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Wednesday, 25 March 2020

You can't Boost your Immunity? or, Debunking the COVID-19 Skeptics.

Kate's elderberry concoction, photograph by Hayley Theyers




Is there anything as useless as the professional Skeptic community in a health  crisis? Some people are paid to be roadblocks, others are educated professionals going well outside their lanes after the witches they despise for getting in their lanes at other times, others are just the sort of people who get an existential thrill from negating what they don't understand, or journalists with a "tough" reputation to uphold and a grab-bag of empty rhetoric.
In the history of science no-one has been wrong more often than the skeptic. What we usually call scepticism in the scientific method is just BEING CAREFUL.
"The first principle is that you must not fool yourself and you are the easiest person to fool." Richard P. Feynman
This is nothing like rushing into print with a negative opinion and a few pejoratives on a subject you haven't studied until now so you're either linking to the first blog that agrees with you on an emotional level, instead of looking at the literature, or you're scanning the literature quickly for reasons to dismiss it.

It's far more useful to point to what we DO know. And the first thing to be said, quite clearly, is that you CAN boost your immune system. See the evidence below. And a fast-acting, broad-spectrum immune response is how we get on top of new pathogens.

Straight up, it needs to be stated that COVID-19 is a new virus, with some specific features. Not everything that applies to previous colds, flus, or pneumonial diseases may apply.  So all older evidence needs to be evaluated carefully. But it's not completely new, this isn't smallpox in the New World, it's a nasty variation on the cold viruses we've seen before and the healthiest immune systems can usually react appropriately, as we see when we consider the high rate of mild cases and the low symptom load in the very young. The pattern so far is characteristic of other pandemics; people with no or light symptoms seem to have had a strong initial immune response and are producing antibodies to COVID-19. Here is a COVID-19 immunological case study of a mild infection, which concludes:
“our study indicates that robust multi-factorial immune responses can be elicited to the newly emerged virus SARS-CoV-2 and, similar to the avian H7N9 disease, early adaptive immune responses might correlate with better clinical outcomes.“
https://www.nature.com/articles/s41591-020-0819-2.pdf

In humans, we can test whether a compound (or organism) improves the recognition of new pathogens by giving it with a vaccine.
Consistently, acetaminophen (tylenol, paracetamol) suppresses this function in infants.
https://www.ncbi.nlm.nih.gov/pubmed/19837254
Effects are dose- and drug-dependent - low-dose aspirin doesn't impair immunity in elderly given flu vaccine, ibuprofen doesn't impair it compared with paracetamol in infants.
Probiotics enhance it.
https://www.sciencedirect.com/science/article/pii/S0264410X17311672

We know that probiotics enhance the immune response in vaccinated infants, but we can't take those infants and then expose them to the disease to learn how significant this is - herd immunity means that the risk is low in a vaccinated population even for people whose vaccines didn't work. We can however do this in animals.
Here's an experiment where zebrafish were vaccinated against a bacterial pathogen, Flavobacterium columnare, then bathed in said pathogen, with varying amounts of echinacea purpurea in their diets.
It's a tough test with, you might think, little possibility of a placebo effect.
The first point is that this vaccine doesn't really work. Only 5% of vaccinated fish are surviving exposure to Flavobacterium columnare. But add the echinacea to their feed, and we see survival climb dose-dependently. 5g echinacea per Kg is the same as none - 5% survival. 10g/Kg = 6%. 20g/Kg = 30%. 30g/Kg = 36%.
https://www.ncbi.nlm.nih.gov/pubmed/25638970
That link is down at sci-hub, so here is a similar study by the same team - without the vaccine.
https://www.researchgate.net/publication/230257632_Effect_of_Echinacea_purpurea_on_growth_and_survival_of_guppy_Poecilia_reticulata_challenged_with_Aeromonas_bestiarum

You're not going to get ethics approval to try this in humans, so make of this what you can. Firstly, why echinacea? The active ingredient is a polysaccharide, and it likely activates a variety of TLR and NOD receptors much as pathogen lipopolysaccharides do.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140398/
Similarly with probiotic cell wall lysates. A company I worked for tested a lysate from a lactobacillus rhamnosus strain many years ago and found it had ligand activity at TLRs 2,4,7,9, and NOD2, which latter is a gamma-interferon pathway.
This is going to enhance the response to a pathogen, which relies on you recognising quickly that it IS a pathogen via PAMPs and DAMPs (q.v.), a signal which compounds with such activity are amplifying.
This is well-known in human vaccine research - such compounds are called adjuvants and play a poorly-understood role in establishing immunodominance (the identification and proliferation of the "right" antibody-producing (B, Th2) immune cell).

Another commonly used herbal supplement, andrographis, has similar adjuvant effects given with vaccines in animal experiments
https://www.ncbi.nlm.nih.gov/pubmed/17321475.

Elderberry has AFAIK not been tested as an adjuvant but has direct antiviral effects in mice exposed to human influenza A.

https://pdfs.semanticscholar.org/8850/575f0665e98360dc6386ad828e66f573d270.pdf

So what is the human evidence? Elderberry (sambucus) is effective for seasonal URT infections in a meta-analysis. The studies only add up to n=180, but the effect is large and consistent (you don't need a high-powered study when something has a decent effect - we're not counting crumbs here, there's a loaf on the table).
https://www.ncbi.nlm.nih.gov/pubmed/30670267

This is likely due to cytokine effects, and some people might ask "what about cytokine storm?"
https://pubmed.ncbi.nlm.nih.gov/11399518/

Cytokines early in infection are the immune system's alert response. If viral levels are controlled early, there is a lower risk of cytokine storm.
The analogy here is the phase one insulin response, which, if inadequate to manage glucose levels, may be followed by an exaggerated and hyperinsulinaemic phase 2 response.
There is some question as to whether COVID-19 mortality is really due to cytokine storm, as in SARS or swine flu, or due to a direct effect of the virus on the lung, where cells producing pulmonary surfactant (Type II alveolar epithelial cells) are damaged by the virus and reduce normal lung function.

Andrographis is effective for reducing cough.
https://www.karger.com/Article/FullText/442111
It has an opposite effect on TNF-alpha from sambucus, so if you are worried that sambucus is too inflammatory use a combined supplement, in my experience these are effective enough for easing the misery and shortening the course of the usual cold and flu.
https://www.ncbi.nlm.nih.gov/pubmed/22026410

An AI-type analysis of data found that andrographis suppressed ACE2 expression most; sambucus and the TCM staple astragalus (another adjuvant) were also on the list.
https://www.preprints.org/manuscript/202002.0047/v1

Now, you may not want ACE2 suppressed if you are in extremis. It is a normal feature of lung function, and vitamin D supplementation (25 ug/Kg) increases ACE2 expression but prevents LPS-induced lung injury in this Wistar rat example.
https://www.researchgate.net/publication/316630691_Effect_of_Vitamin_D_on_ACE2_and_Vitamin_D_receptor_expression_in_rats_with_LPS-induced_acute_lung_injury
The jury is very much still out on ACE inhibitors (which may increase ACE2 expression) and risk.
https://jamanetwork.com/journals/jama/fullarticle/2763803

However - if you use these medicines, the idea is to use them around exposure, or PRN for symptoms, as advised. If they work, the disease will be less serious, if they don't and you do experience pneumonia you're not going to be taking them in the ICU.
Never keep taking something that makes you feel worse.

Interestingly, echinacea, which is a star in the animal studies, has only weak effects in human trials.
https://www.ncbi.nlm.nih.gov/pubmed/24554461
Yet these studies were just as small and had the same potential for bias as the elderberry and andrographis trials. That quite distinct effects or strength of effect appears consistently when different compounds are tested answers the specificity test of a Bradford Hill analysis of the "immune boosting" question. In fact every Bradford Hill criteria is being well-met, whatever the limitations of the human research.

The weak effects of echinacea may be due to its relative fragility and variation as an extract, inadequate dosage, or to the timing of its use as a prophylactic. I use these extracts only when I am either obviously exposed, "coming down with something", or actually sick. My opinion, not necessarily what the science says and just the voice of experience, is that echinacea and elderberry, if good extracts in adequate doses, both work if taken soon enough (elderberry was very effective taken within 24 hours in the swine flu but had no effect when given more than 48 hours after symptoms started). Perhaps echinacea is better for colds and sambucus for flus, but even if that were true COVID-19 is not necessarily playing by all rules. I also use Sanderson's Viramax, a mixed supplement of sambucus, andrographis, echinacea and olive leaf extract when I'm sick for PRN symptom relief, on the basis of past satisfaction with its effects. There is some evidence for olive leaf extract, but the active ingredient seems to be found in extra virgin olive oil.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412187/


Apart from herbs and probiotics, what else is there evidence for?

Malnutrition impairs antibody production, obviously, so eat a sensible diet that includes minimally processed animal products, including meat, if you're skeptical about supplements.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033455/

Apart from that, it's well worth supplementing selenium (by Brazil nuts or supplements). A pre-2019 coronavirus encoded for 60 selenocysteine residues per core protein. This is a common viral adaptation and protects the stability of the viral genome (a good thing) while depressing host immunity (a bad thing).
https://www.sciencedaily.com/releases/2001/06/010608081506.htm
Wuhan, Northern Italy, the UK and NZ are all low-selenium areas where deficiency is common. Check the data for your region or county, which is usually available online.

The jury's still out on supplementary vitamin C, and I seemed to stop responding to it when my metabolic health improved, but it's cheap and can't hurt.
Update: high dose vitamin C is being used in New York hospitals.
https://www.dailymail.co.uk/news/article-8149191/New-York-hospitals-treating-corona-patients-6000-milligrams-VITAMIN-C.html
It's the end of winter in the Northern hemisphere so I'd be supplementing vitamin D3 if I lived there.

Inorganic zinc lozenges (especially zinc acetate) seem to have a role to play here, but may be a lot of trouble to maintain for the duration. It might be worth it depending on your level of risk, as the effect is strong enough.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418896/

The spread and virulence of viral infections is in large part a numbers game. Needlestick exposures to HCV had a higher clearance rate than exposures to contaminated blood transfusions. Every line of defense matters, and every proven or even just most-likely barrier to the pathogen establishing dominance over the immune system can be worth investment.

























9 comments:

Kajus said...

The jury's still out on supplementary vitamin C, and I seemed to stop responding to it when my metabolic health improved, but it's cheap and can't hurt.

Studies show that more than 400 mg of vitamin C builds up oxalate in urine. Better to eat paleo ketogenic diet style.

Serdna said...

I'm curious: did you take vitamin C till saturation?

There have been once these 9 years that going to saturation didn't stop symptoms in their tracks (fever in that case) and nevertheless it still took the usual 3–5 days to get well as always.

I still think that this time is a credibility issue and dr. Cathcart has a high predictive value for me with his oral saturation advice.

Good luck everybody.

Passthecream said...

Thanks George for this and the previous essay. I wonder if you could clarify, the Chinese paper I read about covid19 vs ace2 specifically mentioned the ACE2 receptor, not ACE2 the enzyme, so the language and discussion around this is very muddy.
Thanks for linking those refs, sadly too early here for nettles and just too late for sambuca but I liked seeing butyric acid in one of those lists given the amount of butter I eat.

Passthecream said...

Guardian this morning:

"Scientists at the University of Minnesota used X-ray crystallography to create an atomic-scale 3D map of the virus’s spike protein and its corresponding partner on human cells, known as the ACE-2 receptor.

When the virus encounters a human cell, the spike proteins on its surface stick to ACE-2 receptors, if the cell possess them, and allow the virus to gain access and replicate."

Referring to:

https://www.nature.com/articles/s41586-020-2179-y

cavenewt said...

I'm not ordinarily a fan of supplements, but we live in interesting times.

George, I got here from your comment at Hyperlipid. Viramax may not be available in the US, but something similar is made by a company that is actually local to me and run by a friend of mine. For what it's worth: https://www.thesynergycompany.com/rapid-rescue

If this is too much like an ad, please delete.

Puddleg said...

That looks legit to me, very similar to viramax.

Some more computer learning on andrographis and COVID-19:
https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1760136

This paper evaluates the compound Andrographolide from Andrographis paniculata as a potential inhibitor of the main protease of SARS-COV-2 (Mpro) through in silico studies such as molecular docking, target analysis, toxicity prediction and ADME prediction. Andrographolide was docked successfully in the binding site of SARS-CoV-2 Mpro. Computational approaches also predicts this molecule to have good solubility, pharmacodynamics property and target accuracy. This molecule also obeys Lipinski’s rule, which makes it a promising compound to pursue further biochemical and cell based assays to explore its potential for use against COVID-19.

Puddleg said...

Here's another one
https://www.sciencedirect.com/science/article/pii/S2211383520302999

Passthecream said...

Sacharine and relatives are serrine protease inhibitors.

https://pubmed.ncbi.nlm.nih.gov/10390606/

(That's what led to the problems with rat bladders.)

https://pubmed.ncbi.nlm.nih.gov/6812943/


Commonly available without restriction, tolerated although not without concerns:

https://academic.oup.com/ibdjournal/article/22/8/E29/4561963#


But, does it have any capacity to inhibit the specific viral protease that we're all concerned about atm?????

bdgperformancelabsus said...

I think this is a really good article. You make this information interesting and engaging. You give readers a lot to think about and I appreciate that kind of writing.
Boost Immunity