ABSTRACTPurpose

: To evaluate the effects of SARS-CoV-2 infection on optic nerve, macula and retinal vascular structure.

Methods

: The study included 129 participants recovering from COVID-19 and 130 healthy controls aged 18 to 55 years. The study was designed as observational and cross-sectional and conducted between June 2020 and February 2021. The average thicknesses of the retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and macula were also measured using an SD-OCT (spectral domain optical coherence tomography) analysis. The vessel densities of the superficial and deep capillary plexus (SCP and DCP) of the macula, foveal avascular zone (FAZ), and the vessel density of the radial peripapillary capillary plexus (RPCP) for the optic disc were quantified by OCT-A (optical coherence tomography angiography).

Results

: In all quadrants, RNFL and GCC were thinner in patients with neurological symptoms of COVID-19 (P<.05). None of the measurements of the ETDRS regions significantly differed between the patients with and without COVID-19 symptoms (P >.05). The FAZ area, perimeter, circularity index and VDs (%) of the global, inner and outer circles of SCP and DCP and global, superior and the inferior halves of the RPCP measurements were found to significantly differ between the symptomatic COVID-19 group and the asymptomatic COVID-19 and control groups (P<.05).

Conclusion

: RNFL and GCC thickness evaluation with OCT and VD evaluation with OCT-A can be considered remarkable diagnostic methods for retinal neurovascular abnormalities and a biomarker for microvascular abnormalities after the infection of SARS-CoV-2.

Keywords

INTRODUCTION

The pathogen of the novel coronavirus disease (COVID-19), known as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), is an RNA virus that primarily affects the upper and lower respiratory tracts.[1-3] The novel type of coronavirus disease (COVID-19), first detected in Wuhan, China in December 2019, was declared a pandemic by the World Health Organization (WHO) in March 2020.[4] As is known, COVID-19 is a disease that has effects on the central nervous and cardiovascular systems, as well as the respiratory system.[5-7] In individuals who have had COVID-19 disease, retinal tissue may also vary depending on the effects on the central nervous or vascular system.[8-9]

The SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors on cell surfaces and the virus-receptor interaction is thought to reduce ACE2 action and increase levels of angiotensin II, a strong capillary vasoconstrictor; that propagates microvascular damage.[10]

This study aimed to investigate the possible effects of COVID-19 disease on the optic nerve, macula, and retinal vascular structure.

MATERIAL AND METHOD

The study was designed as observational and cross-sectional and conducted in the ophthalmology, pulmonology and infectious diseases departments of Erzincan Binali Yildirim University Faculty of Medicine between June 2020 and February 2021. Ethical approval was obtained from the local ethics committee (approval number: E-21142744-804.99-70916), and detailed informed consent was taken from all the participants. The principles of the Declaration of Helsinki were adhered to throughout the study.

Study design and participants

Patients diagnosed with COVID-19 confirmed by laboratory-confirmed SARS-CoV-2 infection based on a positive polymerase chain reaction (PCR) test by an infectious diseases specialist and/or a pulmonologist were included in the study. All the patients in the COVID-19 group included in the study were called for ophthalmological examinations after PCR negativity was observed. All the patients were included in the study at the earliest 29 and at the latest 45 days after COVID-19 PCR positivity was detected. The participants with COVID-19 were divided into three groups according to their admission symptoms as neurological, non-neurological (respiratory, cardiovascular and gastrointestinal), and asymptomatic/paucisymptomatic. Asymptomatic patients included in the study consisted of patients who had a history of contact with patients with COVID-19 and who wanted to have a PCR test without any complaints. Systemic examination results of the COVID-19 group at presentation are showed in table 2. Patients were also divided as symptomatic and asymptomatic in COVID-19 group.

The demographic and clinical data of 184 patients who completely recovered from COVID-19 were evaluated. Fifty-five participants were excluded from the study based on the criteria given in the following section. The final sample included 129 participants recovering from COVID-19 and 130 controls aged between 18 and 55 years, with a visual acuity of ≥20/20, axial length of 22-24.5 mm, refractive error spherical equivalent of ≤±3D, and intraocular pressure (IOP) of ≤21 mm Hg. All the controls were evaluated between 2018-2019 for the ‘Normative Data Assessment of Vessel Density and Foveal Avascular Zone Metrics Using AngioScan Software’ study in our clinic. Only the right eyes of all the participants were included.

Exclusion criteria

Individuals who had systemic diseases, such as hypertension, diabetes mellitus, and cardiovascular and neurological problems, those with ocular disorders, such as glaucoma, cataract, retinal vascular, and/or macular diseases, those with previous ocular surgery and/or trauma, and those who have two or more of the neurological, cardiovascular, respiratory, and gastrointestinal admission symptoms were excluded from the study.

Ophthalmological examinations

A detailed ophthalmological examination was performed, including autorefractometry (Tonoref III, Nidek Co. Ltd, Japan), best-corrected visual acuity (BCVA) analysis, slit lamp biomicroscopy, and IOP measurement with a Goldmann applanation tonometer. The axial length was measured with the ALSCAN (Nidek Co. Ltd, Japan) device in all patients.

Pulmonological examinations

The patients' complaints, such as cough, fever, weakness, fatigue, joint pain, shortness of breath, headache, sore throat, chest pain, back pain, decreased sense of smell and taste, and diarrhea were questioned. Respiratory system examinations (inspection, percussion, palpation, and auscultation) were performed. Laboratory examinations that could suggest macrophage activation syndrome (hemogram, routine biochemistry, acute phase reactants, and parameters such as ferritin, D-Dimer, and fibrinogen) were also examined. In addition, the patients were radiologically evaluated in terms of COVID-19 using thoracic computed tomography (16-slice CT scanner-Sensation 16, Siemens Medical Systems, Germany), postero-anterior chest radiography, and PCR.

Infectious disease examinations

The patients were evaluated in terms of oral cavity mucosal involvement, cervical lymphadenopathies, thyroid sensitivity, cardiac murmurs, abdominal sensitivity, and rashes. The complete blood count, serum C-reactive protein, procalcitonin, D-dimer, and ferritin levels were measured.

COVID-19 treatment algorithm

The treatment algorithm recommended by the Ministry of Health of the Republic of Turkey was followed for the symptomatic patients diagnosed with COVID-19 based on PCR positivity. This algorithm includes favipiravir 1,600 mg/day for three days, 600 mg/day for five days for maintenance and enoxaparin 4,000 miu/cc/day [body mass index (BMI) < 30) or 8,000 miu/cc/day (BMI > 30) for 1 week. In severe cases, the maintenance dose of favipiravir was extended to 10 days and enoxaparin to 14 days.

Optical coherence tomography (OCT) and OCT-angiography (OCT-A) scan procedures

The macular and peripapillary thicknesses were measured using an SD-OCT device (Nidek Co. Ltd., Aichi, Japan). The Nidek RS-3000 Advance OCT system was used to evaluate the SD-OCT images. The average thicknesses of the retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and macula were also determined with an SD-OCT analysis. The RNFL measurements for the mean, superior, inferior, temporal and nasal quadrants were performed from a 6 × 6 mm2 ring centered on the optic nerve head and recorded. From the 6 × 6 mm2 macular map, macular thicknesses were measured from the nine zones described by the Early Treatment Diabetic Retinopathy Study (ETDRS), and the superior and inferior GCC thicknesses were also recorded. The subfoveal choroidal thickness was measured at three points (central foveal, 500 micron nasal, and temporal of the central foveal), and the average of these three values was determined as the final thickness.

The vessel densities (VDs) of the superficial and deep capillary plexus (SCP and DCP) of the macula, foveal avascular zone (FAZ), and the VD of the radial peripapillary capillary plexus (RPCP) for the optic disc were quantified using OCT-A (RS-3000 Advance, Nidek Co. Ltd., Gamagori, Japan). Updated AngioScan software (Navis ver. 1.8.0.) of Nidek's RS-3000 Advance system was used to evaluate the OCT-A images. This software automatically calculates the macular and peripapillary VDs calculated, as well as the FAZ. The fovea was focused on using an OCT-A prototype internal fixation lamp, and 3 × 3 mm2 macula cubes, each consisting of 256 B-scans, were generated. For the retinal peripapillary capillary plexus, the scans included a 2.4 × 4 mm2 disc map centered on the optic nerve head. The updated software of Nidek's RS-3000 Advance device allows removing the projection artefacts of OCT-A scans through the “ALL Layers” projection artifact removal (PAR) feature. From the macular OCT-A scans, the FAZ circularity index (CI) (values closer to “1” indicate higher circularity), area and perimeter, and the VDs of the global ‘whole image’ SCP and DCP, outer and inner superficial capillary plexus, deep capillary plexus rings and nine ETDRS regions were evaluated.

SD-OCT and OCT-A measurements were performed by an experienced ophthalmologist after pupil dilation with a 1% tropicamide eye drop (Tropamid, Bilim Ilac Ltd, Istanbul, Turkey). In cases where the signal strength index quality was <7/10, scanning was repeated. FAZ (with a 3 × 3 mm2 OCT-A measurements field) and the VDs of SCP and DCP were measured. Automated segmentation was performed to determine the en face slab for the superficial and deep retinal layers, extending from the internal limiting membrane to 13 μm below the inner nuclear layer and from 8 μm below the inner nuclear layer to 13 μm below the outer nuclear layer, respectively. VDs was calculated as the percentage area filled by flowing blood vessels in the selected region. The VD of RPCP for the S/I and TSNIT sectors was obtained from the OCT-A scans of the peripapillary area. In the study, all the numerical values of the VDs were obtained automatically by the OCT-A device. The segmentation algorithm was also selected automatically by the device.

Statistical analysis

The Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) version 23.0 was used for the statistical analysis of the data. G-Power analysis was not performed as the study was exploratory. Data of continuous variables were expressed as mean ± standard deviation and those of categorical variables as frequency and percentages. Whether the data were normally distributed was determined with the Shapiro-Wilk test. In the analysis comparing the groups, the analysis of variance (ANOVA) test with the Bonferroni correction was performed for continuous variables with a normal distribution, and the Mann-Whitney U test for the comparison of quantitative data without a normal distribution. The Pearson and Spearman correlation tests were used to evaluate the correlations between variables. After checking collinearity diagnostics, a multivariate regression analysis corrected for age, gender, image quality, intraocular pressure, and axial length was used to determine the associations between the RNFL and GCC thickness as dependent variables and, the VDs of SCP, DCP and RPCP as independent variables in the COVID-19 group. Statistical results were stated at the 95% confidence interval and given with the regression coefficient (B) in the regression analysis. Statistical significance was evaluated at the level of P < .05.

RESULTS

Demographic and clinical data

The demographic and clinical data of the participants are presented in Table 1. A total of 129 participants recovering from COVID-19 and 130 controls were enrolled in the study. Only the right eyes of all the participants were included in the evaluations. All the participants were Caucasian. Sixty-seven of the individuals in the COVID-19 group and 68 in the control group were women (P > .05). The mean age was 42.3 ± 13.8 (range: 18-55) years in the COVID-19 group and 44.9 ± 12.4 (range: 18-55) years in the control group. There were no differences between the two groups in terms of mean age, BCVA, IOP, and axial length (P > .05). And also there was no significant difference between the subgroups in patients with COVID-19 in terms of age and gender (P > .05). Severe cases were hospitalizated. Hospitalization rates were 18/38 (47.4%) in patients with neurological symptoms while 40/59 (67.8%) in patients with non-neurological symptoms. In patients with neurological symptoms 8 (21%) of them were taken oxygen therapy while 34 (57.6%) in patients with non-neurological symptoms. Only the patients who needed intensive care were intubate. All patients needing intensive care unit were admitted with non neurological symptoms.

Table 1Demographic, ophthalmologic and clinical data of the study participants

F: female, M: male, BCVA: best-corrected visual acuity, IOP: intraocular pressure,

AL: axial length

Systemic examination and laboratory results

The results of the systemic examination are shown in Table 2. Thirty-two of the patients with COVID-19 were asymptomatic/paucisymptomatic at the time of admission. Of the remaining patients in the COVID-19 group, 38 had predominantly neurological symptoms and 59 had predominantly non-neurological symptoms (respiratory in 29, cardiovascular in 17, and gastrointestinal in 13) at the time of admission. Laboratory findings of the study participants with COVID-19 at first visit are presented in Table 3.

Table 2: Systemic examination results of the COVID-19 group at presentation

Table 3Laboratory findings of the participants with COVID-19 at first visit

Significant P values are shown in bold style

OCT and OCT-A measurement results

The results of the OCT measurements are shown in Table 4. In all quadrants, RNFL and GCC were thinner in the patients with neurological COVID-19 symptoms (PP > .05).

Table 4OCT measurements of the study groups

RNFLT; retinal nerve fiber layer thickness (μm), MT; macular thickness, CFST: central foveal subfield thickness (1 mm) GCCT; ganglion cell complex thickness, The significant P values expressed with bold style.

*: difference compared to all the remaining groups (ANOVA test). ¥: difference compared to three (non-neurological, asymptomatic and control) groups (ANOVA test)

The mean and standard deviation values of the FAZ area, perimeter and CI, and the VDs of SCP, DCP and RPCP are shown in Table 5. The FAZ area, perimeter and CI, and the VDs (%) of the global, inner and outer circle of SCP and DCP and global, superior and inferior halves of the RPCP measurements were found to significantly differ between the symptomatic COVID-19 group and the asymptomatic COVID-19 and control groups (P

Table 5Measurements of the FAZ area, perimeter and CI, and the VDs of SCP, DCP and RPCP in the study groups

VD; vessel density, FAZ; foveal avascular zone, CI; circularity index, SCP; superficial capillary plexus, DCP; deep capillary plexus, RPCP; retinal peripapillary capillary plexus.

Significant P values are shown in bold style *: difference compared to all the remaining groups (ANOVA test). ¥: difference compared to three (non-neurological, asymptomatic and control) groups (ANOVA test) ɸ: difference compared to symptomatic (neurological and non neurological) groups and non-symptomatic (asymptomatic and control) groups (t-test)

Multiple regression analyses showed in symptomatic COVID-19 patients a significant relationship between reduced average thickness of the RNFL and GCC and impaired OCT-A parameters (r:0.894 and 0.799; P:0.001 and 0.002, respectively), particularly with DCP, RPCP and FAZ measurements (Table 6).

Table 6Multiple Linear Regression Model Between the RNFL and GCC and OCTA Parameters in the symptomatic COVID-19 Group.

RNFL; retinal nerve fiber layer GCC; ganglion cell complex VD; vessel density, FAZ; foveal avascular zone, CI; circularity index, SCP; superficial capillary plexus, DCP; deep capillary plexus, RPCP; retinal peripapillary capillary plexus.

Significant P values are shown in bold style. Multiple linear regression model; ANOVA = analysis of variance; statistical significance P value < .05.

DISCUSSION

In this study, RNFL and GCC measurements were significantly lower in the patients who presented with the neurological symptoms of COVID-19 disease.

In addition, the SCP, DCP and RPCP measurements of the patients with symptomatic COVID-19 were significantly lower than those of the asymptomatic COVID-19 and control groups. In the participants with symptomatic COVID-19, the FAZ area and perimeter measurements were significantly higher, and the FAZ CI measurements were significantly lower.

COVID-19 disease has been found to cause prothrombotic status in patients, but its long-term outcomes remain unknown [11-13]. In COVID-19 disease, many organs and systems are involved due to the direct and indirect effects of the SARS-CoV-2 virus. Therefore, theoretically, COVID-19 can be expected to affect all organs in the body that contain vessels. In patients with symptomatic COVID-19, subnormal oxygenation levels are present, and therefore supplemental oxygen is required for an extended period. This can also account for retinal VD decrease in patients with symptomatic COVID-19. However, the current study was performed after patients had completely recovered from COVID-19 disease, and therefore the acute effects of hypoxia or hyperoxia on retinal VD in SARS-CoV-2 infection remain uncertain. Different studies have shown that oxygen status has effects on retinal VD lasting from a few minutes to a few days [14-16].

The reduction in VDs can be explained by multiple mechanisms due to COVID-19 infection, including thromboinflammatory microangiopathy and angiotensin-converting enzyme (ACE)-2 disruption [17,18]. SARS-CoV-2 related microvascular damage is assumed to occur due to complement activation [19]. Complement-mediated thrombotic vasculopathy activate platelet and leukocyte recruitment, coagulation, and endothelial cell dysfunction [20,21]. Impairment in the local renin-angiotensin system due to endothelial injury causes the high endothelial expression of ACE-2 receptors which are used by SARS-CoV-2 to enter into the cell. Then, endothelial damage results in hypercoagulopathy and microvessel occlusion seen in COVID-19 infection [20]. An important finding that has been previously reported is that the human eye structures, including ciliary body, choroid, retina and retinal pigment epithelium have significant levels of ACE-2 receptors [22]. Thus, COVID-19 infection is considered to damage the chorioretinal vasculature.

Cennamo et al. investigated changes in the retinal VD in the macular and papillary regions in patients with post-SARS-CoV-2 pneumonia using OCT-A and found a decrease in the VD of the retina in those that had recovered from the disease [23]. Zapata et al. showed that patients with moderate and severe SARS-CoV-2 pneumonia had decreased central retinal VDs compared to asymptomatic/paucisymptomatic cases or controls [24]. Similarly, in the current study, the VDs of SCP, DCP and RPCP were significantly lower in the symptomatic COVID-19 group. Savastano et al. reported a reduction in the RPCP VDs of patients one month after they had recovered from COVID-19 [25]. However, Abrishami et al found that the SCP and DCP VDs were reduced in COVID-19 patients vs normal controls and that the FAZ was enlarged [26]. In the current study, the VDs of SCP and DCP and RPCP were reduced in the COVID-19 group according to the OCT-A measurements.

In the current study, OCT and OCT-A showed significant relationship between the RNFL and GCC thickness and the DCP and RPCP in symptomatic COVID-19 patients. Yu et al reported a positive correlation between the RPCP density and RNFL thickness in the same healthy human eyes in their study [27]. There was no relationship between OCT parameters and SCP values in symptomatic COVID-19 patients in the study. The vascular structure of the DCP is characterized by a fine capillary network that makes it more vulnerable to thrombotic events than to the greater vascular diameter of the SCP [28]. These previous studies support the multiple regression analyses results of our study.

This study has certain limitations. First, since the patients were not evaluated in the acute period of the infection, we did not have the chance to observe the possible retinal findings of any patient in the active phase of COVID-19. Second, patients with cardiovascular symptoms were not examined as a separate group, and possible retinal vascular effects were not examined. Third, due to the low number of patients requiring intensive care with very severe COVID-19 findings, we were not able to determine whether OCT-A findings were affected more seriously in this subgroup. Fourth, long-term follow-up data were not available since the disease is caused by a novel coronavirus, and more time is needed to perform a long-term evaluation. Lastly, the study analyzed only the macular and peripapillary retinal VDs, and fluorescein angiography was not undertaken to investigate the peripheral retina.

In conclusion, retinal microvascular changes were observed in OCT-A following COVID-19 infection in clinically asymptomatic eyes. VD evaluation with OCT-A can be considered a remarkable diagnostics method for retinal neurovascular abnormalities and a biomarker for microvascular abnormalities after the infection of SARS-CoV-2. Further studies are needed to evaluate the relationship between the OCT-A parameters and both the onset and the duration of COVID-19 infection.

ACKNOWLEDGMENTS

The authors state no conflict of interest concerning the publication of this manuscript. The study was not funded, and the authors have accepted responsibility for the entire content of this manuscript and approved its submission.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author, [AU]. The data are not publicly available due to [restrictions e.g. their containing information that could compromise the privacy of research participants].

REFERENCES

1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease Control and prevention. J Am Med Assoc 2020.

2. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA.2020;323:1061–1069. doi: 10.1001/jama.2020.1585.

3. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433.

4. The world health organization coronavirus disease 2019 (COVID-19) situation report e61. Available at:-, https://www.who.int/docs/default-source/ coronaviruse/situation-reports/20200321-sitrep-61-covid-19.pdf? sfvrsn¼f201f85c_2. [Accessed 22 March 2020].

5. Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020;12(1):69.

6. Whittaker A, Anson M, Harky A. Neurological Manifestations of COVID-19: A systematic review and current update. Acta Neurol Scand. 2020;142(1):14-22. doi:10.1111/ane.13266.

7. Hendren NS, Drazner MH, Bozkurt B, Cooper LT Jr. Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome. Circulation. 2020;141(23):1903-1914. doi:10.1161/CIRCULATIONAHA.120.047349.

8. Casagrande M, Fitzek A, Püschel K, Aleshcheva G, Schultheiss HP, Berneking L, Spitzer MS, Schultheiss M. Detection of SARS-CoV-2 in Human Retinal Biopsies of Deceased COVID-19 Patients [published online ahead of print, 2020 May 29]. Ocul Immunol Inflamm. 2020;1-5. doi:10.1080/09273948.2020.1770301.

9. Marinho PM, Marcos AAA, Romano AC, Nascimento H, Belfort R Jr. Retinal findings in patients with COVID-19. Lancet. 2020;395(10237):1610. doi:10.1016/S0140-6736(20)31014-X.

10. Liu Y, Ning Z, Chen Y, Guo M, Liu Y, Gali NK, Sun L, Duan Y, Cai J, Westerdahl D, et al. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature. 2020 Jun;582(7813):557-560.

11. Mucha SR, Dugar S, McCrae K, Joseph D, Bartholomew J, Sacha GL, Militello M. Coagulopathy in COVID-19. Cleve Clin J Med 2020;87:461–8.

12. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020;18:1421–4.

13. Kasinathan G, Sathar J. Haematological manifestations, mechanisms of thrombosis and anti-coagulation in COVID-19 disease: a review. Ann Med Surg 2020;56:173–7.

14. Sousa DC, Leal I, Moreira S, Dionísio P, Abegão Pinto L, Marques-Neves C. Hypoxia challenge test and retinal circulation changes – a study using ocular coherence tomography angiography. Acta Ophthalmol 2018;96:e319–e315.

15. Hagag AM, Pechauer AD, Liu L, Wang J, Zhang M, Jia Y, Huang D. Oct angiography changes in the 3 parafoveal retinal plexuses in response to hyperoxia. Ophthalmol Retina 2018;2:329–36.

16. Xu H, Deng G, Jiang C, Kong X, Yu J, Sun X. Microcirculatory responses to hyperoxia in macular and peripapillary regions. Invest Ophthalmol Vis Sci 2016;57:4464.

17. Vinci R, Pedicino D, Andreotti F, Russo G, D'Aiello A, De Cristofaro R, Crea F, Liuzzo G. From angiotensin-converting enzyme 2 disruption to thromboinflammatory microvascular disease: A paradigm drawn from COVID-19. Int J Cardiol. 2021 Mar 1;326:243-247.

18. Gencer S, Lacy M, Atzler D, van der Vorst EPC, Döring Y, Weber C. Immunoinflammatory, Thrombohaemostatic, and Cardiovascular Mechanisms in COVID-19. Thromb Haemost. 2020 Dec;120(12):1629-1641.

19. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H, Zhang H. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 23;382(17):e38.

20. Gavriilaki E, Brodsky RA . Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily. Br J Haematol . 2020;189(6):e227–e230.

21. Bellinvia S, Edwards CJ, Schisano M, Banfi P, Fallico M,Murabito P. The unleashing of the immune system in COVID-19 and sepsis: the calm before the storm? Inflamm Res. 2020;69(8):757–763.

22. Strain WD, Chaturvedi N. The renin-angiotensin-aldosterone system and the eye in diabetes. J Renin Angiotensin Aldosterone Syst . 2002;3(4):243–246.

23. Cennamo G, Reibaldi M, Montorio D, D'Andrea L, Fallico M, Triassi M. Optical Coherence Tomography Angiography Features in Post-COVID-19 Pneumonia Patients: A Pilot Study. Am J Ophthalmol. 2021 Mar 27;227:182-190.

24. Zapata MÁ, Banderas García S, Sánchez-Moltalvá A, Falcó A, Otero-Romero S, Arcos G, Velazquez-Villoria D, García-Arumí J. Retinal microvascular abnormalities in patients after COVID-19 depending on disease severity. Br J Ophthalmol. 2020 Dec 16:bjophthalmol-2020-317953.

25. Savastano A, Crincoli E, Savastano MC, Younis S, Gambini G, De Vico U, Cozzupoli GM, Culiersi C, Rizzo S, Gemelli Against Covid-Post-Acute Care Study Group. Peripapillary Retinal Vascular Involvement in Early Post-COVID-19 Patients. J Clin Med. 2020 Sep 8;9(9):2895.

26. Abrishami M, Emamverdian Z, Shoeibi N, Omidtabrizi A, Daneshvar R, Saeidi Rezvani T, Saeedian N, Eslami S, Mazloumi M, Sadda S, Sarraf D. Optical coherence tomography angiography analysis of the retina in patients recovered from COVID-19: a case-control study. Can J Ophthalmol. 2021 Feb;56(1):24-30.

27. Yu PK, Balaratnasingam C, Xu J, Morgan WH, Mammo Z, Han S, Mackenzie P, Merkur A, Kirker A, Albiani D, et al. Label-Free Density Measurements of Radial Peripapillary Capillaries in the Human Retina. PLoS One. 2015 Aug 7;10(8):e0135151.

28. Lavia C, Bonnin S, Maule M, Erginay A, Tadayoni R, Gaudric A. VESSEL DENSITY OF SUPERFICIAL, INTERMEDIATE, AND DEEP CAPILLARY PLEXUSES USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina:2019;39:2:247-258.

Article InfoPublication History

Accepted: June 23, 2022

Received in revised form: April 10, 2022

Received: January 7, 2022

Publication stageIn Press Accepted ManuscriptIdentification

DOI: https://doi.org/10.1016/j.jcjo.2022.06.016

Copyright

© 2022 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

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