Evaluation of ocular findings in patients with coronavirus disease (COVID-19)

INTRODUCTION

In late 2019, one of the most notable pandemics in modern history, COVID-19 (coronavirus disease 2019), became a worldwide public health catastrophe. A COVID-19 outbreak was documented among Chinese patients in December 2019. Then the disease started to spread rapidly all over the world. The causative organism, SARS CoV 2 (severe acute respiratory syndrome coronavirus), belongs to the betacoronavirus genus under the Coronaviridae family. SARS-CoV-2 has a similar binding receptor to SARS-CoV-1 and similar systemic pathologic features. While the primary focus has been on respiratory complications, emerging evidence suggests that SARS-CoV-2 can affect the eyes, among other organ systems.¹ Ocular manifestations, ranging from conjunctivitis to more severe retinal changes, have been reported in patients with COVID-19, raising concerns about the virus’s potential to impact ocular health.

Through hand contact with the eye or exposure to respiratory droplets, the surface of the eye may act as a port of entry. Likewise, the surface of the eye may be a crucial harbor for viruses that could spread to other people. The susceptibility to ocular surface infection affects not only transmission-related problems but also COVID-19 ocular symptoms. Understanding the prevalence, nature, and clinical significance of these ocular findings is critical, as they may serve as diagnostic markers, influence disease management, or contribute to long-term sequelae.^2–7

The SARS-CoV-2 virus attaches itself to the ACE2 (angiotensin-converting enzyme 2) receptor, which is found in many organs, including the conjunctiva. According to a growing number of reports, conjunctivitis was the first symptom after contact with confirmed patients in certain COVID-19 pneumonia cases.^8,9 The detection of SARS-CoV-2 RNA in the conjunctival swab and tear film suggests that viral conjunctivitis may be one of the early indicators of COVID-19.^10,11

An investigation confirmed that SARS-CoV-2 receptors specific to ACE2 and transmembrane protease serine 2 (TMPRSS2) are expressed by epithelial cells of the conjunctiva and cornea. Ganglionic receptors (e.g., TMPRSS2, ACE2) and sensory nerve terminal receptors (neuropilin 1 [NRP1] and neuropilin 2 [NRP2]) have also been implicated as viral gateways. NRP1, NRP2, and ACE2 receptors are expressed in corneal nerves. Due to this reason, the cornea becomes vulnerable to COVID-19 infection.

In individuals with diabetes, serious COVID-19 infection with oxygen deprivation has been linked to systemic neurological manifestations, including sensory impairment of the cornea, which leads to dry eye disease (DED).^12,13 A correlation between COVID-19 infection and retinal microvascular occlusions would seem to make sense due to the prothrombotic state caused by the virus. Nonetheless, there is a lack of information regarding such a relationship.¹⁴ Neuro-ophthalmic features of COVID-19 are rare but can occur during the acute or recovery phase. Among these, only optic neuritis has been reported in a limited number of cases in the literature.¹⁵

This study aims to systematically assess the ocular findings in 154 patients with COVID-19, exploring their association with disease severity, systemic manifestations, and potential implications for patient care. By elucidating the ocular involvement in COVID-19, this research seeks to enhance the understanding of the disease’s pathophysiology and inform clinical practices to mitigate its consequences on vision.

The findings of our study contrast with those of previously published papers, which frequently emphasize nonspecific irritation or conjunctival hyperemia as the main characteristics. Because ocular signs may reflect systemic inflammatory or thromboembolic processes, offer early diagnostic clues, and affect patient therapy, it is crucial to document these changes. Our study advances our knowledge of the COVID-19 ocular spectrum by revealing unique patterns.

MATERIAL AND METHODS

In this cross-sectional study, 154 patients with positive reverse transcription polymerase chain reaction (RT-PCR) for COVID-19 and ocular symptoms admitted to a tertiary eye hospital between 1 October 2021 and 30 September 2022 were included after obtaining sufficient consent. Non-randomized purposive sampling was done. Post-COVID patients, suspected cases with negative RT-PCR, and patients with pre-existing ocular diseases were excluded. The primary outcome variables of this study were ocular findings, encompassing both signs and symptoms. After getting informed consent from the COVID-19 patients, all new ocular symptoms were noted. All patients underwent a comprehensive ocular examination, including visual acuity evaluation with a Snellen chart, slit-lamp examination to assess anterior segment abnormalities, fundoscopy to evaluate retinal changes, and Schirmer’s test for dry eye assessment.

RESULTS

The study included 154 patients (mean age: 45.6 ± 14.2 years; 58.4% male, 41.6% female). Tables 1 and 2 show ocular symptoms and manifestations that were reported by RT-PCR for COVID-19 patients, respectively. Follicular conjunctivitis patients (n = 94) reported having epiphora (n = 34), foreign body sensation (n = 41), discharge (n = 94), and redness (n = 70). Patients with DED (n = 48) reported having foreign body sensation and mild redness. Episcleritis patients (n = 5) reported redness and mild ocular pain. Patients with retinal vascular occlusion (RVO) (n = 4) and optic neuritis (n = 3) reported diminished vision.

Conjunctivitis and episcleritis were found in the early/mild stage. RVO and optic neuritis were found in the moderate/pulmonary stage. DED, eye strain, and diminished vision were found in the moderate/pulmonary stage.

DISCUSSION

This study evaluated the ocular manifestations in 154 COVID-19 patients, revealing a significant prevalence of various ocular symptoms and signs. The mean age of the participants was 45.6 ± 14.2 years, with a predominantly male representation (58.4%). The most common ocular finding was follicular conjunctivitis (61.04%), followed by DED (31.17%), episcleritis (3.25%), RVO (2.6%), and optic neuritis (1.95%).

Conjunctivitis and episcleritis were found in the early/mild stage. RVO and optic neuritis were found in the moderate/pulmonary stage. DED, eye strain, and diminished vision were found in the moderate/pulmonary stage.

Most of these ocular morbidities were resolved after treatment of COVID, along with specific ocular treatment. But some of them, such as RVO and optic neuritis, left complications. Retinal hemorrhage, ischemia, neovascularization, and optic atrophy were among these complications.

A previous study suggested that bilateral moderate conjunctival erythema, follicles in the inferior palpebral conjunctiva, watery discharge, and tender preauricular lymph node swelling were observed in COVID-19 patients. There was no evidence of subconjunctival hemorrhage or pseudomembrane. Any other signs of keratitis or anterior chamber reaction were also not identified.⁶

Some studies have mentioned follicular conjunctivitis as the only sign or preliminary sign of COVID-19. One in every ten hospitalized non-critical COVID-19 patients developed conjunctivitis during their illness. The presence of follicular conjunctivitis may indicate a direct viral invasion of the conjunctiva or an inflammatory response to the systemic infection.^7,8

In our study, we have found five patients with episcleritis. There have been a few studies that have found that episcleritis can be an initial sign of COVID-19. The cause of episcleritis, though not fully known, can be linked to immune dysregulation, pro-inflammatory cytokine surge, and vascular dysfunction due to COVID-19. A woman in her 50s presented with redness, eye pain, watering, and sensitivity to light (photophobia) in her left eye. These symptoms began 1 week after she tested positive for COVID-19. She was diagnosed with episcleritis in her left eye and was started on topical steroids. As her steroid treatment gradually tapered, she experienced a recurrence of her symptoms. Upon examination of the patient, a sectoral congestion was noted in the conjunctiva and episclera, while the cornea appeared clear, and there was no evidence of scleral involvement. Therefore, the patient was diagnosed with episcleritis and was treated with a topical low-potency steroid. However, 3 days later, the patient returned with symptoms including a headache, fever, and respiratory symptoms. A positive result for COVID-19 was confirmed on a nasopharyngeal swab.^10,11

DED was observed in 48 patients, highlighting the potential for COVID-19 to cause dry eye symptoms. Some studies indicated that COVID-19 patients exhibited a significant decrease in lipid layer thickness (LLT), worsened meibomian gland dysfunction (MGD), and ocular surface neuropathy. All these may induce or exacerbate DED. Based on initial findings, some studies found that dry eye patients who contracted COVID-19 seem to experience a more severe form of dry eye, as indicated by reduced LLT, more severe papillary changes and MGD, and decreased non-invasive keratography tear film breakup time (NIKBUT). Out of the patients examined, twenty-one (91.31%) showed changes in the corneal sub-basal plexus and corneal tissue that are indicative of small fiber neuropathy. Eight individuals experienced heightened sensations of eye dryness following their COVID-19 infection and displayed positive signs of DED. Axonal beadings were observed in more than 80% of the cases, particularly among those who reported symptoms of discomfort in the eyes. Corneal micro-neuromas were detected in more than 60% of the patients, with a higher prevalence among individuals with ocular surface disease index (OSDI) scores exceeding 13. Additionally, dendritic cells were identified frequently in asymptomatic individuals of younger age groups.^12,13

The results of another research indicate that the occurrence of RVO rose following COVID-19 infection; however, these instances are still uncommon, and without randomized control trials, a causal relationship cannot be confirmed. Larger epidemiological studies are needed to more accurately clarify the link between retinal thromboembolic events and COVID-19 infection.¹⁴

More severe ocular complications, such as RVO and optic neuritis, were observed in a smaller subset of patients (four and three patients, respectively).^14,15 These findings underscore the potential for COVID-19 to cause significant ocular morbidity, although these complications appear to be relatively rare. RVO and optic neuritis can lead to permanent visual impairment and warrant prompt diagnosis and management.

An investigation conducted on healthy young individuals who were exposed to prolonged screen time and used face masks as a preventive measure for COVID-19 complained of ocular discomfort symptoms that were suggestive of DED.¹⁶

Based on a different study, the individuals who had COVID-19 frequently experienced sporadic dry eye symptoms. This was measured by an OSDI score, which indicated a mild form of dry eyes. But no correlation was found between OSDI scores and red eyes, NIKBUT, and tear meniscus height. However, in that study, keratography was not done in the moderate to severe group. So, cross-group comparison was not possible. It was noted that patients who were not infected with COVID-19 also complained of red eyes. Therefore, eye redness was not considered to be a particular sign of COVID-19. However, patients diagnosed with COVID-19 showed a raised tear meniscus height in some patterns. This study also found that higher OSDI scores correlated more strongly with positive RT-PCR results from nasopharyngeal or oropharyngeal swabs than with those from conjunctival swabs.¹⁷

However, a hypothesis was stated regarding the dry-eyed individuals’ susceptibility to COVID-19. Interestingly, patients with dry eye illness had an odds ratio greater than that of the population in general when they got COVID-19.¹⁸

It has been suggested that changes in the tear film’s composition may increase the susceptibility to infection. Damage to the tear film composition and the ocular surface’s physical barrier hampers the antibacterial properties, which may lead to infection.¹⁹

A study showed that, in response to the viral antigen that binds the epithelial cells, the conjunctiva functions as an open lymph node, generating B cell follicles with activated T cells and NK cells on its surface. These cells then communicate with inflammatory macrophages, which are generated from monocytes. In some of the ‘asymptomatic’ patients, follicular conjunctivitis and bulbar congestion were found as isolated symptoms, which are caused by which are caused by nucleotide binding domain, leucine rich repeat pyrin domain containing protein 3 (NLRP3) inflammasome. This plays a vital role in the activation of caspase-1, which triggers inflammation by producing interleukins.²⁰

This study’s limitations include a comparatively small sample size and its cross-sectional layout, which makes it challenging to verify the causal relationship. Prospective studies should be done to explore the long-term ocular sequelae of COVID-19.

Our study was conducted from October 2021 to September 2022. During this time, the number of COVID-19 cases was declining, maybe due to the provision of vaccination, which was introduced in early 2021. In late 2022, the world started to adopt a normal lifestyle as the number of COVID cases was reducing. These are the reasons for the limited sample size of our study. This can be considered a limitation of the study. In addition, although regression analysis was not performed to assess associations with COVID-19, the simultaneous manifestation of all symptoms during confirmed COVID-19 positivity may nevertheless suggest a possible underlying association.

CONCLUSION

Ocular manifestations are a notable feature of COVID-19, particularly in patients with moderate to severe disease. These findings highlight the importance of incorporating ocular examinations into the routine assessment of COVID-19 patients to ensure comprehensive care and early detection of ocular complications. In order to comprehend the mechanisms for ocular involvement in COVID-19 and its long-term implications, more research is required.