emphasizes the primacy of safety, validity, and effectiveness. In the novel context of COVID-19, validity in the form of published evidence is lacking. Therefore, “validity” relies upon inferences from the mechanisms of action of individual agents and/or published outcomes data supporting their mitigating effects on illness from other viral strains.

Likewise, data for the “effectiveness” of interventions targeting the viral mechanisms of COVID-19 are nascent and rapidly emerging. In this context, the following recommendations represent the Functional Medicine approach to the COVID-19 crisis:

  • Adherence to all health recommendations from official sources to decrease viral transmission.
  • Optimizing modifiable lifestyle factors in order to improve overall immune function: 
    • Reduces progression from colonization to illness.
    • *Take a look at this list of things that you can do every day to ‘Strengthen Immunity’*
  • Personalized consideration of therapeutic agents that may:
    • Favorably modulate cellular defense and repair mechanisms.
    • Favorably modulate viral-induced pathological cellular processes.
    • Promote viral eradication or inactivation.
    • Mitigate collateral damage from other therapeutic agents.
    • Promote resolution of collateral damage and restoration of function.
  • Treatment of confirmed COVID-19 illness (as per conventional standards and practice):
    • May reduce the severity and duration of acute symptoms and complications.
    • May support recovery and reduce long-term morbidity and sequelae.
Note: Additional references are being collated continuously and will be made available in the near future.

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Clinical Recommendations and Mechanisms of Action

BACKGROUND AND MECHANISMS OF ACTION

We encourage practitioners to learn about the mechanism of invasion, replication, and pathophysiology of the COVID-19 virus. Much of what we know has been extrapolated from basic science research on SARS-CoV-2. Excellent resources are available online, including the free YouTube lectures through Dr. Roger Seheult: 

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 (COVID-19 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 COVID-19 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.

In the recommendations below, the following criteria are used to identify strength of evidence and risk of harm.

Evaluative Criteria

In the recommendations above, the following criteria are used to identify strength of evidence and risk of harm.

*Slide table from right to left to see all the info*

STRENGHT OF EVIDENCE
Conditional: Clinical experience and/or expert opinion and/or conflicting studies; biological mechanism at least partly explained.
Limited: One study showing correlation between intervention and outcome; compelling ATMs and/or PCFs; biological mechanism at least partly explained.
Moderate: Two independent studies (one of which is LOE = 1 or 2) showing correlation between intervention and outcome; biological mechanism at least partly explained.
Strong: Two independent studies (both LOE = 1 or 2) showing correlation between intervention and outcome; biological mechanism fully explained or partly explained and having one additional correlative study.
RISK OF HARM
Mild: Risk of self-limited symptoms; no risk of loss of function or corrective intervention anticipated; observation only.
Moderate: Risk of symptoms; no risk of loss of function or quality of life; minor evaluative and/or therapeutic intervention needed.
Significant: Risk of temporary loss of function or quality of life; significant evaluative and/or therapeutic intervention needed.
Severe: Risk of permanent symptoms, loss of function, quality of life, or death; long-term evaluative and/or therapeutic intervention needed.

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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]

*Slide table from right to left to see all the info*

Intervention Quercetin
Suggested dose Regular: 1 gm orally twice per day; phytosome 500 mg twice per day.
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)

 
Outcomes data supporting their mitigating Reduction of symptoms
Strength of evidence Moderate
Risk of harm:[16],[17] Mild

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CURCUMIN

Curcumin has been shown to modulate the NLRP3 inflammasome,[5] and a preprint suggests that curcumin can target the COVID-19 main protease to reduce viral replication.[18]

*Slide table from right to left to see all the info*

Intervention Curcumin
Suggested dose 500-1,000 mg orally twice per day (of absorption-enhanced curcumin)
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]
Outcomes data supporting their mitigating effects on illness from other viral strains No data available No data available
Strength of evidence Conditional
Risk of harm:[22],[23],[24],[25],[26],[27] Mild

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EPIGALLOCATECHIN GALLATE (EGCG)

Green tea, in addition to modulating the NLRP3 inflammasome and, based on a preprint, potentially targeting the COVID-19 main protease (Mpro)[31] to reduce viral replication, has also been shown to prevent influenza in healthcare workers.[28]

*Slide table from right to left to see all the info*

Intervention Epigallocatechin gallate (EGCG)
Suggested dose 4 cups daily or 225 mg orally daily
Mechanism(s) of action against non-COVID-19 viruses Favorably modulate viral-induced pathological cellular processes:
•Modulation of NLRP3 inflammasome activation[5],[28],[29]
Outcomes data supporting their mitigating effects on illness from other viral strains No data available
Strength of evidence Conditional
Risk of harm:[30],[31],[32],[33],[34],[35] Significant (rare) - Hepatotoxicity

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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]

*Slide table from right to left to see all the info*

Intervention N-acetylcysteine (NAC)
Suggested dose 600-900 mg orally twice per day
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
Strength of evidence Limited
Risk of harm:[37],[38],[39],[40],[41] Mild

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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]

*Slide table from right to left to see all the info*

Intervention Resveratrol
Suggested dose 100-150 mg orally daily
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 strains MERS-CoV[43]
Influenza[44],[45]
Strength of evidence Conditional
Risk of harm:[46],[47],[48],[49],[50],[51],[52],[53] Mild

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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.

*Slide table from right to left to see all the info*

Intervention Vitamin D
Suggested dose 5,000 IU orally daily in the absence of serum levels
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
Strength of evidence Limited
Risk of harm:[79],[80],[81],[82] Mild

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MELATONIN

Melatonin has been shown to have an inhibitory effect on the NLRP3 inflammasome.[94] This has not gone unnoticed by the COVID-19 research community, with two recent published papers proposing the use of melatonin as a therapeutic agent in the treatment of patients with COVID-19.[84],[85]

*Slide table from right to left to see all the info*

Intervention Melatonin
Suggested dose 5-20 mg before bed
Mechanism(s) of action against non-COVID-19 viruses .[83],[84] Favorably modulate viral-induced pathological cellular processes
• Modulation of NLRP3 inflammasome activation .[83],[84]
Outcomes data supporting their mitigating effects on illness from other viral strains Research in progress
Strength of evidence Conditional
Risk of harm:[86],[87],[88],[89],[90],[91],[92],[93],[94] Mild

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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] 

*Slide table from right to left to see all the info*

Intervention Vitamin A
Suggested dose Up to 10,000-25,000 IU per day
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 strains No data available
Strength of evidence Conditional
Risk of harm:[97],[98],[99],[100],[101],[102] Mild if does not exceed this dose; caution: pregnancy

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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.

*Slide table from right to left to see all the info*

Intervention Elderberry
Suggested Dose 500 mg orally daily (of USP standard of 17% anthocyanosides)
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 strains No data available
Strength of evidence Strong
Risk of harm:[103],[107],[113],[114] Mild; caution w/autoimmune disease; uncooked/unripe plant parts toxic; USDA GRAS

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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.

*Slide table from right to left to see all the info*

Intervention Palmitoylethanolamide (PEA)
Suggested dose 300 mg orally twice per day to prevent infection, 600 mg orally twice per day for two weeks to treat infection
 Mechanism(s) of action against non-COVID-19 viruses[115] 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 strains No data available
Strength of evidence Conditional (treatment) Strong (prevention)
Risk of harm:[116],[117],[118],[119] Mild

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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. 

*Slide table from right to left to see all the info*

Intervention Vitamin C
Suggested dose 1-3 grams orally daily
Mechanism(s) of action against non-COVID-19 viruses[120] 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 strains No data available
Strength of evidence Strong
Risk of harm[121] Mild

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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.

*Slide table from right to left to see all the info*

Intervention Zinc
Suggested dose 30–60 mg daily, in divided doses throughout the day.
Zinc acetate, citrate, picolinate, or glycinate orally
Zinc gluconate as lozenge
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
Outcomes data supporting their mitigating effects on illness from other viral strains Prevention, reduced severity of symptoms, reduced duration of illness, prevention of lower respiratory tract infection
Strength of evidence Strong
Risk of harm Mild

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BETA GLUCANS

Beta glucans are known to modulate immune activity, mostly by priming or training innate immune responses through interactions with pattern recognition receptors (PRRs)1,2 and by increasing anti-inflammatory cytokines such as IL-10.3,4,5,6,7 Beta glucans induce activity against viral attack.8,9 Numerous human trials have shown that beta glucans decrease cold and flu symptoms10,11,12 and upper respiratory tract infections compared to placebo.13,14,15,16,17,18,19

Intervention Beta glucans
Suggested dose 250-500 mg daily
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function20 Promoting viral eradication or inactivation8,9
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms 10,11,12,13,14,15,16,17,18,19
Strength of evidence Strong
Risk of harm Mild

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MUSHROOMS

Various mushrooms species have been shown to possess broad immunomodulatory effects. They possess multiple mechanisms of action, including increasing the number of circulating B cells,21 increasing gut immunity,22 stimulating host immunity,23 activating innate immune cells,24 and increasing cytotoxic activity of NK cells.25

Intervention Various medicinal mushrooms, including Shiitake (Lentinula edodes), Lion’s Mane (Hericium erinaceus), Maitake (Grifola frondosa), Reishi (Ganoderma lucidum)
Suggested dose Varied.
Given the variety of active ingredients in mushrooms and the variability of the extraction processes, it is suggested that dosing instructions should be individualized based on research of specific mushroom genus and species.
Mechanism(s) of action against non-COVID-19 viruses Promoting viral eradication or inactivation26,27
Modulation of innate immune response28,29
Outcomes data supporting their mitigating effects on illness from other viral strains Inconclusive, due to variety of species and combinations. Consult knowledgeable healthcare provider.
Strength of evidence Limited
Risk of harm Inconclusive, due to variety of species and combinations.

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CHINESE SKULLCAP (SCUTELLARIA BAICALENSIS)

Chinese skullcap (Scutellaria baicalensis) has been used for centuries in Traditional Chinese Medicine (TCM). In various human trials, participants who took TCM formulations containing Chinese skullcap showed statistically significant decreases in viral infection rates compared to controls.30 Chinese skullcap has anti-inflammatory, antioxidant, antibacterial, and antiviral effects.31,32,33 It has been shown to increase immune surveillance and downregulate NLRP3 inflammasomes,34 IL-6, and TNF-alpha.35

Intervention Chinese skullcap (Scutellaria baicalensis)
Suggested dose 750–1,500 mg daily standardized to flavonoids, baicalin, or baicalein.
Given the variability of standardization, it is suggested that dosing instructions should be based on research of specific standardized extracts.
Mechanism(s) of action against non-COVID-19 viruses Priming innate immune function36,41,42
Promoting viral eradication or inactivation36-41
Favorably modulating pulmonary inflammation38,41,43,44,45,46,47,48
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms49
Strength of evidence Limited
Risk of harm Mild, though combination product showed significant hepatotoxicity.50,51,52,53,54

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LICORICE (GLYCYRRHIZA SPECIES)

Licorice (Glycyrrhiza species) has multiple mechanisms of action, including inhibition of viral replication55,56,57 blocking the ACE2 receptor,58 promoting the activity of Th1 cells,59 and inhibition of pro-inflammatory cytokines,60prostaglandins, and nitric oxide production.61 The inhibition of hydrocortisone metabolism by 11 beta-HSD has also been suggested as a potential mechanism of licorice’s anti-inflammatory action.62 Licorice has been use in traditional Chinese medicine (TCM) formulations against SARS-CoV-1 and H1N1 and reviewed for its effects on SARS-CoV-2.63,64 Two positive human trials have been performed against SARS-CoV-1 using a TCM formulation containing licorice.65,66

Intervention Licorice (Glycyrrhiza glabra)
Suggested dose Licorice root standardized to glycyrrhizin. 200-400 mg daily in divided doses. Short term use: <4 weeks.
Mechanism(s) of action against non-COVID-19 viruses Promoting viral eradication or inactivation55,56,57,63,64,67,68
Favorably modulating inflammation
Outcomes data supporting their mitigating effects on illness from other viral strains Reduction of symptoms69,70
Strength of evidence Moderate
Risk of harm71, 72, 73, 74 Minimal, if short-term use (< 4 weeks)

 

*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.

SPECIAL THANKS TO

Joel Evans, MD (Lead), Robert Rountree, MD, Tom Guilliams, PhD, Michael Stone, MD, Robert Luby, MD, Patrick Hanaway, MD, Kirsten Ramsdell, MS, CN, Sam Yanuck, DC, Helen Messier, MD, and Dan Lukaczer, ND,

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REFERENCES

Quercetin -> Zinc

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  24. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med. 2003;9(1):161-168. doi:10.1089/107555303321223035
  25. Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical use of curcumin in depression: a meta-analysis. J Am Med Dir Assoc. 2017;18(6):503-508. doi:10.1016/j.jamda.2016.12.071
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Beta Glucans -> Licorice 

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