Primary HLH is rapidly progressive and fatal if untreated1

Primary hemophagocytic lymphohistiocytosis (HLH) is a rare genetic disease characterized by life-threatening inflammatory symptoms. 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. 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. Fewer than 100 cases of primary HLH are diagnosed in the US each year.1-5

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, including1,3:

  • 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

THE FACTS AND FEATURES OF PRIMARY HLH

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

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. Historically, a primary HLH diagnosis has been based on a genetic test or fulfillment of 5 of the 8 HLH-2004 criteria. These criteria include the HLH-1994 criteria, plus the addition of ferritin, low NK cells, and SIL2R.2,3,6-8

dIagnosis- challenging
HLH-1994 Criteria

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 per our other pieces. 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, so it is not a pivotal criterion, despite the name of the condition.
HLH-2004 Criteria1
  • 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, so it is not a pivotal criterion, despite the name of the condition.
GENETIC Mutations Associated with Primary HLH8
  • FHL3 - UNC13D
  • X-linked Lymphoproliferative Disorder 1
  • FHL2 - PRF1
  • X-linked Lymphoproliferative Disorder 2
  • Griscelli Syndrome type 2 (RAB27A)
  • FHL1 - Unknown
  • FHL5 - STXBP2 (UNC18B)
  • Chediak-Higashi Syndrome - LYST
  • FHL4 - STX11

Further testing and screening

While the HLH-2004 criteria are useful for detecting common symptoms of HLH, ancillary testing and flow cytometric screening go beyond these criteria and help differentiate between primary and secondary HLH. This approach helps find the triggers or underlying causes of HLH and prevents misdiagnosis.9,10

ANCILLARY TESTING to help rule out secondary HLH

Consider running the following tests9:

  • CT of chest/abdomen/neck
  • MRI of brain
  • Viral PCRs (EBV, CMV, adenovirus, etc.)
  • PET-CT to evaluate lymphoma
  • Test for tick- or mosquito-borne diseases in areas at risk
flow cytometric screening to help confirm primary HLH

Consider checking for decreased levels of9,10:

  • Perforin/granzymeB
  • XIAP protein (in males)
  • SAP protein (in males)
  • CD107a

IFNγ is a driver of primary HLH

IFNy is central to the cytokine "storm"—an uncontrolled release of inflammatory cytokines and overactivation of phagocytes that give the syndrome its name.11

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