Keratitis Sicca (Ocular Graft‑Versus‑Host Disease)

Overview

Keratitis sicca, also called dry‑eye disease secondary to ocular graft‑versus‑host disease (oGVHD), is an inflammatory condition of the ocular surface that occurs when donor immune cells attack the recipient’s eye tissues after an allogeneic hematopoietic stem‑cell transplant (HSCT). The resulting immune‑mediated damage reduces tear production, disrupts the tear film, and leads to chronic inflammation of the conjunctiva and cornea.

While any patient undergoing HSCT can develop oGVHD, it most commonly affects:

• Adults aged 30‑65 years (median onset 6‑12 months post‑transplant)
• Patients receiving peripheral blood stem cells or bone‑marrow grafts from unrelated donors
• Individuals with a prior history of acute GVHD involving the skin, liver or gastrointestinal tract

Worldwide, the incidence of chronic GVHD after allogeneic HSCT ranges from 30‑70 %^[1]. Of those, ocular involvement occurs in 40‑60 % of chronic GVHD cases, and keratitis sicca is the most frequent manifestation.^[2]

Symptoms

Symptoms may be mild at first but often progress if untreated. Typical ocular complaints include:

• Dryness or gritty sensation – a feeling of sand in the eye.
• Burning or stinging – especially after prolonged visual tasks.
• Foreign‑body sensation – even when nothing is present.
• Redness (conjunctival hyperemia) – often bilateral.
• Photophobia – discomfort in bright light.
• Blurred vision – can fluctuate throughout the day.
• Excessive tearing (reflex tearing) – paradoxically occurs as a response to dryness.
• Eye fatigue – difficulty keeping eyes open for reading or screen use.
• Mucous or stringy discharge – from damaged goblet cells.
• Crusting or eyelid adhesions – especially upon waking.
• Sensitivity to wind or air conditioning.

Because oGVHD is systemic, many patients experience concurrent skin, oral, or genital dryness, which can help clinicians suspect ocular involvement.

Causes and Risk Factors

Pathophysiology

After HSCT, donor T‑lymphocytes recognize host antigens as foreign and mount an immune attack. In oGVHD, the ocular surface becomes a target:

1. Immune-mediated lacrimal gland injury – reduces aqueous tear secretion.
2. Conjunctival goblet‑cell loss – diminishes mucin layer, destabilizing the tear film.
3. Meibomian gland dysfunction – alters lipid layer, increasing evaporation.
4. Direct inflammation of corneal epithelium – leads to keratocyte apoptosis and ulceration.

Major Risk Factors

• Allogeneic HSCT (especially with unrelated donors).
• History of acute GVHD (skin, liver, gut) – increases likelihood of chronic ocular disease.
• Female donor to male recipient mismatch (higher allo‑immune reactivity).
• Pre‑existing autoimmune dry‑eye disease (e.g., Sjögren’s syndrome).
• Older age (≥50 years) – natural decline in tear production.
• Use of systemic steroids or immunosuppressants that mask early ocular signs.
• Prolonged use of topical ophthalmic preservatives (e.g., benzalkonium chloride).

Diagnosis

Diagnosis is clinical but supported by objective testing. A multidisciplinary approach—hematology/oncology together with ophthalmology—is recommended.

History & Physical Examination

• Detailed ocular symptom inventory (using OSDI or DEQ‑5 questionnaires).
• Assessment for systemic GVHD signs (skin, liver, GI).
• Slit‑lamp examination to visualize corneal staining, conjunctival hyperemia, and lid margin changes.

Key Diagnostic Tests

Test	What It Measures	Typical Findings in Keratitis Sicca (oGVHD)
Schirmer I test (without anesthesia)	Aqueous tear production (mm/5 min)	≤5 mm = severe tear deficiency
Phenol red thread test	Rapid tear volume (mm/15 sec)	Reduced length
Tear Break‑Up Time (TBUT)	Stability of tear film	≤5 seconds (unstable)
Fluorescein & Lissamine Green staining	Corneal and conjunctival epithelial damage	Patchy or diffuse staining graded by Oxford scheme
Meibography	Structure of meibomian glands	Dropout or truncation indicative of dysfunction
In‑vivo confocal microscopy	Cellular‑level imaging of cornea & conjunctiva	Inflammatory infiltrates, nerve fiber loss
Serum biomarkers (e.g., IL‑6, TNF‑α)	Systemic inflammation	Elevated in active GVHD, but not routine

When the clinical picture is unclear, a conjunctival biopsy can demonstrate lymphocytic infiltration, confirming GVHD involvement.

Treatment Options

Treatment aims to restore tear film, suppress ocular surface inflammation, and prevent vision‑threatening complications. Therapy is usually staged—from lubricants to systemic immunomodulation.

1. Lubrication & Protective Measures

• Preservative‑free artificial tears – 4–6 times daily; choose high‑viscosity formulations at night.
• Ophthalmic ointments (e.g., cyclosporine‑free lubricating ointment) – applied before sleep.
• Moisture‑chamber goggles – especially in dry environments.
• Punctal plugs (silicone or collagen) – block tear drainage; consider reversible plugs for early disease.

2. Anti‑Inflammatory Topicals

• Corticosteroid eye drops (e.g., prednisolone acetate 1 %) – short‑term for acute flares; monitor IOP.
• Topical calcineurin inhibitors – Cyclosporine A 0.05 % (Restasis®) or 0.1 % (Cequa®); Lifitegrast 5 % (Xiidra®) for chronic inflammation.
• Topical corticosteroid‑sparing agents – e.g., loteprednol etabonate 0.5 % (low‑potency, safe for longer use).

3. Systemic Immunomodulation (for moderate‑severe oGVHD)

• Systemic corticosteroids – initial high dose tapering schedule.
• Calcineurin inhibitors – oral tacrolimus or cyclosporine; monitor renal function.
• Mycophenolate mofetil – often combined with steroids.
• Ruxolitinib – JAK1/2 inhibitor; FDA‑approved for steroid‑refractory chronic GVHD (including ocular).
• Extracorporeal photopheresis (ECP) – useful for resistant ocular disease.

Systemic therapy should be coordinated with the transplant team, as it influences overall GVHD management.

4. Procedural Interventions

• Amniotic membrane transplantation (AMT) – promotes epithelial healing in severe keratitis.
• Upper and lower eyelid tarsorrhaphy – temporary closure to protect cornea.
• Autologous serum eye drops – contain growth factors; 20‑30 % concentration, used 4–6 times daily.
• Platelet‑rich plasma (PRP) drops – emerging therapy with promising early data.

5. Lifestyle & Environmental Adjustments

• Humidifiers (≥40 % relative humidity) in home/office.
• Avoid direct air‑flow from fans, vents, or car A/C.
• Take regular “blink breaks” during screen use – 20‑20‑20 rule.
• Wear wrap‑around sunglasses outdoors to reduce evaporation.
• Stay hydrated (≥2 L water per day) and maintain omega‑3 fatty‑acid intake (fish oil or flaxseed).

Living with Keratitis Sicca (ocular graft‑versus‑host disease)

Chronic eye disease after HSCT can be frustrating, but a structured routine can improve quality of life.

Daily Management Checklist

1. Morning: Clean eyelids with warm compresses (5 min) and gentle lid scrub.
2. Apply preservative‑free artificial tears (4–5 drops) before and after each screen session.
3. Mid‑day: Re‑apply drops and perform a quick blink exercise (10 slow blinks).
4. Evening: Use lubricating ointment before bed; if prescribed, insert punctal plugs.
5. Weekly: Review medication schedule with ophthalmologist; note any new redness, pain, or vision change.
6. Monthly: Attend ophthalmology follow‑up for slit‑lamp exam and tear‑film testing.

Psychosocial Support

• Join a GVHD support group (online or in‑person) – sharing experiences reduces anxiety.
• Consider counseling if chronic symptoms affect mood or sleep.
• Coordinate care with a transplant survivorship clinic for holistic management.

Prevention

While graft‑versus‑host disease cannot be completely avoided, several strategies lower the risk of ocular involvement:

• Early prophylactic use of preservative‑free lubricants after HSCT (within 1 month).
• Prompt treatment of acute GVHD skin or gut flares—reduces progression to chronic disease.
• Minimize exposure to known dry‑eye triggers (smoke, wind, low humidity).
• Choose mydriatic‑free, preservative‑free topical meds whenever possible.
• Regular ophthalmic screening: baseline exam before transplant and at 3, 6, and 12 months post‑HSCT, then annually (or sooner if symptoms arise).

Complications

If left untreated, keratitis sicca can lead to serious ocular sequelae:

• Corneal epithelial breakdown → persistent erosions.
• Corneal ulceration – risk of infection and scarring.
• Neovascularization – abnormal vessels compromising corneal clarity.
• Scarring and irregular astigmatism – permanent vision loss.
• Secondary bacterial, fungal, or viral keratitis – requires urgent antimicrobial therapy.
• Conjunctival fibrosis – restricts eye movement.
• Reduced quality of life – chronic pain, photophobia, and reading difficulties.

When to Seek Emergency Care

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References:

1. Jagasia MH, et al. "National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft‑Versus‑Host Disease." *Biol Blood Marrow Transplant.* 2015;21(3):389‑401. PMCID: PMC6610600
2. Cleveland Clinic. "Ocular Graft‑Versus‑Host Disease." 2023. Cleveland Clinic
3. Mayo Clinic. "Dry Eye (Keratitis Sicca)." 2022. Mayo Clinic
4. World Health Organization. "Guidelines for the Management of Chronic Graft‑Versus‑Host Disease." 2021. WHO Publication
5. National Eye Institute (NEI). "Understanding Dry Eye Disease." 2022. NEI
6. Rogers BK, et al. "Ocular GVHD: Update on Pathogenesis and Treatment." *Ophthalmology.* 2020;127(4):556‑573.