About primary HLH

Primary HLH: A hyperinflammatory condition of immune dysregulation1,2

Primary HLH is rapidly progressive and often fatal1

Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, hyperinflammatory condition of immune dysregulation. It is characterized by interferon gamma (IFNγ)-activated macrophages that release an uncontrolled surge of proinflammatory cytokines.1,2 This surge is also known as the cytokine storm. The resulting hyperinflammation can quickly lead to organ damage and become life-threatening.3

Clock with alert icon

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

Primary HLH can present in adulthood3-5

Primary HLH is increasingly recognized as a disease that can present across the lifespan.4 The threshold model provides a framework 
for understanding how inherited genetic susceptibility and hyperinflammatory burden may interact to influence when disease becomes clinically apparent.3,5

Individuals with genetic variants that partially impair cytolytic function or other genetic alterations that increase susceptibility to HLH may remain below the threshold for clinically apparent disease until a significant inflammatory trigger—such as infection, malignancy, or another immune challenge—pushes them above it.3,5

What influences when primary HLH becomes clinically apparent?

The threshold model of HLH is a framework for viewing the disease as a biological continuum. The model can be used to reflect how genetic susceptibility* and hyperinflammatory contributors may contribute to the manifestation of primary HLH.3,5

Threshold Model of Hemophagocytic Lymphohistiocytosis (HLH)
Threshold model chart showing that HLH develops when combined genetic susceptibility and hyperinflammatory burden cross the HLH threshold.

*Note that the genetic susceptibility that drives HLH can include innate and somatic genetic mutations.3,6

As a subtype, primary HLH can be visualized by placing examples along the continuum, based on individual patient presentation.3

Primary HLH Legend
Primary HLH Legend
Primary HLH Pediatric Threshold Example
Primary HLH Pediatric Threshold Example
Primary HLH Adult Threshold Example 1
Primary HLH Adult Threshold Example 1
Primary HLH Adult Threshold Example 2
Primary HLH Adult Threshold Example 2

Primary HLH Pediatric Example

High genetic predisposition + small amount of infection pushes over threshold. This illustrates a more "classic" presentation of primary HLH.

Primary HLH Adult Example #1

High genetic predisposition (somatic) + moderate amount of infection pushes over threshold

Primary HLH Adult Example #2

Lower genetic predisposition + higher amount of infection pushes over threshold

Evidence of primary HLH in adults

In a retrospective review of 1,531 patients referred for genetic testing because of suspected HLH, investigators evaluated 175 adults (≥18 years) to determine whether mutations in HLH-associated genes were present. Adult patients underwent sequencing of PRF1, MUNC13-4, and STXBP2, with accompanying immunologic testing when available. Researchers assessed the prevalence and characteristics of HLH-associated mutations in adults presenting with suspected HLH.4

14% of Adults

with suspected HLH (n=25) carried mutations in PRF1, MUNC13-4, or STXBP24

18-75 Years

Adult-onset primary HLH occurred across a broad age range4

Hypomorphic Mutations

Most identified variants were hypomorphic, supporting partial cytotoxic dysfunction rather than complete loss of function4

While primary HLH is commonly associated with pediatric patients, genetic mutations associated with primary HLH may contribute to the development of the syndrome later in life following a significant inflammatory challenge.4

Early identification of primary HLH is critical but challenging1

Primary HLH may present with nonspecific clinical and laboratory signs, which often delay diagnosis.1

Fever, Rash, Infection Icon
  • Persistent high fever  (>102°F [38.9°C], lasting ≥4 days)
  • Infection
  • Rash
Liver, Kidney Icon
  • Hepatosplenomegaly
  • Liver function impairment (eg, elevated liver enzymes)
Blood Cells Icon
  • Hyperferritinemia
  • Coagulation defects
  • Severe cytopenia (affecting hemoglobin, platelets, and/or neutrophils)
Brain Icon
  • Seizures and central nervous system involvement

Recognize the pattern

A pattern of common clinical and laboratory findings can raise suspicion3:

FEVER

FERRITIN

FALLING BLOOD COUNTS

Consider these findings together and in the context of the patient's clinical presentation when evaluating for primary HLH.3

Explore how primary HLH is diagnosed

Many patients with primary HLH are admitted to the intensive care unit due to delays in diagnosis1

Collaboration between various specialists can help shorten the time it takes to identify this rare condition.7 These include:

  • Emergency room physicians
  • Immunologists
  • Pathologists
  • Clinical pharmacologists
  • Rheumatologists
  • Neurologists
  • Hematologists
  • Oncologists
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