Ophthalmic Manifestations of Coronavirus Disease 2019 and Ocular Side Effects of Investigational Pharmacologic Agents

Daniel J. Olson; Arko Ghosh; Alice Yang Zhang


Curr Opin Ophthalmol. 2020;31(5):403-415. 

In This Article

Coronavirus Disease 2019 Treatments and Their Ocular Side Effects

As COVID-19 spread across the globe, scientists and clinicians have explored potential treatment options with the utmost urgency, evaluating both existing and experimental medications alike. Table 1 provides a summary of drugs that have been, are currently being used, or are being developed for the treatment of COVID-19 with their associated ocular side effects. The following classes of drugs will be discussed in greater detail: antiviral, interferon, antimalarial, antimicrobial, antibody, immune modulators, plasma-based therapy, cytokine removers, steroids, vaccines, and others. 30% of these studies are being conducted in China, the original epicenter of this infection, and almost 20% are being conducted in the United States. More than 50 countries are currently involved in clinical trials involving COVID-19 treatment. The majority of these trials are in phase II or III of development.


Many antiviral agents are currently being trialed for the treatment of SARS-CoV-2. Multiple mechanisms are being studied, namely, protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), polymerase inhibitors, and others that interfere with viral replication. Remdesivir was found to be superior to placebo in decreasing recovery time of hospitalized COVID-19 patients.[35]

Not all antiviral agents have data in the literature reporting ocular side effects. However, of note, a case series reported that NRTIs have been shown to 'unmask' Leber's hereditary optic neuropathy in genetically susceptible patients.[36] In addition, uveitis has been reported as a complication in some antiviral agents (i.e., ledipasvir, lopinavir, sofosbuvir, ritonavir).[37,38] Serious complications such as acute angle closure glaucoma and retinal vein thrombosis have been noted in systemic oseltamivir and ribavirin use, respectively.[39,40]


Interferon therapy is a unique, cytokine-based treatment with antiviral and immunomodulatory properties that have been used effectively to treat chronic viral infections and autoimmune diseases. Despite interferon's known efficacy as an antiviral agent, systemic interferon therapy has been associated with a number of ocular complications.

The most significant ocular side effects of interferon therapy are those that involve the retina. The reported incidence of interferon retinopathy is quite variable, ranging from 18 to 86%, depending on the initial dose of treatment.[41] Posterior segment signs include retinal microvascular changes such as cotton wool spots, retinal hemorrhage, disc swelling, and macular edema, and detachments. Decreased and total loss of vision has been reported, but is rare.[42] Less severe, but noteworthy complications include anterior segment pathologies, such as conjunctivitis, subconjunctival hemorrhage, uveitis, eye pain, and dry eye.[43,44]


A few antimalarial treatments are currently being studied for potential therapeutic effects versus SARS-CoV-2. Most notably, chloroquine and hydroxychloroquine have shown to have potential inhibitory effects on viral fusion with the host cell; as such, they presented a unique treatment mechanism that is currently being studied in multiple clinical trial phases.[45] While initial data showed some positive results,[46] new research has shown no benefit of hydroxychloroquine in patients with COVID-19.[47] This remains a controversial topic; however, this is currently considered controversial.[46]

Notably, chloroquine and hydroxychloroquine are known to have severe ocular complications associated with their chronic use. While corneal verticillata and cataract formation have been reported, the most serious complication is an irreversible toxic retinopathy with parafoveal damage, known commonly as 'bull's-eye maculopathy'.[43,47] These, however, are typically late findings seen in patients on long-term treatment or excessively high doses and are rarely seen with less than 5 years of use.[48] The ocular effects of using higher doses of antimalarials for a shorter period of time are unknown at this time. The ocular effects of using higher doses of antimalarials for a shorter period of time is unknown, but experts believe that regimen not pose a great risk for the development of retinopathy when used in the short term.[49]


Some antibiotics are being investigated for the supplementary treatment of COVID-19. A number of trials are studying the efficacy of azithromycin, specifically as an antibiotic to prevent secondary bacterial infection; in addition, azithromycin has been shown to have some anti-inflammatory properties.[50,51]

Azithromycin has not been reported in the literature to cause significant ophthalmological complications, with the exception of rare reports of conjunctivitis and color-vision defects during the treatment period.[43,51]


Many mAb treatments are being investigated for their highly specific targets and immunomodulatory properties. Programmed cell death protein 1 (PD-1) inhibitors (i.e., camrelizumab) are checkpoint inhibitors that enhance the immune response.[52] Antiangiogenic agents (i.e., bevacizumab) are being investigated for the potential that they may prevent or minimize lung injury.[50] Multiple antibodies (i.e., ixekizumab, sarilumab, tocilizumab) targeting the interleukin pathway are being investigated. All antibodies and their respective antibody targets are listed in Table 1.

Though not all antibody treatments are associated with ocular adverse effects, some antibody therapies are associated with serious complications. Adalimumab, a TNF-α inhibitor, has been reported to lead to optic neuritis.[38] PD-1 inhibitors, such as camrelizumab, are associated with ocular inflammation, such as uveitis, conjunctivitis, and vision changes.[52] IL-6 inhibitors, such as sarilumab and tocilizumab, have been associated with uveitis and papilledema, respectively.[53]

Immune Modulators

Immunomodulatory therapy is also being explored to treat SARS-CoV-2. Antibody-based molecules (i.e., CD24Fc) with unique anticytokine properties may provide targeted immunosuppression to treat the infection. Interleukins are being studied to induce regulatory T-cell activity to help protect against lung injury.[43] Other molecules (i.e., polyinosinic–polycytidylic acid, PUL-042, thalidomide) have immunomodulatory properties that may confer therapeutic benefit. Ulinastatin is a protease inhibitor with anti-inflammatory properties.[50]

Most immunomodulatory therapeutics have not been reported to have any ocular adverse effects. However, scotomas, palinopsias, and other abnormal visual phenomena have been described with the use of IL-2.[43]

Plasma-based Treatment

Plasma-based therapy, specifically plasma from patients who had contracted SARS-CoV, is being explored as a potential therapy for COVID-19. Convalescent plasma with antiviral antibodies from recovered patients has been used for other diseases, such as Ebola, and is being explored for similar therapeutic potential.[50]

There are no data in the literature of ocular side effects from convalescent plasma.

Cytokine Removal

Research has shown evidence that a significant inflammatory response contributes to the morbidity and mortality seen in COVID-19 patients. As such, there is belief that moderating the cytokine response can decrease the inflammation and provide a therapeutic outlet. Multiple modalities [i.e., CytoSorb (CytoSorbents Corporation, Monmount Junction, New Jersey, USA), mesenchymal stem cells (MSCs), natural killer (NK) cells] are being studied. CytoSorb is a cytokine filtration device that helps reduce circulating cytokines and other proinflammatory proteins. MSCs and NK cells are thought to have immunomodulatory properties that can help augment the body's natural immune response.[50]

CytoSorb, MSC and NK cell treatments have no ocular adverse effects reported in the literature.


Due to the significant inflammation that contributes to poor outcomes with COVID-19, corticosteroids are being studied as potential immunosuppressive agents. Methylprednisolone is chiefly the corticosteroid under investigation for its protection against cytokine release.[43]

Systemic corticosteroid therapy has been documented in the literature to have several, potentially serious ocular complications, such as papilledema, infection, central serous retinopathy, retinal embolic events, and diplopia.[44] Commonly, increased intraocular pressure is observed, and cataracts can occur. Less serious complications include subconjunctival hemorrhage.[43,44]


At the time of this study, three vaccines are currently being investigated. Ad5-nCoV is a vaccine that encodes for a spike protein that is found on SARS-CoV-2 (phase II). The COVID-19/aAPC vaccine is a synthetic gene that has been used to modify antigen-presenting cells and is thought to confer immunity upon injection (phase I). mRNA-1273 is another vaccine that is a mRNA-based and encodes for the spike protein of SARS-CoV-2. Phase I trials yielded promising results, and patients are currently being recruited for the phase II trial.[54,55] Additionally, unique vaccine delivery mechanisms are currently being studied for the treatment of SARS-CoV-2. Researchers are actively exploring a novel gene-based vaccine, AAVCOVID. An adeno-associated virus (AAV) vector is used to deliver the genetically sequenced portions of the SARS-CoV-2 surface antigens to help the body's immune system mount an antibody response to SARS-CoV-2. AAV technology has been used extensively as a gene delivery vector with excellent results success.[56]

No ocular side effects have been reported for these vaccines under investigation.


Many other drugs of various mechanisms are also being studied for potential treatment of COVID-19. While mechanisms are not entirely clear, some drugs (i.e., bismuth, dipyridamole, GD31) are thought to interfere with viral metabolism. Some agents (i.e., losartan, sildenafil, sodium aescinate) are thought to have potential protective effects against lung damage. Other treatments (i.e., lipoic acid, pirfenidone, tetrandrine, tranilast) may confer some resistance to the inflammatory response and oxidative processes.[54]

Photophobia has been reported with pirfenidone use.[57] Sildenafil has been reported in association with a number of ocular side effects. Serious side effects include nonarteritic anterior ischemic optic neuropathy and macular edema. Other side effects include photophobia, decreased color vision, conjunctival hyperemia, eye pain, and increased intraocular pressure.[43]