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

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.

• Dynamic retinal vessel analysis (DVA) (Diagnostic test): 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.
• Optical coherence tomography (OCT) (Diagnostic test): OCT is an imaging technique which applies low-coherence light to capture high resolution images from the ocular fundus.
• Biochemistry and immune phenotyping (Diagnostic test): Blood sample collection for clinical chemistry and isolation of PBMCs for FACS analysis.
• Handgrip strength test (Diagnostic test): Measure the maximum isometric strength of the hand and forearm muscles and their fatiguability.
• Questionnaires (Patient reported outcomes) (Diagnostic test): The questionnaires evaluate anxiety, depression, chronic fatigue, quality of life, and post-covid typical symptoms

Primary outcomes

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

Secondary outcomes

• PCS patients show an impaired retinal vessel responsiveness at baseline when compared with infection naïve participants. [Baseline]: Static and dynamic parameters of the retinal vessel analysis.
• PCS patients with improved symptoms show a change in retinal vessel responsiveness after 6 months when compared with baseline parameters. [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.
• Symptom severity of PCS in patients correlates with impaired retinal vessel responsiveness. [Baseline]: Correlation between PCS severity scores with static and dynamic parameters of the retinal vessel analysis.
• 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. [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.
• PCS patients with impaired RVA show a reactivation of EBV. [Baseline]: Using PCR to measure EBV reactivation in patients plasma .
• Characterization of immune cell composition in PCS patients and comparison with COVID-19 recovered and COVID-19 infection naïve participants. [Baseline]: Using flow cytometry to detect different T-cell and monocyte subpopulations.
• PCS patients show a decrease in vessel density in OCT-A when compared with COVID-19 recovered participants. [Baseline]: Parameters of OCT-A.

Sex: All, ages: 18 Years to any, accepts healthy volunteers

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

• 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. PMID 35875815
• Results publication: Wallraven T, Gunthner R, Lethen I, Ribeiro A, Lech M, Oertel FC, Reess LG, Haller B, Streese L, Hanssen H, Basta-Wunderle M, Schmaderer C. Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum: a prospective observational case-control study. BMC Med. 2026 Aug 19;24(1):456. doi: 10.1186/s12916-026-05144-9. PMID 42625188
• Results publication: Wunderle M, Ribeiro A, Lethen I, Schmaderer C, Wallraven T. Persistent impairments in muscle function and symptom burden in post-COVID syndrome: a prospective longitudinal study. J Transl Med. 2026 Jul 7;24(1):871. doi: 10.1186/s12967-026-08579-z. PMID 42415070
• Results publication: Kuchler T, Hausinger R, Braunisch MC, Gunthner R, Wicklein R, Knier B, Bleidissel N, Maier M, Ribero A, Lech M, Adorjan K, Stubbe H, Kotliar K, Heemann U, Schmaderer C. All eyes on PCS: analysis of the retinal microvasculature in patients with post-COVID syndrome-study protocol of a 1 year prospective case-control study. Eur Arch Psychiatry Clin Neurosci. 2024 Dec;274(8):1847-1856. doi: 10.1007/s00406-023-01724-5. Epub 2023 Dec 2. PMID 38041762
• Results publication: Kuchler T, Gunthner R, Ribeiro A, Hausinger R, Streese L, Wohnl A, Kesseler V, Negele J, Assali T, Carbajo-Lozoya J, Lech M, Schneider H, Adorjan K, Stubbe HC, Hanssen H, Kotliar K, Haller B, Heemann U, Schmaderer C. Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation. Angiogenesis. 2023 Nov;26(4):547-563. doi: 10.1007/s10456-023-09885-6. Epub 2023 Jul 28. PMID 37507580

• Christoph Schmaderer, Prof. Dr., Principal investigator, Technical University Munich