COVID19 update, May 13, 2020: more on Vitamin D and on N-acetylcysteine (NAC); Kawasaki disease; “corona poverty” in Belgium

(1) John Campbell has been tirelessly plugging Vitamin D supplementation on his YouTube channel, particularly if you have dark skin and live at Northern latitudes, but even if you have light skin and don’t get outside much. About 40% of the population in Northern Europe and the USA is vitamin D deficient.

Now JoAnn E. Manson, MD, DrPH, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, (Harvard Medical School and Brigham&Women’s Hospital) throws her weight behind it on MedScape. (Video is free, transcript requires free registration.)

[Transcript of video with links.].

I’d like to talk with you about vitamin D and COVID-19. Is there potentially a protective role?

We’ve known for a long time that it’s important to avoid vitamin D deficiency for bone health, cardiometabolic health, and other purposes. But it may be even more important now than ever. There’s emerging and growing evidence that vitamin D status may be relevant to the risk of developing COVID-19 infection and to the severity of the disease.

Vitamin D is important to innate immunity and boosts immune function against viral diseases. We also know that vitamin D has an immune-modulating effect and can lower inflammation, and this may be relevant to the respiratory response during COVID-19 and the cytokine storm that’s been demonstrated.

There are laboratory (cell-culture) studies of respiratory cells that document some of these effects of vitamin D. There’s also evidence that patients with respiratory infections tend to have lower blood levels of 25-hydroxy-vitamin D.

There’s now some evidence from COVID-19 patients as well. In an observational study from three South Asian hospitals, the prevalence of vitamin D deficiency was much higher among those with severe COVID illness compared with those with mild illness. In fact, there was about an eightfold higher risk of having severe illness among those who entered with vitamin D deficiency compared with those who had sufficient vitamin D levels.

There’s also evidence from a meta-analysis of randomized clinical trials of vitamin D supplementation looking at acute respiratory tract infections (upper and lower). This was published in the British Medical Journal 2 years ago, showing that vitamin D supplementation was associated with a significant reduction in these respiratory tract infections. Overall, it was only a 12% reduction, but among the participants who had profound vitamin D deficiency at baseline (such as a blood level of 25-hydroxy-vitamin D of less than 10 ng/mL), there was a 70% lower risk of respiratory infection with vitamin D supplementation.

So the evidence is becoming quite compelling. It’s important that we encourage our patients to be outdoors and physically active, while maintaining social distancing. This will lead to increased synthesis of vitamin D in the skin, just from the incidental sun exposure.

Diet is also important. Everyone should be reading food labels which list the vitamin D content. Food sources that are higher in vitamin D include fortified dairy products, fortified cereals, fatty fish, and sun-dried mushrooms.

For patients who are unable to be outdoors and also have low dietary intake of vitamin D, it’s quite reasonable to consider a vitamin D supplement. The recommended dietary allowance of vitamin D is 600-800 IU/daily, but during this period, a multivitamin or supplement containing 1000-2000 IU/daily of vitamin D would be reasonable.

(2) Kawasaki Disease. This is a rare inflammatory disease in children, of uncertain origin — though an autoimmune origin is suspected by some. Now it has been spotted in children who have been exposed to COVID19 infections — in the US, in the UK, France, and now in Belgium.

There is no proof of a COVID19 link (rather than accidental simultaneous infection), and correlation is not causation, but it’s a rather interesting coincidence that this suddenly pops up — considering all the immune shenanigans of the virus. Here is Dr. Seheult on Kawasaki “systemic vasculitis in childhood”: https://www.youtube.com/watch?v=Ja-jhcXMGj0

(3) I had promised some further remarks about N-acetylcysteine (probably better known to Americans as “NAC”). 

red=oxygen, black=carbon, blue=nitrogen, white=hydrogen, yellow=sulfur

You likely know that amino acids are the building blocks of proteins. These all have the same basic structure: a carboxylic acid (-COOH) group on one end, an amine on the other, and a “side chain” specific to each amino acid (e.g., just hydrogen  of H- for glycine, CH3- for alanine, HO-CH2- for serine,…)

Two amino acids have sulfur in the side chain, namely, methionine (CH3-S-CH2-) and cysteine (HS-CH2-). The HS- group is what chemists call a thiol or mercaptan. (Have you wondered why rotting eggs smell the way they do? Right, decomposition of cysteine gives rise to H2S, HS-CH3, and other smelly stuff that our noses are extremely sensitive to. Likewise with the gaseous, er, digestive byproduct of eating foods rich in cysteine.)

But what is the function of the cysteine side chain really? In a word, disulfide bonds — the “rebar” of biochemistry. If you want to tie adjacent strands of protein together (e.g., strands of keratin in hair), the -SH….HS- pairs in adjacent strands can be oxidized (in the chemical sense) and tied together into a disulfide bond like this: -S—S-

This sort of thing often happens in your lungs when you have a chest cold or a flu, and thus you get a mucous mass that you struggle a bit to cough up.

Enter N-acetylcysteine (NAC), where you have a CH3-C(=O)- group stuck on the nitrogen of the amino acid. What this will do is act as an antioxidant — it will use up the oxidant before it can weld the rebar together.Hence NAC has been in use for a long time as a mucolytic, a.k.a. expectorant (“sputum loosener”) in people with acute or chronic respiratory infections.  (I have used it plenty during chest colds or mild bouts of flu [frequent air travel tends to lead to these ;)]: here in Israel, it’s sold over the counter at pharmacies as effervescent tablets, 200mg of active ingredient per tablet, recommended dose 1 tablet 3x a day dissolved in a glass of water. In the USA, “NAC” can be found in food supplement sections of drugstores etc.)

Turns out, however, that in COVID19 it has other beneficial effects (see yesterday’s bonus video from Dr. Seheult). Especially after being converted in the body to the antioxidant glutathione [*], it will reduce oxidative stress in severe inflammatory reactions. But in addition, it will prevent formation of “rebar” between individual units of von Willebrand Factor (vWF). If such rebar does form, you get long chains of vWF polymer, to which platelets can bind, and you have the beginning of a blood clot. (See also http://biorxiv.org/lookup/doi/10.1101/2020.03.08.982447  for more on disulfide bonds and vWF.)

Unlike more aggressive blood thinners like heparin and warfarin, however, NAC does not significantly increase the risk of hemorrhage. (In stroke patients, overdoing warfarin or low-MW heparins such as https://en.wikipedia.org/wiki/Enoxaparin_sodium runs the risk of exchanging risk of renewed stroke for risk of cerebral hemorrhage — exactly thus Prime Minister Ariel Sharon z”l ended up in a permanent vegetative state

(4) Miscellaneous: 

  • The economic ravages of long lockdowns, for those not lucky enough to be able to work from home or draw guaranteed salaries. are not limited to the USA anymore — even in a “nanny state par excellence” like Belgium it’s becoming an issue.  De Standaard has an article (in Dutch) about “Corona poverty” in the Flemish cities of Antwerp and Ghent.
  • What about COVID19 poverty and Israel? And how much of it because of lockdowns? The tourism industry has been devastated, but that would have happened with or w/o lockdown. A small minority of “gig economy” workers actually saw increased income (delivery drivers for restaurants, in particular) but many small and medium business owners (and their employees) absorbed blows. However, our lockdown was given a “horizon” up front (end of Passover), and we are now largely unlocked except for cafés and restaurants (takeaway and delivery only for now). I will be curious to see our unemployment figures — which have shot up drastically — shake out over the next month or two as furloughed employees return to the workplace.
    Quite a few salaried employees here used up their annual vacation days to wholly or partially bridge the lockdown period.
  • “Gender gap”: indications that men have more ACE2 receptors (the virus’s “point of entry”) than women, making them more vulnerable to infection? https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa414/5834646 (via the NYPost, via Sarah Hoyt)
  • Could this new Israeli drug, MesenCure, prevent lung damage in COVID19?
  • Pfizer wants to expand its human trial for a COVID19 vaccine (developed in collaboration with German drugmaker BioNTech) and is making what in a PR release it has called “risk investments” aiming for an October mass production timeframe.
  • The Times of Israel on how also in Israel, doctors treating severe COVID19 patients have moved away from invasive ventilation in favor of noninvasive options—even as they are divided on the reasons why.

[*] For that reason, It is also used intravenously as an antidote in acetaminophen/paracetamol/Tylenol overdose

7 thoughts on “COVID19 update, May 13, 2020: more on Vitamin D and on N-acetylcysteine (NAC); Kawasaki disease; “corona poverty” in Belgium

  1. It would be interesting to know if the children who have come down with “Kawasaki” have been vaccinated with MMR.
    Apparently some 29% of the RNA of Wuhan matches that of Rubella. That overlap could be an explanation for the (general) lack of Wuhan problems seen in children

    Wuhan like any flu does not kill directly. Death comes from indirect causes exacerbated by the immune response so that ANY treatment which enhances the immune system OR reduces any immune over-reaction is a good step.
    Search for Critical Care Protocol for a treatment centered view of what Wuhan actually does and how to treat it starting with HCQ +zinc.

  2. Missed one sentence: Myguess would be that the sick kids have Not been vaccinated and came down with Wuhan flu where the immune systems of vaccinated kids shucks off the virus

  3. ‘Asian Boss’ has another video featuring Professor Woo-Joo Kim from Korea University Guro Hospital, “Leading Korean Coronavirus Expert Reacts To COVID-19 Conspiracy Theories”.

    Dr. Kim discusses the origin of the virus (bats and the wet market in Wuhan) and specifically addresses the concern that the virus was created in the Wuhan biolab (he doesn’t believe that it was). Since his previous videos have been, IMO, valuable, I’m inclined to consider his opinion.

    Perhaps his most radical idea (to me, who lives in a pro-hunting-wild game State) is that to prevent the next pandemic, people should stop eating wild animals worldwide.

  4. I appreciate you summary and perspective. I also follow Medcram and Dr John Campbell’s video series. Both have been hugely informative. There is a small typo in your note N-acetyl cysteine has a C2H3O group attached to the N rather than a CH3O

  5. […] (3) The American Chemical Society has a special virtual issue on COVID-19 research across its extensive portfolio of research journals in various areas of chemistry, plus (alas) some what I shall charitably describe as “advocacy papers” and opinion pieces. But that still leaves a lot of original research papers: one that jumped out at me was this one about the role of glutathione deficiency (see our earlier blog post) […]

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