Diagnosis and Management of Ocular Graft-Versus-Host Disease

Severity scores (points)

Schirmer’s test (mm)

Corneal fluorescein staining


Conjunctival injection




















OSDI ocular surface disease index. Total score (points); (Schirmer’s test score + corneal fluorescein staining score + OSDI score + conjunctival injection score) = 0–4 (none); 5–8 (mild/moderate); 9–11 (severe)

Table 6.2
Diagnosis of chronic ocular GVHD

None (points)

Probable GVHD (points)

Definite GVHD (points)

Systemic GVHD (−)




Systemic GVHD (+)




From: With permission from International Chronic Ocular Graft-vs-Host-Disease (GVHD) Consensus Group: Proposed Diagnostic Criteria for Chronic GVHD [1]

Given his exam findings and absence of systemic GVHD, he scores zero in both eyes and does not have ocular GVHD.

Can You Perform Any Other Tests to Determine If He Has Any Signs of Ocular Inflammation?

Several laboratory tests can be performed to assess for early signs and markers of dry eye disease and ocular inflammation. Tear fluid osmolarity and noninvasive Keratograph tear break-up time (NIKBUT) are two tests that can aid in the diagnosis of dry eye disease. Tear fluid osmolarity test measures the osmolarity of human tears. The lower the water content of tears, the higher the osmolarity of tears and the more severe the dry eye. Normal tear osmolarity ranges from 280 to 295 mOsm/L, which is equivalent to normal blood osmolarity (citation 5 from tear lab cards). Measurements >300 mOsm/L or an inter-eye difference >8 mOsm/L demonstrates loss of homeostatic osmolarity regulation. NIKBUT measures tear film stability by measuring the first and mean break-up times without the need for fluorescein.

The ocular redness score using Keratograph , and tear matrix metalloproteinase-9 (MMP-9) level, can suggest early ocular surface inflammation if positive. The oculus Keratograph scans the exposed bulbar conjunctiva and generates a bulbar redness (BR) score . The BR score range between 0.0 and 4.0. MMP-9 are proteolytic enzymes that play a role in wound healing and inflammation. They have been shown to be higher in tears of individuals with dry eye disease. The InflammaDry test is used to detect MMP-9 levels in the tear film. A positive result indicates the presence of MMP-9 ≥ 40 ng/ml.

We performed NIKBUT, which was reduced in both eyes (3.70 s in the right eye and 2.68 s in the left eye) which indicates rapid breakup of the tear film and is suggestive of early dry eye disease. The tear fluid osmolarity was high in both eyes (330 in the right eye and 315 in the left eye) suggestive of dry eye disease. The ocular redness score using Keratograph was 1.1 in the right eye and 0.8 in the left eye, which is also high normal and may suggest early ocular surface inflammation. MMP-9 was positive in both eyes suggestive of ocular surface inflammation.

How Do These Laboratory Tests Help You in Counseling and Treating This Patient?

Taken together, despite the clinical signs pointing to “none” ocular GVDH, the laboratory tests suggest that early dry eye disease and ocular surface inflammation may be present. Therefore it would be reasonable to initiate mild anti-inflammatory therapy to hopefully prevent development of overt signs and symptoms.

We suggested he perform warm compresses, start cyclosporine eye drops twice a day, and use artificial tears as needed. The patient needs to be followed up every 3 months to check for signs of ocular GVHD.

Case 2

CL is a 65-year-old female with history of chronic GVHD and dry eyes, referred for evaluation of ocular GVHD . She was diagnosed with multiple myeloma 2 years ago and underwent HSCT 4 and 10 months following her diagnosis. She was diagnosed with chronic GVHD because she had clinical signs of her skin, mouth, and eyes.

She experiences dry eyes in both eyes; however her right eye is worse than her left eye. She has eye discomfort, soreness, irritation, and redness. Her symptoms are worse in the morning and evenings. She uses lubricating drops at bedtime and wears contact lenses in both eyes during the day.

Her best corrected visual acuity is 20/20 in both eyes. She has minimal symptoms of ocular discomfort (OSDI = 2.08), severe tear deficiency in the right eye (Schirmer I = 0 mm), and borderline tear deficiency in the left eye (Schirmer I = 8 mm). Her corneal fluorescein staining showed moderate ocular surface disease (5 points OD, 2 points OS). She had extensive conjunctival staining of the right eye as well. Given these findings her disease severity is mild/moderate in both eyes (total points: 6 OD, 4 OS). In the presence of systemic chronic GVHD, these scores lead to a diagnosis of “definite” ocular GVHD in the right eye and “probable” ocular GVHD in the left eye.

We performed laboratory tests to see if she had other markers of dry eye disease and ocular inflammation. NIKBUT was reduced in both eyes (5.93 s OD and 2.48 s OS), which indicates rapid breakup of the tear film. The tear fluid osmolarity was high in both eyes (347 OD and 308 OS). Both of these tests are suggestive of dry eyes. The MMP-9 test was positive in both eyes, and the ocular redness score using Keratograph was 1.2 OD and 1.4 OS, which is also high—these tests are suggestive of ocular surface inflammation.

Why Are Her Ocular Symptoms Asymmetric?

Even though ocular GVHD is a systemic disease, patients can present with asymmetric symptoms and clinical signs. Both eyes are usually affected; however one eye can be more symptomatic and show more clinical signs. Studies have shown some patients with asymmetric disease have differences in their corneal nerve fiber density between both eyes. The morphological changes in corneal nerves also may explain the lack of correlation between signs and symptoms in dry eye patients [2].

Despite having less symptoms, a greater Schirmer I test, and decreased corneal staining in the left eye, her other laboratory tests suggested she had ocular inflammation in the left eye. Given the laboratory tests were very similar between the two eyes, her contact lenses could have been masking her symptoms in the left eye greater than the right eye. Soft contact lenses have been shown to decrease dry eye symptoms and improve visual acuity without significantly affecting the Schirmer test, tear break-up time, or corneal staining, in patients with ocular GVHD [3].

How Do You Treat This Patient, Given She Has Minimal Symptoms (OSDI = 2.08)?

A symptom sign disconnect in dry eye is very well known. She has definite ocular GVHD in the right eye and probable GVHD in the left eye, and laboratory tests suggest inflammation in both eyes. Therefore, aggressive control of inflammation is warranted in both eyes despite her mild symptoms.

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Jan 14, 2018 | Posted by in OPHTHALMOLOGY | Comments Off on Diagnosis and Management of Ocular Graft-Versus-Host Disease

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