Types of Hemophagocytic Lymphohistiocytosis
HLH is classified into two main types: Primary (genetic/familial) HLH and Secondary (acquired) HLH, with the secondary form further subdivided based on the underlying trigger. 1
Primary (Genetic/Familial) HLH
Primary HLH is caused by inherited mutations affecting lymphocyte cytotoxicity and immune regulation 2. This form:
- Predominantly occurs in children but can present in adolescents and young adults 1
- Includes several genetically heterogeneous conditions:
- Familial HLH types 2-5
- Griscelli syndrome type II
- X-linked lymphoproliferative syndromes 2
- Results from mutations in genes involved in the T cell and NK cell cytotoxicity pathway 3
Secondary (Acquired) HLH
Secondary HLH is by far the most common form in adults 1 and represents a group of disorders triggered by various conditions rather than a stand-alone disease entity 2.
Subtypes Based on Trigger:
1. Infection-Associated HLH
- Most frequent trigger overall 2
- Particularly associated with:
- Epstein-Barr virus (EBV)
- Cytomegalovirus (CMV)
- Other viral infections 2
2. Malignancy-Associated HLH
- Can occur in two distinct scenarios 2:
- Malignancy-Triggered HLH: Presenting feature at disease onset or relapse
- HLH During Chemotherapy: Occurs during or shortly after chemotherapeutic treatment, frequently with an infectious trigger in the setting of immunosuppression 2
3. Macrophage Activation Syndrome (MAS-HLH)
- A specific subset arising on a background of systemic auto-inflammation/autoimmunity 1
- Should be restricted to patients with:
- Still's disease
- Systemic lupus erythematosus
- Vasculitis
- Other related autoimmune systemic diseases 1
- Treatment may differ from other forms of secondary HLH, justifying its separate classification 1
Key Clinical Distinction
All HLH types share a common terminal pathway of hyperferritinemic hyperinflammation but have different pathogenetic roots 1. This distinction is critical because:
- Primary HLH typically requires definitive hematopoietic stem cell transplantation
- Secondary HLH treatment focuses on controlling inflammation while addressing the underlying trigger
- MAS-HLH may respond better to treatments targeting the autoimmune/autoinflammatory process
The blurred distinction between primary and secondary HLH has become increasingly recognized with improved genetic sequencing, revealing that many cases previously classified as secondary HLH actually have underlying genetic predispositions 4. This supports conceptualizing HLH as a threshold disease where genetic and environmental factors interact to trigger uncontrolled inflammation 4.