Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue

Abstract

Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell’s score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p < 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: −4.5; −0.92)). The model included variables of age, gender and Bell’s score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS.

Keywords: COVID-19; OCT angiography; chronic fatigue; chronic fatigue syndrome; functional GPCR autoantibodies; long COVID syndrome; post-COVID-19 syndrome; retinal microcirculation.

Figure 1

Boxplots of VDs in the SVP (a), ICP (b) and DCP (c) in patients with post-COVID-19 syndrome (PCS) and controls, considering the cofactor of age: a decrease in VD in all retinal layers was observed with increasing age in PCS patients and controls. SVP—superficial vascular plexus, ICP—intermediate capillary plexus, DCP—deep capillary plexus.

Figure 2

Scatter plot of vessel density differences in patients with post-COVID-19 syndrome (PCS) in relation to gender: matrix showing the relationship between vessel densities in the SVPs, ICPs and DCPs of patients with PCS. Each set of vessel density data is color-coded according to gender (male, blue; female, red), with 95% prediction ellipses. Female patients with PCS and CF showed lower VDs. SVP—superficial vascular layer, ICP—intermediate capillary plexus, DCP—deep capillary plexus.

Figure 3

Panel plot overlaying the predicted values for male (blue line) and female (red line) vessel densities in the superficial vascular layer (SVP) among patients with post-COVID-19 symptoms: women patients showed significantly lower VDs in the SVP compared to men with increasing age.