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。     

Elevated circulating levels of interleukin-1 receptor antagonist but not IL-1 agonists in hemophagocytic lymphohistiocytosis

The familial form of hemophagocytic lymphohistiocytosis (HLH) is an inherited disease with disturbed immunomodulation and characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, and coagulopathy, i.e., findings which are similar to many of the reported biological effects of the inflammatory cytokines. Due to the previously shown hypercytokinemia in active HLH with elevated levels of interleukin (IL)-6, tumor necrosis factor-α, and interferon-gamma, it has been suggested that cytokine dysregulation may be of pathophysiological importance. Here we have assayed the serum levels of the members of the IL-1 ligand family, the two agonists IL-1α and IL-1β and the antagonist IL-1 receptor antagonist (IL-1ra), in nine children with HLH and cerebrospinal fluid (CSF) specimens from four children. Serum IL-1ra was elevated in all patients with active disease to a degree which correlated well with disease activity. Furthermore, the levels decreased day by day during treatment of a patient who suffered a relapse. Moreover, high levels of IL-1ra were also detected in CSF during active disease. However, IL-1β levels were all within normal limits and circulating IL-1α levels were normal in all but two patients. © 1996 Wiley-Liss, Inc.     

Serum ferritin is a cost-effective laboratory marker for hemophagocytic lymphohistiocytosis in the developing world

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease in children and presents many diagnostic difficulties. Without prompt intervention, the disease typically runs a rapidly fatal course. Diagnostic criteria were proposed by the Histiocyte Society in 1991 and have since been modified. Included in these criteria is a ferritin level >500 mcg/L. Although not diagnostic, a high ferritin level is highly suggestive of HLH. Serum ferritin assays are more accessible and cost-effective compared with other biochemical markers, particularly in resource-limited settings. Fifteen patients with HLH were treated at Red Cross War Memorial Children's Hospital between 1991 and 2010. Hyperferritinemia was a consistently reliable finding (93%) compared with either serum fibrinogen or triglycerides, which were elevated in only half of the patients. It is our contention that analysis of a complete blood count and serum ferritin (in addition to clinical criteria and tissue examination of marrow and/or cerebrospinal fluid) is probably the single most cost-effective and clinically helpful means to make the diagnosis of HLH when laboratory access is limited.     

儿童噬血细胞综合征穿孔素基因突变筛查及临床研究

了解穿孔素基因（PRF1）突变和序列变异在中国儿童噬血细胞综合征（HLH）中的发生情况,探讨基因突变型与临床表现之间可能的关系。方法　应用聚合酶链反应（PCR）结合直接测序方法,对2006年1月至2008年5月在首都医科大学附属北京儿童医院治疗的临床诊断为HLH的30例患儿（HLH组）及50名新生儿（对照组）PRF1基因外显子编码区进行突变筛查。 结果　在3例HLH患儿的PRF1基因外显子编码区发现3个杂合错义突变,这3个突变均导致氨基酸改变（C102F、S108N 和T450M）,而在对照组中却未发现。1例患儿为复合杂合错义突变（S108N和 T450M）,从遗传学上可明确诊断为家族性HLH亚型2（FHL2）;1个同义序列变异 （Q540Q） 在1例患儿中发现,而在对照组中未发现;在HLH组和对照组的PRF1基因编码区发现2个单核苷酸多态位点（SNP） （A274A、300H）,但这2个SNP的基因型频率在HLH组和对照组之间的分布差异无统计学意义（P均 > 0.05）。结论　我国HLH患儿中存在PRF1基因突变,而突变位点（C102F和S108N）目前仅在中国患儿中发现。显示了我国HLH患儿PRF1基因突变具有自身的特点。对于无HLH家族史和起病年龄较晚的HLH患儿,也要考虑家族性HLH的可能。     

Adverse outcomes in primary hemophagocytic lymphohistiocytosis

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by abnormal proliferation of macrophages. Although the mortality rate in children diagnosed with primary HLH is high, little has been described about the nature of adverse events. This review evaluates unfavorable events in children with primary HLH to suggest methods of improving outcomes. METHODS: Charts of patients who met diagnostic criteria for primary HLH at the Hospital for Sick Children between January 1985 and June 2000 were retrospectively reviewed. The primary outcome measure was an adverse event, defined as death, the subsequent diagnosis of malignancy, or developmental delay. RESULTS: Twenty children were diagnosed with primary HLH. The median age at diagnosis was 6.5 months (range 1-78 months). Nineteen children received chemotherapy and two underwent matched sibling donor bone marrow transplantation. Of the 20 children, 12 (60%) died. These deaths were attributed to progressive HLH in 4 cases and invasive infection in 8 cases. These infections consisted of disseminated cytomegalovirus infection (n = 1), sepsis (n = 1), and invasive fungal infections (n = 6). Eight children survived. Two were subsequently diagnosed with malignancy. Two others were found to have significant developmental delay. CONCLUSIONS: The overall mortality rate was 60% in our series of 20 children with primary HLH; 50% of deaths were directly attributable to invasive fungal infection. Developmental delay and the diagnosis of malignancy are important events in this cohort.     

穿孔素基因多态性与儿童噬血细胞综合征的相关性研究

目的了解穿孔素基因(PRF1)多态性在噬血细胞综合征(HLH)患儿中的分布情况,探讨PRF1基因多态性与HLH是否存在易感相关性。方法收集2009年1月至2013年12月确诊为HLH的48例患儿(HLH组)及100名健康体检儿童(对照组)的临床资料,应用聚合酶链反应(PCR)结合直接测序方法对两组患儿的PRF1基因编码区(包括3个外显子和2个内含子)进行基因多态性位点筛查。结果 48例HLH患儿中,在PRF1基因编码序列中共发现3个SNP位点,而在非编码序列中共发现7个SNP位点;PRF1基因非编码序列中还有2个SNP位点rs10999426和rs10999427分别仅在5例对照组儿童中发现(5%);以上12个SNP位点在HLH组和对照组中的基因型及等位基因频率分布差异均无统计学意义(P0.05)。连锁不平衡分析提示rs10999426和rs10999427紧密连锁(D=1,r2=1),但上述2个位点构建的A-T单体型在HLH组和对照组中的分布频率差异无统计学意义(P0.05)。结论 PRF1基因多态性与HLH发病存在易感相关性的可能性不大;rs10999426和rs10999427存在连锁不平衡关系,其构建的A-T单体型虽仅在对照组中发现,但发生率低,可能不是家族性HLH的保护性因素。     

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.     

Cytokine profiles in children with primary Epstein–Barr virus infection

Primary Epstein–Barr virus (EBV) infection causes infectious mononucleosis and hemophagocytic lymphohistiocytosis (HLH) in children, where EBV infects B and CD8⁺ T cells, respectively. We measured pro‐inflammatory and anti‐inflammatory cytokines in both diseases. Significantly higher concentrations of various mediators, including interferon‐γ, neopterin, interleukin (IL)‐6, IL‐10, IL‐18, and heme oxygenase‐1, were observed in EBV‐HLH. Because of their similarity to the profile of familial HLH, this profile was likely a consequence of HLH, but not ectopic infection. TNF‐α levels were elevated in both diseases. Elevation of those mediators may contribute to the disease pathogenesis of EBV‐HLH by activating and inhibiting host immune responses. Pediatr Blood Cancer 2013; 60: E46–E48. © 2013 Wiley Periodicals, Inc.     

Hemophagocytic lymphohistiocytosis and Kawasaki disease: Combined manifestation and differential diagnosis

Both hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) are diagnosed in patients with prolonged resistant fever by using a scoring system. Concurrent manifestation of both conditions has been reported previously. We describe an infant of 7 weeks whose condition fulfilled the criteria of HLH, but who, after clinical response to treatment, suddenly died from a myocardial infarction at 11 weeks. Post‐mortem examination revealed a previously unknown coronary arteritis typical for KD. Since it is difficult to distinguish between KD and HLH, both diseases should be considered in young children with overlapping symptoms. Repeated echocardiograms may be helpful in these cases. Pediatr Blood Cancer 2009;53:493–495. © 2009 Wiley‐Liss, Inc.     

Th1/Th2细胞因子谱在儿童噬血细胞综合征诊断中的意义

目的 探讨Th1/Th2细胞因子检测在儿童噬血细胞综合征(HLH)诊断中的意义。方法 用流式细胞微球阵列术(CBA)检测50例HLH患儿血清的Th1/Th2细胞因子水平,包括γ干扰素(IFN-y)、肿瘤坏死因子(TNF)、白介素(IL)-10、IL-6、IL-4、IL-2共6种。同时设健康对照（250例健康儿童）及感染对照组（235例脓毒症患儿）。结果 50例患儿在HLH急性期各细胞因子水平的中位值如下：IFN-γ为1138.5(49.2～5000.0)ng/L、TNF为3.4(1.0 ～25.1 )ng/L、IL-10为740.5(26.5 ～ 5000.0) ng/L、IL-6为66.1 (3.9 ～ 4472.6) ng/L、IL-4为3.9( 1.0 ～ 32.8) ng/L、IL-2为4.0(1.0～51.1)ng/L,缓解后各细胞因子的水平明显下降。其中IFN-γ、IL-10和IL-6的急性期水平均明显高于缓解期和健康对照组（P均＜0.001）。而脓毒症组IFN-y、IL-10和IL-6水平分别为3.1(1.0～150.1)ng/L、46.5（3.1～5000.0）ng/L和251.3(8.4 ～ 5000.0) ng/L,其中IL-6水平明显高于HLH组(P＜0.001),但IFN-γ和IL-10却显著低于HLH患儿（P均＜0.001）。根据ROC曲线设定HLH的细胞因子诊断标准如下：IFN-y＞ 100 ng/L,IL-10＞ 60 ng/L,且IFN-γ水平高于IL-6水平。在本研究队列的HLH和脓毒症患儿中,该标准对于HLH诊断的敏感度88.0％、特异度98.7％,阳性预测值93.6％、阴性预测值97.5％。结论IFN-y和IL-10显著升高,IL-6中等升高的Th1/Th2细胞因子谱对于HLH有很高的敏感度和特异度,对于HLH的诊断具有重要的参考价值。     

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目的探讨噬血细胞综合征(HLH)-2004方案(简称HLH-2004方案)治疗儿童HLH的疗效及影响疗效的相关因素。方法回顾性分析华中科技大学同济医学院附属同济医院2005年1月至2009年12月符合国际组织细胞协会HLH-2004诊断标准的28例患儿的临床特点,根据国际组织细胞协会2004年提出的疗效标准,观察其对HLH-2004方案治疗反应及转归,并分析可能影响HLH患儿疗效的相关因素。结果 28例HLH患儿接受HLH-2004方案治疗,随访时间2周至22个月,获得完全缓解或治愈17例(60.7%);出院失访9例(32.1%),其中获临床有效或好转出院失访3例,未获缓解自动出院失访6例;死亡2例(7.2%)。结论 HLH-2004是诊断和治疗儿童HLH的有效方案,早期积极治疗原发病及采用HLH-2004免疫化疗方案,有效地控制病情,提高患儿治愈率及生存率。     

CCR2基因rs1799864多态性与儿童噬血性淋巴组织细胞增生症的关联研究

目的 探讨CCR2基因单核苷酸多态性(SNP)位点V64I(rs1799864)与儿童噬血性淋巴组织细胞增生症(HLH)发病的关联性.方法 收集2007年1月至2013年12月确诊为HLH的86例患儿的临床资料,采用SNaPshot基因分型技术对HLH患儿和128例健康对照进行CCR2基因rs1799864位点分型,比较两组该SNP位点基因型和等位基因频率的差异;以及HLH患儿不同临床特征与rs1799864位点基因型分布的关系.结果 与对照组相比,HLH组rs1799864位点的基因型和等位基因频率差异均无统计学意义(均P>0.05);就发病年龄是否<1岁、治疗后1 d体温是否恢复正常及治疗后2~3周血小板是否恢复正常等不同临床特征的HLH患儿基因型分布进行比较后发现差异均具有统计学意义(均P<0.05).结论 CCR2基因 rs1799864位点多态性与儿童HLH的发病无关,但其基因型不同可能与HLH患儿的临床表现及预后有关.     

Familial hemophagocytic lymphohistiocytosis in two brothers with X-linked agammaglobulinemia

Hemophagocytic lymphohistiocytosis (HLH) is often familial and is associated with high mortality. Primary (familial) HLH is known to occur in children with mutations in perforin, Munc13-4, or syntaxin 11. We describe a case series of two brothers who developed HLH in the setting of X-linked agammaglobulinemia (XLA, Bruton's disease) and adenovirus infection. Further studies revealed absence of Bruton's tyrosine kinase (BTK) protein expression and a novel BTK mutation.     

儿童慢性活动性EB病毒感染18例病例系列报告

目的探讨慢性活动性EB病毒感染（CAEBV）患儿的临床表现、实验室检查、治疗和预后,为其诊治提供参考。方法回顾性分析2010年1月1日至2017年12月31日18例CAEBV患儿的临床资料,包括起病方式、临床表现、实验室检查（EB病毒DNA及抗体谱、细胞因子等）、治疗和随访情况。结果18例CAEBV患儿进入本文分析,男8例、女10例。发病年龄1.0~13.9岁。该病起病方式13例为EB病毒再发感染,5例为EBV相关噬血细胞综合征（EBV-HLH）。临床表现主要为反复发热,肝、脾、淋巴结肿大,肝功能损害,血细胞减少;18例EB病毒衣壳抗原（VCA）-IgM首次检测均阴性,EB VCA-IgG均强阳性,血清（18/18）、骨髓（14/14）及活检组织EBV-DNA（肝1/4,淋巴结2/3）强阳性;IL-4、IL-10及IFN-γ升高者分别占67%（12/18）、89%（16/18）、72%（13/18）。B细胞、总T细胞及CD8+T细胞、NK细胞比例降低。患儿主要接受抗病毒药物、丙种球蛋白、免疫抑制剂、联合化疗、利妥昔单抗和造血干细胞移植等治疗。1例失访,14例（78%）死亡,EBV-HLH起病者生存期明显缩短。结论CAEBV起病方式、临床表现多样,治疗方案差异较大,病死率高,预后差。EBV DNA及抗体谱、细胞因子及淋巴细胞亚群改变呈一定的特异性,可为该病的早期诊断、进行有计划造血干细胞移植等提供参考。     

儿童慢性活动性EB病毒感染18例病例系列报告

目的探讨慢性活动性EB病毒感染（CAEBV）患儿的临床表现、实验室检查、治疗和预后，为其诊治提供参考。方法回顾性分析2010年1月1日至2017年12月31日18例CAEBV患儿的临床资料，包括起病方式、临床表现、实验室检查（EB病毒DNA及抗体谱、细胞因子等）、治疗和随访情况。结果18例CAEBV患儿进入本文分析，男8例、女10例。发病年龄1.0~13.9岁。该病起病方式13例为EB病毒再发感染，5例为EBV相关噬血细胞综合征（EBV-HLH）。临床表现主要为反复发热，肝、脾、淋巴结肿大，肝功能损害，血细胞减少；18例EB病毒衣壳抗原（VCA）-IgM首次检测均阴性，EB VCA-IgG均强阳性，血清（18/18）、骨髓（14/14）及活检组织EBV-DNA（肝1/4，淋巴结2/3）强阳性；IL-4、IL-10及IFN-γ升高者分别占67%（12/18）、89%（16/18）、72%（13/18）。B细胞、总T细胞及CD8+T细胞、NK细胞比例降低。患儿主要接受抗病毒药物、丙种球蛋白、免疫抑制剂、联合化疗、利妥昔单抗和造血干细胞移植等治疗。1例失访，14例（78%）死亡，EBV-HLH起病者生存期明显缩短。结论CAEBV起病方式、临床表现多样，治疗方案差异较大，病死率高，预后差。EBV DNA及抗体谱、细胞因子及淋巴细胞亚群改变呈一定的特异性，可为该病的早期诊断、进行有计划造血干细胞移植等提供参考。     

Extremely elevated cerebrospinal fluid protein levels in a child with neurologic symptoms: Beware of haemophagocytic lymphohistiocytosis

Neurologic symptoms can be the initial manifestation of haemophagocytic lymphohistiocytosis (HLH). In this case study, we present a 3-year old boy with a clinical picture of encephalitis, a cerebrospinal fluid (CSF) protein level up to 1165 mg/dl and diffuse cerebral MRI abnormalities. The diagnosis of HLH was established only 6 weeks after initial presentation. The boy recovered after HLH therapy with persisting mild cognitive defects. Genetic investigation demonstrated X-linked lymphoproliferative disease (XLP) as the underlying cause of HLH. The extremely elevated protein level in CSF in this case has not yet been reported in patients with HLH.     

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。     

EB病毒感染患儿CD163表达及其临床意义

目的　通过检测EB病毒(EBV)感染患儿CD163水平, 探讨CD163在EBV相关噬血细胞综合征(HLH)的诊断、病情监测及预后中的意义。方法　将因不同感染就诊的94例患儿分为EBV阳性组(n=55)和EBV阴性组(n=39, 对照组), 进一步将EBV阳性患儿分为传染性单核细胞增多症(IM)组(n=47)和HLH组(n=8)。应用酶联免疫法检测血清可溶性CD63(sCD163)水平; 流式细胞术检测外周血单核细胞表面CD163表达率。结果　HLH患儿血清sCD163水平均>10 000 ng/mL, 其中3例>30 000 ng/mL; HLH组患儿血清sCD163水平远高于对照组和IM组(P<0.05)。EBV阳性患儿血清sCD163水平与EBV-DNA拷贝数、乳酸脱氢酶和血清铁蛋白水平呈正相关, 与白细胞计数、中性粒细胞计数、血红蛋白和血小板计数呈负相关(P<0.05)。HLH患儿sCD163水平在治疗后逐步下降, 但随病情反复又升高。结论 EBV感染患儿的CD163水平与临床严重程度密切相关, sCD163>10 000 ng/mL的EBV感染患儿需警惕并发HLH。     

Severe bacteria-associated hemophagocytic lymphohistiocytosis in an extremely premature infant

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition with high mortality. We report an extremely premature girl, born in the 24th gestational week (BW 732 g), that during her second month developed a severe HLH subsequent to a Serratia marcescens septicemia, with hepatosplenomegaly, cytopenias, hyperbilirubinemia (mostly conjugated, total bilirubin 916 mumol/L), hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia (21266 mug/L), and elevated sIL-2 receptor levels. Genetic analysis revealed no PRF1, STX11 or UNC13D gene mutations. Treatment was provided according to the HLH-2004 protocol with etoposide, dexamethasone, and immunoglobulin, but no cyclosporin because of immature kidneys. She recovered fully from the HLH but developed a severe retinopathy as well as green teeth secondary to the hyperbilirubinemia. We conclude that secondary, bacteria-associated HLH can develop in premature infants, and that HLH can be treated with cytotoxic therapy also in premature infants. It is important to be aware of HLH in premature infants, since it is treatable.     

Hemophagocytic lymphohistiocytosis preceded by Kikuchi disease in children

Background  Kikuchi disease (KD) is a type of benign, self-limiting lymphadenitis, but it has also been associated with hemophagocytic lymphohistiocytosis (HLH). To date, only a few reports have suggested an association between HLH and KD. Objective  To report the imaging findings and clinical characteristics of KD accompanied by HLH in children. Materials and methods  Five children with a prolonged fever and cervical lymphadenopathy were diagnosed as having HLH accompanied by KD. The authors retrospectively analyzed the clinical characteristics and the imaging findings in these children. The histology of excision biopsy samples of cervical lymph nodes in all children confirmed the diagnosis of KD. HLH was confirmed by bone marrow biopsy and laboratory criteria provided by the Histiocyte Society. Results  The greatest dimension of the enlarged nodes ranged from 0.5 cm to 2.5 cm and the nodes were most frequently located at level V. CT scans visualized perinodal infiltrates in most of the affected cervical nodes (four of five children) and extracervical nodes (three of three children). On enhanced CT scans, nonenhancing necrosis within the affected cervical nodes was noted in three children. Conclusion  KD might be related to HLH in children. Systemic evaluations and follow-up of children with KD might help to identify HLH related to KD.