Part One of this article touched on the available research done on the role of the immune system in fighting off coronavirus, an factor that has gone largely unexplored during the crisis.

There have been enough articles on natural herbs and supplements to boost immune function, some excellent and some questionable, and I have little intention of adding another article to this growing list. Instead, I would like to start building a picture for those who have already consumed these articles and find themselves asking the same question: with all these immune boosting supplements out there, which one(s) should I take?

This starts with identifying differences in the mechanisms provided, then considering which ones may be most needed or more beneficial in your own personal circumstances. Let’s begin with the six items I have received most questions on:

ZINC

MECHANISMS

Mechanisms identified: inhibition of viral entry into cells and viral replication; enhancing function of macrophages and enhancing Th1 cytokines

EVIDENCE

1984 study gave subjects 23mg of zinc gluconate (lozenge) and tracked them for six months, finding a 45% drop in infections. Similar studies in Western populations are less impressive.

ANTIGEN PRESENTING CELLS (MACROPHAGES & DENDRITIC CELLS)
Zinc increases number of macrophages, increases phagocytic (disposal) activity and contributes to healthy cytokine signalling (ref). Zinc regulates over-active Th17 response in dendritic cells (ref)
PROLIFERATION OF T HELPER (CD4+) AND CYTOTOXIC (CD8+) CELLS
High-dose zinc supplementation increased production of CD4+ cells (ref), and in vitro studies indicate a moderate increase in CD8+ cells with a strong increase in CD4+ (ref)
TH1 ACTIVITY (vs TH2 OR TH17 BRANCHES)
Zinc required for robust Th1 response (ref)
IMMUNOGLOBULIN PRODUCTION
Zinc has mixed or no effects on antibody production (ref, ref)
IFN-y AND IL-21 PRODUCTION
Zinc important for production of interferon (ref) and enhances activity of interferon (ref)
ENDOPLASMIC RETICULUM FUNCTION
Zinc important for normal ER function (ref) and protects against ER stress (ref)

VITAMIN D

EVIDENCE

  • 2018 study showed ‘drastically reduced’ rate of respiratory infections for those supplemented with Vitamin D vs controls (86 adults, 1000iu); A meta-analysis concluded 70% reduction in infections through correcting infections
ANTIGEN PRESENTING CELLS (MACROPHAGES & DENDRITIC CELLS)
Vitamin D regulates macrophage function (ref) and but can discourage formation and inflammatory activity of dendritic cells (ref)
PROLIFERATION OF T HELPER (CD4+) AND CYTOTOXIC (CD8+) CELLS
Vitamin D may discourage proliferation of CD4+ (ref) and CD8+ cells (ref)
TH1 ACTIVITY (vs TH2 OR TH17 BRANCHES)
High doses may suppress Th1 cytokines at baseline but permits Th1 activity in disease (ref), while correcting deficiency does not appear to impact Th1 (ref)
IMMUNOGLOBULIN PRODUCTION
Vitamin D may discourage antibody production after vaccines (ref) but not during infection (ref)
IFN-y AND IL-21 PRODUCTION
Vitamin D may discourage release of IFN-y (ref) but, again, IFN-y permitted in disease (ref)
ENDOPLASMIC RETICULUM FUNCTION
Vitamin D protects against oxidative stress and endoplasmic reticulum stress (ref)

VITAMIN C

MECHANISMS

enhances Interferon production and overall Th1 response in early stage of infections; supports immunity via modulation of the stress response

EVIDENCE

Swiss study in 1961 showed that 1g Vitamin C per day reduced respiratory infections by 20%; a similar study over six months showed a 30% drop

ANTIGEN PRESENTING CELLS (MACROPHAGES & DENDRITIC CELLS)
Activated macrophages need more Vitamin C (ref) and supplementation boosts antimicrobial effect (ref). Vitamin C can enhance rate of antigen presentation in dendritic cells (ref)
PROLIFERATION OF T HELPER (CD4+) AND CYTOTOXIC (CD8+) CELLS
Vitamin C important for T cell population (ref) and may support optimal activity of CD8+ cells (ref)
TH1 ACTIVITY (vs TH2 OR TH17 BRANCHES)
Vitamin C encourages production of Th1 cytokines (ref)
IMMUNOGLOBULIN PRODUCTION
Vitamin C boosts IgM production in animal models (ref)
IFN-y AND IL-21 PRODUCTION
Vitamin C can boost interferon in some cell lines (ref) and in animal models (ref)
ENDOPLASMIC RETICULUM FUNCTION
Vitamin C protects against endoplasmic reticulum stress (ref)

IODINE

MECHANISMS

‘robustly’ supports lactoperoxidase and H202 activity that oxidizes viruses in saliva, tears and breastmilk

EVIDENCE

hardly studied in recent decades but a 1945 trial demonstrated a protective effect from an influenza mist in mice – minimal human trials on resistance to infection

ANTIGEN PRESENTING CELLS (MACROPHAGES & DENDRITIC CELLS)
No research
PROLIFERATION OF T HELPER (CD4+) AND CYTOTOXIC (CD8+) CELLS
No research
TH1 ACTIVITY (vs TH2 OR TH17 BRANCHES)
High-dose iodine may enhance Th1 activity (ref)
IMMUNOGLOBULIN PRODUCTION
Iodine can enhance IgG production (ref)
IFN-y AND IL-21 PRODUCTION
High-dose iodine may enhance IFN-y levels (ref)
ENDOPLASMIC RETICULUM FUNCTION
Not studied in humans but excess iodine may cause endoplasmic reticulum stress (ref)

GARLIC

MECHANISMS

ajoene (metabolite of allicin) blocks viral attachment; also supports antioxidant status and cardiovascular health

EVIDENCE

2012 review noted that Garlic supplementation reduces incidences of the common cold by 63% (146 people, 12 weeks observation, 180mg allicin content)

ANTIGEN PRESENTING CELLS (MACROPHAGES & DENDRITIC CELLS)
Garlic enhances activity of macrophages and dendritic cells (ref)
PROLIFERATION OF T HELPER (CD4+) AND CYTOTOXIC (CD8+) CELLS
Garlic may reduce production of CD4+ and CD8+ cells (ref)
TH1 ACTIVITY (vs TH2 OR TH17 BRANCHES)
Garlic can induce increased Th1 activity (ref) but may induce more Th2 activity at very high doses (ref)
IMMUNOGLOBULIN PRODUCTION
Garlic enhances antibody production (ref)
IFN-y AND IL-21 PRODUCTION
Garlic induces a large increase in interferons production in both in vitro and human trials (ref, ref)
ENDOPLASMIC RETICULUM FUNCTION
Garlic shown to induce ER stress in cancer cells (ref) but have a modulatory effect in healthy cells (ref)

ELDERBERRY

MECHANISMS

elderberry polyphenols bind directly with viruses to inhibit cell entry; reduce viral replication in early stages and boost host immune response

EVIDENCE

credited with controlling 1993 flu pandemic in Panama by researchers

ANTIGEN PRESENTING CELLS (MACROPHAGES & DENDRITIC CELLS)
Elderberry may stimulate macrophage activity (ref)
PROLIFERATION OF T HELPER (CD4+) AND CYTOTOXIC (CD8+) CELLS
No research available
TH1 ACTIVITY (vs TH2 OR TH17 BRANCHES)
Shown to induce Th1 cytokines (ref)
IMMUNOGLOBULIN PRODUCTION
No research available
IFN-y AND IL-21 PRODUCTION
Elderberry increases interferon production (ref)
ENDOPLASMIC RETICULUM FUNCTION
No research available

Of course, there are many other herbal products that have been used for their anti-viral benefits (such as Pau D’arco, Grapefruit Seed Extract, Andrographis, etc), many more than have been demonstrated to influence Th1/Th2 balance (such as Reishi, Astragalus, Gynostemma, etc) and a range of nutrients that play key roles in immune response (such as Vitamin A, B12 and Copper, etc) but I chose to focus on the six compounds above to avoid information overload. Equally, I have not explored fully the role of Vitamin C in supporting individuals who have developed complications in COVID-19 infections (although doctors from Ruiijing Hospital in Shanghai report that 50 patients with problems were treated with IV Vitamin C and achieved a 100% recovery rate, which deserves attention).

Nonetheless, a reasonable examination of the six compounds still highlights some key principles:

  • As well as their direct antimicrobial effects, every item exerts important effects on the immune system. In other words, the performance of the immune system is a key factor in yielding the benefits we want from supplementation
  • No ‘perfect’ antiviral supplement exists. Take Vitamin D for example, a so-called immunomodulator due to the way it both boosts antiviral defences (via antiviral peptides) but reduces activity in other parts of the immune system (adaptive system); its unique properties show the importance of avoiding deficiency yet avoiding excessive intake (mega-dosing, an experimental approach that has been deployed in autoimmune conditions such as MS, could be a risky strategy if antiviral defences are important to you).
  • We would benefit from more research on these compounds. Plenty of the research referenced above is on human subjects but many of it is preliminary/mechanistic studies (which leaves us with ideas on how it works, but without sufficient confirmation). Sadly, regardless of the benefits it may bestow on the human race, we are unlikely to see pharmaceutical funds suddenly diverted into this area
  • Rather than taking the whole lot, understanding the relative differences in each item (which functions it boosts, which function it inhibits) allows us to begin customizing the recommendations we provide for each individual

 

Personalized nutrition for immune support

 

I hope that this two-part article makes the case for role of the immune system in fighting off infection and how the most-discussed immune ‘boosters’ exert their effect through a variety of mechanisms but that such effects depend on their interaction with multiple structures of the immune system.

When we consider the issue through this lens, it should become clear how each of us may have difference strengths and weaknesses. Some of these differences may be genetic (for example, differences in the Vitamin D receptor activity), many more will relate to the microbiome (the source of countless genes influencing our metabolism and arguably the most powerful factor in regulating immune activity) and then there is our environment; the food we eat, the amount of sleep we get, the stress burden we face, our physical fitness and the neural wiring bestowed upon us via socialisation during childhood. Then there is our exposure to toxic chemicals and our existing infection burden. I could go on (but I won’t).

The point I wish to make here is that there are so many ways that my metabolic function may differ to yours. What I wish to do now is to use the ‘levers’ identified in the first part of this article as references points to consider the different needs we have at these key junctures. If you wish to take further action on immune function, consider speaking with your practitioner about the following tests:

  • Complete Blood Count (blood). This is one of the most basic tests in medicine and one of the first things doctors offer when doing a check-up. This provides a breakdown of your white blood cells (immune cells), such as lymphocytes, neutrophils, monocytes, eosinophils and basophils. Together, these can flag up some issues that call for further investigation and highlight signs of existing infections.
  • Heart Rate Variability (HRV) and stress. Ongoing activation of the stress response is known to alter the macrophage activity through altered activity of the vagus nerve. HRV can be measured using any smartphone and an app such as Camera HRV. Further information on the stress response can be generated by an Adrenal Stress Profile (salivary) or DUTCH panel (urine).
  • Vitamin D pathway (blood test which includes Calcidiol, Calcitriol and Parathyroid Hormone). As mentioned above, Vitamin D plays a crucial role in the initial defence process (via the production of antimicrobial peptides). But it also plays a vital role in regulating activity of dendritic cells. Measuring the pathway provides much more information than just the Calcidiol test (which is the one most commonly undertaken at doctors’ offices). The ratio of calcidiol-to-calcitriol can provide feedback on current levels of inflammation, while the level of calcitriol-to-PTH can inform us about the level of activity at the Vitamin D receptor itself. Sometimes people just need more sun, sometimes they need a strategy to support the receptor.
  • Vitamin A (blood test for retinol). Vitamin D uses Vitamin A-dependent structures for many of its functions. Plus Vitamin A almost made it onto my list above due to its well-characterized role in fighting infections.
  • Thyroid Panel (ideally should include Reverse T3 and antibodies, but must include TSH, T4 and T3 as a minimum). Your immune system works best at the right temperatures. I don’t expect that to happen if there is insufficient thyroid action.
  • Total Immunoglobulins (blood) cheap test to look for any differences in total immunoglobulin (antibody) levels.
  • There are a number of factors that can result in stress on the endoplasmic reticulum, although Homocysteine is the best-characterized and easiest to test for.
  • Active B12 (blood, bloodspot or urine). B12 is rarely discussed when it comes to immune function, yet it plays a major role and deficiency is common. For more information (and for an explanation of why the ‘active B12’ test is vital), look out for an upcoming video-article.

 

 

NOTE: the above discusses mechanisms, which are excellent tools to aid understanding and generate hypotheses but do not guarantee effectiveness of interventions. Equally, the research on immune activity in this disease is preliminary and it is important to reiterate that no ideas shared on this page constitute a COVID-19 treatment plan in any way).