Hemophagocytic Lymphohistiocytosis

General

• Characterized by dysregulated immunity leading to significant immune activation and inflammation

  • Primary/familial: underlying genetic defect or family history of HLH (5 subtypes with associated genetic defects). ie perforin (PRF-1) mutation associated with FHLH-2 

  • Secondary: Occurs in setting of infection, underlying rheumatologic disorder, or malignancy

    • Viral associated HLH most common (EBV, CMV)

Signs and Symptoms

• Affects all age groups (although more commonly seen in infants and young children)

• High grade fever

• Cytopenias

• Liver dysfunction

• Neurologic symptoms such as seizure or altered mental status

• Coagulopathy

• Colitis

• Hypogammaglobulinemia

• Estimated that tertiary pediatric hospitals should expect 1 case of HLH per 3000 inpatient admissions (Allen CE et al, Blood Cancer 2008)

Pathophysiology

• Normally, cytotoxic NK and T cell function is required to clear viral infections and terminate inflammation- defects lead to ineffective clearance of infection, prolonged antigen presentation, and thus prolonged cytotoxic T-cell activation

• Cytokine storm as a result of T-cell and macrophage activation

  • Defects in lymphocyte cytotoxicity with activation and expansion of macrophages and cytotoxic T cells

  • Elevation in cytokines including IL-1, IL-6, and IFN-γ

  • Elevated TNF-a leads to hypofibrinogenemia and hypertriglyceridemia

  • Overall, despite significant immune activation, represents an immunodeficient state

Macrophage Activation Syndrome

• Special form of HLH occuring in autoimmune diseases such as systemic JIA, systemic lupus erythematosus, etc. (estimated to occur in ~7% of patients with systemic JIA with mortality of 10-20%

• Cytopenias generally less severe although cardiac involvement and coagulopathy more common

Diagnosis

• Ferritin of >10,000 ug/L 90% sensitive and 96% specific for HLH (Allen CE et al, Blood Cancer 2008)

Treatment

• Acute treatment meant to control the hyperinflammatory state and support potentially failing organs

  • Control and eliminate infectious trigger

  • Stop T cell proliferation/activation: Dexamethasone/etoposide 8 week course (remission induction rate 71% and 5 year post-HCT survival 54% (Trottestam et al, Blood 2011) followed by maintenance with cyclosporine

  • ATG, cyclosporine

  • Alemtuzumab (CD52 monocolonal antibody)-Campath

  • Block excessive cytokine production/function

  • Rituximab for EBV associated HLH

• Long term therapy with stem cell transplant to correct the underlying genetic defect

  • Significant risk of graft failure (10%) and transplant-related mortality

• Supportive care for multi-organ failure (including mechanical ventilation, CRRT, etc.)

• Vigilance, workup, and treatment of infections

• Soluble IL-2 receptor (sCD25) levels correlates with disease activity (perhaps more consistently than ferritin or other markers)

References

1) Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis: advances inpathophysiology, diagnosis, and treatment. J Pediatr. 2013 Nov;163(5):1253-9. doi: 10.1016/j.jpeds.2013.06.053.

2) Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.

3) . Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How Itreat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.

4) Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:1227-35.