Diagnosing primary HLH

How is primary HLH diagnosed?

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.

Explore what influences the onset of primary HLH

View the threshold model

There are 3 recognized options for identifying this rare condition^2-6:

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

Genetic testing may help identify inherited causes of HLH in adults, where primary HLH may be less readily suspected

OR

Family history consistent with primary HLH

HLH-2004 criteria⁷

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)

*Normal or high fibrinogen should lower suspicion of primary HLH.

^†Note that hemophagocytosis is not specific nor always present in early stages of the disease.¹

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.

In all suspected cases of primary HLH, it's important to rule out underlying triggers or causes such as malignancy, sepsis, SIRS, and viral infection.^1,8

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

CXCL9 as a marker of IFNγ activity

Learn the importance of chemokine (C-X-C motif) ligand 9 (CXCL9) as a signal of IFNγ-driven hyperinflammation, to support diagnosis  and management.⁹

Discover CXCL9

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. 2026.
HLH diagnosis strategy. Cincinnati Children's Hospital. Accessed August 13, 2026. https://www.cincinnatichildrens.org/service/h/hlh/clinical/test
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
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
Henter JI. Hemophagocytic lymphohistiocytosis. N Engl J Med. 2025;392(6):584-598. doi:10.1056/NEJMra2314005
De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-γ in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol. 2021;17(11):678-691. doi:10.1038/s41584-021-00694-z

How is primary HLH diagnosed?

Making a primary HLH diagnosis can be challenging¹

There are 3 recognized options for identifying this rare condition^2-6:

OR

OR

HLH-2004 criteria⁷

Genetic mutations associated with primary HLH^1,2

Accelerate diagnosis with alternatives to genetic testing⁵

CXCL9 as a marker of IFNγ activity

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

How is primary HLH diagnosed?

Making a primary HLH diagnosis can be challenging1

There are 3 recognized options for identifying this rare condition2-6:

OR

OR

HLH-2004 criteria7

Genetic mutations associated with primary HLH1,2

Accelerate diagnosis with alternatives to genetic testing5

CXCL9 as a marker of IFNγ activity

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^2-6:

HLH-2004 criteria⁷

Genetic mutations associated with primary HLH^1,2

Accelerate diagnosis with alternatives to genetic testing⁵