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

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?

Study Overview

• Status: Recruiting
• Conditions: Endothelial Dysfunction; Long Covid19; Post COVID-19 Condition
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Anticipated): 300

Contacts and Locations

• Study Contact: Name: Christoph Schmaderer, Prof. Dr.; Phone Number: 089 4140 5053; Email: christoph.schmaderer@mri.tum.de
• Study Contact Backup: Name: Timon Kuchler; Phone Number: 089 4140 8189; Email: timon.kuchler@mri.tum.de

Study Locations

• Germany
  • Bavaria
    • München, Bavaria, Germany, 81675
      • Recruiting
      • Klinikum rechts der Isar
      • Contact: Timon Kuchler; Phone Number: 089 4140 8189; Email: timon.kuchler@mri.tum.de
      • Contact: Christoph Schmaderer, Prof. Dr; Phone Number: 089 4140 5053; Email: christoph.schmaderer@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.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Community sample, Post-Covid ambulance, general practitioner

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Technical University of Munich
• Collaborators: Ludwig-Maximilians - University of Munich
• Investigators: Principal Investigator: Christoph Schmaderer, Prof. Dr., Technical University Munich

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2022
• Primary Completion (Anticipated): February 21, 2023
• Study Completion (Anticipated): July 21, 2023

Study Registration Dates

• First Submitted: November 18, 2022
• First Submitted That Met QC Criteria: November 30, 2022
• First Posted (Actual): December 2, 2022

Study Record Updates

• Last Update Posted (Actual): December 2, 2022
• Last Update Submitted That Met QC Criteria: November 30, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Inflammation; Autoimmunity; Vasculopathy; Retinal Vessel Analysis; Retinal microvasculature
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 2022317PCS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No