Effect Of Interferon-gamma And Interleukin-10 Gene Polymorphisms On Hemophagocytic Syndrome In Childhood

Hemophagocytic syndrome(HPS),also termedhemophagocytic lymphohistiocytosis(HLH),is an aggressive and life threatening lymphoproliferative disorder most frequently observed in infants and young children.Patients with HLH generally show persistent high grade fever,pancytopenia,coagulation abnormality,liver dysfunction,hypofibrinogenemia and hypertriglyceridemia.Studies enrolling a large number of HLH patients is limited till now due to the rare incidence of disease.Diagnosis of HLH is difficult because of lacking specific criteria and markers.Excessive cytokines production,especially interferon gamma(IFN-?)and interleukin-10(IL-10)increase significantly at early stage of disease and play a critical role in the pathogenesis of HLH.Increase of IFN-? and IL-10 level has been shown to be a useful tool in HLH for early diagnosis,distinguishing from other hyper-inflammatory conditions,and monitoring disease activity.Polymorphism of IFN-? and IL-10 has been reported to involve in the susceptibility,severity and clinical outcome of several inflammatory immune diseases.However,the association between IFN-? and IL-10 polymorphism and the susceptibility of HLH is unclear.Therefore,the current study retrospectively analyzed clinical characteristics,treatment,and prognosis of 40 children with HLH in Xuzhou Children's Hospital,which will help to know the current diagnosis and treatment staus of HLH in China.Moreover,the current study for the first time analyzed polymorphism of IFN-? and IL-10 in children with HLH,to identify new risk factor,as well as precisely diagnosis HLH.Part I: Clinical analysis of 40 children with HLHObjective: To investigate the clinical characteristics,family history,as well as the efficiency and prognosis of children with HLH diagnosed and treated by HLH-2004 regime.Methods: A total of 40 children with HLH diagnosed in Xuzhou Children's Hospital from Jan 2011 to Dec 2014 were enrolled.Clinical data including family history,clinical characteristics,laboratory results,treatment and prognosis of retrospectively analyzed.Results: Amont the 40 cases of HLH children,24 were males and 16 were females.The media age was 1 year old(range from 4 months to 10.5 years old).Two cases had positive family history,27 cases had known primary diseases,while 13 cases had no clear reasons.Main clinical manifestations included fever,hepatosplenomegaly,bleeding,pulmonary infiltration,pleural effusion,central nervous system lesions,rash and so on.Main laboratory abnormalities were cytopenia,abnormal liver function,coagulation abnormalities,hypertriglyceridemia,elevated ferritin,hemophagocytosis in bone marrow.35 cases were treated with HLH-2004 regimen,27 cases survived and 13 cases died.The main death reasons were infection,disseminated intravascular coagulation(DIC)and multiple organ failure.Conclusion: HLH in Chinese children is still an aggressive syndrome with complicated manifestations Treatment with HLH-2004 regime resulted in a relative good result.Part II: Effect of interferon-gamma and interleukin-10 gene polymorphisms on hemophagocytic syndrome in childhoodAim: The aim of the study is to investigate the effect of interferon-gamma and interleukin-10 gene polymorphisms on hemophagocytic syndrome in childhood.Methods:A total of 40 children with HLH and 160 age and gender matched healthy control children from Xuzhou Children's hospital were enrolled in the study.Serum IFN-? and IL-10 levels were measured by ELISA method.Polymorphisms of IFN-? gene at position of +874 and +2109,and IL-10 at position of-1082 were analyzed by allele-specific polymerase chain reaction(AS-PCR)assay.and reconfirmed by DNA sequencing analysis.Result:1.Median serum concentrations of IFN-? and IL-10 were significantly higher in children with HLH compared to those in healthy controls.2.There were significant differences in the distributions of IFN-?+874 and IL-10-1082 genotypes between HLH and control group.The frequencies of IFN-? +874 A/T and T/T genotypes,as well as T allele were significantly higher in the HLH group compared with control group.The frequency of IL-10-1082 G/A genotype and G allele were significantly increased in the HLH patients compared with control.No significant difference was found on the distribution of IFN-?+2109A/G genotype or alleles between the two groups.3.The effect of IFN-?+874 A/T,+2109 A/G,and IL-10-1082 G/A genotypes on serum levels of IFN-? and IL-10 in children with HLH was further analyzed.The median(range)serum level of IFN-? was significantly higher in children with IFN-?+874 T/T genotype.No effect of IFN-?+2109 gene polymorphism on serum level of IFN-? was observed.On the other hand,median(range)serum concentrations of IL-10 was significantly higher in children with IL-10-1082 G/A genotype.Conclusion: This study presents preliminary evidence for the association between IFN +874 A/T,T/T,IL-10-1082 G/A genotypes and HLH susceptibility in children with HLH.