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Hemophagocytic lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic syndrome, is a clinicopathologic syndrome encompassing a markedly dysregulated immune response and hypercytokinemia characterized clinically by fever, splenomegaly, and cytopenias, and histologically by hemophagocytosis.

  • Type of cytokine storm syndrome

Aetioclassification

Primary HLH “familial haemophagocytic lymphohistiocytosis (FHL)“

Heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity.

  • Genetic subtypes:
    • FHL1: HPLH1
    • FHL2: PRF1 (Perforin)
    • FHL3: UNC13D (Munc13-4)
    • FHL4: STX11 (Syntaxin 11)
    • FHL5: STXBP2 (Syntaxin binding protein 2)/UNC18-2

Secondary HLH “acquired haemophagocytic lymphohistiocytosis“

Occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy

  • Associated malignant disorders:
    • T cell lymphoma, B cell lymphoma, ALL, AML, and myelodysplastic syndrome.
  • Associated non-malignant disorders:
    • Autoimmune disorders: Juvenile idiopathic arthritis (JIA), juvenile Kawasaki disease, SLE, Still’s disease (juvenile onset and adult onset forms), and rheumatoid arthritis
    • Immunodeficiency disorders: SCID, DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, and dyskeratosis congenita
    • Infections: Epstein-Barr virus (EBV) (40% of HLH), cytomegalovirus (CMV), viral hepatitis, acute HIV seroconversion, bacteria, protozoa, and fungi

Complication of:

  • Chediak-Higashi syndrome
  • After EBV infection in patients with X-linked lymphoproliferative syndrome

Clinical features

Common symptoms:

  • Fever & splenomegaly (M/C clinical signs)
  • Hepatomegaly, lymphadenopathy, jaundice, and maculopapular rash

CNS manifestations:

  • Encephalopathy
  • Meningismus
  • Seizures

Diagnosis

Diagnostic criteria

Molecular diagnosis consistent with HLH:

  • eg. Pathologic mutations of PRF1, UNC13D or STX11 are identified)

or

5 out of 8 criteria listed below:

  1. Fever
  2. Splenomegaly
  3. Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood):
    • Hemoglobin <9 g/100 ml (in infants <4 weeks: hemoglobin <10 g/100 ml)
    • Platelets <100 × 103/ml
    • Neutrophils <1 × 103/ml
  4. Hypertriglyceridemia (fasting, ≥ 265 mg/100 ml)
    and/or
    hypofibrinogenemia (≤150 mg/100 ml)
  5. Hemophagocytosis (in BM, spleen or lymph nodes)
  6. Low/absent NK cell activity
  7. Ferritin ≥ 500 ng/ml
  8. Soluble CD25 (that is, soluble IL-2 receptor) >2400 U/ml (or per local reference laboratory)

Histopathology

  • Hemophagocytosis (pathologic finding of activated macrophages, engulfing erythrocytes, leukocytes, platelets, and their precursor cells)
    • Seen in bone marrow, spleen, and lymph nodes and (rarely) in CNS & skin.
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Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal syndrome despite treatment. It is caused by a dysregulation in natural killer T-cell function, resulting in activation and proliferation of histiocytes with uncontrolled hemophagocytosis and cytokine overproduction. HLH can be either primary, with a genetic etiology, or secondary, associated with malignancies, autoimmune diseases, or infections. There is sparse literature on HLH cases associated with granulomatosis with polyangiitis (GP). Here, we report a 59-year-old woman, with a medical history of GP, chronic anemia, and rapidly progressive glomerulonephritis, who presented with weakness, fatigue, dysuria, cough, and fever with chills for 2 weeks. She developed neutropenia with a white blood cell count of 500/μL and hemoglobin level of 5.1 g/dL, with elevated ferritin levels (>40 000 ng/mL), low haptoglobin level, and increased triglyceride level of 2.66 mmol/L. Bone marrow aspirate and biopsy showed increased histiocytes with intracytoplasmic erythroid precursors, red blood cells, and hemosiderin pigment consistent with hemophagocytic syndrome (panels A-B). Iron stain and CD68 showed histiocytes (panels C-D). The patient was treated with dexamethasone and died within 4 days. Autopsy findings showed arterial thromboemboli with infarcted lungs, liver, and spleen. | Matsuoka, M. (2005). Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL). Retrovirology, 2(1), 27. https://doi.org/10.1186/1742-4690-2-27

Management

  • High-dose corticosteroids
  • Etoposide
  • Cyclosporin
  • IV Ig
  • Methotrexate and vincristine
  • Cytokine targeted therapy
    • Anti-IFN-gamma monoclonal antibody emapalumab (Gamifant)
      • Treatment of pediatric and adult primary HLH

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