What is Hemophagocytic Lymphohistiocytosis (HLH)?

What is Hemophagocytic Lymphohistiocytosis (HLH)?

HLH is a life-threatening hyperinflammatory syndrome caused by uncontrolled activation of cytotoxic T cells, natural killer (NK) cells, and macrophages, resulting in excessive cytokine release and a characteristic constellation of fever, hepatosplenomegaly, cytopenias, and specific laboratory abnormalities. 1

Pathophysiology

HLH results from sustained, aberrant immune activation where cytotoxic cells fail to effectively eliminate target cells and terminate the immune response. 2 This leads to:

• Excessive activation of cytotoxic CD8+ T lymphocytes, NK cells, and macrophages that produce massive amounts of inflammatory cytokines, creating a "cytokine storm" 1, 3
• Inability of the immune system to shut down after responding to infections, resulting in progressive hyperinflammation 4
• Hemophagocytosis (phagocytosis of blood cells by activated macrophages) in bone marrow and other tissues, though this finding is not required for diagnosis 5

Classification: Primary vs. Secondary HLH

Primary (Genetic/Familial) HLH

Primary HLH is caused by hereditary defects in genes controlling cytotoxic cell function, predominantly affecting children. 6 Key genetic forms include:

• Familial HLH types 2-5: mutations in perforin (PRF1), UNC13D, STX11, and STXBP2 genes that impair cytotoxic granule release 6
• Griscelli syndrome type 2: defective cytotoxic granule trafficking in NK cells and T cells 6
• X-linked lymphoproliferative syndromes (XLP1, XLP2): particularly associated with EBV-triggered HLH and lymphoma development 6

Secondary (Acquired) HLH

Secondary HLH occurs in response to specific triggers in individuals without primary genetic defects, and is more common in adults. 6 Major triggers include:

• Infections: EBV and CMV are the most frequent viral triggers; invasive fungi and bacteria can also precipitate HLH, especially in immunosuppressed patients 6
• Malignancies: T-cell and NK-cell lymphomas/leukemias are most commonly associated; B-cell lymphomas (DLBCL, Hodgkin lymphoma) also occur 6
• Autoimmune/autoinflammatory diseases: termed Macrophage Activation Syndrome (MAS) when occurring in this specific context 7
• Chemotherapy-induced immunosuppression: creates vulnerability to infections that trigger HLH 6

Clinical Manifestations

Cardinal Clinical Features

• Persistent high fever (often unresponsive to antibiotics) 6
• Hepatosplenomegaly (enlarged liver and spleen) 1
• Bi- or trilineage cytopenias (low blood cell counts affecting 2-3 cell lines) 6
• Neurological symptoms (altered mental status, seizures, focal deficits) 6, 5

Characteristic Laboratory Abnormalities

• Markedly elevated ferritin (≥500 μg/L, often >10,000 μg/L) 1, 6
• Hypertriglyceridemia (elevated triglycerides) 1
• Hypofibrinogenemia (low fibrinogen, indicating coagulopathy) 1
• Elevated soluble CD25 (IL-2 receptor alpha chain) 1
• Elevated transaminases, lactate dehydrogenase, and d-dimers 1
• Decreased albumin and sodium 1
• Low or absent NK cell activity 6

Diagnostic Criteria

The HLH-2004 diagnostic criteria require either molecular diagnosis consistent with HLH OR at least 5 of the following 8 criteria: 6

1. Fever
2. Splenomegaly
3. Cytopenias (affecting ≥2 cell lines)
4. Hypertriglyceridemia and/or hypofibrinogenemia
5. Hemophagocytosis in bone marrow, spleen, or lymph nodes
6. Low or absent NK cell activity
7. Ferritin ≥500 μg/L
8. Elevated soluble CD25

Important caveat: These criteria were developed for pediatric populations and have not been formally validated in adults, though they remain the diagnostic standard. 3

Clinical Course and Prognosis

• HLH is a medical emergency requiring rapid diagnosis and aggressive treatment to prevent irreversible organ damage and death 8, 6
• Mortality remains high, especially in adults with malignancy-associated HLH 6
• Factors associated with higher mortality: shock at ICU admission, platelet count <30 g/L, and HLH associated with T-cell lymphomas 8, 6
• The disease can have variable presentations: while typically rapidly progressive, some cases may have a slow, smoldering course that delays diagnosis 5

Key Diagnostic Pitfalls

• Substantial overlap between HLH features and features of underlying malignancies makes identification difficult when HLH occurs in cancer patients 1
• Initial bone marrow biopsy may be negative for hemophagocytosis, requiring repeat evaluation if clinical suspicion remains high 5
• Patients may not initially meet full diagnostic criteria, necessitating serial reassessment when clinical suspicion is present 5
• Co-triggers are common: viral infections often act as co-triggers in malignancy-associated HLH, making it difficult to differentiate between malignancy-triggered HLH and HLH during chemotherapy 6