So last week we went to school and I gave you a super sceintific review of our current take on the biology of COVID-19 and how it would impact on MS and be impacted by SARS-Cov-2 infection.
What was the conclusion. The impact will be less than we thought.
For the Quick read of this post, just read the RED
The paper is now in press in multiple sclerosis and related disorders. It will be online soon and will be open access so I am not worried about upsetting the journal, but if you cite it make sure you acknowledge the journal.
I was asked why not try Lancet Neurology or a Nature Journal? Well speed was of the essence to get the views out before the reports surfaced about the actual events in MS. It was not kissing the T cell immunological tush and so it would have a hard time. Importantly it was simply too big for those journals. Indeed if you view the original that went on line, the content has been shaved to reduce the size. We tried to support the views using a number of supportive references….other wise you do immunology101 to COVID-19. This is what most reviews are doing. You have a few facts and fill in the rest with immunology 101.
We have this in a dropbox file. If you want to read it, this should be online in a few days: https://www.dropbox.com/s/vicupqzvhrskkum/Baker%20COVID-19%20MSARDS.pdf?dl=0
The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.David Baker, Sandra Amor, Angray S. Kang, Klaus Schmierer, Gavin Giovannoni
Background: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS.
Objective: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis.
Observations: Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm appears to contribute to the damage in ARDS.
Implications: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic.
What did it say. It suggests that the innate immune system (macrophages and perhaps neutrophils) are important for virus elimination, then CD8 T cells and then antibody and this will help protect from re-infection.
What did it mean?.
If you got COVID-19 then all of the DMT are not going to do much to inhibit the first line of defence against the SARS-CoV-2 virus because the MS drugs are not targeted to the monocyte/tissue macrophage. Therefore hopefully you would all be OK.
There was a theorectical concern that natalizumab could block traffic into infected tissues making more risk of infection, but if you did get infected it could offer you protection. However, if the issue is the blood vessel see below this is less of a concern)
There was a theorectical concern that alemtuzumab depletes CD8, the second line of defence and so increases risk of virus infection, and people with dimethyl fumarate lmyphopenia (low white cell levels) may not clear the virus as quick and had low levels of CD8. Fingolimod also causes some lymphopenia.
There was also a theorectical concern that ocrelizumab/rituximab blocks anti-viral antibody production. The B cells are a third line of defence and the first two lines can deal with the virus and you don’t need antibodies to get rid of the virus. This was found in a study where people who had recovered and made no antibodies. However, the therorectical concern is whether you stop re-infection.
So there was some doom and gloom information or healthy concern as I put it but not the “shit your pants fear” of “Taking an immunosuppressive means you are doomed” concern that we had 4-6 weeks ago. This was the cautious approach taken by the UK government and British Neuros. However, the biology suggests this fear would be unfounded and we should think about changing the cautious approach as there are people that will be offered DMT that are not going to deal with their MS effectively.
The unfolding clinical reality is that this initial fear is probably unfounded. Whilst you are not out of the woods and people on DMT may have subtle increased risks, there have been many hundreds of people on MS-DMT that have recovered. There has been no DMT to be singled out as a problem so far. Admittedly, some people have had a rough ride and a few people have sadly not made it, but most of those people where not being treated with any DMT. Many had the risk of the general population of being older and having co-morbidities. So there seems to be little extra special.
Therefore part 1 of the review remains intact. The ideas for the reveiw above were made around what could be extracted about what COVID-19 does and how MS drugs work.
We are now 2 weeks on from when PART 1 (above) was written and we are now a few thousand bits of informaton further on and more information has surfaced about what COVID virus does. You know me. One of my favourite sayings is “Its behind you” for when the T cell Immunologists are looking for the answer when the B cells are causing mayhem behind.
I have abit more time to learn stuff.
So for COVID-1 we have been focussing on the lung issues but data has emerged to suggest that we should be looking hard at the blood vessels. This better explains the strokes in young people, the heart issues, the different presentation in children. What does this mean for MS and MS treatments……..probably NOTHING…I think this is good news.
Essentially all MS treatments are not going to touch or be touched by this information and so people on DMT will have to deal with these issues just like anybody else. Therefore, it suggests we are “shitting our neurological pants” 🙂 not for the right reasons.
To you can read on or go back to your daily life.
The virus generally infects us via the lung
In most people the virus is attacked by the immune system and you either have no symptoms or your recover with about a week of symptoms
However, in some people who are generally older, overweight, heart issues etc. the virus escapes control of the immune system and causes the lymphocyte numbers to be decreased so they do not finish off the virus. The monocytes/macrophages are unregulated. They go crazy and start pumping out growth factors some people are call a “cytokine storm”. The inflammation in your lung causes fluid to build up. This creates a bigger gap between your lung space and the blood meaning you do not get enough oxygen (hypoxema). The virus and the inflammatory response cause damage to the lung tissue, meaning you are going to need time to get breathing properly again. This is why if you go on a ventilator, it is not a quick exit from hospital.
MS drugs are not going to make this worse and if anything would make this better. So nothing is new in this part of the COVID-19 story. However, the newer focus on the problem is the issue. “It’s behind you” and the greater problem may not be the lung, but the blood vessels within the lung and other tissues.
We know the angiotensin system is involved in the viral infection. We know that the ACE2 (angiotensing converting enzyme two) is the way that the virus gets into peoples cells to divide and replicate. There was a thought that ACE-inhibitors apparenetly increase ACE2 and so you will get worse if you are on a ***pril, which are ACE inhibitors. That is wrong….That was so yesterday…can’t say so last week. There was an element I didn’t bring into the review. This was the renin-angiotensin system, which contols blood pressure amongst other things
This is activity also links to the blood clotting cascade.
This is important because this can form blood clots also known as a thrombus. This is a major problem for the pathology in COVID-19. These are forming in the lung and doing damage when there is no acute respiratory distress syndrome. This is causing strokes and heart problems. What are MS drugs going to do to this?…….
Alemtuzumab can have a side effect that reduces platelets and so would inhibit clotting potential…So what are MS drugs going to do to this? Probably essentially Nothing.
So less to worry about if you are on an MS-DMT
What you want more science….OK for the science nerds…you have twisted my arm. So we had
Now we can bring in the renin-angotensin system. This is an hypothesis and could be wrong. Renin is made in the kidney and makes angiotensin 1 from angoiotensinogen. ACE1 makes angiotensin 2. In conditions of low angiotensin 2, ACE 2 converts angiotensin to angiotensin 1,7 which limits oxidative stress (caused by super oxide (oxygen + extra electron) and hydrogen peroxide). The ACE2 associates with angiotensin receptor and cause relaxation of the blood vessels.
However when there is alot of angiotensin 2 arround the ACE2 dissociates from the angiotensin receptor and triggers constriction of the blood vessels meaning less oxygen reaches tissues.
The virus binds and blocks ACE2 so the default mode is not severe vasoconstriction, this can lead to fluid build up in the lungs.
So that is where we are in part 1 and now we bring in the blood vessles that also have ACE2 on them.
There are factors on the outside of the blood vessel and when damage starts to occur as also happens with the surrounding vessels, factors like von willebrand factor enters the blood. This acts on clotting factors to cause thrombosis (blood clots) which seems to be the problem in COVID-19
So whats this got to do with MS and MS-Drugs essentially nothing so less to be concerned about. However if you are taking alemtuzumab you will have heard of ITP, which is due to autoimmunity to platelets. so there the blood doesn’t clot which is the opposite.
So if anything ACE inhibitors should make things better not worse and we have three papers in New England Jouranal of Medicine saying there is no evidence that taking ACE-inhibitors puts you at greater risk than people who do not take ACE-inhibitors. One study suggested that ACE-inhibitors may have some advantage. So te above may not be a pile of bollocks.
I wonder what will happen to the amatidine story, I would be mining right now….New England Journal beckons…Remeber, you got the idea here first:-). …I can’t do every thing…Reading too many f-ing papers for one thing:-)