Detection of Th1/Th2 Cytokines Is Useful for the Quick and Early Diagnosis of Hemophagocytic Syndrome in Children.

Introduction and objectives Hemophogocytic syndrome (HPS) is an infrequent disease in children with a high mortality rate. Currently, the diagnosis of HPS largely depends on non-specific clinical manifestations, but the clinical features allowing to meet the criteria of diagnosis of HPS usually do not appear simultaneously which make the early diagnosis very difficult. According to the literature, hypercytokinemia has been noticed for this disease. However, the pattern of hypercytokinemia in HPS has not been proposed. In this study, the quick determination of Th1/Th2 cytokines in the sera from patients with HPS was performed and the patterns of the cytokines were analyzed to seek for the possibility of using the cytokine pattern for the early diagnosis of HPS and its prognostic significance.

Patients and Methods A total of 16 children with HPS based on the 2004 HPS criteria from June 2005 ∼ December 2006 were enrolled into this study. Peripheral blood samples were collected at the time of diagnosis, during the induction therapy and at the time of relapse. Sera from 21 healthy children, 17 ALL at remission and 17 with sepsis were used as controls. A cytometric bead assay (CBA) was used to quantitatively determine the Th1/Th2 cytokines including IL-2, IL-4, IL-6, IL-10, TNFα and IFNγ.

Results Levels of IL-6 (22.20 (10.60–139.25) pg/ml), IL-10 (195.60(63.85–918.70)pg/ml) and IFNγ (4740.20(1054.72– >5000.00)pg/ml) from patients with HPS were significantly higher than those of normal control (3.35 (2.50–5.40) pg/ml, P < 0.05; 2.90(2.20–4.80)pg/ml, P<0.01; 52.80(37.50–66.60)pg/ml, P<0.01). Although the IFNγ levels in septic patients were also elevated, the levels (4740.20(1054.72- >5000.00)pg/ml) of IFNγ in HPS patients were much higher than those (52.80(37.50∼66.60)pg/ml, P<0.01) in septic patients. Another important finding was that the levels of IL-6 in HPS (22.20(10.60∼139.25)pg/ml) were significantly less elevated than those in septic patients (526.55(194.80∼979.00)pg/ml, P<0.01). After effective therapy with HLH2004 protocol, the IL-6 (3.30(2.30∼6.80)pg/ml, IL-10(6.60(3.10∼23.20)pg/ml and IFNγ (65.45(27.30∼144.10)pg/ml) levels from patients with HPS sensitive to chemotherapy were significantly decreased as compared to those (22.20(10.60∼139.25)pg/ml, P=0.005; 195.60(63.85∼918.70)pg/ml, P=0.004; 4740.20(1054.72∼ >5000.00)pg/ml, P=0.002) of prior to treatment. While those in patients insensitive to chemotherapy were not significantly reduced (P > 0.05). No significant differences in the IL-2, IL-4 and TNFα levels among patients at acute phase, remission stage and the healthy controls were observed. Univariate analysis showed that the initial IL-10 level >100pg/ml and IFNγ concentration > 4000pg/ml were both unfavorable prognostic factors for HPS (IFNγ, P =0.034; IL-10, P=0.034). Positive correlations between the levels of IFNγ and IL-10(r=0.893, P<0.001), IFNγ and IL-6(r=0.791, P<0.001), IL-10 and IL-6(r=0.676, P<0.001) were found. All of the three parameters stayed at a high level in acute phase and returned to normal when achieving remission.

Conclusion s The quick determination of Th1/Th2 cytokines is a useful approach for the early and quick diagnosis in HPS patients based on the pattern of significant elevations of IFNγ and IL-10 with slight elevation of IL-6 and it can be used for the monitoring of the progress and the prognosis of the disease.