Hemophagocytic Lymphohistiocytosis

By SWA

In short:

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by excessive immune activation and severe inflammation. It occurs when the body's immune system becomes overactive, leading to widespread cytokine release, often referred to as a "cytokine storm."

Key Features of HLH:

  1. Cytokine-mediated hyperinflammation – The immune system produces excessive inflammatory cytokines (such as interferon-γ, TNF-α, and IL-6), leading to severe immune dysregulation.
  2. Fever – Persistent high fever is a hallmark symptom due to uncontrolled inflammation.
  3. Pancytopenia – A reduction in all types of blood cells (red cells, white cells, and platelets) due to bone marrow dysfunction and immune-mediated destruction.
  4. Hemophagocytosis – A process in which activated macrophages engulf and destroy blood cells in the bone marrow, spleen, and liver.
  5. Often fatal – If left untreated, HLH can rapidly progress to multi-organ failure and death.

Causes of HLH:

  • Primary (familial HLH, fHLH) – Genetic mutations in immune regulatory genes (e.g., PRF1, UNC13D, STX11) lead to impaired cytotoxic function of natural killer (NK) cells and cytotoxic T lymphocytes.
  • Secondary HLH – Triggered by infections (especially Epstein-Barr virus), malignancies (such as lymphoma), autoimmune diseases (macrophage activation syndrome in systemic juvenile idiopathic arthritis), or certain medications.

Treatment Approaches:

  1. Anti-inflammatory agents – Steroids (such as dexamethasone) help suppress the hyperinflammatory response.
  2. Etoposide (VP-16) – A chemotherapy agent that selectively destroys hyperactivated immune cells, particularly cytotoxic T cells and macrophages.
  3. Interferon-γ antibody (e.g., emapalumab) – Blocks interferon-γ, a key driver of inflammation in HLH, thereby reducing immune activation.
  4. Other supportive treatments – Immunosuppressive agents (cyclosporine), intravenous immunoglobulin (IVIG), and, in severe cases, hematopoietic stem cell transplantation (for genetic HLH).

Early diagnosis and aggressive treatment are critical, as untreated HLH has a very high mortality rate.

Reference: https://www.nejm.org/doi/full/10.1056/NEJMra2314005

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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