All Eyes on PCS - Analysis of the Retinal Microvasculature in Patients With Post-COVID-19 Syndrome

Study Overview
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Brief Summary
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The goal of this observational, prospective study is to in depth analyze the retinal microvasculature in patients with Post-COVID-19 Syndrome (PCS). The main questions it aims to answer is: Do patients with PCS show a prolonged endothelial dysfunction when compared with fully COVID-19 recovered participants? Does symptom severity in PCS patients correlate with the extend of endothelial dysfunction? Do these changes correlate with improvement in symptoms in the prospective observation?

Detailed Description
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The investigators will recruit patients with PCS, fully COVID-19 recovered participants and COVID-19 infection naïve participants. After comprehensive clarification and given written informed consent, measurements will take place in the Klinikum rechts der Isar. To evaluate the retinal microvasculature dynamic retinal vessel analysis (DVA) and optical coherence tomography (OCT) are used. Patient reported outcomes (PROM) of PCS typical symptoms will be collected using standardized questionnaires. To ensure data quality the investigators will use standard operating procedures (SOP) for both technical measurements and data collection. For DVA measurements all examiners will be trained by a single experienced supervisor and must reach high image accuracy and quality in at least 10 volunteers. Examiners are only involved in data acquisition.

Official Title
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All Eyes on PCS - Analysis of the Retinal Microvasculature in Patients With Post-COVID-19 Syndrome

Conditions
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Endothelial Dysfunction, Long Covid19, Post COVID-19 Condition

Intervention / Treatment
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* Diagnostic Test: Dynamic retinal vessel analysis (DVA)
* Diagnostic Test: Optical coherence tomography (OCT)
* Diagnostic Test: Biochemistry and immune phenotyping
* Diagnostic Test: Handgrip strength test
* Diagnostic Test: Questionnaires (Patient reported outcomes)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Post-COVID syndrome (positive PCR or positive rapid antibody test ≥3 months) with a currently existing, PCS-typical complaint complex, ongoing for at least 2 months and cannot be explained by an alternative diagnosis. Control group: recovered from COVID-19 infection (positive PCR or positive rapid antibody test ≥ 3 months) without residual symptoms. Healthy cohort: no history of COVID-19 infection Exclusion Criteria: Missing or incomplete consent form Age < 18 years Pregnancy Malignancy Diseases associated with a significant change in life expectancy Autoimmune diseases of the rheumatological type Cataract Epilepsy Glaucoma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PCS patients<br>Patients with a COVID-19 infection at least 3 months ago (positive PCR or rapid antibody test) and PCS typical symptoms (e.g. fatigue, breast pain, heart palpitations, cognitive impairment) ongoing for at least 2 months and which cannot be explained by an alternative diagnosis. | Diagnostic Test: Dynamic retinal vessel analysis (DVA)<br>* DVA is an established, non-invasive tool to measure the responsiveness of retinal vessels to flickering light. In addition static retinal vessel parameters are recorded.<br>Diagnostic Test: Optical coherence tomography (OCT)<br>* OCT is an imaging technique which applies low-coherence light to capture high resolution images from the ocular fundus.<br>Diagnostic Test: Biochemistry and immune phenotyping<br>* Blood sample collection for clinical chemistry and isolation of PBMCs for FACS analysis.<br>Diagnostic Test: Handgrip strength test<br>* Measure the maximum isometric strength of the hand and forearm muscles and their fatiguability.<br>Diagnostic Test: Questionnaires (Patient reported outcomes)<br>* The questionnaires evaluate anxiety, depression, chronic fatigue, quality of life, and post-covid typical symptoms<br>|
| COVID-19 recovered participants<br>Participants with Sars-CoV-2 infection at least 3 months ago (positive PCR or positive rapid antibody test) which are fully recovered. | Diagnostic Test: Dynamic retinal vessel analysis (DVA)<br>* DVA is an established, non-invasive tool to measure the responsiveness of retinal vessels to flickering light. In addition static retinal vessel parameters are recorded.<br>Diagnostic Test: Optical coherence tomography (OCT)<br>* OCT is an imaging technique which applies low-coherence light to capture high resolution images from the ocular fundus.<br>Diagnostic Test: Biochemistry and immune phenotyping<br>* Blood sample collection for clinical chemistry and isolation of PBMCs for FACS analysis.<br>Diagnostic Test: Handgrip strength test<br>* Measure the maximum isometric strength of the hand and forearm muscles and their fatiguability.<br>Diagnostic Test: Questionnaires (Patient reported outcomes)<br>* The questionnaires evaluate anxiety, depression, chronic fatigue, quality of life, and post-covid typical symptoms<br>|
| COVID-19 infection naïve<br>No history of COVID-19 infection (exclusion via measurement of specific antibodies). Consists of an already established, pre-pandemic healthy cohort and a cohort recruited during the pandemic. | Diagnostic Test: Dynamic retinal vessel analysis (DVA)<br>* DVA is an established, non-invasive tool to measure the responsiveness of retinal vessels to flickering light. In addition static retinal vessel parameters are recorded.<br>Diagnostic Test: Optical coherence tomography (OCT)<br>* OCT is an imaging technique which applies low-coherence light to capture high resolution images from the ocular fundus.<br>Diagnostic Test: Biochemistry and immune phenotyping<br>* Blood sample collection for clinical chemistry and isolation of PBMCs for FACS analysis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCS patients show an impaired retinal vessel responsiveness when compared with fully recovered COVID-19 participants. | Static and dynamic parameters of the retinal vessel analysis. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCS patients show an impaired retinal vessel responsiveness at baseline when compared with infection naïve participants. | Static and dynamic parameters of the retinal vessel analysis. | Baseline | 
| PCS patients with improved symptoms show a change in retinal vessel responsiveness after 6 months when compared with baseline parameters. | Static and dynamic parameters of the retinal vessel analysis. Test items of the The COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) and PCS questionnaire. Calculation of PCS severity scores (Bahmer, 2022) in each patient with a range of score values from zero (better outcome) to 59 (worse outcome). Comparison of retinal vessel parameters and PCS scores between Baseline and month 6. | Baseline to month 6 | 
| Symptom severity of PCS in patients correlates with impaired retinal vessel responsiveness. | Correlation between PCS severity scores with static and dynamic parameters of the retinal vessel analysis. | Baseline | 
| PCS patients with impaired RVA analysis show elevated levels of markers of endothelial dysfunction and of chronic inflammation when compared with COVID-19 recovered cohort. | Measurement of markers of endothelial dysfunction: Concentration of: sICAM, sVCAM, Thrombomodulin, P-Selectin,E-Selectin, ADMA, SADMA, Endothelin-1, ACE-1, ACE-2, ANG-2, GDF-15. Measurement of markers of chronic inflammation Concentration of IFN-β, IFN-λ1,TNFa. Comparison of marker levels to the COVID-19 recovered cohort. | Baseline | 
| PCS patients with impaired RVA show a reactivation of EBV. | Using PCR to measure EBV reactivation in patients plasma . | Baseline | 
| Characterization of immune cell composition in PCS patients and comparison with COVID-19 recovered and COVID-19 infection naïve participants. | Using flow cytometry to detect different T-cell and monocyte subpopulations. | Baseline | 
| PCS patients show a decrease in vessel density in OCT-A when compared with COVID-19 recovered participants. | Parameters of OCT-A. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Retinal Vessel Analysis, Retinal microvasculature, Autoimmunity, Inflammation, Vasculopathy