Causes of Hemophagocytic Lymphohistiocytosis (HLH)
HLH is fundamentally divided into primary (genetic) and secondary (acquired) forms, with secondary HLH triggered by infections (particularly EBV and CMV), malignancies (especially T-cell/NK-cell lymphomas and Hodgkin lymphoma), autoimmune/autoinflammatory conditions, or occurring during chemotherapy-induced immunosuppression. 1, 2
Primary (Genetic) HLH
Hereditary defects that predispose to primary HLH include: 1
- Familial HLH types 2-5 (mutations affecting perforin, UNC13D, STX11, STXBP2)
- Griscelli syndrome type 2
- Chediak-Higashi syndrome
- X-linked lymphoproliferative syndromes types 1 and 2 (XLP1, XLP2) - XLP1 is particularly associated with EBV-triggered HLH and lymphoma development 1
- Other immunodeficiencies including MAGT1, ITK, and CD27 deficiencies 1
Primary HLH predominantly occurs in childhood but is increasingly recognized in adolescents and adults. 1 These genetic defects impair cytotoxic granule function in NK cells and cytotoxic T lymphocytes, leading to defective killing of target cells and failure to contract the immune response. 3, 4
Secondary (Acquired) HLH
Infectious Triggers
Viral infections are the most frequent triggers of secondary HLH: 1, 2
- Epstein-Barr virus (EBV) - the most common viral trigger 1
- Cytomegalovirus (CMV) 1, 5
- HIV-associated infections 5
- Invasive fungi and bacterial infections - particularly in chemotherapy-induced immunosuppression 1
Malignancy-Associated HLH
Malignancy-Triggered HLH occurs most frequently with: 1
- T-cell and NK-cell lymphomas or leukemias - most common malignancy association 1
- Diffuse large B-cell lymphoma (DLBCL) 1
- Hodgkin lymphoma 1, 6
Malignancy can trigger HLH through two distinct scenarios: as a presenting feature at disease onset or relapse, or during/after chemotherapeutic treatment while patients are frequently in remission. 1 Malignant cells may secrete cytokines (including interferon-γ and interleukin-6) that contribute to hyperinflammation. 1
HLH During Chemotherapy
Chemotherapy-induced immunosuppression creates vulnerability to infections that trigger HLH, with invasive fungi and bacterial infections playing a substantial role beyond the typical viral triggers. 1 This was first recognized in patients receiving immunosuppressive treatment after kidney transplantation. 1
Autoimmune/Autoinflammatory Conditions
Macrophage activation syndrome (MAS) represents HLH occurring in the context of rheumatic diseases and other autoimmune/autoinflammatory disorders. 2, 7, 8, 3
Important Clinical Considerations
In male patients with lymphoma and EBV-driven HLH, genetic or flow cytometric analysis for XLP1 should be strongly considered, as 24% of XLP1 patients develop 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
Co-triggers are common - viral infections may act as co-triggers in malignancy-associated HLH, and it is often difficult to differentiate between malignancy-triggered HLH and HLH during chemotherapy when both malignancy reactivation and infection coexist. 1