The primary outcome of the study was to evaluate the presence of posterior segment alterations through a cross-sectional sample at different stages of the COVID-19, and to the best of our knowledge this is the first study to address this issue in a cohort of hospitalized people positive for SARS-CoV-2. All available evidence in humans is focused on the ocular surface - where almost only conjunctivitis has been described - and most data comes from case reports or findings from human conjunctival samples.17,30,31 In our patients, of whom we carefully considered baseline anamnestic, results of fundus examination seem to demonstrate that neither the retina nor retinal vessels are involved in the active phase of COVID-19 infection.
The rationale in focusing on potential ocular fundus alterations, relies on previous studies conducted in animals infected by viruses belonging to the large sub-family of Orthocoronavirinae. The occasional onset of uveitis or retinitis in feline and murine models has been described and linked to an underlying autoimmune process inducing vasculitis or to a viral-mediated inflammation.9–13 Recent clinical and anatomopathological reports have described the endothelial damage as one of the most prominent causes of the systemic vascular thromboembolic and/or inflammatory manifestations of COVID-19.32–34 In this setting, the retina as a privileged district for non-invasive and in vivo evaluation of systemic diseases, may reveal alterations such as vascular occlusion related to the thrombotic susceptibility and chorioretinitis or vasculitis directly mediated by the virus. Hence, as reported in the brain, we considered the possibility of a direct ocular spread of SARS-CoV-2 through the two blood-retinal barriers (BRBs). In the recent literature on COVID-19 there are only anecdotal reports of virus spread through the blood-brain barrier.35–37 Although two proven cases of positive CSF testing for SARS-CoV-2 have been described and one post-mortem, there is no certain data proving that the virus is able to directly affect central nervous system.38,39 Our findings, on a cohort of subjects in different stages of the disease, including ICU patients, seem to demonstrate that the SARS-CoV-2 may not be able to cross the ocular BRBs. Furthermore, to the best of our knowledge, here we report the first attempt to isolate SARS CoV-2 in human aqueous humour.
With respect to the known thrombotic susceptibility described in COVID-19, we did not find any sign of retinal vascular involvement, such as venous or arterial occlusion. However, it should be considered that all patients in our cohort were treated with LMWH to prevent systemic vascular complications and only one patient addressed the criteria for DIC.
At the present time, there is only one report that described retinal lesions in a little cohort of asymptomatic SARS-CoV-2 positive patients. The authors found cotton-wool-like lesions and microhaemorrhages in 4 out of 12 patients and inner retinal OCT hyperreflective spots in the whole sample. However, apart from “normal blood parameters”, the authors did not provide any specific information enabling the clinical characterization of their patients. Indeed, no data regarding the presence of systemic comorbidities as well as no details regarding the patients’ ongoing therapy were given. Hence, it cannot be excluded that their findings may be ascribed to pre-existing non COVID-19-related systemic diseases affecting the retina, such as hypertensive or diabetic retinopathy or other infectious diseases.40–42 In our cohort, largely composed of subjects with severe COVID-19, we merged retinal findings with baseline anamnestic. Nevertheless, our negative results should also be attributed to the ongoing immune modulating treatment, including steroids or Tocilizumab, that could have concealed ophthalmoscopic findings. Finally, with regard to the patient with chorioretinitis from fungal sepsis, it should be considered that severe COVID-19 patients, especially when hospitalized in an ICU setting, may be affected by super-infection due to several opportunistic pathogens with possible eye localization.43
Regarding the anterior segment findings, literature describes conjunctivitis as a part of the clinical manifestation of COVID-19 with a variable rate of presentation, going from 0 to 32%. Only in 4-7% of cases PCR revealed the presence of SARS-CoV-2 from conjunctival swab.17,19,31,44 In all three patients presenting bilateral conjunctivitis that were observed in our study, the conjunctival swab was negative for SARS-CoV-2. Nevertheless, since other viruses (e.g. herpes and adenovirus) are known to induce and have been detected in conjunctivitis45, we cannot exclude a transient presence of SARS-CoV-2 on the ocular surface at any time before or after our swab. Alternatively, conjunctivitis may represent an epiphenomenon in hospitalized patients. Since it has been definitely demonstrated that COVID-19 affects the peripheral nervous system, as shown by the reported 85-88% rate of olfactory and gustatory dysfunction46, we investigated the possible involvement of trigeminal sensory pathways by exploring the corneal sensitivity. However, results of aesthesiometry seem to demonstrate that, unlike herpes viruses, SARS-CoV-2 does not affect corneal sensitivity.47
One strength of this cross-sectional study is to have explored posterior segment involvement in COVID-19 pneumonia patients at different stages of disease and in patients who had different comorbidities at the time of their hospitalization. Furthermore, considering our brief study period and the actual feasibility of an ophthalmological evaluation in an emergency setting, we obtained data from a relevant sample size even if a larger study population is probably necessary to confirm our findings. Among the shortcomings of our research it should be disclosed potential bias resulting from systemic therapies put in place before the ophthalmological evaluation, and those deriving from the exclusion of patients in CPAP therapy.