Marked histiocytosis in the portal tract in a patient with reactive hemophagocytic syndrome: An autopsy case

We report an autopsy case of reactive hemophagocytic syndrome with peculiar liver histology. A 71-year-old female was diagnosed as having acute myelogenous leukemia and treated with chemotherapy. During her course, methicillin-resistant Staphylococcus aureus (MRSA) was noted in blood culture and she was diagnosed as having MRSA sepsis. She died of respiratory failure 5 months after the onset of leukemia and 10 days after the MRSA sepsis. Ante-mortem liver function tests were within normal ranges. At autopsy, myeloblastic leukemia cells positive for CD13 were present in the bone marrow and, to a much lesser extent, in the spleen and liver. Numerous histiocytes of a bland appearance with erythrophagocytosis were noted in the bone marrow and spleen. The histiocytes were positive for CD68, but negative for S-100 and lysozymes. In the liver, many histiocytes of bland appearance with erythrophagocytosis and CD68 positivity were present in the portal tracts with no Kupffer cell hyperplasia. There were no hepatocellular degeneration, fatty changes or sinusoidal dilations. We consider that this histiocytosis was associated with MRSA infection and diagnosed this as infection-associated hemophagocytic syndrome. In previously reported cases, hemophagocytosis in hyperplastic Kupffer cells was the main liver change of reactive hemophagocytic syndrome. The present case suggests that marked histiocytosis in portal tracts only may be a main feature of liver changes in reactive hemophagocytic syndrome and that such cases may not show abnormal liver function tests.     

Hemi-meningitis with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare lymphoproliferative disorder. HLH may occur as a complication of Epstein-Barr virus (EBV), particularly in patients with immunodeficiencies. Herein, we describe a 16-year-old girl with neurological complications associated EBV-induced HLH. Her cerebral magnetic resonance imaging (MRI) showed contrast-enhanced axial T1-weighted images with enhancement of meningeal surface in the right hemisphere that was consistent with right hemi-meningitis. Hydrocephalus, dilated subdural spaces, delayed myelination, edema, diffuse parenchymal atrophy, calcifications, diffuse/patchy white matter abnormalities have all been previously described with HLH. To the best of our knowledge, this is the first case of hemi-meningitis associated with HLH. We suggest that clinicians should consider HLH with vascular disorders when they determine unilateral meningitis on a brain MRI.     

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report

BACKGROUNDFamilial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (PRF1) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review.CASE SUMMARYWe report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation.CONCLUSIONThe delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.     

儿童EB病毒相关性噬血细胞综合征与传单临床特点比较

目的通过分析比较儿童EB病毒相关性噬血细胞综合征(EBV-HPS)与传染性单核细胞增多症(IM)患者的临床表现及实验室特点,提高对EBV-HPS的认识,减少误诊,降低死亡率。方法回顾性分析45例EBV-HPS患者及同期收治的93例IM患者。EB-HPS组中,男24例,女21例,男女比例为1.14∶1,年龄1~9岁,中位年龄4.2岁;IM组中,男53例,女40例,男女比例为1.32∶1,年龄1~12岁,中位年龄5.8岁。2组病例均以男性多见,前者好发年龄为幼儿期及学龄前期,后者好发年龄为学龄前期及学龄期。对2组临床表现、实验室检查及预后进行比较。结果 EB-HPS组在高热持续时间,肝脾肿大程度均明显高于IM组,差异有统计学意义(P<0.05);实验室检查示血细胞减少及血清铁蛋白升高,差异有统计学意义(P<0.05);肝功能损伤:EBV-DNA载量,纤维蛋白原减低,甘油三酯升高均明显高于IM组,差异有统计学意义(P<0.05)。EB-HPS组56.0%的患者可在骨髓检查中见噬血细胞现象,IM组中仅有9.0%的患者可在骨髓检查中见噬血细胞现象。EBV-HPS组死亡率为23.2%,而IM组为0.0%。结论儿童EBV-HPS好发年龄为幼儿期及学龄前期,IM好发于学龄前期及学龄期,对EBV感染后存在持续发热,肝脾淋巴结肿大患儿早期进行血常规、血清铁蛋白、肝功能、EBV-DNA载量、纤维蛋白原、甘油三酯及骨髓细胞检查能够及时对HPS进行诊断,减少误诊率及死亡率。时对HPS进行诊断,减少误诊率及死亡率。     

以急性肝功能衰竭为表现的噬血细胞综合征临床特点分析

目的探讨以急性肝功能衰竭为表现的噬血细胞性淋巴组织细胞增多症（HLH）的临床特点。方法对14例以急性肝功能衰竭为表现的HLH患者临床资料进行分析,了解其病因、临床特征、肝功能损害的特点及预后,并总结病因和预后的关系。结果 HLH伴发的急性肝功能衰竭病因多样,以非嗜肝病毒、细菌和真菌感染为主,临床表现以发热和肝脾肿大为主,伴有造血系统、肾脏、心脏等多系统损害,肝功能损害的特征除伴有ALT、AST异常,高胆红素血症和低蛋白血症外,常伴有α-羟丁酸脱氢酶（HBDH）、甘油三酯（TG）、铁蛋白（Ferritin）和乳酸脱氢酶（LDH）的升高。LDH、HBDH增高及多器官功能衰竭（MODF）与预后不良具有独立的相关性（P〈0.05）。结论 HLH临床诊断困难,常以急性肝功能衰竭就诊,其肝功能损害的特点有其特殊性,患者预后与病因及肝功能损害程度相关。     

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

Background

Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.

Design and Methods

We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.

Results

All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8⁺ T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal.

Conclusions

Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.     

自身免疫病合并噬血细胞综合征临床分析

目的 通过分析11例自身免疫病(AID)合并噬血细胞综合征(HPS)的临床特点,提高对该病的认识.方法 收集北京协和医院2004年1月-2009年6月住院的AID合并HPS者11例,回顾性分析其发生诱因、各系统受累表现、治疗及预后.结果 11例AID合并HPS患者中男性3例,女性8例,年龄12 74(30.7±18.3)岁.基础病:斯蒂尔病4例,系统性红斑狼疮(SLE)3例,干燥综合征(SS)、类风湿关节炎(RA)、韦格纳肉芽肿(WG)、克罗恩病(CD)各1例.诱发HPS因素:基础病活动4例,基础病活动并发感染6例,单纯感染1例.11例患者均有高热,其中肝脾肿大8例,淋巴结肿大7例,神经系统受累4例,并发弥漫性血管内凝血(DIC)4例.实验室检查:血细胞减少11例,肝功能异常11例,高甘油三酯血症5例,低纤维蛋白原血症9例,铁蛋白＞500 μg/L 6例,NK细胞活性降低4例.骨髓涂片均见吞噬血细胞现象.经大剂量糖皮质激素联合免疫抑制剂、积极抗感染、静脉人免疫球蛋白(IVIG)支持治疗,5例存活,6例死亡,合并DIC 4例均未存活(r=0.69,P=0.019).结论 AID并发HPS不易与活动性AID鉴别.合并DIC预后差、病死率高.糖皮质激素、免疫抑制剂及IVIG对HPS治疗有效,合并感染时加强抗感染治疗至关重要.     

40例噬血细胞综合征的临床特点及预后分析

目的 探讨噬血细胞综合征(HPS)的临床特点和预后影响因素,提高HPS的诊治水平.方法 时2002年1月～2008年3月收治的40例HPS患者临床资料进行回顾性分析.结果 40例HPS中22例(55%)与感染相关,其中EBV感染14例,7例(17.5%)与肿瘤相关,病因不明12例(30%);临床表现均符合HLH-2004诊断标准;经抗感染、糖皮质激素、化疗等联合治疗,死亡率65.2%(15/23);伴随EB病毒感染、恶性淋巴瘤的HPS预后差.结论 HPS病因复杂,预后不良;应掌握HPS的临床特点,早期诊断和治疗.     

Immunophenotypic analysis of Epstein-Barr virus (EBV)-infected CD8(+) T cells in a patient with EBV-associated hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a severe and often fatal condition characterized by uncontrolled activation of T cells and macrophages. In Epstein-Barr virus (EBV)-associated HLH (EBV-HLH), the pathogenic roles of ectopic EBV infection in the T-cell population and of clonal proliferation of EBV-infected T cells has been described. However, the immunophenotype of EBV-infected T cells has not been fully characterized. Here we describe a case of EBV-HLH presenting with a massive clonal proliferation of CD8(+) T cells with TCR VB14. Analysis of in situ hybridization for EBV-encoded small RNA1 showed that only CD8(+) T cells harbored EBV in this patient. The EBV-infected TCR VB14(+) CD8(+) T cells exhibited unique immunophenotypic features including lacked CD5 expression and a markedly bright expression of HLA-DR. After initiation of treatment with prednisolone, etoposide, and cyclosporin A, the percentage of infected cells declined progressively in parallel with other serum markers such as ferritin. These findings suggest that lacking expression of CD5 on CD8(+) T cells with specific TCR VB may serve as a useful marker of dysregulated T-cell activation and proliferation in EBV-HLH.     

中西医结合治疗噬血细胞性淋巴组织细胞增生征

目的:探讨噬血细胞性淋巴组织细胞增生征的病因、临床特征及中西医结合治疗。方法:回顾性分析2008年4月—2010年9月确诊的9例HLH患者。结果:9例患者中有5例与感染相关,其中4例为EB病毒感染相关,4例为肿瘤相关,临床表现均符合HLH-2004诊断标准,本病属祖国医学温病中伏邪温病的范畴。经中西医结合治疗,存活4例,死亡5例。结论:HLH病因复杂,临床表现多样,病情凶险,死亡率高,及早诊断和中西医联合治疗可改善预后。