Corneal blindness is the third leading cause of blindness worldwide.¹ Corneal transplantation remains the only method of restoring vision in eyes with end-stage corneal decompensation and is the most frequently performed type of transplant worldwide.² Due to the immunological and lymphogenic privilege of the avascular cornea, keratoplasty is the most successful tissue transplantation procedure currently performed in humans.³ However, as with most solid-organ transplants, the risk of transmitting infectious diseases and viruses is an important aspect of corneal transplantation that can affect recipients or those handling donor tissue.⁴ Thus, the rapid emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since December 2019 has led to a devastating impact on corneal transplantation worldwide.

To date, the SARS-CoV-2 has infected close to 13 million people and led to  more than 560000 deaths worldwide in a short space of 6 months (WHO COVID-2019 situation report as of July 13, 2020). Since its emergence in Wuhan China, the SARS-CoV-2 has been reported to cause conjunctivitis and detected in tears or conjunctival secretions.⁵ The potential for SARS-CoV-2 to affect the ocular surface had immediate implications for eye banking around the world. Furthermore, travel restrictions and curtailed elective procedures have led to the reduction in the supply, retrieval and demand for corneal transplantation.⁶ Thus, the future of corneal transplantation faces an unprecedented threat, as access to this sight-restoring surgery is affected on a global scale.⁷ Beyond the pandemic, COVID-19 may have lasting effects on corneal transplantation, as healthcare services resume to face long waiting lists and a potential shortage of donors. Therefore, there is an urgent need for a consensus on recommendations for restoring corneal transplantation services, even as the outbreak evolves and we learn more about the SARS-CoV-2.

OCULAR TRANSMISSION OF SARS-COV-2

In order to do this, there are several issues that need to be considered. The first is whether the SARS-CoV-2 is shed in the tears, which may allow transmission of this virus through the ocular surface, either from asymptomatic carriers or infected individuals to close contacts. Conjunctival signs such as injection and chemosis have been reported, ranging from 0.8% in the largest retrospective study from China,⁵ to 5.9%⁸ and 66%⁹ in other smaller studies. In a study of 38 confirmed cases, 12 (31.6%) patients were noted to have conjunctival signs.¹⁰ However, two-thirds of these 12 patients were in critical condition, where third-spacing and ventilation may also have contributed to these ocular signs. Overall, surveillance studies from confirmed COVID-19 positive patients suggest that few patients have conjunctival involvement.⁹ Still fewer have positive RT-PCR results from conjunctival swabs, even in the presence of conjunctival inflammation.⁹ This may be due to a lower diagnostic sensitivity of tear and conjunctival swabs, which have low sample volumes—or it may reflect an inflammatory response, a low viral load or non-infective RNA fragments.⁸ The timing of tear sample acquisition during the course of disease may also play a role, as one case study reported the presence of SARS-CoV-2 RNA in tears up to 27 days after onset of symptoms, although viral culture replication was only performed on the early ocular sample (3 days).¹¹ On the other hand, the tear film has a dynamic turnover with antimicrobial proteins such as lactoferrin, which have been shown to have a protective function by inhibiting the binding of SARS-CoV to the angiotensin‐converting enzyme 2 receptor.^{12 13} Hence, current studies suggest that even if SARS-CoV-2 is present in tears, the risk of direct transmission through the ocular surface is not yet established.

The next issue is whether the SARS-CoV-2 virus infects ocular tissue, which may affect the potential for transmission from corneal donor to recipient.¹⁴ SARS-CoV-2 gains cellular entry through the ACE2 receptor after cellular protease priming via transmembrane serine protease 2 (TMPRSS2) and other co-mediators.¹⁵ While the ACE2 receptor and TMPRSS2 were found to be significantly expressed in conjunctival tissue using immunohistochemistry based on mouse and human studies,^{16 17} high throughput sequencing of mRNA and protein levels suggested no significant expression in healthy and diseased human conjunctiva biopsies for melanoma and squamous cell carcinoma.¹⁸ Nonetheless, emerging studies have now shown both ACE2 and TMPRSS2 expression in cornea and conjunctival epithelium,¹⁹ with expression of other proteins such as cysteine proteases cathepsin B and L that may enable viral entry.²⁰ Hence, the potential ocular infectivity of SARS-CoV-2 transmission through the ocular surface remains a concern based on these molecular and animal studies.²¹ Given the prevalence of asymptomatic carriers, high transmission rates and a possible conjunctival infectivity, current recommendations to exclude potential donors who are PCR positive for SARS-CoV-2 and the duration needed from symptom resolution, requires further discussion. This exclusion criteria would also depend on the availability of SARS-CoV-2 PCR testing, given the limited availability of these assays in various healthcare settings around the world.

A GLOBAL PERSPECTIVE OF CURRENT EYE-BANKING GUIDELINES DURING THE COVID-19 PANDEMIC

In light of these uncertainties, guidelines (frequently updated) from major eye banks such as the Eye Bank Association of America (EBAA) and the Global Alliance of Eye Bank Associations (GAEBA) have recommended excluding donors recently infected with COVID-19, or those at high-risk such as a significant contact history—table 1.⁶ Though this is in line with US Food and Drug Administration (FDA) guidance on human cell, tissue and cellular or tissue-based products, the FDA guidelines further indicate that there is currently no evidence for transmission of respiratory viruses through tissue transplantation in general.²² Moreover, corneal donors are usually double disinfected with povidone iodine before removal and preparation; and/or polyvinylpyrrolidone solution just before storage. Polyvinylpyrrolidone solution (0.23–7.5%) has been shown to be capable of up to 99.99% inactivation of viruses such as SARS-CoV, within 15–60 s at room temperature on inanimate surfaces, but this requires further study specifically for SARS-CoV-2.²³ These studies also need to be replicated on tissue samples and storage media. A review of current eye bank recommendations across the world demonstrates a wide variation in donor exclusion criteria, such as the duration of recovery from COVID-19 or days from positive contact—table 1. These restrictions could greatly impact the availability of corneal donors, as current criteria for exclusion can be rather broad.

RE-OPENING CORNEAL TRANSPLANT SERVICES AROUND THE WORLD

As we emerge from the pandemic and healthcare services are restored, restarting corneal transplant programmes will require cautious planning and execution. The sustainability of corneal donation and eye-banking programmes will also have to be examined carefully. For example, the United Kingdom National Health Service (NHS) has already set out issues for consideration when re-opening transplant programmes (NHS Blood and Transplant: Article POL296/1 dated April 28, 2020). This includes nose, throat and endotracheal swabs for SARS-CoV-2 PCR testing and blood serological testing for all potential deceased organ donors, which should be negative before the donor is deemed suitable. It has been recommended that recipients should also be tested via PCR and serological testing before undergoing surgery, and SARS-CoV-2 positive patients should be taken off the donor waiting-list until two consecutive nose and throat PCR swab tests are negative. The situation is undoubtedly more complicated in solid organ or tissue transplant recipients requiring systemic immune suppression. Some centres in China have also recommended performing CT scans of the lungs in selected potential donors. On the other hand, the Eye Bank Association of Australia & New Zealand (EBAANZ) and European Centre of Disease Control advises against routine testing for donors due to limited test kits, which are also not validated for use in deceased patients. Further studies on the validity of SARS-CoV-2 PCR tests on deceased donors are needed to inform policy decisions on donor testing requirements.

It is also recognised that re-opening corneal transplant programmes require a multi-disciplinary coordination from eye bank technicians to nurses and surgeons, where new infection control protocols require training and familiarisation.²⁴ Patient education with regards to the implications of SARS-CoV-2 PCR results and risks of transmission should be discussed thoroughly, with anticipation of potential delays to the preoperative process and unexpected cancellations. Restrictions to global and regional travel in the longer term may affect transport of corneal donors, leading to delays and shortages in countries which rely heavily on foreign tissue. Protections to eye bank technicians with full personal protective equipment (PPE) and eye protection have been recommended by most eye bank associations. Surgeons performing corneal transplantation under general anaesthesia may consider using full PPE with N95 masks due to the increased risk of aerosolisation during intubation and extubation. Routine PCR recipient testing has been recommended by EBAA and other organisations if available. Antibody testing has gained attention as a potential tool in managing SARS-CoV-2, including patient contact tracing, sero-surveillance and vaccine evaluation.²⁵ However, its utility in screening potential donors and evaluating recipients is currently unclear, as seropositivity may not reflect immunity. Finally, the economic impact of COVID-19 and subsequent measures on eye banking and corneal transplantation, including increased costs from donor transport, testing, and PPE utility, must be considered in the long-term planning and sustainability of resuming corneal transplant services.

In summary, the impact of the COVID-19 pandemic on corneal transplantation may have long-lasting effects. Moving forward, more research is needed to examine the risk of ocular transmission of SARS-CoV-2, both from an eye banking and healthcare provider perspective. In order to resume corneal transplant services, we have summarised some recommendations for future research and consensus required, adapted from two of the largest volume eye bank/organisations that is, the EBAA and European Eye Bank, recommendations—table 2. However, considerations should be made within the context of each healthcare system for these recommendations to be applicable. Donor eligibility criteria and recipient testing should also be individually reviewed by the medical director, as the situation constantly changes during the COVID-19 pandemic. Consensus on guidelines for potential donor exclusion is important for coordination of donor export/import to ensure the cornea donor supply chain remains intact, while mitigating the risk of SARS-CoV-2 transmission to all persons handling the donor tissue, and recipients. Subsequently, the cost of corneal donor processing may increase with testing and infection control measures, affecting the less well-resourced healthcare services. The impact of global travel restrictions and reduced corneal donation may lead to a severe shortage of corneal donor supply, which may necessitate increased utility of available donors of poorer quality through techniques such as anterior lamellar keratoplasty, or accelerate innovation in treatments that reduce reliance on cadaveric corneal donors such as artificial cornea or corneal cell therapies. As we learn more about the SARS-CoV-2 virus and the effect of this global outbreak evolves, it is clear that this pandemic may have a signficant long-term impact on corneal transplantation worldwide.