Hemophagocytic Lymphohistiocytosis

• Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening immune disorder involving hyperinflammation.
• It results from uncontrolled activation of immune cells, leading to cytokine storm and widespread organ damage.
• Symptoms are diverse, often mimicking other severe infections, making early diagnosis challenging.
• Diagnosis relies on clinical criteria, specific laboratory markers, and sometimes genetic testing.
• Treatment involves intensive immunosuppression, chemotherapy, and potentially hematopoietic stem cell transplantation.

What is Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic Lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome resulting from a dysfunctional immune response. In HLH, certain immune cells, specifically T lymphocytes and macrophages, become overactive and fail to properly regulate their activity, leading to excessive production of inflammatory cytokines. This uncontrolled inflammation, often referred to as a “cytokine storm,” damages various organs throughout the body.

HLH can be classified into two main types: primary (or familial) and secondary. Primary HLH is typically genetic, often presenting in infancy or early childhood, though it can manifest later in life. Secondary HLH, which is more common, develops in response to other underlying conditions such as severe infections (viral, bacterial, fungal, parasitic), autoimmune diseases (e.g., juvenile idiopathic arthritis, systemic lupus erythematosus), or malignancies (e.g., lymphomas, leukemias). While rare, affecting an estimated 1 in 50,000 to 1 in 100,000 live births for the familial form, the overall incidence is likely higher when secondary cases are included, as reported by various reliable health organizations.

HLH Symptoms, Causes, and Diagnosis

Understanding HLH symptoms and causes is critical for early detection, as the condition often presents with non-specific signs that can mimic other severe illnesses. Common symptoms arise from systemic inflammation and include persistent fever, hepatosplenomegaly (enlarged liver and spleen), cytopenias (low blood cell counts affecting at least two cell lines), and neurological symptoms such as seizures or altered mental status. Other indicators may include skin rash, lymphadenopathy (enlarged lymph nodes), and jaundice.

The causes of HLH vary depending on whether it is primary or secondary. Primary HLH is caused by inherited genetic mutations that impair the immune system’s ability to properly regulate its response. These genetic defects often affect the perforin pathway, which is crucial for cytotoxic T cells and natural killer cells to eliminate infected or cancerous cells. Secondary HLH is triggered by a severe immune challenge in individuals who may or may not have an underlying genetic predisposition. Triggers include:

• Viral infections (e.g., Epstein-Barr virus, cytomegalovirus)
• Bacterial or fungal infections
• Autoimmune diseases (e.g., Still’s disease, lupus)
• Malignancies (e.g., lymphoma, leukemia)

The process of diagnosing hemophagocytic lymphohistiocytosis involves a combination of clinical evaluation, laboratory tests, and sometimes genetic analysis. Diagnosis is often based on fulfilling specific criteria, such as the HLH-2004 diagnostic criteria, which include clinical findings (fever, splenomegaly) and laboratory abnormalities (cytopenias, hypertriglyceridemia, hypofibrinogenemia, elevated ferritin, elevated soluble CD25, and absent or low natural killer cell activity). Bone marrow examination may reveal hemophagocytosis, where macrophages engulf other blood cells, though this finding is not always present and is not required for diagnosis. Genetic testing is essential for confirming primary HLH and identifying specific mutations.

Hemophagocytic Lymphohistiocytosis Treatment Options

A range of hemophagocytic lymphohistiocytosis treatment options are available, aiming to rapidly suppress the hyperinflammation and address the underlying cause. Treatment protocols are often intensive and require specialized medical care. The initial phase of treatment typically involves immunosuppressive therapy to control the runaway immune response. This often includes corticosteroids, etoposide (a chemotherapy agent), and cyclosporine. In some cases, monoclonal antibodies like anti-thymocyte globulin (ATG) or emapalumab (an interferon-gamma blocking antibody) may be used, particularly for refractory or severe cases.

For patients with primary HLH or those with recurrent secondary HLH, hematopoietic stem cell transplantation (HSCT) is often considered the only curative option. HSCT replaces the patient’s dysfunctional immune system with healthy stem cells from a donor. The decision to proceed with HSCT depends on various factors, including the specific genetic mutation, disease severity, and availability of a suitable donor. Supportive care, including antibiotics for infections, transfusions for cytopenias, and management of organ dysfunction, is also a crucial component of the overall treatment strategy.