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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., (© 2014 Japan Pediatric Society.)

Background: Although mitochondrial respiratory chain disorders (MRCD) are one of the most common congenital metabolic diseases, there is no cumulative data on enzymatic diagnosis and clinical manifestation for MRCD in Japan and Asia., Methods: We evaluated 675 Japanese patients having profound lactic acidemia, or patients having symptoms or signs of multiple-organ origin simultaneously without lactic acidemia on respiratory chain enzyme activity assay and blue native polyacrylamide gel electrophoresis. Quantitative polymerase chain reaction was used to diagnose mitochondrial DNA depletion syndrome (MTDPS). Mutation analysis of several genes responsible for MTDPS was also performed., Results: A total of 232 patients were diagnosed with a probable or definite MRCD. MRCD are common, afflicting one in every several thousand people in Japan. More than one in 10 of the patients diagnosed lacked lactic acidemia. A subsequent analysis of the causative genes of MTDPS identified novel mutations in six of the patients. A 335 bp deletion in deoxyguanosine kinase (DGUOK; g.11692_12026del335 (p.A48fsX90)) was noted in two unrelated families, and may therefore be a common mutation in Japanese people. The proportion of all patients with MTDPS, and particularly those with recessive DNA polymerase γ (POLG) mutations, appears to be lower in Japan than in other studies. This is most likely due to the relatively high prevalence of ancient European POLG mutations in Caucasian populations. No other significant differences were identified in a comparison of the enzymatic diagnoses, disease classifications or prognoses in Japanese and Caucasian patients with MRCD., Conclusion: MTDPS and other MRCD are common, but serious, diseases that occur across all races., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)

Background: The diagnosis of infectious mononucleosis (IM) is usually on serologic tests. The responses of anti-Epstein-Barr virus (anti-EBV) antibodies are weak in infants. The authors encountered some IM infants in whom anti-EBV antibodies were undetectable during early stage, although EBV genome was found in their blood. The aim of the present study was therefore to clarify the frequency of anti-EBV-antibody negative IM cases., Methods: The EBV serostatus of 104 IM children diagnosed on Sumaya criteria was retrospectively studied. The EBV genome in peripheral blood mononuclear cells was measured., Results: The anti-viral capsid antigen-IgM (anti-VCA-IgM)-positive rate in the acute phase was only 25% in infants but 80% in patients ≥ 4 years of age. Twenty percent of the infants were negative for all anti-EBV antibodies and required repeated serologic tests. For infants, the significant rise in anti-VCA-IgG was the most sensitive marker. Three seronegative infants with IM symptoms, with circulating EBV genome during acute phase, were eventually considered as having IM on anti-VCA-IgG seroconversion thereafter., Conclusions: To diagnose IM in infants the serologic test alone in the acute phase is not sensitive enough. It is proposed that the EBV genome be evaluated in peripheral blood mononuclear cells when infants presenting with IM symptoms are negative for anti-EBV antibodies during the acute phase., (© 2010 Japan Pediatric Society.)

Background: Bronchial asthma-like symptoms such as wheezing are commonly associated with respiratory tract infection including respiratory syncytial virus (RSV) infection in infants. No study on the association of wheezing with cytomegalovirus (CMV) infection in infancy has been reported, although CMV infection has been observed to play some role in prolonged and intractable wheezing in limited cases., Methods: The present study investigated 40 hospitalized infants who presented with first-episode wheezing between October 2003 and September 2004. Nasopharyngeal aspirates were tested for RSV, and serum antibodies against CMV were measured. As controls, age-matched infants with no wheezing were examined for CMV serostatus., Results: RSV-antigen was detected in 21 subjects (53%), and seven (18%) were considered primary CMV infection serologically. Primary CMV infection was found more often in the wheezers than in the controls although the difference was not statistically significant (P = 0.06). The incidence of splenomegaly was significantly higher in wheezers with CMV infection (86%) than in those with RSV infection or without either infection. The duration of wheezing, fever, and radiographic and laboratory findings during hospitalization were not significantly different., Conclusions: CMV infection based on serologic diagnosis should be considered in infants with first wheezing episode and particularly those with splenomegaly.

Background: Epstein-Barr virus (EBV) infection can lead to life-threatening post-transplant lymphoproliferative disorder (PTLD). The aim of the present study was to establish EBV monitoring methods to prevent PTLD., Methods: EBV-DNA load was investigated, using real-time polymerase chain reaction (PCR) and anti-EBV antibody titers, in peripheral blood mononuclear cells of 21 renal transplant patients (seven recipients who were EBV-seronegative, R[-]; 14 who were EBV-seropositive, R[+]) before grafting. The mean age at entry and the mean follow-up period was 7.8 years of age (range, 3.3-12.0 years) and 1.8 years (range, 0.4-4.0 years), respectively, in the R(-) group, and 12.5 years of age (range, 3.9-17.7 years) and 3.8 years (range, 0.8-8.2 years) in the R(+) group, respectively., Results: The mean maximum load of the EBV genome was 1071 copies/microg DNA (range, 106-20700 copies/microg DNA) in the R(-) group, and 61 copies/microg DNA (range, <50-552 copies/microg DNA) in the R(+) group. During follow up no patient in the R(+) group had any noticeable symptoms that could be related to EBV, but three recipients in the R(-) group developed EBV-related symptoms including adenoid hypertrophy, cervical lymphadenopathy, and PTLD (B cell lymphoma), in one patient each. In the R(-) group the first leukocyte-associated viremia was detected at 30-180 days, and seroconversion at 43-266 days after transplantation., Conclusions: Viral DNA detection using PCR is a useful tool for EBV surveillance, but the maximum EBV load was not markedly elevated (2474 copies/microg DNA) in a patient with PTLD. Therefore, EBV surveillance using only monitoring of EBV load in peripheral leukocyte may be insufficient. Histology may therefore be necessary to accurately diagnose PTLD.

Background: Although elevated serum levels of immunoglobulins are frequently observed in patients with chronic active Epstein-Barr virus (EBV) infection, there have been no reports concerning levels of IgG subclasses., Methods: Serum levels of IgG subclasses were measured by the enzyme-linked immunosorbent assay (ELISA) in 30 children with severe chronic active EBV infection., Results: Serum levels of IgG1 were elevated in most patients, except for one who showed an abnormally low level of IgG1 and progressive hypogammaglobulinemia. Serum levels of IgG2, IgG3 and IgG4 in the patients were comparable to those in control children, while abnormally low levels of IgG2, IgG3 and IgG4 were observed in six, three and four cases, respectively., Conclusion: Although not always susceptible to bacterial infections, low levels of IgG2 were frequently observed in patients with chronic active EBV infection and elevated IgG1 is responsible for the increase of serum IgG in these patients.

Background: Although a reversed CD4/CD8 ratio and increased proportion of CD8+ HLA-DR+ T cells are well known as the characteristic immune response in infectious mononucleosis (IM), it has not been elucidated whether these immune responses are affected by patient age and pathogenetic viruses., Methods: T cell subsets were analyzed by two-color flow cytometry using fluorescein isothiocyanate- and phycoerythrin-conjugated monoclonal antibodies in 115 infants and children aged from 4 months to 10 years with IM due to Epstein-Barr virus (EBV), cytomegalovirus (CMV) and dual infection with both viruses., Results: A reversed CD4/CD8 ratio and increased proportions of CD4+/HLA-DR+ T cells, CD8+ T cells and CD8+/HLA-DR+ T cells became more prominent as the age of the patients became older. No differences were observed in proportions of T cell subsets between EBV- and CMV-infection among patients aged from 6 to 17 months. Although the responses of these T cells were weak in infants with single virus infection by EBV and CMV, markedly strong T cell responses comparable with those in older children were observed in infants with EBV/CMV dual infection. Clinical symptoms were more severe in patients with EBV/CMV dual infection than those with EBV or CMV alone., Conclusion: The manner of these T cell responses in the acute phase of IM was considered to be age dependent, although strong T cell responses and severe disease were observed in EBV/CMV dual infection irrespective of patient age.