What is secondary hemophagocytic lymphohistocytosis (sHLH)?

Secondary Hemophagocytic Lymphohistiocytosis (sHLH)

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory syndrome characterized by uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in excessive cytokine production and can rapidly progress to death without early treatment. 1, 2

Definition and Pathophysiology

• sHLH represents a cytokine storm triggered by various conditions rather than a standalone diagnosis 2
• Distinguished from primary (familial) HLH by its association with underlying triggers:
  • Infections (particularly viral, like EBV)
  • Malignancies (especially lymphomas)
  • Rheumatic diseases (termed macrophage activation syndrome or MAS in this context)
  • Immunosuppressive medications (including CAR T-cell therapy) 1, 3
• Core pathogenic mechanism: aberrant activation of cytotoxic CD8+ T cells leading to excessive inflammatory cytokine release 4

Diagnostic Criteria

HLH diagnosis requires meeting at least 5 of the following 8 criteria as established by the Histiocyte Society 1:

1. Fever
2. Splenomegaly
3. Cytopenias (affecting ≥2 cell lines)
4. Hypertriglyceridemia and/or hypofibrinogenemia
5. Hemophagocytosis (in bone marrow, spleen, lymph nodes)
6. Low or absent NK cell activity
7. Ferritin ≥500 ng/mL (often markedly elevated)
8. Elevated soluble CD25 (IL-2 receptor)

Clinical Presentation

• Presents as a sepsis-like syndrome with:

  • Persistent high fever
  • Hepatosplenomegaly
  • Neurological changes
  • Liver dysfunction (elevated transaminases)
  • Renal dysfunction
  • Respiratory failure (including pulmonary edema, ARDS)
  • Coagulopathy 1, 5, 6

• Laboratory findings typically include:

  • Bi- or trilineage cytopenias
  • Hyperferritinemia (often markedly elevated)
  • Hypertriglyceridemia
  • Hypofibrinogenemia
  • Elevated liver enzymes
  • Elevated inflammatory markers 6, 4

Management Approach

Treatment must be initiated rapidly and consists of three key components 1:

1. Identify and treat the underlying trigger:

   • Aggressive treatment of infections
   • Chemotherapy for malignancy-associated sHLH
   • Immunosuppression for rheumatic disease-associated sHLH

2. Control hyperinflammation:

   • HLH-specific protocols (HLH-94 or HLH-2004) which typically include:
     • High-dose glucocorticoids
     • Etoposide
     • Cyclosporine A
   • For rheumatic disease-associated sHLH (MAS): glucocorticoids, IL-1 blockade, or cyclosporine A 1, 4

3. Provide supportive care:

   • Management of cytopenias
   • Treatment of infections
   • Neurological support
   • Organ support as needed 1

Prognosis and Pitfalls

• Without early treatment, sHLH can be rapidly fatal, with >10% of patients dying within two months of diagnosis 1
• Adult sHLH carries a particularly high mortality rate, even with aggressive therapy 5
• Common pitfalls:
  • Delayed diagnosis due to nonspecific initial presentation
  • Misdiagnosis as sepsis or liver failure
  • Failure to identify and treat the underlying trigger
  • Using pediatric protocols in adults, potentially resulting in overtreatment and unnecessary toxicity 1

Important Considerations

• A high index of suspicion is necessary for early diagnosis, especially in patients with persistent fever, cytopenias, and organomegaly 6
• Markedly elevated ferritin (often >10,000 ng/mL) is a key diagnostic clue
• sHLH can complicate CAR T-cell therapy in approximately 3.5% of cases, with features overlapping with cytokine release syndrome 1
• Thorough diagnostic evaluation is essential to identify underlying triggers and guide targeted therapy 2