John Campbell 8 Oct 2021: Covid autoimmunity

Covid toe, caused by the immune response to the virus, not the virus itself.
To study skin and blood endothelial and immune system activation.
In chilblain-like lesions (CLL),.
CLL in comparison with healthy controls and seasonal chilblains (SC).
(cold-induced sporadic chilblains occurring during 2015 and 2019).
Observational study.
Saint-Louis Hospital, Paris, France.
N = 50.
Cytokine assays.
Assessment of interferon-stimulated gene expression in whole blood.
Soluble markers of endothelial activation and/or angiogenesis.
Histological examinations.
Lateral flow spike assay.
Circulating endothelial cell counting.
Statistical analysis.
Histological patterns were similar in CLL and SC groups.
Transcriptomic signatures overlapped in both the CLL and SC groups.
Type I interferon.
Cytotoxic–natural killer gene signature.
CLL were characterized by higher IgA tissue deposition.
More complement and angiogenesis factors in CLL compared with SC.
Autoimmune vasculitis.
Confirmed endothelial dysfunction in CLL.
Microangiopathy leading to clinical chilblains.
Disrupt the thrombo-protective state of endothelial cells.
Likely contributing to microvascular thrombosis.
Systemic endothelial activation?.
The PT ratio and aPTT were normal in all patients.
Only three patients (6%) had a moderate increase in D-dimer levels.
Inflammation in the skin in CLL.
Associated with endothelial alteration.
Immune infiltration of cytotoxic and type I IFN-leading to clinical manifestations.
UK podiatrist Dr Ivan Bristow.
like the regular chilblains typically seen during cold spells and in people who have problems with circulation - the lesions usually go away on their own. .
But some may need treatment with creams and other drugs..
The confirmation of the cause will help to develop new treatments to manage it more effectively.
Dr Veronique Bataille, consultant dermatologist, British Skin Foundation.
Covid toe was seen very frequently during the early phase of the pandemic, but has been less common in the current Delta variant wave..
That might be down to more people being vaccinated or having some protection against Covid from past infections. .
Presentations after vaccination are much rarer.
Delayed presentation my mean link is missed.
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Contents hide

0:00:00 | now moving on to covered fingers and

toes now this is from the british association of dermatologists in combination with the zoe symptom tracker data so they’re working together on this and it gives lots of cutaneous of covered here that people have photographed themselves people that are doing the the coverage symptom tracker app and they send in so there’s all sorts of different manifestations in the mouth in the in the skin in the digits legs

0:00:30 | abdomens armpit there so all over the

place different types of rashes but then if we look we’re looking at digits today so if you click on that one we can actually see some covered digits here so it gives you quite a few to choose from in fact there’s more pages of it as well so I think we can see here for example that there’s quite a lot of quite a lot of redness here on the on the toes that looks quite

0:01:00 | red and inflamed you can clearly see

that there I think the red fingernails have got a different course the red toenails have got a different cause or there’s another toe there and again quite quite sore and inflamed looking toe and there’s also there’s also examples from this is some fingers here as well

0:01:30 | yeah there’s some fingers as well so

if we look at this covered digits so we see this kind of red inflamed area here on the on the fingers so do click on that site you’ll be there for ages because lots of interesting things to look at you can look at oral manifestations or urticaria or manifestations or neck and exposed chest eczema tempted to click around a few more night there but we won’t only i’ll leave that

0:02:00 | i’ll leave you to look at that

yourself now what we want to do now is look at the paper that’s just come out on this now this is the paper here it’s from research from france that’s the paper there now if you’re a consultant dermatologist physician or experienced biochemist I would recommend reading this paper for yourself if not I probably wouldn’t bother because it’s about the most difficult paper to read I think we’ve ever reviewed on this on this channel it really is quite a stodgy paper full of jargon and things so I’m it’s taken me a good few hours to

0:02:30 | decode it myself so I’m going to

give you the the gist of it here and there is some pretty interesting stuff coming out so covered toe british diabetic association so that was the one we’ve just looked at the pictures were just looked at that is the link for the paper so the objectives of this study to study skin and blood endothelial and immune system activation so is this activating the immune system is the question now the endothelial endothelium so if

0:03:00 | you take a cross-section of a blood

vessel like that you typically have an outside layer then you have a middle layer like that and then you have a then you your the middle layer’s a bit thicker then you have an inner layer there so that would be the middle layer there that would be the outside fibrous tissue layer there and then on the inside you’ve got this nice smooth layered cells that they’re what you call squamous epithelial cells so the cells are on a basement membrane like this if we take a blow up of a bit of there

0:03:30 | like that and then the nice flat

cells like this that what we call squamous cells and of course the nice and flat cells so it’s easy for the blood to flow over the cells in the vessel without causing turbulence you get nice laminar flow of blood you don’t want turbulence in the blood vessel so that’s the vascular endothelium that they are studying in and it’s the same in all blood vessels really it’s just in a capillary for example all you’ve got is the basement membrane and

0:04:00 | this and then you’ve got smaller vessels

like arterioles and venules where you have differing amounts of elastic tissue and smooth muscle in the walls so anyway what they’re studying here is they’re calling them chill blaine like lesions clls that’s what they’re calling those things we’ve just looked at and they’re looking at chill blade like lesions in comparison with healthy controls and seasonal chill planes which they’re calling sc seasonal chill planes

0:04:30 | and sure blades are cold induced sporadic

chill blades occurring during well the ones they looked at as a comparative group with 2015 to 2019. so what happened what happens with chill planes is people that are prone to this the cold causes inflammation and then they get this area of inflammation called a chill blame which is is often quite quite quite painful for the per for the patient they really have to make a big effort to keep their feet warm but of course in england in england or northern america or canada that’s quite difficult in

0:05:00 | in winter so that’s what they’re comparing

anyway observational study carried out in france so fine now they actually only had 50 patients in here but it was an observational study basically a convenient sample and they looked at cytokines assay means the level to measure the level of cytokines of these if you have one cell there like that one body cell there like that and you have another body cell here maybe a different type of cell then a cytokine is a chemical released

0:05:30 | by one cell that diffuses to another

cell and has an influence on this second cell it’s a cytokine cyto cell kind movement it makes the cell do something not necessarily move of course more likely to be a biochemical change and they also did assessment of interferon stimulated gene expression in whole blood so basically that’s looking at the activity of interferon now we’ve looked at interferon a few times before interferon is a chemical released a cytokine

0:06:00 | released by a virally infected cell that

goes to other cells and tells them wait just a minute there’s a virus in the area so stop producing as many proteins and it has various effects on the cell that protects it against viral infection so if you have a viral infected cell in the middle there interferons are released and that’s going to warn and therefore stimulate defenses in all the cells around about it so it sort of compartmentalizes the viral infection that’s what interferon does it is interfering with the activity of

0:06:30 | other cells but usually usually in a

positive way so they looked at that they also looked at soluble markers of endothelial activation or angiogenesis I told you this was a difficult paper so angio is blood vessel genesis is beginning off so what happens is if these if these blood vessels if a blood vessel is damaged suppose suppose suppose you have some blood vessels there for example taking blood to an area if some blood vessels are damaged that have to be replaced and that process is called

0:07:00 | angiogenesis making new blood vessels or sometimes

called angio neogenesis making of new blood vessels so they were looking at that basically I think that’s as as a response to damage of the blood vessels that new new blood vessel would have to be generated histological histological examination examined the tissues under microscopes they looked at lateral flow spike assays looking for virus in the tissues and in the blood they were able to by sophisticated techniques that are able to look at endothelial cell counting in the

0:07:30 | circulation so the idea here is that

again if you had damage to the to the vascular endothelium some of these cells might break off and therefore circulate in the blood and if you could find these cells circulating in the blood that would be an indicator of endothelial damage as I believe what they’re saying there and then of course they did lots of stats on the whole thing right what were the results histological patterns were similar in shore brain like lesions and seasonal tool blades

0:08:00 | so basically the abnormality the histopathology under

the microscope looked much the same indicating these are both primarily inflammatory conditions primarily inflammatory conditions but it’s not inflammation caused by the sarcoma virus to itself it’s inflammation caused by the body’s immunological reaction to the virus and this is really important because of course the the main life-threatening condition the acute respiratory distress syndrome

0:08:30 | or the the formation of all these

micro emboli these little blood clots you get in the vessels all that is an immunological reaction as well so to understand the immunological reaction that you get to the virus is really very very important part of understanding the whole disease process transcript transcriptomic in other words to do with transcription the the the reading of the the genetic material signatures overlapped in both

0:09:00 | chill brain like lesions and seasonal chill

planes in other words the the reaction that this had on the body cells again was similar the way that the body cells responded started transcribing their dna into rna to make protein via the process of translation was similar in other words the pathophysiological process was similar it was type one interferon that was produced which and now pretty well all cells in the body probably probably all cells certainly most

0:09:30 | cells in the body have interferon receptors

so pretty well any body cell if it’s exposed to interferon that will warn that cell that there’s a viral bacteria that there’s a viral infection around just sorry I said bacteria that I meant to say viable there’s a viral infection around and that the interferon is is the interferon that’s warning the other cells can also cause other inflammatory reactions so that’s that’s why they’re looking for the levels of interferon that’s part of what’s causing this inflammatory reaction

0:10:00 | brain like lesions were characterized by higher

tissue immunoglobulin so there was immunoglobulins in the tissues oh never miss one out sorry let’s go back cytotoxic natural killer gene signature so in other words there’s activation of cytotoxic natural killer cells these nk cells so in in the in the blood we have white cells called lymphocytes there’s a class of cells called

0:10:30 | lymphocytes and there’s two sorts of these

there’s large and the small lymphocytes now the small ones are the b and the the t lymphocytes and the b lymphocytes are the ones that produce the the antibodies they produce immunoglobulins the t you might remember this t helpers there’s t suppressors and this t cytotoxic cells as well so the helpers

0:11:00 | help the b cells to produce the

antibodies they produce the antibodies the b cells produce the antibodies but only when the helper cells help them to the suppressor cells tell us when it’s time to turn that response off and the cytotoxic cells directly kill virally infected cells as do the large lymphocytes so the other class is the large lymphocytes and they also kill virally infected cells so that this is the sort of this is the

0:11:30 | group of small lymphocytes there that’s what

they do then this other class of lymphocytes are the large ones and these are called the nk cells the natural killer cells now we used to think that these acted to kill a lot of different virally infected cells viral infected cells but we now know that these now recognize specific viruses as well so they’re natural these are big cells and they they just kill the whole

0:12:00 | virally infected cell and these are like

straight away whereas these ones take a while to to learn they need to go through a process of clonal expansion the the small t cytotoxic cells before they can start combating the infection whereas these ones will work very quickly so cytotoxic natural killers were activated and there was immunoglobulin type a in the tissues now what happens here is if you get immunoglobulins in the tissues then they’re not really supposed to be there so they

0:12:30 | they generate their own immunological inflammatory reaction

because the immunological cells have chemicals in them that can kill bacteria and kill viruses so for example in in immunological cells like like the white blood cells there’s an enzyme in there called lysozyme that will digest bacteria now that’s fine if it’s all contained inside the cell inside its right vesicles but if that gets out and some does when the salsa damage some gets out and that is very insulting and inflaming to tissues

0:13:00 | in general because it can do things

like digest protein so it causes an inflammatory reaction so that’s the link between the immunity and the inflammation so when you get immunity you tend to get a degree of inflammation as well that’s kind of the way that’s working there’s more complement and angiogenesis factor in covered like lesions now complements another pro-inflammatory cytokine and there is angiogenesis factors so these are factors these are cytokines

0:13:30 | that stimulate the process of blood vessel

healing angiogenesis indicating that blood vessels have been damaged so the body is trying to heal them and in other words this causes an autoimmune vasculitis so vasculitis is inflammation of blood vessels auto is self-immune processes it’s an autoimmune vasculitis confirmed endosthelial dysfunction as well so there’s damage to the lining of the blood vessels so basically what we’re saying is there’s activation of interfere on an activation of natural killer cells that damages the blood vessels and that

0:14:00 | leads on to damage of the tissues

as well through the deposition of immunoglobulin type here in the tissues so you’ve got two causes and the tissues themselves are damaged the skin is damaged in this case and the blood vessels are damaged micro micro angiopathy so micro small angio blood vessel pathy disease off so there’s disease in the small blood vessels and that that’s leads to clinical chill blades so that’s what’s leading to this

0:14:30 | it’s the partly the disruption so it’s

the immunoglobulin type a in the tissues and the disease of the blood vessels which of course is somewhat analogous to what we see in the lungs really isn’t it where there’s disease in the blood vessels and inflammation in the lungs themselves so this could really be giving us vital information about what is killing people in covid19 this is why this is so important it also disrupts the disrupts the thromboprotective status of the endothelial cells so the endothelial cells these cells

0:15:00 | that are aligning the blood vessels you

don’t want blood clots an abnormal blood clot in a blood vessel would be a thrombus you don’t want that so these cells are releasing chemicals that prevent the blood from clotting and that there’s the there’s a homeostasis between pro and anti-clotting factors that normally leads to nice liquid blood so the blood you see in a wound is a bit thick you know the blood blood that comes straight out is liquid it is the clotting things that make it thicken up and eventually clot of course

0:15:30 | so and that can likely leads to

microvascular thrombosis so small blood vessel clots within small blood vessels so if that’s one of your small blood vessels there like that then the microvascular thrombosis would be a blood clot forming inside that small vessel blocking off that vessel meaning the bit of your finger or toe that’s normally supplied with blood by that vessel doesn’t have enough blood supply therefore it becomes ischemic it hasn’t got an upland supply therefore it becomes inflamed

0:16:00 | what about systemic endothelial activation is this

happening all over the body well that the pro-thrombin ratio and the activated pro-thrombin time were normal in all patients so these are measures of blood clotting so what this is saying is the blood clotting was normal so so like if you if you’ve got you know if you if your international normalization ratio is two to one that means your blood’s taking twice as long to plot as normal but what they’re saying is these were one to one the blood clotting was normal in these people indicating to me at least the way I

0:16:30 | understand this is people that had covered

fingers and toes are not likely to have overall body inflammation this seems to be a bit of a separate disease process but using the same pathophysiological mechanisms only three only three patients had a moderate increase in d diamond level so that’s not really that significant now d-dimer is when you get blood so if you get a blood clot if you get a blood clot forming here in imagine that’s let’s have a red pen you get if you get a

0:17:00 | blood clot but you get a blood

clot forming forming there now the body doesn’t want a blood clot because it’s blocking off the blood supply so what you have is you have various mechanisms in the blood that start to dissolve this blood clot a process called thrombolysis and one when you dissolve the blood clots the d-dimer is one of the things that’s released it’s a protein that’s released as the blood clot dissolves so this indeed diamond levels are high that means you’ve got

0:17:30 | thrombosis because the body’s trying to get

rid of the thrombosis but it’s a marker for the presence of thrombosis but that wasn’t systemically raised in most people so it’s saying that systemic thromboembolic complications were not really a big issue conclusions inflammation in the skin associated with endothelial alterations immune infiltration of cytotoxic and type 1 interferons leading to clinical manifestations so there it is it’s basically cytotoxic

0:18:00 | cytotoxic nk cells did I say t

cells then I didn’t mean to they’re not t cells the natural killer large lymphocytes and the interferon leading to these clinical manifestations now practically that that’s the end of the difficult bit dr ivan baristo uk podiatrist look like the regular chill blades typically seen during cold spells and in people who have problems with circulation the lesions usually go on their own so that’s pretty good news

0:18:30 | usually go on their own some may

need treatment with creams and other drugs however and most go away on their own the confirmation of the cause will help to develop new treatments to manage it more effectively which of course is brilliant and then this doctor here is a con spokesman for the british dermatological association a sulfur consultant dermatologist kovitto was seen very frequently during the early phases of the pandemic but it’s less common in the current delta variant wave interesting so but of

0:19:00 | course now we have many more vaccinations

on board and many more people that might be down to more people being that might be down to more people being vaccinated having some protection against infection or infection from immunity from past infection presentations after vaccination are much rarer so vaccination is protecting against this which is probably the main reason and delayed presentation may mean it’s missed in other words some people get this a week or two or three weeks after

0:19:30 | they have the confidence therefore may not

associate it so I don’t think ever has a disease maybe with the exception of hiv which was pretty extensively studied been so rapidly studied new things being discovered all the time okay this my fingers and toes might not sound important but it’s it is to the people that have it but as well as that it’s indicating perhaps something fundamental about the way that this virus is is killing people via the body’s own

0:20:00 | immunological response so sorry that was a

bit stodgy but feel free to watch it again if you’d like to and thank you for watching

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