Testing for primary HLH

Additional testing and CXCL9 in primary HLH

When it comes to treating primary hemophagocytic lymphohistiocytosis (HLH), there’s no time to wait. Prior to receiving genetic testing results, other assessments can help you determine the likelihood of primary HLH so that you can initiate treatment as soon as possible.¹

Flow cytometry testing

Decreased levels of the following can help identify a genetic cause¹

Perforin/granzyme B

Degranulation (CD107a) or T-cell degranulation

SLAM-associated protein (SAP) (for males)

XIAP protein (for males)

CD=cluster of differentiation; SLAM=signaling lymphocytic activation molecule; XIAP=X-linked inhibitor of apoptosis protein.

Flow cytometry for perforin expression and CD107a have high specificity for identifying primary HLH¹

Ancillary testing¹

Quantitative viral PCRs

EBV, CMV, adenovirus, HSV 1, HSV 2, etc

CT of chest, abdomen, and neck

Testing for tick- or mosquito-borne diseases

PET-CT

followed by lymph node biopsy to evaluate for lymphoma

MRI of brain

Lyme disease

CMV=cytomegalovirus; CT=computed tomography; EBV=Epstein-Barr virus; HSV=herpes simplex virus;
MRI=magnetic resonance imaging; PCR=polymerase chain reaction; PET=positron emission tomography.

These tests can help eliminate other conditions and/or define treatable underlying triggers for HLH^1-4

CXCL9

Chemokine (C-X-C motif) ligand 9 (CXCL9) is a type of cytokine released almost exclusively by interferon gamma (IFNγ)-activated macrophages.⁵ The primary function of CXCL9 is to attract T cells into inflamed tissues.⁶

CXCL9 production is induced predominantly by IFNγ.⁵ Evidence suggests CXCL9 is a potential biomarker for IFNγ activity.⁷

Download CXCL9 testing brochure

CXCL9 testing sites

There is growing recognition of testing for CXCL9 as a biomarker for IFNγ activity.⁷ The following organizations offer CXCL9 testing to help with identifying primary HLH:

Machaon Diagnostics
Website	machaondiagnostics.com/test/cxcl9-level
Turnaround time	STAT: <24 hours Routine: <1 week
Lab hours	24/7
Phone	1-800-566-3462 510-839-5600
Fax	510-839-6153

Cincinnati Children’s Hospital
Website	testmenu.com/cincinnatichildrens/Tests/723501
Turnaround time	4 days
Lab hours	Mon-Fri, 8:00 AM to 5:00 PM (ET)
Phone	513-636-4685
Fax	513-636-3861

This is not an exhaustive list of labs offering CXCL9 testing. Please check for the availability of this test within your own institution prior to contacting these sites.

Other tests^1,8

In the absence of an underlying cause, such as malignancy, these tests can be useful for identifying the typical features of primary HLH.^1,8

Complete blood counts
Ferritin
ALT, bilirubin
IL-18

Fibrinogen/coagulation tests
Triglycerides (fasting)
sCD25

ALT=alanine transaminase; IL-18=interleukin-18; sCD25=soluble cluster of differentiation 25.

References

HLH diagnosis strategy. Cincinnati Children’s Hospital. Accessed April 1, 2025. https://www.cincinnatichildrens.org/service/h/hlh/clinical/test
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
Gurunathan A, Boucher A, Mark M, et al. Limitations of HLH-2004 criteria in distinguishing malignancy-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2018;65:e27400. doi:10.1002/pbc.27400
Chinn IK, Eckstein OS, Peckham-Gregory EC, et al. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. Blood. 2018;132(1):89-100. doi:10.1182/blood-2017-11-814244
Bracaglia C, de Graaf K, Pires Marafon D, et al. Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(1):166-172. doi:10.1136/annrheumdis-2015-209020
Cincinnati Children’s. From the Clinical Laboratories of the Cancer & Blood Diseases Institute. CXCL9. 2019.
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
Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811-1822. doi:10.1056/NEJMoa1911326
Data on file. Stockholm, Sweden: Sobi, Inc. 2018.
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

Additional testing and CXCL9 in primary HLH

Flow cytometry testing

Ancillary testing¹

CXCL9

CXCL9 testing sites

Other tests^1,8

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

Additional testing and CXCL9 in primary HLH

Flow cytometry testing

Ancillary testing1

CXCL9

CXCL9 testing sites

Other tests1,8

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

Ancillary testing¹

Other tests^1,8