Persistent capillary rarefication in long COVID syndrome (Osiaevi et al, 2022)

[SNT Gatchaman]

Persistent capillary rarefication in long COVID syndrome
Osiaevi, I., Schulze, A., Evers, G., Harmening, K., Vink, H., Kümpers, P., Mohr, M., Rovas, A.

Background: Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection.

Methods: This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4-25 µm.

Measurements and main results: Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: - 45.16%; D6: - 35.60%; D7: - 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002).

Conclusions: Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

PubMed | PDF

 

[SNT Gatchaman]

Some (edited) quotes —

Long COVID patients showed a significantly lower vascular density compared to healthy controls. Specifically, a μm-precise analysis showed the decrease in vascular density to exclusively affect very small capillaries. Compared with healthy controls, the capillary density of long COVID patients was decreased by 41%.

Surprisingly, [Velocity of Red Blood Cells] was significantly higher in capillaries as well as feed vessels in long COVID patients compared with healthy individuals. Plotting VRBC≥10 μm vs. VRBC4–7 μm revealed a strong dependency between capillaries and feed vessels in both, individuals with long COVID and hospitalized COVID-19 patients (long COVID: R2 = 0.29, p = 0.004; COVID-19: R2 = 0.45, p < 0.0001), indicating impaired capillary (de-) recruitment in these groups. In contrast, capillary VRBC was constant in healthy controls, indicating functioning (de-) recruitment of CBV associated with changes of feed vessel blood flow in healthy subjects.

[Capillary Recruitment] was 29% in long COVID, 17% in COVID-19 patients and 70% in healthy volunteers. This finding suggests that the number of perfused capillaries in long COVID remains fixed and does not adequately respond to local variations of tissue metabolic demand.

In addition, capillary recruitment of COVID long-term patients remains significantly reduced. While healthy controls succeed in maintaining a constant capillary VRBC (almost horizontal slope), long COVID patients as well as acute COVID-19 patients fail to do so (steeper slopes). This finding reflects a persistent fixed number of perfused capillaries, which is insensitive to local tissue variations of metabolic demand.

To what extent this capillary rarefication is mechanical or/and functional remains unclear. Pretorius et al. revealed common clotting pathologies in plasma of acute and long COVID patients, further supporting the existence of persistent microthrombi. Besides that, an insufficient recovery of the initial inflammation accompanied by persistent immunological abnormalities might also be responsible for the observed capillary impairment.

A subtle but exciting feature of the long-haul COVID group is, that the RBC velocities are the highest in our long COVID cohort (indicated by parallel shift of the slope to the upper right). We speculate that this finding could represent a compensatory mechanism to meet metabolic demands. Considering that the measurements were taken at physical rest, it is quite conceivable that this presumed compensatory mechanism is exhausted more quickly during exertion than in healthy individuals, possibly explaining long COVID symptoms.

 

[Consul]

Very nice study. As i understand it there isnt a loss of capillaries but just a reduction in the number of perfused capillaries(?).

If this is because of clotting then maybe the particular capillaries that are perfused will vary from week to week as the clots gets broken down and new ones emerge somewhere else. So maybe having the patients back later to check if the exact same capillaries are perfused or not could verify if clotting is the problem or if its something else.

 

[SNT Gatchaman]

I doubt they'd be able to re-identify individual capillaries at follow-up. I think this is further evidence for thrombosis affecting the microcirculation (possibly amyloid microclots). Back in 2020 there was evidence of this process at the outset of severe acute disease. This year there is evidence of a similar process in long Covid patients via Hyperpolarised Xe MRI.

Image from the above-linked 2020 paper, showing the novel CT findings of "vascular tree-in-bud" pattern and dilated pre-capillary arterioles, which could be explained by thrombosed capillaries.

 

[Consul]

@SNT Gatchaman thanks for providing this info, looks like there is solid evidence for the clots. I saw the Xe MRI study a while back and was hoping for them to scan me/cfs patients as well later.

The problem i have though about the clots being the main driver of the disease (both LC and ME) is that apparently a number of other diseases also have micro clots, e.g rheumatoid arthritis etc but they dont necessarily have ME. So do you have any idea of how to get around this? I view the clot theory as having alot of explanatory power though so would be nice to get this issue out of the way.

 

[borko2100]

Makes sense to me. If the number of (micro)capillaries in the muscles is reduced then the supply of oxygen and other nutrients there will be reduced as well. This then leads to to the muscles getting tired rapidly (rapid muscle fatigueability), reduced endurance, etc. If the capillaries in the brain and the CNS are affected too, then, like with the muscles, the energy supply would be reduced. Reduced supply of oxygen and nutrients to critical cells like neurons could possibly lead to all kinds of issues. From brain fog to depression to nerve pain to POTS, etc., these could all be the effect of this.

What I don't like about the theory though is, if the capillaries are affected everywhere, then one would expect more far-reaching consequences like problems with the liver, kidneys, lungs, eyes, etc. Then again, the theory could still work. Maybe the capillary damage is severe in only certain tissues (muscles, brain, etc.).

In any case, good that they are researching this, it's an area where few if any CFS researchers have looked in the past (AFAIK). Let's hope this study gets replicated and more studies on the subject come our way.

 

[andyguitar]

The problem i have though about the clots being the main driver of the disease (both LC and ME) is that apparently a number of other diseases also have micro clots, e.g rheumatoid arthritis etc but they dont necessarily have ME.

Another finding in me/cfs is abnormalities in Red Blood cells. So perhaps it's a combination of a couple of things that cause symptoms.

 

[SNT Gatchaman]

@Consul yes I'd like to see ME patients having HpXe MRI too. I wouldn't go quite as far as "solid evidence" for circulating microclots, but I do think the evidence is building. Hypercoagulation can probably be regarded as a safe bet though.

Yes agree that finding anomalous microclots in other diseases has muddied the waters, but Prof Pretorius and team found that diabetes, RA etc had milder aberrant clotting. Acute and long Covid had strikingly more. ME seems to have them in increased numbers too but not as much as LC.

The LC patients are by definition, only one to two years in. It's possible that ME patients may have measured like the LC patients early on in their disease course. Maybe the aberrant clotting reduces over time but the capillary impairment remains; maybe microclots are there in similar numbers in ME but "jammed" in compromised capillaries and less present in the venous blood pool to be measured. This might be hard to pin down in the future as Covid remains with us and it becomes hard to diagnose old school ME in someone that hasn't had Covid.

I think the researchers are now suggesting that this is a downstream effect, rather than the primary cause - however it could be a major contributor to symptoms. Potentially downstream of eg immunothrombosis, endothelial dysfunction.

I agree with @andyguitar that RBCs need to be included in the explanation. This study showed faster velocities - thought to be a metabolic compensation. That puts RBCs at risk for damage from increased shear forces - potentially this might contribute to PEM.

 

[andyguitar]

That puts RBCs at risk for damage from increased shear forces - potentially this might contribute to PEM.

I'm thinking this (first pic, last sentence)... that comes from the research in second pic.