• Diagnosis and Management of Ocular Graft vs. Host Disease

    By Ladan Espandar, MD, Majid Moshirfar, MD, FACS, and Stella K. Kim, MD
    Edited by Ingrid U. Scott, MD, MPH, and Sharon Fekrat, MD

    This article is from October 2008 and may contain outdated material.

    Hematopoietic stem cell transplantation is used to treat a variety of malignancies and hematologic, immunogenic and metabolic disorders. Allogeneic stem cell transplantation can cause graft vs. host disease (GVHD), which is associated with high mortality and morbidity. In the past, any manifestation of GVHD within 100 days after transplantation was referred to as “acute GVHD,” and after 100 days it was called “chronic GVHD.” The NIH Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD has changed the classification and staging of GVHD.1

    New classification. According to the NIH classification, acute GVHD includes 1) classic acute GVHD occurring within 100 days after transplantation and 2) persistent, recurrent late-acute GVHD with features of classic acute GVHD, without diagnostic or distinctive manifestation of chronic GVHD, occurring beyond 100 days after transplantation (often seen after tapering or withdrawal of immunosuppressive therapy).

    Chronic GVHD includes 1) classic chronic GVHD without features characteristic of acute GVHD and 2) an overlap syndrome in which features of chronic and acute GVHD appear together.

    The new classification scheme defines diagnostic and distinctive manifestations of chronic GVHD in each organ, recommending that the diagnosis of chronic GVHD require at least one diagnostic or at least one distinctive manifestation confirmed by biopsy, laboratory tests or imaging in the same or another organ.1

    In both acute and chronic GVHD, ocular complications may occur in 60 to 90 percent of patients. Either form of GVHD can result in significant morbidity with a decrease in quality of life and may lead to severe ocular surface disease with corneal perforation.

    Chronic GVHD


    New-onset dry, gritty or painful eyes
    Difficulty opening the eye because of dried mucoid secretions
    Excessive tearing
    Bilaterial episcleritis
    Periorbital hyperpigmentation
    Cicatricial conjunctivitis with or without symblepharon
    Keratoconjunctivitis sicca
    Confluent areas of punctate keratopa-thy, corneal epithelial sloughing
    Superior limbic keratoconjunctivitis
    Conjunctival hyperemia, chemosis and/or serosanguineous exudates
    Pseudomembranous conjunctivitis


    NOTE: Diagnosis of chronic ocular GVHD requires positive biopsy or Schirmer test plus one of the manifestations above.


    Eyewear/Environmental Strategy
    Occlusive eyewear
    Eyelid care/warm compresses/humidified environment
    Bandage contact lens (used with extreme caution)
    Gas-permeable scleral contact lens (Boston scleral lens prosthesis)

    Artificial tears, preservative-free
    Topical corticosteroid drops
    Cyclosporine eyedrops
    Autologous serum eyedrops

    Systemic (Oral, IV)

    Punctal occlusion
    Superficial debridement of filamentary keratitis, pseudomembranes
    Partial tarsorrhaphy

    SOURCES: Filipovich, A. H. et al. Biol Blood Marrow Transplantation 2005;11:945–955; and Couriel, D. et al. Biol Blood Marrow Transplantation 2006;12:375–396.

    Clinical Manifestations of Ocular GVHD

    All layers of the eye can be affected by ocular GVHD, including the eyelid, lacrimal gland, conjunctiva, cornea, vitreous, uveal tract and optic nerve, although posterior segment involvement in ocular GVHD is extremely rare. The ocular surface and lacrimal gland tend to be affected more often than other parts of the eye.

    The ocular surface is frequently involved in ocular GVHD. The severity of ocular surface disease, particularly in the acute setting, has been described in four stages: stage I, hyperemia alone; stage II, hyperemia with chemosis and/ or serosanguineous exudates; stage III, pseudomembranous conjunctivitis; and stage IV, corneal epithelial sloughing. This ophthalmic staging scheme is not related to overall staging or scoring of systemic GVHD, and it is not clear if it is a prognostic indicator for survival of GVHD patients.

    Clinical presentation resembling superior limbic keratoconjunctivitis can occur in chronic ocular GVHD, especially in patients with a positive Schirmer test (without anesthetic) of less than 5 mm. Bilateral episcleritis also can be seen in chronic ocular GVHD. Cicatricial conjunctivitis is quite common in chronic ocular GVHD, so during slit-lamp examination it’s important to check the palpebral conjunctiva and fornices for symblepharon.

    Keratoconjunctivitis sicca (KCS) resulting from lacrimal gland dysfunction is the other major manifestation of both acute and chronic ocular GVHD. The incidence of dry eye syndrome in GVHD varies from 22 to 80 percent. The most common complaints in patients with KCS are: foreign body sensation, ocular dryness and grittiness, conjunctival hyperemia, mucoid discharge and excessive tearing (secondary to reflex secretion).

    The most important findings in the external and slit-lamp examination of patients with keratoconjunctivitis sicca before placement of any drops in the eye are: decreased tear meniscus, increased debris in the tear film, conjunctival pleating, superficial punctate keratopathy (with positive fluorescein, lissamine green and/or rose bengal staining), corneal filaments and corneal epithelial defects or ulceration in more severe cases. A mean Schirmer test— in both eyes, without anesthesia—of less than 5 mm is characteristic of the diagnosis of KCS.1,2

    NIH-Defined Diagnosis of Ocular GVHD

    The diagnosis of ocular GVHD is clinical and requires a thorough ocular history and examination. It’s also important to consider systemic GVHD symptoms such as abdominal pain, diarrhea, rash, shortness of breath, recent infection or fever.

    According to the diagnostic criteria of the NIH Consensus Working Group, there are no definitive manifestations to secure the diagnosis of chronic ocular GVHD, but distinctive manifestations include new onset of dry or painful eyes, cicatricial conjunctivitis, KCS or confluent areas of punctate keratopathy, as well as photophobia, periorbital hyperpigmentation, difficulty in opening the eyes in the morning because of dried mucoid secretions and blepharitis.

    Definitive diagnosis of chronic ocular GVHD requires one of these distinctive manifestations plus positive Schirmer test or biopsy (see “Chronic GVHD”).1,3 Routine screening biopsy is generally believed to serve little benefit for early detection of ocular GVHD.

    The histologic features of conjunctival biopsy in GVHD include lymphocyte exocytosis, satellitosis (accumulation of neuroglial cells around neurons), vacuolization of the basal epithelium and epithelial cell necrosis. Other features are relatively nonspecific, including epithelial attenuation and goblet cell depletion, which themselves are not sufficient for the diagnosis of ocular GVHD.4

    Lacrimal gland biopsy is invasive and risks decreasing the gland’s functional capacity. Pathologic findings in GVHD include alterations in lacrimal gland acinar tissue with prominent infiltration of mononuclear cells around medium-size ducts, with loss of acinar lobules replaced by fibrosis.4

    Management of Ocular GVHD

    The NIH Consensus Working Group established guidelines for ancillary therapy and supportive care in chronic ocular GVHD, including treatment for symptoms and recommendations for patient education, preventive measures and appropriate follow-up.4

    Most symptomatic treatments for ocular chronic GVHD are aimed at relief of dry eye by lubrication and/or by decreasing tear evaporation, tear drainage or ocular surface inflammation (see “Chronic GVHD”).

    For lubrication, the use of preservative-free artificial tears is recommended. Lacrisert (slowly dissolving 5-mg pellets of hydroxypropyl cellulose), inserted once or twice daily into the inferior cul-de-sac, is an option for patients who use artificial tears more than once every hour. Evoxac (cevimeline), a specific agonist of the M3 muscarinic receptor, can stimulate aqueous tear flow and increase ocular surface moisture.

    The liquid corneal bandage provided by a fluid-ventilated, gas permeable scleral lens such as Boston Scleral Lens Prosthetic Device modifies the corneal surface environment, reduces hyperosmolarity, desiccation and shear forces from the lids. It also moderates pathologic neurogenic and immunologic responses at the ocular surface.

    To decrease evaporation, use of warm compresses and eyelid care, avoidance of low humidity and use of eye protection (moisture chamber goggles) should be encouraged. Oral doxycycline can be used to treat meibomian gland dysfunction or associated rosacea.

    To decrease tear loss and drainage from the surface of the eye, temporary occlusion (silicone plug) or permanent occlusion (thermal cauterization) of the puncta may provide additional benefit, especially for severely dry eyes (a Schirmer test of no more than 5 mm without anesthesia).

    To decrease ocular surface inflammation, the use of topical corticosteroids is valuable. They are especially useful for the control of an ocular GVHD exacerbation when systemic immunosuppression is being tapered. In addition to early debridement, topical corticosteroids also may benefit patients with pseudomembrane formation and cicatricial conjunctivitis. Ocular surface inflammation also may be decreased with autologous serum. Serum eyedrops may be produced as an unpreserved blood preparation, are nonallergic and contain a large variety of growth factors, vitamins and immunoglobulins in similar or higher concentrations than natural tears and maintain morphology and support proliferation of corneal epithelial cells.

    To control immune responses at the ocular surface, topical cyclosporine can be prescribed to reduce conjunctival epithelial apoptosis (in experimental studies, apoptosis was evaluated in frozen sections with the ApopTag In Situ Oligo Ligation Kit, which specifically detects DNA fragmentation) and protect against goblet cell loss by inhibiting T lymphocytes.

    Systemic treatment such as corticosteroids, tacrolimus (inhibitor of T-lymphocyte activation), cyclosporine (inhibitor of T-lymphocyte activation) and, more recently, rituximab (anti-CD 20 monoclonal antibody) and photopheresis (the combination of ultraviolet light and 8-methoxypsoralen to induce apoptosis in T cells and antigen presenting cells) also can be used.

    Maximizing systemic immunosuppression is not always an appropriate choice because it can lead to serious infection and an increased chance of cancer; therefore, topical treatment for ocular GVHD is a better choice, if it is effective. However, systemic immunosuppression must be maximized when ocular GVHD with associated systemic GVHD (in the skin, liver and gut) is not controlled. Therefore, the best approach to the local and systemic management of ocular GVHD is a multidisciplinary approach with close collaboration between the ophthalmologist and the hematopoietic transplantation team.


    • GVHD is systemic, so diagnosis and management of ocular GVHD should be approached in a multidisciplinary fashion.
    • The major issue in ocular GVHD is dry eye syndrome. Pre-transplantation ophthalmic examination and Schirmer testing is recommended. Treatment with artificial tears, punctal plugs and even topical cyclosporine or corticosteroid, depending on severity, can slow progression of eye problems.
    • In the case of pseudomembrane formation, early debridement and topical corticosteroid and cyclosporine use are encouraged.
    • Many ocular GVHD exacerbations occur during the tapering of systemic immunosuppressive therapy. Attention to topical treatment, especially pulsed corticosteroids and cyclosporine, is necessary to avoid serious systemic side effects.


    1 Filipovich, A. H. et al. Biol Blood Marrow Transplantation 2005;11:945–955.

    2 Kim, S. K. Curr Opinion Ophthalmol 2006;17:344–348.

    3 Couriel, D. et al. Biol Blood Marrow Transplantation 2006;12:375–396.

    4 Shulman, H. M. et al. Biol Blood Marrow Transplantation 2006;12:31–47.


    Dr. Espandar is an ophthalmic pathology/ research fellow and Dr. Moshirfar is a professor of ophthalmology at the University of Utah, Salt Lake City. Dr. Kim is an associate professor of ophthalmology at the MD Anderson Cancer Center, Houston. The authors have no financial or proprietary interest in any of the products or methods mentioned.