Proposed laboratory diagnostic algorithm for patients presenting with HLH. Because the spectrum and our understanding of primary diseases linked to HLH grow, laboratories would need to constantly update themselves with the latest diagnostic assays. It is recommended that individual laboratories conduct tests to determine local cutoff values for the respective assays. Functional XIAP assay75 should be considered in both males and females in light of recent findings,76,77 reduced iNKT numbers a hallmark of ITK23,78 but cautionary for SAP deficiency with highly variable levels in young children.79,80 Elevated α/β-DNT cells raise suspicion of ALPS.81 The total absence CD27 in all lymphocyte subgroups is indicative of its deficiency,22,82 whereas absence of CD27 specifically in the B-cell compartment is characteristic of SAP deficiency.83 Although functional XIAP and NK/CTL exocytosis assays should be performed on heparinized blood, if EDTA blood is available, it is preferable for phenotyping tests (perforin, SAP, XIAP, CD27, and α/β-DNT) because it is more stable with transport, can be used for DNA extraction, and plasma collected for analyzing cytokine levels. ALPS, autoimmune lymphoproliferative syndrome; DNT, double negative T cells; iNKT, invariant NK T cells; ITK, interleukin-2–inducible T-cell kinase; SAP, SLAM-associating protein; XIAP, X-linked inhibitor of apoptosis protein.
