Persistent capillary rarefication in long COVID syndrome, 2022, Rovas et al

Abstract
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.

Full text

 

Long Covid patients had fewer small capillaries under their tongues (hospitalized acute Covid patients had even fewer):


By measuring the changes in velocity of red blood cells in blood vessels feeding the capillaries and in the capillaries themselves under changing conditions, they were able to calculate a capillary recruitment value:


"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."

Then they found an association between reported neurocognitive dysfunction and capillary density:
"Associating the different symptoms with the capillary density in an explorative manner, revealed a statistically significant capillary rarefication in long COVID individuals presenting with neurocognitive dysfunction (38.50 [25.93–44.41] vs. 49.77 [43.40–64.30], p = 0.049; Supp. Table 1)."

"To assess recovery of microcirculatory parameters over time, we plotted MVHS and capillary density against the length of time between initial infection and presentation to the long COVID study outpatient clinic. Interestingly, no improvement of these parameters was documented, assuming capillary loss due to COVID-19 might be irreversible (Fig. 3B, D)."
It does seem more likely that the capillary loss is due to some other ongoing factor which improves if that factor is reduced (because we know some people do recover from LC).

This study included 12 un-hospitalized patients and 15 hospitalized (8 received oxygen), so not representative of LC in general, but their finding didn't differ between these groups. The majority of the patients were about 1.5 years post-infection.

"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 [10]. Besides that, an insufficient recovery of the initial inflammation accompanied by persistent immunological abnormalities might also be responsible for the observed capillary impairment [6]."

"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."

"If capillary rarefaction were to persist, additional cardiovascular disease (e.g., diabetes, hypertension) will be less well compensated and become symptomatic much earlier."
Perhaps a connection here to the increased risk of diabetes, cardiovascular disease, etc after Covid infection.

This seems like a very significant finding and I hope they are already working on a follow up with more patients.

 

I wonder if this might be related to the findings in this paper (posted by @LarsSG), in which serum from post-COVID syndrome (PCS) patients prompted the formation of new blood vessels in the microcirculation (angiogenesis) to a much greater degree than serum from patients with post-COVID syndrome and ME/CFS symptoms.

The hypothesis for that finding seemed to be that, in PCS, endothelia dysfunction impairs the delivery of blood/oxygen to cells, but that is compensated for by the development of new blood vessels.

For some reason, new micro-blood vessel development was significantly less abundant in PCS patients with ME/CFS symptoms, suggesting that the ME/CFS symptoms might be due to insufficient blood/oxygen reaching the cells.

A diagram from that paper:





This reminds me of Dr. Systrom’s observation that too much oxygen was returning to the hearts of ME/CFS patients, suggesting that oxygen in the blood was not reaching the cells and/or was not being taken up effectively by them.

 

So perhaps some further supportive evidence for ongoing microthrombi affecting the capillaries (following the HpXe MRI findings). Possibly a mechanism for exertional intolerance. Unsure if potentially a relationship to PEM.

When looking back at the start of the COVID story, the initial findings of severe acute disease pointed to microthrombosis in the peripheral pulmonary vasculature at symptom onset, and were supported by later postmortem findings. I.e. that it wasn't a viral pneumonia/pneumonitis, developing secondary vasculopathy but a de novo pulmonary vasculopathy. I think new findings are implicating this process long-term, at least as part of the explanation.

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CT showed peripheral wedge-shaped areas of ground-glass opacity or consolidation, with a newly recognised vascular tree-in-bud pattern, with distended small proximal vessels — quite different to the usual findings in pulmonary embolism.

From COVID-19-induced vascular angiopathy: CTPA signs in critically ill patients other than acute pulmonary embolism and high-lung opacity scores (2021). See also this 20 min video from Nov 2020 where a radiologist was invited to talk to haematologists about this.