Raita Araki

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.

Massive hyper-reactive hematopoietic nests in bilateral iliac bones in a patient with mild aplastic anemia

To the Editor: We encountered a patient with aplastic anemia (AA) whose bone marrow (BM) specimens showed hypercellular marrow with slight dysplastic signs, because relatively massive hematopoietic nests were retained in limited areas, especially in BM biopsy sites. In this situation, it seemed to be hard to think of AA in a differential diagnosis. A 14-year-old male was found to have mild pancytopenia. His complete blood count showed a red blood cell count of 3.24 10/L, hemoglobin level of 11.0 g/dL, MCV of 96.9 fL, and a reticulocyte count of 38 10/L. White blood cell count was found to be 2.85 10/L with a differential count of 36% neutrophils, 58% lymphocytes, 1% eosinophils, 1%

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.

Pathognomonic serum cytokine profiles identify life-threatening langerhans cell histiocytosis.

Keywords: Langerhans cell histiocytosis; cytokine profile; IL18; sTNFR ; haemophagocytic syndrome

Mollaret meningitis associated with occipital dermal sinus.

A 1-month-old female infant was referred with vomiting and fever. The cerebrospinal fluid (CSF) showed a pleocytosis (291 cells/mm). Peripheral blood demonstrated leukocytosis (17 000/mm) and high value of C-reactive protein (1.19 mg/dL). The culture results of CSF were negative. The patient was treated with antibiotics, and the symptoms resolved within 48 hours. One month later, she manifested a second episode of meningitis with pleocytosis in CSF (2506 cells/mm). She was treated with antibiotics and dexamethasone, resulting in the resolution of meningitis within 24 hours. Staphylococcus aureus was detected by the culture of CSF. The cytologic study of the CSF revealed neutrophils, lymphocytes, and large macrophage-like unique cells with foamy abundant cytoplasm and bean-shaped nuclei (Figure 1; available at www.jpeds.com). A magnetic resonance imaging scan revealed a dermoid cyst with occipital dermal sinus (ODS) (Figure 2). A plain radiograph and CT showed a marked defect in the occipital skull vault (Figures 3 and 4; available at www.jpeds.com). With a diagnosis of ODS, a surgical excision of the lesion was performed. At 15 months after surgery, the patient remains asymptomatic. Mollaret meningitis (MM) consists of recurrent episodes of aseptic meningitis. The CSF showed pleocytosis with neutrophils, lymphocytes, and monocytes. In particular, an abundance of large monocytoid cells with unique nuclear shapes is characteristic feature of MM. The etiology of MM is unknown, but the association between MM and dermoid-epidermoid cysts has been reported. ODS is frequently accompanied with dermoid cysts and may be also associated with MM, resulting from episodic release of aseptic dermoid material from the cyst into CSF space. No relapses occurred since the removal of ODS, so we hypothesize that the local infection in ODS may contribute as a trigger to meningitis in this case. The differential diagnosis of recurrent meningitis should include MM with occipital dermal sinus. Cytopathologic analysis of CSF and neuroimaging studies should be performed. n

Hearing impairment accompanied with low-tone tinnitus during all trans retinoic acid containing chemotherapy

To the Editor: All trans retinoic acid (ATRA), a derivative of vitamin A, is a major component of treatment for acute promyelocytic leukemia (APL), but often causes side effects such as ATRA syndrome and intracranial hypertension (ICH). We describe the first case of APL with hearing impairment accompanied with low-tone tinnitus, probably as a side effect of ATRA. A 12-year-old nonobese female patient with APL achieved complete remission (CR) by induction chemotherapy including ATRA. Subsequently, she received multidrug chemotherapy (ATRA 45mg/m2 daily PO, days 4–10, cytarabine IV, days 1–3, mitoxantrone IV, day 1, triple intrathecal therapy [methotrexate, cytrabine, hydrocortisone], day 1) and chemoprophylaxis (fluconazole and trimethoprimsulfamethoxazole). Cerebrospinal fluid opening pressure was elevated (27 cm H2O) but biochemical and cytological findings were normal. She presented with headache and nausea from day 9 and was treated with dexamethasone (DEX). Her symptoms improved immediately and DEX was ceased on day 14. On day 20, she complained of low-tone tinnitus in the right ear with a slight headache and nausea, without vertigo and nystagmus. Pure tone audiometry revealed low-frequency sensorineural hearing loss in the right ear. DEX was restarted and her tinnitus gradually resolved. Pure tone audiometry normalized on day 30. She maintained CR and had no relapse of hearing symptoms by prophylactic use of DEX in the following consolidation phase including ATRA. Although the pathogenesis of ATRA-associated ICH remains uncertain, ATRA and its metabolites are thought to influence intracranial pressure through perturbation of the blood–brain barrier and the structures involved in the production and drainage of cerebrospinal fluid.1 The incidence of ATRA-induced ICH is less than 1% in adults, while it is as high as 10% in children.2 Age-related changes in responses to ATRA stimulation or reduction of RARA receptor expression have been posited to explain this difference.1 Therefore, globally ATRA in childhood APL treatment has been shifted to lower dose (25mg/m2).3–5 ATRA-relatedhearing impairment associatedwith ICHhasnotbeen reportedbefore.However, this clinical phenomenon is perhapsnot surprising because idiopathic ICH causes low-tone tinnitus in response to the spread of ICH via perilymph fluid in the cochlear canal that connects the intracranial cavity to the inner ear, leading to an imbalance of internal and external lymph.6 Though it is not clear how long ICH persists after cessation of ATRA treatment, in a previously reported case of vitamin A-induced ICH, papilledema was slow to improve after vitamin A cessation even though severe symptoms such as headache improved rapidly.7 This suggests that mild-to-moderate ICH without symptoms could linger for some time after vitamin A cessation. Similarly, in our case mild ATRA-associated ICH might have persisted and caused tinnitus later. Hearing symptoms caused by ICH are generally reversible. However, neurological outcomes can sometimes be worse if therapy is not started promptly.8,9 As children seldom complain of tinnitus spontaneously,10 careful observation of pediatric APL patients is warranted to avoid irreversible neurological damagedue toprolongedmild ICH.

Deep spontaneous molecular remission in a patient with congenital acute myeloid leukemia expressing a novel MOZ-p300 fusion transcript

Yasuhiro Ikawa , Ryosei Nishimura, Hideaki Maeba, Toshihiro Fujiki , Rie Kuroda, Kazuhiro Noguchi, Masaki Fukuda, Shintaro Mase, Raita Araki, Yusuke Mitani, Tomohiko Sato, Kiminori Terui, Etsurou Ito, Issay Kitabayashi and Akihiro Yachie Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori Prefecture, Japan; Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan

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.

Feasibility of high-dose iodine-131-metaiodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and hematopoietic stem cell transplantation: a study protocol

Objective(s): High-risk neuroblastoma is a childhood cancer with poor prognosis despite modern multimodality therapy. Internal radiotherapy using 131I-metaiodobenzylguanidine (MIBG) is effective for treating the disease even if it is resistant to chemotherapy. The aim of this study is to evaluate the safety and efficacy of 131I-MIBG radiotherapy combined with myeloablative high-dose chemotherapy and hematopoietic stem cell transplantation. Methods: Patients with high-risk neuroblastoma will be enrolled in this study. A total of 8 patients will be registered. Patients will receive 666 MBq/kg of 131I-MIBG and after safety evaluation will undergo high-dose chemotherapy and hematopoietic stem cell transplantation. Autologous and allogeneic stem cell sources will be accepted. After engraftment or 28 days after hematopoietic stem cell transplantation, the safety and response will be evaluated. Conclusion: This is the first prospective study of 131I-MIBG with high-dose chemotherapy and hematopoietic stem cell transplantation in Japan. The results will be the basis of a future nationwide clinical trial.