COVID Breakfast… Lymphopenia the Bog roll effect.

C

Some people with MS drugs have low levels of white blood cells. This is causing some alarm that you can’t fight infection. I am sure we you can appreciate that is Immunology 101. Something can’t fight something if it is not there.

If we look at people who get covid 19. Those who get severe problems have low white blood cells in their blood. This has been repeated in a number of studies, but it is not universal as you can have severe COVID19 without being lymphopenic. However read the title and you think that this is the cause of the problem

Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang YQ, Wang Q, Miao H. Signal Transduct Target Ther. 2020 Mar 27;5:33. doi: 10.1038/s41392-020-0148-4. eCollection 2020.

People who died of covid had low white blood cell counts from about ten days from symptom onset

Is this the cause of the problems, because if it is people with immunosuppression who have low levels of white blood cells would be at very high risk.

The scientist speculate there are four potential mechanisms leading to
lymphocyte deficiency.

  • The virus might directly infect lymphocytes, resulting in lymphocyte death. Lymphocytes express the coronavirus receptor ACE2 and may be a direct target of viruses.
  • The virus might directly destroy lymphatic organs. Acute lymphocyte decline might be related to lymphocytic dysfunction, and the direct damage of novel coronavirus virus to organs such as thymus and spleen cannot be ruled out. This hypothesis needs to be confirmed by pathological dissection in the future.
  • Inflammatory cytokines continued to be disordered, perhaps leading to lymphocyte apoptosis. Basic researches confirmed that tumour necrosis factor (TNF)α, interleukin (IL)-6, and other pro-inflammatory cytokines could induce lymphocyte deficiency.
  • Inhibition of lymphocytes by metabolic molecules produced by metabolic disorders, such as hyperlactic acidemia. The severe type of COVID-19 patients had elevated blood lactic acid levels, which might suppress the proliferation of lymphocytes.
  • Multiple mechanisms mentioned above or beyond might work together to cause lymphopenia, and further research is needed.

However perhaps they miss the most obvious problem. It may be a consequence of the problem. Disease severity is associated with damage to the lung and whilst the virus does cause damage to the lung, the really severe people appear to do badly because the white blood cells have emptied from the blood and gone into the lung.

To help explain this to the scientists following their altmetrics.

Think of the COVID LOO ROLL ISSUE

Many of us have been looking for toilet paper. They used to be line up in neat rows on shelves in shops.

Remember this a Healthy Shelf. See them as Bood vessels with Whte blood cells

However a few weeks ago as COVID fever arrived the shelves were empty. The worse the panic the more the shelves were cleared

Coronavirus panic buyers told to 'calm down and get a grip' by ...
The Shelves (Blood vessels) are Empty

Now the cause of the Panic Destruction of the Lung (sometime heart) lining, which you and I know, is a Garage.

The reason for the Loo Roll Panic is this Garage

So where do you think the Loo Rolls may be?

Simples inside the Garage. There you go
The Australian who thought they were ordering 48 loo rolls but got 48 Boxes (2000 rolls)

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunologic features in severe and moderate Coronavirus Disease 2019. J Clin Invest. 2020 Mar 27. pii: 137244. doi: 10.1172/JCI137244. [Epub ahead of print].

They say “the SARS-CoV-2 infection may affect primarily T lymphocytes particularly CD4+T and CD8+ T cells, resulting in decrease in numbers as well as IFN-γ production. These potential immunological markers may be of importance due to their correlation with disease severity in COVID-19”.

However if you don’t even look for monocytes, how do you know what is important? So if you have a fixed view that T cells are important, you only look at T cells. Therefore you can see that this type of world view is not special to MS. If you are looking in one way you can’t see other ways such that they see increases an IL-2, IL-6, TNF and IL-10 and get lost in the pro-inflammatory anti-inflammatory view.

However, if you see them as T and B cell growth factors, would it be surprising that if you were losing cells you would try to make new ones. IL-2, IL-6, TNF, IL-10 are all B cell growth and survival factors. IL-2 is well known for supporting T cell growth. Surprise , surprise we get T regs thrown in too. What would a T cell paper be without T regs after all:-)

Maybe COVID is damage the immune cell response check out the comments below which suggests the immune destruction can relate to direct damage of the immune cells, in which case the above may be irrelevant….off to do some more reading..Il’ll be back

NOW THE SERIOUS PART

For your information.

The UK has started a clinical trial of anti-virals and anti-inflammatory agents with enrollment of 3,000 over 3 months agents, in terms of inclusion and exclusion criteric you may not be suitable, but if you are unfortunate enough to be hospitalised this may be an option. Therefore please discuss your wishes with your relatives if you think you are infected and want to volunteer.

Trial details https://www.recoverytrial.net/files/professional-downloads/recovery-protocol-v2-0-2020-03-23.pdf

It says “Informed consent should be obtained from each patient before enrolment into the study. However, if the patient lacks capacity to give consent due to the severity of their medical condition (e.g. acute respiratory failure or need for immediate ventilation), then consent may be obtained from a relative acting as the patient’s legally designated representative.

I suspect before they finish recruitment a full or a partial answer will probably be known as variants of similar trials are being udertaken, notably earlier after symptom onset. As you can see there are 18 trials on hydroxychloroquine, not all at the same time before and after onset. It is logical that the earlier you get the anti-viral the better. However I wonder why is this not better co-ordinated across the globe as you would have an answer in 2-3 weeks. However we have seen with vitamin D and microbiome trials you have the same trial done in many different countries

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MouseDoctor

18 comments

Leave a Reply to Dr Love Cancel reply

    • CMV is a common virus and is normally kept in check…now you mention tysabri and this is a migration blocker so it traps cells in the blood. It is my opinion it is as bit of misinformation to think that tysabri (alpha 4 integrin inhibitor)only stops migration into the brain (blocks alpha4 beta 1 integrin) and the gut blocking alpha 1 beta 7 integrins), it will block trafficiking into a host of other tissues, potentially including the lung, and that may prevent clearing infections. The reason we pick up on PML is because this is usually cleared virus and for it to cause disease, as is the case with CMV, you notice it. But tysabri use is associated with an increased risk of infection. Now for your bloock count it could be that your blood is full of CMV reactive T cells stuck in the blood. Its an opinion what’s yours

      • 1) Is there a possibility of testing the level CMV reactive T cells in the blood? I had a CLL scare a couple of months ago…
        And is there any long term issue (immunosurveliance or else) with having such reactive cells?

        2) Why are we still attached to Lymphocyte Count as an absolute figure to deal with coronavirus, when the locality of those T-Cells is more important that the figure.

        3) Biogen says that there are 2 more primary CMV cases on their Tysabry register (as of a few weeks). Why has the ABN deemed Tysabri safer than S1P agents in light of T-Cells trafficking issues?

        • 1) Testing Level of CMV T cells…I believe this is possible using tetramers but this depends on whether you know your MHC class I type…I suspect you will find this is much of you T cell repetoire.

          Any CMV..I suspect we all have them…thats one way you keep it in check.

          2) Doctors aren’t scientists and noboby has told them to do something differently 🙁

          3) ABN why is one safer…I would look at the australian guidelines at least they explain their logic

          • If 6-Week EID dosing is beneficial to immunosurveliance (per G’s last post), what do you expect will happen to my CMV reactive T-cells after transitioning to EID?
            Would you expect lower total lymphocyte count after 6 months or so?

  • Regarding the theory that lymphocytes are missing from the blood because they have gone to the lungs, shouldn’t only *SARS-CoV-2-specific* lymphocytes be traveling to the lungs, leaving the rest of them to circulate around in the ordinary fashion? Is there some mechanism I’m missing that would cause *overall* lymphocytes in circulation to decline during a pathogen response? (Perhaps fewer naive cells are produced to focus available resources on defending against the virus instead of replenishing the overall repertoire?) (The graph you include shows only the percentage of lymphocytes, yes, but other studies have reported low absolute lymphocyte counts as well, like doi: 10.1172/JCI137244)

    Also, at least one preprint based on postmortem examinations claims that the virus “Directly Decimates Human Spleens and Lymph Nodes” (!), but I’m not sure what to make of this (10.1101/2020.03.27.20045427)

  • What does it means a % in lymphocytes (why did they not work with absolut number)? It seems to me that people with decreasing % of lymphocytes are more likely to face severe outcome, this is very different from saying if you have a low lymphocytes count are more likely to face a severe outcome. As you have one without the other and vice-versa. For instance, you can have a high absolute lymphocyte count at the beginning that is decreasing leading to severe outcomes. The title is misleading. I am for the explanation that Lymphocytes go to attack your lung and if this is true it would be beneficial to have a low lymph count to begin with 🙂

    • A machine called a flow cytometer outputs the results as a percentage, but to understand what happens you have to work in absolute number
      you analyse you have 50,000 cells and you analyse 10,000 cells and you have 10% of cells expressing A you have 5 x 1000 cells = 5,000 cells
      now you do something and you a 20,000 cells you analyse 10,000 and you have 25% of cells expressing A. So is that an increase from 10% to 25% but the actual number of cells is still 5,000 so no change. See alemtuzumab and you will find an explanation

          • A lower percentage at a given time does not mean a lower lymphocyte count between two individuals? So you cannot say from this study low lymphocyte count => higher chance of aggravation of covid – 19. BTW I never had my lymph count as a percentage, how come?

          • Agreed there is a big range within one individual. To know if lymphocyte number is a cause or consequence of aggrevation of COVID we need to find the paper that relates levels to symptoms. I am not aware of a study that shows this.

            You never had a count as a percentage…this is because the testing labs do it property, when scientists start doing stuff you get the percentage nonsence:-)

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