Ocular Graft-versus-host Disease

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:

  • Gastrointestinal system.
  • Liver.
  • Skin.
  • Mouth.
  • Lungs.
  • Eyes.

Traditionally, based on the time of onset, GVHD has been characterised as:

  • Acute.
  • Chronic.

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:

  • Age.
  • Donor cell compatibility.
  • Prophylaxis measures.
  • Host environment.









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Ocular (eye) manifestations vary widely.

Patient may present with ocular symptoms of:

  • Dryness.
  • Irritation.
  • Photophobia.
  • Blurred vision.
  • Redness.
  • Mucoid discharge.

Patients with severe disease frequently demonstrate: 

  • Conjunctival oedema or chemosis. 
  • Pseudo-membrane formation.
  • Corneal infections.

Serious manifestations include:

  • Corneal ulceration.
  • Corneal perforation.
  • Potentially permanent loss of vision.

Established risk factors associated with the development of GVHD which affect the severity of clinical presentation are:

  • Human leukocyte antigen (HLA) mismatch between donor and the recipient.
  • Gender disparity e.g. male donor for female recipient and vice versa.
  • Source of the stem cells.
  • Type of prophylaxis or conditioning regimen undertaken.
  • Advanced donor and recipient age.
  • History of acute GVHD (in cases of chronic GVHD).

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:

  • Features of dry eye.
  • Lacrimal gland dysfunction. 
  • Spontaneous lacrimal punctal occlusion (SLPO). 
  • Cicatricial ectropion. 
  • Cicatricial entropion.  
  • Trichiasis. 
  • Meibomian gland dysfunction (MGD)
  • Conjunctival inflammation and fibrosis. 
  • Cicatricial lagophthalmos.   
  • Sterile conjunctivitis.  
  • Conjunctival oedema or chemosis.
  • Pseudomembrane formation.
  • Punctate keratopathy.
  • Corneal epithelial erosions. 
  • Corneal infections. 
  • Chronic filamentary keratitis.
  • Corneal scarring.
  • Calcareous corneal degeneration.
  • Corneal ulceration.
  • Corneal perforation.
  • Uveitis.
  • Synechiae. 
  • Cataract.   
  • Retinal vasculitis.  
  • Retinal haemorrhage. 
  • Optic neuropathy.



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):

  • Stage I: Hyperaemia.
  • Stage II: Hyperaemia with chemosis and/or serosanguineous exudates.
  • Stage III: Pseudo-membranous/membranous conjunctivitis.
  • Stage IV: Pseudo-membranous/membranous conjunctivitis with corneal epithelial sloughing.

In 1998, Kiang et al. characterised the course of ocular GVHD into four stages.

Stages of Ocular GVHD (Kiang et al. 1998):

  • Stage 1 or Subclinical stage: Tearing, mild nonspecific discomfort and photophobia. Mild chemosis, possible rose bengal staining. It lasts from a few days up to 1 month before other systemic symptoms of GVHD occur or the patient progresses to a more severe form of ocular GVHD.
  • Stage 2 or Active stage: Muco-purulent conjunctivitis. Pseudo-membranous conjunctivitis, punctate keratitis or corneal abrasion. Patients usually have systemic manifestations of GVHD.
  • Stage 3 or Convalescent stage: Secondary sicca. Irregular eyelid margins with obstructed meibomian gland orifices, tarsal and forniceal scarring and punctate corneal epitheliopathy.
  • Stage 4 or Necrotising stage: Corneal melting and possible corneal perforation.

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):

  • Grade 1: Conjunctival hyperaemia occurring on the bulbar or palpebral conjunctiva in at least one eyelid.
  • Grade 2: Palpebral conjunctival fibro-vascular changes occurring along the superior border of the upper eyelid, or the lower border of the tarsal plate of the lower eyelid, with or without conjunctival epithelial sloughing, involving <25% of the total surface area in at least one eyelid.
  • Grade 3: Palpebral conjunctival fibro-vascular changes occurring along the superior border of the upper eyelid, or the lower border of the tarsal plate of the lower eyelid, involving 25- 75% of the total surface area in at least one eyelid.
  • Grade 4: Palpebral conjunctival fibro-vascular changes involving >75% of the total surface area with or without a cicatricial entropion in at least one eyelid.


Clinical tests:

  • Schirmer test: Schirmer test assists in diagnosis of lacrimal function in chronic ocular GVHD. New onset KCS with Schirmer score of 6-10mm or a symptomatic patient with Schirmer score of ± 5mm in presence of other organ involvement forms the criteria for diagnosis of chronic ocular GVHD.
  • Ocular surface disease index (OSDI): Ocular surface disease index (OSDI) is shown to be statistically higher in patients with chronic ocular GVHD than in pre-transplant or post-transplant patients without ocular GVHD (Agomo et al. 2008).
  • Videokeratoscope: Videokeratoscope may be used in the evaluation of patients with higher aberrations in patients of chronic GVHD (Chang-Strepka 2009).



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.


Diagnostic criteria:

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.


Differential diagnosis:

Due to similar clinical features, ocular GVHD should be differentiated from:

  • Autoimmune diseases.
  • Collagen vascular diseases.

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.

  • Environmental modifications: Environmental modifications and decreased exposure to low-humidity settings may reduce DES symptoms. Cool mist humidifiers can be particularly helpful for environmental modifications at home, including bedside use while sleeping.
  • Ultraviolet light exposure: Minimising ultraviolet light exposure also helps.
  • Eye evaluation: Regular eye evaluation may monitor for the development of infection, cataract, and intraocular pressure elevation. Therefore, a thorough ocular exam is recommended prior to HSCT.
  • Topical cyclosporine: Prophylactic use of topical cyclosporine (0.05%) might also reduce severity of disease.


II. Secondary therapeutic approaches:

1. Systemic medical therapy:

  • Immunosuppression: Systemic immunosuppressive medications may be effective in preventing manifestations of GVHD, but this benefit must also be weighed against the associated risks of infection, hepatotoxicity, nephrotoxicity, hypertension, and even death. Agents include tacrolimus, mycophenolate mofetil, cyclosporine, methotrexate, sirolimus, antithymocyte globulin, Ultraviolet (UV) light therapy and corticosteroids. These systemic therapies are often reserved for severe or refractory cases, due to long term adverse events with chronic use. First-line treatments are instead targeted towards specific organ systems with ocular immunosuppressive agents.  

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:

  • Preservative-free artificial tears: Preservative-free artificial tears and ophthalmic lubricating ointments are effective approaches in providing lubrication and diluting inflammatory mediators in the tear film.
  • Punctal occlusion: Punctal occlusion may effectively decrease tear drainage from the ocular surface, with either silicone plugs as temporary measure or permanent thermal cauterisation.
  • Moisture chamber goggles: Moisture chamber goggles may also prove beneficial in reducing tear evaporation and increasing patient comfort.
  • Treatment of Meibomian Gland Dysfunction (MGD): Dry eyes may be exacerbated by dysfunction of Meibomian and Zeis glands, both of which normally serve to produce the outer lipid layer of the tear film. The lipid layer is crucial in minimising evaporation of tears from the corneal surface. Treatment involves:

-       Warm compresses.

-       Lid Hygiene.

-       Oral tetracyclines or azithromycin.

b. Minimising ocular surface inflammation and immunosuppression:

  • Topical corticosteroids: Topical corticosteroid reduces ocular surface inflammation. The mechanism of action is through lymphocyte apoptosis (programmed cell death without releasing harmful substances into the surrounding area) and blockage of cell-mediated inflammation. Topical steroids are often combined with prophylactic topical antibiotic and tapered to avoid potential side effects. Patient is monitored for corticosteroid-induced side effects. They are contraindicated in patients with infiltrates, epithelial defects or stromal thinning of the cornea.
  • Topical cyclosporine A: Topical cyclosporine A is an anti-inflammatory drug, which produces local inhibition of T lymphocytes and cytokine production in the conjunctiva.  Cyclosporine may minimise destruction of lacrimal gland tissue and reduce dry eye. There may be improvement in corneal sensitivity, tear evaporation rate, tear break-up time, vital staining scores, goblet cell density, conjunctival squamous metaplasia and inflammatory cell numbers after treatment with topical cyclosporine. This has been used primarily in patients of chronic GVHD and KCS with minimal improvement, despite treatment with lubrication and topical steroids.


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.

  • Tarsorrhaphy: Tarsorrhaphy may be required to protect the ocular surface. Tarsorrhaphy may be performed with suture, glue adhesive, or botulinum toxin. Suture is the best technique as most patients with severe GVHD require a permanent tarsorrhaphy.
  • Amniotic membrane grafting: Amniotic membrane grafting may be done to protect the corneal surface. Amniotic membrane may be placed with suture or fibrin glue in one or multiple layers, or in conjunction with a carrier, such as with bio-tissue ProKera or AmbioDisc.
  • Cyanoacrylate glue patching: Cyanoacrylate glue patching may be performed in small descemetoceles or corneal perforations.
  • Deep anterior lamellar keratoplasty (DALK): Deep anterior lamellar keratoplasty (DALK) may be done for large descemetocele.
  • Penetrating keratoplasty (PK): Penetrating keratoplasty (PK) may also be performed for large descemetocele. In patients with large corneal perforations, penetrating keraoplasty must be performed on an emergency basis with strong consideration of placement of a concurrent tarsorrhaphy and/or amniotic membrane graft.



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:

  • Conjunctival scarring.
  • Cicatricial scarring of the lacrimal gland.
  • Corneal thinning or epithelial breakdown.
  • Corneal vascularisation.
  • Corneal infection.
  • Corneal ulceration.
  • Corneal perforation.

  • PUBLISHED DATE : Sep 15, 2016
  • PUBLISHED BY : Zahid
  • CREATED / VALIDATED BY : Dr. S. C. Gupta
  • LAST UPDATED ON : Sep 15, 2016


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