In this study, we evaluated the macular SD-OCT findings in retinal and choroidal layers of patients recovered from COVID-19 and found some features of the pachychoroid disorder spectrum including pachyvessels and retinal pigment epitheliopathy along with significantly thicker SFCT in these patients.
Since Li Wenliang, a glaucoma surgeon in Wuhan, described emerging cases of severe pneumonia with unknown etiology, COVID-19 has received significant global attention, and various aspects of its epidemiology, pathophysiology, different kind of disease presentations, and potential treatment were widely investigated.[1] Worldwide, the total number of cases reached almost 75 million patients with near 1.7 million death as November 22, 2020.[16] Initial reports were mainly focused on life-threatening consequences including pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and septic shock.[17, 18] Specific organ involvement studies are being rapidly emerged by many investigators throughout the world. However, there is a paucity of data on ocular involvement, and most of them are limited to the external eye and conjunctival manifestations and tear film viral load.[5, 6, 10, 19]
Marinho and associates were the first investigators who reported abnormal retinal OCT findings in 12 patients with COVID-10.[12] They noticed hyperreflective lesions at the level of GCL and IPL, but not at any other retinal or choroidal layers. The authors proposed that the GCL and IPL findings might be correlated with the central nervous system manifestations that have been described in animal studies of COVID-19 and patients with neurological sequels of the disease. In a recent editorial, Vavvas and colleagues questioned the significance of OCT findings in the Marinho et al report and proposed that the hyperreflective bands may be normal retinal vessels.[13] We observed some hyperreflective lesions in all retinal layers as reported by Marinho and colleagues; however, similar to Vavvas and colleagues, we believe that these hyperreflective bands are probable the retinal vessels and the prominence of these findings in COVID-19 patients could be due to the vascular involvement (i.e., micro thrombosis and vasodilation) associated with this infection. Besides, we noted some features of the pachychoroid spectrum of disorders, including increased SFCT, presence of pachyvessels, and retinal pigment epitheliopathy. In a recent report, Savastano and associates highlighted peripapillary vascular changes in patients recovered from COVID-19, which indicate the involvement of ocular vasculature in this disease.[14]
SARS-CoV-2 uses the angiotensin-converting enzyme (ACE) 2 receptor to enter the host cells and downregulates the ACE2.[20, 21] The ACE2 is a major role player in the renin-angiotensin-aldosterone system (RAAS). This system has fundamental roles in several biological and pathological processes, including fluid and electrolytes hemostasis, regulation of blood pressure, fibrosis, cell migration and proliferation, inflammation, neovascularization, and oxidative damage.[22–24] RAAS is a highly complex system with multiple components. The first detected component was renin which was identified in 1898.[25] ACE2 was cloned in 2000 and has since been identified in multiple organs such as kidney, heart, brain, liver, intestine, and lung.[25, 24] ACE2 is a potent regulator of RAAS, which is critical in maintaining the homeostasis of RAAS and counter-balancing the ACE.[26, 27] ACE2 is also a facilitator of amino-acid transport in the kidney and intestine.[20] ACE2 expression is increased by aging,[24] smoking,[28], and several chronic diseases,[24] which partially explains higher COVID-19 frequency in these groups.
Besides the systemic RAAS, there are accumulating pieces of evidence that there is a local RAAS in the retina with components most frequently detected on retinal microvessels, glia (e.g. Müller cells), and neurons (ganglion cells).[29] Components of the RAAS have also been found in other ocular structures such as the uveal tract.[29] ACE2 was detected in aqueous humor, retina, and retinal pigmented epithelium (RPE) of humans.[30] It has also been identified in INL and Müller cells of rodent retina.[31] Notably, RAAS dysfunction has been contributed in several ocular pathologies,[32] including diabetic retinopathy,[33–35] central serous chorioretinopathy (CSC),[36, 37] age-related macular degeneration,[38] and retinopathy of prematurity.[39, 40]
With this background in the mind, there are several hypothetical explanations for the SD-OCT findings in our patients. Pulmonary dysfunction and multiorgan failure due to ischemia are fundamental findings in COVID-19.[20] It is well expected that tissues with high oxygen demand have greater damage and the retinochoroidal findings can be due to these ischemic events. Moreover, loss of ACE2 regulatory functions, result in increased RAAS pathologic process including inflammation, fibrosis, vascular damage, and leakage. It has been demonstrated that ACE2 dysfunction is accompanied by impaired migration and function of hematopoietic stem/progenitor cells,[35] retinal leukostasis, and upregulation of adhesion molecules.[29, 40, 39] As the SARS-CoV-2 RNA has been identified in the retinal layers of infected patients,[11] the source of retinal and choroidal vasculopathy can be the involvement of vascular endothelial cells by the virus. Müller cells and blood vessels are a potential target of the virus and their processes/branches cross all retinal layers which potentially explain the pan-retinal findings in COVID-19. Also, it has been shown that the virus interacts with hemoglobin molecules and alter iron homeostasis.[41] Indeed, patients with COVID-19 can have hyper-ferritinemia and it has been suggested as an indicator of more severe disease.[41, 42] Tissue damage by free iron and its deposition in retinal layers can be another explanation for our observations in macular SD-OCT. Finally, the retinal findings can be attributed to the side effects of treatments. As an instance, ritonavir is one of the antiviral treatments suggested for COVID-19.[43, 44] Retinal toxicity of ritonavir has been previously reported in a patient with human immune deficiency virus (HIV) infection under treatment with this drug.[45] The authors reported thickened and irregular RPE with loss of integrity in overlying inner-segment/outer-segment (IS/OS) junction at fovea along with ELM irregularity.[45] The drug has also been reported to cause bull’s eye maculopathy.[46] In a recent report, Savastano and colleagues also reported a correlation between antiviral therapy and peripapillary vascular changes in COVID-19 patients.
We also noticed some features of pachychoroid,[47] including increased choroidal thickness, abnormal dilation of Haller’s layer vessels, and irregular elevation of RPE in our patients. In a recent article by Savastano and colleagues, the authors reported a higher choroidal thickness in patients recovered from COVID-19; however, the difference was not statistically significant.[14] The average SFCT in our patients was almost 70 µm higher than the previously reported thickness in normal subjects with the same ethnic background. Rahman and coworkers reported that a change in SFCT more than 32 µm is more than interobserver variability and could be a true change;[48] however, they used the enhanced depth imaging (EDI) protocol on a different machine (Spectralis; Heidelberg Engineering, Heidelberg, Germany) to measure SFCT.[48] Interestingly, aldosterone contributes to the maintenance of normal retinal function by regulating ion/water channels in the Müller cells.[36, 29] As mentioned earlier, CSC is a well-known example of pachychoroidal disease caused by a disturbance in RAAS function,[36] and the same pathogenic process can result in choroidal thickening in COVID-19 patients.
Our study had some limitations, including a small sample size and minimal diversity of COVID-19 severity, a short follow-up period, and a lack of a control group. In addition, our OCT machine had a limited resolution, especially for the evaluation of choroidal changes. Using swept-source OCT devices can potentially yield more useful information. Despite these, to the best of our knowledge, this is the first report on remarkable choroidal thickening and involvement in COVID-19 patients.
In conclusion, we found that in COVID-19, patients can demonstrate choroidal changes that resemble those in the pachychoroid spectrum and choroidal vascular changes may be a prominent clinical finding in this infection.