Late presentation of opsoclonus-myoclonus-ataxia syndrome in a child with stage 4S neuroblastoma

Opsoclonus-myoclonus-ataxia syndrome (OMA) in children is most commonly associated with occult neuroblastoma (NB). Although children with OMA and NB have decreased mortality, they suffer from increased neurologic morbidity. The pathogenesis of OMA in NB is not well understood, but current research and treatments support an immune-mediated process. The authors describe an unusual presentation of OMA occurring following 6 months of chemotherapy in a child with stage 4S NB who presented with partial Horner syndrome. Histopathologic examination of his primary cervical tumor showed NB maturation, which may have played a role in precipitating OMA syndrome. Further study of unusual cases of OMA in NB may provide better understanding of the syndrome and additional treatment options for these children.     

Hyperexcitable blink reflex preceding the diagnosis of neuroblastoma

The diagnosis of neuroblastoma is sometimes preceded by development of a paraneoplastic syndrome, most commonly opsoclonus-myoclonus-ataxia (OMA). The authors describe a patient who developed a hyperexcitable blink reflex, without symptoms of OMA, prior to his oncologic diagnosis. The authors believe this may represent a distinct paraneoplastic process caused by increased dopaminergic stimulation of the blink reflex and suggest that children manifesting an unexplained hyperexcitable blink reflex should be screened for occult neuroblastoma.     

Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature

Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplantation. The vast majority of PTLD are Epstein-Barr virus (EBV)-related infections that manifest as B-cell malignancies. We report an unusual case of an EBV-associated T-cell lymphoma in a 10-year-old boy who had previously undergone liver transplantation at age 4 years. He presented with hemophagocytic syndrome (HPS) and active EBV infection, with positive serum titers and polymerase chain reaction (PCR) for EBV in blood, colon, and antral samples.     

Current research on chronic active Epstein–Barr virus infection in Japan

Epstein–Barr virus (EBV) infection is usually asymptomatic and persists lifelong. Although EBV‐infected B cells have the potential for unlimited proliferation, they are effectively removed by the virus‐specific cytotoxic T cells, and EBV‐associated lymphoproliferative disease develops only in immunocompromised hosts. Rarely, however, individuals without apparent immunodeficiency develop chronic EBV infection with persistent infectious mononucleosis‐like symptoms. These patients have high EBV‐DNA load in the peripheral blood and systemic clonal expansion of EBV‐infected T cells or natural killer (NK) cells. Their prognosis is poor with life‐threatening complications including hemophagocytic lymphohistiocytosis, organ failure, and malignant lymphomas. The term “chronic active EBV infection” (CAEBV) is now generally used for this disease. The geographical distribution of CAEBV is markedly uneven and most cases have been reported from Japan and other East Asian countries. Here we summarize the current understanding of CAEBV and describe the recent progress of CAEBV research in Japan.     

Epstein-Barr virus associated with immune thrombocytopenic purpura in childhood: a retrospective study

OBJECTIVE: Although Epstein-Barr virus (EBV) is known to cause immune thrombocytopenic purpura (ITP), the epidemiology of this pathogen in children with ITP is not known. In the present study, the clinicoepidemiology and laboratory characteristics of EBV-associated ITP in childhood were analysed retrospectively. METHODS: The study cohort consisted of 108 children in whom ITP was diagnosed between 1990 and 1998. Patients were divided into EBV or non-EBV groups according to their serological status at diagnosis. RESULTS: Thirty-five (32.4%) of 108 children had ITP associated with acute EBV infection. The clinical manifestations and laboratory data were similar in children with and without acute EBV. Responses to various modalities of therapy were analysed. The average time to achieve complete remission (platelet count > or =150 x 10(9)/L) in EBV and non-EBV groups was 26 and 16 days, respectively. CONCLUSIONS: The incidence of childhood ITP associated with acute EBV infection is relatively high in Taiwan. Patients with EBV-associated ITP tended to resolve more slowly than those without EBV infection.     

91例EB病毒相关疾病儿童血浆EB病毒DNA的检测

目的了解EB病毒(EBV)感染患儿外周血血浆中游离EBVDNA的拷贝数,确定EBV原发感染后外周血血浆中EBV游离DNA的拷贝数与发病天数及病情轻重的关系。方法应用荧光定量PCR方法,测定73例EBV原发感染和18例EBV相关重症疾病患儿外周血血浆中EBV游离DNA。结果①原发EBV感染患儿外周血血浆中EBV游离DNA随发病天数呈下降趋势,发病2周后很难检测到。②EBV相关重症疾病组患儿外周血血浆中EBV游离DNA阳性率明显高于原发EBV感染组,差异有显著性(89%vs16%,P<0.05)。结论原发EBV感染后随病程天数的增加,病毒复制水平逐渐下降。血浆中EBV游离DNA检测对评价EBV相关疾病的严重程度有一定参考价值。     

Chronic high Epstein–Barr viral load carriage in pediatric small bowel transplant recipients

Lau AH, Soltys K, Sindhi RK, Bond G, Mazariegos GV, Green M. Chronic high Epstein–Barr viral load carriage in pediatric small bowel transplant recipients.
Pediatr Transplantation 2010: 14:549–553. © 2010 John Wiley & Sons A/S. Abstract: The development of EBV infection and PTLD is normally associated with a high EBV load in peripheral blood. Often, children undergoing primary or reactivation of EBV infection subsequent to ITx will have chronically elevated EBV loads. To better understand this phenomenon and its consequences, we retrospectively reviewed the records of children who underwent ITx (either isolated or part of multivisceral transplantation) at our center from 1992 to 2007, to identify chronic high EBV load carriers in this population. CHL state was defined as the presence of high load for >50% of samples for greater than or equal to six months following either asymptomatic infection or complete clinical resolution of EBV disease/PTLD. Thirty‐five CHL carriers were identified from our patient population. Pretransplant serologies were available on 34 of these patients: 17 were EBV negative and 17 seropositive; one had unknown EBV serostatus prior to transplant. Seven of the 17 seronegative patients developed their CHL carrier state at the time of their primary EBV infection. Thirteen of the 35 (37%) HLC patients developed EBV disease after meeting the definition of high‐load carrier states. EBV‐related diseases developing in CHL carriers included EBV adenitis (n = 1), EBV enteritis (n = 7), PTLD (n = 4), and EBV+ spindle cell tumor (n = 1). Disease was seen in 7/17 of the seronegative (one PTLD) and 6/17 of the seropositive patients (three PTLD). Thirteen of 35 patients (37%) resolved their CHL state without apparent sequelae while nine remain asymptomatic CHL carriers. Three children have had more than one episode of CHL. These data provide important information about the outcome of chronic EBV high‐load carriage in pediatric intestinal transplant recipients.     

Epstein-Barr virus burden in adolescents with systemic lupus erythematosus

OBJECTIVE: We sought to determine whether patients with systemic lupus erythematosus (SLE) and a presumed primary or reactivated Epstein-Barr virus (EBV) serologic response had evidence of an active EBV infection. BACKGROUND: Patients with SLE often have what appears to be a primary or reactivated EBV serologic response. If these patients then present with fever, fatigue, adenopathy or leukopenia, it is not clear whether these symptoms are caused by worsening SLE or EBV infection. Establishing the correct diagnosis is crucial for management. METHODS: We examined the EBV burden in 13 adolescents with SLE and a presumed primary or reactivated EBV serologic response. All were taking prednisone; 2 each were also on azathioprine or intravenous pulse cyclophosphamide. EBV serologies were performed for all, and EBV burdens were assessed via immortalization assays and EBV DNA amplification of blood and saliva at least once. RESULTS: Seven patients had serologic patterns indicative of a primary EBV infection, while six had serologies indicative of a reactivated (secondary) EBV infection. Two of the latter were the only ones in whom a small amount of biologically active EBV was detected. CONCLUSION: In our series active EBV infection was not seen in most patients, despite serologic data that could be interpreted as a primary or reactivated infection. Thus the serologic profiles were more likely a consequence of immune dysregulation secondary to SLE or its therapy rather than rampant infection with EBV.     

Kawasaki disease with a concomitant primary Epstein-Barr virus infection

A two year old boy exhibited not only clinical manifestations which suggested a recurrence of Kawasaki disease (KD) but also evidence of a primary infection by Epstein-Barr virus (EBV) including tonsillitis, splenomegaly and atypical lymphocytosis in the peripheral blood. An inverted CD4/CD8 ratio in lymphocyte subsets suggested the presence of infectious mononucleosis (IM). Epstein-Barr virus titers (viral capsid antigen-immunoglobulin G 1:20; Epstein-Barr virus-associated nuclear antigen < 1:10) showed an acute EBV infection and the presence of EBV genome in the blood was determined by the polymerase chain reaction technique. In Japan, the peak incidence of KD and IM is in children under 4 years of age. From the investigation of EBV titers, it has been reported that some patients with KD develop an associated, unusual primary EBV infection. Kawasaki disease concurrent with a primary EBV infection as in this case, suggests the possibility of an etiologic agent related to the KD rather than to the EBV infection itself.     

91例EB病毒相关疾病儿童血浆EB病毒DNA的检测

目的:了解EB病毒（EBV）感染患儿外周血血浆中游离EBV DNA的拷贝数,确定EBV原发感染后外周血血浆中EBV游离DNA的拷贝数与发病天数及病情轻重的关系。方法:应用荧光定量PCR方法,测定73例EBV原发感染和18例EBV相关重症疾病患儿外周血血浆中EBV游离DNA。结果:①原发EBV感染患儿外周血血浆中EBV游离DNA随发病天数呈下降趋势,发病2周后很难检测到。②EBV相关重症疾病组患儿外周血血浆中EBV游离DNA阳性率明显高于原发EBV感染组,差异有显著性(89% vs 16%, P＜0.05）。结论: 原发EBV感染后随病程天数的增加,病毒复制水平逐渐下降。血浆中EBV游离DNA检测对评价EBV相关疾病的严重程度有一定参考价值。［中国当代儿科杂志,2009,11（11）：897-900］     

EB病毒检测与EB病毒感染诊断的研究

目的 探讨EB病毒(EBV)检测在EBV感染诊断中的临床意义.方法 应用酶联免疫吸附方法 和荧光定量PCR方法 同步检测38例疑诊EBV感染患儿入院时及起病1、3、6、9个月血浆中EBV VCR-IgM及外周血全血、血浆、单个核细胞(PBMC)中EBV DNA,比较EBV感染患儿病程中4种检测方法 的检出率.结果 在疑诊EBV感染初期,全血和PBMC中EBV DNA阳性率最高,与EBV VCR-IgM及血浆EBV DNA相比,差异具有显著性(P<0.05);起病后的1、3、6及9个月,4种检出方法 的阳性率均逐渐减低,但PBMC中EBV DNA敏感性始终高于其他3种方法 .结论 EBV感染初期,检测全血和PBMC中EBV DNA是早期、快速、敏感的检测方法 ;EBV可长期存在于PBMC中,荧光定量PCR法检测外周血PBMC中EBV DNA对EBV感染的诊断有重要价值,可作为判断疗效及监测病情的一种有效手段.     

Lymphocytic vasculitis involving the central nervous system occurs in patients with X‐linked lymphoproliferative disease in the absence of Epstein–Barr virus infection

X‐linked lymphoproliferative disease (XLP) is an immunodeficiency caused by defects in the adaptor molecule SAP. The manifestations of XLP generally occur following Epstein–Barr virus (EBV) infection and include fulminant mononucleosis, hypogammaglobulinemia and lymphoma. In this report, we describe two unrelated patients with fatal T‐cell‐mediated central nervous system vasculitis for whom repeated serologic and molecular testing for EBV was negative. In both patients, clonal T‐cell populations were observed, but neither demonstrated evidence of lymphoma. Thus, loss of SAP function can lead to dysregulated immune responses characterized by the uncontrolled expansion and activation of T cells independent of EBV infection. Pediatr Blood Cancer 2009;53:1120–1123. © 2009 Wiley‐Liss, Inc.     

Epidemiology and outcome of chronic high Epstein‐Barr viral load carriage in pediatric kidney transplant recipients

The development of EBV infection and PTLD is normally associated with a high EBV viral load in peripheral blood. Observations have previously identified existence of a CHL carrier state that demonstrated variable outcomes based upon the organ which was transplanted. Data defining the incidence and outcome of CHL in pediatric KTx are not well described. The charts of children undergoing isolated KTx at Children's Hospital of Pittsburgh between January 2000 and December 2014 were retrospectively reviewed. EBV loads in the peripheral blood were routinely measured as part of surveillance protocols at our center. CHL was defined as the presence of high load for >50% of samples for ≥6 months. PTLD was defined histologically using WHO definitions. Of 188 isolated KTx recipients, we identified a total of 16 (8%) children who developed CHL carrier state. No patient developed EBV‐driven late‐onset PTLD. Age at the time of KTx was significantly lower in the CHL group (median 3.9 years, interquartile range: IQR 2.9‐6.6, P = .0004). Children in the CHL group were more likely to be EBV‐seronegative prior to KTx (94%, 15/16), compared to the UVL and LVL groups (55% and 50%, respectively, P < .002). The median duration of CHL carrier state was 20 months (IQR 10.7‐35.8). Fifteen of the 16 CHL carriers experienced spontaneous resolution of CHL carrier state. Children in the CHL group were younger at the time of primary EBV infection (P = .023). Finally, antiviral medication was not effective in either preventing or decreasing the EBV viral load in blood (P = .84). Overall incidence of late‐onset PTLD is very low compared to heart and intestinal transplant, even though KTx recipients can develop CHL carrier state. The CHL carriers in KTx recipients were EBV‐seronegative prior to transplant and were younger both at the time of KTx and at the time of primary EBV infection compared to those in the UVL and HVL groups. Antivirals did not prevent EBV infection or decrease EBV viral loads.     

A rare presentation of childhood pompe disease: cardiac involvement provoked by Epstein-Barr virus infection

Myocarditis attributed to Epstein-Barr virus (EBV) as the sole cause is a rare manifestation. Myocarditis ascribed to EBV infection in combination with other factors has been reported in a few more cases. We report a child who experienced active EBV infection and later, at 19 months of age, received a diagnosis of Pompe disease (acid alpha-glucosidase deficiency) with predominant cardiac involvement. The cardiac symptoms resolved at the end of the EBV infection. When the patient was recently seen, at 8 years of age, she had an increased left ventricular wall thickness but normal cardiac function. DNA analysis identified this patient as compound heterozygote for a mutant Tyr292Cys and a null allele. In light of genotype-phenotype correlation, it is notable that a Spanish patient with a functionally similar genotype (Tyr292Cys/Arg854Stop) also had childhood Pompe disease with peripheral muscular involvement.     

Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children's Cancer Group Study

BACKGROUND: Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic neurologic syndrome affecting 2-3% of children with neuroblastoma. Although children with OMA and neuroblastoma may have higher survival, many experience a significant amount of late neurologic impairment, which may be immunologically mediated. The aim of this study was to compare the outcome of neuroblastoma patients with and without OMA, relating to prognostic factors, treatment, and the presence or absence of anti-neuronal antibodies. PROCEDURE: Questionnaires were mailed out requesting information on the current neurologic status of patients who submitted sera at diagnosis to the Children's Cancer Group serum bank from 1980 to 1994. Information was requested on clinical and biological patient characteristics as well as clinical aspects of the patients identified as having OMA syndrome, including presentation and treatment for OMA, late sequelae of OMA, the presence or absence of antineuronal antibodies, and survival. Sera from 16 of the OMA patients and 48 case-controls with neuroblastoma were assayed for anti-neuronal antibodies. RESULTS: Of the 675 responses received, 21 patients had OMA. Ninety percent of OMA patients presented with non-metastatic disease, vs. 35% of non-OMA patients. Estimated 3-year survival for the OMA patients with nonmetastatic disease (stage I, II, III) greater than 1 year of age was 100% vs. 77% for similar non-OMA patients (P = 0.0222). At follow-up, 14/19 evaluable OMA patients displayed some form of developmental or neurologic abnormality. There was no significant correlation of late sequelae with antineuronal antibodies, age, time between OMA symptoms and diagnosis, or treatment given for tumor or OMA. There was a significant correlation of late sequelae with lower stage disease (I and II) compared to more advanced disease (III and IV). CONCLUSIONS: Patients with OMA and neuroblastoma have excellent survival but a high risk of neurologic sequelae. Favorable disease stage correlates with a higher risk for development of neurologic sequelae. The role of anti-neuronal antibodies in late sequelae of OMA needs further clarification.     

Epstein‐Barr viral load monitoring for diagnosing post‐transplant lymphoproliferative disorder in pediatric liver transplant recipients

This study aimed to investigate the incidence of PTLD in pediatric liver transplant recipients and the risk factors for the development of PTLD. We also determined clinically useful quantitative EBV PCR parameters for aiding in the diagnosis of EBV‐associated PTLD in the pediatric liver transplant recipients at our institute. We reviewed children < 18 years old who had undergone liver transplantations and quantitative analysis of whole blood EBV load at our institute from January 2006 to March 2015. A total of 142 liver transplant recipients were included, and their median age was 1.5 years. Clinically significant high‐level EBV DNAemia ≥ 10 000 copies/mL at least twice was observed in 53.5% and PTLD occurred in 9.9%. Among PTLD group, graft failure and mortality rate were as high as 21.4% and 14.3%, respectively. Deceased donor, presence of high‐level EBV DNAemia, and primary CMV infection following transplant were associated with an increased risk for PTLD in the multivariate analysis. The peak titer at 10 875 copies/mL could be used as a cutoff value with a sensitivity of 92.9% and a specificity of 37.9%; the rate of increase in EBV load suggested a sensitivity of 64.3% and a specificity of 70.9% at the cutoff value of 44 000 copies/mL/week. In conclusion, the incidence of PTLD following liver transplant in children was as high as 10%. PTLD is associated with significant morbidity and mortality. Close monitoring of EBV DNAemia is crucial for the early diagnosis and proper treatment of PTLD in pediatric liver transplant recipients.     

Asymptomatic high Epstein-Barr viral load carriage in pediatric renal transplant recipients

High viral load carriage of EBV is one of the risks for PTLD in transplant recipients. We reviewed retrospectively in pediatric renal transplant recipients with EBV seronegative. EBV loads in peripheral blood and EBV-CTLs were measured every 1-3 months in 13 patients after grafting. Immunosuppressants were reduced when the patients were considered to have persistent high EBV loads (>1000 copies/μgDNA for over six months). All showed primary EBV infection: six with asymptomatic persistent high EBV loads (group A) and seven with neither EBV-associated symptoms nor persistent high EBV loads (group B). No patient developed PTLD in either group. Chronic rejection occurred in one patient in group A after immunosuppressants' reduction. There was no difference in renal dysfunction rates between the two groups. The maximum and increase rates in EBV loads were significantly higher in group A. The CTLs' percentage was significantly lower in group A when EBV loads first rose above 100 copies/μg DNA. This study suggests the possibility that EBV loads and CTLs' monitoring may be useful for avoidance of PTLD, as patients with asymptomatic persistent high EBV loads had higher EBV loads and lower percentages of CTLs.     

Primary Epstein-Barr virus infection in 2-year-old children: report of 3 cases

Some children less than four years old have Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM). Because primary EBV infection in infants and young children is usually asymptomatic or subclinical, EBV infection diagnosis may not be easy among young children. To illustrate the clinical characteristics and diagnostic procedures for EBV infection in young children, the authors report herein three cases of primary EBV infection in two-year-old children with an evaluation of their initial clinical symptoms. The results showed that the common initial clinical manifestations are puffy eyelids and hepatosplenomegaly, and that these signs suggest a tentative diagnosis of IM. In conclusion, EBV capsid immunoglobulin (Ig)M antibodies and atypical lymphocytes are useful diagnostic measurements in very young children with symptoms suggestive of IM.     

Association of Epstein-Barr virus infection and pulmonary exacerbations in patients with cystic fibrosis.

We observed severe pulmonary exacerbations during primary Epstein-Barr virus (EBV) infection in adolescent patients with cystic fibrosis. Since EBV is not a known respiratory tract pathogen in cystic fibrosis, we studied retrospectively all EBV-susceptible patients ages 6 to 18 years with chronic Pseudomonas respiratory tract colonization hospitalized for a pulmonary exacerbation during an 18-month period. Patients with serologic evidence of primary EBV infection (n = 5) were compared to control patients without EBV (n = 7). Before admission the groups had similar pulmonary function tests, clinical scores and frequency of hospitalization. On admission patients with EBV had significant weight loss, lower pulmonary function tests and lower clinical scores compared with controls. All remained significantly different 6 months after admission. Frequency of exacerbations requiring hospitalization increased after EBV infection but remained unchanged in controls. Primary EBV infection can be associated with severe pulmonary exacerbations and subsequent deterioration in clinical course in cystic fibrosis patients.     

From Burkitt's lymphoma to chronic active Epstein-Barr virus (EBV) infection: an expanding spectrum of EBV-associated diseases

Epstein-Barr virus (EBV) is one of 8 known human herpesviruses. EBV infection usually occurs in early childhood and is subclinical. However, primary infection in adolescence or adulthood causes infectious mononucleosis in approximately half of infected individuals. Recently, the spectrum of human diseases associated with EBV infection has increased, primarily due to methodological advances in EBV detection. Initially, EBV was isolated from a cultured Burkitt lymphoma cell line, and has been felt to be etiologically linked to the development of Burkitt lymphoma, as well as other human malignancies. This review mainly focuses on pathogenetic mechanisms, many of which remain enigmatic, for the various human diseases, which are considered to be associated with EBV infection.