Ocular manifestations of hemophagocytic lymphohistiocytosis (HLH)

Key Points at a Glance

Key Points of This Disease

• HLH (hemophagocytic lymphohistiocytosis) is a rare multi-organ disease caused by immune dysregulation and may involve ocular symptoms.
• The most common ocular symptom is retinal hemorrhage (55 out of 152 patients, 36%).
• Cases where ocular symptoms precede systemic symptoms have been reported in familial HLH.
• Known causative genes for familial HLH include PRF1, UNC13D, STX11, and STXBP2.
• Diagnosis uses the HLH-2004 criteria (meeting 5 out of 8 items).
• There is no specific treatment for ocular symptoms; systemic treatment (etoposide, dexamethasone, cyclosporine) is the mainstay.
• Untreated familial HLH is fatal within 1–2 months after diagnosis. The mortality rate for secondary HLH in adults is high at 41–75%.

1. Ocular Symptoms of Hemophagocytic Lymphohistiocytosis (HLH)

HLH (hemophagocytic lymphohistiocytosis) is a rare multi-organ disease caused by immune dysregulation. It is characterized by excessive activation of macrophages and histiocytes, which phagocytose the body’s own blood cells.

HLH is broadly classified into two types.

• Familial HLH (primary HLH): Caused by genetic mutations in PRF1, UNC13D, STX11, STXBP2, etc. The mean age at diagnosis is 1.8 years, with early onset common. The incidence is reported as 1 to 225 per 300,000 births. ¹⁾
• Secondary HLH (acquired HLH): Triggered by infections (most commonly EBV), autoimmune diseases, malignancies, or drugs (e.g., immune checkpoint inhibitors). ^{2, 3, 4, 5)} The mean age at diagnosis is approximately 50 years.

Characteristics of HLH patients with ocular symptoms (aggregated from a literature review of 152 patients) are shown below.

• Mean age at ocular symptom onset: 30.21±14.42 years
• Sex: male 62%, female 38%
• Breakdown: familial 14, secondary 138

Q What is the most common ocular symptom in HLH?

A

In a literature review of 152 patients, retinal hemorrhage was the most common, occurring in 55 patients (36%). This was followed by conjunctivitis (approximately 22%), keratitis (approximately 10%), and optic disc swelling (10%).

2. Main symptoms and clinical findings

Subjective Symptoms

The following subjective symptoms have been reported as ocular manifestations associated with HLH.

• Decreased visual acuity: Caused by retinal hemorrhage, serous retinal detachment, optic nerve lesions, etc.
• Eye pain and redness: Due to complications of conjunctivitis, keratitis, or uveitis.
• Diplopia and strabismus: Occur when ocular motility disorders develop. A case of acute esotropia (15 prism diopters) as the initial symptom in PRF1-related familial HLH has been reported. ¹⁾
• Eyelid swelling: Due to infiltration around the orbit and eyelids.

Clinical Findings

The main findings confirmed by ophthalmic examination are shown by site.

Site	Main Findings
Posterior segment (retina)	Retinal hemorrhage (36%), serous retinal detachment (7%), perivascular sheathing
Optic nerve	Optic disc swelling (10%)
Anterior segment	Conjunctivitis (approx. 22%), keratitis (approx. 10%)
Eye movement	Abduction limitation, slow saccadic and pursuit movement disorders

In a case of familial HLH (11-year-old boy, PRF1 mutation), fluorescein fundus angiography (FFA) showed localized vascular leakage corresponding to perivascular sheathing, and no ischemia was confirmed. Macular OCT was normal. ¹⁾

Histopathologically, histiocytic infiltration is observed in the trabecular meshwork and choroid.

Q Can ocular symptoms precede systemic symptoms?

A

Yes. In PRF1-related familial HLH, cases have been reported where acute esotropia and intermediate uveitis (snowballs, perivascular sheathing) appeared as initial symptoms, preceding systemic symptoms. ¹⁾ Ophthalmic evaluation is also important during systemic workup for HLH.

3. Causes and Risk Factors

Causes of HLH

• Familial: PRF1 (perforin), UNC13D, STX11, and STXBP2 gene mutations are the main causes. In a multicenter study in Saudi Arabia (25 cases), PRF1 mutation was the most frequent. ¹⁾
• Infectious (secondary): EBV infection is the most common pathogen. EBV encephalitis-associated HLH complicating childhood SLE has also been reported. ⁴⁾
• Drug-induced (secondary): HLH caused by immune checkpoint inhibitors (ICIs) has been reported. There is a case report of atezolizumab-induced HLH. ³⁾
• Autoimmune disease-associated (secondary): Occurs in association with SLE, adult-onset Still’s disease, etc. HLH onset in SLE patients receiving IFN-alpha has also been reported. ⁵⁾

Risk factors for ocular complications

Wang et al. identified ocular abnormalities in 133 of 1,525 patients (approximately 39%). The following are listed as risk factors for ocular complications.

• Advanced age
• Comorbid autoimmune disease
• Erythrocytopenia
• Thrombocytopenia
• Elevated fibrinogen (Fib)

Specialist supplement

Thrombocytopenia directly causes retinal hemorrhage. Increased vascular permeability due to cytokine excess is involved in the mechanism of serous retinal detachment. Ophthalmic evaluation is an important component in the management of HLH.

4. Diagnosis and Testing Methods

HLH-2004 Diagnostic Criteria

The HLH-2004 criteria are used for the diagnosis of HLH. Diagnosis is made when 5 or more of the following 8 items are met. ^{1, 2, 4)}

1. Fever
2. Splenomegaly
3. Cytopenia (affecting ≥2 lineages): Hb <9 g/dL, PLT <100×10⁹/L, Neu <1.0×10⁹/L
4. Hypertriglyceridemia (TG ≥3.0 mmol/L) or hypofibrinogenemia (Fib ≤1.5 g/L)
5. Hemophagocytosis in bone marrow, spleen, or lymph nodes
6. Decreased or absent NK cell activity
7. Hyperferritinemia (≥500 μg/L)
8. Elevated sIL-2R (≥2400 IU/mL)

HLH-2004 Criteria

Target: Diagnostic criteria mainly used for familial HLH and pediatric cases.

Sensitivity: Requires fulfillment of 5 or more out of 8 items.

Molecular diagnosis: Definitive diagnosis is possible by identifying mutations such as PRF1 c.1081A>T p.(Arg361Trp). ¹⁾

H-score

Target: A scoring tool useful for adult and secondary HLH (reactive hemophagocytic syndrome).

Cutoff: 138–169 points. A cutoff of 169 points yields 90% correct classification. ³⁾

Features: Supports diagnosis probabilistically based on clinical and laboratory findings.

Ophthalmic Examination

Ophthalmic examination includes the following:

• Slit-lamp microscopy: Evaluation of anterior chamber inflammation and corneal findings
• Dilated fundus examination: Confirmation of retinal hemorrhage, optic disc swelling, and perivascular sheathing
• Fluorescein angiography (FFA): Assessment of vascular leakage and ischemia¹⁾
• Optical coherence tomography (OCT): Evaluation of macular morphology
• OCT angiography (OCTA) and ICGA: Detailed assessment of vascular structure

Systemic examination

If HLH is suspected, the following systemic examinations are important.

• Genetic testing (WES): Identification of mutations in PRF1, UNC13D, etc.¹⁾ Whole-exome sequencing is useful for diagnosis in PRF1-related familial HLH.
• MRI: Evaluation of neurological HLH. T2/FLAIR hyperintensity and contrast enhancement may be observed. ¹⁾
• Bone marrow biopsy: Confirmation of hemophagocytosis

5. Standard treatment

There is no specific treatment for ocular symptoms. Ocular symptoms improve with systemic treatment of HLH. ¹⁾

Familial HLH (children)

The HLH-2004 protocol is the standard treatment.

• Remission induction: dexamethasone (10 mg/m²/day) + etoposide + monthly IVIG (17 weeks) ¹⁾
• Intrathecal methotrexate (MTX): added for neurological HLH
• Hematopoietic stem cell transplantation (HSCT): required for long-term remission. Performed after remission induction. ¹⁾

In a case of PRF1-related HLH, the patient did not respond to intravenous methylprednisolone, IVIG, and plasma exchange, so the regimen was switched to the HLH-2004 protocol, and the patient was transferred for HSCT after 17 weeks. In this case, ocular findings remained stable during the course, and no progression of posterior segment findings was observed. ¹⁾

Secondary HLH (adult)

• Basic regimen: steroids + IVIG + etoposide + cyclosporine (CsA) ²⁾
• Example (SLE complication): methylprednisolone pulse 200 mg/day × 5 days + etoposide 100 mg × 3/week (cumulative 1000 mg) + CsA 50 mg twice daily⁵⁾
• ICI-induced HLH case: dexamethasone 20 mg + tocilizumab 8 mg/kg + anakinra + MMF + etoposide 100 mg/m²³⁾
• EBV-associated HLH cases: IVIG + CsA + prednisolone⁴⁾

Novel Targeted Therapy

• ruxolitinib (JAK1-2 inhibitor): may be effective in blocking cytokine signaling³⁾
• anakinra (IL-1 inhibitor): expected to have anti-inflammatory effects³⁾
• tocilizumab (IL-6 inhibitor): used to control cytokine storm ³⁾
• emapalumab (anti-IFN-γ antibody): being studied for application in familial HLH ¹⁾

Treatment considerations

• Long-term steroid use requires caution for steroid-induced glaucoma.
• Untreated familial HLH is fatal within 1–2 months after diagnosis. Early treatment initiation is essential.
• Mortality rate for adult secondary HLH is 41–75%, with a median overall survival of 4 months reported in a US cohort (n=68). ²⁾

Q Is there specific treatment for ocular symptoms?

A

There is no specific treatment for ocular symptoms. Systemic treatment for HLH (HLH-2004 protocol mainly with etoposide, dexamethasone, and cyclosporine) also improves ocular symptoms. ¹⁾ However, caution is needed for steroid-induced glaucoma due to long-term steroid use.

6. Pathophysiology and Detailed Pathogenesis

Ocular complications of HLH are thought to occur through the following mechanisms.

Cytokine Storm and Immune Dysregulation

• Overproduction of Th1 cytokines: IFN-γ, TNF-α, IL-6, IL-10, IL-12, and sIL-2R are markedly elevated.
• Persistent activation of CD8⁺ T cells: Continues due to immune dysregulation.
• PRF1 deficiency (familial HLH): Perforin dysfunction prevents cytotoxic T cells from killing target cells, leading to persistent abnormal immune activation. ¹⁾

Effects on Ocular Tissues

• Retinal hemorrhage: Mainly caused by thrombocytopenia (platelet count <100×10⁹/L).
• Serous retinal detachment: Caused by cytokine-induced increased vascular permeability and histiocyte infiltration into the choroid.
• Perivascular sheathing: Inflammatory changes due to lymphocytic and histiocytic infiltration around blood vessels. ¹⁾
• Optic disc swelling: due to increased intracranial pressure or histiocytic infiltration around the optic nerve.
• Histopathological findings: histiocytic infiltration of the trabecular meshwork and choroid has been confirmed in autopsy cases.

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7. Latest Research and Future Perspectives (Investigational Reports)

For Patients: Please Read

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Understanding the Actual State of Ocular Complications through Large-Scale Screening

Wang et al. (2023) conducted a screening study of 1,525 individuals and reported that 133 (approximately 39%) had ocular abnormalities. Risk factors for ocular complications included advanced age, autoimmune disease, erythrocytopenia, thrombocytopenia, and elevated fibrinogen.

Report of a Case with Initial Ocular Symptoms in PRF1-Related Familial HLH

Alzuabi et al. (2025) reported an 11-year-old boy with a homozygous missense mutation (c.1081A>T p.(Arg361Trp)) in the PRF1 gene who presented with acute esotropia (15 prism diopters) and intermediate uveitis (snowballs, perivascular sheathing) preceding systemic symptoms. ¹⁾ This case suggests that ocular symptoms can be the initial and only manifestation of HLH.

Development of Novel Targeted Therapies

Rubio-Perez et al. (2022) reported a case of atezolizumab-induced HLH treated with a multi-target regimen including ruxolitinib, anakinra, and tocilizumab, achieving a therapeutic response. ³⁾ Cytokine-targeted therapies such as JAK inhibition, IL-1 inhibition, and IL-6 inhibition are being studied as new approaches for steroid-resistant HLH.

Emapalumab (anti-IFN-γ monoclonal antibody) is expected to be indicated for familial HLH, and its main mechanism of action is being studied as control of cytokine storm through blockade of the IFN-γ pathway. ¹⁾

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8. References

1. Alzuabi アカントアメーバ角膜炎, et al. Ocular inflammation as first presenting feature of PRF1-associated familial hemophagocytic lymphohistiocytosis: a case report and literature review. BMC Ophthalmol. 2025;25:394.
2. Wi W, et al. Secondary hemophagocytic lymphohistiocytosis associated with heat stroke: a case report. Medicine. 2023;102(21):e33842.
3. Rubio-Perez J, et al. Treatment-related hemophagocytic lymphohistiocytosis due to atezolizumab. J Med Case Rep. 2022;16:365.
4. Cheawcharnpraparn K, et al. Epstein-Barr virus encephalitis associated hemophagocytic lymphohistiocytosis in childhood-onset systemic lupus erythematosus. Pediatr Rheumatol. 2024;22:98.
5. Zeng Z, et al. Interferon-alpha induced systemic lupus erythematosus complicated with hemophagocytic lymphohistiocytosis. Front Immunol. 2023;14:1223062.