Hiromichi Taneichi

Clinical Significance of Cloned Expansion and CD5 Down-Regulation in Epstein-Barr Virus (EBV)- Infected CD8 + T Lymphocytes in EBV-Associated Hemophagocytic Lymphohistiocytosis

Epstein-Barr virus (EBV) is the pathogen that most commonly triggers infection-associated hemophagocytic lymphohistiocytosis (HLH) and ectopically infects CD8(+) T cells in EBV-associated HLH (EBV-HLH). We recently described an EBV-HLH patient who had a clonally expanded population of EBV-infected CD8(+) T cells with CD5 down-regulation. To determine whether this finding could serve as a useful marker for EBV-HLH, we investigated 5 additional patients. We found a significant increase in the subpopulation of CD8(+) T cells with CD5 down-regulation and bright human leukocyte antigen (HLA)-DR expression in all patients with EBV-HLH but not in patients with infectious mononucleosis or in control subjects. Such T cells were frequently found to be larger cells that stained positive for a specific T cell receptor VB. We also demonstrated that those cells were the major cellular target of EBV, and their numbers progressively declined in parallel with the serum ferritin levels. All together, our findings reveal the immunophenotypic characteristics of EBV-infected CD8(+) T cells and may provide a valuable tool for the diagnosis of EBV-HLH.

Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death

Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the probands maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor-acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death.

Severe neutropenia in Japanese patients with X-linked agammaglobulinemia

X-linked agammaglobulinemia (XLA) is clinically characterized by recurrent bacterial infections during early infancy. Although it is not a phagocytic disorder, XLA is sometimes associated with neutropenia. We conducted a nation-wide survey to determine the frequency of neutropenia among Japanese XLA patients. Responses were received from 87 (86%) of 101 patients in which BTK mutations were previously identified, and of these, 16 (18%) had neutropenia. All episodes of neutropenia occurred before initiation of intravenous immunoglobulin (IVIG) replacement therapy. Two XLA patients died of multiple organ failure caused by severe neutropenia and Pseudomonas sepsis before initiation of IVIG replacement therapy. These results suggest that, in some cases, severe bacterial infections in XLA patients might be caused not only by antibody deficiencies but also by neutropenia.

Cytokine profiles of patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome

Proinflammatory cytokines are related to the pathogenesis of enterohemorrhagic Escherichia coli (EHEC) infection and hemolytic-uremic syndrome (HUS). We assessed the kinetics of the release of cytokines such as neopterin, interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α and the soluble forms of type I and II TNF receptors during EHEC O111-induced HUS (EHEC O111/HUS). Fourteen patients with EHEC O111/HUS were enrolled in this study. Serum concentrations of all cytokines other than TNF-α were significantly elevated in patients with severe HUS compared with those in patients with mild HUS. Although serum concentrations of TNF-α were not significantly higher in patients with severe HUS, most patients with acute encephalopathy showed elevated TNF-α levels. Serum concentrations of these cytokines rapidly and markedly increased, and massive hypercytokinaemia developed 1 day before the diagnosis of HUS in patients with severe HUS. Changes in the number of white blood cells and concentration of serum lactate dehydrogenase were significantly larger between the onset of hemorrhagic colitis and the time of the diagnosis of HUS in patients with severe HUS compared with those in patients with mild HUS. Proinflammatory cytokines play an important role in the pathogenesis of EHEC infection and development of severe complications, including HUS and encephalopathy. Monitoring the cytokine profile may be useful for assessing disease activity of EHEC O111 infections.

Clinical and radiologic features of encephalopathy during 2011 E coli O111 outbreak in Japan

Objective: To elucidate the clinical and radiologic features and analyze factors associated with neurologic outcomes of encephalopathy secondary to Shiga toxin–producing Escherichia coli (STEC) O111. Methods: We reviewed medical records and neuroimaging in 22 patients with neurologic symptoms among 86 with STEC O111 infection. Results: Twenty-one (6 males and 15 females, 10 children and 11 adults) of the 22 patients were diagnosed with encephalopathy. All patients with encephalopathy also presented with hemolytic-uremic syndrome. Five patients died, from day 1 to 6 months (days 1–5 in 4 patients), due to progressive encephalopathy with severe cerebral edema observed in neuroimaging (4 patients). Fifteen of the 16 surviving patients clinically recovered completely. Statistical analysis revealed differences between patients with poor (n = 6) and good (n = 15) outcomes in the interval from hemolytic-uremic syndrome presentation to encephalopathy, creatinine levels, and the methylprednisolone administration ratio. Conclusion: We note a high incidence of encephalopathy in the Toyama STEC O111 outbreak. All fatal cases resulted from progressive encephalopathy. Methylprednisolone pulse therapy represents a possible therapeutic choice. Classification of evidence: This study provides Class III evidence that methylprednisolone pulse therapy increases the probability of a good outcome for patients with encephalopathy associated with STEC O111.

Clinical and genetic analyses of presumed shwachman-diamond syndrome in Japan

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities. SBDS was identified as a causative gene for SDS in 2003, and genetic analyses of SDS have been performed.We performed genetic analysis of 13 Japanese patients with presumed SDS and found that 10 of them had SBDS mutations. Most patients had recurrent mutations (181-184TA→CT and 258+2T→C); however, 2 patients had unique mutations (259-1G→A and 428C→G). Although genetic analysis is useful for definitive diagnosis and for genetic counseling of SDS patients and families, SDS appears to be a genetically heterogeneous disorder. In addition, presumed SDS patients without SBDS mutations may be included in other disorders.

Extensive serum biomarker analysis in patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome

Proinflammatory cytokines are related to the pathogenesis of enterohemorrhagic Escherichia coli infection and hemolytic-uremic syndrome (HUS). We employed an antibody array that simultaneously detects 174 serum cytokines. We identified five serum biomarkers, namely insulin growth factor-binding protein-2, angiopoietin-2, soluble interleukin-6 receptor, soluble tumor necrosis factor receptor type II, and matrix metalloprotease protein-3 whose levels increased with the development of HUS. Furthermore, the levels of these cytokines were significantly increased in severe HUS compared with mild HUS. These cytokines might play an important role in the pathogenesis of HUS and may also be used to predict the severity of HUS.

Guidelines for the management and investigation of hemolytic uremic syndrome.

The first guidelines for the diagnosis and treatment of HUS following the Shiga toxin producing Escherichia coli (STEC) infection was published by The Japanese Society of Pediatric Nephrology (JSPN) in 2000. Since then, there has been considerable advancement in the understanding and treatment of acute encephalopathy one of the most serious complications in HUS. Furthermore, the etiology, conditions and treatments of atypical HUS have been elucidated. Therefore, a set of comprehensive guidelines for HUS that reflects recent clinical evidence is necessary. The aim of this set of guidelines is to provide a support, tool for daily medical practice and to contribute to the standardization and accessibility of HUS-related medical care, as well as to improve level of safety for HUS patients.

Serum tau protein as a marker of disease activity in enterohemorrhagic Escherichia coli O111-induced hemolytic uremic syndrome

Tau protein levels in cerebrospinal fluid (CSF) and serum are elevated in patients with various central nervous system diseases. We investigated whether serum tau protein levels are useful for predicting and assessing disease activity of acute encephalopathy (AE) in enterohemorrhagic Escherichia coli (EHEC) O111-induced hemolytic uremic syndrome (HUS; EHEC encephalopathy). Serum samples were obtained from 14 patients with EHEC O111/HUS, 20 patients with non-EHEC-related AE, and 20 age- and sex-matched healthy controls. CSF samples were obtained from 2 patients with EHEC encephalopathy and 20 patients with non-EHEC-related AE. Tau protein levels and levels of several proinflammatory cytokines were quantified by enzyme-linked immunosorbent assays. Results were compared with the clinical features of EHEC encephalopathy, including magnetic resonance image (MRI) findings. Serum tau levels in patients with EHEC encephalopathy were significantly elevated compared with those in patients with EHEC O111/HUS without encephalopathy, patients with non-EHEC-related AE, and healthy controls. The ratio of CSF tau levels to serum tau levels was >1.0 in all patients with non-EHEC-related AE but <1.0 in 2 patients with EHEC encephalopathy. Serum tau protein levels increased rapidly and markedly in patients with severe EHEC 0111/HUS and encephalopathy when HUS occurred, but were not elevated in mild patients, even in the HUS phase. Furthermore, changes in serum tau protein levels in patients with EHEC encephalopathy were consistent with abnormalities on brain MRI and were positively correlated with proinflammatory cytokine levels. Our results indicate that serum tau protein might be useful to predict and assess disease activity of EHEC encephalopathy.

Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed‐onset adenosine deaminase deficiency

Kanegane H, Taneichi H, Nomura K, Wada T, Yachie A, Imai K, Ariga T, Santisteban I, Hershfield MS, Miyawaki T. Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed‐onset adenosine deaminase deficiency.