Association of self-reported chronic fatigue and retinal microcirculation in patients with post-COVID-19 syndrome

In a recent study posted to the medRxiv* preprint server, researchers examined the possible association between self-reported chronic fatigue (CF) and retinal microcirculation in patients with post-COVID-19 (coronavirus disease 2019) syndrome (PCS).

Study: Post-COVID-19 syndrome: retinal microcirculation as a potential marker of chronic fatigue. Image credit: Monet_3k/Shutterstock


PCS refers to persistent (>12 weeks) sequelae after infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and CF and dyspnoea are the most commonly reported PCS symptoms. Studies have reported that SARS-CoV-2 infection may be caused by persistence of SARS-CoV-2 in blood vessels despite vascular damage, including epitheliopathy, microvasculature disorders, thrombosis, extracellular neutrophil traps (NETs), hypercoagulation, chronic immunologic dysregulation, renin- Dysregulation of the angiotensin-aldosterone system (RAAS) and autoimmunity/hyperinflammation as possible pathophysiological mechanisms of the PCS.

However, the pathogenesis of PCS is not well characterized and requires further investigation. The retinal capillary system is representative of the microcirculation of the whole human body and may represent systemic microvascular changes in systemic diseases. Studies have shown that blood flow disorders can be a possible PCS trigger.

Optical coherence tomography angiography (OCT-A) allows non-invasive visualization of retinal peripapillary and macular capillary plexuses in real time without contact with the human eye, based on temporal intravascular erythrocyte changes. In addition, the OCT equipment is easy to handle.

About the study

In the current prospective study, researchers investigated whether retinal microvasculature circulation could be an objective biomarker of the subjectively reported CF in PCS patients.

The study was conducted at the Department of Ophthalmology of the University of Erlangen-Nuremberg in Germany and involved 201 subjects, including 173 PCS patients and 28 control patients. Retinal microcirculation assessments were performed based on OCT-A analysis and were quantified as the vascular density (VD) for peripapillary vessels and macular. In addition, the participants underwent ophthalmic examinations such as non-contact intraocular pressure (IOP), best-cured visual acuity (BCVA), and axial length measurements.

Self-reported anamnestic CF data was documented and CF was also assessed based on age, gender and ‘bell score’ variables. DCP (deep capillary plexus), ICP (intermediate capillary plexus) and SVP (superficial vascular plexus) VD were analyzed 12 times and mixed modeling was performed to detect potential least squares (LS) mean differences between the groups analyzed.

In the first model, PCS patients were compared to controls, with gender and age as covariates. In the second model, the control group was excluded with CF as the independent variable, and the bell score was added as a predictive variable with the same covariates. SARS-CoV-2 infections were confirmed by positive real-time RT-PCR (reverse-transcription-polymerase-chain reaction) analysis reports.

results and discussion

The mean time after SARS-CoV-2 infection was 231 days. Post-COVID symptoms such as CF, difficulty concentrating, hair loss, postural orthostatic tachycardia syndrome (POTS), and subjectively cooler hands were reported by 92%, 83%, 63%, 19%, and 12%, respectively. Among PCS patients, the LS means for total VD were 30, 22, and 24 for SVP, ICP, and DCP, respectively. The corresponding values ​​for controls were 0.1, 22.6 and 23.7, respectively.

Age had a significant and inverse effect on SVP, ICP and DCP-VD values ​​between PCS patients and controls, and female PCS patients showed a lower SVP VD than male PCS patients. The first model analysis showed that the ICP VD values ​​were significantly lower in PCS patients than in the control group. The second model (age, sex, bell scores) analysis revealed significant differences in SVP VD values ​​between PCS patients with CF and patients without CF.

PCS patients with PCS and CF showed LS means of VD of 30, 22 and 23 for SVP, ICP and DCP, respectively. The corresponding VD values ​​for PCS patients without CF were 28, 22 and 24, respectively. SARS-CoV-2 can directly infect endothelial cells of the retinal microvasculature via angiotensin-converting enzyme 2 (ACE2) and can lead to inflammation and fibrosis , as ACE2, a serine protease receptor essential for SARS-CoV-2 entry, is located in the retinal ICP.


Overall, the study results showed that OCT-A measured retinal microvascular circulation could be an objective biomarker for the subjectively reported CF in PCS patients, using the human eye, as a diagnostic organ for the whole human body.

*Important announcement

medRxiv publishes preliminary scientific reports that are not peer reviewed and therefore should not be considered conclusive, should guide clinical practice/health related behavior or be treated as established information.

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