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. 2026 Sep 14;17:1933805. doi: 10.3389/fimmu.2026.1933805

Figure 2.

Flowchart outlining the assessment and management of HLH. Patients with persistent fever, cytopenias, and elevated ferritin receive supportive care followed by HLH assessment using pediatric HLH-2004/2024 or adult HScore criteria, with parallel investigation for possible triggers and early genetic testing. If the trigger is unknown, primary or familial HLH is treated with dexamethasone and etoposide, with CNS-directed therapy when indicated, followed by response assessment, salvage or targeted therapy for refractory disease, and bridge to HSCT. If a secondary or acquired trigger is identified, treatment is directed at the underlying cause, including EBV-HLH, macrophage activation syndrome, malignancy-associated HLH, immune effector cell–associated HLH, infection-related HLH, and drug-induced HLH. Relapsed or refractory disease may require targeted or salvage therapy, including emapalumab, followed by HSCT. Patients with organ dysfunction should be referred to an ICU/HSCT-capable center.

Evidence-based treatment algorithm for HLH. Note: If etoposide is used, the dose and frequency should be adjusted to 50–100 mg/m² (from 150 mg/m²) and limited to 1–2 doses in older patients. Adult HLH treatment cannot be standardized and should be individualized according to the underlying condition and HLH-triggering factors, including infection, malignancy, autoimmune/autoinflammatory disease, drug exposure, or other causes. In secondary HLH, the use of emapalumab for relapsed or refractory disease is off-label but has shown reasonable efficacy. allo-SCT, allogeneic stem cell transplantation; CAEBV-HLH, chronic active Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis; CBC, complete blood count; CNS, central nervous system; EBV-HLH, Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis; HLH, hemophagocytic lymphohistiocytosis; HSCT, hematopoietic stem cell transplantation; ICU, intensive care unit; IEC-HS, immune effector cell–associated hemophagocytic syndrome; IL-6, interleukin-6; IVIG, intravenous immunoglobulin; MAS-HLH, macrophage activation syndrome-associated hemophagocytic lymphohistiocytosis; M-HLH, malignancy-associated hemophagocytic lymphohistiocytosis; NGS, next-generation sequencing. .