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Hemophagocytic Lymphohistiocytosis (HLH)

A life-threatening hyperinflammatory syndrome of cytokine storm and macrophage activation.

Written by: Saygı Hospital Health Guide Editorial Board
Last updated:

This content has been compiled by the Saygı Hospital Health Guide Editorial Board and is periodically reviewed by a specialist physician.

References (5)

This content is for informational purposes only and does not constitute medical advice. You can book an appointment at our Dahiliye (İç Hastalıkları) department. Book Appointment →

What is Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation in which uncontrolled T-lymphocyte and macrophage proliferation leads to massive cytokine release. Primary (familial) HLH results from genetic defects in cytotoxic granule perforin or trafficking pathways, while secondary HLH is triggered by infections (especially Epstein-Barr virus), malignancies (lymphomas), or autoimmune disease (macrophage activation syndrome).

Diagnosis requires either a known genetic mutation or fulfillment of five of eight HLH-2004 criteria: persistent fever, splenomegaly, cytopenia in two or more lineages, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis on bone marrow or lymph node biopsy, low or absent NK-cell activity, hyperferritinemia (>500 ng/mL, often >10,000), and elevated soluble CD25.

Treatment with the HLH-94 / HLH-2004 protocol combines etoposide, dexamethasone, and cyclosporine A. EBV-driven cases also receive rituximab. Trigger control (treatment of infection or malignancy) and allogeneic hematopoietic stem cell transplantation in genetic disease are essential. Mortality remains high (30-60 percent), so early recognition is critical.

Symptoms

Persistent unexplained fever
Hepatosplenomegaly
Bicytopenia or pancytopenia
Hyperferritinemia (often >10,000 ng/mL)
Coagulopathy and hypofibrinogenemia
Lymphadenopathy
Encephalopathy or seizures
Hyperbilirubinemia and transaminitis

Risk Factors

Inherited HLH gene mutations
Epstein-Barr virus infection
T-cell or NK-cell lymphoma
Systemic juvenile idiopathic arthritis (MAS)
Adult-onset Still disease
Immune-checkpoint inhibitor therapy
Underlying primary immunodeficiency

When to See a Doctor?

If you experience any of the following symptoms, seek medical attention promptly:

  • Fever lasting more than seven days
  • Cytopenia with massive splenomegaly
  • Ferritin level above 10,000 ng/mL
  • Sudden coagulopathy with bleeding
  • Encephalopathy in a febrile patient

Treatment Methods

01
Urgent admission to a tertiary hematology center
02
HLH-94 protocol: etoposide and dexamethasone
03
Cyclosporine A as adjunctive immunosuppression
04
Rituximab for EBV-driven HLH
05
Aggressive trigger therapy (antiviral, antineoplastic)
06
IL-1 or IL-6 blockade in macrophage activation syndrome
07
Allogeneic hematopoietic stem cell transplant in primary HLH

Which Department to Visit?

You can visit our Dahiliye (İç Hastalıkları) department for these complaints. Our specialist physicians will create the most suitable treatment plan for you.

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Health Disclaimer: The information on this page is prepared for general informational purposes only. It does not replace medical diagnosis and treatment. Please consult your physician for your complaints. Saygı Hospital does not accept responsibility for actions taken based on the information on this page.