Why have MS-DMT not impacted on #MSCOVID19 and vice versa…Simples it may not be an immune issue

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Since the COVID-19 story broke we have been focusing on the immune system, because after all the immune system will ultimately get rid of the virus. We have made the point that many MS-DMT may not grossly inhibit the cells responsible for the anti-viral response and so MS-DMT may not stop you responding sufficiently to the SARS-CoV-2 virus. More recently we have been suggesting that a central part of the pathology of COVID was due to damage to the vasculature (blood vessels) and clots and that MS and MS-drugs were unlikely to be impacted by this and are unlikely to impact on this. Obviously this is a ongoing story and we have to modify the view as new evidence emerges, at present I do not feel I need to do this yet. Indeed the concept has gained more and more support.

When we first started with our ideas we had knowledge of immunology 101, but was looking to the pathology. So as the neutrophil club was getting their science consortium to get mega bucks in grants, I was asking where are the Neutrophils in the lesions. I had spotted the microthrombi but did not get their significance, because I am not a vascular biologist. It was hard because I was having to use Google translate to try and understand what was going on as most of the articles were written in Chinese and the programme only translated so many characters at a time. I could see blood patches in the lungs but thought theu may be haemorrhage (blood leaking from the vessels rather than blood clots), I got it two days after the first review was revised and submitted and wish I could have updated it. However you have had that information weeks ago.

In this study they looked a severe flu and severe covid and the noticable difference “The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular (inside the cell) virus and disrupted cell membranes”. As we said many weeks ago such damage would liberate clotting factors. There were 9 times more clotting in COVID than in flu and attempts were there to make new blood vessels to get round the problem of clotted vessels

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D.N Engl J Med. 2020 May 21. doi: 10.1056/NEJMoa2015432.

Background: Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.

Methods: We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro-computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.

Results: In patients who died from Covid-19-associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. 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 angiogenesis – was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).

Conclusions: In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.).

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MouseDoctor

14 comments

  • I’m really bored with Covid 19. Thankfully, where it has been has been fatal, it has mainly affected elderly people with pre existing conditions (dementia, diabetes…). It’s a tragedy for those who have lost a relative, but the world needs to learn lessons and move on. Thankfully, there have been improvements in how those who end up in hospital are treated which means that the chance of dying from the disease are lower than at the start of the pandemic. Better therapies to treat the disease look likely and there is a reasonable chance of a vaccine in the next 12-18 months.

    Team G have thrived on the Covid 19 pandemic, producing papers at unprecedented speed and highlighting their knowledge of the immune system and how it tackles the virus.

    Team G now needs to move on. There are 130,000 people with MS in the U.K. who all face a future of increasing disability and a shorter than average life-span (7-10 years shorter on average, but with many years of increasing disability preceding death). We still have no treatment to stop progression, protect nerves or encourage repair. I would like to see Team G get as enthusiastic about MS as they have been about Covid 19. I feel Covid 19 has been a distraction for Team G which has meant that MS research has been in hibernation for the last 3-4 months and 2020 will end up being a write-off in terms of research / trials which will benefit MSers. As we emerge from lockdown, what can we expect from Team G in the next 6 months in terms of exciting MS research? I really hope we don’t see an endless stream of papers about DMTs and Covid 19 which will be of academic interest, but of no real benefit to MSers.

    • I am bored with COVID-19 too. Yes, COVID-19 has not only been a distraction for Barts-MS, but the NHS and the country at large. We are all working on grant applications that tackle many other aspects of MS. MD is working on a neuroprotection grant, NDG on an immune-stimulating grant, MM on an anti-CD20 adaptive-dosing grant, ProfK on his attack-MS proposal, Alison is working on the next phase of Digesting Science and her Under&Over project, Ruth on an MS Prevention grant (infectious mono) and myself on an EBV study and induction-maintenance treatment grant and the list goes on. None of these has anything to do with COVID-19.

      I have also moved on intellectually from SARS-CoV-2 and COVID-19 as well. I predict that the pandemic will peter out long before a vaccine becomes available. I wouldn’t be surprised if the virus loses its foothold in Europe and the UK by the end of the summer. i.e. zero new cases. If all countries get their whack-a-mole strategy in place the virus will have nowhere to hide. Coronaviruses need a host to remain in circulation; let’s hope it is not our feline friends the domestic cat.

      • Prof G,

        Thanks for the response. It was good to see the list of work going on / planned. Like most MSers, I live on the hope that I might see some breakthroughs in my life time. In the meantime I have done all I can – IRT 13 years ago, plenty of exercise and Low Carb diet (best thing I have done following your excellent advice).

        Good luck with all the MS research. In my crystal ball I can see Mr & Mrs G enjoying a nice break on a Greek island in late Summer.

    • As we emerge from lockdown, what can we expect from Team G in the next 6 months in terms of exciting MS research? You will just have to wait and see. I think we will find that we have got more papers out in the lockdown than at other times. You feel that Covid19 has been a distraction and we need to get back to work….but it is not that simple. We were not allowed to work (wet lab) and it is not clear how this resumes with social distancing. All research has been in hiberation…MS and non-MS…Clinical trials have been put on hold and it is not just 2020 that may go but 2021 too….Governments are focussing their resources on COVID so we can have 5-6 papers on the same thing but importantly the Charties have shut up shop…There are probably no grant rounds for this year and as it takes a year to get one, this wipes out 2021 too. Labs will shrink. MS output will go.

  • Thank you for all the extremely interesting Covid-19 and MS research. It would be great to hear more on the blog about the EBV/MS study you mentioned that you are working on.

    Overall, I would really like to see more research done in the UK on whether tackling one of the root causes of MS can help PWMS even once they’re into SPMS.

    I haven’t seen any recent results of the EBV/T-cell immunotherapy trials being done by Prof Michael Pender in Queensland, but what I read about them in 2018 sounded promising.

    • “but what I read about them in 2018 sounded promising.”

      Yes..the older study seemed more promising. Since all the higher
      doses improved..but in the latest..seems not so many improve.

      Atara’s ATA188 data summary
      Subjects showing disability improvement by EDSS

      Cohort Dose (cells) 6 mths 12 mths
      1 5 million 1/6 1/6
      2 10 million 0/6 0/6
      3 20 million* 1/6 2/5**
      4 40 million 2/6

      https://www.evaluate.com/vantage/articles/events/conferences/ean-2020-ataras-multiple-sclerosis-plan-slowly-takes-shape

      • Atara’s approach is to use allogenic cells throwing alot of immunology 101 out of the window as the original approach was on using autologous (recipient was the donor of the cells)

        • “the original approach was on using autologous ”

          But that was why some failed..their tcells were so exhausted they couldn’t be boosted enough. Phase 2 autologous is on the back burner for now affirmed at investor q and a..committed to allogeneic.

          • That is marketing babble I suspect, allogeneic makes it mass production, Prof Pender could have used allogeneic if it made sense, to me, it doesn’t, allogenic MHC can recognise a host of other major histocompatibility complex antigens and in rare circumstances could elicit a graft verses host disease maybe they is the plan.

          • Remember the presentation on this at MS at the Limits in January and have to say I wasn’t particularly impressed. Allogeneic to me too, makes no sense.

  • Nice reasoning Mouse

    What about Tocilizumab ,anti il-6

    Used in Rheumatoid arthritis

    Neuromyelitis optica

    Cytokine release syndrome

    Was used in covid 19 severe patients and they got better

    Clearly an immune system drug

    • I am not saying the immune system in not involved but the IL-6 thing is perhaps not a T and B issue, it is a innate immune issue, MS drugs are not monocyte/macrophage inhibiting drugs they are T and B cell drugs. Inflammation contribiutes to the vascular damage.

      Anti-IL-6 is not necessarily the universal solution

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