A case of neurodegenerative Langerhans cell histiocytosis exhibiting high osteopontin in cerebrospinal fluid without specific radiological abnormalities.

Neurodegenerative Langerhans cell histiocytosis (ND-LCH) manifests several years after onset of LCH, with progressive neurological symptoms and characteristic brain imaging features. Although ND-LCH has a dismal neurological prognosis, distinct treatment strategies are not available owing to the unknown pathophysiology. We describe the case of a 6-year-old boy who developed left convergent strabismus four years after onset of multisystem LCH (MS-LCH). Although radiological imaging showed no abnormalities, the osteopontin level in the cerebrospinal fluid (CSF-OPN) was highly elevated without other abnormal CSF findings, leading to a diagnosis of ND-LCH. The patient received monthly intravenous immunoglobulin therapy for four years, without symptoms worsening. To investigate the relevance of OPN levels in LCH, we retrospectively analyzed serum and CSF OPN levels in eight LCH patients. Serum OPN levels were markedly elevated in the two MS-LCH patients with macrophage activation (400 and 445 ng/mL) compared to the other six patients (mean: 59 ng/mL). CSF-OPN levels were elevated in the ND-LCH patient (620 ng/mL) compared to the two patients with pituitary involvement (160 and 182 ng/mL), suggesting that the pathophysiology of ND-LCH reflects its inflammatory status. Analysis of CSF-OPN levels would be a useful tool to detect and treat ND-LCH.

Utility of 18F-FDG-PET for detecting acute lymphoblastic leukemia: a case series of pediatric acute lymphoblastic leukemia without hematological symptoms.

Acute leukemia is typically diagnosed from presenting features related to hematological symptoms, but certain patients present with prominent musculoskeletal pain without signs of hematological abnormality. We reviewed the medical records of 58 children diagnosed with acute lymphoblastic leukemia (ALL) at our hospital to evaluate initial features. Forty six of these patients had hematological symptoms, anemia, or hemorrhage (Group H), while 12 patients had prominent musculoskeletal pain without hematological symptoms (Group P). Diagnosis of leukemia took significantly more time for those 12 patients (Group H, 17.1 days; Group P, 48.5 days). In three of the 12 patients in Group P, localized abnormal imaging findings and unremarkable blood test results led to initial diagnoses of chronic recurrent multifocal osteomyelitis, bone fracture, and septic osteomyelitis. However, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) revealed multiple intense bone foci or systemic bone marrow uptake, leading to the diagnosis of ALL. A review of 18F-FDG-PET results from 23 patients with ALL who underwent a PET scan (Group H, n = 15; Group P, n = 8) showed multiple bone foci or systemic bone marrow uptake in all cases. In conclusion, lack of hematological symptoms in ALL patients can delay diagnosis, and 18F-FDG-PET is useful for diagnosing leukemia in such cases.

Half of 'Micrococcus spp.' cases identified by conventional methods are revealed as other life-threatening bacteria with different drug susceptibility patterns by 16S ribosomal RNA gene sequencing.

Bacterial infection during chemotherapy is a fatal complication, therefore precise identification of the pathogenic microorganism is required for treatment. We report that 2 of 4 pediatric patients with malignancy who were diagnosed with Micrococcus spp. infection by conventional methods were finally revealed to have Kytococcus schroeteri and Kocuria marina infection by 16S ribosomal RNA gene sequence analysis (16S rRNA analysis). Although K. schroeteri is morphologically similar to Micrococcus spp., its drug susceptibility profile is quite different from that of Micrococcus spp. K. schroeteri is resistant to penicillin and cephalosporin, which are effective for Micrococcus spp. In fact, penicillin-resistant lethal pneumonia caused by K. schroeteri has been reported in compromised hosts. Based on our results, Micrococcus spp. determined by conventional methods could contain other life-threatening bacteria with different drug susceptibility patterns from Micrococcus spp. To develop an effective empirical treatment for immunocompromised hosts, accumulation of pathogen data by 16S rRNA analysis is required.

Accurate detection of renal leukemic involvement in children using 3-D computed tomography modeling.

BACKGROUND: The rate of renal involvement in pediatric acute lymphoblastic leukemia (ALL) at diagnosis varies between reports because renal involvement is diagnosed on renal size larger than aged-matched standards on conventional modalities. We propose a new method for precise renal involvement detection using 3-D enhanced computed tomography (CT) reconstruction. METHODS: Twenty-five children with ALL were evaluated utilizing 3-D enhanced CT reconstruction to measure renal volume before and after induction therapy, renal mass lesions and renal axis at diagnosis. Renal involvement was defined as a marked decrease of renal volume or the presence of mass lesions. RESULTS: According to the 3D-CT criteria, nine of 25 patients (36%) had renal involvement. All of them had bilateral mass lesions except for one who had diffuse nephromegaly alone. This method detected renal involvement more accurately than ultrasonography. When using conventional criteria based on the length of the renal axis, 19 of 25 (76%) had renal involvement, including many cases of false-positive nephromegaly. Patients with renal involvement had significantly more extramedullary involvement according to the 3D-CT-based criteria. CONCLUSIONS: The use of 3D-CT reconstruction was accurate in detecting renal involvement in childhood ALL, most of which consisted of piled up mass lesions. Patients with renal involvement should be worked up for the detection of other extramedullary lesions.

Improvement of refractory acyclovir-resistant herpes simplex virus type 1 infection by continuous acyclovir administration.

Resistant herpes simplex virus type 1 (HSV-1) infection is sometimes fatal for immunocompromised patients. Here, we report 10-year-old girl receiving hematopoietic stem cell transplantation developed refractory HSV-1 infection, which was persisted to intermittent acyclovir (ACV) or foscarnet (FOS) administrations but was improved by continuous ACV administration. The isolates from the lesion were identified with low susceptibilities to ACV and FOS by plaque reduction assay due to DNA pol gene mutation. Continuous ACV administration overcomes the efficacy of intermittent administration and could be the best option to treat severe HSV-1 infectious patients.

A characteristic flow cytometric pattern with broad forward scatter and narrowed side scatter helps diagnose immune thrombocytopenia (ITP).

Various disorders cause severe thrombocytopenia, which can lead to critical hemorrhage. Procedures that rapidly support the diagnosis and risk factors for serious bleeding were explored, with a focus on immune thrombocytopenia (ITP). Twenty-five patients with thrombocytopenia, including 13 with newly diagnosed ITP, 3 with chronic ITP, 6 with aplastic anemia (AA), and 3 with other thrombocytopenia (one acute myeloid leukemia, one acute lymphoblastic leukemia, and one hemophagocytic lymphohistiocytosis), were reviewed. In addition to platelet-related parameters obtained by an automated hematology analyzer, flow cytometric analysis of platelets was performed. A characteristic flow cytometric pattern with broad forward scatter and narrowed side scatter, which is specific to ITP, but not other types of thrombocytopenia, was found. CD62P-positive platelets were increased in newly diagnosed ITP cases compared to control (P < 0.0001), AA (P = 0.0032). Moreover, detection of dramatic changes in these parameters on sequential monitoring may suggest internal hemorrhage, even absent skin or visible mucosal bleeding. The bleeding score for visible mucosae had a negative correlation with platelet count and a positive correlation with immature platelet fraction (%), forward scatter, and CD62P. This characteristic flow cytometric pattern makes it possible to distinguish ITP from other thrombocytopenic disorders.

Minimal contribution of severe hypertriglyceridemia in L-asparaginase-associated pancreatitis developed in a child with acute lymphocytic leukemia.

A 10-year-old girl developed L-asparaginase (ASP)-associated pancreatitis during chemotherapy for acute lymphocytic leukemia. Her symptoms showed alleviation with continuous regional arterial infusion of protease inhibitor and systemic somatostatin analog therapy. She had intermittent and marked hypertriglyceridemia, an initial trigger for pancreatitis, probably as a side effect of ASP and steroids. However, we considered the pancreatitis to have developed mainly because of factors other than hypertriglyceridemia as lipoprotein analysis confirmed chylomicron levels to be nearly undetectable. Extremely large chylomicrons contribute directly to the onset of pancreatitis by causing blockage of small vessels. Although it is necessary to examine patients for dyslipidemia developing as a side effect of ASP, therapeutic intervention for hypertriglyceridemia is not considered to prevent the onset of ASP-associated pancreatitis.

Agranulocytosis after infectious mononucleosis.

We report the case of a 5-year-old boy with agranulocytosis after infectious mononucleosis (IM). Antibodies against anti-human neutrophil-specific antigens (HNA)-1 were detected in his serum. A literature review on agranulocytosis after IM and our case suggest that anti-HNA-1 antibodies play important roles in agranulocytosis associated with IM.

Successful treatment of primary sclerosing cholangitis with a steroid and a probiotic.

Primary sclerosing cholangitis (PSC) is a serious disease that not only affects quality of life but can also have a significant effect on patient survival. The treatment for PSC is primarily supportive with the aim of controlling cholestatic symptoms and preventing complications. Ursodeoxycholic acid may induce biochemical improvements in affected patients; however, long-term pediatric studies to determine its possible benefits in young patients are lacking. Thus, the treatment of pediatric PSC remains a significant clinical challenge. We describe a patient with PSC and undetermined colitis who was treated with a combination of a steroid, salazosulfapyridine, and a probiotic. This treatment provided benefits both for PSC and the undetermined colitis. These findings suggest that bacterial flora and gut inflammation are closely associated with the pathogenesis of inflammatory bowel disease-related PSC. Suppression of bowel inflammation and maintenance of bacterial homeostasis may be important for treating PSC.

[Monitoring of Epstein-Barr virus-infected cells by flow cytometer permits early diagnosis and evaluation of disease progression in EBV-associated hemophagocytic lymphohistiocytosis].

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is characterized by clonal expansion of EBV-infected CD8(+)T-cells. We have recently demonstrated that detection of a clonally expanded population of EBV-infected CD8(+)T-cells with CD5 down-regulation was a useful tool to distinguish EBV-HLH from EBV-related disorders such as severe infectious mononucleosis. A 5-year-old girl who presented with fever, pancytopenia and liver dysfunction was diagnosed by this method in addition to conventional diagnostic tests. Further, EBV-infected cells were identified as CD5(-)HLA-DR(+) TCR V ß3(+) CD8(+)T cells, an increase or decrease of which over time reflected the disease severity in this patient. Treatment of patients with EBV-HLH varies from steroid alone to intensive chemotherapy or hematopoietic stem cell transplantation. Easy monitoring of EBV-infected cells by using flow cytometry over time may provide useful information to choose an appropriate treatment for each individual patient with EBV-HLH.

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.