Primary Immunodeficiency Diseases and Epstein-Barr Virus-induced Lymphoproliferative Disorders

Increased incidence of malignant disorders is noted in patients with both primary and acquired immunodeficiency diseases. The pathogenetic mechanism(s) for these disorders remain unclear. Defective immunosurveillance of these patients, however, is mainly postulated to be responsible for the increased risk of these malignant disorders. Of the malignant disorders, Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPD) have been increasingly reported, possibly due to improved therapeutic management techniques such as bone marrow transplantation, which results in prolonged survival periods for the primary immunodeficiency; the dramatic development of immunosuppressive treatments for transplant recipients; and the growing numbers of acquired immunodeficiency syndrome (AIDS) patients.
This review focuses on the primary immunodeficiency diseases and EBV-induced LPD, and discusses pathogenetic mechanism(s) for the increased incidence of these malignant disorders.     

Effect of Monocytes on Transformation of B-Lymphocytes by Epstein-Barr Virus

The transformation of human B-lymphocytes by Epstein-Barr virus (EBV) was studied in microwell culture by determining ³H-thymidine incorporation seven days after infection. B-lymphocytes were obtained from four human umbilical cord blood samples, four children, and five adults. The level of ³H-thymidine incorporation was highest in the cord blood group and lowest in the children, although the difference between each group was statistically not significant for a wide range of individual variations. Correlation between the rate of surface immunoglobulin (SIgM) positive cells and percentage of EBV-associated nuclear antigen (EBNA) positive cells 24 hrs after infection of ³H-thymidine incorporation seven days after infection was not significant. Addition of autologous monocytes suppressed the transformation by EB virus in two cases out of four cord blood specimens, and three cases out of five adult specimens, while it enhanced the transformation in one case out of four child specimens. Also, on clonal transformation by EB virus in agar culture, the effect of addition or monocytes was remarkably suppressive in one of two cases.     

Asymptomatic small bowel intussusception associated with post-transplant lymphoproliferative disease

Abstract:  A 2-yr-old boy who had undergone orthotopic liver transplantation for biliary atresia 6 months prior presented with generalized lymphadenopathy. Physical exam revealed lymphadenopathy only; the patient had no gastrointestinal signs or symptoms. CT was used to evaluate the patient's lymphadenopathy. The findings were consistent with PTLD, and an incidental intussusception causing small bowel obstruction was found. The intussusception was successfully managed expectantly, and the patient's PTLD responded to administration of rituximab. The etiology, diagnosis and management of intussusception is discussed.     

The Rate of Clonal Transformation of B-Lymphocytes by Epstein-Barr Virus in Childhood

The rate of clonal transformation of the B-lymphocyte by Epstein-Barr virus (EBV) in children was studied in semisolid agar culture. A remarkable influence of the cell donor's age on the rate was found: In the order of age, the rate was highest in cord blood, lower in infants, lowest in young children, somewhat higher in school children and high in adults. The rate of EBV-associated nuclear antigen (EBNA)-positive cells 24 h after infection showed little age-dependent difference. The only significant difference was found between cord blood and young children. From these results, the age-dependent difference in the rate of clonal transformation seemed to be mainly in the process after EBNA expression through transformed cell colony formation. In the children with trisomy 21 or ataxia-telangiectasia, who have a high risk of leukemia or malignant lymphoma, the rate of clonal transformation was not higher than in age-matched control groups.     

761例住院儿童EB病毒感染分析

目的：了解儿童EB病毒（EBV）感染情况,并分析其相关疾病谱,从而为EBV感染及相关疾病的防治提供科学的理论依据。方法：采用real-time PCR法检测2010年8月至2011年7月收治的761例（年龄22 d至14岁）疑似EBV感染儿童血浆中EBV-DNA载量,并对EBV-DNA检查结果及相关疾病进行统计学分析。结果：761例血浆标本中EBV-DNA阳性标本109例,阳性率为14.3%;不同年龄组EBV-DNA阳性检出率差异有统计学意义（P<0.05）,其中婴儿组（<1岁）的阳性检出率最低（P<0.05）;不同季节间阳性检出率差异有统计学意义（P<0.05）,其中夏季阳性检出率高于冬季（P<0.05）。109例阳性标本的EBV-DNA载量范围为2.13～6.69,中位数为3.72。对62例EBV-DNA阳性住院患儿最终临床诊断分析得出,呼吸系统疾病占39%,主要为急性支气管炎、急性上呼吸道感染及急性支气管肺炎。结论：不同年龄组及不同季节间EBV-DNA阳性检出率不同;儿童EBV感染相关疾病以呼吸系统疾病为主;Real-time PCR法检测血浆EBV-DNA有助于临床上EBV感染的早期诊断。     

Rapid response to rituximab in a pediatric liver transplant recipient with post-transplant lymphoproliferative disease and maintenance with sirolimus monotherapy

A 12-yr-old girl with end-stage renal disease secondary to primary hyperoxaluria type I received a living related (left lateral segment) liver transplant from her brother as the first step of a staged liver and kidney transplant. Renal transplantation was planned for a later date from the same donor. Nine weeks after transplantation she developed polymorphic PTLD of the tonsils and adenoids. Initial treatment with surgical resection and withdrawal of immunosuppression was insufficient as she developed recurrence of the PTLD lesion 1 wk after surgical resection and reduction of immunsuppression. Treatment with the chimeric monoclonal anti CD20 antibody, rituximab (Mabthera, Hoffman-La Roche AG, Grenzach-Whylen, Germany), resulted in quick response and complete recovery from PTLD within 2 wk, with no recurrence up to 8 months after treatment. Rejection prophylaxis was successfully achieved with Sirolimus (Rapamune, Wyeth Pharmaceuticals Inc., Philadelphia, PA, USA) monotherapy, with no episodes of acute rejection.     

原发性EB病毒感染后特异性T细胞免疫功能的研究进展

原发性EB病毒(EBV)感染后机体产生针对裂解期和潜伏期病毒抗原特异性CD8~+/CD4~+细胞毒性T细胞(CTL),清除病毒控制EBV感染.EBV原发感染后临床表现多样,造成这一现象的原因尚不明确,其特异性T细胞对控制病毒感染起到关键作用.随访研究发现EBV原发感染后针对裂解期和潜伏期病毒抗原特异性T细胞功能变化不同,同时对EBV特异性T细胞亚群的分析发现,T细胞的迁移活化在EBV感染机制中亦起到重要作用.     

手足口病合并川崎病7例临床分析

目的分析手足口病(HFMD)合并川崎病(KD)患儿的临床特点。方法回顾性分析2013年6月—2015年6月就诊的7例HFMD合并KD患儿的临床资料。结果 7例患儿中5例球结膜充血,6例口唇红、皲裂、杨梅舌。2例符合典型KD诊断标准,5例符合不完全KD诊断标准。7例患儿脑脊液结果均符合病毒性脑炎。咽拭子培养5例肠道病毒71型(EV71)阳性,1例柯萨奇病毒A16(CVA16)阳性。6例合并冠状动脉损伤,2例右束支传导阻滞。结论HFMD合并KD患儿多为不完全KD,常合并中枢神经系统感染以及冠状动脉损伤。     

Hodgkin-like Post-transplant Lymphoproliferative Disorder in Children: Does It Differ from Post-transplant Hodgkin Lymphoma?

Epstein-Barr virus (EBV)-mediated lymphoid proliferations occur in patients who are immunocompromised and are reported following bone marrow or solid organ transplantation. Most post-transplant lymphoproliferative disorders (PTLD) are polymorphic in appearance; some are monomorphic and can resemble conventional malignant lymphomas. PTLD that resembles Hodgkin lymphoma has been reported infrequently. We herein report seven cases of PTLD that have large numbers of Reed-Sternberg-like (RS-like) cells and highlight differences in the phenotype of these cases that may distinguish Hodgkin-like PTLD (HL-PTLD) from true Hodgkin lymphoma/disease (HD). All patients were in the second decade of life and were 8 months to 13 years following transplant. HL-PTLD involves lymph nodes that contain a mixed population of small to intermediate-sized lymphocytes with large mononuclear and occasionally binucleate RS-like cells. The large cells of HL-PTLD are pleomorphic B cells that react strongly for CD20 and/or CD79a, express CD30, but are usually negative for CD15 and have few mitoses. They are positive for EBV early RNA (EBER) using an EBER-1 probe, as are some of the background small lymphocytes. A single case of true Hodgkin lymphoma has highly atypical RS-like cells that contain numerous mitoses, does not have CD20 or CD79a reactivity, has CD15 and CD30 staining, and the EBER-1 probe is confined to the large cells only. All patients were managed by withdrawal of immunosuppression and variably treated with either antiviral or anti-CD20 monoclonal antibody, or with chemotherapy. A unique instance of evolution from a HL-PTLD to true HD is also illustrated. In conclusion, HL-PTLD and HD appear to be two related but immunophenotypically and biologically distinct forms of lymphoproliferation in post-transplant patients and may require different protocols for their management. This study was presented in part at the Society for Pediatric Pathology Interim Meeting, Cincinnati, Ohio, USA, October 2003.     

Chronic kidney disease, pediatric nephrologists, and tobacco counseling: perceptions and practice patterns. A study from the Midwest Pediatric Nephrology Consortium

We sought to identify practice patterns of pediatric nephrologists for tobacco counseling, because of a high incidence of secondhand smoke exposure and tobacco use in adolescents with chronic kidney disease. Counseling was minimal for several reasons, thus increasing the risk for heart disease inherent in children with chronic kidney disease.     

Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey

OBJECTIVES: To evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in a series of patients with inherited complete IFN-gamma receptor 1 (IFNgammaR1) deficiency. STUDY DESIGN: We report 8 patients who received altogether 11 HSCT from family donors, including 10 HLA-identical (5 siblings and 5 relatives) and 1 HLA-haplo-identical donors. Five grafts were T-cell depleted, and conditioning regimens varied in intensity. RESULTS: Four patients died within 8 months after HSCT. Two of these deaths were due to specific complications related to mycobacterial infection. There was no or very low (2%) donor cell engraftment in 2 survivors. Only 2 patients are in full remission of mycobacterial disease 5 years after HSCT. These are the only patients who received non-T-cell-depleted grafts from an HLA-identical sibling after a fully myeloablative conditioning regimen. CONCLUSIONS: HSCT can lead to prolonged remission of mycobacterial disease in children with complete IFNgammaR1 deficiency. However, optimal control of mycobacterial infection before HSCT and the use of a non-T-cell-depleted transplant from an HLA-identical sibling after a fully myeloablative conditioning regimen are recommended.     

Acute thrombocytopenic purpura associated with primary Epstein-Barr virus infection

Acute idiopathic thrombocytopenic purpura (ITP) often appears to be related to the sensitization by some viral infections. However, the causative viral agents are not identified in most cases. Although the primary infection with Epstein-Barr virus (EBV) occurs during early childhood in Japan, the majority of cases are usually asymptomatic. A minority are associated with acute infectious mononucleosis (IM), which is characterized by fever, tonsillitis, lymphadenopathy, splenomegaly and liver dysfunction. In this report, three cases are described of children with EBV-induced ITP who clinically had atypical findings of IM. Their primary EBV infections were confirmed by serological test and, in addition, were verified by the enhanced expression of activation antigens (HLA-DR and CD45RO) on T cells as well as the inverted ratio of CD4⁺ to CD8⁺ subsets. These observations imply that ITP can occur as one of the host responses during primary EBV infections, irrespective of clinical manifestations. Evaluation of lymphocyte subpopulations may be useful for the assessment of primary EBV infection in ITP.     

Wiskott-Aldrich综合征患儿异基因造血干细胞移植后EB病毒相关淋巴组织增殖性疾病1例报告并文献复习

目的 探讨儿童Wiskott-Aldrich综合征(WAS)异基因造血干细胞移植术(allo-HSCT)后EB病毒(EBV)相关淋巴组织增殖性疾病(PTLD)的治疗.方法 回顾分析1例行allo-HSCT的WAS患儿的临床资料,并检索复习相关文献.结果 12岁男性WAS患儿,获骨髓库人类白细胞抗原(HLA)配型10/1...     

��Ⱦ�Ե���ϸ������֢������ؼ����ٴ��ص����

目的探讨传染型单核细胞增多症(传单)、类传单和EB病毒(EBV)感染病例的临床特点。方法对重庆医科大学附属儿童医院2003—2004年收治的602例传单、类传单和EBV感染患儿的相关资料进行回顾性分析。结果传单组的临床表现较EBV感染组典型,淋巴结肿大和眼睑水肿的发生率显著高于类传单组,传单组眼睑水肿的发生率(62.7%)已接近常见的典型表现出现的比率;类传单组病例微小病毒(HPVB19)的感染率为54.8%,显著高于传单组;3组病例肝功能改变都以酶学改变为主,其中LDH改变最为明显;血液系统并发症表现为贫血、粒细胞减少和血小板减少,各组发生率没有统计学差异;类传单组病例肺炎发生率显著高于传单组;EBV感染组出现传单组没有的ITP病例和脑炎病例。结论眼睑水肿对传单有着与其它典型表现同样重要的诊断意义;HPVB19是类传单的一个重要病原;EBV感染后部分病例发展为传单,部分病例仍以EBV感染状态存在,可能存在异常的免疫反应。     

Epstein-Barr virus-associated Hodgkin''s disease in a patient with Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is a primary immunodeficiency syndrome in which the majority of malignant complications are non-Hodgkin's lymphoma. We report here a Wiskott-Aldrich syndrome patient who developed Epstein-Barr virus-positive Hodgkin's disease in the bilateral pulmonary hilar lymph nodes. The treatment was successful as the patient achieved a complete response and event-free survival for more than 4 y. CONCLUSION: This case is very rare, but highly suggestive of the immune-mediated mechanisms in the pathogenesis of Epstein-Barr virus-associated Hodgkin's disease in an immunodeficiency patient.     

A novel form of non-X-linked hyperigm associated with growth and pubertal disturbances and with lymphoma development

HyperIgM syndrome is a heterogenous immunodeficiency characterized by impaired class-switch recombination due to different molecular abnormalities. We report on two female patients affected by a novel syndrome associating HIGM, growth and pubertal disturbances, and severe lymphoid hyperplasia with eventual development into lymphomas, suggesting a DNA repair defect.     

Increased Ig-null B lymphocytes in the peripheral blood of pediatric solid organ transplant recipients with elevated Epstein-Barr viral loads

Abstract:  In this study, the characteristics of Ig-null B cells in high viral load carriers were examined by four-color flow cytometry. The frequency of Ig-null B cells in patients with high, low or undetectable virus loads was found that while patients with a high load had more Ig-null cells, these cells were also present in the low and undetectable load groups. As Ig-null cells from patients with no viral load were EBV-negative, EBV infection was not absolutely required for the generation or survival of Ig-null cells. Ig-null cells were CD19⁺, sIg^-, CD5⁻, CD10⁻, CD27⁻, CD23⁻, CD38⁻, and CD69⁻ with variable surface expression of CD20 and CD40. Ig-null cells did not have a proliferating cell phenotype (Ki67^-) and a high proportion were HLA class I^- and class II^-. Virus copy number in CD19⁺ Ig-null cell populations may be much higher than in CD19⁺ Ig⁺ cell populations. EBV infected Ig-null cells were common in blood specimens from pediatric solid organ transplant recipients and infected Ig-null cells may pose potential problems for immunotherapies that target infected B cells directly.     

The X-Linked Lymphoproliferative Disease: From Autopsy Toward Cloning the Gene 1975-1990

Although X-linked lymphoproliferative disease (XLP) is rare (1-2 males per 1 × 10⁶), it serves as a model for discerning diverse diseases caused by Epstein-Barr virus (EBV) ranging from agammaglobulinemia to fatal infectious mononucleosis following infection with the virus. The study of patients with XLP has also paved the way to understanding how EBV induces diseases in children with primary immunodeficiency diseases, organ transplant recipients, and those with acquired immunodeficiency syndrome. This review is dedicated to the memory of Gordon Vawter, M.D., who generously provided insights into the causes of pathogenesis of immune deficiency and lymphoproliferative disorders.