Corneal Graft Rejection Clinical Presentation

Diagnosis of corneal graft rejection should be made only in grafts that have remained clear for at least 2 weeks following keratoplasty. By observing this guideline, graft rejection can be easily distinguished from other causes of graft failure that are more common in the early postoperative period (eg, primary donor failure). A sensitized host may rarely exhibit immunologic graft rejection before this 2-week period. Graft rejection has been observed to occur as late as 20 years after transplantation. 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:

  • Decrease in visual acuity
  • Redness
  • Pain
  • Irritation
  • Photophobia
• 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.

• 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 presents in one of two manners, as follows:

  • 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 on their own after several weeks.
  • Both types of epithelial rejection are steroid responsive, but, in many cases, the patient is either 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.
• 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 rejections include the following:^[1]

  • 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 is typically 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.

• Risk factors for rejection

  • 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, being able to identify and treat those patients at highest risk for graft rejection is important. Unfortunately, patients undergoing corneal transplantation represent a heterogeneous population, and proving that certain factors uniformly increase the risk of graft rejection is difficult. Differences in study designs exacerbate these difficulties.
  • Potential risk factors for corneal graft rejection are outlined below.
    • Host corneal vascularization
    • Larger and eccentric grafts
    • Human leukocyte antigen A (HLA-A) and human leukocyte antigen (HLA-B) and ABO blood type incompatibility
    • Presence of donor epithelium upon transplantation
    • History of previous graft failure of any cause
    • Bilateral penetrating keratoplasty
    • Pretransplantation corneal tissue media and preservation
    • Host age (lower risk with age >60 y, much higher risk in infants)
  • Of these risk factors, the only factor that has been decidedly proven to increase the risk of rejection is host corneal vascularization. Multiple studies have confirmed an increased risk of 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 unclear, although it is believed to be due to the relative loss of immune privilege that accompanies the usually avascular central cornea.
  • The other risk factors listed above remain in some 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. In particular, studies regarding the role of the major histocompatibility complex and HLAs have yielded contradictory data, although several studies indicate a trend toward a decreased incidence of graft rejection occurring in matched corneal grafts. At the present time, corneal grafts are not HLA typed and matched, unlike other organ transplants. Further evidence is needed to justify the added cost and complexity of performing HLA typing prior to corneal transplantation.