Risk Factors for Hemophagocytic Lymphohistiocytosis (HLH)
HLH risk factors fundamentally divide into genetic predisposition (primary HLH) and acquired triggers (secondary HLH), with the latter being far more common in adults and driven primarily by infections, malignancies, and autoimmune diseases. 1
Primary (Genetic) Risk Factors
Germline bi-allelic loss-of-function mutations in genes essential for cytolytic granule formation and release represent the core genetic risk:
- PRF1 (perforin)
- UNC13D (MUNC13-4)
- STX11 (syntaxin 11)
- STXBP2 (syntaxin-binding protein 2)
These mutations result in markedly reduced or absent CD8 T-cell and NK-cell-mediated killing, creating the immunologic foundation for primary HLH. 1 While familial HLH predominantly affects children, it can present in adolescents and young adults. 2
Secondary (Acquired) Risk Factors
Infectious Triggers
Infections are the dominant trigger for secondary HLH in adults, with specific pathogens carrying particularly high risk:
- Epstein-Barr virus (EBV): The most common infectious trigger, identified in 57.1% of infection-associated HLH cases 3, 4
- Leishmania: Emerging as a significant pathogen (14.3% of cases) 3
- Other viral, bacterial, fungal, and parasitic infections 2, 1
Malignancy-Associated Risk Factors
Hematological malignancies represent the primary cause of HLH in adults with fever of unknown origin (6.4% incidence). 5 Lymphomas pose particularly high risk, with L-HLH representing a life-threatening complication requiring urgent recognition. 6
History of malignant disease is an independent risk factor for adverse outcomes in infection-associated HLH. 3, 4
Autoimmune/Autoinflammatory Triggers
Autoimmune disorders can trigger macrophage activation syndrome (MAS-HLH), particularly:
- Idiopathic inflammatory myopathies (dermatomyositis, polymyositis, clinically amyopathic dermatomyositis) with 4.2% HLH prevalence 7
- Systemic lupus erythematosus
- Adult-onset Still's disease
- Other rheumatic conditions 2, 1
Clinical Risk Factors for Developing HLH
When evaluating patients with potential HLH triggers, specific clinical and laboratory features predict higher risk:
In Fever of Unknown Origin Patients:
- Skin rash
- Elevated alanine aminotransferase (ALT)
- Elevated total bilirubin
- Elevated triglycerides
- Elevated lactate dehydrogenase (LDH)
- Elevated ferritin 5
In Inflammatory Myopathy Patients:
- Higher on-admission disease activity
- Acute exacerbation of interstitial lung disease (AE-ILD)
- Concurrent infection 7
In Pediatric Populations:
- Prolonged fever duration
- Elevated serum ferritin
- Elevated D-dimer
- Decreased fibrinogen
- Elevated triglycerides
- Younger age at onset 8, 9
Critical Pitfalls in Risk Assessment
Do not overlook leishmaniasis as an emerging infectious trigger, particularly in endemic areas or travelers, as it is associated with protracted time to diagnosis and severe disease courses. 3
Recognize that secondary HLH in adults lacks the bi-allelic mutations characteristic of primary HLH, but patients may still harbor heterozygous variants or other genetic susceptibilities that lower the threshold for hyperinflammation when exposed to strong immunologic triggers. 1
Understand that infection-associated HLH carries intermediate mortality (39.3%) compared to autoimmune-triggered HLH (better prognosis) and paraneoplastic HLH (worse prognosis), making trigger identification essential for risk stratification. 3
Monitor patients with elevated soluble IL-2 receptor (sIL2R) >6,000 IU/mL and thrombocytopenia <40 G/L closely, as these predict adverse outcomes and increased bleeding risk in infection-associated HLH. 3 Patients with elevated sIL2R:ferritin ratios warrant assessment for occult malignancy. 3