What is Hemophagocytic Lymphohistiocytosis (HLH)?

What is Hemophagocytic Lymphohistiocytosis (HLH)?

HLH is a life-threatening hyperinflammatory syndrome caused by excessive, uncontrolled activation of cytotoxic T cells, NK cells, and macrophages, resulting in a cytokine storm that leads to multi-organ damage and has high mortality if untreated. 1

Core Pathophysiology

HLH represents sustained but ineffective immune system activation where cytotoxic lymphocytes and macrophages become pathologically hyperactivated, releasing massive amounts of inflammatory cytokines (particularly interferon-γ, TNF-α, and IL-6) that cause progressive tissue damage despite the body's attempt to control the initial trigger. 2, 3 This excessive immune activation occurs because the normal mechanisms for contracting the immune response after eliminating a threat are impaired or overwhelmed. 4

Classification: Two Distinct Forms

Primary (Genetic) HLH

• Hereditary defects affecting cytotoxic function, including familial HLH types 2-5 (mutations in perforin, UNC13D, STX11, STXBP2), Griscelli syndrome type 2, and X-linked lymphoproliferative syndromes. 4
• Predominantly occurs in childhood but can present later with hypomorphic mutations. 1
• Requires hematopoietic stem cell transplantation for cure after initial disease control. 5

Secondary (Acquired) HLH

• Triggered by infections (most commonly EBV and CMV), malignancies (especially T-cell/NK-cell lymphomas), autoimmune conditions (macrophage activation syndrome), or chemotherapy-induced immunosuppression. 1, 4
• More common in adults and requires treatment of both the hyperinflammation and the underlying trigger. 6

Cardinal Clinical Features

The classic presentation includes: 1, 4

• Persistent high fever (often unresponsive to antibiotics)
• Hepatosplenomegaly (enlarged liver and spleen)
• Bi- or trilineage cytopenias (low blood cell counts affecting 2-3 cell lines)
• Neurological symptoms (altered mental status, seizures, focal deficits in 30-70% of cases)

Characteristic Laboratory Abnormalities

Key laboratory findings that distinguish HLH from other inflammatory conditions: 1, 4

• Markedly elevated ferritin (typically >500 μg/L, often >10,000 μg/L)
• Hypertriglyceridemia (elevated triglycerides)
• Hypofibrinogenemia (low fibrinogen, distinguishing it from sepsis where fibrinogen is usually elevated)
• Elevated soluble CD25 (IL-2 receptor alpha chain, reflecting T-cell activation)
• Elevated transaminases, LDH, and d-dimers
• Low or absent NK cell activity
• Decreased albumin and sodium

Formal Diagnostic Criteria (HLH-2004)

Diagnosis requires either molecular/genetic confirmation OR meeting 5 of these 8 criteria: 4, 7

1. Fever
2. Splenomegaly
3. Cytopenias affecting ≥2 lineages (hemoglobin <9 g/dL, platelets <100,000/μL, neutrophils <1,000/μL)
4. Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
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

Critical caveat: Hemophagocytosis itself is neither sensitive nor specific—it may be absent early in disease or present in other conditions like sepsis, so diagnosis relies on the constellation of findings, not just bone marrow pathology. 7

Why HLH is Diagnostically Challenging

The presentation mimics many common conditions: 6, 8

• Overlaps substantially with sepsis, severe infections, and multi-organ failure
• In malignancy patients, features overlap with disease progression or chemotherapy toxicity
• Non-specific symptoms delay recognition, yet early treatment is critical for survival

High index of suspicion is mandatory when: 6

• Fever persists despite appropriate antimicrobial therapy
• Cytopenias worsen unexpectedly
• Ferritin rises to extreme levels (>10,000 μg/L is highly suggestive)
• Coagulopathy develops with low fibrinogen (not typical of sepsis)

Prognosis and Urgency

Mortality remains extremely high without treatment: 7, 3

• 30-day survival in malignancy-associated HLH is only 56-70%
• Factors predicting worse outcomes include shock at ICU admission, platelets <30,000/μL, and T-cell lymphoma association
• Early recognition and prompt treatment are essential to prevent irreversible organ damage—delays of even days can be fatal

The rapidly progressive nature means HLH is a medical emergency requiring immediate intervention once suspected, even before all diagnostic criteria are formally met. 6, 5