Microvascular Remodeling and Endothelial Dysfunction Across Post-COVID-19 and ME/CFS: Insights from the All Eyes on PCS Study

BackgroundPost-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. MethodsAll 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. ResultsCompared 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 {micro}m vs. 183.3 {+/-} 15.9 {micro}m, 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). ConclusionsPCS 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 RegistrationThe All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552). Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABS- PCS and ME/CFS are associated with persistent endothelial dysfunction and increased long-term cardiovascular risk. - Neurocognitive symptoms in post-viral syndromes have been linked to impaired neurovascular coupling. - Retinal vessel analysis provides a validated, non-invasive readout of systemic and cerebral microvascular health. What new information does this article contribute?- PCS is characterized by persistent functional and structural retinal microvascular dysfunction - Retinal endothelial dysfunction scales continuously with post-viral disease severity and is most pronounced in patients fulfilling ME/CFS criteria. - Retinal microvascular alterations are linked to inflammatory-endothelial activation and iron dysregulation, identifying a biologically coherent vascular phenotype. 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.