Persistent capillary rarefication in long COVID syndrome

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.

Keywords: COVID-19; Endothelial glycocalyx; Endotheliopathy; Long COVID microcirculation; Microvascular health score; Sublingual microscopy.

Fig. 1

Microvascular phenotyping by quantitative sublingual video microscopy. A Median and IQR values of vascular density of healthy controls (green), and long-haul COVID-19 (orange) patients based on the diameter class from 4 to 25 µm. A historical cohort of hospitalized COVID-19 patients (pink) is shown for reference. *q < 0.05, **q < 0.01, ***q < 0.001. B–D Boxplots of B capillary density (D_4–6 µm) and C PBR_4–25 µm and D MVHS™ of healthy controls (green), long-haul COVID individuals (orange), COVID-19 patients (pink). COVID-19 Coronavirus disease 2019, CR capillary recruitment, D diameter, PBR perfused boundary region, RBC red blood cell, VRBC red blood cell velocity, MVHS™ microvascular health score

Fig. 2

Red blood cell velocities and recruitment capacity. A, B Boxplots of A VRBC in capillaries (D ≤ 7 µm) and B VRBC in feed vessels (D ≥ 10 µm) of long COVID individuals (orange), hospitalized COVID-19 patients (pink) and healthy controls (green). C Scatter dot plots and simple linear regression (slope) with 95% confidence intervals of VRBC in capillaries plotted against VRBC in feed vessels of long COVID individuals (orange), hospitalized COVID-19 patients (pink) and healthy controls (green). D Bar charts showing the capillary recruitment (CR), defined as 1 − slope [VRBC (D ≤ 7 µm) vs. VRBC (D ≥ 10 µm)] per group

Fig. 3

Sensitivity analyses in individuals with long COVID. A, C Boxplot of (A) MVHS and (C) density of long COVID individuals based on the clinical course of their acute COVID-19 infection. B, D Scatter dot plots and simple linear regression (slope) with 95% confidence intervals of (B) MVHS and (D) capillary density plotted against the days after the COVID-19 infection. COVID-19 Coronavirus disease 2019, MVHS microvascular health score, ns not significant