Coronaviruses are known to involve organs and systems other than the respiratory tract, including the digestive system, nervous system and ocular tissues.10,11 Substantiating the previous reports, suggest ocular infection in the recent SARS-CoV-2 epidemic, and ocular transmission might a potential route of SARS-CoV-2 infection.12,13 Despite the fact that several months has gone by since the epidemic, not much is published with regards to the SARS-CoV-2 pathogenic mechanisms, especially with respect to the ocular tissues. This study, evaluated the ocular findings detected in the recovered COVID-19 patients, using clinical examination, OCT, and OCT angiography imaging, after mean time of two months , which were compared with normal population .
In this study of 51 patients with confirmed COVID-19 infection, it is noteworthy to say that all 51 patients (100%) had a normal ophthalmology examination and imaging.
None of the recovered COVID -19 patients had ocular or retinal finding. Visual acuity and pupillary reflexes were normal in all eyes, and we did not detect any symptoms or signs of intraocular inflammation.
Marinho reported more prominent hyper-reflective lesions at the level of ganglion cell and inner plexiform layers at the papillomacular bundle in the symptomatic populations, using dilated fundus examination and OCT2. Previous studies of state of the retinal vascularisation in patients after COVID-19 are summarized in Tables 5. Turker et al.4 examined the 54 eyes from 27 hospitalized patients with COVID -19 within 1 week of discharge and compared with 54 eyes of 27 volunteers and reported a reduced vessel density of the retinal capillary plexus in COVID-19 patients.
Abrishami et al.5 evaluated the macular density of 31 patients at least 2 weeks after recovery from systemic COVID-19 using optical coherence tomography angiography (OCTA) analysis and compared with 23 healthy normal controls, and suggested that recovered patients displayed alterations in the retinal microvasculature, including a significantly lower vessel density in the superficial and deep capillary plexus.
González-Zamora et al.6 evaluated the presence of retinal and microvascular alterations in hospitalized COVID-19 patients compared to age- and sex-matched controls using OCT angiography, 14 days after hospital discharge and suggested that ,COVID-19 patients presented lower vessel density in the foveal region and a greater FAZ area than controls.
Savastano et al.7 compared OCT angiography and structural OCT of 70 post-COVID-19 patients after 1-month hospital discharge and 22 healthy control subjects and found no or minimal retinal vascular involvement by SARS-CoV-2.
Hazar et al.8 compared 50 patients with SARS CoV2 pneumonia 55 healthy age- and gender-matched controls using OCT angiography one month after discharged with recovery.and reported low vessel density in some sectors in both superficial and deep layers with no change in FAZ.
These different findings could be attributable to the different period between acute infection and ophthalmological examination. Our investigation revealed that the frequency of ocular findings might be related to infection time, as our patients were on a mean time approximately 63 days (40 to 95 days) after the onset of COVID-19. Among these studies in recovered patients, time from onset of infection were not the same and no longer than one month (between 1 week to one months), which might have led to higher number of retina findings.
Zapata and associates,9 analyzed and quantified retinal microvascular by OCT angiography in COVID- 19 infected patients during the last 3 months since onset of disease and found patients with moderate and severe disease had decreased central retinal vessel density as compared with that of asymptomatic or paucisymptomatic cases or control subjects. and difference in time of imaging from disease onset.
In mentioned report, mean days from PCR-confirmed diagnosis to ophthalmological examination time were 72 days in moderate disease and 70 days in severe disease which it is almost the same as our study. The discrepancy may be due to the difference in disease severity, differences in device and image analysis. Also, in our study, for evaluated the net retinal effect of COVID-19, we excluded the comorbidity diseases ( smoking, diabetes history or treatment with ACE inhibitors) which effect on vascular density and patients who need ICU care, but in past study all of patients included in the study. Importantly, our recovered COVID- 19 subjects are significantly higher than the aforementioned report; besides we have a comparative control healthy populations before the COVID-19 pandemic.
Genomic and structural analyses shows that SARS-CoV-2 infect host cells via the angiotensin-converting-enzyme-2 (ACE2) receptor on endothelial cells14 and viral replication can cause inflammatory cell infiltration, endothelial cell apoptosis, which can have microvascular prothrombotic effects. 15
COVID-19 endotheliitis can contribute to microcirculatory impairment and clinical sequelae, such as thrombosis and ischemia, cerebrovascular complications in younger patients, myocardial ischemia and micro- and macrocirculatory thromboembolic complications that can be explained by The endotheliopathy. 15-17
An active local intraocular renin–angiotensin system (RAS) exist in the human eye, and systemic antihypertensive drugs that inhibit RAS can reduce IOP.ACE-2 does exists in the aqueous humour and retina, but not on conjunctival or corneal epithelia.18 Furthermore, additional investigation is warranted to explore the hypothesis of SARS-CoV-2 ocular infection via ACE2.
Vascular abnormalities in OCT angiography were rare in COVID -19 participants, which can be an underestimation; whereas vascular variations can be detected, using fluorescein angiography that allows for a dynamic assessment of the retinal and choroidal vasculature.
The present study did not find a significant difference in the average and sectoral peripapillary vessel density between the two groups. In addition, the deep and superficial layer macular vessel densities were evaluated and superficial and deep foveal, parafoveal and perifovel VDs were found to be similar between eyes in the recovered COVID-19 vs. the healthy eyes.
Since human ocular studies of Corona virus infections are rear in the literature, studying the ocular manifestation of Corona viruses in various animals is of value. Animal studies have revealed that ocular lesions might present itself in the form of optic neuritis, neuroretinitis .19,20
The retina is an extension of the brain and retinal anatomy, function, response to injury, and immune responses similarly to those in the brain and spinal cord. A retinal ganglion cell (RGC) is a type of neuron located in the ganglion cell layer of the retina and in the thalamic region form direct synaptic connections with the CNS. 21
According to The Lancet, ganglion cell and plexiform layer might be associated with central nervous system manifestations that were previously described in animal studies and in COVID-19 neurological findings.20,22
The macula has the highest density of (retinal ganglion cells) RGCs, which exist in the inner retinal layer and gets its oxygen supply from superficial retinal capillary plexuses23-24. The central macular and parafoveal and perifovel superficial as well as deep VD did not differ between the recovered COVID-19 eyes and healthy controls. Microvascular dropouts, secondary to retinal neurodegenerative changes, such as GCC thinning, which might be one possible explanation for coordination between neural atrophy and vascular insufficiency was not observed in this study.
To the best of our knowledge, this is the first study to assess the ocular findings of COVID-19 patients without comorbidities after recovery to 3 months. It is worth noting that our groups were matched in terms of age and gender, and historical control participants examination and imaging were performed before the COVID-19 outbreak.
The latest version of built-in software was used in this study, which automatically provides VD at various retinal layers, and removes large vessels from peripapillary images. Also, our regional analysis coverage of involved area is higher, using large scan size (whole6×6mm2scanning field).
This study has several limitations, and the main one is the small number of recovered COVID-19 patients which none of them needed intensive care, as well as the limited follow-up time. Further studies with larger sample size are required to reassess our findings. Another limitation is that all of the patients were of Iranian origin, which cannot reflect upon the entire population of recovered COVID-19 patients. In addition, some patients may have received medical intervention once they were suspected of having or confirmed to have infection, which could have affected the ocular findings, but this was not accounted for in this study. Since BCVA of 20/40 or better were used, this might have skewed the outcomes and would potentially introduce bias and select for patients with less disease. Finally, OCT-A is a relatively new technique and its limitations must be taken into account. Apart from the artifacts, the obtained images and data analyzing techniques, might in fact lead to different results and must be taken into account when comparing the results of different studies.
In conclusion, the recovered COVID19 patients without comorbidity had similar peripapillary and (superficial and deep) macular VDs in comparison with the healthy eyes matched for age and gender. The results suggest that the pathogenic mechanisms affecting vascular damage may not be involved in the eyes’ tissue. Finally, the theory that vascular changes in COVID -19 is significant should be further investigated in larger prospective studies.