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Corneal Allograft Rejection Three Years Status Post Penetrating Keratoplasty

HomeExternal Disease and CorneaDiagnosis and Management of Immune-Related Disorders of the External Eye

Title: Corneal Allograft Rejection Three Years Status Post Penetrating Keratoplasty

Author: Charlotte L. Marous, B.S., M.S.G.H.; Brian E. Zaugg M.D. July 2016

Photographer: James Gilman

Image or Video:

Figure 1: Slit lamp photo demonstrating healthy corneal graft with full clarity and intact sutures status post penetrating keratoplasty for keratoconus.

Figure 1: Slit lamp photo demonstrating healthy corneal graft with full clarity and intact sutures status post penetrating keratoplasty for keratoconus.

Figure 3 (right): Slit lamp photo of aggressive allograft rejection with active stromal vascularization and haze indicative of active graft rejection.

Figure 3 (right): Slit lamp photo of aggressive allograft rejection with active stromal vascularization and haze indicative of active graft rejection.

Figure 2 (left): Slit lamp photo of a penetrating keratoplasty with peripheral vascularization and stromal haze. The eye appears quiet and likely represents a chronic or past rejection.

Figure 2 (left): Slit lamp photo of a penetrating keratoplasty with peripheral vascularization and stromal haze. The eye appears quiet and likely represents a chronic or past rejection.

Keywords/Main Subject: Keratoconus, Penetrating Keratoplasty, Transplant Rejection, Corneal Graft Rejection, Allograft Rejection, Corneal Vascularization, Immunosuppressives

Diagnosis: Corneal Transplant Rejection, Keratoconus


Chief Complaint:  blurry vision of left eye for two weeks

History of Present Illness: A 35-year-old Caucasian female with bilateral keratoconus status post bilateral penetrating keratoplasty three years prior was referred for progressive blurry vision of the left eye for the past two weeks. Exam one year ago showed a healthy graft and clear cornea OU with visual acuity of 20/20 OD uncorrected and 20/20 OS corrected with a contact lens. The patient denied pain, discomfort, or discharge, stating only that the blurriness is “annoying.” No vision complaints OD. Using 1 drop of prednisolone acetate 1% once daily OU.

Past Ocular History:  Keratoconus OU status post penetrating keratoplasty OU. Phacoemulsification with toric IOL for posterior subcapsular cataract OD, levator resection for ptosis OU, and a nuclear cataract OS currently stable under observation.

Medical history: FAP Gardner’s Syndrome

Family History: None

Social History: denies smoking, alcohol, illicit drugs

Medications: 1 drop prednisolone acetate 1% daily OU

Allergies: Morphine

Ocular Examination:


Corneal transplant rejection OS


Prednisolone 1% every hour OS

Preservative free tears hourly OS

Follow-up in 2 weeks



Corneal graft transplant is the most widely practiced and successful type of solid organ transplantation in humans.1 Approximately 60,000 procedures are performed annually worldwide for diseases such as keratoconus, psuedophakic or phakic bullous keratopathy, trauma, infections, and corneal dystrophies or ectasias.1 It is associated with a high survival rate of 86% at 1-year post initial graft, largely attributed to the immune privilege of the eye.2 However, the 15-year graft acceptance rate declines to 55%, similar to survival rates in other forms of organ transplant.3 Graft rejection is one of the leading causes of corneal graft failure in the immediate and late postoperative period.1 Immune rejection and graft-related problems constitute the most important emergent presentations in graft patients. Long-term prophylactic use of topical steroids and immunosuppressive drugs can improve graft survival rate, but do not eliminate the risk, especially in “high-risk” recipients, and can be accompanied by side effects and potential toxicity.1 Novel biologic agents are showing promise in these patients unable to tolerate steroids.


Corneal graft rejection is a reversible immune response against donor antigens.  If signs of immunologic graft rejection do not clear within 2 months, the diagnosis of graft failure is made. Graft failure is the irreversible loss of graft clarity. It is important to rule out other common causes of loss of graft clarity before declaring failure. These include, but are not limited to infection, surgical trauma, glaucoma, and aging. Graft rejection is the most common cause of ultimate graft failure, accounting for >30% of cases.2


The immune privilege of the cornea is maintained by the absence of blood vessels and lymphatics that deliver antigens to T cells in lymph nodes, scarcity of mature antigen presenting cells (APCs) in the central cornea, unusually low expression of major histocompatibility complex (MHC) antigens, and expression of the FAS ligand that induces apoptosis of stimulated Fas+ T cells.1 This privilege can be revoked by inflammation, infection, or trauma that induce neovascularization and lymphatic growth into the cornea; thus permitting APCs to enter the corneal stroma.1 Infection also induces pro-inflammatory cytokines that upregulate MHC antigen expression on corneal cells. Once the host immune system recognizes these foreign histocompatibility antigens on the cells of the corneal allograft, an immune cascade and response is initiated against these antigen, leading to eventual decompensation of the graft tissue.1 This rejection represents a form of delayed-type hypersensitivity response mediated by CD4+ T cells.2

Allograft rejection can affect one or more layers of the cornea (epithelium, stroma, and endothelium). The endothelium possesses minor regenerative properties and is a key player to maintaining corneal deturgescence.2 Thus, when >50% of the corneal endothelium is lost, graft rejection is likely to progress to graft failure.

 Risk factors

Donor, host, and intraoperative factors influence graft rejection in corneal transplant recipients (Table 1). “High Risk” is defined as deep stromal vascularization of the host cornea of two or more quadrants, or a previous graft rejection in the affected eye.1

Table 1: Risk factors predisposing to graft rejection



·         High antigenic load (depends on HLA/ABO compatibility between donor/host)

·         Longer duration of storage of donor cornea (may reduce rejection)

·         Pretreatment of donor tissue with UV radiation (may reduce rejection by preventing activation of cytotoxic T cells)



·         Vascularization of host cornea

·         History of previously rejected graft (pre-sensitizes the host)

·         Ocular surface diseases  (severe dry eye, chemical burns, radiation burns, ocular pemphigoid, Stevens-Johnson Syndrome, neuroparalytic disease)

·         Active keratitis

·         Pediatric patients (immune systemic of children is more active than adults)


Intraoperative Factors ·         Large/eccentric graft

·         Synechiae at graft host junction

·         Penetrating grafts

·         Previous anterior segment surgical reconstruction

·         Bilateral graft

·         Suture removal (may trigger immune rejection)

 Clinical Signs and Symptoms:

Patients may be asymptomatic or may complain of increased blurry vision, redness, pain, irritation, or photophobia. Signs of graft rejection include:

 Rejection can be classified based on corneal layer involvement (Table 2).1 Chronic focal endothelial rejection is the most common cause of graft rejection constituting 50% of cases. Epithelial rejection and stromal rejection represent roughly 2% and 1% of graft rejections, respectively.4

Table 2: Differentiating Features in Corneal Graft Rejection

Epithelial ·         Epithelial rejection line at the host graft junction

·         Asymptomatic

·         No edema, keratic precipitates, or infiltrate

Stromal ·         Circumferential limbal injection

·         Patches of stromal infiltrate and haze

·         Stromal edema

·         Lymphocytes and plasma cells outside endothelial capillary wall

Endothelial ·         Endothelial line

·         Stromal and epithelial edema

·         Keratic precipitates on graft endothelium

·         Cell and flare possible, but difficult to visualize due to edematous cornea

Adapted from Panda A, Vanathi M, Kumar A, et al. Corneal graft rejection. Survey of Ophthalmology. 2007; 52: 375-95.

Differential Diagnosis of Corneal Graft Rejection:


Diagnosis is based on history and slit lamp examination. Important questions to be considered include: time since corneal transplantation, current eye medications, compliance with eye medications and postoperative follow-up, recent changes in topical steroid regimen, and inquiry into the initial indication for the corneal transplant. On slit lamp exam, inspect for endothelial rejection line, keratic precipitates, subepithelial infiltrates, edema, and cells in anterior chamber.

Prevention Practices and Immunosuppressive Agents:

Prevention can be subdivided into preoperative, intraoperative, and postoperative measures. Preoperatively, minimizing the antigenic difference between the host and donor tissue (tissue matching) and reducing the antigenic load of the donor tissue (UV light exposure) can help diminish the risk of rejection. Intraoperative measures of preventing immune-mediated allograft rejection are achieved by meticulous surgical techniques including good graft-host apposition and sterile suturing. Close follow-up monitoring for IOP, intact sutures, and compliance to immunosuppressive medications contribute to post-operative risk reduction.

Immunosuppressive medications play a fundamental role in the reduction of graft rejection. Current practice guidelines suggest “low risk” patients be put on long-term once daily prophylactic topical steroids (1% prednisolone drops), while “high risk” recipients adhere to a more stringent prophylactic regimen of long-term daily topical steroid plus a systemic immunosuppressive.1 Topical and oral steroids control the host immune system by preventing invasion by IL-1 and IL-6 producing macrophages and initiation of T-cell responses. Given the side effect profile of prolonged steroid use including cataract formation, glaucoma, and impaired wound healing, newer preventative therapeutics are becoming more widely available. Calcineurin inhibitors including cyclosporine (CsA), tacrolimus (FF-506), and mycophenolate mofetil (MMF) have been shown to be effectively substituted for steroids.5 Intraocular delivery of immunosuppressants in “high risk” rabbits was associated with reduced rate of graft rejection compared to those treated with topical or oral agents alone; supporting another potential route of prophylaxis.2 Novel biologic agents blocking receptors of TNF-a, VEGF, and CCL2 are also showing promise as prophylactic treatment in patients affected by high immune risk and corneal neovascularization.6 These agents work by reducing corneal inflammation, vascularization, angiogenesis, lymphangiogenesis; all factors common to graft rejection.2


Despite prophylactic efforts, graft rejection may transpire. Management is aimed at reducing the active immune response. The likelihood of reversibility is largely dependent on the corneal layer affected. For epithelial and subepithelial acute rejections, which have a higher rate of reversibility, primary treatment involves topical steroids (1% prednisolone) six times per day along with preservative-free artificial tears that hydrate the ocular surface.7 Severe endothelial rejection requires hourly topical steroids in combination with systemic therapy (40 to 80 milligrams of oral prednisone daily, or 1-2 intravenous doses of 400 milligrams of methylprednisolone with or without subconjunctival betamethasone 3 milligrams in 0.5 milliliters).7 Careful monitoring for IOP and resolution of the inflammation should be assessed every 3-7 days until improvement is noted, at which point steroids may be slowly tapered and maintained at a long-term low dose.

Alternatives to Normal Corneal Tissue Grafts in “High Risk” Patients:

One alternative for patients with multiple failed corneal grafts is a Boston keratoprosthesis, an artificial cornea.  This is a synthetically generated cornea FDA-approved for use in patients with severe corneal opacification and high risk of transplant failure. Donor corneal tissue is secured between a rigid polymethyl methacrylate optic front plate and back plate lined with holes to allow for communication with the aqueous for nutrition and hydration of the cornea. The plates are snapped together and sutured into the recipient eye, similar to a typical corneal transplant.8-9 A prospective case series of 141 cases across 17 centers reported visual acuity of 20/40 in 23% of patients and 20/200 in 57% of patients after keratoprosthesis placement.10 Failure for visual acuity improvement and post-operative complications included epithelial defects, stromal thinning, dellen formation, retroprosthetic membrane formation, retinal detachment, and development of glaucoma.2,11

Bioengineered corneal equivalents represent another possible option. These biosynthetic implants are equivalent to corneal stromal extracellular matrix and are based on chemically crosslinked collagen designed to function as regeneration templates. The idea is that regeneration of endogenous corneal layers and functional corneal nerves occur in the collagen matrix, thus hydrogel implants that mirror this natural cornea structurally may promote active regeneration of endogenous corneal epithelial and stromal cells.2 A recent 4-year follow-up clinical study provided strong evidence supporting high acceptance and adaptation of the hydrogel with improved visual acuity and central nerve ingrowth.12 The major limitation of this method resides in the fact that positive outcomes are limited to lamellar keratoplasty, in which host endothelium is still intact. This would not be helpful in patients requiring penetrating keratoplasty.


  1. Panda A, Vanathi M, Kumar A, et al. Corneal graft rejection. Surv Ophthalmol. 2007;52:375-95.
  2. Yu T, Rajendran V, Griffith M, Forrester JV, Kuffova L. High-risk corneal allografts: a therapeutic challenge. World J Transplant. 2016;6:10-27.
  3. Williams KA, Esterman AJ, Bartlett C, Holland H, Hornsby NB, Coster DJ. How effective is penetrating corneal transplant? Factors influencing long-term outcome in multivariate analysis. Transplantation. 2006;81:896-901.
  4. Guilbert E, Bullet J, Sandali O, Basli E, Laroche L, Borderie VM. Long-term rejection incidence and reversibility after penetrating and lamellar keratoplasty. Am J Ophthalmol. 2013;155:560-69.
  5. Hill JC. Systemic cyclosporine in high-risk keratoplasty: long-term results. Eye (Lond). 1996;9:422-28.
  6. Fasciani R, Mosca L, Giannico MI, Ambrogio SA, Balestrazzi E. Subconjunctival and/or intrastromal bevacizumab injections as preconditioning therapy to promote corneal graft survival. Int Ophthalmol. 2015;35:221-7.
  7. Bagheri N, Wajda BN. The Wills Eye Manual: office and emergency room diagnosis and treatment of eye disease, 7th edition. Philadelphia: Lippincott Williams and Wilkin, 2017:98-99.Print.
  8. Ilhan-Sarac O, Akpek EK. Current concepts and techniques in keratoprosthesis. Curr Opin Ophthalmol. 2005;16:246-50.
  9. Birkholz ES, Goins KM. Bostom keratoprosthesis: an option for patients with multiple failed corneal graft. March 9, 2009; Available from:
  10. Zerbe BL, Belin MW, Ciolino JB. Boston type 1 keratoprosthesis study group, results from the multicenter Boston Type 1 Keratoprosthesis study. Ophthalmol. 2006;113:1779.
  11. Ray S, Khan BF, Dohlman CH, D’Amico DJ. Management of vitreoretinal complications in eyes with permanent keratoprosthesis. Arch Ophthalmol. 2002; 120: 559–566.
  12. Fagerholm P, Lagali NS, Ong JA, Merrett K, Jackson WB, Polarek JW, Suuronen EJ, Liu Y, Brunette I, Griffith M. Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials. 2014; 35: 2420-27.

Faculty Approval by: Brian E. Zaugg, M.D.

Copyright:  Charlotte L Marous © 2016. For further information regarding rights to this collection, please visit:

Identifier: Moran_CORE_21656

Disclosure (Financial or other): The authors have no financial conflicts of interest.