Relationship of the main indicators of systemic COVID-associated endotheliopathy with the morphofunctional state and hemodynamics of the retina and chorioid in the acute period of the disease

Abstract

BACKGROUND: Nonspecific angio- and retinopathy is one of the clinical manifestations of a new coronavirus infection. The frequency of occurrence of these changes in people with severe COVID-19 does not exceed 55%. The causes, course and consequences of these microcirculatory disorders of the retina are currently not well understood.

AIM: To study and compare of retinal morphometric parameters and systemic endothelial dysfunction markers, as well as the main clinical and laboratory parameters in patients with moderate and severe coronavirus infection during convalescence.

MATERIALS AND METHODS: The study involved 44 patients (86 eyes) who had COVID-19 during the previous 3 months, who were divided into 2 groups: with moderate and severe disease. The control group consisted of 18 healthy volunteers (36 eyes). All patients underwent a standard ophthalmological examination and optical coherence tomography, which included an assessment of the choroidal thickness (CT) and measurement of the mean diameter of the peripapillary arteries (MAD) and veins (MVD). During hospitalization, all patients underwent a laboratory study of venous blood parameters, as well as an assessment of the microcirculation of the sublingual plexus by examining the density of the endothelial glycocalyx (PBR) using the GlycoCheck.

RESULTS: In patients who underwent COVID-19, there was a significant increase in CT relative to the control group, amounting to 308, 344 and 392 μm, respectively. The most pronounced difference was observed between MVD in patients with severe infection and the control group (119.1 μm vs. 99.2 μm). In patients with moderate and severe COVID-19, MAD and MVD were positively correlated with TC, with r = 0.389 and r = 0.584, respectively. MVD also correlated with the level of leukocytes (r = 0.504), the ESR value (r = 0.656). Correlations between MVD and data characterizing the state of the glycocalyx in the sublingual vascular plexus were revealed: the filling of small capillaries with erythrocytes (r = –0.587), as well as the marginal perfusion value in large capillaries 20–25 μm (r = 0.479) and PBR (r = 0.479). Only significant differences and correlations are shown (p < 0.005).

CONCLUSIONS: In patients who underwent moderate and severe COVID-19 during the convalescence period (up to 30 days), an increase in the diameter of peripapillary vessels and TC is observed, proportional to the severity of COVID-19, laboratory markers of systemic inflammation and hypercoagulation (the number of leukocytes, the ESR value, D-dimer and prothrombin), which indicates the inflammatory nature of the changes. The severity of postcovid retinal microangiopathy correlates with indicators detecting a decreasing of the endothelial glycocalyx thickness in the sublingual capillary plexus, which indirectly indicates a connection with systemic endotheliopathy.

Keywords

COVID-19 / coronavirus infection / optical coherence tomography / peripapillary artery diameter / peripapillary vein diameter / choroidal thickness / endothelial glycocalyx / endothelial dysfunction

References

[1] de Miguel Buckley R, Díaz-Menéndez M, García-Rodríguez J, Arribas JR. Seasonal coronavirus pneumonia after SARS-CoV-2 infection and vaccination: new frenemies? J Infect Dis. 2022;225(4): 741–743. DOI: 10.1093/infdis/jiab421

[2] de Miguel Buckley R., Díaz-Menéndez M., García-Rodríguez J., Arribas J.R. Seasonal coronavirus pneumonia after SARS-CoV-2 infection and vaccination: new frenemies? // J Infect Dis. 2022. Vol. 225, No. 4. P. 741–743. DOI: 10.1093/infdis/jiab421

[3] Yamaoka-Tojo M. Vascular endothelial glycocalyx damage in COVID-19. Int J Mol Sci. 2020;21(24):9712. DOI: 10.3390/ijms21249712

[4] Yamaoka-Tojo M. Vascular endothelial glycocalyx damage in COVID-19 // Int J Mol Sci. 2020. Vol. 21, No. 24. ID 9712. DOI: 10.3390/ijms21249712

[5] Mahdjoubi A, Bousnina Y, Barrande G, et al. Features of cotton wool spots in diabetic retinopathy: a spectral-domain optical coherence tomography angiography study. Int Ophthalmol. 2020;40: 1625–1640. DOI: 10.1007/s10792-020-01330-7

[6] Mahdjoubi A., Bousnina Y., Barrande G., et al. Features of cotton wool spots in diabetic retinopathy: a spectral-domain optical coherence tomography angiography study // Int Ophthalmol. 2020. Vol. 40. P. 1625–1640. DOI: 10.1007/s10792-020-01330-7

[7] COVID-19 and vascular disease. EBioMedicine. 2020;58:102966. DOI: 10.1016/j.ebiom.2020.102966

[8] COVID-19 and vascular disease // EBioMedicine. 2020. Vol. 58. ID102966. DOI: 10.1016/j.ebiom.2020.102966

[9] Bansal R, Markan A, Gautam N, et al. Retinal involvement in COVID-19: results from a prospective retina screening program in the acute and convalescent phase. Front Med. 2021;8:681942. DOI: 10.3389/FMED.2021.681942

[10] Bansal R., Markan A., Gautam N., et al. Retinal involvement in COVID-19: Results from a prospective retina screening program in the acute and convalescent phase // Front Med. 2021. Vol. 8. ID681942. DOI: 10.3389/FMED.2021.681942

[11] Illarionova AR, Potapova OM, Kosareva OA, Kuznetsova YuR. Frequency of retinal changes in patients with COVID-19: an observational study. Sechenov Medical Journal. 2020;11(2):40–49. (In Russ.) DOI: 10.47093/2218-7332.2020.11.2.40-49

[12] Илларионова А.Р., Потапова О.М., Косарева О.А., Кузнецова Ю.Р. Частота ретинальных изменений у пациентов, перенёсших заболевание COVID-19: обсервационное исследование // Сеченовский вестник. 2020. Т. 11, № 2. С. 40–49. DOI: 10.47093/2218-7332.2020.11.2.40-49

[13] Lani-Louzada R, do Val Farreira Ramos C, Cordeiro RM, Sadun AA. Retinal changes in COVID-19 hospitalized cases. PLoS ONE. 2020;15(12): e0243346. DOI: 10.1371/journal.pone.0243346

[14] Lani-Louzada R., do Val Farreira Ramos C., Cordeiro R.M., Sadun A.A. Retinal changes in COVID-19 hospitalized cases // PLoS ONE. 2020. Vol. 15, No. 12. ID e0243346. DOI: 10.1371/journal.pone.0243346

[15] Invernizzi A, Torre A, Parrulli S, et al. Retinal findings in patients with COVID-19: Results from the SERPICO-19 study. EClinicalMedicine. 2020;27:100550. DOI: 10.1016/j.eclinm.2020.100550

[16] Invernizzi A., Torre A., Parrulli S., et al. Retinal findings in patients with COVID-19: Results from the SERPICO-19 study // EClinicalMedicine. 2020. Vol. 27. ID100550. DOI: 10.1016/j.eclinm.2020.100550

[17] Jidigam VK, Singh R, Batoki JC, et al. Histopathological assessments reveal retinal vascular changes, inflammation and gliosis in patients with lethal COVID-19. Graefes Arch Clin Exp Ophthalmol. 2021;2(5). DOI: 10.1101/2021.02.25.21251531

[18] Jidigam V.K., Singh R., Batoki J.C., et al. Histopathological assessments reveal retinal vascular changes, inflammation and gliosis in patients with lethal COVID-19 // Graefes Arch Clin Exp Ophthalmol. 2021. Vol. 2, No. 5. DOI: 10.1101/2021.02.25.21251531

[19] Landecho MF, Yuste JR, Gándara E, et al. COVID-19 retinal microangiopathy as an in vivo biomarker of systemic vascular disease? J Intern Med. 2020;289(1):116–120. DOI: 10.1111/joim.13156

[20] Landecho M.F., Yuste J.R., Gándara E., et al. COVID-19 retinal microangiopathy as an in vivo biomarker of systemic vascular disease? // J Intern Med. 2020. Vol. 289, No. 1. P. 116–120. DOI: 10.1111/joim.13156

[21] Turgel VА, Tultseva SN. Study of the retina and optic nerve microvascular bed using optical coherence tomography-angiography in post-COVID-19 patients. Regional blood circulation and microcirculation. 2021;20(4):21–32. (In Russ.) DOI: 10.24884/1682-6655-2021-20-4-21-32

[22] Тургель В.А., Тульцева С.Н. Исследование микрососудистого русла сетчатки и зрительного нерва методом оптической когерентной томографии-ангиографии у пациентов, перенёсших COVID-19 // Регионарное кровообращение и микроциркуляция. 2021. Т. 20, № 4. С. 21–32. DOI: 10.24884/1682-6655-2021-20-4–21-32

[23] Huertas A, Montani D, Savale L, et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? Eur Respir J. 2020;56:2001634. DOI: 10.1183/13993003.01634-2020

[24] Huertas A., Montani D., Savale L., et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? // Eur Respir J. 2020. Vol. 56. ID2001634. DOI: 10.1183/13993003.01634-2020

[25] Teuwen L-A, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020;21:389–391. DOI: 10.1038/s41577-020-0343-0

[26] Teuwen L.-A., Geldhof V., Pasut A., Carmeliet P. COVID-19: the vasculature unleashed // Nat Rev Immunol. 2020. Vol. 21. P. 389–391. DOI: 10.1038/s41577-020-0343-0

[27] Harrison DG, Cai H. Endothelial control of vasomotion and nitric oxide production. Cardiol Clin. 2003;21(3):289–302. DOI:10.1016/s0733-8651(03)00073-0

[28] Harrison D.G., Cai H. Endothelial control of vasomotion and nitric oxide production // Cardiol Clin. 2003. Vol. 21, No. 3. P. 289–302. DOI:10.1016/s0733-8651(03)00073-0

[29] Gavriilaki E, Brodsky RA. Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily. Br J Haematol. 2020;189(6):227–230. DOI: 10.1111/bjh.16783

[30] Gavriilaki E., Brodsky R.A. Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily // Br J Haematol. 2020. Vol. 189, No. 6. P. 227–230. DOI: 10.1111/bjh.16783

[31] Petrishchev NN, Khalepo OV, Vavilenkova YA, Vlasov TD. COVID-19 and vascular disorders (literature review). Regional blood circulation and microcirculation. 2020;19(3):90–98. (In Russ.) DOI: 10.24884/1682-6655-2020-19-3-90-98

[32] Петрищев Н.Н., Халепо О.В., Вавиленкова Ю.А., Власов Т.Д. COVID-19 и сосудистые нарушения (обзор литературы) // Регионарное кровообращение и микроциркуляция. 2020. Т. 19, № 3. С. 90–98. DOI: 10.24884/1682-6655-2020-19-3-90-98

[33] Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7:803–815. DOI: 10.1038/nri2171

[34] Pober J.S., Sessa W.C. Evolving functions of endothelial cells in inflammation // Nat Rev Immunol. 2007. Vol. 7. P. 803–815. DOI: 10.1038/nri2171

[35] Aşıkgarip N, Temel E, Hızmalı L, et al. Retinal vessel diameter changes in COVID-19 infected patients. Ocul Immunol Inflamm. 2021;29(4):645–651. DOI: 10.1080/09273948.2020.1853783

[36] Aşıkgarip N., Temel E., Hızmalı L., et al. Retinal Vessel Diameter Changes in COVID-19 Infected Patients // Ocul Immunol Inflamm. 2021. Vol. 29, No. 4. P. 645–651. DOI: 10.1080/09273948.2020.1853783

[37] Gündoğan M, Vural E, Bayram N, et al. Change in retinal vessel diameter and choroidal thickness in patients with severe COVID-19: Change in retinal parameters in patients with severe COVID-19. Photodiagnosis Photodyn Ther. 2021;37:102674. DOI: 10.1016/j.pdpdt.2021.102674

[38] Gündoğan M., Vural E., Bayram N., et al. Change in retinal vessel diameter and choroidal thickness in patients with severe COVID-19: change in retinal parameters in patients with severe COVID-19 // Photodiagnosis Photodyn Ther. 2021. Vol. 37. ID 102674. DOI: 10.1016/j.pdpdt.2021.102674

[39] Cennamo G, Reibaldi M, Montorio D, et al. Optical coherence tomography angiography features in post-COVID-19 pneumonia patients: a pilot study. Am J Ophthalmol. 2021;227:182–190. DOI: 10.1016/j.ajo.2021.03.015

[40] Cennamo G., Reibaldi M., Montorio D., et al. Optical coherence tomography angiography features in post-COVID-19 pneumonia patients: a pilot study // Am J Ophthalmol. 2021. Vol. 227. P. 182–190. DOI: 10.1016/j.ajo.2021.03.015

[41] Guemes-Villahoz N, Burgos-Blasco B, Vidal-Villegas B, et al. Reduced macular vessel density in COVID-19 patients with and without associated thrombotic events using optical coherence tomography angiography. Graefes Arch Clin Exp Ophthalmol. 2021;259(8): 2243–2249. DOI: 10.1007/s00417-021-05186-0

[42] Guemes-Villahoz N., Burgos-Blasco B., Vidal-Villegas B., et al. Reduced macular vessel density in COVID-19 patients with and without associated thrombotic events using optical coherence tomography angiography // Graefes Arch Clin Exp Ophthalmol. 2021. Vol. 259, No. 8. P. 2243–2249. DOI: 10.1007/s00417-021-05186-0

[43] González-Zamora J, Bilbao-Malavé V, Gándara E, et al. Retinal microvascular impairment in COVID-19 bilateral pneumonia assessed by optical coherence tomography angiography. Biomedicines. 2021;9(3):247. DOI: 10.3390/biomedicines9030247

[44] González-Zamora J., Bilbao-Malavé V., Gándara E., et al. Retinal microvascular impairment in COVID-19 bilateral pneumonia assessed by optical coherence tomography angiography // Biomedicines. 2021. Vol. 9, No. 3. ID247. DOI: 10.3390/biomedicines9030247

[45] Oren B, Aksoy Aydemır G, Aydemır E, et al. Quantitative assessment of retinal changes in COVID-19 patients. Clin Exp Optom. 2021;104(6):717–722. DOI: 10.1080/08164622.2021.1916389

[46] Oren B., Aksoy Aydemır G., Aydemır E., et al. Quantitative assessment of retinal changes in COVID-19 patients // Clin Exp Optom. 2021. Vol. 104, No. 6. P. 717–722. DOI: 10.1080/08164622.2021.1916389

[47] Dag Seker E, Erbahceci Timur IE. COVID-19: more than a respiratory virus, an optical coherence tomography study. Int Ophthalmol. 2021;41(11):3815–3824. DOI: 10.1007/s10792-021-01952-5

[48] Dag Seker E., Erbahceci Timur I.E. COVID-19: more than a respiratory virus, an optical coherence tomography study // Int Ophthalmol. 2021. Vol. 41, No. 11. P. 3815–3824. DOI: 10.1007/s10792-021-01952-5

[49] Hernandez M, González-Zamora J, Recalde S, et al. Evaluation of macular retinal vessels and histological changes in two cases of COVID-19. Biomedicines. 2021;9(11):1546. DOI: 10.3390/biomedicines9111546

[50] Hernandez M., González-Zamora J., Recalde S., et al. Evaluation of macular retinal vessels and histological changes in two cases of COVID-19 // Biomedicines. 2021. Vol. 9, No. 11. ID 1546. DOI: 10.3390/biomedicines9111546

RIGHTS & PERMISSIONS

Turgel V.A., Tultseva S.N.