peony (@peony386.bsky.social)

Microvascular Remodeling and Endothelial Dysfunction Across Post-COVID-19 and ME/CFS: Insights from the All Eyes on PCS Study Background Post-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular (CV) risk after acute infection highlights the need for accessible tools to quantify microvascular health. Methods All Eyes on PCS is a prospective, observational study investigating the retinal microcirculation using retinal vessel analysis (RVA). We compared RVA parameters in 102 PCS patients with 204 age- and sex-matched healthy controls (HC, matched from n = 303). Secondary matched analyses included never infected controls (NI, n = 96), recovered individuals (n = 102), PCS patients, and ME/CFS patients (n = 62). Laboratory variables, circulating markers of endothelial dysfunction (ED) and inflammation were compared between cohorts and their associations with RVA parameters were examined. Results Compared with HC, PCS patients showed reduced venular flicker-induced dilation (3.7 ± 2.2% vs. 4.5 ± 2.7%, p = 0.005), narrow retinal arterioles (CRAE, 178.3 ± 15.5 µm vs. 183.3 ± 15.9 µm, p = 0.009), and lower arteriolar-to-venular ratio (0.83 ± 0.06 vs. 0.86 ± 0.07, p = 0.004). Findings persisted after adjustment for CV factors and remained evident in an extended secondary matched analysis across NI, recovered, and PCS patients. ME/CFS patients showed the most pronounced alterations. PCS severity correlated with lower AVR (r = -0.21, p = 0.037) and reduced arteriolar FID (r = -0.21, p = 0.039), particularly for neurocognitive symptoms. IL-6, ICAM-1 and VCAM-1 were elevated in PCS and ME/CFS and lower AVR correlated with inflammatory and iron-related markers (all adjusted p < 0.01). A combined model discriminated ME/CFS patients with good accuracy (AUC = 0.80). Conclusions PCS is associated with persistent ED, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. RVA may provide a noninvasive, readout of ED in post-viral syndromes. Trial Registration The All Eyes on PCS Study has previously been registered at ClinicalTrials.gov ([NCT05635552][1]). What is known? What new information does this article contribute? What new information does this article contribute? This study provides the first comprehensive human in vivo assessment of retinal microvascular structure and function across the full post-COVID-19 spectrum, from never infected controls to recovered individuals, PCS patients, and those fulfilling ME/CFS criteria. Using retinal vessel analysis as a surrogate of neurovascular and endothelial function, we demonstrate that endothelial dysfunction persists in patients with ongoing post-viral symptomatology. Retinal venular flicker-induced dilation, arteriolar caliber, and autoregulatory capacity decline progressively with increasing clinical severity, indicating a dose-response relationship between microvascular injury and post-infectious disease burden. Importantly, these vascular alterations are linked to sustained inflammatory and endothelial activation and to disturbances in iron homeostasis, indicating an inflammatory-endothelial axis rather than isolated cardiovascular risk. By integrating microvascular phenotyping with symptom profiles and circulating biomarkers, this work identifies retinal endothelial dysfunction as a mechanistically informative and clinically accessible marker of post-viral disease severity. These findings advance understanding of post-infectious vascular pathology and provide a translational framework for biological stratification and risk assessment in PCS and ME/CFS. ### Competing Interest Statement The authors declare that they have no conflicts of interest related to this work. FCO reports current research grants by the German Research Foundation (DFG, TRR418), Hertie foundation, German ME/CFS foundation, Novartis and UCB - not related to this project. She also reports past fellowship support by the American Academy of Neurology and the National MS Society (until 2023) and past research grant by the DGN (Germany Neurology Association) and DFG-TWAS program. FCO declares speaker honoraria by UCB and Novartis, and travel support by Guthy Jackson Charitable Foundation, the European Committee for Research and Treatment in Multiple Sclerosis and American Academy of Neurology. She is academic editor at DGNeurologie and Neurological Research & Practice, board member at the IMSVISUAL consortium and co-chair of the committee for Neuroophthalmology and Neurootology by the German Neurology Association. ### Clinical Trial NCT05635552 ### Clinical Protocols <https://pubmed.ncbi.nlm.nih.gov/38041762/> ### Funding Statement This work was supported by the Clinical Scientist Program of the TUM School of Medicine and Health. This study is part of the VADYS-ME (to Schmaderer, Oertel) project which is supported by the Federal Ministry of Education and Research (BMBF). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the Ethics Committee of the Technical University of Munich, School of Medicine and Health, Klinikum rechts der Isar (approval number: 2022-317-S-SR). The study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to inclusion. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets used during the current study are available from the corresponding author on reasonable request. * aFID : Arteriolar flicker-induced dilation ANOVA : Analysis of variance ATO : Average treatment effect in the overlap population AVR : Arteriolar-to-venular ratio BBB : Blood–brain barrier BMI : Body mass index CCL-5 : CC-Chemokine-Ligand-5 CK : Creatine kinase CRAE : Central retinal artery equivalent CRP : C-reactive protein CRVE : Central retinal vein equivalent CV : Cardiovascular C19-YRS : COVID-19 Yorkshire Rehabilitation Scale CXCL10 (IP-10) : C-X-C motif chemokine 10 (Interferon gamma-induced protein-10) DVA : Dynamic retinal vessel analysis ED : Endothelial dysfunction EQ-5D-5L : EuroQol five-dimension five-level questionnaire FID : Flicker-induced dilation FMD : Flow-mediated dilation FSS : Fatigue Severity Scale GAD-7 : Generalized Anxiety Disorder-7 HC : Healthy controls HIF : Hypoxia-inducible factor ICAM-1 : Intercellular adhesion molecule-1 ICTRP : International Clinical Trials Registry Platform IgG : Immunoglobulin G IL-6 : Interleukin-6 ME/CFS : Myalgic encephalomyelitis/chronic fatigue syndrome MCP-1 : Monocyte chemoattractant protein-1 NI : Never infected NO : Nitric oxide NV : Neurovascular OCT-A : Optical coherence tomography angiography PCS : Post-COVID-19 syndrome PEM : Post-exertional malaise PHQ-9 : Patient Health Questionnaire-9 POH : Post-occlusive reactive hyperemia PROMs : Patient-reported outcome measures PWV : Pulse-wave velocity ROC : Receiver operating characteristic RVA : Retinal vessel analysis SD : Standard deviation SVA : Static retinal vessel analysis VCAM-1 : Vascular cell adhesion molecule-1 VEGF : Vascular endothelial growth factor vFID : Venular flicker-induced dilation WHO : World Health Organization [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05635552&atom=%2Fmedrxiv%2Fearly%2F2026%2F01%2F25%2F2026.01.22.26344661.atom https://www.medrxiv.org/content/10.64898/2026.01.22.26344661v1