Corneal Graft Rejection

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Background

Although described for more than 100 years, corneal transplantation has become increasingly common since the 1960s. In 2021, approximately 80,000 corneal transplantations were performed in the United States.[1] Corneal graft rejection is the most common cause of graft failure in the late postoperative period.[2]

Examples of corneal graft rejection are shown in the images below.



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This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Joh....



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This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.

Pathophysiology

Corneal transplantation has a high success rate in part because of the relative immune privilege of the cornea. The cornea is avascular, limiting access of lymphocytes and other immune responsive cells.[3] There are no associated lymphatics vessels or lymph nodes; therefore, the opportunity for presentation of foreign antigen to antigen-presenting cells and T cells also is limited. The cornea expresses MHC antigens to a lesser extent than other tissues, contributing to immune privilege. However, this can be compromised by prolonged inflammation, extensive vascularization, and other factors, resulting in rejection.

The term graft rejection refers to the specific immunologic response of the host to the donor corneal tissue. Because it is a specific process, it should be distinguished from other causes of graft failure that are not immune-mediated. A corneal graft that has suffered this immunologic response may or may not ultimately fail. 

Synthetic or bioengineered alternatives to human corneal tissue are being researched to reduce the risk for rejection.[4]

 

Epidemiology

Frequency

United States

In 2021, 79,614 corneal transplantations were performed in the United States.[1] Corneal graft rejection is the most common cause of graft failure in the late postoperative period.[2] The incidence of graft rejection varies widely depending on the study design, type of transplantation, and risk factors for rejection. Overall graft survival rates also can vary among different indications for keratoplasty. Published data reveals a long-term graft survival rate of penetrating keratoplasty (PK) ranging from 52% to 98.8%. At 5 years’ follow-up in the Cornea Donor Study, 23% of subjects had at least one rejection event, and 37% of the eyes with a rejection event had graft failure.[5] Another recent study of 405 eyes undergoing PK resulted in a graft survival rate of 73.5% and graft rejection rate of 14.1%, whereas another study demonstrated a rejection rate of 33.5%.[6, 7]

The reported incidence of graft rejection is lower in partial thickness corneal transplantation.[8] The success rate for deep anterior lamellar keratoplasty (DALK) ranged from 77.0% to 99.3%.[9, 10] The incidence of graft rejection following DALK may range from 6% to 19.7%.[9, 7]

Descemet stripping endothelial keratoplasty (DSEK) or Descemet stripping automated endothelial keratoplasty (DSAEK) usually is indicated for eyes with endothelial disease alongside other comorbidities (eg, glaucoma, iris defect, history of vitrectomy).[11] A retrospective study involving ultra-thin DSAEK (UT-DSAEK) demonstrated a graft survival rate of 99.1% and a rejection rate of 3.4% at one-year follow-up, and a survival rate of 94.2% and rejection rate of 6.9% at five-year follow-up.[12]

Descemet membrane endothelial keratoplasty (DMEK) graft survival rates range from 92% to 100%, largely via reports from single-center data.[8] One recent retrospective study demonstrated a graft survival rate of 94.7% with a graft rejection rate of 1.7%.[6] Other large series data from single centers demonstrate a cumulative < 1% probability of graft rejection episode within 2 years following DMEK.[13, 14, 15] A meta-analysis of 10 retrospective studies showed a 60% lower risk of graft rejection following DMEK as compared with DSAEK.[16]

Mortality/Morbidity

Corneal graft rejection is the most common cause of graft failure in the late postoperative period.

Race

No difference in corneal graft rejection between different races is known.

Sex

No sex predilection for corneal graft rejection is known.

Age

Host age may influence the risk for corneal graft rejection. Some investigators have concluded that hosts older than 60 years have a lower risk for corneal graft rejection, although this has not been confirmed. The effect of donor age on corneal graft survival has been debated. The Cornea Donor Study found no association between donor age and corneal graft survival among corneal transplants at moderate failure risk.[17] Corneal transplantation in the neonatal period (< 6 months) has a lower risk for rejection due to neonatal immune tolerance, with less active B cells. However, the immune system is fully developed and hyperactive by age 6 months, and thus the risk for graft rejection increases thereafter.[18]

Prognosis

The sooner an episode of graft rejection is detected clinically and therapy is begun, the better the prognosis for graft survival. The rate of reversal of corneal endothelial graft rejection has been reported from 51-63.8%, depending on the clinical setting.[19, 20] In general, the prognosis is good if therapy is immediately instituted.

Depending on the degree of irreversible damage to the graft endothelium, even markedly edematous grafts may clear again. Once endothelial destruction has progressed to the point where the remaining endothelial function is inadequate to maintain deturgescence, the graft fails and becomes irreversibly edematous. Unfortunately, the endothelium has no or at best a very limited capacity for repair through mitosis.

Patient Education

No symptoms are related universally to graft rejection.

Astute patients may complain of a decrease in visual acuity, redness, pain, irritation, and photophobia. Patients also may be asymptomatic. A useful pneumonic to use for patient education is “RSVP” (an acronym for Redness, Sensitivity to Light, Vision, and Pain), all representing symptoms that should be reported to the patient’s physician.

Any patient with a corneal graft should be instructed to seek ophthalmologic care urgently if these symptoms persist for more than a few hours.

History

Diagnosis of corneal graft rejection should be made only in successful grafts that have remained clear for at least 2 weeks following keratoplasty.[8] By observing this guideline, graft rejection can be distinguished from other causes of graft failure that are more common in the early postoperative period (eg, primary donor failure). However, an immunologic reaction may occur prior to this arbitrarily-defined time period, particularly in the cases of a sensitized host, such as is the case in repeat corneal transplants.[21, 22] Graft rejection has been observed to occur as late as 20 years after transplantation. The incidence of graft rejection is greatest in the first year following transplantation.

No symptoms are related universally to corneal graft rejection, although astute patients may complain of the following:

Depending on the severity of the graft rejection, patients may be asymptomatic. Any patient with a corneal graft should be instructed to seek ophthalmologic care if these symptoms occur for more than a few hours.

Physical

Animal models of graft rejection reveal that the 3 corneal layers, epithelium, stroma, and endothelium, can be rejected separately. Although these separate rejection processes have been observed in humans, many patients present with combinations of epithelial, stromal, and endothelial rejection.

Epithelial rejection

Epithelial rejection presents in one of two manners.

The first type is characterized by an irregular, elevated epithelial rejection line that stains with fluorescein or rose bengal. The rejection line progresses rapidly across the cornea over several days to 2 weeks. A variant of this presentation may occur in which the epithelial rejection line takes the form of a ring, concentric with the limbus, which begins peripherally at the graft-host junction and progresses by shrinking centrally to a point. The rejection line represents a region of destruction of donor epithelium; the resulting epithelial defect is covered by host epithelium that grows inward from the remaining host cornea and limbus to cover the graft.

The second type of epithelial rejection is characterized by the presence of subepithelial infiltrates. These infiltrates consist of leukocytes and frequently have an appearance similar to the subepithelial infiltrates seen in adenoviral keratoconjunctivitis. These lesions may change location and shape over time, and they generally disappear without intervention after several weeks.

Both types of epithelial rejection are steroid responsive, but, in many cases, the patient either is asymptomatic or has symptoms only of minimal irritation. As a result, the patient may not present to the ophthalmologist during these episodes. Although epithelial rejection generally is self-limited and tends not to cause visual disturbance on its own, it should be treated when found on examination as it may herald a more severe endothelial rejection.

Stromal rejection

Generally, stromal rejection in humans accompanies endothelial rejection and is difficult to demonstrate alone. It is characterized by peripheral full-thickness haze with limbal injection in a previously clear graft. An arc-shaped infiltrate may be noted peripherally at the graft-host junction that progresses centrally.

Endothelial rejection

Classic endothelial rejection presents with an endothelial rejection line (Khodadoust line) that usually begins at a vascularized portion of the peripheral graft-host junction and progresses, if untreated, across the endothelial surface over several days. The rejection line consists of mononuclear white cells that damage endothelial cells as the line sweeps across the endothelium.

Generally, a mild-to-moderate anterior chamber reaction is present. The damaged endothelium is unable to properly dehydrate the corneal graft; as a result, the donor cornea is clear ahead of the rejection line and is cloudy and edematous behind it.

A second variant of endothelial rejection is more diffuse in character, with scattered keratic precipitates and an anterior chamber reaction indicative of endothelial rejection and damage. In this type of endothelial rejection, stromal edema typically is not localized, but rather generalized throughout the graft, consistent with the generalized endothelial damage. The combination of keratic precipitates, an anterior chamber reaction, circumcorneal injection, and regions of corneal edema should be diagnosed as corneal graft rejection. In some cases, it may be difficult to distinguish graft edema from rejection and graft edema from endothelial insufficiency. Because rejection may be reversible, treating patients as if they have graft rejection is best.[23]

Allograft rejection after endothelial keratoplasty

The most commonly performed techniques for posterior lamellar keratoplasty are Descemet stripping automated endothelial keratoplasty (DSAEK) and DMEK. Allograft rejection after DSAEK and DMEK may have a different clinical course with a slower onset than after penetrating keratoplasty, with significant reductions in the risk of developing endothelial graft failure.[24, 25]

If clinically examined soon after immunologic rejection manifests, anterior chamber cells may be seen without flare or graft abnormality. Later, slit lamp examination may further reveal keratic precipitates, an endothelial line with precipitates along the host-donor interface, or edema that may be generalized or localized to a graft rejection line. Visible precipitates, representing aggregated alloreactive cells adherent to graft endothelium, are focal and irreversible areas of endothelial cell loss, frequently resulting in stromal edema.[26] Cellular changes indicative of ongoing allograft rejection after endothelial keratoplasty may be detected via specular microscopy months prior to clinical manifestations of disease, thus characterizing rejection as a slow-onset immunologic process rather than an acute one.[27, 28]

Causes

A great deal of energy has been expended in trying to determine clinical risk factors for corneal graft rejection. Because corneal graft rejection is the leading cause of graft failure in the late postoperative period, it is important to identify and treat those patients at highest risk for graft rejection. Unfortunately, patients undergoing corneal transplantation represent a heterogeneous population, and proving that certain factors uniformly increase the risk for graft rejection is difficult. Differences in study designs exacerbate these difficulties.

Risk factors for corneal graft rejection can be divided into host and donor risk factors.

Potential host risk factors include the following:

Potential donor risk factors include the following:

One factor that has been decidedly proven to increase the risk for rejection is host corneal vascularization. Multiple studies have confirmed an increased risk for corneal graft rejection with increasing host vascularization, ranging from rates of 0-10% of graft rejection in avascular host corneas to rates of up to 25-50% in severely vascularized host corneas. The precise cause for this increased risk is believed to be the relative loss of immune privilege that accompanies the usually avascular central cornea.[33]

Some of the risk factors listed above remain in dispute. In some cases, multiple studies have yielded contradictory results, whereas, in other cases, an insufficient number of clinical studies exist. In all cases, these risk factors are modified by the particular clinical situation. It is prudent to minimize ocular surface inflammation and neovascularization prior to keratoplasty. Studies regarding the role of the major histocompatibility complexes (MHCs) and HLAs have yielded contradictory data, although several studies indicate a trend toward a decreased incidence of graft rejection occurring in matched corneal grafts. Currently, corneal grafts are not routinely HLA typed and matched in the United States, unlike other organ transplants. Further evidence is needed to justify the added cost and complexity of performing HLA typing prior to corneal transplantation.[31]

The effect of donor age on corneal graft survival has been debated. The Cornea Donor Study did not find an association between donor age and corneal graft survival among corneal transplants at moderate failure risk.[17] Graft rejection rates are higher in infants than in adults.

Laboratory Studies

Graft failure is a clinical diagnosis; laboratory studies are not indicated for use in diagnosis.

Imaging Studies

Graft failure is a clinical diagnosis; imaging studies are not generally indicated for use in diagnosis.

Other Tests

Specular endothelial microscopy can be performed to determine endothelial cell density, pleomorphism, and polymegethism.[27] Changes in these parameters may help to determine ongoing corneal graft rejection prior to the onset of clinically identifiable symptoms.[34] Elevations in the presence of sub-basal or endothelial immune cells, as measured via in vivo confocal microscopy (largely a research tool at this time), may also be of value in identifying preclinical graft rejection.[35]

Pachymetry or anterior segment ocular coherence tomography (AS-OCT) can be performed to measure corneal thickness.[36] This can be helpful to determine involvement and extent of stromal edema in rejection.

Other tests may be warranted in narrowing down the differential of corneal graft rejection. For example, several cases of CMV endotheliitis, which presents similarly to graft rejection, have been reported in the literature. An anterior chamber paracentesis may be of diagnostic value if this is suspected.[37, 38]

Medical Care

Treatment of graft rejection depends on the type of rejection; however, in all cases, topical corticosteroids are the mainstay of treatment. Epithelial or stromal rejection without endothelial involvement usually does not progress to graft failure. As previously noted, epithelial rejection may be a self-limited process. Nonetheless, epithelial and stromal rejection should be aggressively treated, because they indicate host immunologic recognition of the graft and may precede a more severe endothelial rejection. Topical corticosteroids (eg, dexamethasone 0.1%, prednisolone acetate 1%) are prescribed 4-6 times a day until the signs of rejection resolve, followed by a slow tapering of the topical medication. These patients should be followed closely to be certain that the signs of rejection are improving and that endothelial rejection has not developed.

In cases of endothelial rejection, treatment must be more aggressive if the episode is to be reversed. Topical corticosteroids (eg, dexamethasone 0.1%, prednisolone acetate 1%) should be used every hour while awake and as frequently as possible at night for 2-3 days, followed by every two hours while awake. Treatment with higher potency topical ophthalmic steroids (eg, difluprednate) also can be considered. Steroid ointment may be used at bedtime. Therapy should be continued until signs of rejection resolve. Topical medications should be tapered slowly over several weeks to a few months depending upon the patient's response to treatment. Therapy should be continued for at least 4 weeks in the absence of a response before judging that the graft has failed.

Other routes of administration of corticosteroids can be used in more severe endothelial rejections, in recurrent rejections, or if the patient is at high risk (eg, alkali burns, patients with vascularized corneas). Corticosteroids may be given by subconjunctival injection (eg, dexamethasone phosphate 2 mg, betamethasone 3 mg in 0.5 mL). Another option is a collagen shield soaked in corticosteroids and applied to the cornea combined with frequent corticosteroid eye drops. The shield acts as a depot reservoir for the drug that slowly releases its contents during the period between topical applications.

In cases of severe endothelial rejection or high-risk cases, systemic steroids or immunosuppressants (eg, oral prednisone, IV methylprednisolone, IV cyclosporine) are used, based largely on surgeon judgment and with wide variability in treatment use.[33] Oral prednisone generally is started at dosages of 60-80 mg daily and continued for as long as 1-2 weeks before tapering. Pulsed steroids (a single IV administration of 500 mg methylprednisolone) have been shown to improve the percentage of graft survival compared with oral steroids in patients who present early (within the first 8 days) in a rejection episode.[39] A nonsignificant trend toward improved survival in all episodes of rejection in favor of pulsed steroids exists. In addition, pulsed steroids reduce the risk for subsequent rejection episodes, which may be a significant benefit in higher risk corneal grafts. Pulsed steroids also avoid prolonged administration of oral steroids.

In all cases of rejection, intraocular pressure should be monitored closely, especially when frequent corticosteroids are used. If necessary, elevated intraocular pressure should be controlled by topical medications to prevent glaucoma and to improve the chance of graft survival.

Surgical Care

No surgical care has proven beneficial during an episode of acute graft rejection.

Some transplant surgeons scrape the donor corneal epithelium to reduce the antigen load. However, no solid evidence suggests that removing the donor epithelium is beneficial in reducing the risk for subsequent graft rejection.

If an acute graft rejection episode progresses to graft failure, repeat corneal transplantation may be indicated, typically endothelial keratoplasty.

Diet

No dietary restrictions have been identified.

Activity

No activity restrictions have been noted.

Complications

Depending on the degree of injury sustained by the graft, graft rejection episodes can progress to graft failure due to rejection.

Long-Term Monitoring

Patients should receive close follow-up care with an ophthalmologist for corneal graft rejection.

Frontiers in Corneal Graft Rejection Therapy

Topical corticosteroids are the mainstay of treatment after corneal transplant surgery, including full-thickness and partial-thickness keratoplasties. Given significantly lower rejection rates among lamellar and endothelial keratoplasty, there have been reports of cessation of long-term steroids; however, most authors and clinicians recommend prolonged or indefinite use of low-potency topical steroids in the absence of contraindications.[11] In high-risk cases, topical immunosuppressive agents have been used adjunctively with goals of reducing the onset or exacerbation of graft rejection, as well as reducing dependence of long-term topical steroids. For example, these agents may be employed in the postoperative period in cases of steroid-induced glaucoma.[33] However, data regarding their efficacy in reducing graft rejection remains unclear. Topical cyclosporine A (CsA, at concentrations of 0.05-2%) and topical tacrolimus (commonly 0.03%) have shown promise, whereas topical sirolimus and systemic mycophenolate mofetil (MMF) remain other studied options.[11, 40, 41] In a recent randomized study involving patients receiving high-risk PK, graft rejection among patients receiving topical tacrolimus 0.1% exhibited a significantly decreased graft rejection rate compared with the group receiving CsA 1%.[42] Current data also supports the use of systemic MMF in high-risk keratoplasties, with statistically significant reductions in occurrences of rejection compared with controls and mostly reversible side effects.[43, 44]   However, It always is important to consider adverse effect profiles before starting any of these immunosuppressant agents – a thorough medical evaluation and review of patient medical history are warranted prior to initiation. Cost, affordability, and insurance coverage are other important considerations.

Other immunosuppressive modalities that may be explored as monotherapy or adjunctive therapy to topical or systemic steroids include basiliximab (monoclonal antibody negatively inhibiting activated T cells via the CD25 receptor),[45]  rapamycin,[46]  azathioprine,[47]  corneal shields to enhance CsA penetration,[48]  intracameral steroids, and oral tacrolimus.[49] Further human studies are needed to elucidate their efficacy in reducing rejection alongside varying safety profiles.

Reducing corneal neovascularization has the potential to reduce graft rejection, but many of the treatments to reduce corneal neovascularization have limited efficacy including off-label use of subconjunctival bevacizumab or ranibizumab, topical bevacizumab, or fine-needle thermal cauterization of visible corneal neovascularization.[50, 51] Corneal crosslinking also has been explored to reduce corneal neovascularization, prior to or concurrent with high-risk PK.[52]

Future studies and innovations in the frontiers of regenerative stem cells,[53]  gene transfer,[54]  and xenotransplantation[55] may one day play a role in corneal health and graft survival.

Medication Summary

Corticosteroids are the mainstay of treatment of acute graft rejection. They can be given topically, via subconjunctival injection, or systemically.

Prednisolone acetate 1% (Omnipred, Pred Forte)

Clinical Context:  Most commonly used topical corticosteroid. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.

Dexamethasone (Decadron)

Clinical Context:  For various allergic and inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Also used for subconjunctival injections.

Prednisone (Deltasone, Rayos)

Clinical Context:  May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Single pulsed dose of IV steroids prior to PO steroids may improve final outcome.

Class Summary

These agents provide anti-inflammatory activity to suppress the natural immune response that leads to acute graft rejection.

Tacrolimus (Astagraf XL, Envarsus XR, Prograf)

Clinical Context:  Tacrolimus suppresses humoral immunity (T-cell activity). It is a calcineurin inhibitor with two to three times the potency of cyclosporine. Tacrolimus can be used at lower doses than cyclosporine can, but it has severe adverse effects, including renal dysfunction, diabetes, and pancreatitis. Levels are adjusted according to renal function, hepatic function, and adverse effects.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Clinical Context:  Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-versus-host disease for various organs.

Class Summary

Agents in this category inhibit key factors involved in the immune response. They may be used when graft rejection is not controlled adequately by systemic corticosteroids. 

Author

Michael Taravella, MD, Director of Cornea and Refractive Surgery, Rocky Mountain Lions Eye Institute; Professor, Department of Ophthalmology, University of Colorado School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: J&J Vision (Consultant)/Proctor<br/> for: Coronet Surgical (Consultant), no income received.

Coauthor(s)

Divy Mehra, DO, Resident Physician, Department of Ophthalmology, Dartmouth Hitchcock Medical Center

Disclosure: Nothing to disclose.

William G Gensheimer, MD, Chief of Ophthalmology, White River Junction VA Healthcare System; Associate Professor of Surgery, Geisel School of Medicine at Dartmouth

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of the Cornea Service, Wills Eye Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: AAO; OMIC; American Society of Ophthalmic Trauma (ASOT)<br/>Received income in an amount equal to or greater than $250 from: AAO; OMIC.

Chief Editor

Hampton Roy, Sr, MD, † Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Jack L Wilson, PhD, Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center College of Medicine

Disclosure: Nothing to disclose.

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This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Johnson syndrome.

This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.

This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Johnson syndrome.

This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.