Dark, wooded forest

It takes a HERO to uncover the evidence

Look for clinical features that may indicate primary hemophagocytic lymphohistiocytosis (pHLH) with HERO 1

  • H

    High
    temperature

  • E

    Elevated
    ferritin

  • R

    Reduced
    blood counts

  • O

    Oversized spleen
    and/or liver*

While these 4 signs alone are not enough to make a diagnosis of pHLH,
their presence is a cause for concern. 1

* Though not a diagnostic criterion of HLH-2004, enlarged liver is a typical finding of pHLH and
provides strong supportive evidence for diagnosis. 1

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If you suspect pHLH, consult with a hematologist/oncologist to confirm the diagnosis

When the signs of pHLH are present, time is of the essence 1

HLH-2004 diagnostic criteria

According to the HLH-2004 diagnostic criteria, a diagnosis of pHLH calls for the fulfillment of 5 out of the 8 criteria, with no evidence of infections, malignancies, or rheumatologic diseases. 1

  • Thermometer icon

    Fever

  • Spleen icon

    Splenomegaly

  • Bone marrow icon

    Hemophagocytosis*

    in bone marrow, spleen, or lymph nodes

  • Cluster of blood cells icon

    Cytopenias

    (at least 2 out of 3 lineages):

    • Hemoglobin <90 g/L

    • Platelets <100 x 10 9 /L

    • Neutrophils <1 x 10 9 /L

  • Downward arrow with circle icon

    Low or absent natural killer–cell activity

  • Upward arrow with circle icon

    High ferritin (≥500 μg/L)

  • DNA double helix icon

    Hypofibrinogenemia ≤1.5 g/L OR
    hypertriglyceridemia ≥265 mg/dL

  • Upward arrow with two circles icon

    High soluble CD25

    (soluble CD25 interleukin-2 receptor ≥2400 U/mL)

* Hemophagocytosis is not specific nor always present in early stages of the disease. 2

Genetic testing and family history can also aid in the diagnosis of pHLH 1

Clinical presentation of pHLH can vary

Hover over the tiles to see how pHLH appears differently at each age

  • Infants
    (aged <1 year) 2

    Infant icon

    Infants
    (aged <1 year) 2

    • Fever

    • Cytopenias

    • Hypofibrinogenemia

    • Hepatosplenomegaly

    • Hemophagocytosis* in the absence of malignancy

  • Children and adolescents 2

    Child icon

    Children and adolescents 2

    • Similar to the presentation in infants, but varies widely in severity

    • Isolated central nervous system inflammation

    • Ferritin and soluble CD25 lab values are consistently elevated

    • Most commonly activated by Epstein-Barr virus or cytomegalovirus infection

  • Adults 3

    Adult person icon

    Adults 3

    • Hypomorphic genetic mutations (partial loss of gene function) often present

    • May exhibit a milder or relapsing clinical course

* Hemophagocytosis is not specific nor always present in early stages of the disease. 2

Understanding misdiagnosis

This rare disease can be hard to detect 1,4,5

Because of its heterogeneous nature, the clinical signs and symptoms of pHLH may be confused with:

  • Infections
  • Malignancies
  • Rheumatologic diseases

This can cause a delay in diagnosis, which can be fatal. That's why a high index of suspicion is required to accurately diagnose pHLH.

Know the initial signs.
Refer to a hematologist/oncologist

References: 1. Henter JI, Horne A, Aricò M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer . 2007;48(2):124-131. doi:10.1002/pbc.21039 2. Jordan MB, Allen CE, Greenberg J, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer . 2019;66(11):e27929. doi:10.1002/pbc.27929 3. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood . 2011;118(22):5794-5798. doi:10.1182/blood-2011-07-370148 4. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood . 2011;118(15):4041-4052. doi:10.1182/blood-2011-03-278127 5. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med . 2014;5:69-86. doi:10.2147/JBM.S46255