儿童感染及相关疾病的诊断讲演示文稿

1、儿童感染及相关疾病的诊断讲演示文稿第一页，共五十九页。优选儿童感染及相关疾病的诊断讲第二页，共五十九页。Burkitts lymphoma in KenyaEpstein-Barr virus (EBV)1964, discovered from Burkitts lymphoma tissue by Epstein, Achong, and Barr1968, the etiologic agent for infectious mononucleosis1970, nasopharyngeal carcinoma1980, non-Hodgkins lymphoma第三页，共五十九页。EB

2、V双链DNA病毒，疱疹病毒科，亚科，基因组Genome: 172282 bp，有环状和线性两种形式人群感染率高，我国35岁儿童95%已血清转化EBV原发感染在婴幼儿及学龄前儿童主要为亚临床感染，在青少年和成人致IM（国外）EBV与许多疾病相关第四页，共五十九页。Circular form of the EBV genome (latent infection)Linear form of the EBV genome (lytic infection)第五页，共五十九页。EBV 相关疾病传染性单核细胞增多症（Infectious mononucleosis，IM）慢性活动性EB病毒感染（Chr

3、onic active EBV infection，CAEBV）EB病毒相关性嗜血细胞综合征（EBV-associated hemophagocytic syndrome, EBVAHS)第六页，共五十九页。EBV相关疾病伴性淋巴增殖综合征（X-linked lymphoproliferative syndrom）鼻咽癌（Nasopharyngeal carcinoma）Burkitts 淋巴瘤（Burkitts lymphoma）何奇金淋巴瘤（Hodgkins lymphoma）第七页，共五十九页。BCD21gp350MHC-IIEBVAsymptomatic infectionSympto

4、matic infection（IM)Primary EBV InfectionLatent infectionEBV-related other diseases 第八页，共五十九页。SalivaOropharynxLymphoid tissue and peripheral bloodResting B cellEpitheliumLytic EBV-infected B cellEBV-infected B-cell blastReactivated EBV-infected B-cellLytic EBV-infected B cellEBVEBVLatently infected,

5、resting memory B cellsCytotoxic T cell Cytotoxic T cell Natural killer cell LMP-1LMP-1LMP-2LMP-2LMP-2LMP-2Primary infectionPersistent infectionEBNAsEBNAsEBNA-1Cohen, JI N Engl J Med 343:481-492, 2004Model of EBV infection in humans第九页，共五十九页。传染性单核细胞增多症（Infectious mononucleosis，IM）第十页，共五十九页。IMIM嗜异白细胞阳

6、性：EBV 嗜异白细胞阴性：EBV CMV Rub HHV6 Adv第十一页，共五十九页。EBV-IM的临床表现发热： 约1周，严重者2周或更久，幼儿可不明显淋巴结肿大：任何淋巴结，颈部最易受累咽炎：50有渗出物，25上腭有瘀点脾肿大：病程23周，50出现肝炎：肿大1015，而GPT升高80皮疹：红斑、斑丘疹或麻疹样疹，50可有眼睑浮肿第十二页，共五十九页。EBV-IM的临床表现其它：1.间质性肺炎2.CNS: 脑炎、格林巴利综合征等3.心肌炎4.血液系统：溶血性贫血、再障、粒细胞减少5.肾炎6.关节炎7.胰腺炎第十三页，共五十九页。IM的诊断IM的拟诊：临床表现（发热+渗出性咽峡炎+淋巴结肿

7、大、脾肿大） +异型淋巴细胞升高（10）第十四页，共五十九页。EBV-IM的诊断嗜异白细胞凝集抗体特异性EBV抗原的抗体检测:衣壳抗原（CA）IgM荧光定量PCR检测外周血中EBV-DNA第十五页，共五十九页。嗜异白细胞抗体IgM抗体IM病人的血清在经吸收几内亚猪肾抗原后引起山羊红细胞的凝集第12周出现，持续约6个月；小于5岁者，很可能阴性第十六页，共五十九页。外周血中EBV-DNA检测普通PCR荧光定量PCR：荧光定量PCR检测 EBV-DNA（血清、血浆、全血、外周血单核细胞），急性期（病程10天内）敏感性和特异性100第十七页，共五十九页。衣壳抗原（CA）IgM一般情况下：一周左右升高，

8、持续存在48周，类风湿因子和IgG抗体可致结果假阳性临床要注意以下情况：1、有的病人抗EB病毒CA-IgM产生延迟2、少部分病人感染EBV后，CA-IgM持续阴性3、也有的病人CA-IgM持续几个月阳性第十八页，共五十九页。抗体亲合力检测机体在受到病原体入侵时首先产生低亲合力抗体，随感染的继续和进展，抗体亲合力升高。因此，低亲合力抗体的检出提示原发性急性感染。原发EBV感染，100的病人在第一个月内可检测到抗EB病毒CA-IgG低亲合力抗体第十九页，共五十九页。原发性EBV感染后的免疫抗体反应IM第二十页，共五十九页。EBV抗体四项VCA-IgGVCA-IgMEA-IgGNA-IgGVCA-I

9、gG亲合力第二十一页，共五十九页。EBNA-IgG阴性VCA-IgG阳性VCA-IgG阴性未感染VCA-IgM阳性原发感染VCA-IgM阴性EAIgG强阳性原发感染（ VCA-IgG 低亲合力）、感染后复发、或感染晚期抗EBNA抗体降低（ VCA-IgG 高亲合力）EAIgG阴性感染后复发或感染晚期抗EBNA抗体降低（ VCA-IgG 高亲合力）第二十二页，共五十九页。EBNA-IgG阳性仅VCA-IgG阳性晚期感染VCA-IgG阳性和EA-IgG强阳性或VCA-IgA强阳性或VCA-IgM阳性感染后复发第二十三页，共五十九页。Cervical lymphadenopathy第二十四页，共五十

10、九页。Cervical lymphadenopathy第二十五页，共五十九页。Hepatosplenomegaly第二十六页，共五十九页。Eyelid edema第二十七页，共五十九页。Palatal petechiae第二十八页，共五十九页。Atypical lymphocytes第二十九页，共五十九页。慢性活动性EBV感染第三十页，共五十九页。 CAEBV is characterized by severe, chronic or recurrent infectious mononucleosis-like symptoms after a primary EBV infection,

11、 and has a high morbidity and mortality from hepatic failure, lymphoma, sepsis, or hemophagocytic syndrome.1. Unusual pattern of anti-EBV antibodies (high levels of IgG anti-VCA and EA, absence of anti-EBNA) High EBV viral load in peripheral bloodClonal expansion of EBV-infected T cells and NK cells

12、第三十一页，共五十九页。Historical milestones of CAEBV1948, Issacs: prolonged fever, malaise, lymphadenopathy, hepatosplenomegaly1975, Horwitz et al:such clinical manifestations with mildly or moderately high or positive IgG against VCA and EA1982, Tobi et al: similar atypical illness associated with serologica

13、l evidence of persistent EBV infection第三十二页，共五十九页。Historical milestones of CAEBV1984, Dubois et al: criteria for such cases termed chronic mononucleosis syndrome:(1) disabling fatigue and malaise;(2) low-grade afternoon fever;(3) variable other nonspecific symptoms: myalgias, sore throat, depression

14、,lasting 6 months or longer, with EBV serologies of (1)VCA-IgG160, (2)EA-IgG 5, (3) postive anti-EBNA, (4)absent VCA-IgM, (5) absent Paul-Bunnell heterophil antibody.第三十三页，共五十九页。发病机制EBV感染的T细胞或NK细胞克隆性增殖存在的问题：1.如何感染T细胞或NK细胞2.如何引起临床症状第三十四页，共五十九页。EBV-infected cells in Japanese patients with CAEBV第三十五页，共

15、五十九页。临床表现发热：间断性发热淋巴结肿大肝脾肿大间质性肺炎贫血肝炎眼葡萄膜炎第三十六页，共五十九页。第三十七页，共五十九页。第三十八页，共五十九页。Diagnostic criteria of CAEBVI. Severe illness of greater than 6 months duration that:1. Began as primary EBV infection OR2. Is associated with grossly abnormal EBV antibody titers(IgG to VCA1:5,120; antibody to EA1:640; or a

16、ntibodyto EBNA1:2), AND(Straus S.E.)第三十九页，共五十九页。II. Histological evidence of major organ involvement, such as:1. Interstitial pneumonia2. Hypoplasia of some bone marrow elements3. Uveitis4. Lymphadenitis5. Persistent hepatitis6. Splenomegaly, ANDIII. Detection of increased quantities of EBV in affec

17、ted tissues by1. Anticomplementary immunofluorescence for EBNA, or2. Nucleic acid hybridization Reproduced from Straus S.E. (1988, J. Infect. Dis. 157:405_/412) 第四十页，共五十九页。CAEBVCEBV: persistent IM-like illness with relatively good prognosisSCEBV: rather severe manifestation with generally poor progn

18、osis第四十一页，共五十九页。Diagnostic criteria of a case definition for SCAEBV CategoryCriteriaClinicalHematologicVirologicalOtherIntermittent fever, lymphadenopathy, and hepatosplenomegalyAnemia, thrombocytopenia, lymphocytopenia or lymphocytosis, neutropenia, and polyclonal gammopathyElevated antibody titers

19、 and positivity for antibodies to EBV-related antigens (VCA IgG5,120; VCA IgA, positive; EA D IgG640; EA D IgA, positive; and EA D and EA R IgG640) and/or detection of EBV genomes in affected tissuesChronic illness which cannot be explained by other known disease processesbReproduced from Okano M.,

20、et al. (1991, Clin. Microbiol. Rev. 4:129_/135) (Okano M)第四十二页，共五十九页。Revise of Criteria of CAEBV2001,Kimura et al. extremely high antibody titers against EBV-replicative antigens are not absolutely necessary, but demonstrated significantly increased circulating EBV-DNARevised virological criteria: e

21、ither or both extrmely against EBV-repicative antigens and/or increased genome copies in tissues.第四十三页，共五十九页。伴性淋巴增殖综合征（X-linked lymphoproliferative syndrom）第四十四页，共五十九页。历史1975年，Purtilo等发现一个家系中，18个男性有6个人出现良性或恶性淋巴细胞增生和组织细胞增加等征候，取名Duncan病1998年，缺陷基因被确定： SH2D1A/DHSP or SAP (SLAM-associated protein）第四十五页，共

22、五十九页。Called “Duncans disease”after the family name第四十六页，共五十九页。SH2D1A编码含128个氨基酸的蛋白质- SAP (signaling lymphocytic activation molecule SLAM-associated protein), 表达于活化的T和NK细胞表面，通过与SLAM及其他免疫球蛋白超家族如2B4等结合，参与信号传递，调节CTL的功能，如产生IFN-gamma 的能力第四十七页，共五十九页。第四十八页，共五十九页。临床表现家族史，仅见男性发病年龄从6个月22岁（原发性EBV感染后）IM样症状：发热、咽峡炎

23、、淋巴结和肝脾肿大、异型淋巴细胞增加免疫球蛋白异常：无球蛋白血症、多克隆性高球蛋白血症高IgM的免疫不全症患者血清中EBV抗体阴性第四十九页，共五十九页。临床分型A型：属于急性致死性IM,多发病4周后死亡，占55B型：同时有急性致死性IM和恶性淋巴瘤，占15C型：EBV感染后免疫机能不全、低球蛋白血症、骨髓增生低下、EBV抗体能力产生低下，占15D型：无明显EBV感染表现而发生的恶性淋巴瘤，占15第五十页，共五十九页。诊断标准（Hamilton）6个月至22岁男性有2个以上下述表现型 1. 增殖性改变 （1）有致死性或慢性IM （2）有B免疫母细胞性淋巴肉瘤 （3）有非何杰金氏淋巴瘤 （4）I

24、M继发高IgM免疫不全症 2. 非增生性改变 （1）粒细胞缺乏症或再生障碍性贫血 （2）球蛋白异常：获得性无或低球蛋白血症 3. 先天异常 （1）心血管系 （2）中枢神经系第五十一页，共五十九页。诊断标准在母系直系亲属中有2人以上具备上述表现型者，可诊断本征本征男性的B淋巴细胞体外感染EBV后，能自发的发育增殖；患者的唾液可使脐带血中的淋巴细胞发生形态改变；患者血清中缺乏EBV抗体第五十二页，共五十九页。鉴别诊断CAEBV: chronic active EBV infectionGLPD: granular lymphoproliferative disorderALPS: autoimmune lymphoproliferative syndrome第五十三页，共五十九页。CAEBVGLPDXLPALPSHeredity?X-linkedAD(AR)SexM & FM & FMM & FGene localization?Xq2510q23Responsible gene?SH2D1A/SAPFas/FasL/caspase 10Clinical manifestationLPDLPDFIM/LPD/AGLLPDVAHS+Lymphadenopathy+/malig benign+/malig benign+/malig+/ benign