What is Hemophagocytic Lymphohistiocytosis (HLH)?

What is Hemophagocytic Lymphohistiocytosis (HLH)?

HLH is a life-threatening hyperinflammatory syndrome caused by excessive activation of cytotoxic T cells, NK cells, and macrophages, resulting in uncontrolled immune system activation that damages multiple organ systems. 1

Pathophysiology

HLH represents a spectrum of immune dysregulatory disorders where defective cytotoxic function leads to sustained, aberrant activation of CD8+ T cells and resultant inflammatory cytokine release. 1, 2 This excessive immune activation drives the characteristic clinical and laboratory manifestations of the syndrome. 3

Classification

HLH is divided into two main categories:

• Primary (Genetic/Familial) HLH: Caused by mutations affecting lymphocyte cytotoxicity and immune regulation, including familial HLH 2-5, Griscelli syndrome type II, and X-linked lymphoproliferative syndromes. 1 This form predominantly occurs during childhood but can present in adolescents and young adults. 4

• Secondary (Acquired) HLH: More common in adults and triggered by specific conditions. 3 The most frequent triggers include:

  • Infections: Particularly viruses like Epstein-Barr virus (EBV) and cytomegalovirus (CMV) 1, 3
  • Malignancies: Especially lymphomas, with T-cell lymphomas carrying worse prognosis than B-cell lymphomas 4
  • Autoimmune/autoinflammatory disorders 1, 3

Clinical Manifestations

The cardinal clinical features include:

• Persistent high fever 3
• Hepatosplenomegaly 1, 3
• Bi- or trilineage cytopenias 3
• Neurological symptoms 3

Laboratory Abnormalities

Characteristic laboratory findings include:

• Elevated: Ferritin (often >10,000 μg/L is highly suspicious), triglycerides, soluble CD25 (IL-2 receptor), transaminases, lactate dehydrogenase, d-dimers 1, 4
• Decreased: Fibrinogen, albumin, sodium 1
• Low or absent NK cell activity 3

Diagnostic Criteria

The HLH-2004 diagnostic criteria require either a molecular diagnosis consistent with HLH OR at least 5 of the following 8 criteria: 3, 4

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. Soluble CD25 ≥2,400 U/mL

Important Diagnostic Caveats

• Hemophagocytosis alone is neither sensitive nor specific for HLH and may be present in other conditions such as septicemia. 4
• Hyperferritinemia >10,000 μg/L should always prompt consideration of HLH in the differential diagnosis in adults. 4
• The substantial overlap between HLH features and features of underlying malignancies makes identification particularly difficult in cancer patients. 1

Prognosis and Mortality

Mortality remains high, especially in adults with malignancy-associated HLH. 3 Key prognostic factors include:

• Shock at ICU admission 3
• Platelet count <30 g/L 3
• HLH associated with T-cell lymphomas (worse prognosis than B-cell lymphomas) 3, 4
• 30-day survival rates of 56-70% for malignancy-associated HLH 4
• Median overall survival of 36-230 days for malignancy-associated HLH 4

Early recognition and prompt treatment are essential to prevent irreversible organ damage and improve survival. 3