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Primary HLH is rapidly progressive and fatal if untreated1

Primary hemophagocytic lymphohistiocytosis (HLH) is a rare genetic disease characterized by life-threatening inflammatory symptoms.1,2 Though primary HLH can affect adults and teenagers, the majority of patients are very young children—often in the first months or years of their lives.1,3 Due to the rapidly progressive nature of the disease, immediate therapy is required to temper the “cytokine storm”—a massive release of cytokines that leads to the signs and symptoms of primary HLH.1,4

Without timely diagnosis and effective treatment, the median survival for patients with primary HLH is under 2 months.1

symptoms

Primary HLH presents as a heterogeneous syndrome of rapidly progressive, life-threatening inflammatory symptoms, including1,2:

  • Persistent high fevers (above 102°F, lasting 4-41 days)
  • Infections
  • Rashes
  • Hepatosplenomegaly
  • Liver function impairment
  • Jaundiced appearance
  • Seizures and central nervous system involvement
  • Hyperferritinemia
  • Coagulation defects
  • Severe cytopenia
  • Pulmonary dysfunction

THE FACTS AND FEATURES OF PRIMARY HLH

To date, general consensus in the scientific community on primary HLH is as follows1,3:

PRIMARY HLH
Mortality rate High mortality rate
Clinical presentation Heterogeneous
Age of presentation Typically infants/early childhood; documented cases also exist in teens and adults
Cause Testable genetic mutation
Family history May be positive for the disease
Recurrence Likely
Resolution Usually requires hematopoietic stem cell transplant (HSCT)

DIagnosis can be challenging

The symptoms of primary HLH, along with their differing levels of severity, combine to form a broad spectrum of disease presentation that varies from patient to patient and within the same patient over time. Although scientific consensus of the appropriate diagnostic criteria continues to evolve, 2 recognized options for confirming a diagnosis of primary HLH exist2,3,5,6:

  • A positive genetic test for mutations associated with primary HLH

OR:

  • The fulfillment of 5 of the 8 HLH-2004 criteria in the absence of an underlying cause, such as malignancy
diagnosis-challenging
HLH-1994 Criteria5

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 Criteria5
  • 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.
GENETIC Mutations Associated with Primary HLH6,7
  • 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.1,8,9

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

Consider running the following tests9:

  • CT (computed tomography) of chest/abdomen/neck
  • MRI (magnetic resonance imaging) of brain
  • Viral PCRs (polymerase chain reactions) (EBV, CMV, adenovirus, etc)
  • PET (positron emission tomography)-CT (computed tomography) 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 of 9,10:

  • Perforin/granzymeB
  • 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.10

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