Ophthalmologists need to stay vigilant for ocular manifestations of COVID-19

At the end of March, Wu and colleagues published online in JAMA Ophthalmology the first report on 12 cases of conjunctivitis in 38 patients hospitalized with COVID-19 in China’s Hubei province.

These findings were crucial in spreading the alarm about possible SARS-CoV-2 infection through the eye and the need for protecting eye health professionals. Since then, several other cases have been reported, and more has been discovered about ocular manifestations potentially related to SARS-CoV-2.

As of Aug. 3, a search in the WHO database on global literature related to COVID-19 found 220 publications including the word “ocular,” 351 including the word “eye” and 169 including the word “ophthalmology.”

“In a paper published in May by Chen et al, only 5% of 534 cases presented with conjunctivitis. However, other symptoms not always related with conjunctivitis were reported, including dry eye, blurred vision and foreign body sensation,” Healio/OSN Board Member Laura M. Periman, MD, a globally recognized expert in immunology as well as ocular surface disease, said.

From her experience, and the experience of a large group of colleagues she personally surveyed, other manifestations have emerged.

With the neurotrophic and coagulopathic aspects of SARS-CoV-2, ophthalmologists are seeing increases in cases of several ophthalmologic manifestations such as episcleritis. “It used to be a few a year, and now it is an average of one a week for some colleagues, while corneal neuropathies, optic neuritis, uveitis, retinitis and an exacerbation of dry eye are noted by others in terms of prevalence and severity. One of my retina colleagues reported more cases of multiple evanescent white dot syndrome, and others report atypical forms of optic nerve edema, including one case associated with cerebral venous thrombosis in a young adult. Rapid, reliable testing for SARS-CoV-2 has been a problem, so we don’t really know if all these cases are related to the virus, but an increasing number of reports are now coming out in clinical discussions and in the literature,” she said.

Immune dysregulation

SARS-CoV-2 has a high binding affinity to ACE2 human receptors, which serve as the entry point for the virus into cells of the lungs, brain, arteries, heart, kidney and intestine. As the virus invades the cells, it causes a uniquely strong immune response, a cytokine storm that leads to severe and often lethal damage to multiple organs.

“The natural killer cells and T-cell response may be suppressed or insufficient, leading to lymphopenia as well as an imbalance of pro-inflammatory and immunoregulatory mechanisms. Viral-induced neuroinflammation may occur via leukocyte migration across the blood-brain barrier and direct viral infection of neurons and microglia via the ACE2 receptors,” Periman said, which may help explain the late-stage neurologic sequelae such as impaired consciousness, brain edema, seizures, dementia, encephalopathy and stroke.

As a consequence, she expects to see in the future a significant uptick in eye diseases that involve immune dysregulation, inflammation and neurologic damage, such as dry eye, episcleritis, uveitis, retinitis, corneal neuropathy and optic neuritis.

Routes of infection

Both viral and immune diseases can lead to ocular manifestations, but the pathogenesis of the ophthalmic involvement is difficult to determine, according to Jorge L. Alió, MD, PhD.

“There are two types of conjunctivitis related to COVID-19. The first, occurring early in the disease, is follicular conjunctivitis, in which SARS-CoV-2 is detected by PCR in conjunctival secretions and is more likely related to direct virus infestation,” he said. “The second is usually just hyperemia presenting later in the course of the disease, in which the test on the conjunctiva is negative, and this is likely to be a secondary immune reaction, an inflammatory complication of the disease due to the release of cytokines.”

Citing a review published by Seah and Agrawal in Ocular Immunology and Inflammation, Alió said that there are three potential routes through which SARS-CoV-2 can infect the eye: by direct contact of the conjunctiva with infected droplets, by touching the eyes with the hands or by migration of upper respiratory tract infection through the nasolacrimal duct.

In a review published in Ophthalmology and Therapy, Alió and his group wrote that contact with infected eyes could be one route of disease transmission.

“Despite conjunctivitis generally being a self-limited and benign condition, it is an important route of viral transmission and, therefore, prevention is the most important aspect to remember as ophthalmologists to protect our patients and ourselves,” they wrote.

In the Chen paper, two-thirds of patients with COVID-19 conjunctivitis had a history of touching their eyes with their hands, Periman said.

“This reinforces the importance of rigorous hand washing and to avoid touching your face. As surgeons, we are trained to not touch potential contaminants from the earliest stages of our training, and this is for us a definite advantage at this time,” she said.

Conjunctivitis as first sign of COVID-19

Because patients with COVID-19 have been hospitalized in ICUs or isolated at home, it is difficult to have a clear picture of what the prevalence of ocular manifestations might be.

“A lot of the information we have is supported by intensive care specialists and general practitioners, but not so much by ophthalmologists. There has been no proper investigation, and there is a lot we don’t know yet,” Alió said.

On the other hand, ophthalmologists volunteering in ICUs have been collecting data, and telehealth has helped with remote detection and monitoring of cases.

Dominique Brémond-Gignac, MD, PhD, of Hopital Universitaire Necker, APHP, was involved as an ocular surface disease specialist in the telehealth management of a 27-year-old Argentinian patient in which unilateral conjunctival hyperemia was the presenting sign of COVID-19.

“He had no other symptoms and was prescribed topical antibiotics and steroids on a telemedicine consultation. Three hours later, he developed severe headache and fever, followed after 12 hours by cough and severe dyspnea impairing speech. The RT-PCR test was positive for SARS-CoV-2,” she said.

Eleven days later, ocular signs had resolved, although cough and dyspnea persisted. The case was published with the title “Ocular manifestation as first sign of coronavirus disease 2019 (COVID-19): Interest of telemedicine during the pandemic context” in Journal Français d’Ophtalmologie.

“Ocular manifestations have been observed more frequently in the already advanced stages of COVID-19, but we should be aware, as ophthalmologists, that in some cases ocular signs might precede the development of respiratory distress and be an alert,” Brémond-Gignac said.

She warned against the risk for misdiagnosing these manifestations of COVID-19 as bacterial or allergic conjunctivitis. She also hypothesized that patients who present with conjunctivitis as a first sign are likely to have been infected by droplets directly through the ocular route.

“It might be a sign for severe forms because if the eyes are infected by direct droplet contact transmission, the viral load going into the respiratory system is high,” she said.

Hemorrhagic conjunctivitis

A case of pseudomembranous and hemorrhagic conjunctivitis occurring later in the course of the disease was published in American Journal of Ophthalmology by Navel and colleagues. The patient was a 63-year-old man already in intensive care when the first ocular manifestations occurred with conjunctival hyperemia and clear secretions. A few days later, petechiae and tarsal hemorrhages, mucous filaments and tarsal pseudomembranous were observed.

Despite the severity of these ocular manifestations, no bacteria or viruses were identified in the conjunctiva and tears.

“Conjunctival swabs seem to be often negative, complexifying the diagnosis,” the authors wrote.

Due to intubation, “slit lamp and other evaluations of anterior segment complications (such as uveitis or intraocular hypertension) were not performed,” while fundus examination with a Schepens ophthalmoscope “did not identify any vitreous inflammation or retinal abnormalities.”

Anterior uveitis

“In the midst of the pandemic, on March 23, a 30-year-old student at our university was sent to me by a colleague. We were only accepting urgent and emergent cases, but this girl [presented] because she had bilateral hyperemia with loss of vision in the right eye. She had been on antibiotics for 2 weeks, but the therapy had had no effect, and the symptoms had worsened,” Cosimo Mazzotta, MD, PhD, said.

Eye examinations showed follicular conjunctivitis and anterior uveitis with pigmented and whitish precipitates on the anterior capsule, in addition to incipient anterior lens opacity. A mild anterior chamber flare was present, and the cornea was [not involved by typical] keratic precipitates (see Figure, page 12). The patient also indicated that she had been shivering and feeling extremely tired for some time and had an altered sense of taste.

“I referred her to the hospital for a swab test, which turned positive for SARS-CoV-2,” Mazzotta said.

Conjunctivitis and uveitis were treated and resolved within a couple of weeks, while the other symptoms of COVID-19 persisted, aggravated by fever and anosmia, even after the patient finally tested negative for SARS-CoV-2 infection.

“False negatives are not rare with COVID-19 because the tests are far from perfect. However, we have learned from experience that the combination of fever, dysgeusia and anosmia is unequivocally a clinical manifestation of COVID-19,” Mazzotta said.

Another interesting finding in this patient was the association of uveitis and significant leukopenia.

“Uveitis is normally associated with a leukocyte count above the normal range, but leukopenia is among the hematological changes induced by SARS-CoV-2,” he said.

Nodular episcleritis

On June 1, Méndez Mangana and colleagues published a letter to the editor in Acta Ophthalmologica about the first case of episcleritis in a patient with COVID-19.

As the authors noted, episcleritis is a unique manifestation of the recent novel coronavirus, as it was never associated with the coronavirus family before.

The case involved a 31-year-old patient working in a health care center who developed cough, myalgia, anosmia and ageusia and tested positive for COVID-19. Seven days after onset, anosmia and ageusia resolved, but the patient presented at the Centro de Oftalmología Barraquer, Barcelona, Spain, with red eye, foreign body sensation, epiphora and photophobia. A slightly elevated epibulbar area with hyperemia at the inferotemporal sector without fluorescein defect was observed, and the patient was diagnosed with nodular episcleritis.

“Due to the lack of PCR tests available in Spain in those weeks, and given the overall low positive rate of SARS-CoV-2 tested by PCR in tears and conjunctival secretion, we did not perform the PCR test in tears and conjunctival surface on this patient, only nasopharyngeal test with a positive result,” Carlos Méndez Mangana, MD, first author of the study, said.

All the signs and symptoms disappeared after 2 weeks of treatment with fluorometholone, administered five times a day for 3 days and gradually tapered.

The pathophysiology of this manifestation in the context of COVID-19 may include immunovascular factors and/or coagulation disorders, according to the authors.

“There is a relationship between immune disorders that induce vascular inflammation in episcleritis. In addition, a high rate of thromboembolic phenomena was reported in intensive care unit patients with COVID-19,” Méndez Mangana said.

However, further studies are needed to confirm this hypothesis, he said.

Retinal changes

In a comment published in The Lancet in early May, a group of ophthalmologists at the University of São Paulo and Vision Institute, Brazil, reported on retinal findings possibly associated with COVID-19 infection.

“It is important to clarify that we never said that those lesions were directly caused by the SARS-CoV-2. Rather, they are likely to be an outcome of the inflammatory process triggered by the virus,” Paula M. Marinho, MD, said. “But we have sufficient evidence that those retinal changes are related to COVID.”

The idea of an OCT study to evaluate the retina of patients infected by SARS-CoV-2 goes back to when two of her physician friends working in ICU got infected.

“I have a specialization in uveitis, I was a student of Prof. Rubens Belfort, and both my friends accepted to be seen. They were young, and neither of them had previous eye complaints. We were expecting to see some sort of uveitis or inflammatory sign, but that was not what we found. There were subtle changes in the retina. We could not clearly understand what they were, but they were certainly worth further investigation,” Marinho said.

At the time the comment was published, 14 patients had been examined, and 12 had the alterations described in the paper as “hyper-reflective lesions at the level of ganglion cell and inner plexiform layers more prominently at the papillomacular bundle in both eyes.”

“Obviously there is something going on in that area, increasing the signal strength of the OCT. Whether it is condensed material, proteins or cells, we do not know yet. We know now that it is not blood vessels because we selected the horizontal slice of the OCT where we could cross-check OCT findings with angiogram data. The shadowing of the OCT images is different from the typical shadowing of vessels, which is dense, and obscures the anterior retina structures. Ganglionar lesions have a light shadowing in spite of being a very condensed structure,” Marinho said.

Four patients presented with subtle cotton wool spots and microhemorrhages along the retinal arcade, observed on fundus examination, color fundus photography and red-free imaging.

More than 100 patients have been examined so far, and about one-third have the same presentation as well as other alterations in the retina.

“We are now able to create a more logical process of what happens in the retina, and we are about to publish more papers with more detailed analyses,” Marinho said. “As we follow up on those patients, we are seeing that those lesions change over time. Depending on how much time has passed from the onset of symptoms and how severe is the disease, the lesions present in different forms and change over time. We are also trying to determine the consequences of those lesions in patients who have recovered.”

From the first publication, all the patients who were examined had no comorbidities, most of them were young, and most were physicians and health care workers; four were ophthalmologists.

“This was on purpose because we wanted patients with a clear and well-documented medical history. With COVID-19 patients who never had an eye exam, which is common in Brazil, there would be many possible unknown confounders. Many of the patients we included had previous fundus photos, and we were sure that those lesions were new. One of them had recently had cataract surgery and did not have any underlying condition,” Marinho said.

No correlation has been found so far between drug use and those retinal lesions.

Stay vigilant

“We are going to see an increasing number of papers published with cases of ocular findings related to COVID-19. Many, I presume, are currently undergoing peer review, and many others will come out as we see and discover more on the multiple viral infection-related inflammatory, neurotrophic and coagulopathic processes triggered by the novel coronavirus,” Periman said.

It is still early days, and whatever is said is hypothesis, raising further questions. What can be said for sure is that COVID-19 has multiple presentations, variable manifestations and multiphasic complications and is therefore difficult to treat and hard to pin down.

“Depending on the response of the immune system, manifestations can be totally overwhelming or very mild,” Periman said.

As far as disease management is concerned, the only certainties are that aggressive infection control measures, early detection and isolation are mandatory.

“I have some very good news, however,” Periman said. “When I first looked at ClinicalTrials.gov on March 26, there were 81 registered trials for COVID-19, 1 month later there were over 1,000, and now, on July 14, they are 2,575. Science and medicine are working very hard, and the rapid growth in our collective knowledge is inspiring.”

Her message to ophthalmologists is to practice excellent universal precautions and to stay vigilant for unusual presentations, infectious reactions as well as short-term and long-term complications. “We anticipate seeing an uptick in chronic inflammatory diseases, such as dry eye, as well as potential immunologic, coagulopathic and neurologic complications of COVID-19,” she said.

• References:
• Amesty MA, et al. Ophthalmol Ther. 2020;doi:10.1007/s40123-020-00260-y.
• Chen L, et al. Acta Ophthalmol. 2020;doi:10.1111/aos.14472.
• Chen L, et al. Br J Ophthalmol. 2020;doi:10.1136/bjophthalmol-2020-316304.
• Daruich A, et al. J Fr Ophtalmol. 2020;doi:10.1016/j.jfo.2020.04.002.
• Mao L, et al. JAMA Neurol. 2020;doi:10.1001/jamaneurol.2020.1127.
• Marinho PM, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31014-X.
• Méndez Mangana C, et al. Acta Ophthalmol. 2020;doi:10.1111/aos.14484.
• Navel V, et al. Am J Ophthalmol Case Rep. 2020;doi:10.1016/j.ajoc.2020.100735.
• Seah I, et al. Ocul Immunol Inflamm. 2020;doi:10.1080/09273948.2020.1738501.
• Wu P, et al. JAMA Ophthalmol. 2020;doi:10.1001/jamaophthalmol.2020.1291.
• Xia J, et al. J Med Virol. 2020;doi:10.1002/jmv.25725.

• For more information:
• Jorge L. Alió, MD, PhD, can be reached at Vissum Corporation, Avenida de Denia, s/n, 03016 Alicante, Spain; email: jlalio@vissum.com.
• Dominique Brémond-Gignac, MD, PhD, can be reached at Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris, France; email: dominique.bremond@aphp.fr.
• Paula M. Marinho, MD, can be reached at Instituto da Visão, Federal University of São Paulo, São Paulo 04023-062, Brazil; email: paula.marinho@gmail.com.
• Cosimo Mazzotta, MD, PhD, can be reached at Department of Ophthalmology, University of Siena, and Siena Cross-Linking Center, Via Sandro Pertini 7, 53100 Siena, Italy; email: cgmazzotta@libero.it.
• Carlos Méndez Mangana, MD, can be reached at Centro de Oftalmología Barraquer Calle muntaner 314, Barcelona 08021, Spain; email: cmendez@uic.es.
• Laura M. Periman, MD, can be reached at Periman Eye Institute, 320 W. Galer St., Suite 201, Seattle, WA 98119; email: dryeyemaster@gmail.com.

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