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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
(From Jordan M et al, Blood 2011)

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


(From Jordan M et al, Blood 2011)


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)

(From Jordan et al, Blood 2011)


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.