人类免疫缺陷病毒阴性儿童马尔尼菲篮状菌感染11例外周血免疫学特征及基因变异分析

Peripheral immune profile and gene variations of 11 immunodeficiency virus-negative children with Talaromyces marneffei infection

目的探讨人类免疫缺陷病毒(HIV)阴性儿童马尔尼菲篮状菌(TM)感染的外周血免疫学特征及基因变异结果, 以提高儿童TM感染的诊疗水平。方法回顾性分析2010年1月至2022年12月广州医科大学附属广州市妇女儿童医疗中心诊治的11例TM感染的HIV阴性患儿的临床资料, 包括临床特征、外周血免疫学特征以及基因检测结果。结果 11例患儿中, 男9例, 女2例, 中位年龄19个月。常见的临床表现为发热(10/11, 90.91%)、咳嗽(10/11, 90.91%)和肝大(7/11, 63.64%)。常见的严重并发症包括急性呼吸窘迫综合征(7/11, 63.64%)和脓毒性休克(5/11, 45.45%)。最终2例患儿死亡。6例患儿(6/11, 54.55%)病程中出现一过性中性粒细胞减少;4例分别出现淋巴细胞减少和免疫球蛋白(Ig)G降低, 6例出现IgA降低, 3例出现IgM降低, 5例出现IgE降低, 3例出现IgM升高, 2例出现IgE升高。1例T细胞和B细胞计数均下降。所有患儿进行基因检测, 均发现基因突变, 8例患儿结合基因突变结果明确诊断为出生免疫错误(IEIs), 其中4例发现CD40LG基因突变诊断为CD40配体缺陷, 1例发现IL2RG基因突变诊断为严重联合免疫缺陷, 1例发现STAT3基因自发突变结合临床表现诊断为信号传导和转录激活因子3(STAT3)相关高IgE综合征, 1例发现STAT1基因突变诊断为功能获得型信号传导和转录激活因子1(STAT1)免疫缺陷, 1例发现CARD9复合杂合突变诊断为家族性念珠菌病2型。另3例中2例患儿基因变异为可能致病, 1例患儿为致病未明确。结论 TM感染在HIV阴性儿童中临床表现不典型, 严重并发症多, 病死率高。早期识别并积极进行基因检测, 发现潜在IEIs, 有助于改善患儿远期预后。

Objective To explore the immunological characteristics of peripheral blood and genetic variations of 11 immunodeficiency virus(HIV)-negative children with Talaromyces marneffei(TM)infection,thus enhancing the diagnostic and therapeutic levels of TM infection in children.Methods Clinical data of 11 HIV-negative children with TM infection who presented to Guangzhou Women and Children′s Medical Center,Guangzhou Medical University from January 2010 to December 2022 were retrospectively analyzed,including clinical characteristics,peripheral immune profile and genetic test results.Results A total of 11 HIV-negative children with TM infections were recruited,involving 9 males and 2 females with a median age of 19 months.The main clinical manifestations were fever(10/11,90.91%),cough(10/11,90.91%)and hepatomegaly(7/11,63.64%).Common severe complications included acute respiratory distress syndrome(7/11,63.64%)and septic shock(5/11,45.45%).Finally,2 children died.Transient neutropenia occurred in 6 cases(6/11,54.55%),and lymphocytopenia combined with serum immunoglobulin(Ig)G decrease was observed in 4 cases(4/11,36.36%).IgA decrease,IgM decrease,IgE decrease,IgM increase and IgE increase were observed in 6 cases,3 cases,5 cases,3 cases,and 2 cases,respectively.Both T-lymphocyte and B-lymphocyte counts decreases was observed in 1 case.Genetic testing was performed in all recruited children,and genetic variations were detected in all of them.Inborn errors of immunity(IEIs)were diagnosed in 8 cases,including 4 diagnosed as CD40 ligand deficiency with CD40LG variation,1 of severe combined immunodeficiency with IL2RG variation,1 of Signal transduction and activator of transcription 3(STAT3)-hyper-IgE syndrome with STAT3 variation and 1 of familial candidiasis type 2 with CARD9 compound heterozygous mutations.In the other 3 cases,2 carried genetic variations that were likely pathogenic,and 1 case was considered uncertain.Conclusions The clinical manifestations of HIV-negative children with TM infection are atypical,which is characterized as serious complications and high mortality.Early identification and gene testing to detect potential IEIs can improve the prognosis of TM infection.