What is Hemophagocytic Lymphohistiocytosis (HLH)?

From the Guidelines

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells, characterized by excessive immune system activation, severe inflammation, and potential for multiple organ failure. This condition can be primary (genetic/familial) or secondary (acquired due to infections, malignancies, or autoimmune disorders) 1. The symptoms of HLH include persistent high fever, enlarged liver and spleen, cytopenia (low blood cell counts), high ferritin levels, liver dysfunction, and neurological abnormalities 1.

Key Characteristics of HLH

• Excessive immune system activation
• Severe inflammation throughout the body
• Potential for multiple organ failure
• Can be primary (genetic/familial) or secondary (acquired)
• Symptoms include fever, enlarged liver and spleen, cytopenia, high ferritin levels, liver dysfunction, and neurological abnormalities

Diagnosis and Treatment

The diagnosis of HLH in adults is challenging due to the lack of validated diagnostic criteria, and the presentation may be similar to sepsis or multiple organ dysfunction syndrome 1. Treatment typically involves immunosuppressive therapy with dexamethasone and etoposide according to the HLH-94 or HLH-2004 protocols, along with treating any underlying triggers 1. The decision to start HLH-directed treatment depends on clinical judgment and assessment of organ function, and individualized modified HLH-94–like treatment has been suggested in secondary HLH (sHLH) 1.

Management Considerations

• Pulsed corticosteroids and elements of HLH-94 may be used
• Etoposide dose reduction is recommended if renal function is impaired
• Addition of IV immunoglobulin (IVIG) may be considered for its anti-inflammatory potential
• Anakinra may reduce mortality in sepsis patients with macrophage activation syndrome (MAS) features 1
• Weekly reevaluation of the need for continued etoposide therapy is recommended 1

From the Research

Definition and Characteristics of Hemophagocytic Lymphohistiocytosis (HLH)

• HLH is a rare, life-threatening, hematologic disorder characterized by extreme inflammation and unregulated immune activation 2, 3, 4, 5, 6.
• It is manifested by clinical findings such as fevers, hepatomegaly or splenomegaly, and bi- or trilineage cytopenias 2.
• Elevated liver enzymes, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia are commonly seen in HLH patients 2, 5, 6.

Forms and Triggers of HLH

• HLH can occur in both congenital (primary) and adult (secondary) forms 2.
• It can be triggered by infections, malignancies, or autoimmune diseases 3, 5, 6.
• In some cases, the underlying cause of HLH may not be identified 6.

Clinical Presentation and Diagnosis

• The initial presentation of HLH often mimics other diseases, making diagnosis challenging 3, 5.
• Common features of HLH include fever, splenomegaly or hepatomegaly, hyperferritinemia, cytopenias, coagulopathies, abnormal liver enzymes, and hypertriglyceridemia 5.
• Diagnosis is established based on laboratory and bone marrow biopsy findings 3, 6.
• Tools such as the HScore, HLH-2004/2009, and hyperferritinemia thresholds can be used to risk-stratify patients 5.

Treatment and Prognosis

• Treatment of HLH typically involves immunosuppressive therapy, such as glucocorticoids and etoposide 3, 6.
• In some cases, targeted therapy, such as emapalumab, may be used 4.
• Despite aggressive treatment, the prognosis for HLH is often poor, with high mortality rates ranging from 20% to 80% 5, 6.