What are the causes of pediatric Hemophagocytic Lymphohistiocytosis (HLH)?

Causes of Pediatric Hemophagocytic Lymphohistiocytosis (HLH)

Pediatric HLH is caused by either primary genetic defects affecting cytotoxic cell function or secondary triggers (infections, malignancies, autoimmune conditions) that provoke hyperinflammation, with primary genetic forms being more common in children than adults. 1

Primary (Genetic) HLH

Primary HLH results from hereditary defects that impair the ability of cytotoxic T lymphocytes and natural killer cells to kill target cells and properly terminate immune responses. 2

Familial HLH Types

• Familial HLH types 2-5 are caused by mutations in genes affecting perforin (PRF1), UNC13D, STX11, and STXBP2, with UNC13D variants being the most common (65% of familial cases in pediatric cohorts). 1, 3
• These mutations affect the transport, processing, and function of cytotoxic granules, leading to defective killing of target cells and failure to contract the immune response. 1, 2

Immunodeficiency Syndromes with HLH Predisposition

• Griscelli syndrome type 2 impairs cytotoxic granule function in NK cells and cytotoxic T lymphocytes, causing defective target cell killing. 1
• X-linked lymphoproliferative syndromes types 1 and 2 (XLP1, XLP2) are particularly associated with EBV-triggered HLH and lymphoma development, with 24% of XLP1 patients developing malignancy (usually Hodgkin lymphoma). 1
• Hypomorphic biallelic perforin mutations confer predisposition to both late-onset HLH and hematologic malignancies, particularly BCR-ABL positive acute lymphoblastic leukemia. 1

Important Genetic Considerations

• Biallelic gene mutations are diagnostic for primary HLH, though most variants identified are missense mutations rather than complete loss-of-function. 4, 3
• Heterozygous variants in HLH-related genes can be found in patients with secondary HLH, suggesting genetic predisposition may lower the threshold for developing HLH even with secondary triggers. 4, 3

Secondary (Acquired) HLH

Secondary HLH arises from immune triggers in patients without complete loss of cytotoxic function, though some may harbor unidentified genetic predispositions. 5

Infectious Triggers

• Epstein-Barr virus (EBV) is the most frequent viral trigger of secondary HLH in pediatric patients, identified in 65% of secondary HLH cases in one pediatric cohort. 1, 3
• Cytomegalovirus (CMV) is another common viral trigger of secondary HLH. 1
• Invasive fungi and bacterial infections can trigger HLH, especially in patients with chemotherapy-induced immunosuppression. 1

Malignancy-Associated HLH

• T-cell and NK-cell lymphomas or leukemias are the most common malignancy associations with HLH in pediatric patients. 1, 5
• B-cell lymphomas (including diffuse large B-cell lymphoma and Hodgkin lymphoma) are also associated with HLH. 1, 5
• Viral infections often act as co-triggers in malignancy-associated HLH, making it difficult to differentiate between malignancy-triggered HLH and HLH during chemotherapy when both conditions coexist. 1

Autoimmune/Autoinflammatory Disorders

• Systemic juvenile idiopathic arthritis can trigger macrophage activation syndrome (MAS), a form of HLH. 5
• Systemic lupus erythematosus and other autoimmune conditions can provoke HLH. 5
• Auto-inflammatory syndromes (such as those caused by MVK variants) can present with HLH-like features. 3

Iatrogenic Causes

• CAR T-cell therapy can induce HLH with an incidence of 3.5%. 5
• Chemotherapy-induced immunosuppression creates vulnerability to infections that subsequently trigger HLH. 1

Clinical Pitfalls and Diagnostic Considerations

• In male patients with lymphoma and EBV-driven HLH, genetic or flow cytometric analysis for XLP1 should be strongly pursued given the high malignancy risk and specific inheritance pattern. 1
• Co-triggers are common, with viral infections frequently acting as co-triggers in malignancy-associated HLH, complicating the clinical picture. 1
• The distinction between primary and secondary HLH is less straightforward than previously thought, as patients with apparent secondary HLH may harbor genetic variants that predispose to hyperinflammation. 4
• Rare presentations exist, including HLH with persistent rhabdomyolysis and regional ischemic immune myopathy, which can delay diagnosis. 6
• Genetic testing should be pursued in all pediatric HLH cases to identify primary forms requiring hematopoietic stem cell transplantation for cure. 3, 2