Additional testing for HLH icon

Additional testing and CXCL9

These tests can help with identifying HLH

Genetic testing takes time, and patients with HLH often require immediate treatment to control their hyperinflammation.1 There are a range of other tests that can be conducted in the meantime to help identify potential underlying triggers and to help confirm or rule out an HLH diagnosis.

Flow cytometry testing

Screening studies for genetic causes of HLH2
Perforin/granzyme B
SLAM-associated protein (SAP) (for males)
Degranulation (CD107a) or T-cell degranulation
XIAP protein (for males)

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

Flow cytometry for perforin expression and CD107a have high specificity for identifying HLH with a genetic basis.3

Ancillary testing2,4

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 identify an underlying trigger for patients with HLH, or to rule out other conditions.2

Other tests2

Complete blood counts
ALT, bilirubin
Fibrinogen/coagulation tests
Triglycerides (fasting)

ALT=alanine aminotransferase; CXCL9=chemokine (C-X-C motif) ligand 9; IL=interleukin.

These tests are useful for identifying the typical features of HLH.5 There is evidence suggesting that CXCL9 testing can be helpful for measuring the IFNγ levels in patients with HLH.6

CXCL9 and IFNγ

CXCL9 is a chemokine (a type of cytokine) released almost exclusively by IFNγ-activated macrophages. The primary function of CXCL9 is to attract T cells into inflamed tissues.6

CXCL9 being released from macrophages that have been activated by interferon gamma
CXCL9 being released from macrophages that have been activated by interferon gamma

References: 1. 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 2. Cincinnati Children’s Diagnosing HLH. Accessed October 23, 2023. 3. Marsh RA, Haddad E. How I treat primary haemophagocytic lymphohistiocytosis. Br J Haematol. 2018;182(2):185-199. doi:10.1111/bjh.15274 4. Jongbloed EM, Hermans MAW, Wabbijn M, van Kampen JJA, van Laar JAM. HLH caused by an HSV-2 infection: a case report and review of the literature. Neth J Med. 2020;78(5):282-285. 5. 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 6. Sylvest S. From the Clinical Laboratories of the Cancer & Blood Diseases Institute. Cincinnati Children’s Hospital. Winter 2019;(15):1-4. 7. 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