Add retinal damage to the long and growing list of potential sequelae of Covid-19.

Researchers at the University of Missouri have shown that the SARS-CoV-2 virus responsible for triggering the ‘classic’ respiratory and immunologic symptoms of Covid can also pass the blood-retinal barrier, causing retinal damage and visual impairment.

Like the blood-brain barrier, the blood-retina barrier is an anatomical and physiological system that protects the highly sensitive tissues of the eye from microbial pathogens, blood-borne toxins, and other potentially noxious stimuli. Generally speaking, it does an excellent job of that.

But U of Missouri ophthalmologist, Pawan Kumar Singh, PhD, and his colleagues have shown that SARS-CoV-2 can evade this defense system.

The UM researchers used a ‘humanized’ ACE2 strain of mice, and infected the animals intranasally with the Covid virus. They were later able to detect the virus and viral remnants in the cells comprising the blood-retinal barrier inside the eyes of the mice. There was clear evidence of an inflammatory response in the retinal tissue of the affected animals.

Breaching the Retinal Barrier

“Our findings reveal that SARS-CoV-2 not only reaches the eye during systemic infection but induces a hyperinflammatory response in the retina and causes cell death in the blood-retinal barrier,” said Dr. Singh in a press release announcing the findings.

“The longer viral remnants remain in the eye, the risk of damage to the retina and visual function increases.”

Singh’s lab is focused on research into the role of infectious pathogens that can cause visual impairment, and the discovery of new therapeutic options for preventing blindness. The SARS-CoV-2 findings were posted in April in the online open-access journal, PLoS Pathogens. 

Early on in the Covid pandemic, researchers and clinicians alike recognized that the virus could directly infect the external surface of the eye. Discovery of viral RNA in corneal and conjunctival tissue, along with the finding that there are ACE2 receptors on cells comprising the surface of the eye led some to hypothesize that the eyes might, in fact, be a point of systemic entry for the virus and/or a route of viral transmission.

Singh’s work has put a dent in that notion. His team found that ocular exposure to SARS-CoV-2 does not lead to respiratory infection or life-threatening illness in the mice they studied.

But intranasal and respiratory exposure very definitely can lead to internal ocular infection, as well as a hyperinflammatory immune response in retinal tissue.

A Conducive Environment

The researchers found that the cells of the murine blood-retina barrier were a highly conducive host for viral replication. Presence of viral remnants in the retina caused a variety of aberrations including microaneurysm, retinal pigmented epithelium (RPE) mottling, venous and arterial occlusion retinal atrophy, and vascular leakage.

Though some researchers had previously suspected that SARS-CoV-2 can cross into the eye and cause damage, the Singh Lab’s study is the first to provide direct evidence that this can occur.

Covid-induced retinal damage has not been directly documented in human subjects in the way that Singh and colleagues were able to do in their mice experiments. But the findings do have clinical relevance because they corroborate clinical observations that have been published practically since the beginning of the pandemic.

Clinically Relevant

In 2020, ophthalmologists at the Federal University of São Paulo, Brasil, published a paper in The Lancet describing Covid-associated retinal abnormalities—detected by Optical Coherence Tomography—in 12 adults, within one month of acute infection with SARS-CoV-2 (Marinho PM, et al. Lancet. 2020). Several other studies and case reports since then have also linked the virus with retinal vascular occlusions and other anomalies in humans.

“The longer viral remnants remain in the eye, the risk of damage to the retina and visual function increases.”

Pawan Kumar Singh, PhD, University of Missouri

There’s little doubt that the virus can cross the blood-brain barrier (BBB), leading to the “brain fog” and other cognitive impairments many people experience during and after Covid episodes. So, it is certainly plausible that this pathogen could also directly cross the retinal barrier as well.

The fact that ACE2 receptors—the primary target for viral spike protein attachment—are abundant in human retinal tissue provides further circumstantial evidence to support the notion that the virus can reach and damage the human retina.

Hyperglycemia Raises Risk

Though practitioners should be on the lookout for retinal damage or other ocular problems in patients who’ve had Covid, Dr. Singh stressed that generally speaking the human blood-retina barrier is very good at keeping out viruses and other pathogens. However, his team’s research has also shown that hyperglycemic states tend to enhance the ability of SARS-CoV-2 to get past this line of defense.

Hyperglycemia increases viral entry receptor expression, while simultaneously rendering cells more susceptible to virally-induced cell death. That’s an important thing to keep in mind, given the widespread prevalence of diabetes and metabolic syndrome.

Other Ocular Sequelae

Aside from retinal damage, SARS-CoV-2 has been linked with several other ocular disorders including:

• Conjunctivitis: This is a well-documented Covid-related condition. According to a metanalysis by Loffredo and colleagues published in 2020, roughly 3% of all patients with severe acute Covid-19 had conjunctivitis. For mild cases, the prevalence was just under 1% of those with mild Covid. Covid patients admitted to hospitals were 3 times more likely to have “pink-eye” than non-Covid patients (Loffredo L, et al. J Med Virol. 2020). RNA from the virus has been identified in conjunctival swab samples from Covid patients.  
• Optic Neuritis: Though far less common than conjunctivitis, there are several case reports of optic neuritis in connection with COVID-19. Symptoms include vision loss and eye pain following COVID-19 infection (Jossy A, et al. Indian J Ophthalmol. 2022. Sawalha K, et al. J Investig Med. 2020.) There are also a number of papers documenting optic neuritis following Covid-19 vaccination (Wan-Ju AL, QJM. 2022. Sachdeva V. Oman J Ophthalmol. 2023). Such occurrences are rare, and usually mild.
• Uveitis: Though rare, there are reports of uveitis in association with COVID-19 infection (Feng H, et al. BMC Ophthalmol. 2024). As with optic neuritis, there are also multiple reports from all over the world suggesting that uveitis sometimes occurs following Covid-19 vaccination. Most authors have concluded that the problem is usually mild and self-limiting, and not cause for vaccine avoidance (Cherif Y, et al. Vaccines (Basel). 2022).
• Endophthalmitis: Inflammation of the interior of the eye cavity is extremely rare, but has been reported in association with Covid-19 (Markan A, et al. Ocular Immunol Inflamm. 2023). In some of these cases, the endophthalmitis was caused by fungal pathogens, and required surgery and/or high-dose corticosteroid therapy.
• Dry Eye Syndrome: Though not likely to cause permanent damage, severe dry eye syndrome has been seen in COVID-19 patients. It is sometimes the result of prolonged mask use, especially among workers whose occupations require long periods of full facial masking. Some researchers have suggested that increased computer or smartphone screentime during the pandemic is a contributing factor.

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