Disease Overview 

Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening immune disorder characterized by excessive activation and proliferation of histiocytes and lymphocytes, leading to uncontrolled inflammation and tissue damage. 

Etiology

This condition can occur in both children and adults, though it is more commonly diagnosed in infants and young children. The estimated incidence of HLH is approximately 1 to 2 cases per million individuals per year.HLH can be classified into two main forms: primary (genetic/familial) HLH, which is inherited due to mutations affecting immune regulation genes, and secondary HLH, which is triggered by infections, autoimmune diseases, malignancies, or certain medications. Primary HLH typically presents in infancy or early childhood, whereas secondary HLH can occur at any age.

Evaluation/Diagnosis

Diagnosis of HLH involves fulfilling diagnostic criteria established by the Histiocyte Society, which include clinical signs (fever, hepatosplenomegaly, cytopenias), biochemical abnormalities (elevated ferritin, triglycerides, liver enzymes), and evidence of hemophagocytosis (engulfment of blood cells by activated macrophages) in bone marrow, spleen, or lymph nodes. Genetic testing is crucial for confirming primary HLH.

Clinical Presentation

Clinical presentation varies widely but often includes persistent fever, hepatosplenomegaly, jaundice, cytopenias (low blood cell counts), and signs of multiorgan dysfunction such as neurological symptoms, respiratory distress, and coagulopathy. Prompt diagnosis and treatment initiation are critical due to the rapid progression and high mortality associated with HLH.

Management

Management of HLH involves a combination of immunosuppressive therapy to suppress hyperinflammation and treatment of the underlying trigger. Initial therapy typically revolves around high-dose corticosteroids, such as dexamethasone or methylprednisolone, which suppress cytokine production and immune cell activation. These are administered intravenously at first and then tapered based on clinical response. Etoposide, a cytotoxic agent, is often combined with corticosteroids to further inhibit macrophage function and reduce cytokine release, especially in severe cases or those unresponsive to steroids alone. Another crucial agent, cyclosporine A, acts as a calcineurin inhibitor, targeting T-cell activation and cytokine release, particularly beneficial in primary HLH or refractory secondary cases. In cases resistant to initial treatments, anti-thymocyte globulin (ATG) may be employed to deplete T lymphocytes, modulating the immune response. Rituximab, targeting CD20-positive B lymphocytes, is used in select cases, particularly when B-cell dysregulation contributes to the disease pathogenesis. The combination of these therapies aims to achieve disease control by addressing the underlying immune dysregulation and cytokine storm characteristic of HLH. Close monitoring and adjustment of therapy are essential to manage potential side effects and optimize treatment outcomes.

Non-pharmacological approaches focus on supportive care, including close monitoring for signs of disease progression, infection prevention strategies, and addressing specific complications such as coagulopathy or organ failure. Long-term management involves regular follow-up to monitor disease remission, manage potential relapses, and address late effects of treatment or transplantation.