Diagnosing primary HLH

Recognized options for diagnosing primary HLH

Making a primary HLH diagnosis can be challenging¹

The symptoms of primary hemophagocytic lymphohistiocytosis (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.

There are 3 recognized options for identifying this rare condition^2-5:

Fulfillment of 5 of the 8 HLH-2004 criteria in the absence of an underlying cause, such as malignancy, especially lymphoma, or viral infection

OR

A positive genetic test for mutations associated with primary HLH

OR

Family history consistent with primary HLH

HLH-2004 criteria⁶

Fever
Splenomegaly
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 x10⁹/L
- Neutrophils <1.0 x 10⁹/L

Hypertriglyceridemia (fasting triglycerides, ≥265 mg/dL) and/or hypofibrinogenemia (≤1.5 g/L)
Hemophagocytosis* in bone marrow, spleen, or lymph nodes
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.⁷

Genetic mutations associated with primary HLH^1,2

FHL3-UNC13D
FHL2-PRF1
FHL1-Unknown
FHL5-STXBP2 (UNC18B)
FHL4-STX11

X-linked lymphoproliferative disorder 1
X-linked lymphoproliferative disorder 2
Griscelli syndrome type 2 (RAB27A)
Chediak-Higashi syndrome (LYST)

Keep in mind that not all genetic causes that can lead to HLH have been identified. This is an area that is continually being studied.

CD=cluster of differentiation.

Accelerate diagnosis with alternatives to genetic testing⁵

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 with identification.⁵

Explore ancillary testing options

IFNγ is a driver for primary HLH⁸

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

Discover the role of IFNγ

References

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
Sepulveda F, de Saint Basile G. Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol. 2017;49:20-26. doi:10.1016/j.coi.2017.08.004
Marsh RA, Haddad E. How I treat primary haemophagocytic lymphohistiocytosis. Br J Haematol. 2018;182(2):185-199. doi:10.1111/bjh.15274
Gamifant (emapalumab-lzsg) prescribing information. Stockholm, Sweden: Sobi, Inc. 2025.
HLH diagnosis strategy. Cincinnati Children’s Hospital. Accessed April 1, 2025. https://www.cincinnatichildrens.org/service/h/hlh/clinical/test
Henter J, Horne A, Aricò M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124-131. doi:10.1002/pbc.21039
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
Price B, Lines J, Lewis D, Holland N. Haemophagocytic lymphohistiocytosis: a fulminant syndrome associated with multiorgan failure and high mortality that frequently masquerades as sepsis and shock. S Afr Med J. 2014;104(6):401-406. doi:10.7196/samj.7810
La Rosée P. Alleviating the storm: ruxolitinib in HLH. Blood. 2016;127(13):1626-1627. doi:10.1182/blood-2016-02-697151

Recognized options for diagnosing primary HLH

Making a primary HLH diagnosis can be challenging¹

There are 3 recognized options for identifying this rare condition^2-5:

OR

OR

HLH-2004 criteria⁶

Genetic mutations associated with primary HLH^1,2

Accelerate diagnosis with alternatives to genetic testing⁵

IFNγ is a driver for primary HLH⁸

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

Recognized options for diagnosing primary HLH

Making a primary HLH diagnosis can be challenging1

There are 3 recognized options for identifying this rare condition2-5:

OR

OR

HLH-2004 criteria6

Genetic mutations associated with primary HLH1,2

Accelerate diagnosis with alternatives to genetic testing5

IFNγ is a driver for primary HLH8

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

Making a primary HLH diagnosis can be challenging¹

There are 3 recognized options for identifying this rare condition^2-5:

HLH-2004 criteria⁶

Genetic mutations associated with primary HLH^1,2

Accelerate diagnosis with alternatives to genetic testing⁵

IFNγ is a driver for primary HLH⁸