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

• ClinicalTrials.gov Identifier: NCT05635552
• Recruitment Status: Recruiting
• First Posted: December 2, 2022
• Last Update Posted: December 2, 2022
• Sponsor: Technical University of Munich
• Collaborator: Ludwig-Maximilians - University of Munich
• Information provided by (Responsible Party): PD Dr. Christoph Schmaderer, Technical University of Munich

Study Description

Brief Summary:

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?

Condition or disease	Intervention/treatment
Long Covid19; Post COVID-19 Condition; Endothelial Dysfunction	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)

Detailed Description:

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.

Study Design

• Study Type: Observational
• Estimated Enrollment: 300 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: All Eyes on PCS - Analysis of the Retinal Microvasculature in Patients With Post-COVID-19 Syndrome
• Actual Study Start Date: October 17, 2022
• Estimated Primary Completion Date: February 21, 2023
• Estimated Study Completion Date: July 21, 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
PCS patients; 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); 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.; Diagnostic Test: Optical coherence tomography (OCT); OCT is an imaging technique which applies low-coherence light to capture high resolution images from the ocular fundus.; Diagnostic Test: Biochemistry and immune phenotyping; Blood sample collection for clinical chemistry and isolation of PBMCs for FACS analysis.; Diagnostic Test: Handgrip strength test; Measure the maximum isometric strength of the hand and forearm muscles and their fatiguability.; Diagnostic Test: Questionnaires (Patient reported outcomes); The questionnaires evaluate anxiety, depression, chronic fatigue, quality of life, and post-covid typical symptoms
COVID-19 recovered participants; 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); 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.; Diagnostic Test: Optical coherence tomography (OCT); OCT is an imaging technique which applies low-coherence light to capture high resolution images from the ocular fundus.; Diagnostic Test: Biochemistry and immune phenotyping; Blood sample collection for clinical chemistry and isolation of PBMCs for FACS analysis.; Diagnostic Test: Handgrip strength test; Measure the maximum isometric strength of the hand and forearm muscles and their fatiguability.; Diagnostic Test: Questionnaires (Patient reported outcomes); The questionnaires evaluate anxiety, depression, chronic fatigue, quality of life, and post-covid typical symptoms
COVID-19 infection naïve; 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); 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.; Diagnostic Test: Optical coherence tomography (OCT); OCT is an imaging technique which applies low-coherence light to capture high resolution images from the ocular fundus.; Diagnostic Test: Biochemistry and immune phenotyping; Blood sample collection for clinical chemistry and isolation of PBMCs for FACS analysis.

Outcome Measures

Primary Outcome Measures :

1. PCS patients show an impaired retinal vessel responsiveness when compared with fully recovered COVID-19 participants. [ Time Frame: Baseline ]
   Static and dynamic parameters of the retinal vessel analysis.

Secondary Outcome Measures :

1. PCS patients show an impaired retinal vessel responsiveness at baseline when compared with infection naïve participants. [ Time Frame: Baseline ]
   Static and dynamic parameters of the retinal vessel analysis.
2. PCS patients with improved symptoms show a change in retinal vessel responsiveness after 6 months when compared with baseline parameters. [ Time Frame: Baseline to month 6 ]
   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.
3. Symptom severity of PCS in patients correlates with impaired retinal vessel responsiveness. [ Time Frame: Baseline ]
   Correlation between PCS severity scores with static and dynamic parameters of the retinal vessel analysis.
4. 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. [ Time Frame: Baseline ]

   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.

5. PCS patients with impaired RVA show a reactivation of EBV. [ Time Frame: Baseline ]
   Using PCR to measure EBV reactivation in patients plasma .
6. Characterization of immune cell composition in PCS patients and comparison with COVID-19 recovered and COVID-19 infection naïve participants. [ Time Frame: Baseline ]
   Using flow cytometry to detect different T-cell and monocyte subpopulations.
7. PCS patients show a decrease in vessel density in OCT-A when compared with COVID-19 recovered participants. [ Time Frame: Baseline ]
   Parameters of OCT-A.

Biospecimen Retention:   Samples With DNA

Blood and saliva samples are collected from the participants.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Community sample, Post-Covid ambulance, general practitioner

Criteria

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

Contacts and Locations

Contacts

Contact: Christoph Schmaderer, Prof. Dr.; 089 4140 5053; christoph.schmaderer@mri.tum.de

Contact: Timon Kuchler; 089 4140 8189; timon.kuchler@mri.tum.de

Locations

Germany

Klinikum rechts der Isar; Recruiting

München, Bavaria, Germany, 81675

Contact: Christoph Schmaderer, Prof. Dr 089 4140 5053 christoph.schmaderer@mri.tum.de

Contact: Timon Kuchler 089 4140 8189 timon.kuchler@mri.tum.de

Principal Investigator: Christoph Schmaderer, Prof. Dr.

Sub-Investigator: Timon Kuchler

Sub-Investigator: Renate Hausinger

Sub-Investigator: Matthias Braunisch, PD. Dr.

Sub-Investigator: Roman Günthner, Dr.

Sub-Investigator: Rebecca Wicklein, Dr.

Sub-Investigator: Stanislas Werfel, Dr.

Sub-Investigator: Andrea Ribero, Dr.

Principal Investigator: Maciej Lech, Prof. Dr.

Sponsors and Collaborators

Technical University of Munich

Ludwig-Maximilians - University of Munich

Investigators

• Principal Investigator: Christoph Schmaderer, Prof. Dr.; Technical University Munich

More Information

Publications:

Bahmer T, Borzikowsky C, Lieb W, Horn A, Krist L, Fricke J, Scheibenbogen C, Rabe KF, Maetzler W, Maetzler C, Laudien M, Frank D, Ballhausen S, Hermes A, Miljukov O, Haeusler KG, Mokhtari NEE, Witzenrath M, Vehreschild JJ, Krefting D, Pape D, Montellano FA, Kohls M, Morbach C, Stork S, Reese JP, Keil T, Heuschmann P, Krawczak M, Schreiber S; NAPKON study group. Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multi-centre, population-based cohort study. EClinicalMedicine. 2022 Jul 18;51:101549. doi: 10.1016/j.eclinm.2022.101549. eCollection 2022 Sep.

• Responsible Party: PD Dr. Christoph Schmaderer, Principal Investigator, Technical University of Munich
• ClinicalTrials.gov Identifier: NCT05635552
• Other Study ID Numbers: 2022317PCS
• First Posted: December 2, 2022
• Last Update Posted: December 2, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PD Dr. Christoph Schmaderer, Technical University of Munich:

Retinal Vessel Analysis; Retinal microvasculature; Autoimmunity; Inflammation; Vasculopathy

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases