Ocular Manifestations of COVID-19

Abstract

The SARS-CoV-2 is a highly infective virus, which is transmitted by exposure to infectious respiratory fluids. Ocular manifestations occur in 10% of the patients. The main ophthalmologic manifestation described so far has been conjunctivitis with mild follicular reaction. The clinical signals usually are conjunctival hyperemia, foreign body sensation, tearing, dry eye, and photophobia, but there is a wide range of ocular signals and symptoms described. Fragments of viral RNA could be detected in the tears of some of these patients. The virus recognizes the ACE-2 receptor in the corneal epithelium and then gains circulation and spreads to other sites. That would demonstrate that there may be a tropism from the new SARS-COV-2 with the eye.

1. Introduction

COVID-19 is caused by SARS-CoV2 an enveloped, single-stranded RNA virus of the Coronaviridae family that emerged in China in 2019 with rapid worldwide spread becoming a pandemic within months. SARS-CoV-2 is a highly infectious virus, transmitted by exposure to contaminated respiratory fluids.

Laboratory diagnosis of COVID is usually done by detecting viral fragments in the upper respiratory tract, but in some patients, these fragments can be detected in the tear that confirms the ocular route as a possible route of viral inoculation. It has even been found that detection of viral fragments on the ocular surface can occur earlier than systemic symptoms (D2 of infection) and remain up to day 29, even with a negative nasopharyngeal swab.

2. Physiopathology

There are some theories proposed to explain the pathophysiology of viral inoculation into the human conjunctiva. The main ones are direct inoculation of infected droplets on the ocular surface (cornea and conjunctiva); migration of the virus from the upper respiratory tract through the nasolacrimal duct to the ocular surface; and hematogenous infection of the lacrimal gland. All these theories are based on the presence of the ACE2 receptor, essential for the entry of SARS-CoV2 into human cells, in several structures of the human eye [1, 2, 3].

Figure 1 shows an illustration of the theory of direct inoculation of the virus on the ocular surface by binding to the ACE2 receptor.

Figure 1.

Source: Cortesy by Cunha CEX, 2020. This figure was designed using freepik.com resources (https://br.freepik.com/). The physiopathology illustrated was described by Napoli et al.

SARS-CoV-2 enters the target cells by binding the viral Spike (S) protein to the ACE2 receptor, followed by its initiation by the (TMPRSS2) protein. The ACE2 receptor is present in several organs of the body, including various structures of the human eye such as the cornea, conjunctiva, iris, ciliary body, and aqueous humor.

Note in Figure 2 this distribution in different tissues of the body.

Figure 2.

Source: Cortesy by Cunha CEX, 2020. This figure was designed using freepik.com resources (https://br.freepik.com/). Distribution of the ACE2 receptor in different tissues of the body as presented by Amesty et al.

3. Ocular manifestations

In general, ocular manifestations of COVID-19 are rare. The prevalence of ocular disease is about 11.03% (ranging from 2% to 32%) [4, 5, 6, 7].

This data suggest that approximately one out of 10 patients shows at least one ocular symptom.

According to Nasiri et al., the weighted mean between the onset of ocular manifestations and systemic disease was 0.04 days (range, 1–3 days). However, the weighted mean between systemic disease and ocular manifestations was 1.5 days (range, 2–21 days) [5].

The most prevalent ocular manifestation in patients with COVID-19 is follicular conjunctivitis, corresponding to 90% of ocular findings [5, 8]. Most frequent symptoms are dry eye or foreign body sensation (16%), eye redness (13.3%), tearing (12.8%), and itching (12.6%) (see Table 1).

Characteristics	N (%)
Symptom and sign (n = 932)
Dry eyes or foreign body sensation	138 (16.0)
Redness	114 (13.3)
Tearing	111 (12.8)
Itching	109 (12.6)
Eye pain	83 (9.6)
Discharge	76 (8.8)
Blurred vision or decreased vision	71 (8.2)
Photophobia	62 (7.2)
Chemosis	42 (4.9)
Irritation	21 (2.4)
Gritty feeling	14 (1.6)
Burning sensation	8 (0.9)
Lid edema	8 (0.9)
Subconjunctival hemorrhage	3 (0.3)
Pseudomembrane and hemorrhage	2 (0.2)
Pseudodendrite	1 (0.1)
Subepithelial Infiltrates	1 (0.1)
Water secretion	1 (0.1)
Disease (n = 89)
Conjunctivitis	79 (88.8)
Keratitis	2 (2.2)
Episcleritis	2 (2.2)
Keratoconjunctivitis	2 (2.2)
Pingueculitis	1 (1.1)
Hordeolum	2 (2.2)
Posterior ischemic optic neuropathy	1 (1.1)

Table 1.

Symptoms and diseases of ocular manifestation in COVID-19 infection included in the reviewed studies (n = 1,021).

The association between COVID and dry eye is uncertain because this condition might be related to wearing face masks and the stream of air against the ocular surface as well as the overuse of digital devices leading to an evaporative dry eye.

Since conjunctivitis is a common eye condition, ophthalmologists may be the first medical professionals to evaluate a patient with COVID-19. Therefore, attention to ocular manifestations, especially conjunctivitis, could increase the sensitivity of COVID-19 detection among patients during pandemic. As said before, SARS-CoV-2 can be transmitted by tear, so ophthalmologists (mainly given their close contact) and healthcare providers should wear protective devices, such as protective gears and face masks while examining a patient [9].

Other less common conditions are keratitis, episcleritis, keratoconjunctivitis, hordeolum, pingueculitis, and posterior ischemic optic neuropathy. Reports show associations of COVID-19 with uveitic, retinovascular, and neuro-ophthalmic disease due to microvascular injury and inflammation [4, 5, 10, 11, 12, 13, 14, 15, 16].

3.1 Cornea and conjunctiva

Unspecific signs of mild viral conjunctivitis: unilateral or bilateral bulbar conjunctiva injection, follicular reaction of the palpebral conjunctiva, watery discharge, and mild eyelid edema [4].

Bilateral chemosis alone may represent third-spacing in a critically ill patient rather than a true ocular manifestation of the virus [4].

Cheema et al. described the first case of keratoconjunctivitis: corneal findings that developed rapidly over 3 days, including transient pseudodendritic lesions and diffuse subepithelial infiltrates with overlying epithelial defects [8].

Navel et al. observed a case of severe hemorrhagic conjunctivitis and pseudomembrane formation [17].

3.2 Sclera and episclera

Cases of episcleritis, anterior scleritis, and necrotizing anterior scleritis have been reported [18, 19, 20].

3.3 Anterior chamber

Acute anterior uveitis has also been reported both in isolation and in association with COVID-19-related multi-system inflammatory disease [10, 11].

3.4 Retina and choroid

Vascular, inflammatory, and neuronal changes induced by the virus cause posterior segment manifestations. These are less frequent than anterior segment findings.

There are some case reports showing that the most common retinal involvements are microvascular changes, such as cotton wool spots and microhemorrhages. Usually, these patients had normal visual acuity and pupillary reflexes. Physiopathology is related to a complement-induced prothrombic and inflammatory state causing endothelial damage and microangiopathic injury [6, 21].

Deep retinal capillary plexus ischemia is involved in acute macular neuro-retinopathy (AMN) and paracentral acute middle maculopathy (PAMM), both observed as hyperreflective changes at the level of the outer plexiform and inner nuclear layers [22, 23, 24, 25]. Increased tortuosity of retinal vessels has also been described, but a true relation between such occurrences and COVID-19 has yet to be established [26].

Central vein occlusion is an important complication of COVID-19 and can occur in healthy patients as SARS-CoV-2 infection causes endothelial damage and increases the risk of thrombosis. However, retinal artery occlusion occurred mostly in patients with additional underlying conditions, such as hypertension, obesity, and coronary artery disease [26].

In addition, some studies showed hyper-reflective lesions at the level of ganglion cell and inner plexiform layers more prominently at the papilomacular bundle in patients with COVID-19 [27].

Other studies evaluated changes in retinal microvasculature and retinal layers in patients who recovered from COVID-19 with spectral domain optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA).

OCT-A was performed in patients 6 months post SARS-CoV-2 pneumonia and revealed a significant reduction in vessel density of the superficial capillary plexus and deep capillary plexus as well as retinal nerve fiber layer (RNFL) thinning. These findings are probably related to thrombotic microangiopathy events [28, 29]. There is evidence that retinal layers can be affected, especially in patients with headache and ocular pain symptoms during the COVID-19 period [29].

Other retinal findings were seen in patients with COVID-19: Vitritis; hyperreflective lesions at the level of the inner plexiform and ganglion cell layers in OCT (optical coherence tomography); cotton wool spots, microhemorrhages, dilated veins, and tortuous vessels (due to vascular damage); Purtscher-like retinopathy and acute retinal necrosis (ARN) in immunocompromised patients (probably related to a reactivation of latent herpesvirus and breakdown of blood–retinal barrier allowing an increased inflammatory response) [6, 14, 15, 16, 21, 22, 23].

Posterior uveitis was observed following COVID-19 infection and vaccine. Cases of serpiginous, ampiginous, and multifocal choroiditis also have been reported. It is believed that autoimmunity is involved in these manifestations [22, 23, 24, 25, 30].

3.5 Neuro-ophthalmologic manifestations

Several neuro-ophthalmologic manifestations have been observed: Optic neuritis, papillophlebitis (only one case reported), Adie’s tonic pupil, cranial nerve palsy, neurogenic ptosis, Miller Fisher syndrome, and ocular myasthenia gravis [4, 6, 31, 32, 33, 34, 35, 36, 37].

It is already known that the SARS-CoV-2 virus has a neurotropism. Some cases of bilateral optic neuritis have been described, but it is possible that this is a consequence of an immune-mediated insult caused by the virus as these patients presented with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies and cerebrospinal fluid (CSF) did not reveal virus presence. There have also been reports of acute optic neuritis following vaccination for COVID-19 [4, 6, 31, 38, 39, 40, 41].

A case of multiple sclerosis following COVID-19 infection was reported by Palao et al. These cases suggest that SARS-CoV-2 can either trigger or exacerbate the inflammatory and demyelinating disease [39].

3.6 Orbital manifestations

There have been reports of sinusitis, orbital cellulitis, mucormycosis, orbital myositis, and dacryoadenitis. The most significant of those is mucormycosis as it is an opportunistic pathogen. The hypoxic respiratory environment induced by SARS-CoV-2 added to an immunocompromised state induced by high-dose steroids and immunosuppressive therapies creates the perfect environment for this fungal infection [42, 43, 44, 45, 46, 47, 48].

Singh et al. published a systematic review of 101 reported cases of COVID-19 patients with mucormycosis; these patients were predominantly male (79%), 80% of which had diabetes and 15% with concomitant diabetic ketoacidosis [49].

4. Differential diagnosis

COVID has several features that are highly unspecific and can simulate a lot of other common conditions and most of the time indistinguishable from other etiologies.

Differential diagnoses are those which present red eye and tearing, for example:

• Other viral conjunctivitis (e.g., adenovirus)

• Bacterial conjunctivitis

• Allergic conjunctivitis

• Herpes simplex virus keratitis

• Anterior uveitis

• Corneal abrasion

• Foreign body

• Dry eye syndrome

• Exposure keratopathy in an intubated patient

• Chemosis in a critically ill patient

5. Ophthalmologic evaluation

A thorough history is necessary regarding the onset, duration, and characteristics of symptoms. All patients should be questioned about recent fever and respiratory symptoms. Ophthalmologic evaluation must be complete to rule out other differential diagnoses. Measurement of visual acuity, intraocular pressure, pupil and dilated fundus examination, color testing to evaluate patients for evidence of optic neuropathy, extraocular motility (searching for nystagmus or cranial neuropathies), visual field testing (to investigate deficits related to stroke or optic neuropathy).

In the presence of optic neuritis or neurologic symptoms, neuroimaging must be done. Additional serum or cerebrospinal fluid testing may be useful [6].

6. Treatment/Management

As with other viral infections, COVID-19 conjunctivitis is presumed to be self-limited and can be managed with symptomatic care. In the absence of mild symptoms, patients can be managed remotely with preservative-free artificial tears and cold compresses [6].

7. Guidance and screening recommendations for corneal transplantation (Eye Bank Association of America, Updated Guidance – March 14, 2022)

EBAA guidance and screening recommendations for COVID-19 pandemic are based on the latest guidelines from the FDA and CDC as well as available scientific evidence [50].

The most current set of guidelines specifies criteria for:

1. Donor ineligibility – Donors should be considered ineligible who in the 10 days prior to death:

   1. Were diagnosed with acute COVID-19; OR

   2. Tested positive for COVID-19 by direct viral testing methods (e.g., NAAT and/or antigen); OR

   3. Had close contact with a person diagnosed with or suspected to have COVID-19 and developed signs and symptoms of COVID-19, regardless of a plausible alternative etiology or vaccination history

2. Donors eligibility – Donors should be evaluated for eligibility by a Medical Director who:

   1. In the 10 days prior to death, without a known close contact with a person diagnosed with or suspected to have COVID-19, developed new signs and/or symptoms consistent with acute COVID-19 not explained by a plausible alternative etiology; OR

   2. In the 10 days prior to death, had known close contact with a person diagnosed with or suspected to have COVID-19 AND was asymptomatic; OR

   3. In the 11 to 20 days prior to death had a positive test for SARS-CoV-2 AND had ongoing signs and/or symptoms of COVID-19

EBAA contraindications to transplant are active ocular or intraocular inflammations, such as conjunctivitis, keratitis, scleritis, iritis, vitritis choroiditis, or retinitis.

Current EBAA Medical Standards require that 5% povidone–iodine solution shall contact the entire surface of any ocular tissue intended for transplantation at least twice between the time of the donor’s death and tissue preservation, as povidone–iodine has been documented in vitro viricidal activity against coronaviruses.

Global Alliance of Eye Bank Associations (GAEBA) declared on November 12, 2020 that there is no evidence that coronaviruses can be transmitted by human tissue or cell transplantation and therefore measures in this response are precautionary, as there have been no reported cases of transmission of SARS-CoV-2, MERS-CoV, or any other coronavirus via transplantation of human ocular tissue [6, 51].

The European Eye Bank Association (EEBA) and European Association of Tissue and Cell Banks (EATCB) refer to guidance provided by the ECDC (European Centre for Disease Prevention and Control 1st update, April 2020): corneal transplants are usually disinfected with povidone (PVP) iodine and then stored in organ culture at 30–37°C for at least 14 days. The presence of viruses capable of reproduction after this procedure seems very unlikely. These data and the absence of known ocular transmission cases indicate that the risk of COVID-19 cases entering the eye donor pool and subsequent transmission is theoretical [52, 53].

8. Discussion

SARS-CoV-2 is a highly infectious virus, transmitted by exposure to contaminated respiratory fluids causing mainly respiratory illness. Transmission by tear is not unlikely, and the eye can be a way for viral infection. This can be explained by the ACE2 coronaviruses receptor in the eye cells and that is why protecting the eyes is essential, especially for healthcare providers.

One out of 10 COVID-19 patients presents at least one ocular manifestation. The most prevalent ocular manifestation in patients with COVID-19 is follicular conjunctivitis, corresponding to 90% of ocular findings. The most frequent symptoms are dry eye or foreign body sensation, eye redness, tearing, itching, eye pain, and discharge.

It is important to know that the mechanism of dry eye or foreign body sensation is uncertain as during the pandemic screen time and face masks could also contribute to tear evaporation.

Attention to ocular manifestations, especially when combined with other COVID-19 manifestations like respiratory symptoms or fever, could help improve COVID-19 diagnosis, although ocular involvements are rare and nonspecific. There is evidence showing that conjunctivitis-related symptoms may occur prior to the onset of respiratory symptoms and could be the precursors for early diagnosis. Loffredo and colleagues reported that conjunctivitis in COVID-19 patients was significantly correlated with disease severity.

Posterior segment findings are less common than anterior segment manifestation. A few studies showed retinal layer attenuation in OCT. It should be noted that there is an important correlation between COVID-19 and Central Retinal Vein Occlusion, even in patients without comorbidities.

Ophthalmic manifestations are varied in terms of presentation, severity, and timing. Usually, ocular symptoms are mild and improve without further complications.

9. Conclusion

In general, ocular manifestations of COVID-19 are rare but can be the first symptom of the disease. Follicular conjunctivitis is the most common eye condition, but there are described manifestations of COVID-19 in all eye segments. Attention to ocular manifestations in combination with other COVID-19 manifestations could help improve COVID-19 diagnosis. SARS-Cov-2 can be transmitted by tear, so ophthalmologists (mainly given their close contact) should wear protective devices while examining a patient.