Retinal Neurovascular Coupling in Patients Previously Infected With COVID-19

Study Overview
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Brief Summary
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The Study objective is to measure retinal neurovascular coupling and blood flow parameters in patients previously infected with COVID-19, long COVID-19 and healthy age- and sex- matched control subjects

Detailed Description
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The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is affecting almost all countries in the world and because of its worldwide spread has been declared as pandemic in March 2020. While respiratory symptoms are the main manifestation of acute infection, there is also increasing evidence that neurological and vascular symptoms occur, and it is unknown whether residuals remain after patients have recovered. A recent report shows that changes in the human retina are even present one month after onset of symptoms. The eye, as an extension of the brain, offers the advantage that blood vessels as well as neural tissue can be visualized non-invasively in-vivo. Neurovascular coupling is the ability of neural tissue to adapt its blood flow to its metabolic demands, a phenomenon that does not only occur in the brain, but also in the retina. In the retina, neurovascular coupling can be studied by stimulating the retina with flicker light and measuring the response of the vessels. Retinal neurovascular coupling has been found to be impaired in diseases of the central nervous system (CNS) as well as in diseases associated with endothelial dysfunction. Since COVID-19 comes with CNS manifestations as well as endothelial dysfunction, we speculate that retinal neurovascular coupling might be impaired in patients even after they have recovered from COVID-19 infection. In the current study, retinal neurovascular coupling will be measured in patients who have recovered from COVID-19 infection with and without long COVID-19 and in healthy age- and sex-matched controls with no history of COVID-19 infection. In addition, retinal oxygen saturation, vessel diameters, vessel density as well as retinal and optic nerve head blood flow will be measured. To assess structural changes, measurement of central retinal thickness as well as retinal nerve fiber layer thickness will be performed.

Official Title
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Retinal Neurovascular Coupling in Patients Previously Infected With COVID-19

Conditions
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COVID-19, Post-COVID-19 Syndrome

Intervention / Treatment
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* Device: Dynamic Vessel Analyzer (DVA)
* Device: Fourier domain optical coherence tomography (FDOCT)
* Device: Optical coherence tomography (OCT)
* Device: Laser Speckle Flowgraphy (LSFG)
* Diagnostic Test: Proteomics and Metabolites in Plasma, tear fluid and finger sweat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for healthy subjects Men and women aged over 18 years Non-smokers Normal findings in the medical history unless the investigator considers an abnormality to be clinically irrelevant No previous history of COVID-19 infection Negative testing for SARS-CoV-2 seroprevalence using nucleocapsid antibody tests Negative PCR test for SARS-CoV-2 Normal ophthalmic findings, ametropy < 6 Dpt. Inclusion criteria for subjects with history of COVID-19 infection Men and women aged over 18 years Non-smokers History of COVID-19 infection (confirmed by a positive PCR test for SARS-CoV2 in the medical history) within the last 6 months Positive testing for SARS-CoV-2 seroprevalence using spike protein IgG antibody tests Negative PCR test for SARS-CoV-2 Inclusion criteria for subjects with long COVID-19 Men and women aged over 18 years Non-smokers History of COVID-19 infection (confirmed by a positive PCR test for SARS-CoV2 in the medical history) Positive testing for SARS-CoV-2 seroprevalence Negative PCR test for SARS-CoV-2 Long Covid according to the latest WHO-Guidelines Exclusion Criteria: Any of the following will exclude a healthy control subject from the study: Symptoms of a clinically relevant illness in the 3 weeks before the first study day Presence or history of a severe medical condition as judged by the clinical investigator Participation in a clinical trial in the 3 weeks preceding the study Blood donation during the previous three weeks History or family history of epilepsy Presence of any abnormalities preventing reliable measurements in the study eye as judged by the investigator Best corrected visual acuity < 0.8 Snellen Pregnancy, planned pregnancy or lactatin History of epilepsia Any of the following will exclude a subject with history of COVID-19 infection from the study: Blood donation during the previous three weeks History or family history of epilepsy Presence of any abnormalities preventing reliable measurements in the study eye as judged by the investigator Best corrected visual acuity < 0.8 Snellen Ametropy >6 Dpt Pregnancy, planned pregnancy or lactating History of epilepsia Any of the following will exclude a subject with long COVID-19 from the study: Blood donation during the previous three weeks History or family history of epilepsy Presence of any abnormalities preventing reliable measurements in the study eye as judged by the investigator Best corrected visual acuity < 0.8 Snellen Ametropy >6 Dpt Pregnancy, planned pregnancy or lactating History of epilepsia Diabetes mellitus

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 |
| --- | --- |
| subjects previously infected with COVID-19<br>subjects previously infected with COVID-19 | Device: Dynamic Vessel Analyzer (DVA)<br>* Retinal neurovascular coupling, Retinal vessel diameters and Retinal oxygen saturation will be assessed using the DVA<br>Device: Fourier domain optical coherence tomography (FDOCT)<br>* Retinal blood velocities and Retinal blood flow will be assessed using the FDOCT<br>Device: Optical coherence tomography (OCT)<br>* Retinal nerve fiber layer thickness, Central retinal thickness and Retinal vessel density will be assessed using the OCT<br>Device: Laser Speckle Flowgraphy (LSFG)<br>* Normalized blur and Relative flow volume will be assessed using the LSFG<br>Diagnostic Test: Proteomics and Metabolites in Plasma, tear fluid and finger sweat<br>* Proteomics and Metabolites in Plasma, tear fluid and finger sweat will be assessed using a Blooddraw, filter paper and Schirmer-test<br>|
| subjects with long COVID-19<br>subjects with long COVID-19 according to the WHO-guideline | Device: Dynamic Vessel Analyzer (DVA)<br>* Retinal neurovascular coupling, Retinal vessel diameters and Retinal oxygen saturation will be assessed using the DVA<br>Device: Fourier domain optical coherence tomography (FDOCT)<br>* Retinal blood velocities and Retinal blood flow will be assessed using the FDOCT<br>Device: Optical coherence tomography (OCT)<br>* Retinal nerve fiber layer thickness, Central retinal thickness and Retinal vessel density will be assessed using the OCT<br>Device: Laser Speckle Flowgraphy (LSFG)<br>* Normalized blur and Relative flow volume will be assessed using the LSFG<br>Diagnostic Test: Proteomics and Metabolites in Plasma, tear fluid and finger sweat<br>* Proteomics and Metabolites in Plasma, tear fluid and finger sweat will be assessed using a Blooddraw, filter paper and Schirmer-test<br>|
| healthy age-and sex- matched control subjects with no history of COVID-19 infection<br>healthy age-and sex- matched control subjects with no history of COVID-19 infection | Device: Dynamic Vessel Analyzer (DVA)<br>* Retinal neurovascular coupling, Retinal vessel diameters and Retinal oxygen saturation will be assessed using the DVA<br>Device: Fourier domain optical coherence tomography (FDOCT)<br>* Retinal blood velocities and Retinal blood flow will be assessed using the FDOCT<br>Device: Optical coherence tomography (OCT)<br>* Retinal nerve fiber layer thickness, Central retinal thickness and Retinal vessel density will be assessed using the OCT<br>Device: Laser Speckle Flowgraphy (LSFG)<br>* Normalized blur and Relative flow volume will be assessed using the LSFG<br>Diagnostic Test: Proteomics and Metabolites in Plasma, tear fluid and finger sweat<br>* Proteomics and Metabolites in Plasma, tear fluid and finger sweat will be assessed using a Blooddraw, filter paper and Schirmer-test<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retinal neurovascular coupling | Retinal neurovascular coupling will be assessed using the DVA | Day 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retinal vessel diameters | Retinal vessel diameters will be assessed using the DVA | Day 0 | 
| Retinal oxygen saturation | Retinal oxygen saturation will be assessed using the DVA | Day 0 | 
| Retinal blood velocities | Retinal blood velocities will be assessed using FDOCT | Day 0 | 
| Retinal blood flow | Retinal blood flow will be assessed using FDOCT | Day 0 | 
| Ocular perfusion pressure | Ocular perfusion pressure is going to be calulated | Day 0 | 
| Retinal nerve fiber layer thickness | Retinal nerve fiber layer thickness will be assessed using OCT | Day 0 | 
| Central retinal thickness | Central retinal thickness will be assessed using OCT | Day 0 | 
| Retinal vessel density | Retinal vessel density will be assessed using OCT | Day 0 | 
| Normalized blur | Normalized blur will be assessed using LSFG | Day 0 | 
| Relative flow volume | Relative flow volume will be assessed using LSFG | Day 0 | 
| Proteomics and Metabolites in Plasma | Proteomics and Metabolites in Plasma will be assessed through a Blood Sample | Day -14 to -1 | 
| Proteomics and Metabolites in tear fluid | Proteomics and Metabolites in tear fluid will be assessed using Schirmer | Day 0 | 
| Proteomics and Metabolites in finger sweat | Proteomics and Metabolites in finger sweat will be assessed using finger sweat filters | Day 0 |