Clinical Characteristics Of Children Secondary Hemophagocytic Syndrome And The Significance Of Related Single Allelic Mutations:A Single-center Analysis

Objective:Through the analysis of the clinical characteristics and gene mutation results of children’s secondary hemophagocytic syndrome(s HLH)in our center,we explored the clinical characteristics of s HLH and the significance of related single allele mutations,and provided some clinical experience for the diagnosis,treatment and prognosis evaluation of this disease.Methods:The subjects of the study were children diagnosed with s HLH for the first time at Qingdao Women and Children’s Hospital,Qingdao University from August 2017 to October 2022 and who had completed hemophagocytic lymphohistiocytosis(HLH)-related gene testing.The clinical data of the children were collected,including general medical history data,laboratory tests,imaging tests,genetic test results,treatment prognosis,etc.According to whether they carry 15 mutated genes closely related to HLH(including AP3B1,BLOC1S6,CD27,IL2 RG,ITK,LYST,MAGT1,PRF1,RAB27 A,SH2D1A,STX11,STXBP2,TCN2,UNC13 D,XIAP),the children were divided into Mutation group(monoallelic mutation,that is,single/double gene heterozygous mutation)and no mutation group,the clinical characteristics and treatment prognosis were compared between the two groups.Results:1.Clinical features: A total of 29 children were included in this study,the youngest was 2 months old,the oldest was 15 years old,and the median age was 1.75 years old.The children all went to see a doctor because of recurrent fever,and the symptoms of the respiratory system were more common,and some of them could be accompanied by symptoms of digestive and nervous systems.Splenomegaly occurred in 16 cases(55.2%),and serous cavity effusion occurred in 22 cases(75.9%).Epstein-Barr virus(EBV)infection was found in 22 children(75.9%),which was the main pathogen detected in this cohort.In the early stage of onset,the laboratory indexes of children with s HLH can be shown as hemocytopenia,liver function damage,coagulation dysfunction,immune function disorder and so on.The increase of ferritin and soluble IL-2 receptor(s CD25)and bone marrow hemophagocytosis may occur at the time of diagnosis.2.Gene detection results: 12 children(41.4%)detected gene mutations closely related to HLH,including six gene mutations: LYST,PRF1,ITK,UNC13 D,TCN2,and STXBP2.Among them,LYST and UNC13 D gene mutations were the most common.A total of 13HLH-related gene mutation sites were detected in 12 children,and no new mutation sites were found,including 12 missense mutations and 1 synonymous mutation.3.Comparison of clinical data between the mutation group and the non-mutation group: The patients were divided into two groups according to whether they carried HLHrelated single allele mutations: 12 cases(41.4%)in mutation group and 17 cases(58.6%)in non-mutation group.Comparing the general baseline characteristics and treatment prognosis between the two groups,the levels of platelet(PLT)and absolute neutrophil count(ANC)at onset in the non-mutation group were significantly lower than those in the mutation group(P=0.049、P=0.023);The ANC level at diagnosis was also significantly lower than that in the mutation group(P=0.028).The number of children with s CD25≥15000U/ml diagnosed in the non-mutation group was significantly higher than that in the mutation group(P>0.003).4.Treatment and prognosis: 79.3%(23/29)of children were treated with etoposidebased chemotherapy immediately after diagnosis,and non-standardized treatment schemes such as hormone shock and gamma globulin immune support were used for some mild patients(20.7%,6/29).Among them,28 patients were followed up regularly,1 patient lost follow-up by telephone after discharge,23 children reached the state of disease inactivity or complete remission after treatment,which were classified as good prognosis group,and5 children with disease activity or disease reactivation were classified as poor prognosis group.In the good prognosis group,there were 9 cases in the mutation group and 14 cases in the non-mutation group;in the poor prognosis group,there were 2 cases in the mutation group and 3 cases in the non-mutation group.There was no significant difference in the prognosis between the mutation group and the non-mutation group(P=1.000).Comparing the prognosis of the mutation group and the non-mutation group under the same treatment regimen,there was no significant difference in prognosis between the two groups(P>0.05).Conclusion:1.The etiology of s HLH in children is complex,and infection is the most common predisposing factor,especially EBV infection.2.HLH closely related gene mutations were detected in 41.4% of the patients,and LYST and UNC13 D were the most common mutations.3.Children with s HLH who do not carry single allele mutations closely related to HLH have significantly reduced PLT and ANC in the early stages of the disease,and significantly increased s CD25,but have no impact on prognosis.4.Disease predisposing factors,genetic background,and different early treatment methods jointly affect the development of s HLH,and the weight changes of different factors will affect the disease progression.