Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease, 2023, Liew et al.

Discussion in 'Long Covid research' started by SNT Gatchaman, Jun 21, 2023.

  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease
    Felicity Liew; Claudia Efstathiou; Sara Fontanella; Matthew Richardson; Ruth Saunders; Dawid Swieboda; Jasmin K. Sidhu; Stephanie Ascough; Shona C. Moore; Noura Mohamed; Jose Nunag; Clara King; Olivia C. Leavy; Omer Elneima; Hamish J.C. McAuley; Aarti Shikotra; Amisha Singapuri; Marco Sereno; Victoria C Harris; Linzy Houchen-Wolloff; Neil J Greening; Nazir I Lone; Matthew Thorpe; A. A. Roger Thompson; Sarah L. Rowland-Jones; Annemarie B. Docherty; James D. Chalmers; Ling-Pei Ho; Alexander Horsley; Betty Raman; Krisnah Poinasamy; Michael Marks; Onn Min Kon; Luke Howard; Daniel G. Wootton; Jennifer K. Quint; Thushan I. de Silva; Antonia Ho; Christopher Chiu; Ewen M Harrison; William Greenhalf; J. Kenneth Baillie; Malcolm G. Semple; Rachael A. Evans; Louise V. Wain; Christopher Brightling; Lance Turtle; Ryan S. Thwaites; Peter J.M. Openshaw; ISARIC4C Investigators and the PHOSP-COVID collaborative group

    One in ten SARS-CoV-2 infections result in prolonged symptoms termed ‘long COVID’, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms.

    Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct).

    Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

    Link | PDF (Preprint: MedRxiv)

    Link to published article here
     
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  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    A few quotes —

     
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  3. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    It would be amazing if this depth of research was applied to ME.

    But, wait a minute, in-depth research has been done by the NIH, but we're still waiting to see results. It's been almost 7 years so far - the study started in late 2016. The first publication is still many months to one year away, according to journalist Brian Vastag.

    See this thread:
    USA: National Institutes of Health (NIH) intramural ME/CFS study
     
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  4. Hutan

    Hutan Moderator Staff Member

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    Note that all of the participants had been hospitalised with COVID-19. Measurement 6 months after the infection.
    So, those findings and others in the paper need to be interpreted in the light of the whole sample having had a severe enough infection to have been hospitalised.
     
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  5. Hutan

    Hutan Moderator Staff Member

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    That's a pretty solid odds ratio - so elevated IL1R2 at six months was a predictor of fatigue at six months.

    Note that IL1R2 isn't the same as IL-1. It's a receptor of IL-1, so it binds IL-1. It apparently inactivates IL-1, unlike a competing receptor IL1R1 which generates a signal.

    From Wikipedia:
    From IL-1 receptor 2 (IL-1R2) and its role in immune regulation (2013):
    That paper has a good diagram that helps to understand how IL-1 and various receptors are thought to work.
     
    Last edited: Jun 21, 2023
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  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I think we need to keep in mind that these are people in whom no actual inflammation was found (as far as I can see) and the CRP, a good marker of macrophage-driven inflammation (monocyte is not the right term here), was normal. Also I don't see any big difference reported from controls? Just correlations of some things with some symptoms. The correlation of IL1R2 with fatigue at 1.5 is reasonably substantial but the others look minimal.

    I don't see this revealing 'mechanistic subtypes' to be honest. I can think of a lot of confounders in the analysis.
     
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  7. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    It is good to see people at leat trying to measure these things. I guess I wish they would be more realistic about interpretation.

    I have not had time to read the whole paper. I am wondering if we can be sure that the people with the symptoms and raised markers have symptoms because of Covid or maybe they are ill for other reasons and these markers tend to go with those symptoms. It would be easy to discount that if the picture was black and white but statistical relations can so often turn up for other reasons.
     
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  8. Hutan

    Hutan Moderator Staff Member

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    That 2013 paper is given as a reference in this 2023 Long Covid paper, for this statement in the 2023 paper:
    The 2013 paper tells us that IL-1R2 is found on cell membranes and free in the plasma (where it's called sIL-1R2). It's the plasma sIL-1R2 that is reported in this study.
    Even though the 1.5 of 'elevated IL-1R2' is a decent odds ratio and the difference is statistically significant, the scatter chart isn't terribly convincing. There's an awful lot of people with fatigue with perfectly normal sIL-1R2. I guess it's possible that the people with ME/CFS-like Long Covid are the ones with high IL-1R2, but it's also possible that it is those with a co-morbidity of some sort, such as heart disease.

    Screen Shot 2023-06-21 at 8.13.47 pm.png
     
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  9. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Yes. My grouse is that you need to distinguish between monocytes in blood that might by drawn out into tissues full of cytokines from all sorts of sources, like neutrophils, and inflammation full of macrophages making cytokines that call in more cells and therefore drive the inflammation.

    Monocytic inflammation is an oxymoron because monocytes are what we call cells that have not yet reached a site of inflammation. It is a technical distinction but people do not make the mistake if they understand the compartmental aspects of inflammation - the same problem as calling it inflammation when there are cytokines in blood but no tissue changes.
     
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  10. Trish

    Trish Moderator Staff Member

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  11. John Mac

    John Mac Senior Member (Voting Rights)

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  12. John Mac

    John Mac Senior Member (Voting Rights)

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    Science Media Centre

    expert reaction to study looking at long Covid subtypes and inflammatory signs in people with long Covid after Covid hospitalisation

    A study published in Nature Immunology looks at long Covid subtypes and inflammatory signs.

    Prof Eleanor Riley, Professor Emerita, Immunology and Infectious Disease, University of Edinburgh.
    Dr Emily Fraser, Consultant in Respiratory Medicine, Oxford University Hospitals NHS Foundation Trust, and clinical lead of the Post COVID clinic in Oxford.
    Prof Kevin McConway, Emeritus Professor of Applied Statistics, Open University.

    https://www.sciencemediacentre.org/...-with-long-covid-after-covid-hospitalisation/
     
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  13. Lindberg

    Lindberg Established Member (Voting Rights)

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  14. Simon M

    Simon M Senior Member (Voting Rights)

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    I'm not up pon LC research, but I wonder about the relevance of this to ME, or even most LC.
    It only looks at people hospitalised with Covid, and effectively operationalises LC as anyone with ANY LC symptoms at 3 months, which is pretty broad. The vast majority of people with LC were not hosptitalised.

    Fig 1b maps the cohort by symptoms:
    LC hospitalsed Apr 24 Fig 1.png
    E.g. the largest group have fatigue and cardio-respiratory symtpoms but not e.g. cognitive. Could this be linked to lung damage from a severe respiratory infection?

    Almost all ME folk have cognitive symptoms yet these make up the smallest group in this study (<100), and about 20% of these have no fatigue. I'm sure it's a very useful study looking at why people don't recover after hospitalised infections, but there is quite a lot of broader speculation in the media.

    [QUOTE Fig 1 legend ]b, An UpSet plot describing pooled LC groups. The horizontal colored bars represent the number of patients in each symptom group: cardiorespiratory (Cardio_Resp), fatigue, cognitive, GI and anxiety/depression (Anx_Dep). Vertical black bars represent the number of patients in each symptom combination group. To prevent patient identification, where less than five patients belong to a combination group, this has been represented as ‘<5’. The recovered group (n = 233) were used as controls. .[/QUOTE]

    That said, the results for the 'cognitive' symptom group showed the biggest effect, for neurofascin (shown below, Fig 1h, the abstract mentions C1QA):
    LC hospitalsed Apr 24 Fig 1g.png
    Would be interesting to see results for this/these molecules in LC and ME.
     
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  15. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Commentary: Immune dysregulation in long COVID (2024, Nature Immunology, paywall). Concludes —

    (3) This paper
    (4) Persistent complement dysregulation with signs of thromboinflammation in active Long Covid (2024, Science)
     
  16. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    CD41a was also noted on extracellular vesicles in Comparative Analysis of Extracellular Vesicles in Patients with Severe and Mild Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2022, Frontiers in Immunology) —

     

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