What is Hemophagocytic Lymphohistiocytosis (HLH)?

What is Hemophagocytic Lymphohistiocytosis (HLH)?

HLH is a life-threatening hyperinflammatory syndrome characterized by excessive, uncontrolled activation of cytotoxic T cells, natural killer cells, and macrophages, resulting in a cytokine storm that causes multi-organ damage and high mortality if not promptly recognized and treated. 1, 2

Core Pathophysiology

HLH represents a failure of immune system regulation where cytotoxic lymphocytes and macrophages become persistently activated but cannot effectively eliminate their targets, leading to sustained inflammatory cytokine release. 1, 3 This results in:

• Uncontrolled proliferation of activated T cells and macrophages that infiltrate organs, particularly the liver, spleen, bone marrow, and central nervous system 1, 2
• Massive cytokine release (interferon-gamma, TNF-alpha, IL-6, IL-18) driving systemic inflammation 3
• Hemophagocytosis (macrophages engulfing blood cells) in bone marrow, spleen, or lymph nodes, though this finding is neither sensitive nor specific 2, 4

Classification: Two Distinct Forms

Primary (Genetic) HLH

• Hereditary defects in cytotoxic cell function, including familial HLH types 2-5 (mutations in perforin, UNC13D, STX11, STXBP2), Griscelli syndrome type 2, and X-linked lymphoproliferative syndromes 2
• Predominantly occurs in childhood but can present later with hypomorphic mutations 2
• Requires hematopoietic stem cell transplantation for cure after stabilization with chemotherapy 5

Secondary (Acquired) HLH

• Triggered by infections (especially Epstein-Barr virus and cytomegalovirus), malignancies (particularly T-cell and NK-cell lymphomas), or autoimmune/autoinflammatory diseases 1, 2
• More common in adults than primary HLH 4, 3
• Treatment focuses on addressing the underlying trigger while controlling hyperinflammation 5, 2

Cardinal Clinical Features

The clinical presentation includes:

• Persistent high fever (often >38.5°C) that is unresponsive to antibiotics 2, 4
• Hepatosplenomegaly (enlarged liver and spleen) 1, 2
• Bi- or trilineage cytopenias (anemia, thrombocytopenia, neutropenia) 2, 4
• Neurological symptoms in 30-70% of cases, ranging from irritability and seizures to altered mental status 2

Characteristic Laboratory Abnormalities

HLH produces a distinctive laboratory signature:

• Extreme hyperferritinemia (typically >500 μg/L, often >10,000 μg/L) 2, 4
• Hypertriglyceridemia (≥265 mg/dL) and hypofibrinogenemia (≤150 mg/dL) 2
• Elevated soluble CD25 (IL-2 receptor alpha chain, >2,400 U/mL) 2
• Elevated transaminases, lactate dehydrogenase, and d-dimers 1
• Low or absent NK cell activity 2
• Decreased albumin and sodium 1

Diagnostic Criteria (HLH-2004)

Diagnosis requires either:

1. Molecular diagnosis consistent with HLH (genetic mutations), OR
2. At least 5 of 8 clinical/laboratory criteria: fever, splenomegaly, cytopenias (≥2 lineages), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen/lymph nodes, low/absent NK cell activity, ferritin ≥500 μg/L, elevated soluble CD25 2

Critical pitfall: The diagnostic criteria were developed for pediatric primary HLH and may be less sensitive in adults with secondary HLH, where the presentation can be more subtle or overlap with the underlying trigger. 2, 4 A high index of suspicion is essential, as delayed diagnosis significantly increases mortality. 5, 4

Why Early Recognition Matters

• Mortality remains 20-40% even with treatment, and approaches 100% without treatment 3
• Irreversible organ damage (particularly neurological) occurs rapidly once HLH is established 5, 2
• The syndrome mimics sepsis, multiorgan failure, and other critical illnesses, leading to diagnostic delays 6, 7
• Shock at ICU admission, platelet count <30 g/L, and malignancy-associated HLH are associated with the highest mortality 5, 2

Distinguishing MAS from Other HLH Forms

Macrophage Activation Syndrome (MAS) is a specific subtype of secondary HLH that occurs exclusively in patients with underlying autoimmune/autoinflammatory diseases (systemic juvenile idiopathic arthritis, adult-onset Still's disease, systemic lupus erythematosus). 8 While MAS and other forms of HLH share the same terminal hyperinflammatory pathway, they have different pathogenetic roots and treatment implications. 8