Histomorphological view of the cornea investigated by laser confocal microscopy in keratoplasty

Introduction. Corneal transplantation is the most successful and commonly performed allotransplantation procedure as compared with other organs and tissues. Over 100,000 corneal transplantations are performed worldwide every year.Purpose. This study investigated whether in vivo confocal microscopy (IVCM) can aid in the diagnosis of a graft rejection reaction by detecting changes in cellular structures and density of immune cells after penetrating keratoplasty.Materials and methods. The study included thirty-four eyes of 34 patients who underwent penetrating keratoplasty (7 eyes with corneal graft rejection, 27 without rejection). The average age of patients is 51.1 ± 13.6 years (from 23 to 76 years). The follow-up period ranged from 12 to 36 months (24.5 ± 4.84 months). Follow-up was performed at 1, 3, 6, 12 months and annually after PKP. To study the morphology of the cornea all patients underwent IVCM to assess the basal epithelium, subbasal layer, stroma and endothelium. Immune cells were identified and evaluated for the shape, length of the processes and their density.Results. Patients with corneal graft rejection demonstrated significant accumulation of corneal dendritic-like immune cells compared to patients with non-rejected grafts. In addition, the cells acquired a more mature morphology (grade 2–3). The density of dendritic cells (DC) was 809.17 ± 342.19 (p < 0.001). A positive correlation was found between DC density and graft rejection (p < 0.001). As well the patients showed signs of endothelial failure with low endothelial cell density and pleomorphism, increased light scattering and hyperreflectivity of the stroma.Conclusions. In a complex of diagnostic measures, confocal microscopy may provide a valuable clinical adjunctive tool in diagnosis and management of early corneal graft rejection.

Acute corneal graft rejection after anti-severe acute respiratory syndrome-coronavirus-2 vaccination: A report of four cases

Purpose This study intends to add to previous reports on acute corneal graft rejection following anti-severe acute respiratory syndrome-coronavirus-2 vaccination, providing data to corroborate a possible causative relationship between anti-COVID-19 immunization and corneal graft rejection, regardless of vaccine or graft type. Methods and Results This report describes 4 cases of acute-onset rejection as early as 5 days following the first dose of anti-severe acute respiratory syndrome-coronavirus-2 vaccine types not yet referred for corneal allograft. Patients were individually given the Moderna messenger RNA-1273 COVID-19 vaccine (2 patients) and the AstraZeneca COVID-19 vaccine, Vaxzevria, AZD1222 (2 patients). Conclusions Even though a direct causative effect is hard to prove, temporal proximity between anti-severe acute respiratory syndrome-coronavirus-2 vaccines of different types and consecutive reports of corneal graft rejection indicates the need for further investigation. Consistent advice must be given to corneal transplant patients regarding such risk.

Dual Corneal-Graft Rejection after mRNA Vaccine (BNT162b2) for COVID-19 during the First Six Months of Follow-Up: Case Report, State of the Art and Ethical Concerns

Present mass vaccination against Coronavirus Disease-19 (COVID-19) is the most widely used health policy and the most promising approach to curb the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic globally. However, new side effects are emerging from the mass vaccination not described during the experimental stages. In the present study, we discuss a case of acute corneal graft rejection, which has occurred 25 years after transplantation and 13 days after the administration of the BNT162b2 vaccine (Comirnaty, BioNTech/Pfizer), which was followed-up for a period of six months. In this period, the corneal inflammation appeared twice but was successfully managed with topical therapy and supplementation of Vitamin D. A risk of corneal graft rejection must be included in the list of potential vaccine complications, in order to inform the transplanted patient to undergo a preliminary and a follow-up ocular examination, and eventually to include corneal graft in the list of contraindications to vaccination.

Clinical Course of Different Types of Immune Reactions following Keratoplasty

Background Immune-mediated corneal graft rejection (IR) is a leading cause of corneal graft failure. The endothelium, stroma, epithelium, or a combination can be affected. Little is known about the long-term outcomes of different types of IR. Methods We reviewed the medical records of all keratoplasties that had been performed at our eye centre between 2003 and 2016 (n = 3934) for any kind of IR that occurred between the surgery and 2019. All patients with a definite diagnosis of IR and sufficient clinical data were included in the analysis. IRs were grouped according to the affected part of the graft (endothelial, stromal, epithelial, and mixed). We analysed the dynamics of recovery and the clinical outcomes. Results We identified a total of 319 patients with IR. Twenty-seven of those were lost to follow-up and were excluded from further analysis. Of the IRs, 89% affected the endothelium. Endothelial IR resulted more frequently in a considerable loss of endothelial cell density than other forms of IR. Stromal IR showed a lower relapse rate and a better visual recovery than other types of IR and resulted less often in a failure of the graft. Conclusions We herein report comprehensive data about the prognosis regarding functional recovery after different types of IR following keratoplasty. Our data underline that timely recognition and correct classification of IR are important because they determine the clinical course and prognosis.

Prediction of corneal graft rejection using central endothelium/Descemet’s membrane complex thickness in high-risk corneal transplants

To determine whether measurements of Endothelium/Descemet complex thickness (En/DMT) are of predictive value for corneal graft rejection after high-risk corneal transplantation, we conducted this prospective, single-center, observational case series including sixty eyes (60 patients) at high risk for corneal graft rejection (GR) because of previous immunologic graft failure or having at least two quadrants of stromal vascularization. Patients underwent corneal transplant. At 1st, 3rd, 6th, 9th, and 12th postoperative month, HD-OCT imaging of the cornea was performed, and the corneal status was determined clinically at each visit by a masked cornea specialist. Custom-built segmentation tomography algorithm was used to measure the central En/DMT. Relationships between baseline factors and En/DMT were explored. Time dependent covariate Cox survival regression was used to assess the effect of post-operative En/DMT changes during follow up. A longitudinal repeated measures model was used to assess the relationship between En/DMT and graft status. Outcome measures included graft rejection, central Endothelium/Descemet’s complex thickness, and central corneal thickness (CCT). In patients with GR (35%), the central En/DMT increased significantly 5.3 months (95% CI: 2, 11) prior to the clinical diagnosis of GR, while it remained stable in patients without GR. During the 1-year follow up, the rejected grafts have higher mean pre-rejection En/DMTs (p = 0.01), compared to CCTs (p = 0.7). For En/DMT ≥ 18 µm cut-off (at any pre-rejection visit), the Cox proportional hazard ratio was 6.89 (95% CI: 2.03, 23.4; p = 0.002), and it increased to 9.91 (95% CI: 3.32, 29.6; p < 0.001) with a ≥ 19 µm cut-off. In high-risk corneal transplants, the increase in En/DMT allowed predicting rejection prior to the clinical diagnosis.

Topical corticosteroids with topical cyclosporine A versus topical corticosteroids alone for immunological corneal graft rejection

Purpose: To assess the efficacy and safety of supplementing topical cyclosporine A (CsA) to topical corticosteroids (CS), in the prophylaxis and treatment of corneal graft rejection following penetrating keratoplasty (PK). Methods: Meta-analysis. Search was performed in PubMed, CENTRAL, ClinicalTrials.gov, reference lists of articles and conference proceedings. Primary outcomes: 1-year rejection-free survival rate (prophylaxis); resolution rate of rejection episodes (treatment). Secondary outcomes: 6- and 24-month rejection-free graft survival rate, number of rejection episodes during follow-up, time-to-resolution of rejection episode, 12- and 24-months graft survival rate, adverse events. Subgroup analyses were planned for high-risk grafts; primary vs. secondary prophylaxis of graft rejection episodes; and CsA concentrations of 0.05%, 1%, and 2%. Results: Five studies of moderate methodological quality were included (one retrospective, four RCT), assessing 459 eyes (CS + CsA 226, CS 233). In the prophylaxis setting, supplemental CsA was associated with a higher rejection-free survival rate at 12-months (RR 1.25, 95% CI: 1.00–1.56, p = 0.05) and 24-months post-PK (RR 1.56, 95% CI: 1.15–2.11, p < 0.01), though no differences were found at the 6-months timepoint ( p = 0.93). This effect was mostly verified using CsA 2% in the high-risk subset of patients. In the treatment setting, no differences were found in the resolution rate of rejection episodes ( p = 0.23). No differences existed on drug-related adverse events. Conclusion: In the prophylaxis of rejection episodes post-PK, the combined regimen of CS + CsA was associated with a higher 1- and 2-year rejection-free graft survival rate. Subgroup analysis mostly supported the use of CsA 2% for high-risk grafts. Further studies are needed to validate these results.

Understanding Immune Responses to Surgical Transplant Procedures in Stevens Johnsons Syndrome Patients

Stevens Johnsons syndrome (SJS) is a mucocutaneous disorder caused by an autoimmune response most commonly to medications. Unless it is properly managed in the acute setting, this entity can affect the ocular surface causing chronic cicatrizing conjunctivitis with limbal stem cell deficiency and lid anomalies which ultimately result in corneal opacities that may limit patients' visual acuity. When this stage is reached, some patients might need to undergo some form of corneal and/or limbal stem cell transplantation that exposes an already sensitized immune system to a new alloantigen. While the innate immunity plays a role in corneal graft survival, adaptive immune responses play a major part in corneal graft rejection and failure, namely through CD4+ T cell lymphocytes. Hence, the management of the immune response to surgical transplant procedures in SJS patients, involves a dual approach that modulates the inflammatory response to a new alloantigen in the context of an autoimmune sensitized patient. This review will explore and discuss current perspectives and future directions in the field of ocular immunology on how to manage SJS immune responses to ocular surgical procedures, reviewing systemic and local immunosuppressive therapies and protocols to adequately manage this debilitating condition.