INTRODUCTION

COVID-19, caused by the SARS-CoV-2, emerged from Wuhan, China, in December 2019 and has become a global health threat, being declared a pandemic by the WHO on 11 March 2020.

Although patients with COVID-19 usually present with fever and respiratory tract symptoms, it has been shown that COVID-19 can affect other organ systems, manifesting as cardiovascular, neurological, gustatory, gastrointestinal, hepatic, renal, olfactory, haematological, cutaneous and ocular symptoms.¹

The ocular manifestations of SARS-CoV-2 infection are not completely understood; most studies have reported ocular surface disorders.^2–4 Marinho et al posed the hypothesis of retinal involvement by SARS-CoV-2 and reported hyper-reflective lesions on optical coherence tomography at the level of ganglion cell and inner plexiform layers of 12 patients diagnosed with COVID-19 and mild-to-moderate symptoms.⁵ An autopsy study also identified viral RNA of SARS-CoV-2 in retinas of deceased patients with COVID-19.⁶ The pro-thrombotic status reported in critically ill patients with COVID-19 may also lead to retinal injuries in addition to retinal damage by the direct activity of SARS-CoV-2.^{7 8}

The objective of this study was to identify retinal findings using dilated eye examinations, which are possibly related to SARS-CoV-2 infection in hospitalised patients with confirmed severe COVID-19.

RESULTS

Retinal findings

The median time (IQR) between confirmatory examination of COVID-19 (RT-PCR for SARS-CoV-2) and dilated eye examination was 11.5 (8) days. Ten of the 18 patients (55.6%; 95% CI 33.7 to 75.4) had abnormalities on dilated eye examination (table 2A and B). The main findings were flame-shaped haemorrhages (N=4; 22.2%, 95% CI 9 to 45.2) and cotton wool spots (N=3; 16.7%; 95% CI 5.8 to 39.2), with one patient having both cotton wool spots and flame-shaped haemorrhage (figure 1). One patient had retinal sectorial pallor suggestive of acute retinal ischaemia (5.6%; 95% CI 0.3 to 25.8). Other findings included peripheral retinal haemorrhages (N=2; 11.1%; 95% CI 2.0 to 32.8), retinal pigment epithelium hyperplasia (N=1; 5.6%; 95% CI 0.3 to 25.8), choroidal naevus (N=1; 5.6%; 95% CI 0.3 to 25.8) and macular haemorrhages and hard exudates (N=1; 5.6%; 95% CI 0.3 to 25.8).

View this table:

• View inline
• View popup

Table 2

Retinal findings on dilated eye examination of inpatients with severe COVID-19

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Main retinal findings of patients with severe COVID-19. Panels (A–C) represent three different patients with no baseline comorbidities. (A) Colour fundus photography and red-free imaging of the right eye of a female patient in her 60s revealing well-delimited sectorial pallor at the lower temporal arcade (black arrow). Vasoactive pharmacological support was not necessary during hospitalisation. (B) Colour fundus photography of the left eye of a male patient in his 40s revealing a peripapillary flame-shaped haemorrhage (black arrow). Vasoactive pharmacological support was necessary during hospitalisation. (C) Colour fundus photography of the left eye of a female patient in her 60s revealing a cotton wool spot (black arrow) and adjacent flame-shaped haemorrhage (white arrow) at the lower temporal arcade. Vasoactive pharmacological support was not necessary during hospitalisation.

DISCUSSION

To the best of our knowledge, this is the first report of retinal findings in hospitalised patients with severe COVID-19. Our study was designed to evaluate possible retinal involvement by SARS-CoV-2 because of the hypothesis generated regarding patients with mild-to-moderate COVID-19.⁵ The SARS-CoV-2 belongs to the group of coronaviruses that are known to cause ocular infections in various animal species.¹⁰

We found that 10 of the 18 patients had abnormalities on dilated eye examination, not necessarily related to SARS-CoV-2 infection, because chronic alterations like retinal pigment epithelium hypertrophy and choroidal naevus were observed. However, inner retinal vasculature acute lesions such as flame-shaped haemorrhages and cotton wool spots were the main findings, and one patient had retinal sectorial pallor suggestive of recent retina ischaemia. In some cases, these lesions appeared in the absence of vasoactive pharmacological support, DM, or systemic HBP, suggesting that they might be related to COVID-19 itself.

The retina could be affected either by direct tissue damage by SARS-CoV-2 and its immunogenicity¹¹ or by the thrombotic complications that have been reported to have a remarkably high incidence in patients with COVID-19 admitted to the ICU.⁷

Direct infection and immune injury are thought to be involved in nerve damage in COVID-19.¹¹ The inner retina is a neuronal tissue, and may also be injured by SARS-CoV-2 as has been reported for the central nervous system.¹² SARS-CoV-2 RNA has already been identified in retinas of deceased patients with COVID-19,⁶ and other viruses are known to cause similar retinal injuries. These include HIV, dengue virus and Zika virus.^{13 14}

It has been reported that critically ill patients with COVID-19 in the ICU have thrombotic complications at rates as high as 31%.⁷ Although more information is needed, the coagulopathy appears to be related to the profound inflammatory response against the SARS-CoV-2 and not to intrinsic viral activity.⁸ This is because the retina is one of the most metabolically active tissues in the body and its terminal circulation is particularly sensible to ischaemic events.¹⁵ We found cotton wool spots, which are thought to result from occlusion of terminal retinal arterioles in the nerve fibres and ganglion cell layer, with consequent retina ischaemia and infarction, and retinal sectorial pallor, possibly caused by branch arterial occlusion secondary to thromboembolic phenomena.¹⁴

This study had several limitations. First, there was relatively small sample size. Second, there were potential confounding factors such as baseline comorbidities and therapeutic approaches. HBP and DM are known to cause retinal lesions similar to the ones we found. Because of their high prevalence among elderly and because they are risk factors for severe presentations of COVID-19, excluding patients with HBP and DM would make the study unfeasible. Furthermore, vasoactive pharmacological support could also be a confounding factor because acute peaks of blood pressure could also cause similar lesions. Third, the ophthalmological evaluation was limited to dilated eye examination. Complementary exams such as optic coherence tomography would provide a deeper understanding of our findings; however, this was impracticable because of the patients’ clinical statuses and contact precautions. Patients will be followed up as their clinical status and contact precautions allow for multimodal retinal imaging and further investigation.

Our results suggest that the retina might be affected in patients with COVID-19. However, given the clinical characteristics of the disease, confounding factors are difficult to control. Further studies with larger samples are necessary to assess this possibility. Nevertheless, we are sharing these preliminary results in an effort to inform the scientific community about the possibility of retina lesions in patients with severe COVID-19.