#MSCOVID19. Am I lucky to be on a DMT?

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I think the current view is that the COVID19 disease is a disease of two stages.

Stage I. Viral removal by the innate immune system notably the monocyte/macrophage and also perhaps CD8 T cells abit later.

These cells are working to get rid of the virus, whilst the virus is trying to evade this immune attack. The balance of this determines what may happen next. It seems that for most people the balance falls in favour of the monocyte and it kicks some viral-butt, before it causes too much havock. Many people perhaps about 50% of people do not notice they have been infected.

For example, a couple of days ago, I woke up and my breathing was a bit heavier than usual, my nose was blocked and I blew my nose and this is what I saw….

Image
Too hard a blow or time to be worried?

…..a bit of bloody, nose-juice….ShI I thought “is this COVID19?”. I then got a runny nose and then a few hours later it was gone..I suspect ..and hope it was just a common cold that was dealt with. If we weren’t all bricking it , I wouldn’t have thought anything of it…as we are in the time of the sniffle and snuffle. However, living with someone who may have COVID-19 also focuses the mind.

About 80% of people do notice something, So OK and again I would bet the balance is in favour of the macrophage kicking some viral butt. The NHS and your GP say stay at home, isolate, and wait and see what happens, as most people recover. I would be much happier, if I was getting an anti-viral agent, because if the macrophage looses the battle, maybe a lot of your lung cells are going to get infected.

So the white blood cells in people with severe covid19 problems have lower white cell counts. Now you could say low white cell counts are the cause of severe disease. However the more likely issue is that they are a consequence of severe disease because they are being sucked out of the blood into the lung. There are other ideas

It is better to stop the infection developing, than firefighting once it has become established.

What happens in SARS (SARS-COV-1 infection)

Looking at this it says the innate (Macrophages and neutrophils are important in early protection as are CD8 T cells. It looks like B cells are less important early on. Then you look at what drives recovery and it seems to be CD8 T cellls which we know do an antiviral job. They persisted in SARS for over 6 years compared to the B cell response. Optimal viral removal requires T and B cells

Some of you know this approach. Do nothing? take a CRAB? or “watch and wait” for the lazy neurologist…However, by the time the SH1-hits the fan and you think better start using alemtuzumab, HSCT etc. it is too late and the damage is done. So whilst you may get some benefit the major benefit-value has been lost.

This is a monkey infected with the COVID19 virus and you can see the virus in the nose peaks after about 3 days and is gone by 9 days. There is no signficant anti-viral response in the blood until 14-21 days . Suggesting that something other than antibodies are important for clearing the virus. When they give more virus when there is an antibody response and the virus is gone
In this case you can see that the viral levels drop by 4-5 days, but the antibody response does not occur until after that suggesting that something else is importnat for clearing the virus,. If you look the macrophages they drop in the blood, I suspect they are inthere fighting the virus as the first line of defence
There were cases where people had cancer and had bits of their lung removed and they had sub-clinical COVID and in these lungs there were lots of macrophages supporting the idea that macrophages are important first line. In people who have had severe problems their lungs were full of mononuclear cells probably CD8 T cells. So they are good and bad guys

This is what I suspect happens in the 20% who are destined to do badly. Some anti-virals and it gives those macrophages a better chance and avoids you needing the NHS. Why no anti-virals…there are non-proven to work. So we have to wait for trials to complete. Therefore, the general public will get a taste of what its like to have to wait for useful drugs. However maybe some of you are lucky here.

I have two friends (and maybe our patient zero) and both probably have been infected with SARS-CoV-2…one had the runs, abdominal pains and a bad head and as they are getting better a cough. The other has had fever, cough, shortness of breath and has been in hosptial three times in a week due to difficulty in breathing…What’s the difference?…Not genetic. They are identical twins…but one is immunosuppressed…not with a DMT….but with a baby, pressing on the lungs is probably not helping things. Fingers crossed. So I can appreciate the worry some of you have. But my friend did not get any anti-virals, You may be luckier and not that immunosuppressed. Pregnancy drops the relapse rate by about 50%

The virus blocks the action of interferons that are produced by the tissues to stop viral replication. So you may be in luck, if terflunomide is anti-viral (no evidence I think but hypothetical) or perhaps if you are getting beta interferon, this could take the job of alpha interferon, as long as the virus does not block the signalling of the interferon receptor. This would stop viral load, allowing the macrophages to kick some viral-butt. There is some evidence that beta interferon blocks coronavirus (SARS) replication.

Stage II. The Shitstorm. Viral removal by killing the infected cells

  1. The virus gets inside cells, hijack the cells machinery to produce more virus and the cell bursts and dies and so the lining of your lungs are being removed and probably underpins the cough.
  2. CD8 T cells see virally infected lung cells and kill them damaging the lining of your lungs and creates pneumonia
  3. Antibodies bind to infected lung cells and get destroyed by direct attack or by attack by immune cells, leading to difficulties in breathing.

If this occurs too quickly you probably can’t repair the damage to the lungs quick enough as pneumonia sets in and bacteria get in the lungs and make your life harder.

At this point having an over-active immune system is perhaps not the best news and this is maybe where you say thank heavens for some immunosuppression as it may take some of the destructive edge off the damaging immune response that kills the virus but damages the lungs whilst doing so. Although this is an idea and unproven. Apparently there are plans to test an MS drug to seee what happens in severe disease

So what makes me think a strong immune response is damaging.

If you look at people who make the highest level of anti-SARS-CoV-2 response they get or have much more severe disease

Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, Wang X, Yuan J, Li T, Li J, Qian S, Hong C, Wang F, Liu Y, Wang Z, He Q, Li Z, He B, Zhang T, Fu Y, Ge S, Liu L, Zhang J, Xia N, Zhang Z.Clin Infect Dis. 2020 Mar 28. pii: ciaa344

The people requiring critcal care had much higher levels (green) of antibodies against SARS-CoV-2. This is probably because the antibodies are killing off infected cells and this is damaging your lung

Here lies the worry and it is already happened. People will think that anti-bodies for people who have recovered from COVID-19, will neutralize the infectivity of the COVID virus…which it probably will, but utilmately it could make infected people worse because it could kill off virally-infected cells. Look above the people with the highest level of anti-COVID antibodies got more severe disease.

The plan is to take antibodies from recovering people and put them into people before exposure to the virus, whcih may be a good idea, and put them into sick people, whcih for some basd on the graph above will be a bad idea, but as this group can do badly will they notice the occasional bad effect

https://www.jci.org/articles/view/138003

We are racing to make a vaccine, which will gear to make antibody, they may rush to give it to someone already infected…which probably won’t work very well as vaccines work best for people who have not, but it could make them worse. We have to learn from past mistakes because this happened with vaccines against Respiratory Syncytial virus, which is another lower lung virus like SARS-CoV-2

Kim WH et al Respiratory syncytial virus dease in infants despite, prior administration of antigenic inactivated vacccine. Am J Epidemio 1969; 69:422. The said “It seems clear that ……who received this vaccine were not protected against natural infection and also, when they became naturally infected their illness was more severe” and concluded ” These findings together suggest that RS virus illness in infants is an immunologic phenomenon wherein the virus and serum antibody interact to produce severe illness” “Vaccine-induced RS virus serum antibody alone does not protect against illness

https://dm5migu4zj3pb.cloudfront.net/manuscripts/138000/138003/large/JCI138003.f1.jpg

A monoclonal antibody (Motavizumab) was also made agains the RS virus and development of this was terminated die to some adverse event. Today we hear that they have made antibodies that block binding of SARS-COV-2.

Blood from people recovered from COVID19 have apparently injected into sick people, but it only take a few adverse events to stop development

COI Multiple

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MouseDoctor

38 comments

  • Thank you for the information mouse doctor, I hope I will still get the third full ocrelizumab dose in august in that case. Seems to all be a learning curve at the moment there is so much disinformation peddled on various media outlets that one doesn’t know what to believe or not. Thanks for presenting unbiased scientific fact.

  • Wait – my wife is 14 weeks pregnant.
    In plain English, what do you mean by “but one is immunosuppressed…not with a DMT….but with a baby”
    Tony

    • When you are pregnant you are immune-modulated as such there is documented evidene that your relapse rate drops by about 50% so you are in the realms of DMF, fingolimod. This is probably an adaptation so that the mother does not reject the fathers elements. As the foetus gets larger I am sure one can appreciate that you get fake obesity and the foetus and intestines etc could limit the movement of the diaphragm. However there is an increasing literature on pregnacy and COVID and not all good.

    • It looks like the oldies don’t clear the virus as well as the youngies so we get a higher viral load, more viral load higher the risk of the shitstorm. Is this a case for metformin…however diabetes is a risk factor so I could be talking SH1.

      • I hope too that you are doing well Mouse Doctor. There will be some of us older doctors with increased risks who are being re-registered and re-licensed and asked to help. That will be a dilemma for the over 60’s like me with, I have to admit, forgetfulness, impaired executive functioning and dodgy brainstems. I will ponder this.

        • I feel OK thanks, and I am sure the nation appreciate your call to arms and the dilema. Age and co-morbidity is a major killer as far as COVID is concerned and we have already seen deaths in retired doctors, coming back to help. I am sure it would help if you knew you had been infected and were immune and to me this would help inform in a safer deployment of people. MrsMD asked for a test, but was told they are only testing people who have fever and a cough and they won’t do viral screening past 5 days. We have seen the weakness of some of the government advice and they are still seem to be pursuing the herd immunity approach but by stealth. The suggestion that people are no longer infective after 7 days of symptoms, is something that flies in the face of WHO advice and the countless papers. Likewise the potential U turn on use of masks flies in the face of common sense, yet we see people doing swabs to detect infection with the most reduimentary protection.

  • Hopefully you are doing ok.
    Saw a very interesting YouTube about Senescent cells being a better host for viruses to set up shop.
    https://youtu.be/2DvJwthiMPk
    Azithromycin and Hydroquinolone discusse and much more.
    Got me thinking of course about inflammation of my neurological system in response to MS.
    Also EBV. I’m not clear on people who are younger getting Covid 19 and doing poorly.
    Best Wishes

  • ‘I would be much happier, if I was getting an anti-viral agent”
    MD Didn’t you get hold of some chloroquine/hydroxychloroquine?
    Yeah, I know not yet clearly shown to be effective, but both drugs with well known and fairly limited side-effects and looking better than anything else that has been tried against COVID19.

    • ProfK wouldn’t give me any:-) when I spotted this about 5-6 weeks ago…said best save it for people who need it. Make sure you are zinced up just in case this important to its action

    • Regarding chloroquine, some reliable info is here.
      Bottom line, too early to really know and whatever you do, don’t self-medicate.

  • if I understand correctly those who are dying from COVID 19 can be put into 2.camps.
    1) immune unable to cope and die. Because of underlying conditions and age when the immune has become too specialised in monitoring a few conditions
    2) Powerful immune reaction probably kills the virus but becomes a runaway reaction and starts a autoimmune response targeting health lung cells kill the patient from lack of o2.

    Okay case 1 can only be saved with antivirals. In case 2 couldn’t partial alemtuzumab depletion be used to dampen the immune response till anti inflammatory response kicks in?

  • Question: If it’s the monocytes that kick butt early on in the Covid19 disease process, what would monocyte levels look like if blood work is done? Would they be reduced?

    Just trying to tease out whether the illness may have caused or contributed to, rather than Mavenclad alone, the blitzing of my monocyte levels by week 5. My husband had brought home a very strange “flu” from a conference in January and we were both slammed by high fevers, cough, difficulty breathing and I developed severe central sleep apnea which has mostly resolved. I started Mavenclad shortly after, likely decimating any chances of building immunity to it, sadly.

    This virus has certainly escalated management issues and decision-making with little background info for those living with MS! As it has for everyone.

    • Mavenclad on the whole does not blitz monocytes, but there are people who are probably super susceptible just as there are people who are not. Some people will deplete their monocytes and even neutrophils. There are a few people on alemtuzumab that deplete their neutrophils as also occurs with other agents. If we look at white blood cells on mavenclad, there is a massive spread of responses and perhaps 5-10% do not deplete their lymphocytes however most deplete their B cells. Once we have some medical students we will test this as we have the ethics in place.

      Next up is what is the need for monocytes verse what can be done by the alveolar macrophages. These are resident macrophages in the lung. Perhaps the answer here will be how people do on natalizumab.

      Flu high fever, difficulty in breathing, cough are flu/Covid symptoms if that was COVID then as you are still here, you have recovered and are immune to it. Memory CD8 T cells were only reduced by 10-20% for round one and possibly antibody forming cells remain. Simple answer is you need to have the antibody test to see if you have had the virus. However on the internet there are people have got through mavenclad

      • Good news! I had read (here?) that it took up to five weeks to develop the antibodies. so this is reassuring. I hope we can get antibody testing done at some point.

        It occurred to me that I am also on antivirals for EBV (not one being tested), vitamin C and NAC (being used in Japan for the virus). SO possibly a case of also having a lot of helpful things in place coincidentally.

        Thank you so much for your thoughtful reply, MD. I hope you are feeling better!

        • In Chinese studies it was 100% within a month,

          There is a trial in the UK that has started RECOVERY. Standard of care i.e nothing v Kaletra v Hydroxychloroquine v beta interferon inhaler v dexamethomone in hostpital admissions…So they are likely to missing the problem as they dont want you contacting them for first week, when the virus is multiplying. The dexcamethosome is a steroid so this is anti-inflammatory.

          So just like MS trials other countries are doing the same trial

          There is a European Consortia from France called DISCOVER
          Drug: Remdesivir
          Drug: Lopinavir/ritonavir (Kaletra)
          Drug: Lopinavir/ritonavir + Interferon Beta-1A
          Drug: Hydroxychloroquine
          Other: Standard of care

          At least these are all anti-viral.

          So you will get confimation of success or failure quickly but not much choice is seen. Get a positive and the trial may become very big to show something is better.

          Thanks for your thoughts…I’m not concerned about me…at least yet I haventhad the virus or am a super, MrsMouse has a normal temp being hypothermic for the past few ways

          • I’ve been on acyclovir for over a year. Not as good as Mavenclad for my pesky b memory cells (this has been my theory for a while; my research led me to this blog) but at least I function! I wonder if it somehow helped me throw this virus thing.

            My anecdotal observation is that when not on acyclovir, I continue to progress MS-wise (gait, walking speed, and I am NEVER sick). Acyclovir allows my immune system to work as it should. I have obvious illnesses, and get better.

            Thanks again!

  • So the pregnant friend is doing worse because of immunosuppression? But you still think it is a potentially good thing to be on a DMT causing immunosuppression? I’m a bit confused (doesn’t take much admittedly)

    • Who knows it is a hypothesis.

      Pregnant friend may be doing worse because of where they are being seen. They are perhaps part of an NHS experiment they are in a hospital where the policy is no drugs (no evidence of efficacy) compared to another hospital where the policy is anti-virals (Can read and can see there may be value)

      This is my opinion and I an not a doctor and it is not advice but surely one of the worse things at the moment is to have to go into hospital (the staff may be infected and most resource is in intensive care)

      1a) The first phase of the Protection may be via macrophages…If true most high efficacy drugs do not do much against this cell type, however they may be affected.

      1b) The intermediate wave of protection may be via the CD8 T cell…Some MS drugs do litle against this cell type, alemtuzumab and HSCT
      are the most inhibitory and this effect is transient

      2) The shitstorm is a product of an over active immune system, if is possible that MS DMT offer benefit…This is hypothetical and hypothectical only. You will have to clear the virus to get back to health and ideally you will make a protective immune response

  • Two questions- 1) from your writing, I can’t tell which of the friends is the pregnant one- the one which has been in hospital or the other, and is the runs and a headache twin better or worse than the shortness of breath twin?

    2) Can we jump then, to a prediction based on your observation, that if some DMTs generally suppress the immune system in a helpful way with the virus, then would we expect to see, over time, that untreated pwMS also do worse with the virus, more so than people without MS or pwMS on those DMT’s?

    • 1. Pregnant one, with breathing issues tested positive is in hosptial, the other runs and the headache and no major breathing issues

      2. I’m hopeful pwMS will do well, I have a few predictions but will wait until the data arrives

      • I am untreated and at first thought this would go in my favour with covid but from what I have read it could be the opposite. I have joined the ms register so my data will be added in the event of infection.
        Best wishes for a quick recovery to mr and mrs md and many thanks for your continued work on the blog, we are lucky to have you keeping us informed.

  • Nice reasoning

    Dont know if you are aware that the neutrophil/lymphocyte ratio is a predictor of poor response in patients with covid 19

    Patients with high neutrophil/lymphocyte tend to do worst

    Also anti il-6 Tocilizumab make the ratio go down and aparently save patients

    See Daniel Griffin MD doctor working in the front line in New York

    min: 5:16 and min 17.43

    https://www.youtube.com/watch?v=myaXkQesY5c

    obrigado

    • The problem with ratio is it one goes up or the other goes down…Can you point me to the neutrophil stuff I havn’t read too much on them.

      Yes I know about the tocilizumab as they have noticed that IL-6 goes up and tocililzumab is approaved for cytokine release syndrome there were some good vibes comming from Italy on this

      • Acording to the doc he said that having an Nlr greater than 20 its no good

        And then we talk about an

        Irish gentleman 30 years old wiith Nlr greater than 20

        No comorbidities got so bad that even 100% on the ventilator oxigen would not go above 90%

        They turn the man face down oxigen start to go up

        And they give him (of label) Tocilizumab Nlr starts to drop and patient is feeling much better

        He said in 24 hours the lymphocytes came back up and the neutrophills came down

        He thiks that its driven by cytokine strong (il1 ,il6,il 10 driven)

        So when you stop il6 you stop that mal-adaptive immune response

        He think that high neutrophill are Immunopathology rather than response to viral load

        Why?
        Acording to him the this is happening when the viral load is on the way down

        we start to having and adaptive immune response (between day 7 and 14)

        And thats when the neutrophills which should be coming down, because you dont need the inate system anymore thats when you ned the lymphocytes on so mal-adaptive immune response

        He said that whwn the neutrophill star to go down the oxygen requirement of the patients goes down and they feel better

        https://www.youtube.com/watch?v=myaXkQesY5c

        min:17:43

  • Where can I have the data that you present in the graph about antibodies production? There are several countries planning to produce hyperimmune plasma concentrates but this may cause the opposite effect and cause an advance in the complication of the patients.

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