P HLHS INV

Utility of various diagnostic assays

Study	Rationale
Common laboratory studies
CBC, hepatic panel, fibrinogen, triglycerides Ferritin Cultures, viral PCRs: EBV, CMV, adenovirus	Essential to define typical features of HLH. Though not part of diagnostic criteria, hepatitis is extremely common in HLH. Usually (but not always) very elevated Search for triggering infection
Specialized laboratory studies
Markers of immune activation: sCD25, granzyme B expression, CXCL9 IL‐18 level Measurement of proteins affected in familial HLH: perforin, SAP, XIAP Functional studies: lymphocyte degranulation (CD107a mobilization), NK cell function Lymphocyte subsets, T‐cell subsets, immune globulin levels Genetic testing (multigene panel or whole exome)	Essentially always elevated in untreated HLH; very sensitive, but not specific. sCD25, and perhaps CXCL9, are also useful for monitoring response to therapy Elevated in HLH associated with inflammasome‐opathies (XIAP, NLRC4, soJIA) Helpful to quickly confirm a suspected familial HLH diagnosis May help to fulfill diagnostic criteria. Degranulation is the preferred functional assay over NK cell function.102 Screening studies for PID Essential for defining HLH recurrence risk
Imaging
Body cavity CT's (chest/abd/pelvis) Consider PET‐CT if suspicion of lymphoma MRI of brain	Should be routinely performed to help rule out malignancy, or unusual infections if trigger is unknown (CXR/abdominal ultrasound may suffice) PET‐CT very helpful for guiding biopsy if concern for lymphoma Brain MRI complements LP for CNS assessment
Tissue sampling
Bone marrow biopsy Lumbar puncture Other tissue biopsies as appropriate: liver, lymph node, masses	Essential to rule out malignancy, identify hemophagocytosis, and identify CNS involvement