Hemophagocytic Lymphohistiocytosis (HLH)



High mortality without prompt recognition and management. HLH is a critical diagnostic consideration in febrile illness with cytopenias and organ dysfunction.



1. What is HLH?

• Definition: HLH is a life-threatening hyperinflammatory syndrome caused by uncontrolled activation of the immune system.

• Key Characteristics: Persistent fever, organ dysfunction, cytopenias, hepatosplenomegaly.

• Prognosis: Fatal if untreated; early recognition and treatment are essential.

• In all patients with the HLH syndrome, a search for and treatment of the underlying trigger (or triggers) is crucial; if the trigger is difficult to find in an adult, it is often a cancer.



2. Types of HLH

• Primary (Familial) HLH:

   - Genetic basis: Autosomal recessive mutations.

   - Onset: Usually in infancy or early childhood.

   - Associated genes: PRF1, UNC13D, STX11, STXBP2

• Secondary (Acquired) HLH:

   - Common in: Adults.

   - Triggers:

    ▪ Infections (e.g., EBV)

    ▪ Malignancies

    ▪ Autoimmune diseases (often termed MAS-HLH: Macrophage Activation Syndrome)



3. Clinical Presentation

• Common Signs and Symptoms:

   - Persistent high fever

   - Splenomegaly

   - Cytopenias (anemia, thrombocytopenia, neutropenia)

   - Hyperferritinemia

   - Elevated liver enzymes

   - Coagulopathy



4. Pathophysiology

• Immune dysregulation: Impaired cytotoxic function of NK cells and CD8+ T cells.

• Cytokine storm: Overproduction of pro-inflammatory cytokines (e.g., IFN-γ, TNF, IL-6).

• Tissue damage: Due to uncontrolled immune activation and hemophagocytosis.



5. Diagnostic Criteria - Diagnosis requires 5 of 8 HLH-2004 criteria or a molecular diagnosis: HScore

  a. Fever  

  b. Splenomegaly  

  c. Cytopenias (≥2 lineages)  

  d. Hypertriglyceridemia and/or hypofibrinogenemia  

  e. Hemophagocytosis in bone marrow/spleen/lymph nodes  

  f. Low/absent NK-cell activity  

  g. Ferritin ≥500 μg/L (often >10,000 μg/L in HLH)  

  h. Elevated soluble IL-2 receptor (sCD25)



6. Treatment Approach

• Initial management: Immunosuppression (e.g., dexamethasone, etoposide).

• Treat underlying trigger: Infections, malignancy, autoimmune disorder.

• Curative option for familial HLH: Hematopoietic stem cell transplantation (HSCT).

• Emerging therapies: JAK inhibitors, anti-IFN-γ antibodies (e.g., emapalumab).



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