Patricia A. Ple-Plakon and Shahzad I. Mian

Introduction

Hematopoietic stem cell transplantation (HSCT) is an increasingly common treatment for hematologic, immunologic, metabolic and neoplastic diseases. Graft-versus-host disease (GVHD) is a complication of allogeneic HSCT where an immunologic response by donor cells against host tissues occurs due to incompatibility between the recipient and donor cells. The prevalence of GVHD varies between 10% and 90% depending on age, donor cell compatibility, host environment, and prophylaxis protocols.1,2 Human leukocyte antigen (HLA) markers are the most important factors, triggering the immune response and leading to the onset of GVHD. Tissues most commonly targeted by donor cells include, the gastrointestinal system, liver, lungs, skin and eyes.

GVHD has traditionally been characterized as acute and chronic, based on the time of onset. Acute GVHD occurs within the first 100 days after HSCT, while chronic GVHD occurs after that time. Ocular complications are most commonly associated with chronic GVHD.

Clinical Manifestations

Ocular GVHD affects 60–90% of patients with chronic systemic GVHD and may be the initial presentation of systemic GVHD.3,4 Ocular manifestations vary widely from mild findings, to severe ocular sequelae and can affect the eyelid, lacrimal gland, conjunctiva, tear film, cornea, lens, vitreous, retina and optic nerve.^3,5–7 The most common presentation includes diseases of the ocular surface and lacrimal gland, with symptoms of dryness, irritation, blurred vision, photophobia, redness, and mucous discharge. Dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) occurs in 70% of GVHD patients. Patients, especially those with severe disease, frequently demonstrate conjunctival edema, chemosis, and pseudomembrane formation. Disease progression may lead to punctate keratopathy, corneal epithelial erosions, and corneal infections and ulcerations (Fig. 23.1). In addition to keratoconjunctivitis sicca, frequent manifestations of ocular GVHD include, conjunctival inflammation and fibrosis, cicatricial lagophthalmos, sterile conjunctivitis and uveitis.^6,8 It may also manifest with lacrimal gland dysfunction, spontaneous lacrimal punctual occlusion (SLPO), cicatricial ectropion or entropion, trichiasis, meibomian gland dysfunction, calcareous corneal degeneration, corneal perforation, synechiae, cataract, retinal vasculitis, retinal hemorrhage and optic neuropathy.^5–7,9–12 Ocular GVHD can have clinical manifestations similar to those of autoimmune and collagen vascular diseases affecting the eye, but ocular GVHD does not typically affect the posterior chamber.

Appropriate and timely treatment of ocular GVHD is critical, as a delay can lead to more serious manifestations, including chronic filamentary keratitis, corneal scarring, ulceration, and corneal perforation. This can result in significant morbidity and potentially permanent vision loss.

Pathophysiology

The immune response in GVHD is based on the role of donor T-lymphocytic cells in mounting an attack against host tissues. The primary cells responsible for this attack are the donor T-helper type 1 cells in acute GVHD and the donor T-helper type 2 cells in chronic GVHD. While the mechanism behind chronic GVHD has not been fully elucidated, there is a decreased tolerance to self-antigens and inflammatory reactions in multiple organ systems.

Conjunctivitis is commonly observed as a localized ocular reaction in GVHD. Although the mechanism is not fully understood, flow cytometry has demonstrated the proliferation of T cells in subconjunctival immunogenic inflammation.¹³ Histopathology has revealed lymphocyte exocytosis and satellitosis, dyskeratotic cells, epithelial cell necrosis, subepithelial microvesicle formation and eventually, total separation of the epithelium in the conjunctiva of patients with GVHD.^6,14 Epithelial attenuation and goblet cell depletion have also been observed.⁹

In GVHD, donor lymphocytes infiltrate the lacrimal gland, leading to widespread fibrosis and aqueous tear deficiency.¹⁵ Histopathology of the lacrimal gland in patients with chronic GVHD and DES reveals PAS-positive material accumulation in the acini and ductules, predominant T-cell infiltration in periductal areas, increased number and activation of stromal fibroblasts and excessive extracellular matrix fibrosis.¹⁶ There is also prominent fibrosis of the glandular interstitium, similar to the chronic skin GVHD changes with generalized sclerodermal lichenoid.⁹ Postmortem autopsy studies of the lacrimal gland in patients with GVHD have shown stasis of lacrimal gland secretions, epithelial cell debris within the lumina of lacrimal glands and periductal inflammation and fibrosis.¹⁵ Additionally, immunohistochemical studies show primarily CD4 and CD8 T-cell infiltration in periductal areas of lacrimal glands of patients with chronic GVHD.¹⁵

Meibomian gland dysfunction (MGD) can also lead to dry eye symptoms in patients with GVHD. The meibomian glands secrete the lipid component of the tear film in order to retard tear evaporation. A recent study reported that 63% of chronic GVHD patients had MGD, with significant correlation in severity of DES symptoms.⁶

Diagnosis

A thorough patient history and ocular examination are necessary for the clinical diagnosis of ocular GVHD. Essential components of the history include extent of systemic GVHD, as well as systemic medications. The diagnostic criteria for ocular GVHD were established by the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease in 2005. The Diagnosis and Staging Working Group has stated that a mean Schirmer value of 5 mm at 5 minutes or new onset of keratoconjunctivitis sicca by slit lamp examination, with a mean Schirmer value of 6–10 mm, is sufficient for the diagnosis of chronic GVHD, if accompanied by involvement of at least one other organ system.¹⁷

Conjunctival biopsy may also aid in the diagnosis of ocular GVHD. Histopathology may reveal lymphocyte exocytosis and satellitosis, dyskeratotic cells, epithelial cell necrosis, subepithelial microvesicle formation and eventual total separation of the epithelium in the conjunctiva of patients with GVHD.6,14

Classification

Multiple classification systems have been used to categorize ocular GVHD. In 1989, Jabs et al. proposed a clinical staging system for conjunctival involvement in ocular GVHD (Table 23.1).¹⁴ In 1998, Kiang et al. characterized the course of ocular GVHD into four stages (Table 23.2).¹⁸