CD38high/HLA‐DR⁺CD8⁺ T lymphocytes display pathogen‐specific expansion regardless of hemophagocytic lymphohistiocytosis

The characteristic expansion of T CD38 high /HLA‐DR + CD8 + lymphocytes observed in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) proved able to distinguish HLH/MAS from sepsis and systemic juvenile idiopathic arthritis. However, the performance of this marker in differentiating HLH/MAS from other pediatric febrile conditions with similar clinical onset and yet entirely different treatments remains unexplored. CD38 high /HLA‐DR + CD8 + frequencies measured in the peripheral fresh blood of pediatric patients attended for suspicion of HLH/MAS were retrospectively recorded and clinical characteristics were retrieved. CD38 high /HLA‐DR + CD8 + frequencies in HLH/MAS patients (15 patients; median: 22.0%, IQR: 11.0–49.0%) were compared with those who presented febrile conditions other‐than‐HLH (28 patients; median: 13.0%, IQR: 3.9–28.7%; p = 0.24). HLH and non‐HLH patients were subsequently regrouped based on the presence of an identified infection (22 patients; median: 27.0%, IQR: 15.2‐72.1%) and compared with those without infections (21 patients; median: 7.6%, IQR: 3.7–24.3%; p = 0.0035). CD38 high /HLA‐DR + CD8 + percentages were significantly higher only in the infection group compared with the noninfection one, with a patent pathogen‐specific expansion in Epstein–Barr virus primoinfection and visceral leishmaniasis regardless of the presence of HLH. CD38 high /HLA‐DR + CD8 + frequencies do not appear as an HLH‐specific marker as they naturally expand in other clinical situations that are common in childhood and may mimic HLH initial presentation.