Serum cytokine pattern in children with hemophagocytic lymphohistiocytosis

This study aimed to compare the serum levels of 34 cytokines of children with hemophagocytic lymphohistiocytosis (HLH) and explored the specific cytokine pattern of HLH subtypes and the relationship between cytokine levels and prognosis. This retrospective study assessed the clinical data and cytokine levels of newly diagnosed children with HLH in Beijing Children's Hospital, Capital Medical University, from January 2017 to December 2021. A total of 101 children were enrolled in the study. The levels of IFN-gamma and IL-18 increased in more than 90% of patients, and MIP-1 alpha, SDF-1 alpha, IP-10, IL-6, IL-8, IL-10, IL-1 RA, and TNF-alpha increased at different levels in more than 50% of patients. The levels of IL-10 in EBV-HLH increased significantly, followed by IFN-gamma and IL-18, while IL-10 and IFN-gamma in CAEBV-HLH had a slight increase. Except for IL-10, the levels of IL-6, Eotaxin, IL-13, IL-18, IFN-gamma, and MIP-1 beta in Rh-HLH increased significantly. F-HLH had significantly high IL-10 levels and a slight increase in IL-13. We showed that various cytokines could assist in differentiating HLH subtypes with ROC curve analysis. When IL-10/IL-6 was 1.37, the sensitivity and specificity of diagnosing EBV-HLH were higher than 80% (AUC = 0.837, p < 0.001). The effect of cytokine ratio on classifying HLH subtypes (17/22, 77.3%) was more significant than the single cytokine (5/22, 22.7%). The 3-year overall survival (OS) rate of children with F-HLH was the lowest during the follow-up. The 3-year OS of patients with EBV-HLH and CAEBV-HLH was significantly higher than that with F-HLH (88.1%+/- 5.0% vs. 94.1% +/- 5.7% vs. 57.1% +/- 14.6%, p = 0.017). Cox proportional hazards model revealed that elevated GM-CSF and MCP-1, as well as CNS involvement, were independent risk factors for poor outcomes for patients with HLH. Various cytokines play important roles in HLH. Different subtypes of HLH have their specific cytokines pattern, and the ratio of cytokines may be more significant in differentiating HLH subtypes than the single one. Elevated GM-CSF and MCP-1 could be useful biomarkers for a poor prognosis for patients with HLH.

Automated summary

This study compared the serum levels of 34 cytokines in children with HLH and explored the specific cytokine pattern of different HLH subtypes. The levels of IFN-gamma and IL-18 were elevated in more than 90% of patients, while other cytokines showed varying levels of increase. Different HLH subtypes exhibited distinct cytokine patterns, and the ratio of cytokines was more significant in differentiating subtypes. Elevated GM-CSF and MCP-1 were identified as independent risk factors for poor prognosis in HLH patients. Various cytokines play important roles in HLH and can be useful biomarkers for prognosis.