儿童噬血细胞性淋巴组织细胞增生症28例临床分析

目的分析儿童噬血细胞性淋巴组织细胞增生症(HLH)的病因、临床特点、治疗及预后。方法对郑州大学第一附属医院2010年5月-2012年7月收治的28例HLH患儿入院时的临床表现、实验室检查指标和治疗转归进行回顾性分析。结果 (1)病因:EB病毒感染相关10例,巨细胞病毒感染相关3例,肺炎链球菌感染相关1例,支原体感染相关1例,淋巴瘤相关3例,急性淋巴细胞白血病(ALL)相关1例,余9例无明确病因;(2)儿童HLH早期临床表现以持续高热(100%),脾肿大(96%),肝肿大(85%)最为常见;(3)实验室检查可表现为铁蛋白(SF,100%)和LDH(100%)明显升高,血细胞减少(96%),肝酶升高(93%),骨髓噬血现象(82%),低蛋白血症(70%),低钠血症(61%),NK细胞比例下降(58%),低纤维蛋白原血症(52%)及高三酰甘油血症(29%);(4)所有患儿均采用HLH-2004方案进行化疗,16例疾病缓解,2例有效,2例放弃治疗,8例死亡。结论HLH多继发于EB病毒感染,早期症状缺乏特异性,联合检测SF和LDH可能具有重要临床价值。HLH-2004是有效的治疗方案。     

儿童噬血细胞性淋巴组织细胞增生症175例临床特征及预后分析

目的探讨噬血细胞性淋巴组织细胞增生症(HLH)的临床特征及预后因素。方法回顾分析2015年1月至2020年10月收治的175例HLH患儿的临床资料,比较存活组和死亡组的临床特征,采用log-rank检验及COX比例风险回归模型进行生存分析。结果 175例HLH患儿中男91例、女84例,中位年龄2.0(1.0～8.0)岁,以婴幼儿期起病最常见(54.3%)。原发性HLH 9例,继发性HLH 166例。继发性HLH中以感染相关性HLH最常见(66.9%)。临床以发热、脾大为突出表现,血清乳酸脱氢酶(LDH)升高最为显著。与存活组相比,死亡组患儿白细胞计数和血红蛋白较低,活化部分凝血活酶时间、凝血酶原时间较长,纤维蛋白原(FIB)较低,中枢神经系统受累率较高,差异均有统计学意义(P<0.05)。中枢神经系统受累、FIB≤1.5 g/L是影响患儿总生存期的独立危险因素(P<0.05)。结论 HLH多见于婴幼儿,临床表现以发热最多见,血清LDH大多异常升高。中枢神经系统受累及FIB水平对初诊HLH患儿疗效评估及预后判断具有重要意义。     

阿齐霉素与氯霉素治疗儿童恙虫病疗效比较

目的　探讨阿齐霉素与氯霉素治疗恙虫病的疗效。方法　将 6 7例研究对象随机分为A、B两组。A组 34例使用阿齐霉素治疗 ,B组 33例使用氯霉素治疗 ,比较两组的临床疗效。结果　A、B组治愈率分别为91.2 %、93.9% ,统计学处理无显著性差异 (P >0 .0 5 ) ;A组 4病例出现胃肠道反应 ,B组有致骨髓抑制的风险性。结论　阿齐霉素治疗恙虫病效果好 ,副作用少 ,且用药方便 ,可替代氯霉素成为治疗恙虫病首选药     

小儿噬血细胞性淋巴组织细胞增生症的研究

组织细胞疾病主要涉及两大类细胞,一类为参与抗原递呈的朗格罕细胞和树突状细胞。过去诊断为勒-雪病、韩-薛-柯病和骨嗜酸细胞性肉芽肿的组织细胞疾病均证实为朗格罕细胞组织细胞增生性疾病。另一类为参与抗原处理过程的单核细胞和巨噬细胞。噬血细胞性淋巴细胞组织细胞增生症(HLH)通常与噬血细胞综合征(HPS)同义,占巨噬细胞相关疾病的绝大部分。     

儿童噬血细胞淋巴组织细胞增生症20例分析

目的了解噬血细胞淋巴组织细胞增生症(HLH)的病因,临床特点,治疗及预后。方法回顾性分析20例HLH患儿的发病相关因素,临床特点,实验室检查指标的变化,治疗效果以及转归。结果所有病例均以持续高热起病,均有肝脾肿大,50%患儿有淋巴结肿大;所有患儿二系以上外周血细胞减少,肝功能异常,凝血功能异常有17例(85%),高甘油三脂血症15例(75%),血清铁蛋白增高13例(65%)。17例(85%)骨髓涂片可见组织细胞增生。12例(60%)和感染因素相关,其中8例(40%)明确与EB病毒感染有关。有6例(3%)按HLH-2004方案正规化疗,达到临床治愈。14例(70%)不规范化疗患儿,8例(40%)仍有肝功能异常和体温波动,5例(25%)死亡。结论HLH起病急重,进展快,病死率高。有明显血象、骨髓细胞学、肝功能改变,高甘油三酯血症以及血清铁蛋白改变。对高度怀疑为HLH的患儿,应及早行诊断性治疗,规范按照HLH-2004方案化疗,改善预后。     

儿童噬血细胞综合征临床及基因突变筛查研究

目的研究SH2D1A、XIAP、PRF1、UNC13D、STX11、STXBP2、RAB27A、AP3B1、LYST及ITK等10种儿童噬血细胞综合征(HLH)相关突变基因在HLH分布情况及相关临床特点。方法收集2012年7月-2015年11月期间按照国际组织细胞协会HLH-2004标准确诊为HLH的37例患儿的血液样本并行基因测序,对测序结果进行突变位点分析。结果37名HLH患儿的中位年龄为2.6岁,检出基因突变组(22例)与未检出基因突变组(15例)中位年龄分别为2.09岁、2.67岁,差异无统计学意义(P0.05)。22例患儿检测出基因突变,均为杂合突变未见纯合突变。UNC13D突变例数最多(50%)以内含子剪切位点突变为主(38%),同时存在错义突变和移码突变。多位点突变与单一位点突变、无突变组在发病年龄、粒细胞及血小板减少程度、NK细胞数量上无明显差异。70.3%HLH患儿同时合并有EB病毒感染。4例复发、1例初诊时死亡患儿均来源于基因突变组,其中4例存在EB病毒感染,1例疾病初期无EB病毒感染,而复发时检测出EB病毒阳性。结论 UNC13D突变在中国人群的HLH较多,基因突变与患儿年龄、病情严重程度无明显相关性。     

Secondary hemophagocytic lymphohistiocytosis in Turkish children

Between January 1998 and January 2005, a total of 18 children 2 weeks-72 months of age were diagnosed as having secondary hemophagocytic lymphohistiocytosis. The frequency of secondary hemophagocytic lymphohistiocytosis among total hospitalized patients during this period was 0.05% (18 of 34,250). Of the 18 patients, 8 (44.5%) had bacterial infections; cytomegalovirus and Epstein-Barr virus infections were present in 5 (28%) and 1 (5.5%), patient, respectively. Leishmaniasis was diagnosed in 2 patients (11%), and herpes simplex virus was diagnosed in 2 patients (11%). Six patients died during treatment, and 1 patient was lost to follow-up. The survival rate was 61%.     

Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children

Two children presented with a history of fever and rash. Lab values revealed pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both children quickly developed respiratory distress and hypotension requiring admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies for Ehrlichia returned positive. The patients were started on doxycycline and treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery. In both patients, testing for MUNC and perforin genes were found to have no mutation. These two cases demonstrate the importance of considering Ehrlichiosis as a possible trigger of HLH.     

Primary hemophagocytic lymphohistiocytosis in Turkish children

Nineteen children with hemophagocytic lymphohistiocytosis (HLH) were studied in the Department of Pediatric Hematology, Hacettepe University. Patients were divided into two groups. Group 1 : Thirteen patients were classified as having a genetic etiology (7 familial, 6 presumed familial) on the basis of an affected sibling and consanguinity. There was a history of consanguineous marriage in 13 of the families. Seven of them had a history of a sibling with HLH. Group 2 : Six patients were diagnosed with sporadic HLH. The age at presentation for familial patients was 0.7-84 months (mean 21.9 ±24.9 months), and for sporadic cases it was 2.5-48 months (mean 22.7 ±19.8 months). The clinical and laboratory data of these two groups were similar at diagnosis. Thirteen cases were diagnosed premortem by bone marrow aspiration. Splenic biopsy was performed in 2 patients. Four patients were diagnosed by postmortem examination. Elevated LDH levels were found in all patients tested. No significant differences for clinical and laboratory data were found between the two groups.     

儿童噬血细胞性淋巴组织细胞增生症XIAP基因突变筛查

目的 了解X 连锁凋亡抑制因子（XIAP）基因突变和序列变异在儿童噬血细胞性淋巴组织细胞增生症（HLH）中的发生情况。方法 应用聚合酶链反应（PCR）结合直接测序方法,对2009 年1 月至2012年12 月诊断为HLH 的65 例患儿（病例组）及70 例健康儿童（对照组）XIAP 基因外显子（1-1、1-2、2~6）编码区进行序列分析。结果 在HLH 患儿XIAP 基因外显子编码区未发现突变;仅在XIAP 外显子5 发现1 个非同义单核苷酸多态性（SNP）位点rs5956583,但此SNP 位点的基因型和等位基因频率在病例组和对照组之间的分布差异均无统计学意义（均P>0.05）。结论 由XIAP 基因突变导致的儿童HLH 可能比较罕见;XIAP 基因SNP 位点rs5956583 可能与儿童HLH 发病关系不大。     

儿童噬血细胞性淋巴组织细胞增生症的预后因素分析

目的：通过总结儿童噬血细胞性淋巴组织细胞增生症(HLH)的临床特征,分析相关因素与预后的关系,探索影响HLH患儿预后的因素。方法：回顾性分析63例HLH患儿的病例资料,使用Kaplan-Meier法绘制生存曲线,采用COX模型对影响预后的相关因素进行单因素分析,筛选出有意义的因素进行多因素COX回归分析。结果：患儿的3年及5年生存率均为62.9%;确诊后第1天至4个月,生存率由98.4%降至73.2%。影响疾病预后单因素分析中,具有统计学意义的因素只有治疗后2~3周血小板恢复情况（P=0.002）;在使用依托泊苷治疗的患儿中,治疗1 d后体温恢复情况对预后的影响具有统计学意义（P=0.016）。结论：HLH患儿的预后较为满意,但确诊后的前4个月生存率下降快。治疗2~3周后血小板恢复情况以及使用依托泊苷1 d后体温恢复情况影响患儿预后。     

儿童噬血细胞综合征中枢神经系统病变临床分析

目的总结儿童噬血细胞综合征(HLH)中枢神经系统病变的临床表现、头颅MRI特点及治疗方案。方法回顾分析3例有中枢神经系统症状的HLH(CNS-HLH)患儿的临床表现、脑脊液检查结果、中枢神经系统影像学特点及治疗、转归。结果 (1)CNS-HLH于重症HLH(2例)或在HLH疾病进展时(2例)发生;(2)CNS-HLH临床主要表现为头痛、呕吐、嗜睡、昏迷及抽搐;(3)脑脊液检查见蛋白、淋巴细胞增高,1例发现噬血细胞;(4)头颅MRI表现为硬膜下积液及脑实质局灶性T2高信号;(5)以替尼泊苷(150 mg/m2,每周1次)替代标准HLH-2004方案中的依托泊苷(3例)及给予兔抗人胸腺细胞免疫球蛋白2.5mg/(kg.d),5 d(2例),CNS-HLH和全身症状缓解2例,治愈1例。结论 CNS-HLH通常发生在重症HLH,病情严重,进展快。其临床表现、脑脊液检查、头颅MRI改变等均缺乏特异性。可应用强免疫抑制剂如替尼泊苷及兔抗人胸腺细胞免疫球蛋白替代标准HLH-2004方案无法控制的高细胞因子风暴,为造血干细胞移植赢得时间。     

儿童EBV阳性噬血细胞综合征的遗传分析及其与Th1/Th2细胞因子的关系

目的 探讨遗传变异对EBV阳性噬血细胞综合征（HLH）患儿预后的影响及其与细胞因子的关系。方法 选取81例EBV阳性且已进行相关基因测序的HLH患儿，根据有无基因突变分为无突变组（n=35）和突变组（n=46），再根据基因突变方式分为单杂合突变（SHM）亚组、双杂合突变（DHM）亚组和纯合或复合杂合突变（H-CHM）亚组。测定各组患儿血清细胞因子水平，分析其与HLH基因突变的关系。结果 UNC13D基因突变出现频率最高（13/46，28%）。STXBP2 c.575G > A （p.R192H）和UNC13D c.604C > A （p.L202M）基因突变首次被报道，均判定为“可能致病的”。突变组TNF-α水平高于无突变组，IFN-γ水平低于无突变组（P < 0.05）。DHM亚组IL-4水平高于无突变组，H-CHM亚组IL-4水平低于DHM组（P < 0.0083）。H-CHM亚组的1年总生存率（39%±15%）低于无突变组、SHM亚组和DHM亚组（分别为85%±6%、86%±7%和91%±9%，P=0.001）。结论 具有基因突变的HLH患儿IFN-γ水平显著降低；H-CHM患儿的预后较差，而其他突变对其预后影响不显著，这可能有助于医生进行临床决策。     

Clinical assessment of Mycoplasma pneumoniae-associated hemophagocytic lymphohistiocytosis

Background: Mycoplasma pneumoniae has been reported to be an etiologic pathogen of infection-associated hemophagocytic lymphohistiocytosis (HLH), but few case reports have been available to date.
Methods: The clinical features of four childhood cases of M. pneumoniae -associated hemophagocytic lymphohistiocytosis (Mp-HLH) were retrospectively assessed to obtain data that might be useful for early diagnosis and effective management. The previous English-language literature pertaining to Mp-HLH was also reviewed.
Results: The patients were two boys and two girls, aged between 1 and 11 years of age. One patient was demonstrated to have concurrent infection with rubella. All the patients had typical radiographic features of M. pneumoniae pneumonia, and one patient also had encephalopathy as a complication. All the children underwent bone marrow examination because of antibiotic-refractory fever, mild hepatosplenomegaly, cytopenia, hyperferritinemia and elevated levels of urine β2-microglobulin. Cytopenia and hepatosplenomegaly in the present patients were relatively mild as compared to those in cases of other infection-associated HLH such as Epstein–Barr virus infection-associated HLH. Treatment with corticosteroids resulted in prompt and complete resolution in two cases, and i.v. high-dose gammaglobulin therapy achieved a complete response in another child. Spontaneous resolution under treatment with antibiotics alone was observed in one case.
Conclusion: Although Mp-HLH is a rare complication of M. pneumoniae infection, it should always be considered in patients with antibiotic-refractory M. pneumoniae infections with cytopenia. Mp-HLH might be effectively treated by corticosteroids or high-dose gammaglobulin. To clarify the diverse clinical manifestations of M. pneumoniae infections, immunological interactions between M. pneumoniae and the host immune system should be further investigated.     

儿童噬血细胞淋巴组织细胞增生症诊治进展

噬血细胞淋巴组织细胞增生症(hemophagocytic lymphohistiocytosis,HLH)是以发热、肝脾大、血细胞减低、高甘油三脂血症及低纤维蛋白原血症为特点的一组临床综合征,是免疫异常基础上严重威胁患儿生命的过度炎症反应性疾病,免疫化疗使该病的生存率得到显著提高.随着对HLH认识的不断深入,诊断为该病的患儿也在逐年增多,发病率要远高于以往的认识.除遗传性HLH外,感染、肿瘤、结缔组织疾病等多种疾病均可继发HLH,近几年在高致病性禽流感H5N1患者中也发现了继发HLH.由于与HLH相关的疾病种类繁多,对患儿所造成的危害极为严重,使得明确HLH发病机制并探究更有效的治疗迫在眉睫.     

儿童真菌感染继发噬血细胞性淋巴组织细胞增生症 3 例分析

目的提高对儿童真菌感染继发噬血细胞综合征的临床认识。方法总结3例确诊为真菌感染继发噬血细胞综合征患儿的相关资料。结果 3例患儿,男2例,女1例,年龄1岁7个月到3岁1个月,均以反复发热为主诉,2例伴咳嗽,1例伴呕吐,体检发现有肝脾及浅表淋巴结肿大。通过病原学检查确诊为真菌感染的时间均是入院后5天,在有效抗真菌治疗无效后进一步诊断为噬血细胞性淋巴组织细胞增生症。患儿血常规检查早期表现为白细胞计数升高,而血小板及血红蛋白不同程度降低。在抗真菌治疗基础上,2例按照HLH-2004方案进行化疗,1例仅增加地塞米松治疗,3例在治疗过程中均使用丙种球蛋白。最终3例患儿均好转出院。结论儿童真菌感染继发噬血细胞综合征临床少见,在抗真菌治疗基础上增加免疫抑制能改善患儿预后。     

Incidence and treatment of hemophagocytic lymphohistiocytosis in hospitalized children with Ehrlichia infection

We report a large cohort of pediatric patients with human monocytic ehrlichiosis (HME), enabling an estimated incidence of secondary hemophagocytic lymphohistiocytosis (HLH) in hospitalized children with HME. Among 49 children with PCR‐confirmed Ehrlichia infection, 8 (16%) met current criteria for HLH. Those with HLH had more significant hematologic abnormalities and longer durations from symptom onset to admission and definitive anti‐infective therapy. Among these eight, three received chemotherapy plus doxycycline, one of whom died; the other five were treated with doxycycline without chemotherapy, and all survived without HLH recurrence. Our findings demonstrate that antimicrobial therapy alone can successfully resolve Ehrlichia‐associated HLH.     

HLH-2004方案诊断治疗小儿噬血细胞综合征结果分析

目的 了解我国小儿噬血细胞综合征(HLH)的发病情况和治疗效果,并开展HLH的穿孔素(perforin)基因研究.方法 研究对象为符合国际组织细胞协会HLH-2004诊断标准的18例患儿,分析患儿起病时及治疗后的临床资料.用流式细胞仪和基因测序法检测患儿的穿孔素基因.结果 流式细胞仪检测发现1例患儿的穿孔素在CD8+T细胞和NK细胞中的表达几乎完全缺如,而且基因测序发现该患儿的穿孔素基因存在错义突变(G47C),确诊为原发性HLH.14例接受HLH-2004治疗,随访时间2周～39个月,临床缓解4例,复发4例,持续活动4例,失访2例.共死亡7例.结论 HLH-2004是诊断和治疗小儿HLH的有效方案,提高生存率需积极开展造血干细胞移植.为鉴别原发性和继发性HLH应进行相关基因检测.