[Preprint] Post-COVID syndrome associated with capillary alterations, macrophage infiltration & distinct transcriptomic signatures in skeletal muscles

Post-COVID syndrome is associated with capillary alterations, macrophage infiltration and distinct transcriptomic signatures in skeletal muscles
Tom Aschman, Emanuel Wyler, Oliver Baum, Andreas Hentschel, Franziska Legler, Corinna Preusse, Lil Meyer-Arndt, Ivana Buettnerova, Alexandra Foerster, Derya Cengiz, Luiz Gustavo Teixeira Alves, Julia Schneider, Claudia Kedor, Rebekka Rust, Judith Bellmann-Strobl, Aminaa Sanchin, Peter Vajkoczy, Hans-Hilmar Goebel, Markus Landthaler, Victor Corman, Andreas Roos, Frank L. Heppner, Helena Radbruch, Friedemann Paul, Carmen Scheibenbogen, Werner Stenzel, Nora F. Dengler

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also caused innumerable cases of post-infectious syndromes, colloquially referred to as long COVID. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms.

We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues, but transcriptomic analysis revealed distinct gene signatures compared to the two control cohorts, indicating immune dysregulations and altered metabolic pathways.

We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Link

 

A couple of other papers related to capillary reduction post-Covid —

Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue (2022)
Persistent capillary rarefication in long COVID syndrome (2022)

 

Although an interesting study with relevance to ME, this hypothesis seems to suggest that Long Covid with PEM results from a fixed term/one off event resulting in structural changes during the acute viral infection. Does this then imply after the causal infection the ongoing condition should be stable or gradually remitting as the body attempts to repair itself?

Would ME and I suspect Long Covid meeting the diagnostic criteria for ME be better characterised as an ongoing process?

Certainly a characteristic feature of ME is its variability both within and between individuals. My initial experience of ME could fit in with the idea of a one off onset event triggered by an acute infection, EBV/glandular fever, which though fluctuating displayed overall improvement over a number of years and again my first major relapse was associated with a bout of seasonal flue with subsequent overall improvement albeit slower again over a number of years are not inconsistent with this hypothesis. However in contrast my next rapid onset major relapse began as PEM the day after a twelve mile hike followed by even slower improvement over a number of years, and my current severe impairment involved more gradual deterioration over a number of years with no easily identified trigger events. I don’t think the variation in individuals’ condition is explainable, without out recourse to other factors, as a one off acute event, nor is the different courses of the condition seen in different sufferers, ranging from gradually improving, to stable, to relapsing/remitting to ongoing deterioration.

It would be interesting to understand what changes in the microvasculature occur within individuals over time and if they correlate with the severity of symptoms over time.

 

I read it more that the virus sets up the milieu whereby immune dysregulation has a number of deleterious downstream events, esp on the endothelium. I would expect onset to be slow and inexorable, but at the same time homeostatic mechanisms that can partly compensate could keep symptoms variable in degree and location, and sometimes under control in the initial stages.

For me at the start, I would have weeks of postural tachycardia which would then subside, with two to three weeks of normality. This cycled for a couple of months before symptoms bedded in, and then proceeded to worsen a few months later.

 

CD68 is a general macrophage marker. CD169 probably equates to active scavenger macrophages with antigen-presenting capabilities. I am not sure that it tells us more than that macrophages have recently been called in. it may do.

I would be interested to know what these muscles look like stained for CD55 or CD16. As I have mentioned before, different tissues carry different signalling molecules adsorbed on to fibrillin fibres in their elastic networks. These molecules are normally thought of as functioning on cell surfaces but seem to get painted on to the matrix network as well, where they may provide a 'response memory' for the tissue. I can imagine that after an acute infection these signalling proteins may get left on fibrillin for months, possibly acting as a sump for immune complex binding and low grade cytokine activation.

Looking for cells is of interest but always leaves the question as to whether they are causing a problem or responding to one. Finding changes in matrix might help sort that out.

 

I think this is the first time I have seen an academic paper not written by patients that correctly frames it as exertion intolerance, rather than about exercise. My memory being bad, no more than a handful for sure. Kudos for that alone, it's rare to pay attention to the right details, even after 3 years.

Bit funny to speak of localized immune responses talking about one of the two organs that span every single part of the body. Not saying this is the case but it'd be kind of funny if, basically: good news, we found the problem in one organ, bad news, that organ is everywhere, and I do mean literally everywhere. It's localized everywhere, basically. But at least it restricts the search space anyway.

Is there good expertise in vascularity that isn't simply a subset of cardiology and still views the heart as the only interesting part? Seems like an area that isn't especially large or exciting.

 

VEGF is going to end up being a thingee here...

 

Now published as Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles.

 

Am I correct in thinking that this study provides experimental support for Fluge and Mella’s proposed pathological mechanism of endothelial dysfunction? They published a study on it this year.

In any case, this study seems important on its own.