Abstract
BackgroundHaemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation, and HLH patients with mutations in genes including PRF1, UNC13D, STX11, STXBP2, SH2D1A, XIAP, and ITK were reported to be primary HLH. Due to the different treatment options, the differentiation between primary and secondary HLH is critical. Our previous studies have showed that a Th1/Th2 cytokine profile is diagnostic for HLH, yet the cytokine profiles between primary and secondary HLH have not been compared. The aim of the study was to test whether the Th1/Th2 cytokine profile could be used as a tool to differentiate between primary and secondary HLH.MethodsA total of 45 hospitalized Chinese children with HLH during the period of February 2010 through September 2012 were enrolled in the study. Fifty healthy children were enrolled as controls. Primary HLH related genes were sequenced using genomic DNA samples. The Th1/Th2 cytokine levels including interferon-γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-10, IL-6, IL-4 and IL-2 were quantitatively determined by cytometric bead assay techniques.ResultsPrimary HLH group (n = 4) included one patient with biallelic heterozygous mutations in PRF1 gene, and three patients with hemizygous mutation in SH2D1A gene. Based on the available genetic data, the other 41 patients were classified into the secondary HLH group. When compared the cytokine levels between the two groups, IL-4 level in primary-HLH was significantly lower than that in secondary HLH (P = 0.025), while IFN-γ level in primary HLH had a tendency of statistically lower than that in secondary HLH (P = 0.051). Area under receiver operating characteristic (ROC) curves of IL-4 and IFN-γ, IL-10, TNF-α, IL-2, and IL-6 levels were 0.841, 0.799, 0.506, 0.494, 0.457, and 0.250, respectively. ROC curves showed that 1.7 pg/ml of IL-4 had sensitivity and specificity for differentiation between primary and secondary HLH as 70.7 and 100.0 %, while 433.9 pg/ml of IFN-γ had sensitivity and specificity as 51.2 and 100.0 %, respectively.ConclusionsHLH patients with lower IL-4 and IFN-γ levels have higher possibility to be primary HLH. The cytokine profile may be used as an additional tool for the quick differential diagnosis between primary and secondary HLH.Electronic supplementary materialThe online version of this article (doi:10.1186/s13052-016-0262-7) contains supplementary material, which is available to authorized users.
Highlights
Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation, and hemophagocytic lymphohistiocytosis (HLH) patients with mutations in genes including PRF1, UNC13D, STX11, STXBP2, SH2D1A, XIAP, and ITK were reported to be primary HLH
All variants classified as pathogenic were not detected in the controls, while those classified as single nucleotide polymorphisms (SNPs) were found in both HLH patients and healthy controls
Based on the available genetic data, the other 41 patients were classified into the secondary HLH group, including nine HLH patients with single heterozygous mutation
Summary
Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation, and HLH patients with mutations in genes including PRF1, UNC13D, STX11, STXBP2, SH2D1A, XIAP, and ITK were reported to be primary HLH. Due to the different treatment options, the differentiation between primary and secondary HLH is critical. The aim of the study was to test whether the Th1/Th2 cytokine profile could be used as a tool to differentiate between primary and secondary HLH. Epstein–Barr virus (EBV) infections seem to be very common in HLH patients, especially in Asian countries [3,4,5,6,7]. The clinical features are identical in primary and secondary HLH, and both forms are often triggered by infections, so it is difficult to distinguish between these two types [8]. The diagnosis of HLH based on the current combination of clinical, laboratory and immunological criteria is challenging because all of the criteria are not diagnostic for any HLH subtypes
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