arameter disease severity is assessed by grading patients as none, mild/moderate and severe (Table 2). Based on the total scores assessed and the assessment of presence or absence of systemic GVHD, the diagnosis of oGVHD is made (Table 3).

Severity classification

Total score points are the sum of Schirmer’s test score, CFS score, OSDI Score and Conjunctival injection score.

・ None = 0 - 4;

・ Mild/Moderate = 5 - 8;

・ Severe = 9 ? 11.

3) Grading Scales for Ocular GVHD

A) NIH consensus criteria

In the NIH consensus, the criteria for diagnosing oGVHD is as mentioned in section 6.2.1.

The NIH eye score has a range of 0 - 3 as shown in Table 4.

Figure 2. Conjunctival hyperaemia grading.

Table 2. Severity scale used in grading of chronic ocular GVHD.

Table 3. Diagnosis of chronic ocular GVHD.

Table 4. NIH consensus criteria: Ocular GVHD staging.

B) Japanese dry eye score

The Japanese dry eye criteria [35] for diagnosis is as follows:

1) Presence of symptoms related to dry eye

2) Abnormality of the tear film to be seen by doing Schirmer’s and TBUT test

a) If Schirmer’s1 test values ≤5 mm

b) If Tear film breakup time values ≤5 seconds

3) The damage to the conjunctivocorneal epithelial surface to be noted as follows:

c) With Fluorescein staining, score of ≥3 points

d) With Rose Bengal staining score of ≥3 points

e) With Lissamine Green staining score of ≥3 points

The positive result in at least one of the above tests indicates the conjunctivocorneal epithelial surface damage.

Definite dry eye: Diagnosis of definite dry eye is considered if all three above written criteria are fulfilled.

Probable dry eye: Diagnosis of probable dry eye is considered if either one or two out of 3 above mentioned criteria are fulfilled.

Normal eye: If none of the above written criteria is getting fulfilled.

With this Japanese dry eye scoring system the severity of the dry eye is scored with a range of 0 - 2.

・ Score of 0 = No dry eye if no manifestations/symptoms seen;

・ Score of 1 = Mild dry eye if symptoms present along with Schirmer’s test ≤ 5 mm but fluorescein and rose bengal score are <3 points;

・ Score of 2 = Severe dry eye is diagnosed if symptoms, Schirmer’s test ≤ 5 mm are there along with fluorescein and rose bengal scores are ≥ 3 points.

C) DEWS 2007 score

In DEWS 2007 classification scores of 0 - 4 are given which are determined by evaluating 9 parameters including symptoms of dry eyes, scoring on Schirmer’s test, tear film breakup time, and other abnormalities noted in the conjunctiva, cornea, tear, lid, and meibomian glands [36] .

0 = No dry eye,

1 = Mild dry eye,

2 = Moderate dry eye,

3 = Severe dry eye,

4 = Very severe dry.

6.3. Clinical Features of oGVHD

The oGVHD disease includes wide range of clinical manifestations which affects almost all layers of the eye like the lids, lacrimal glands, conjunctiva, cornea, the vitreous and the choroids. The involvement of the posterior segment is less likely [37] [38] .

6.3.1. The Ocular Surface Manifestations in oGVHD

The outcome of both direct or an indirect conjunctival goblet cell involvement, of lacrimal gland stasis caused by immunosuppression or total body irradiation can give rise to the ocular surface and corneal complications of GVHD [38] . The corneal and conjunctival findings include epithelial thinning, keratinization and squamous metaplasia [39] .

Patients of aGVHD can present with both corneal and conjunctival findings and the severity of their ocular signs generally correlates with the severity of systemic disease.

In aGVHD pseudo membranous conjunctivitis has been documented in 12% - 17% of patients and it is marker of systemic involvement associated with a poor prognosis [40] . The pseudo membranous conjunctivitis can arise after conjunctival hyperaemia associated with epithelial sloughing which subsequently leads to scarring. In severe cases corneal epithelial sloughing presents along with the pseudo membranous changes which occurs in up to one third of patients [40] . Documentation of strong correlation of Dry-eye syndrome or kerato conjunctivitis sicca (KCS) with aGHVD is there in literature [25] .

Chronic GVHD manifestations include new onset of dry, gritty, or painful eyes, excessive tearing, burning sensation, light sensitivity, blurring of vision, cicatricial conjunctivitis, kerato conjunctivitis sicca, and confluent areas of punctate keratopathy [41] .

6.3.2. Dry Eye

In literature dry eye syndrome (DES) is reported as the most frequent complication and documented to be found in 40% to 76% of GVHD patients. The main cause of DES in cGVHD is fibrosis of the acini and ductules proceeded by lymphocytic infiltration of the accessory and major lacrimal glands [29] [30] . However other contributing factors include irradiation, chemotherapy, immunosuppressive therapy, infection and meibomian gland dysfunction [29] .

Though the median time of development of dry eyes is around six months, but it can develop any time between few weeks up to 100 months after transplantation. Most of the patients start experiencing dry eye or foreign body sensation with associated ocular fatigue and discharge which later on progress further to severe dry eye like Sjogren’s syndrome. Burning, stinging, itching, soreness and heaviness sensations in eyelids, and photophobia are among the other symptoms [38] .

6.3.3. Conjunctiva

Conjunctival involvement is found to be rare in aGVHD, though if present, it is a poor prognostic factor and marker for severe systemic involvement. The manifestations of conjunctival involvement vary from mild erythema to pseudo membranous and cicatrizing conjunctivitis similar to Ocular cicatricial pemphigoid.

In aGVHD ulcerative and haemorrhagic conjunctivitis are the more common manifestations, which subsequently progress to scarring and symblepharon formation. These cicatricial changes progress further during chronic phase of GVHD [39] [40] .

Conjunctival Grading in Acute and Chronic GVHD

A) Classification of Conjunctivitis in Acute GVHD [40]

Grade 0―None.

Grade 1―Hyperaemia.

Grade 2―Hyperaemia associated with serosanguinous discharge.

Grade 3―Pseudo membranous conjunctivitis.

Grade 4―Pseudo membranous conjunctivitis with associated corneal epithelial sloughing.

B) Classification of Conjunctivitis in Chronic GVHD [42]

Grade 0―None.

Grade 1―Hyperaemia.

Grade 2―If fibro vascular changes in palpebral conjunctiva seen with or without epithelial sloughing.

Grade 3―If fibro vascular changes in palpebral conjunctiva involve 25% - 75% of total surface area.

Grade 4―If more than 75% of total surface area involved with or without cicatricial entropion.

6.3.4. Corneal Involvement

Corneal involvement is more commonly seen in cGVHD than in aGVHD. In aGVHD features like filamentary keratitis and corneal epithelial keratitis are common. Chronic GVHD mostly shows features of keratoconjunctivitis sicca. Severe dry eyes may present which in turn can cause filamentary keratitis, corneal ulceration, corneal neovascularization, and ultimately corneal perforation if not treated [43] [44] .

6.3.5. Lacrimal Gland Involvement

Lacrimal gland dysfunction is found to be the most common ocular manifestation of ocular GVHD in past literature. In cGVHD disease there is documented tear dysfunction due to infiltration of mononuclear cell into major as well as accessory lacrimal of Kraus and Wolfring [30] .

6.3.6. Cataract

Even though cataract formation is the most common cause of visual acuity loss in these patients, its incidence increase further because of side effects of corticosteroid or total body irradiation therapy [44] .

6.3.7. Other Findings

Anterior uveitis is not very commonly seen during exacerbations of systemic GVHD. It is important to distinguish infectious aetiology or neoplastic masquerade syndrome from non-infectious uveitis [45] [46] .

Posterior segment complications are seen in around 12% of patients. The common vitreoretinal complications seen in GVHD are retinal microvasculopathy including features like intraretinal or vitreous haemorrhage and cotton wool spots [47] .

Central serous chorioretinopathy (CSCR) is not commonly seen in HSCT patients. GVHD itself has been reported to affect the choroidal vasculature leading to choroidal hyper permeability and the development of CSCR.

Association of acute ocular GVHD with posterior scleritis has also been documented in past [48] -[50] . Posterior segment infections such as infectious retinitis due to cytomegalovirus (CMV), herpes simplex virus and varicella zoster virus had also been reported as complications in literature [38] . The manifestation of disc oedema although irreversible is reported to be due to the toxic effects of treating drugs like chemotherapeutic agents for example cyclosporine A and due to coexisting medical conditions [47] .

6.4. Patient Workup

The following parameters should be checked while doing work up of patients suspected of having chronic ocular GVHD [20] .

・ Vision assessment.

・ Slit lamp examination for tear-film break-up time and Schirmer’s test.

・ Intraocular pressure measurement (IOP).

・ Staining the conjunctival surface with lissamine green and cornea with fluorescein dye and then grading of corneal fluorescein staining by using either the National Eye Institute scale or the modified Oxford grading scale.

・ Perform conjunctival or corneal swabs or scrapes for microbiological evaluation in cases of questionable aetiology.

・ Tear film osmolarity and confocal microscopy to help in deciding the treatment modality and follow-up assessment.

・ A dilated fundus examination to rule out posterior segment manifestations of chronic GVHD or cytomegalovirus.

・ Slit lamp examination of Lens, IOP measurement and visual field examination is required to assess any posterior capsular cataract or glaucoma development due to prolonged steroid use or radiation.

・ Symptoms evaluation can be performed by using the Ocular Surface Disease Index (OSDI).

・ Video keratoscope can be used to see difference of higher aberrations of indices in patients with chronic ocular GVHD as compared to normal counterparts.

6.5. GVHD Management Strategies

1) Systemic GVHD prevention and prophylaxis

To prevent GVHD following strategies should be followed:

・ Optimal HLA-matching is must for the prevention of GVHD both MHC class I and II loci between donor and recipient should be matched.

・ The use of Calcineurin inhibitors like cyclosporine and tacrolimus have been reported for the prophylaxis of GVHD. Tacrolimus along with the low doses of methotrexate use is documented for the prophylaxis of acute GVHD. Tacrolimus when used was found to have a lower rate of aGVHD occurrence as compared to cyclosporine [18] .

6.5.1. Acute GVHD Treatment

Systemic immune suppression is the most important aspect while managing GVHD. Steroid therapy, although considered the gold standard for treatment of GVHD due to its antilymphocytic and anti-inflammatory properties, can help in complete remission in less than 50% of patients only and the severe cases more likely don’t respond to steroid therapy alone. Such cases may require a more effective prophylaxis and treatment [51] . 5-year survival rates are also low in the steroid-resistant cases, implying a poorer prognosis. Although MMF, ATG, TNF inhibitors, and other agents are commonly used as second line agent, there is no data to support their use as the same [20] .

6.5.2. Chronic GVHD Treatment

Corticosteroids are the mainstay of therapy for chronic GVHD. Even though they are not totally satisfactory, no other agent has been demonstrated to be better than steroids in the treatment of chronic GVHD in a randomized trial [52] .

The newer treatment modalities which are under trial include:

・ Regulatory T cells modulation using ultra-low dose IL-2 [53] .

・ ECP (Extracorporeal photopheresis) has been shown to be effective in acute steroid refractory GVHD with better long term survival [54] .

・ Imatinib meslylate has shown promising results as an adjunctive therapy in sclera dermatous chronic GVHD [55] .

The most essential step of GVHD management is to avoid infections by giving supportive care in the form of either prevention, prophylaxis and giving treatment. After transplantation during the first year prescription of Acyclovir for viral prophylaxis and trimethoprim sulfamethoxazole or atovaquone for pneumocystis prophylaxis are advised and can be given later on also, if systemic immune suppression is indicated for chronic GVHD [20] .

6.5.3. Ocular GVHD Treatment

The systemic treatments for GVHD help in oGVHD too, but the severity of systemic disease cannot be directly correlated with the ocular manifestations. Therefore increasing the systemic immunosuppression is not the best approach to treat oGVHD. An organ specific approach is more desirable [20] .

The treatment modalities in oGVHD target the following: [56]

・ Ocular surface lubrication and support for the tear film;

・ Control of inflammation;

・ Epithelial and mucosal support;

・ Prevention of tear evaporation.

1) Ocular Surface Lubrication and Support for the Tear Film

Frequent topical lubrication with artificial non-preserved free tears is usually the mainstay of treatment in ocular GVHD with severe aqueous deficiency dry eye [1] . Lubricating medications assist in the dilution of the inflammatory mediators present at the ocular surface.

・ Acetylcysteine (5% - 10%) eye drops can be useful in patients presenting with ocular surface adherent filament [20] .

・ To preserve tears punctal occlusion can be done either with thermal cauterization or with silicone punctual plugs. These when used with autologous serum were found to increase the retention of the same [57] .

Although they haven’t been specially studied in GVHD patients systemic selective muscarinic agonists such as cevimeline or pilocarpine may be used to increase aqueous tear flow [58] .

2) To Control Inflammation

・ Topical steroids

Topical steroids have been shown to be beneficial in aGVHD due to its immunosuppressive action by Kim et al. [59] . Topical steroids have also been shown to be beneficial in cGVHD patients with cicatricial changes without having corneal epithelial defects, infiltrate and stromal thinning [42] .

・ Topical cyclosporine

Topical cyclosporine (CsA) eye drops are useful in patients with chronic ocular GVHD and KCS where other treatment modalities are not successful. Mechanism of action of CsA is to inhibit release of lymphokines from their activated T cells present in the conjunctiva by inhibiting proliferation and production of lymphokines itself. It also increases the conjunctival goblet cell density and decreases the epithelial cell turnover. Topical cyclosporine role in improving corneal fluorescein staining, by improving basal tear secretion in ocular GVHD patients is well documented [60] -[62] .

・ Tacrolimus (FK506)

Tacrolimus (FK506) is a macrolide antibiotic which is similar to CsA in terms of mechanism of action and its pharmacokinetics. Although Systemic tacrolimus has been shown to have a beneficial effect in some cases of ocular GVHD, not enough data is available for the use of topical tacrolimus in these patients. Tam et al have reported successful treatment of a case of oGVHD using topical tacrolimus [63] .

・ Topical Tranilast

Topical tranilast is an anti allergic medication which acts by inhibition of production and release of various ocular inflammatory mediators as well as cytokines. It interferes with migration and the proliferation of vascular medial smooth muscle cells along with inhibition of collagen synthesis and TGF-b induced matrix production. A small group of GVHD patients on treatment with topical tranilast were reported to have shown improvement in reflex tearing and Rose Bengal scores [64] .

3) For Epithelial Support

・ Autologous serum eye drops

In literature autologous serum had been documented to be not only safe but effective modality for the treatment of severe dry eye associated with chronic GVHD. Various factors for example epithelia trophic growth factors, nerve growth factors, cytokines and vitamins present in autologous serum helps in proliferation, differentiation, maturation as well as in maintaining integrity of the both corneal and conjunctival epithelial surfaces [57] .

・ Contact lenses

Contact lenses can be used in moderate to severe dry by stabilising the tear film and also improve the epithelial cells turn over. Significant improvement in dry eye manifestations in terms of both symptoms and visual acuity has been documented in patients with dry eye due to GVHD with the use of silicon hydrogel contact lenses by Russo et al. [65] . Scleral lenses help in relieving the symptoms in dry eye patients by creating a tear filled vault over the cornea [66] .

・ Surgical interventions like limbal stem cell transplantation, amniotic membrane transplantation and penetrating keratoplasty had also been documented as an option to treat severe dry eye. However one should keep in mind the poor prognosis associated with the allografts in these patients is due to poor ocular surface and tear deficiency [67] .

4) For the Prevention of Tear Evaporation

The evaporation of tears may be prevented by maximising the Meibomian gland output by using measures like warm compresses, lid hygiene, topical erythromycin and oral doxycycline therapy. Doxycycline has both antibiotic and anti-inflammatory properties. The latter is due to the inhibition of matrix metalloproteinase and IL-1 activity [68] [69] .

Other treatment modalities that could be used include nutritional supplements such as flax seed oil and fish oil (omega-3 fatty acids), moist chamber glasses and retinoic acid [70] .

5) Use of Systemic Immunosuppression for Ocular GVHD

To avoid unwanted systemic side effects systemic immunosuppression is not suggested in patients with ocular GVHD alone. It is advised in chronic ocular GVHD patients only if, not getting benefit from topical treatment. In terms of ocular surface improvement extracorporeal photopheresis is one another option in chronic GVHD. Imatinib improved the Schirmer’s scores in a small series of patients with chronic GVHD and has shown promise.

7. Conclusion

To summarize, it can be said that transplantation related morbidity has been decreased due to advances in technology used for transplantation these days as well as treatment modality. Though ocular GVHD is contributed mainly by conjunctival and lacrimal gland abnormality but involvement of other ophthalmic structures is also documented especially in chronic GVHD. In chronic ocular surface disorder disease severity can vary from dry eye to severe inflammation and scarring which can lead to sight threatening sequel. In past ocular GVHD was overlooked due to deficiency of exact diagnostic criteria. However, future advances by involving biomarkers for disease identification as well as targeted individual based therapy will lead to focused management protocol and optimal visual outcomes.

NOTES

*Corresponding author.

Cite this paper
Nair, S. , Vanathi, M. , Ganger, A. and Tandon, R. (2016) Ocular Graft versus Host Disease: A Review of Clinical Manifestations, Diagnostic Approaches and Treatment. Open Journal of Ophthalmology, 6, 20-33. doi: 10.4236/ojoph.2016.61004.
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