Increased frequency of CD38^high/HLA-DR⁺CD8⁺T cells is a robust marker of active HLH, irrespective of clinical context. (A) CD8:CD4 ratio is modestly elevated in patients with HLH, compared with controls, but not patients with sepsis. (B) Ratio of CD38^high/HLA-DR⁺ CD8⁺ to CD38^high/HLA-DR⁺ CD4⁺ T cells in individual patients with HLH. (C-D) Frequency of CD38^high/HLA-DR⁺ CD8⁺ or CD4⁺ T cells in patients with HLH is plotted, comparing presence of HLH-associated mutations, identifiable infection at diagnosis, or subsequent survival. (E) Frequency of CD38^high CD8⁺ T cells is plotted with either sCD25 or ferritin across time in 2 patients receiving etoposide and dexamethasone for HLH. Data are representative of 27 pediatric controls, 9 patients with sepsis, and 18 to 22 patients with HLH. Error bars represent median with 95% CI. Differences between indicated groups were calculated using the unpaired Student t test. *P < .05.