ICU resources for COVID-19, vitamin D and the immune system

Marik Protocol; Front Line COVID-19 Critical Care Working Group Protocol; Farid Jalali's beautiful detective work hypothesising about exactly what is happening in the lungs of COVID-19 patients; Vitamin D to stabilize the endothelium . . .

Robin Whittle .   2020-04-09  Last update 2020-08-07 06:40 UTC

The updates/ page lists all the significant updates to these cv19 pages.

To the main COVID-19 page of this site: , concerning nutritional supplements - especially vitamin D and boron - for all adults and some children ASAP, to reduce or eliminate the tendency for their immune system to be weak and/or dysregulated (overly-aggressive, pro-inflammatory and so self-destructive) - which is what causes severe symptoms with COVID-19.   There you will find multiple articles recommending that everyone should have at least 40ng/ml (100nmol/l) 25OHD levels - and this starts with expectant mothers and their newborns.

If everyone in the world was already replete in vitamin D alone (with the current very poor boron status) then I believe that far fewer people would be dying or seriously harmed due to COVID-19.    In the absence of proper vitamin D levels, it is possible that boron repletion (such as 6mg a day, instead of the usual 1mg or so) would be helpful too.   See the main page for more on boron and immunity.

Obesity ../obesity/ would still be a problem, as would some particular patterns of genes ../#haplotypes - but the outcomes would be far less extreme than they are now, with many or most of these people seriously deficient in vitamin D and probably other nutrients.  Please see the ../obesity/  page for links to research concerning excess adipocytes expressing ACE2, releasing pro-inflammatory cytokines and existing as ectopic adipocytes in the cells of the alveoli.

Be sure to read the Disclaimer!


COVID-19 patients need vitamin D to ensure Th1 lymphocytes in their lungs shut down and so reduce inflammation

This is highly significant:

An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19
Reuben McGregor et al. 2020-07-19

Th (T helper lymphocytes AKA CD4+) cells which enter the Th1 program of development play an important role in fighting viral infection and then, ideally, in reducing inflammation.  

25 researchers from the USA, the UK, Chile and New Zealand conducted ex-vivo research on fluids and blood samples from COVID-19 patients with severe symptoms, including analysing the behaviour of Th1 cells, the genes which are activated inside them and how this changes with vitamin D (25OHD) levels.  

The Th1 cells produce IL-6, which is generally a pro-inflammatory cytokine and is found at dangerously high levels in many conditions, including COVID-19 severe symptoms, sepsis, ARDS etc.  The researchers show that there is an important autocrine (signaling within the cell W) pathway which is not operating as it should in these COVID-19 patients. 

This pathway involves IL-6 stimulating the production of the anti-inflammatory cytokine IL-10, as part of the cell ending its Th1 program.

The researchers show that this pathway is completely dependent on 25OHD levels, since the signaling involves the upregulation of genes for both the vitamin D receptor VDR and for the CYP27B1 enzyme which converts, inside the cell, 25OHD into 1-25OHD, the form of vitamin D which activates the receptor.   Once activated, the 1-25OHD-VDR complex migrates to the nucleus and alters gene expression, upregulating numerous genes and downregulating others.

Without sufficient 25OHD (from the blood and so interstitial fluid) these Th1 cells remain stuck in their aggressive phase of operation, in part by producing the pro-inflammatory cytokine IL-17.

With sufficient vitamin D, the cells stop producing IL-17 and produce IL-10 instead. 

With sufficient vitamin D, in these conditions, with the autocrine pathway operating as it should. the set of genes which are upregulated share a significant number of genes with the geneset upregulated by anti-inflammatory steroids, such as the dexamethasone.  

The researchers use the term "VitD-depressed geneset" to refer to the set of genes downregulated by the successful operation of this pathway.  When comparing the activation of genes in Th1 cells from COVID-19 patients with severe symptoms, to those from healthy controls:

The VitD-repressed geneset was within the top 1% of all genesets at distinguishing patient from healthy Th cells . . .

This means that in healthy cells, this autocrine pathway was working correctly - presumably due to the presence of adequate 25OHD and no-doubt other conditions - while in these COVID-19 patients, it was not operating, despite the Th1 cells producing plenty of IL-6 and the presence of other factors which should activate this pathway.   The implication is that the IL-6 cells in the patients were unhealthy due to lack of vitamin D, since by supplying 25OHD in the lab, this autocrine pathway started operating correctly again.

Dexamethasone, a cortico-steroid drug, has recently been shown to reduce mortality from severe COVID-19, presumably through immunosuppression. A significant number of the genes that were modulated by VitD were shared by cortico-steroids. Steroids, including dexamethasone, enhance the effects of VitD by increasing transcription of VDR. These data suggest that, in patients with severe COVID-19, addition of VitD to other immunomodulatory agents might be beneficial. From experience in other diseases, it is unlikely that VitD will be effective as monotherapy. Combination therapy (at lower doses) could ameliorate the significant adverse effects of high dose steroid treatments, including over-immunosuppression or metabolic side-effects.

In summary, we have shown that complement [W] initiates Th1 shutdown via orchestrating an autocrine/paracrine autoregulatory VitD loop. VitD causes epigenetic re-modeling, induces and recruits a set of transcription factors including STAT3, c-JUN and BACH2, that collectively repress Th1 and Th17 programs and induces IL-10 via IL-6 - STAT3 signaling. We show that this program is down-regulated in the lungs of patients with severe COVID-19 and could be potentially exploited therapeutically by using adjunct VitD treatment in patients with COVID-19.

Also, it is obvious to me and not stated in the article, if people already had sufficient vitamin D levels - 40ng/ml or more - then their immune system response to the virus may well prevent it infecting the lungs, and if the virus did replicate there, the resultant immune response would be properly regulated, and not the overly-aggressive, hyperinflammatory, self-destructive response which is always found in (and so arguably causes) severe symptoms in COVID-19.  The same surely applies for sepsis, ARDS etc. all of which only tend to happen to people with very low vitamin D levels.

See the main page ../ for research on COVID-19 severe symptoms being associated with, and so presumably at least partly caused by, low vitamin D levels.


Review article on Vitamin D and COVID-19

Vitamin D and COVID-19
John P. Bilezikian, Daniel Bikle, Martin Hewison, Marise Lazaretti-Castro, Anna Maria Formenti, Aakriti Gupta, Mahesh V. Madhavan, Nandini Nair1, Varta Babalyan, Nicholas Hutchings, Nicola Napoli11, Domenico Accili, Neil Binkley, Donald W. Landry, Andrea Giustina  2020-08-04

This is a review of observations and mechanisms.  I haven't had a chance to read it yet.


Farid Jalali's hypothesis of vascular damage and shunting via diffuse pulmonary-bronchial anastomoses

Be sure to read this beautiful detective work which offers the best explanation yet for many perplexing aspects of COVID-19.  The first link is to a video podcast with PDF and discussion and the second is to a text and graphic presentation with comments by Cameron Kyle-Sidell MD:

Scott Weingart. EMCrit Wee – A Theoretical Model of the Pathophysiology of COVID-19 with Farid Jalali (Not a Single Thing Verified–Pure Musings). EMCrit Blog. 2020-05-18  Excellent diagrams PDF

Cameron Kyle-Sidell's appreciative comments begin with:

I applaud Dr. Jalali for proposing a model for COVID-19 injury based on seemingly sound physiologic principles.  This model does provide explanations for anecdotal observations made by bedside physicians treating COVID-19 patients.  For example, the presence of dorsal-predominant shunting would explain why proning leads to marked oxygenation improvement that is not sustained once the patient returns to the supine position.

This work highlights the importance of protecting the integrity of the endothelium and limiting vasoconstriction, which is caused by excessive angiotensin II, resulting from SARS-CoV-2 destroying the ACE2 receptors.  See #2020-Kim below regarding how important vitamin D 1,25OHD is for protecting endothelial cells and inducing vasodilation

This is not necessarily just 1,25OHD in the plasma in general, but could be released in a paracrine fashion (short distance signaling between nearby cells [W]) after it is produced internally (in part for autocrine [W] signaling) and then diffuses out of the cell.  Autocrine cell signaling (Khan Academy explanation) is a big part of how immune cells control gene expression, and with leakage of the internally produced 1,24OHD, we have the possibility of paracrine reception of this on membrane-bound vitamin D receptors of nearby cells, such as the endothelial cells described by #2020-Kim , where it would upregulate endothelial protection and nitric oxide mediated vasodilation. 

What proportion of endothelial cell vitamin D receptors are on the apical surface, and so exposed to plasma 1,25OHD, plus any locally secreted by immune cells there?  What proportion are on the other side (outside the vessel or capillary = basolateral) and so, I guess less affected by the normal bone and calcium regulating level of 1,25OHD as a hormone, and more affected by the actions of immune cells in the surrounding tissue?

See also ../obesity/ According to the research I review there, the excess adipocytes of obesity express ACE2 receptors and so can be infected with SARS-CoV-2.  These are in the outer lining of the heart and there are also ectopic adipocytes in the cells which make up the alveoli.  I had never heard of these, but assuming it is true, then obese people would have further infection in their lungs combined with extra inflammation.


Farid Jalali's hypothesis of serotonin (5-HT) playing a major role in COVID-19 lung pathology

In late June 2020, Farid Jalali released a text-only document:

in which he proposes that serotonin, especially that released by platelets in the clotting cascade, plays a major role in making things much worse in SARS-CoV-2 infected lungs.  He suggests that the normal clearance mechanisms, which are in the lungs themselves, can no longer function, so serotonin builds up in the whole circulation causing further trouble.

As with the above diagrammatic hypothesis, I think only a handful of people - pulmonolgists and the like - could fully appreciate and critique what he is proposing.

However, I understand enough of it to envisage these as possible explanations for the extreme levels of damage which occur with the worst symptoms of COVID-19.

"Vitamin D" does not appear in either of these documents.  The big question is why is there so much inappropriate inflammation in these patients.  Surely low vitamin D levels - anything below 40ng/ml 250HD - plays a role in this immune system dysfunction.  I also suspect that low boron plays a role as well.  See: ../#08-boron and ../#boron-ra .


Respiratory epithelial cells convert 25OHD to 1,25OHD

Further to the discussion above on intracrine and paracrine signaling of 1,25OHD, here is a pertinent article, from 2008.  The lead author is a critical care pulmonologist in Iowa.

Respiratory Epithelial Cells Convert Inactive Vitamin D to Its Active Form: Potential Effects on Host Defense
Sif Hansdottir et al. J Immunol November 15, 2008, 181 (10) 7090-7099
Google Scholar 505 citations

. . . primary lung epithelial cells express high baseline levels of activating 1α-hydroxylase and low levels of inactivating 24-hydroxylase.  The result of this enzyme expression is that airway epithelial cells constitutively convert inactive 25-dihydroxyvitamin D3 to the active 1,25-dihydroxyvitamin D3.

Also, a 2011 article:

A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency
Gerry K. Schwalfenberg Mol. Nutr. Food Res. 2011, 55, 96–108 (Payalled.)
Google Scholar 265 citations

Toll like receptors (TLRs) respond to extracellular fragments of pathogens and/or of cellular damage, upregulate CYP27B1 (1a-hydroxylase) which converts 25OHD to 1,25OHD.  This activates the vitamin D receptor (the production of which is also upregulated by the activation of TLRs) and the activated receptor travels to the nucleus and upregulates genes specific to the particular cell type.  This diagram depicts some of the actions.  (I have another diagram somewhere depicting autocrine 1,25OHD signaling between cells.) 

He suggests 25OHD levels of 40 to 60ng, which I agree with.


Angiogenesis; ACE2-positive lymphocytes. alveolar and endothelial cells

Also of interest is this analysis of COVID-19 damage to lung tissue differs from that resulting from  H1N1 influenza in 2009:

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
Maximilian Ackermann et al. NEJM 2020-05-21

The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive [splitting] angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).

Are these new blood vessels or capillaries fed by the pulmonary or bronchial artery? To what extent were they clogged with microthrombi?  To what extent could they participate in gas exchange?  Although the accompanying editorial notes that the H1N1 samples are not directly comparable, this graph indicates that angiogenesis is a very prominent feature in COVID-19.  This analysis is from autopsies - so this progression is for the patients with the worst symptoms.

79 inflammation-related genes were differentially regulated only in specimens from patients with Covid-19, whereas 2 genes were differentially regulated only in specimens from patients with influenza; a shared expression pattern was found for 7 genes.

This suggests to me a high immune system involvement, in addition to direct viral damage, in both the COVID-19 and H1N1 affected lungs.  Low vitamin D drives inappropriate, self-harming, overly-inflammatory responses, as well as weak antiviral defense mechanisms.

Loss of ACE2 receptors is a prominent part of Farid Jalali's hypothesis (above), driving excessive angiotensin II.  To what extent is this due to direct viral damage (virus attaches to ACE2 which is then internalised with the virus and so no longer remains active on the cell membrane) or due to immune system destruction of infected cells, and perhaps those nearby even if uninfected?

Why, in these illnesses are ACE2 receptors more frequently found on epithelial and endothelial cells?  Are these cells sensing excessive blood pressure due to microthrombi blocking the capillaries and/or vasoconstriction there?  If so, do they sprout ACE2 receptors in an attempt to reduce angiotensin II levels and so reduce vasoconstriction?

If so, then these extra ACE2 receptors make them vulnerable to viral infection and the whole situation can spiral out of control.

Fraction of cells with ACE2 receptors
Alveolar epithelial
Endothelial cells

Why do ACE2 receptors appear on lymphocytes?  Are these lymphocytes also acting to reduce local angiotensin II to reduce vasoconstriction?

If so, then the virus is well adapted: it gets into cells which already express the ACE2 receptor, taking these receptors, and then the cells, out of action.  This reduces angiotensin II levels, driving vasoconstriction and microembolisms which cause multiple cell types which normally express few, if any, ACE2 receptors to express lots of them, in an attempt to reduce vasoconstriction - so the virus can infect them too.  Inducing lymphocytes to express ACE2 and so be infected is quite a twist.

This article seems be relevant, mentioning ACE2-positive lymphocytes, but I have not attempted to pursue this line of inquiry further.  Please suggest pertinent articles and discussions.  ../#contact .

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa
Hao Xu et al. International Journal of Oral Science volume 12, Article number: 8 (2020)
Google Scholar 249 citations


Vitamin D and Endothelial Function

Your COVID-19 patients are (according to Philippino and Indonesian research I cite here cv19/) generally seriously deficient in vitamin D.  Surely you can improve their chances of survival with vitamin D supplements. 

Cholecalciferol (D3) takes days to convert to 25OHD in the liver - and the liver may not be functioning well.  So high dose oral D3 - such as 50,000 or 100,000IU, ideally with a meal including fats - when they arrive in hospital, is one way to start.  If you can do oral of IV 25OHD (calcifideol = Rayaldee) then this would be faster.  Most immune system cells require plasma 25OHD for their internal synthesis of 1,25OHD to activate their internal (intracrine) vitamin D receptor signaling.  So the whole of immune regulation depends on a good 25OHD level. 

Other cells, such as endothelial cells, require 1,25OHD calcitriol at their membrane bound vitamin D receptors, and so may not rely directly on plasma 25OHD levels. 

Please see this recent review article:

Vitamin D and Endothelial Function
Do-Houn Kim et al. Nutrients 2020, 12(2), 575

Adequate vitamin D activation of endothelial cells achieves numerous functions:
NO is a primary vasoactive substance that works as a potent vasodilator in addition to other vasoprotective properties such as protection from vessel inflammation and lesion formation.

Endothelium-derived NO acts on adjacent vascular smooth muscle cells in a paracrine manner and induces vascular muscle relaxation . . .

. . . protects the vessel from developing atherosclerosis by inhibiting platelet adherence and aggregation, and leukocyte activation.


The trinity of COVID-19: immunity, inflammation and intervention

Here is an excellent paper, from researchers in Singapore and Liverpool regarding the role of inappropriate, over-inflammatory, immune responses in severe symptoms with COVID-19.

There's no mention of vitamin D - though deficiency in this clearly drives weakened and dysregulated immune responses which allow disease progression and which, as this article documents, drive a lot of the damage which occurs.  Nor is there any mention of coagulation or vasoconstriction - both key elements in the material above, which was developed after this late April article would have been finalised.

The trinity of COVID-19: immunity, inflammation and intervention
Matthew Zirui Tay et al. Nature Reviews Immunology 2020-04-28
Google Scholar 36 citations

. . . aggressive inflammatory responses strongly implicated in the resulting damage to the airways.  Therefore, disease severity in patients is due to not only the viral infection but also the host response.

In addition, the vast release of cytokines by the immune system in response to the viral infection and/or secondary infections can result in a cytokine storm and symptoms of sepsis that are the cause of death in 28% of fatal COVID-19 cases. In these cases, uncontrolled inflammation inflicts multi-organ damage leading to organ failure, especially of the cardiac, hepatic and renal systems.

Pyroptosis is a highly inflammatory form of programmed cell death that is commonly seen with cytopathic viruses.  A wave of local inflammation ensues, involving increased secretion of the pro- inflammatory cytokines and chemokines IL-6, IFNγ, MCP1 and IP-10 into the blood of afflicted patients.

Notably, there exists a highly inflammatory monocyte-derived FCN1+ macrophage population in the bronchoalveolar lavage fluid of patients with severe but not mild COVID-19.  Also, patients with severe disease show a significantly higher percentage of CD14+CD16+ inflammatory monocytes in peripheral blood than patients with mild disease. These cells secrete inflammatory cytokines that contribute to the cytokine storm, including MCP1, IP-10 and MIP1α.

Unrestrained inflammatory cell infiltration can itself mediate damage in the lung through excessive secretion of proteases and reactive oxygen species, in addition to the direct damage resulting from the virus.  Notably, virus was found in T lymphocytes, macrophages and monocyte-derived dendritic cells. Direct virus killing of lymphocytes could contribute to the observed lymphopenia in patients. 

Viral infection in immune cells such as monocytes and macrophages can result in aberrant cytokine production, even if viral infection is not productive. The degree to which SARS-CoV-2 targets these cells remains poorly defined.

Understanding the precise drivers of immune dysfunction is crucial to guide the application of appropriate immunomodulatory treatments.

Indeed.  The pages you are reading explain most or all of this immune system dysfunction in terms of individual genetic variation, lack of helminths, some dietary excesses and some very common nutritional deficiencies - especially vitamin D, boron, omega-3 fatty acids, vitamin C and potassium.


COVID-19: the vasculature unleashed

Here's another article concerning endothelial failure in the lungs, with the researchers not knowing why this happens to some people.

COVID-19: the vasculature unleashed
Laure-Anne Teuwen et al. Nat Rev Immunol (2020).

I wonder who created this beautiful illustration.

During homeostasis, the endothelium, surrounded by mural cells (pericytes [W]), maintains vascular integrity and barrier function. It prevents inflammation by limiting EC - immune (EC = Endothelial Cell) cell and EC - platelet interactions and inhibits coagulation by expressing coagulation inhibitors and blood clot-lysing enzymes and producing a glycocalyx (a protective layer of glycoproteins and glycolipids) with anti-coagulation properties.

Interestingly, recent studies using single-cell transcriptomics revealed endothelial phenotypes that exhibit immunomodulatory transcriptomic signatures typical for leukocyte recruitment, cytokine production, antigen presentation and even scavenger activity. Compared with ECs from other organs, lung ECs are enriched in transcriptomic signatures indicating immunoregulation, and a subtype of lung capillary ECs expresses high levels of genes involved in MHC class II-mediated antigen processing, loading and presentation.

After the initial phase of viral infection, ~30% of hospitalized patients with COVID-19 develop severe disease with progressive lung damage, in part owing to an overreacting inflammatory response.

These would be mainly the patients with the weakest and most dysregulated immune systems - the primary, currently known (I suspect boron deficiency as well) preventable cause of which is vitamin D deficiency.  Yet vitamin D is not mentioned in this article.

Mechanistically, the pulmonary complications result from a vascular barrier breach, leading to tissue oedema (causing lungs to build up fluid), endotheliitis, activation of coagulation pathways with potential development of disseminated intravascular coagulation (DIC) and deregulated inflammatory cell infiltration.

Reduced ACE2 activity indirectly activates the kallikrein–bradykinin pathway, increasing vascular permeability.

Immune cells, inflammatory cytokines and vasoactive molecules lead to enhanced EC contractility and the loosening of inter-endothelial junctions.  In turn, this pulls ECs apart, leading to inter-endothelial gaps. Finally, the cytokines IL-1β and TNF activate glucuronidases that degrade the glycocalyx but also upregulate hyaluronic acid synthase, leading to increased deposition of hyaluronic acid in the extracellular matrix and promoting fluid retention.  Together, these mechanisms lead to increased vascular permeability and vascular leakage.

Vascular integrity and EC death leads to exposure of the thrombogenic basement membrane and results in the activation of the clotting cascade.

"Finally" just refers to this initial stage of the zombie apocalypse which overcomes all these cell types in the lungs.  Note that in the description so far, and in what follows, there is little or no mention of viral activity.  Most people deal with the virus pretty well, and things never get as bad as just described.  If you have read this page and most of the ../cv19/ page you will be at least roughly aware of the protective, largely vitamin D dependent mechanisms in these cells which protect them from damage by pathogens, and disallow the storm of destruction described so well here, which is primarily driven by a weakened and dysregulated immune response.

Moreover, ECs activated by IL-1β and TNF initiate coagulation by expressing P-selectin, von Willebrand factor and fibrinogen, to which platelets bind. In turn, ECs release trophic cytokines that further augment platelet production. Platelets also release VEGF, which triggers ECs to upregulate the expression of tissue factor, the prime activator of the coagulation cascade, which is also expressed by activated pericytes.  In response, the body mounts countermeasures to dissolve fibrin-rich blood clots, explaining why high levels of fibrin breakdown products (D-dimers) are predictive of poor patient outcome. As a result of the DIC and clogging/congestion of the small capillaries by inflammatory cells, as well as possible thrombosis in larger vessels, lung tissue ischaemia develops, which triggers angiogenesis and potential EC hyperplasia.  While the latter can aggravate ischaemia, angiogenesis can be a rescue mechanism to minimize ischaemia.  However, the newly formed vessels can also promote inflammation by acting as conduits for inflammatory cells that are attracted by activated ECs.

We're not done yet . . .

Many patients with severe COVID-19 show signs of a cytokine storm. The high levels of cytokines amplify the destructive process by leading to further EC dysfunction, DIC, inflammation and vasodilation of the pulmonary capillary bed.    

This explanation differs from that of Farid Jalali's #2020-Jalali-b above - in which angiotensin II levels force vasoconstriction.  The above words seem to indicate that the unspecified mechanisms of vasodilation (I guess nitric oxide, as noted above) prevail. 

This results in alveolar dysfunction, ARDS with hypoxic respiratory failure and ultimately multi-organ failure and death

EC dysfunction and activation likely co-determine this uncontrolled immune response

Yes, but why?  This is where anyone who has read the research I have read - and which you will read if you follow my links - thinks of the low 25OHD levels of these patients, and how this will reduce the ability for numerous types of immune cell (and it seems we should count some or all endothelial cells as immune cells too) to act strongly and successfully against the virus, while regulating the destructive responses which cause almost all the harm described in this article.
This is because ECs promote inflammation by expressing leukocyte adhesion molecules, thereby facilitating the accumulation and extravasation of leukocytes, including neutrophils, which enhance tissue damage.  This is because ECs promote inflammation by expressing leukocyte adhesion molecules, thereby facilitating the accumulation and extravasation of leukocytes, including neutrophils, which enhance tissue damage [Neutrophils are one of the immune system's professional phagocytes. W  Moreover, we hypothesize that denudation of the pulmonary vasculature could lead to activation of the complement system, [W] promoting the accumulation of neutrophils and pro-inflammatory monocytes that enhance the cytokine storm

As I wrote on the main page cv19/ most of the death resulting from influenza is also due to weakened, dysregulated, immune systems, with the same primary causes (cv19/#helminthsgone): lack of helminths, individual genetic variation, dietary excesses and nutritional deficiencies, most particularly of vitamin D.
This is based on the observation that during influenza virus infection, pulmonary ECs induce an amplification loop, involving interferon-producing cells and virus-infected pulmonary epithelial cells. Moreover, ECs seem to be gatekeepers of this [destructive and quite likely deadly] immune response, as inhibition of the sphingosine 1 phosphate receptor 1 (S1PR1) in pulmonary ECs dampens the cytokine storm in influenza infection. This raises the question whether pulmonary ECs have a similar function in the COVID-19 cytokine storm and whether S1PR1 could represent a therapeutic target. Another unexplained observation is the excessive lymphopenia in severely ill patients with COVID-19 and whether this relates to the recruitment of lymphocytes away from the blood by activated lung ECs.

Yes they are a therapeutic target - along with every other type of cell in our bodies.  Everyone should run their bodies better by giving all their cells the nutrients they require for proper operation.  This starts with 40 to 60ng/ml 25OHD.

When they don't do this, and their levels are 30ng/ml or less, sometimes down to 10ng/ml or less (and see ../#21authors for an article written by 21 experts who regard vitamin D deficiency as being only below 10ng/ml) they can get by - until a virus, bacteria or some other insult triggers this weak and dysregulated immune response.  Then they suffer sepsis, pneumonia etc. - or in the case of COVID-19 and even worse horror story because of the way the virus, during this self-destructive cascade, infects immune cells which respond to the troubles by expressing ACE2 receptors, driving a hypercoagulative storm which wreaks likely permanent harm all over the body.

When people get to hospital, in these conditions, the first thing doctors should do is try to raise their 25OHD levels to something healthy, like 40ng/ml.  Perhaps it will be too late, but I am exceedingly perplexed, spending these months knowing how low 25OHD is not being treated, and is condemning hundreds of thousands of people to terrible suffering, lasting harm and death.

We should remember that the wholesale 1kg ex-factory cost of D3 for 4000IU a day is US 9 cents per year.

All these people are boron deficient too.  Boron's half life is 20 hours or so, and they start of boron deficient in ordinary life, getting about 1mg or so a day, and become even more deficient in hospitals since doctors don't even recognise it as a nutrient.  Yet boron has numerous anti-inflammatory properties, similar to vitamin D, but also in some ways unique to itself.

100mg of borax a day gives 11.4mg boron a day, which is surely sufficient for repletion.  This is 36 grams of borax a year, which costs (retail, USD$10/kg) US 36 cents per year.

Additional circumstantial evidence suggests a link between ECs, pericytes and COVID-19. First, risk factors for COVID-19 (old age, obesity, hypertension and diabetes mellitus) are all characterized by pre-existing vascular dysfunction with altered EC metabolism.  As hijacking of the host metabolism is essential for virus replication and propagation, an outstanding question is whether EC subtypes or other vascular cells in specific pathological conditions have a metabolic phenotype that is more attractive to SARS-CoV-2.

Old age - in the absence of 4000IU or more D3 a day supplementations - is strongly correlated with even lower 25OHD levels than is normal middle age.  These risk factors are caused, in large part, by vitamin D and other deficiencies, the lack of helminths etc. and excessive dietary fats, sugars and other carbohyrates, and frequently lack of proper exercise. 

So even if the actual conditions were not risk factors in themselves (and they are, especially obesity) then the correlation between these conditions and risk for serious COVID-19 symptoms would be to a large extent explained by a lifetime of inadequate vitamin D.

Second, occasional clinical reports suggest an increased incidence of Kawasaki disease, a vasculitis, in young children with COVID-19.

I had never heard of Kawasaki disease.  It took me less than a minute with Google Scholar, searching for it with "vitamin D" to find the article I link to here ../#2015-Stagi which shows that the only children who suffer and die from this terrible condition have exceedingly low (rickets levels) of 25OHD.

Other articles on COVID-19 endothelial pathology

There are no doubt other articles with detailed accounts of COVID-19 pathology in the epithelium of the lungs.  I don't have time to find or read them all, but here are some of potential interest:

Overcoming Barriers The Endothelium As a Linchpin of Coronavirus Disease 2019 Pathogenesis
Dakota Gustafson et al. Arterioscler Thromb Vasc Biol. 2020;40:00–00

Coronavirus Disease 2019 Coagulopathy: Disseminated Intravascular Coagulation and Thrombotic Microangiopathy - Either, Neither, or Both
Marcel Levi and Jecko Thachil Semin Thromb Hemost 2020-06-08


Vitamin K depletion in severe COVID-19 contributing to coagulation?

I haven't read this yet.  Would vitamin K supplementation reduce the most destructive aspect of severe COVID-19: the hypercoagulative state?

Reduced Vitamin K Status as a Potentially Modifiable Prognostic Risk Factor in Covid-19
Anton S.M. Dofferhoff et al.

#2020-Front #2020-FLCCC

MATH+ Protocol for early intervention to reduce cytokine storm and so reduce or eliminate the deadly hypercoagulative state

The website of the Front Line COVID-19 Critical Care Alliance is:

(Previously Front Line COVID-19 Critical Care Working Group and before that: .)

Please follow all the links to protocol, press release and other documents there, as well as documents linked from theirs:

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections
Meduri & Chrousos

Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis
Jose Iglesias et al.

A 2018 article about this by Paul Marik and colleagues: Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation contains a big diagram and explanation.

The protocol concerns the early use of methylprednisolone, intravenous vitamin C, thiamine (), low molecular weight heparin and other compounds, including vitamin D and melatonin to reduce or prevent the development of the cytokine storm which causes the hypercoagulative state which is what harms and kills people.  Other elements are nasal cannula oxygen with prone positioning and avoidance of incubation as much as possible.  


The Marik Protocol

Paul Marik MD is a member of the FLCCC Alliance mentioned above.  His work predates COVID-19 and is applicable to most ICU patients, especially those with sepsis and lung injury.  His protocol is available from:

Paul Marik's approach was discussed in March 2017 at .  At that page, the second video is of some nurses at the East Virginia Medical School hospital.  At 1:09, Team Coordinator Kathi Hudkins recalls her team's initial thoughts on Dr Marik's protocols:

"This had to be some soft of fallacy.  It just seemed too simple."

But then their patients started getting better.

Despite the obvious necessity of supplementing a micronutrient which is essential to immune function, Paul Marik faces an uphill battle having his ideas accepted - and he considers it unethical to do an RCT, since half his patients would be denied a treatment which he knows works.

Dr Paul Marik has written over 400 peer-reviewed journal articles, 50 book chapters and 4 critical care books.  In 2017 he said:

My colleagues, when I told them what was going on, thought it was  the biggest load of nonsense they had ever seen.  But then they actually saw that none of our patients were dying.  And then our CEO saw that none of the patients were dying.  So this has become instituted through the whole healthcare system.

"We were going to do a randomised clinical trial, but we couldn't - because it would have been unethical."

At this page there is also a 2020-05-28 video - which is actually at YouTube - in which Professor Marik discusses COVID-19 in general and how he and his team treat it.  His part in the video starts at 45 minutes. 

At 50:30 he mentions vitamin D status as one of the factors affecting COVID-19 outcomes - and the effect of high geographical latitude on low vitamin D levels.  In US states north of 40° there is a much higher risk of COVID-19 mortality.

COVID-19 results in a very high expression of inflammatory cytokines, chemokines, IL-6 and IL-1  [much more so than common respiratory viruses, including influenza]. 

What makes this virus so unique and so smart is that while it upregulates the inflammatory response, it downregulates the expression of interferons. 
Interferon type 1 and type 3 are the major host defenses against viral infections.  COVID-19, as opposed to influenza, results in a limited antiviral response. So there is a marked imbalance between the host immune response in getting rid of the virus and this profound inflammatory response.

EMCrit discussion on timing of corticosteroids

Josh Farkas and commenters discuss the timing and strength of corticosteroid use with COVID-19:

Dr Cameron Kyle-Sidell's videos on how different COVID-19 is from what he trained for

His impassioned video: .  A later interview with John Whyte in which he mentions that his view of what was good for the patient was incompatible with the guidelines followed by the rest of his ICU team, so he resigned his position to work in the ER: .

L. Gattinoni et al. on L and H "phenotypes"


Dr Farid Jalali's COVID-19 diagram concerning cytokine storm and resulting hypercoagulative state

Farid Jalali tweeted a detailed diagram depicting the cytokine storm turning a moderately PAI-1 elevated coagulative state, which apparently can be controlled with heparin, into a hypercoagulable Progressive Thrombotic Cascade.  The long progression of this thrombosis apparently enables the oxygen levels to drop slowly enough that the patient copes with it better than would be the case with normal ARDS.  This leads to microvascular thrombosis in the lungs, heart, kidney, gut, pancreas, skin and CNS - and so frequently to death.

He states that COVID-19 is cytopathic to the endothelium and that this degenerates (as far as I know, in the absence of vitamin C etc. treatment) into the Severe COVID-19 cytokine storm.  This makes me think that the vitamin C, corticosteroid etc. treatment prevents the virus and the consequent (at least in these patients) immune response doing so much harm to the endothelium.

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