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Although scientific consensus of the appropriate diagnostic criteria continues to evolve, 3 recognized options for confirming a diagnosis of primary HLH exist1-4:
 

  • The fulfillment of 5 of the 8 HLH-2004 criteria in the absence of an underlying cause, such as malignancy
     
  • A positive genetic test for mutations associated with primary HLH
     
  • Family history consistent with primary HLH
     
diagnosis-challenging
HLH-1994 Criteria3

In 1994, as part of the HLH-94 clinical trial, the Histiocyte Society proposed a standard definition of HLH. Click to expand this version.

  • Fever
  • Hypertriglyceridemia (fasting, ≥265 mg/dL) and/or hypofibrinogenemia (≤1.5 g/L)
  • Splenomegaly
  • Hemophagocytosis* in bone marrow, spleen, or lymph nodes
  • Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood)
    • Hemoglobin <90 g/L (in infants <4 weeks: hemoglobin <100 g/L)
    • Platelets <100 x 109/L
    • Neutrophils <1.0 x 109/L
  • *Note that hemophagocytosis is not specific nor always present in early stages of the disease.
HLH-2004 Criteria3
  • Fever
  • Hypertriglyceridemia (fasting, ≥265 mg/dL) and/or hypofibrinogenemia (≤1.5 g/L)
  • Splenomegaly
  • Hemophagocytosis* in bone marrow, spleen, or lymph nodes
  • Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood)
    • Hemoglobin <90 g/L (in infants <4 weeks: hemoglobin <100 g/L)
    • Platelets <100 x 109/L
    • Neutrophils <1.0 x 109/L
  • Ferritin ≥500 μg/L
  • Low or absent natural killer (NK)-cell activity
  • Soluble CD25 (interleukin [IL]-2 receptor) >2400 U/mL (or per local reference laboratory)
*Note that hemophagocytosis is not specific nor always present in early stages of the disease.5
GENETIC Mutations Associated with Primary HLH4,5
  • FHL3 - UNC13D
  • X-linked lymphoproliferative disorder 1
  • FHL2 - PRF1
  • X-linked lymphoproliferative disorder 2
  • FHL1 - Unknown
  • Griscelli syndrome type 2 (RAB27A)
  • FHL5 - STXBP2 (UNC18B)
  • Chediak-Higashi syndrome - LYST
  • FHL4 - STX11

Accelerate diagnosis with alternatives to genetic testing

When it comes to treating primary HLH, there is no time to wait. Prior to receiving the results of a genetic test, ancillary testing and flow cytometry can be used, where available, to help differentiate between primary and secondary HLH. This approach helps find the triggers or underlying causes of HLH and prevents misdiagnosis.3,5,7,8

ANCILLARY TESTING to help eliminate other conditions and/or define treatable underlying triggers for HLH

Consider running the following tests3:

  • Computed tomography (CT) of chest/abdomen/neck
  • Magnetic resonance imaging (MRI) of brain
  • Viral polymerase chain reactions (PCRs)
    (eg, EBV, CMV, adenovirus)
  • Positron emission tomography (PET)-CT to evaluate lymphoma
  • Test for tick- or mosquito-borne diseases in areas at risk
flow cytometric screening to help rapidly confirm a clinical diagnosis of primary HLH

Consider checking for decreased levels of3,7:

  • Perforin/granzyme B
  • XIAP protein (in males)
  • SAP protein (in males)
  • CD107a

IFNγ is a driver of primary HLH

IFNγ is central to the "cytokine storm"—an uncontrolled release of inflammatory cytokines and overactivation of phagocytes that give the syndrome its name.9

Learn more