Hemophagocytic lymphohistiocytosis

Etiologies

• Infection
  • Viral
    • EBV (most common)
    • CMV, parvovirus, HSV, VZV, measles, HHV-8, H1N1 influenza virus, parechovirus, and HIV
    • SARS-CoV-2, possibly
  • After anti-TNF therapy: tuberculosis, CMV, EBV, or histoplasmosis
  • Rare: Brucella, gram-negative bacilli, tuberculosis, Leishmaniasis, malaria, and fungal infections
• Malignancy, most commonly lymphoid cancers and leukemias, but also solid cancers
• Rheumatologic disease
  • Systemic juvenile idiopathic arthritis (Still disease)
  • Rheumatoid arthritis, dermatomyositis, systemic sclerosis, mixed connective tissue disease, antiphospholipid syndrome, Sjögren syndrome, ankylosing spondylitis, vasculitis, and sarcoidosis
• Immunodeficiency
  • Primary immunodeficiency
  • HIV, stem cell transplant, kidney transplant, liver transplant

Differential Diagnosis

• Macrophage activation syndrome
• Severe sepsis
• Liver failure
• Multiple organ dysfunction syndrome
• Encephalitis
• Autoimmune lymphoproliferative syndrome
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Kawasaki disease
• Cytophagic histiocytic panniculitis
• TTP/HUS/DITMA
• Transfusion-associated graft-versus-host disease

Diagnostic Criteria (HLH-2004)

The diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled:

1. A molecular diagnosis consistent with HLH is made.
2. Diagnostic criteria for HLH are fulfilled (5 of the 8 criteria below):*
   • Fever
   • Splenomegaly
   • Cytopenias (affecting ≥ 2-3 lineages in the peripheral blood):
     • hemoglobin < 90 g/L (in infants < 4 weeks of age, hemoglobin < 100 g/L)
     • platelets < 100x10^9^/L
     • neutrophils < 1.0x10^9^/L
   • Hypertriglyceridemia and/or hypofibrinogenemia:
     • fasting triglycerides ≥ 3.0 mmol/L (ie, ≥ 265 mg/dL)
     • fibrinogen ≤ 1.5 g/L
   • Hemophagocytosis in BM, spleen, or lymph nodes
   • Low or absent NK-cell activity (according to local laboratory reference)
   • Ferritin ≥ 500 g/L
   • Soluble CD25 (ie, sIL2r) 2400 U/mL†

• Supportive criteria include neurologic symptoms, cerebrospinal fluid pleocytosis, conjugated hyperbilirubinemia and transaminitis, hypoalbuminemia, hyponatremia, elevated D-dimers, and lactate dehydrogenase (see text for details). The absence of hemophagocytosis in the BM does not exclude a diagnosis of HLH.

† New data show normal variation by age. Level should be compared with age-related norms.