Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue, 2022, Schlick et al

[SNT Gatchaman]

Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue
Sarah Schlick, Marianna Lucio, Alexander Johannes Bartsch, Adam Skornia, Jakob Hoffmanns, Charlotte Szewczykowski, Thora Schroeder, Franzi Raith, Lennart Rogge, Felix Heltmann, Michael Moritz, Lorenz Beitlich, Julia Schottenhamml, Martin Herrmann, Thomas Harrer, Marion Ganslmayer, Friedrich E. Kruse, Robert Laemmer, Christian Mardin, Bettina Hohberger

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.

Link | PDF (MedRxiv)

See post #3 for link to published paper.

 

[SNT Gatchaman]

An age effect on VD was observed in patients and controls (p<0.0001). Gender analysis yielded that especially women with PCS showed lower VD levels in SVP compared to male patients (p=0.0015). Previous studies revield that women show a ratio of PCS of 3:1 ratio compared to male.

In addition, the present data go conform with clinical observations that women with PCS had a higher probability of fatigue and anxiety/depression throughout 6-month-follow up. Patients with PCS showed significant lower VD of ICP compared to controls (p=0.0001, [CI: 0.32; 1]), considering the age and gender effect. Instead, in the 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]). In the model was included age, gender, and the variable ‘Bell score’, representing a subjective marker for CF. The variable ‘Bell score’ was always significant for each VD. Thus, the eye as window in the human body might offer a diagnostic option by measuring retinal microcirculation objectively in self-reported CF of patients with PCS.

DCP = deep capillary plexus
ICP = intermediate capillary plexus
PCS = post-covid syndrome
SCP = superficial capillary plexus
VD = vessel density

See also Sex-Specific Characteristics of the Microcirculation

 

[Sly Saint]

now published
https://www.mdpi.com/1422-0067/23/22/13683

 

[Hutan]

I want this idea of reduced retinal capillaries to be true. But the differences between the post-covid-19 syndrome results and those of the controls seems so small as a percentage of the total numbers:

LS means of overall VD were 29.97 ± 0.06 (SVP), 21.96 ± 0.05 (ICP) and 23.62 ± 0.06 (DCP) in patients with PCS. Controls showed LS means of overall VD of 30.13 ± 0.19 (SVP), 22.62 ± 0.17 (ICP) and 23.73 ± 0.19 (DCP).
Significant effects for age and gender were observed with respect to VD in the SVP, ICP and DCP (p < 0.0001). Considering the influence of age, we observed that, with increasing age, VD in the SVP, ICP and DCP decreased (Figure 1). Estimated values were −0.06 (SVP), −0.06 (ICP) and −0.07 (DCP) in patients with PCS.

They had to adjust for age and gender. Figure 1 just doesn't look that convincing, and I'm not even sure that there really is an age effect.

See for example Fig 1a for the superficial vascular plexus layer. What seems to be happening is that most of the people with PCS look like the healthy controls, but there are a substantial number of 'outliers' with much lower vessel densities.

I've found this paper hard to get to grips with. I don't fully understand Figure 2. What do others think?

 

[SNT Gatchaman]

That figure 2 is confusing and the 95% prediction ellipse is obscured, which isn't helpful.

As a general comment though: in comparison to the capillary decrease that can be seen in muscle, perhaps the retina is relatively protected or resilient. (Perhaps from an evolutionary perspective, if you can avoid the predator altogether you don't have to run fast). If the retinal function had been more easily compromised, that would be overt and we might have had something like a "Day of the Triffids" scenario. However, when researchers look, they find — even if the changes are not marked. The eye is the window to the vasculature (as well as the soul) but will be a clue and not be fully representative.

From the thread Assessment of early and long-COVID related retinal neurodegeneration with optical coherence tomography (2022) —

Ischemic events in different retinal capillary beds after COVID-19 infection had been demonstrated by several studies. In our study, patients with mild symptoms recovered from COVID-19 had decrease in central and inferonasal quadrants of pRNFL thickness; ONL thickness in inner ring and mRNFL thickness in outer ring in early and long-term follow-up visits may indicate subclinic markers of ischemic events in retinal layers.

That paper also says —

In OCTA [optical coherence tomography angiography] studies, as a consequence of COVID- 19-induced microvascular angiopathy in retina, retinal vascular changes were obtained in early and late periods after recovery. Structural retinal changes are inevitable with microvascular angiopathic process. Neurodegeneration and thinning in retinal layers were obviously demonstrated in Diabetes Mellitus, a microvascular angiopathic disease, without retinal findings.

That last sentence references —

Study of inner retinal neurodegeneration in Diabetes Mellitus using spectral domain optical coherence tomography (2021)
Neurodegeneration in Patients with Type 2 Diabetes Mellitus without Diabetic Retinopathy (2019)

See also
Retinal vessels modifications in acute and post-COVID-19 (2021)
The impact of acute COVID-19 on the retinal microvasculature assessed with multimodal imaging (2022)

 

[duncan]

Again, I am brought back to VEGF.

Wish they were talking cognitive decline....

 

[Hutan]

The impact of acute COVID-19 on the retinal microvasculature assessed with multimodal imaging (2022)

That study looks at acute Covid-19.

Purpose
To quantify retinal microvascular findings in the acute phase of COVID-19 using multimodal imaging and compare them with healthy, age-matched controls.

Methods
Hospitalized patients in the acute phase of COVID-19 without known systemic comorbidities (n = 75) and healthy controls (n = 101) aged 18–65 were enrolled in this prospective cross-sectional study. The retinal microcirculation and microvasculature impairments were assessed using fundus photography, swept-source optical coherence tomography, and swept-source optical coherence tomography angiography in the COVID-19 unit and compared with healthy, age-matched controls.

Results
Retinal findings were predominately observed in patients with severe disease (P = 0.006). Patients with severe disease were shown to have increased both mean vein diameter (Coef. = 19.28, 95% CI: 7.34–31.23, P = 0.002) and mean artery diameter (Coef. = 11.07, 95% CI: 0.84–21.67, P = 0.044). Neither blood vessel diameters were correlated with any confounding variables (age, sex, treatment with oxygen, LDH, or ferritin). Patients with severe COVID-19 were shown to have significantly increased retinal nerve fiber layer thickness in the superior and inferior quadrants both in the inner (S: P = 0.046; I: P = 0.016) and outer (S: P = 0.026; I: P = 0.014) ring and significantly increased GCL thickness in the outer temporal quadrant (P = 0.038). There were no statistically significant differences in vessel density or the foveal avascular zone area between the groups.

Conclusion
The severity of COVID-19 was significantly correlated with the presence of retinal microangiopathy, which could become a biomarker of angiopathy in patients with COVID-19.

They didn't find any difference between hospitalised patients and controls with respect to vessel density.

 

[Hutan]

Again, I am brought back to VEGF.

Wish they were talking cognitive decline....

I don't understand @duncan, what is the link?

 

[duncan]

?

I don't understand @duncan, what is the link?

Sorry. I'm tired. This link is worrisome to me. I'm probably wrong. But who of us has tested our serum VEGF? I have over several years, off and on. What cursory searching I've found is that often it doesn't have a good outcome, at least with cognitive stuff. I test weird so of course I wonder. Sorry to hog conversation. But I've done some digging and the cognitive stuff concerns me. I apologize for commanding too much bandwidth.

High Vegf has a bad look looking at most things. Look at low Vegf.

 

[Hutan]

I apologize for commanding too much bandwidth.

No need to apologise, you don't. Besides, people posting is what keeps the forum alive. I'll make a thread to discuss it, if we don't have one.

Here: VEGF - Vascular Endothelial Growth Factor

 

[SNT Gatchaman]

That study looks at acute Covid-19.

True, but I thought it was a good recent paper that shows some of the complexities of assessment and gives an overview and references prior literature —

Pooled analysis of the studies has shown an 8.86-fold increase in the prevalence of retinal micro-vasculopathy in recovered COVID-19 patients compared to healthy controls.

... this is the first study including patients in the acute phase of COVID-19 without known systemic conditions that could affect the retina. The purpose of the study was to quantify possible impairment of the retinal microcirculation and microvasculature using ... and compare it with healthy, age-matched controls.

They didn't find any difference between hospitalised patients and controls with respect to vessel density.

Yes, but I thought this point from that same paper was important (I hope it's ok to keep in this thread) —

The retina is part of the central nervous system, and its energy demands have been linked to those of the brain, making it particularly susceptible to the effects of ischemia and oxidative stress. Due to the blood-retinal barrier, its intrinsic autoregulatory response maintains a constant blood flow, not influenced by either autonomic innervation or hormonal mediators and neurotransmitters.

Firstly, it is known that retinal veins dilate in response to impaired drainage, and arteries dilate in response to either hypoxia or hypercapnia. Furthermore, studies have shown the potential role of inflammatory mediators on the increased diameter of both veins and arteries.

The retinal plexuses are composed of terminal vessels without anastomotic connections, making them more susceptible to ischemia. In addition, the retina has high metabolic demands, which makes it more vulnerable to the stress induced by acute COVID-19. Therefore, the thickening of [Ganglion Cell Layer] and [Retinal Nerve Fibre Layer] could reflect ischemic edema resulting from a combination of endothelial damage and micro-thrombi-induced end-capillary closure.

Even though the measured differences in our study are small, especially in the [Mean Arterial Diameter], they are clearly visible in the fundus photographs.

This last point was made in the context of experienced independent raters, with good reliability. (MAD reliability not given I think.)

Fundus photographs were reviewed for the presence of hemorrhages, cotton wool spots, and dilated and tortuous vessels. The vessels were defined as dilated if all three examiners marked them as dilated in their notes.
...
The inter-rater reliability was 1 for retinal hemorrhages and cotton wool spots and 0.96 for dilated veins.

 

[Hutan]

I've tried again, but it still does my head in a bit.

LS means of overall VD were 29.97 ± 0.06 (SVP), 21.96 ± 0.05 (ICP) and 23.62 ± 0.06 (DCP) in patients with PCS. Controls showed LS means of overall VD of 30.13 ± 0.19 (SVP), 22.62 ± 0.17 (ICP) and 23.73 ± 0.19 (DCP).

Instead, in the PCS patients, the complete model (including age, gender and Bell’s score variables) revealed a significant difference between patients with chronic fatigue (CF) and those without CF with respect to VD in the SVP (p = 0.0033, (CI: −4.5; −0.92)) (Table 2). No notable differences were observed for the other retinal layers (p > 0.05). Patients with PCS and CF showed LS means of VD of 30.3 ± 0.28 (SVP), 21.89 ± 0.25 (ICP) and 23.08 ± 0.24 (DCP). Patients with PCS without CF showed LS means of VD of 27.59 ± 0.91 (SVP), 21.58 ± 0.84 (ICP) and 23.69 ± 0.8 (DCP).

So, for the whole sample, the controls had a mean vessel density in the SVP of 30.1. The paper makes a big thing of patients with the symptom of chronic fatigue (CF). This group (with fatigue as one of the symptoms of their post-covid illness) had a mean of 30.3, slightly higher than the controls. People without chronic fatigue but with persisting symptoms had 27.6. For example, here's the abstract:

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.

How can retinal microcirculation be an objective biomarker for chronic fatigue in post-Covid syndrome, if the retinal density is basically the same in people with chronic fatigue and in the controls? I don't think I've seen an analysis of how different those two groups are - the authors just compare the groups with and without chronic fatigue within the bigger group with persisting symptoms.