Tag: retina

Microvascular remodeling and endothelial dysfunction across the post-COVID-19 spectrum: a prospective observational case-control study

Abstract:

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: The “All Eyes on PCS” is a prospective observational study assessing the microcirculation using retinal vessel analysis (RVA). Both dynamic and static parameters (DVA and SVA) were compared across never SARS-CoV-2 infected individuals (NI, n = 96), SARS-CoV-2 recovered individuals (n = 102), and PCS patients (n = 102), including a subgroup fulfilling ME/CFS criteria (n = 62). Analyses were complemented by propensity score-based weighting and multivariable adjustment. Associations with symptom severity and circulating biomarkers of endothelial dysfunction and inflammation were examined.

Results: PCS patients showed reduced venular flicker-induced dilation compared with recovered individuals (3.7% ± 2.2 vs. 4.8% ± 3.0, p = 0.006) and narrower retinal arterioles (CRAE) compared with both recovered (178.3 ± 15.5 μm vs. 186.1 ± 15.7 μm, p = 0.001) and NI individuals (184.4 ± 14.3 μm, p = 0.009). Arteriolar-to-venular ratio (AVR) was lower in PCS compared with NI (0.83 ± 0.06 vs. 0.87 ± 0.06, p < 0.001) and recovered participants (0.86 ± 0.07, p = 0.034). Findings remained largely consistent after age and sex balancing and adjustment for CV risk factors, although the association for AVR was attenuated. PCS patients fulfilling ME/CFS criteria showed the most pronounced retinal microvascular alterations, and a combined model discriminated ME/CFS patients with good accuracy (AUC = 0.79). Higher symptom burden was associated with lower AVR (r = – 0.21, p = 0.037), particularly for neurocognitive symptoms. IL-6, ICAM-1, and VCAM-1 were elevated in PCS and ME/CFS, and lower AVR was associated with inflammatory and iron-related markers (all adjusted p < 0.01).

Conclusions: PCS is associated with persistent endothelial dysfunction, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. These findings support the potential use of RVA as a non-invasive tool for assessing and monitoring endothelial health in post-viral syndromes, with implications for cardiovascular risk stratification.

Trial registration: The All Eyes on PCS Study has previously been registered at ClinicalTrials.gov (NCT05635552).

Source: Wallraven T, Günthner 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. https://link.springer.com/article/10.1186/s12916-026-05144-9 (Full text)

Subclinical neurovascular and immune correlates of post-COVID-19 syndrome detected by retinal imaging

Abstract:

Background: Post-COVID-19 Syndrome (PCS) encompasses a range of persistent symptoms, including cognitive and autonomic disturbances, potentially linked to microvascular or neuroinflammatory mechanisms. Retinal imaging provides a non-invasive window into the central nervous system and vascular integrity. This study aimed to assess retinal structural and microvascular alterations in PCS patients and explore their relationship with symptom severity.

Methods: In this monocentric, cross-sectional, exploratory study, we performed Optical Coherence Tomography (OCT) and OCT Angiography (OCTA) in patients with PCS and a group of COVID-19 recovered individuals. Multiple circulating biomarkers reflecting endothelial dysfunction and chronic inflammation were measured. Associations with validated symptom scores (PCS Score, C19-YRS, PHQ-9, GAD-7) were evaluated.

Results: After adjusting for age and gender, no significant differences were observed in OCTA-derived vessel density (VD) or foveolar avascular zone (FAZ) between PCS patients and COVID-19-recovered controls. However, PCS patients exhibited significant thinning of the peripapillary retinal nerve fibre layer (pRNFL), ganglion cell inner plexiform layer (GCIP), and total macular volume (TMV). Lower values of these structural parameters were consistently observed in patients with higher symptom severity. Vascular parameters (VD and FAZ) were not related to clinical scores. Higher MCP-1 levels, a chemokine associated with chronic inflammation, were linked to lower inner nuclear layer and GCIP thickness.

Conclusion: Structural retinal alterations in PCS were associated with symptom burden and may reflect underlying neuroinflammatory or neurodegenerative processes. OCT parameters could serve as potential non-invasive biomarkers, warranting further investigation in longitudinal, multicenter studies.

Source: Wunderle M, Wicklein R, Ribeiro A, Carbajo-Lozoya J, Wöhnl A, Negele J, Kesseler V, Wild A, Niedermayer S, Lethen I, Lech M, Menten MJ, Kreitner L, Schmaderer C, Wallraven T. Subclinical neurovascular and immune correlates of post-COVID-19 syndrome detected by retinal imaging. Brain Behav Immun Health. 2026 Jul 25;56:101315. doi: 10.1016/j.bbih.2026.101315. PMID: 42571220; PMCID: PMC13451791. https://pmc.ncbi.nlm.nih.gov/articles/PMC13451791/ (Full text)

Case report: A case of Acute Macular Neuroretinopathy secondary to Influenza A virus during Long COVID

Abstract:

Ocular abnormalities have been reported in association with viral infections, including Long COVID, a debilitating illness caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This report presents a case of a female patient diagnosed with Acute Macular Neuroretinopathy (AMN) following an Influenza A virus infection during Long COVID who experienced severe inflammation symptoms and ocular complications. We hypothesize that the rare occurrence of AMN in this patient could be associated with the immune storm secondary to the viral infection during Long COVID.

Source: Zhang J, Xia Y, Li X, He R, Xie X. Case report: A case of Acute Macular Neuroretinopathy secondary to Influenza A virus during Long COVID. Front Immunol. 2024 Jan 15;14:1302504. doi: 10.3389/fimmu.2023.1302504. PMID: 38288123; PMCID: PMC10822910. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10822910/ (Full text)

Hypothesis: Symptomatic myodesopsia/vitreous floaters may constitute a risk factor for Long COVID and ME/CFS

Abstract:

The ophthalmological condition known as myodesopsia or vitreous floaters results from aggregates of proteins or cellular debris in the vitreous body casting shadows onto the retina that are perceived as objects moving through the visual field. While this is commonly viewed as a benign condition associated with aging, a growing body of research suggests that for some patients it can severely impact visual function and quality of life. Myodesopsia is often caused by posterior vitreous detachment, but can also result from other conditions such as asteroid hyalosis, uveitis, or myopic vitreopathy.

There are strong reasons to suspect that its presence may be indicative of a susceptibility to collagen degradation in response to inflammatory triggers, which may represent a risk factor for the development of Long COVID, ME/CFS, or related chronic illnesses. Evidence for such susceptibility includes the presence of collagen-degrading enzymes in the vitreous, associations with other connective tissue disorders, and links between myodesopsia and infections with various pathogens.

Source: Mazewski, M. (2023). Hypothesis: Symptomatic myodesopsia/vitreous floaters may constitute a risk factor for Long COVID and ME/CFS. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 13-20 https://patientresearchcovid19.com/hypothesis-symptomatic-myodesopsia-vitreous-floaters-may-constitute-a-risk-factor-for-long-covid-and-me-cfs-pghj-issue1-may2023/ (Full text)

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Abstract:

Background: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.

Methods: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n=41, matched out of n = 204).

Measurements and main results: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vmax; 3.42% ± 1.77% vs. 4.64 % ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5 – 190.2] vs. 189.1 [179.4 – 197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8 – 0.9] vs. 0.88 [0.8 – 0.9], p = 0.007). When combining AVR and vmax, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R= -0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.

Conclusion: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.

Source: Timon Kuchler, Roman Günthner, Andrea Ribeiro et al. Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation, 22 May 2023, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2952588/v1 (Full text)

Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue

Abstract:

Post-COVID-19 syndrome (PCS) summarizes persisting sequelae after infection with the severe-acute-respiratory-syndrome-Coronavirus-2 (SARS-CoV-2). PCS can affect patients of all covid-19 disease severities. As previous studies revealed impaired blood flow as a provoking factor for triggering PCS, it was the aim of the present study to investigate a potential association of self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker.

A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT-Angiography (OCT-A) and quantified by the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic Fatigue (CF) was assessed with the variables ‘Bell score’, age and gender. The VD in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed considering the repetitions (12 times). Taking in account of such repetitions a mixed model was performed to detect possible differences in the least square means between different groups of analysis.

An age effect on VD was observed between patients and controls (p<0.0001). Gender analysis yielded that women with PCS showed lower VD levels in SVP compared to male patients (p=0.0015). The PCS patients showed significantly lower VD of ICP as compared to the controls (p=0.0001, [CI: 0.32; 1]). Moreover, considering PCS patients, the mixed model reveals a significant difference between chronic fatigue (CF) and without CF in VD of SVP (p=0.0033, [CI: -4.5; -0.92]). The model included age, gender and the variable ‘Bell score’, representing a subjective marker for CF. Consequently, the retinal microcirculation might be an objective biomarker in subjective-reported chronic fatigue of patients with PCS.

Source: Sarah Schlick, Marianna Lucio, Alexander Bartsch, Adam Skornia, Jakob Hoffmanns, Charlotte Szewczykowski, Thora Schröder, Franziska Raith, Lennart Rogge, Felix Heltmann, Michael Moritz, Lorenz Beitlich, Julia Schottenhamml, Martin Herrmann, Thomas Harrer, Marion Ganslmayer, Friedrich E. Kruse, Robert Lämmer, Christian Mardin, Bettina Hohberger. Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue. medRxiv 2022.09.23.22280264; doi: https://doi.org/10.1101/2022.09.23.22280264 https://www.medrxiv.org/content/10.1101/2022.09.23.22280264v1.full-text (Full text)

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Abstract:

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation.

The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT-angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.

Source: Szewczykowski C, Mardin C, Lucio M, Wallukat G, Hoffmanns J, Schröder T, Raith F, Rogge L, Heltmann F, Moritz M, Beitlich L, Schottenhamml J, Herrmann M, Harrer T, Ganslmayer M, Kruse FE, Kräter M, Guck J, Lämmer R, Zenkel M, Gießl A, Hohberger B. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation. Int J Mol Sci. 2022 Jun 29;23(13):7209. doi: 10.3390/ijms23137209. PMID: 35806214. https://www.mdpi.com/1422-0067/23/13/7209/htm (Full text)

Retinal nerve fiber layer thinning in chronic fatigue syndrome as a possible ocular biomarker of underlying glymphatic system dysfunction

In a recent article published in Medical Hypotheses, my colleague and I speculated that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome (CFS) [1]. We further postulated that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain. In this context, it would be helpful to have a predictive biomarker that can identify CFS patients who are good candidates for this specific treatment. For reasons discussed below, I believe that retinal nerve fiber layer (RNFL) thinning may be a sign of underlying glymphatic system dysfunction in neurodegenerative diseases that result from protein toxicity.

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