COVID-19 disease, caused by the coronavirus SARS-CoV-2, was first identified in December 2019. This virus quickly caused a widespread global pandemic, and many lives were lost as a result.
Primarily transmitted through respiratory droplets, the virus mainly impacts the respiratory system, less commonly, it can also manifest as conjunctivitis or intraocular inflammation.
As the COVID-19 pandemic progressed, pharmaceutical companies worldwide raced to develop beneficial vaccines and eventually formulated several different types.
Although vaccination has significantly reduced the severity of cases, a small percentage of patients may experience adverse effects and imposed risks, including corneal graft rejection.
Overview of keratoplasty
Corneal transplantation, or keratoplasty, is a surgical procedure to replace damaged or diseased cornea with tissue from a healthy donor. Major corneal impairments that require this procedure include corneal scarring, edema, dystrophy, keratoconus, and complications from eye surgeries or trauma.1
Depending on the indications, corneal transplantations can involve either the entire corneal thickness (penetrating keratoplasty [PK]), or partial replacement, such as anterior lamellar keratoplasty (ALK), deep anterior lamellar keratoplasty (DALK), Descemet stripping automated endothelial keratoplasty (DSAEK), and Descemet membrane endothelial keratoplasty (DMEK).2
Despite promising and improving results over the years, healthcare providers should still be aware of potential issues with graft rejection with vaccination, including against COVID-19.
COVID-19 vaccination and stimulated immune response
The cornea is the most commonly allo-transplanted tissue in the United States, and graft rejection rates are low due to its ocular immune privilege.4
Several mechanisms contribute to its immune quiescence, which include:5
- Lack of vascularization
- Low levels of major histocompatibility (MHC) antigen expressions
- The presence of high levels of cytokines that suppress immune cells
- T-cell apoptotic factors
- Dormant antigen-presenting cells
The mechanism of corneal graft rejection remains uncertain. Despite the cornea’s protective mechanisms, a potential cause for the association between COVID-19 vaccination and corneal graft rejection is a phenomenon known as “cytokine storm,” marked by immune-cell hyperactivation and an increased release of proinflammatory cytokines.6
This boost in immune response, in concert with vaccination, is postulated as a reason for transplant rejection. It has also been hypothesized that vaccination can increase vascular permeability, which can breach the protective barrier of the cornea and induce antigen expression that targets MHCs found on the donor corneal tissue.
Furthermore, antibodies produced in response to vaccinations have been found to trigger a strong CD4+ T-cell response, which is believed to be one of the main contributors to corneal graft rejection.7
COVID-19 vaccination and the cytokine storm
In 2022, an article described a possible link between COVID-19 vaccination and the production of a cytokine storm.6 Four cases of patients who died 1 to 10 days after receiving their second boost of vaccination were compared to two patients who died 16 and 94 days after vaccination.6 The autopsies performed on the original four postmortem patients revealed no signs of changes to primary organs.
After sequencing RNA obtained from peripheral blood, it was ultimately found that genes associated with neutrophil degranulation and cytokine signaling were significantly upregulated in this group, supporting the hypothesis of an intensified immune response.6
COVID vaccination and corneal graft rejection
It is believed that an induced “cytokine storm” is the most likely contributor to transplant rejection. According to a systemic review of corneal complications after COVID-19 vaccination, acute corneal graft rejection was the most common adverse event following vaccination.5,6,8
Specifically, 21 reported cases occurred from 1 day to 6 weeks post-vaccination.6 Another study highlighted an association between the COVID-19 vaccination and vaccine-associated graft rejection observed in 55 eyes of 46 patients.5
In a case series published in 2022, four patients demonstrated acute corneal transplant rejection associated with COVID-19 vaccination:3
- Case 1: The patient had undergone DMEK 6 months prior and presented with graft rejection 3 weeks after the first vaccination.
- Case 2: The patient had a history of PK 3 years prior and presented with graft rejection 9 days after the second vaccination.
- Case 3: They had a history of DSAEK and presented with graft rejection 2 weeks after the second vaccination.
- Case 4: Included another patient post-PK, who presented with graft rejection 2 weeks after the second vaccination.
Corneal graft rejection risk and treatment
There may be other factors that put patients at a higher risk of corneal transplant rejection. These patients tend to have an underlying compromised immune system and poor ability to accept transplanted organs. They may exhibit increased antibodies against the donor tissue, a previous history of transplant rejection, pre-operative inflammation, and corneal neovascularization.
Patients who experience corneal graft rejection typically present with clinical symptoms such as corneal edema, keratic precipitates, corneal vascularization, stromal infiltrates, an epithelial rejection line, or subepithelial infiltrates.9 Graft rejection can occur at either the epithelial, endothelial (most common), or stromal layer of the cornea.
Rejection may cause irreversible loss of donor endothelial cells, stromal edema, and visual disturbances. Patients should be diagnosed and treated early to avoid further complications.
Topical, oral, and subconjunctival corticosteroids have shown favorable outcomes as a treatment for graft rejection. Calcineurin inhibitors such as cyclosporine A and tacrolimus may be used if topical corticosteroids are contraindicated.9
Conclusion and takeaways
Immunizations against COVID-19 demonstrate some of the greatest advancements in healthcare and have undoubtedly saved many lives since their inception.
Due to an increased immune response (which is the basis for most vaccinations—not just COVID-19), there is a postulated risk of graft rejection in corneal transplant patients, as demonstrated in the literature.
Patients may present with clinical signs that physicians should promptly diagnose and treat with topical corticosteroids to prevent irreversible graft damage.
Because contradictory evidence has been found and the sample size in many cases was limited, further studies would be needed to define a true causal relationship between transplant rejection and vaccination.
However, healthcare providers can consider recommending transplant surgeries well after patients receive their vaccinations and should closely monitor these patients.
