Primary and Secondary Hemophagocytic Lymphohistiocytosis¶

Chapter 68 | Part 2: Cardinal Manifestations and Presentation of Diseases

KEY CLINICAL POINTS¶

HLH is a life-threatening condition characterized by uncontrolled inflammation, hypercytokinemia, and multiorgan failure.
Primary HLH is genetic (e.g., familial HLH, XLP, Griscelli syndrome) while secondary HLH is acquired (infections, malignancies, autoimmune diseases).
Diagnosis requires fulfillment of at least 5 of 8 HLH-2004 criteria, including fever, cytopenias, organomegaly, and elevated ferritin/sIL-2R.
Treatment includes etoposide, corticosteroids, HSCT for primary HLH, and targeted therapy for secondary HLH.
Early diagnosis is critical due to high mortality and potential CNS complications.

1. DEFINITION & OVERVIEW¶

Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening condition characterized by uncontrolled inflammation, hypercytokinemia, and multiorgan failure. It exists in primary (genetic) and secondary (acquired) forms. Primary HLH is Mendelian-inherited, while secondary HLH is triggered by infections, malignancies, or autoimmune diseases. HLH is often described as a cytokine storm involving IFN- γ , IL-1 β , IL-6, and TNF- α . The clinical presentation is similar across forms, with sepsis-like inflammation, cytopenias, and organ failure.

Table 68-1 Simplified Classification of Hemophagocytic Lymphohistiocytosis (HLH)¶

Category	Conditions
Primary HLH: Mendelian Conditions	FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX11), FHL5 (STXBP2), XLP1 (SH2D1A), Griscelli syndrome type 2 (RAB27A), Chédiak-Higashi syndrome (LYST), XLP2 (BIRC4), NLRC4, Lysinuric protein intolerance (SLC7A7), Wolman disease (LIPA)
Secondary HLH (Non-Mendelian)	Infection-associated HLH, Virus-associated HLH, Bacteria-associated HLH, Parasite-associated HLH, Fungal-associated HLH, Malignancy-associated HLH, Autoimmune-associated HLH (MAS-HLH), HLH with SoJIA, HLH with SLE, HLH with vasculitis, Transplant-associated HLH

1.1 Primary vs. Secondary HLH¶

Primary HLH is genetic (e.g., familial HLH, XLP, Griscelli syndrome) and typically affects children. Secondary HLH is acquired and more common in adults, often triggered by infections, malignancies, or autoimmune diseases. Both forms share similar clinical features but differ in etiology and management.

1.2 Diagnostic Criteria¶

Diagnosis requires fulfillment of at least 5 of 8 HLH-2004 criteria: fever, splenomegaly, bicytopenia, hypertriglyceridemia/hypo-fibrinogenemia, hemophagocytosis, ferritin ≥ 500 µg/L, sIL-2R ≥ 2400 U/mL, and NK cell dysfunction. The HScore system is used for secondary HLH.

2. EPIDEMIOLOGY¶

Familial HLH (FHL) has an incidence of 1 in 50,000 live births, with 10–20% of cases presenting in adolescence/adulthood. Secondary HLH is more common in adults, with infections (50%), malignancies (48%), and autoimmune diseases (13%) as leading triggers. Annual incidence of malignancy-associated HLH is 6.2 per million adults in Sweden.

2.1 Risk Factors¶

Genetic mutations in PRF1, UNC13D, STX11, STXBP2, or RAB27A increase risk of primary HLH. Secondary HLH is associated with infections (viral/bacterial), malignancies (lymphomas, leukemias), and immunosuppression (HIV, chemotherapy).

2.2 Demographics¶

Primary HLH predominantly affects children, while secondary HLH is more common in adults. FHL is autosomal recessive, more prevalent in consanguineous populations. Secondary HLH can occur in all ages but is most common in adults.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

Primary HLH is caused by genetic defects in cytotoxic T cell function (PRF1, UNC13D, STXBP2, STX11) leading to uncontrolled inflammation. Secondary HLH results from triggers like infections (EBV, HIV), malignancies, or autoimmune diseases, causing cytokine storm and hyperinflammation. IFN- γ plays a pivotal role in both forms.

3.1 Genetic Defects¶

FHL is autosomal recessive, caused by mutations in PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), STXBP2 (FHL5), or RAB27A (Griscelli syndrome). These defects impair cytotoxic granule exocytosis and NK cell function.

3.2 Pathophysiology¶

Defective cytotoxic T cell function leads to uncontrolled activation of CD8+ T cells and macrophages, resulting in cytokine storm (IFN- γ , IL-1 β , IL-6, TNF- α ). This causes hemophagocytosis, organ failure, and multiorgan dysfunction.

4. CLINICAL FEATURES¶

HLH presents with fever, cytopenias (thrombocytopenia, anemia, neutropenia), hepatosplenomegaly, and CNS involvement. Secondary HLH resembles sepsis with unresponsive inflammation. Neurological symptoms (seizures, ataxia, coma) are common in FHL. Laboratory findings include elevated ferritin, sIL-2R, and hypertriglyceridemia.

4.1 Symptoms and Signs¶

Fever, splenomegaly, hepatomegaly, cytopenias, and CNS symptoms (seizures, ataxia, meningismus). Infections (EBV, HIV) or malignancies may be present. Disseminated intravascular coagulation and jaundice are common.

4.2 Complications¶

Multiorgan failure, CNS damage, endocrinopathies, and long-term neurological sequelae (psychomotor retardation, epilepsy). Secondary HLH may mimic sepsis with disproportionate inflammatory markers.

5. DIFFERENTIAL DIAGNOSIS¶

HLH must be differentiated from sepsis, autoimmune diseases (SLE, Still’s disease), viral infections (EBV, HIV), and malignancies. Key differentiators include persistent fever, cytopenias, and elevated ferritin/sIL-2R without infection or malignancy.

6. INVESTIGATIONS & DIAGNOSIS¶

Diagnostic workup includes CBC, ferritin, sIL-2R, liver enzymes, and bone marrow biopsy for hemophagocytosis. HLH-2004 criteria and HScore are used. Genetic testing confirms primary HLH. Flow cytometry assesses NK cell function.

6.1 Laboratory Tests¶

Elevated ferritin (>500 µg/L), sIL-2R (>2400 U/mL), hypertriglyceridemia, hypo-fibrinogenemia, and hyperbilirubinemia. Bone marrow shows hemophagocytosis in 50–70% of cases.

6.2 Imaging and Biopsy¶

MRI for CNS involvement, liver biopsy for chronic hepatitis-like changes. Bone marrow biopsy confirms hemophagocytosis. Flow cytometry assesses NK cell activity.

7. MANAGEMENT & TREATMENT¶

Treatment includes etoposide, corticosteroids, and HSCT for primary HLH. Secondary HLH requires addressing the trigger (infection/malignancy) and immunosuppressive therapy. JAK inhibitors and IL-1/IL-6 blockers are used in refractory cases.

7.1 Primary HLH¶

Allogeneic HSCT is curative. Pretransplant therapy with etoposide, dexamethasone, and rituximab. Immunosuppressive agents (cyclosporin A, IVIG) may be used for mild cases.

7.2 Secondary HLH¶

Treat underlying cause (infection/malignancy). Use HLH-2004 protocol: etoposide, corticosteroids, and rituximab. JAK inhibitors (ruxolitinib) and IL-1/IL-6 blockers (anakinra, tocilizumab) are adjuncts.

7.3 Special Cases¶

EBV-HLH: Treat with etoposide and rituximab. Mal-HLH: Prioritize malignancy treatment. Autoimmune HLH (MAS): Use corticosteroids and IL-1/IL-6 inhibitors.

8. PROGNOSIS & COMPLICATIONS¶

Untreated FHL is rapidly fatal (median survival 1–2 months). Early treatment improves survival (80–90% with HSCT). Long-term complications include neurologic sequelae (25% psychomotor retardation, 10% epilepsy), endocrinopathies, and organ failure.

8.1 Survival Rates¶

FHL: 85–90% survival with HSCT. Secondary HLH: 70–80% survival with etoposide-based therapy. Asymptomatic siblings have near 100% survival.

8.2 Late Effects¶

Neurological deficits (ataxia, hemiplegia), endocrinopathies, and chronic fatigue. Secondary HLH may lead to irreversible CNS damage if untreated.

9. SPECIAL CONSIDERATIONS¶

Pregnancy: Avoid immunosuppressive drugs. Pediatrics: Early diagnosis critical. Elderly: Higher mortality due to comorbidities. Autoimmune diseases (SLE, Still’s disease) may mimic HLH. Transplant patients: Monitor for EBV reactivation.

9.1 Pregnancy¶

Avoid corticosteroids and immunosuppressants. HSCT is contraindicated in pregnancy. Autoimmune HLH (MAS) is linked to SLE, Still’s disease, and vasculitis. Treat with corticosteroids, IL-1/IL-6 inhibitors, and address underlying autoimmune disease.

10. KEY POINTS & CLINICAL PEARLS¶

Diagnose HLH using HLH-2004 criteria ( ≥ 5/8) and HScore. 2. Primary HLH requires HSCT; secondary HLH needs trigger-specific treatment. 3. Early intervention is critical to prevent multiorgan failure. 4. Monitor ferritin and sIL-2R for disease severity. 5. EBV-HLH responds to etoposide and rituximab. 6. Avoid immunosuppressants in pregnancy. 7. Neurological symptoms are common in FHL and may be the first presentation.