Ocular graft-versus-host disease (GVHD) is a complication of allogeneic haematopoietic stem cell transplantation (HSCT), where an immunologic response by donor cells against host tissues occurs due to incompatibility between the recipient and donor cells. Haematopoietic stem cell transplantation (HSCT) is a common treatment for haematologic, immunologic, metabolic and neoplastic diseases. HSCT is limited due to GVHD, which is a major cause of morbidity following allogeneic HSCT. Human leukocyte antigen (HLA) markers are the most important factors, triggering the immune response and leading to the onset of GVHD.
Types of transplantation depend upon the source of donor cells, though it is covered under the term bone marrow transplantation (BMT). Sources include autologous (from self), syngeneic (genetically identical), and allogeneic (other individual). The donor cells may be harvested not only from bone marrow but also from peripheral blood and blood from the placental cord.
GVHD is an immune response by the donor cells (graft) against the recipient (host), resulting in an immunological attack against organ systems.
Tissues most commonly targeted by donor cells include:
Traditionally, based on the time of onset, GVHD has been characterised as:
Acute GVHD occurs within the first hundred days after HSCT, while chronic GVHD occurs after that time. Ocular complications are most commonly associated with chronic GVHD.
This hundred days separation between acute and chronic held true in the myeloablative era (Myeloablative means killing of cells in bone marrow by chemotherapy or radiotherapy), but it was seen that non- myeloablative allogeneic HSCT and reduced intensity conditioning were associated with a two month delay in onset of acute GVHD, while acute and chronic GVHDs were found to present simultaneously in patients treated, for example, with lymphocyte infusions. Thus, with current consensus, it is primarily the clinical manifestations and not the time of onset of symptoms after transplant that determines the classification of GVHD as acute or chronic.
The prevalence of GVHD varies depending upon:
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Ocular (eye) manifestations vary widely.
Patient may present with ocular symptoms of:
Patients with severe disease frequently demonstrate:
Serious manifestations include:
Established risk factors associated with the development of GVHD which affect the severity of clinical presentation are:
Optimally HLA- matched transplant recipients may also present with GVHD mainly due to mismatch of potential minor histocompatibility antigens, which are not accounted for in routine typing.
The immune response in GVHD is based on the role of donor T-lymphocytic cells attacking against host tissues. The primary cell 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 localised ocular reaction in GVHD. Although the mechanism is not understood, flow cytometry has demonstrated the proliferation of T cells in subconjunctival immunogenic inflammation. Histopathology has revealed lymphocyte exocytosis and satellitosis, dyskeratotic cells, epithelial cell necrosis, sub-epithelial micro-vesicle formation and eventually, total separation of the epithelium in the conjunctiva of patients with GVHD. Epithelial attenuation and goblet cell depletion have also been reported.
In GVHD, donor lymphocytes infiltrate the lacrimal gland, leading to widespread fibrosis and aqueous tear deficiency. Histopathology of the lacrimal gland in patients with chronic GVHD and DES reveals Periodic acid Schiff (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. There is also prominent fibrosis of the glandular interstitium, similar to the chronic skin GVHD changes with generalised sclera-dermal lichenoid. Autopsy studies of the lacrimal gland in patients with GVHD have shown stasis of lacrimal gland secretions and epithelial cell debris within the lumina. Immunohistochemical studies show primarily CD4 (cluster of differentiation 4) and CD8 T-cell infiltration in periductal area of lacrimal glands of patients with chronic GVHD.
Meibomian gland dysfunction (MGD) can also lead to dry eye symptoms in patients with GVHD. The meibomian gland secretes lipid component of the tear film.
A thorough patient history and ocular examination is necessary for the clinical diagnosis of ocular GVHD. Essential components of the history include extent of systemic GVHD, as well as systemic medications taken.
Ocular GVHD may 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 (extremely rare).
Ocular GVHD affects 60-90% of patients with chronic systemic GVHD and may be the initial presentation of systemic GVHD. 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.
Most common presentation includes diseases of the ocular surface and lacrimal gland.
Appropriate diagnosis and management of ocular GVHD is important in order to maintain visual acuity and good quality of life in cases treated with HSCT.
Dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) occurs in 70% of GVHD patients.
Besides the symptoms of dryness, irritation, blurred vision, photophobia, redness and mucous discharge, patient may have any of the following signs:
Multiple classification systems have been used to categorise ocular GVHD.
In 1989, Jabs et al. proposed a clinical staging system for conjunctival involvement in ocular GVHD.
Clinical Staging System for Conjunctivitis in Ocular GVHD (Jabs et al. 1989):
In 1998, Kiang et al. characterised the course of ocular GVHD into four stages.
Stages of Ocular GVHD (Kiang et al. 1998):
An alternative classification system was proposed by Robinson et al. in 2004. In this system, clinically relevant grading criteria for conjunctival GVHD is based on conjunctival pathology, observed in chronic GVHD patients.
Clinical Grading Criteria for Conjunctival GVHD (Robinson et al. 2004):
Histopathology of the conjunctival biopsy may reveal lymphocyte exocytosis and satellitosis, dyskeratotic cells, epithelial cell necrosis, sub-epithelial micro-vesicle formation and eventual total separation of the epithelium in the conjunctiva of patients with GVHD.
The diagnostic criteria for ocular GVHD were established by the National institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD in 2005. The Diagnosis and Staging Working Group has stated that a mean Schirmer value of 5mm at 5 minutes or new onset of keratoconjunctivitis sicca by slit lamp examination, with a mean Schirmer value of 6- 10mm, is sufficient for the diagnosis of Chronic GVHD, if accompanied by involvement of at least one other organ system.
The NIH Health Consensus Development Project defined findings of new-onset dry, gritty, or painful eyes, cicatricial conjunctivitis, KCS, and confluent areas of punctuate keratopathy, as well as periorbita hyper-pigmentation, difficulty in opening the eyes in the morning because of dried mucoid secretions, and blepharitis as ‘distinctive signs’ (seen in chronic GVHD but insufficient, alone, to establish a diagnosis of chronic GVHD). As per report, a diagnosis of chronic GVHD could be made in the presence of one diagnostic sign or the presence of a distinctive sign (confirmed by biopsy and laboratory testing) and/or distinctive signs in one other organ system. This formed the basis for the addition of two new categories to the existing classification of GVHD: persistent, recurrent, or late-onset acute GVHD (>3 months) and overlap syndrome (no temporal relation) in which features of acute and chronic GVHD appear together. Chronic GVHD based only on ocular findings (presence of one distinctive sign) can be confirmed on the basis of biopsy evidence of KCS or Schirmer test and if accompanied by distinctive manifestations in at least one other organ. Routine screening biopsy serves little benefit for early detection of ocular GVHD. Lacrimal gland biopsy is invasive and risks decreasing the functional capacity of the gland.
Due to similar clinical features, ocular GVHD should be differentiated from:
Management should be carried out under medical supervision.
A multidisciplinary approach that incorporates collaboration with other medical teams is essential for GVHD patients. This includes collaboration with the haematology and oncology services and stem cell transplantation services.
The management of ocular GVHD includes:
I. Primary prevention
II. Secondary therapeutic approaches which includes medical, both local and systemic, and surgical therapies.
I. Primary prevention:
Prevention of disease plays an important role in decreasing the morbidity associated with ocular GVHD.
II. Secondary therapeutic approaches:
1. Systemic medical therapy:
2. Local medical therapy:
Successful treatment modalities include eye lubrication, reduction of tear evaporation, minimising ocular surface inflammation, and immunosuppression.
a. Lubrication and Reduction of Tear evaporation:
- Warm compresses.
- Lid Hygiene.
- Oral tetracyclines or azithromycin.
b. Minimising ocular surface inflammation and immunosuppression:
c. Autologous serum eye drops: Autologous serum eye drops (20-50%) have been used safely and effectively in the treatment of DES in patients with ocular GVHD. Unlike artificial tears, they contain albumin, epidermal growth factor, fibronectin, vitamin A, neurotrophic growth factor, and hepatocyte growth factor, all of which may help in maintaining stable tear film. A potential concern with this treatment is the risk of contamination which may produce infection.
d. Scleral contact lenses: Scleral contact lenses have also been used in patients with severe or refractory dry eye disease. These larger contact lenses create a tear-filled vault on the corneal surface without corneal contact. These include Jupiter lenses, as well as the custom-designed PROSE (Prosthestic Replacement of the Ocular Surface Ecosystem) lenses.
e. Mucolytic agents: Mucolytic agents such as acetylcysteine (10%) may be used to treat severe filamentary keratitis.
f. Newer treatment modalities: Newer agents include topical immunomodulator tranilast (rizaben), topical tacrolimus, and retinoic acid, although large scale studies are needed.
3. Surgical therapy:
Surgical therapy may be needed in most severe cases of GVHD where maximal medical therapy may fail in reducing symptoms and protecting the ocular surface.
Ocular involvement, though rare in systemic acute GVHD, is considered a poor prognostic factor for mortality caused by systemic acute GVHD. Though known to impair the quality of life and activities of daily living, ocular GVHD usually does not lead to permanent visual loss.
Untreated GVHD may produce complications and sequlae like: