Clinical effectiveness of four neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) for children with influenza A and B in the 2014-2015 to 2016-2017 influenza seasons in Japan.

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).

Prophylactic administration of voriconazole with two different doses for invasive fungal infection in children and adolescents with acute myeloid leukemia.

BACKGROUND: Pediatric patients under treatment for acute myeloid leukemia (AML) are at high risk for invasive fungal infection (IFI). We evaluated the efficacy of prophylactic administration of voriconazole (VRCZ) with two different doses. METHODS: Between October 2005 and June 2011, 17 children and adolescents (aged 0-20 years) undergoing chemotherapy for AML were prophylactically administered with 5 mg/kg/d of oral VRCZ. Furthermore, 22 AML patients (aged 0-19 years) were administered 10 mg/kg/d of oral VRCZ between July 2011 and December 2014. The incidences of IFI with two different doses of VRCZ were compared. RESULTS: Irrespective of the dosage of VRCZ, eight patients developed IFI. Of these eight patients, four belonged to the 5 mg/kg/d group and four to the 10 mg/kg/d group. Cumulative incidences of IFI at 180 days after the initiation of chemotherapy were not different between the 5 mg/kg/d and 10 mg/kg/d groups. The trough plasma VRCZ concentration in the 10 mg/kg/d group ranged from < 0.09 µg/mL to 2.17 µg/mL, with a median level of 0.27 µg/mL, and patients with the targeted trough concentration (1-4 µg/mL) comprised only 18.8% of the evaluable patients in this group, whereas the trough plasma VRCZ concentration of the evaluable patients in the 5 mg/kg/d group were all below the limit of sensitivity (< 0.09 µg/mL). CONCLUSION: More dose escalation is required based on this study. As VRCZ concentration is considerably influenced by genetic polymorphisms and drug-drug interactions, VRCZ should be used under therapeutic drug monitoring to keep effective drug concentrations.

Risk factors for sepsis-related death in children and adolescents with hematologic and malignant diseases.

BACKGROUND: The aim of this study was to elucidate risk factors for mortality after developing sepsis in pediatric patients with hematologic and malignant disorders. METHODS: A total of 90 patients (43 boys, 47 girls) with various hematologic and malignant diseases who experienced sepsis between June 2006 and March 2014 were enrolled. Clinical and laboratory features of 134 episodes of sepsis observed in the 90 patients were compared between those with and without sepsis-related death which was defined as death within 14 days after sepsis. RESULTS: Age at hospitalization, sex, and type of underlying disease did not differ between patients with and without sepsis-related death. Sepsis episode-based univariate analysis identified patients with a history of relapse or in a refractory state of underlying disease (p<0.01), those with high C-reactive protein concentrations (≥50 mg/L) at the beginning of fever (p<0.01), those who had undergone hematopoietic stem cell transplantation (p<0.01), and those who were forced to change initial antibiotics (p = 0.02) because of being at high risk of sepsis-related death. The former two factors were further confirmed by multivariate analysis. More than half (52.9%) the isolates from sepsis-related death were Gram-positive cocci resistant to ß-lactam antibiotics, but susceptible to vancomycin. CONCLUSION: It was found that a history of relapse, a refractory state of underlying disease, and high C-reactive protein concentrations at the beginning of fever were significant risk factors for mortality after developing sepsis. Survival rate of patients with risk factors raised in this study might be improved by early introduction of vancomycin.

Pretransplant paranasal sinus disease is associated with a high incidence of transplant-related mortality in hematopoietic stem cell transplantation for children and adolescents.

To determine whether pretransplant PSD affects the clinical outcomes in HSCT, a retrospective cohort analysis of 73 pediatric and adolescent patients who underwent HSCT was performed. Pretransplant PSD was defined as the presence of a fluid level or mucosal swelling or total opacity on sinus X-ray or CT examination performed before HSCT. Pretransplant PSD was observed in 21 (29%) patients. The probability of 2-year OS after HSCT was 42% in patients with pretransplant PSD (PSD group), and 64% in those without (non-PSD group) (P=.012). The cumulative incidence of 2-year TRM was 48% in the PSD group, and 17% in the non-PSD group (P=.005). The cumulative incidences of pulmonary complications and respiratory failure at 2 years after HSCT were significantly higher in the PSD group (41% vs 15%, P=.022; 44% vs 14%, P=.009, respectively). PSD at the time of HSCT should be recognized as an additional potential risk factor for mortality. Further investigation is required to clarify the reasons for the present findings to improve the outcomes of patients with pretransplant PSD.

Analysis of Risk Factors for Hyponatremia During or Following Chemotherapy in Children With Cancer: A Hospital-based, Retrospective Cohort Study.

Hyponatremia is the most common electrolyte abnormality in hospitalized patients. The objective of this study was to identify risk factors for hyponatremia during chemotherapy in children. A total of 111 consecutive pediatric patients (age, 0 to 18 y) with hematological malignancy (n=87) or solid tumor (n=24) who received chemotherapy in our hospital between 2010 and 2014 were enrolled. The number of chemotherapy cycles reviewed was 472, with a median of 3 (range, 1 to 8) per patient. Hyponatremia was defined as a serum sodium level of <135 mmol/L. Hyponatremia was observed in 80 of 111 (72%) patients, and 138 of 472 (29%) cycles. Neurological sequelae were seen in 2 of 111 (2%) patients, and 2 of 472 (0.4%) cycles. Multivariate logistic regression identified age 10 to 18 years (odds ratio [OR]=3.24, 95% confidence interval [CI], 2.07-5.07), total parenteral nutrition (OR=8.15, 95% CI, 2.17-30.5), first or second chemotherapy cycle (OR=1.74, 95% CI, 1.12-2.70) as independent risk factors for hyponatremia. Clinical conditions of patients and chemotherapeutic agents may have a profound impact on the development of hyponatremia. Patients with these factors should be managed carefully to prevent severe symptoms and sequelae caused by hyponatremia.

Stem cell transplantation for acute myeloid leukemia with pulmonary and cerebral mucormycosis.

BACKGROUND: Mucormycosis is one of the most refractory invasive fungal infections and often causes fatal infection in immunocompromised patients, such as those with severe diabetes mellitus and hematologic malignancies. METHODS: We retrospectively evaluated the efficacy of stem cell transplantation for a pediatric patient with refractory acute myeloid leukemia (AML) who developed mucormycosis. RESULTS: An 8-year-old boy with acute myeloid leukemia (AML) received chemotherapy, but relapsed 3 months after discontinuation of treatment. Subsequent chemotherapy was ineffective, and then, while in non-complete remission, he developed pulmonary and cerebral mucormycosis. On gene analysis the fungus was identified as Lichtheimia ramosa. Cord blood transplantation was conducted in combination with high-dose liposomal amphotericin B therapy. He successfully achieved complete remission without progression of mucormycosis. CONCLUSIONS: Stem cell transplantation could reduce the mortality of patients with hematologic disease who develop mucormycosis.

Voriconazole Concentrations in Cerebrospinal Fluid During Prophylactic Use in Children with Acute Myelogenous Leukemia.

We report analysis of voriconazole (VRCZ) concentration of cerebrospinal fluid (CSF) during prophylactic use in children and adolescents with acute myelogenous leukemia. The median CSF/plasma ratio was 0.57 (range, 0.35-1.04). There was a significant positive correlation between the VRCZ concentrations in CSF and plasma. The CSF/blood ratio negatively correlated with age, body weight and VRCZ concentration in plasma and CSF. VRCZ is more highly transferred to CSF at low plasma concentrations, and the rate is lower at high plasma concentrations. The exact mechanism of VRCZ penetration though blood-brain barrier is not known.

Spontaneous improvement in a pediatric patient with peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is rare in children, and it has a poor prognosis compared with other types of lymphoma. We report the case of a 7-year-old boy with spontaneous improvement of PTCL complicated by hemophagocytic syndrome as the initial symptom. He complained of pain and swelling of the right neck and presented with high fever. Pancytopenia, liver dysfunction, elevated ferritin and soluble interleukin 2 receptor were noted on laboratory tests. Peripheral blood plasma and white blood cells were positive for Epstein-Barr virus (EBV) genome but, after several days, the fever abated and laboratory data improved. On histopathology of lymph node biopsy, he was diagnosed as having PTCL not otherwise specified (PTCL-NOS) with EBV infection. He received no chemotherapy and was disease free at the last follow up, 6 years 8 months after onset. This is probably the first case of spontaneous improvement in PTCL-NOS. Careful treatment planning is therefore necessary in PTCL-NOS, given the possibility of spontaneous improvement of symptoms.

Successful treatment of immune tolerance induction with rituximab in a patient with severe hemophilia B and inhibitor.

Inhibitor development is one of the major problems in hemophilia patients. Whereas the inhibitor incidence in hemophilia A is estimated to be as high as 25-30%, it appears to be less frequent in hemophilia B, occurring in about 1-3% of hemophilia B patients. There are only a few case reports about immune tolerance induction (ITI) for hemophilia B patients. The present report describes ITI with rituximab in a patient with severe hemophilia B and inhibitor. The patient was diagnosed with severe hemophilia B at 9 months. He received prophylactic replacement therapy with plasma-derived factor IX (pd FIX). After 19 exposure days, inhibitor of factor IX was detected in his plasma, and replacement therapy was stopped. However, as he suffered from intracranial hemorrhage at the age of 1 year, he underwent first ITI at the age of 1 year. Unfortunately, this failed to reduce the level of the inhibitor, and this strategy was stopped after 2 years. Second ITI with pd FIX also failed. At the age of 14 years, ITI with rituximab was performed after obtaining informed consent. The patient received rituximab 375 mg/m once a week for four doses and received 40 u/kg of pd FIX every day. At 4 weeks after the start of ITI with rituximab, the level of the inhibitor of factor IX was diminished and was undetectable for 1 year after therapy. In this patient, ITI with rituximab was well tolerated and effective. This method should be considered for patients with hemophilia B and inhibitor.

Refractory sacrococcygeal germ cell tumor in Schinzel-Giedion syndrome.

We describe a boy with Schinzel-Giedion syndrome who developed refractory sacrococcygeal germ cell tumor with elements of embryonal carcinoma and immature teratoma. He developed local recurrence soon after tumor resection. The tumor was highly resistant to platinum-based combination chemotherapy, local irradiation, and salvage chemotherapy. Frequent infections resulted in a delay in treatment, although apparent fragility had not been observed clinically. He died from tumor progression at 32 months of age. Intensification of chemotherapy does not seem to be feasible for tumors in patients with Schinzel-Giedion syndrome.

Comparison between piperacillin/tazobactam and cefepime monotherapies as an empirical therapy for febrile neutropenia in children with hematological and malignant disorders: A prospective, randomized study.

To evaluate the efficacy and safety of piperacillin/tazobactam (PIPC/TAZ) or cefepime (CFPM) monotherapy for febrile neutropenia (FN) in children, a total of 53 patients with 213 febrile episodes were randomly treated with either PIPC/TAZ 337.5 mg/kg/day, or CFPM 100 mg/kg/day. No significant differences were observed in the success rates of the PIPC/TAZ and CFPM treatments (62.1% vs. 59.1%, P = 0.650). Furthermore, no differences were noted in the rates of new infection and mortality, and no serious adverse effects occurred in either of groups. Both PIPC/TAZ and CFPM were effective and safe as an empirical therapy for FN in children. Pediatr Blood Cancer 2015;62:356-358. © 2014 Wiley Periodicals, Inc.

Tumor lysis syndrome as a risk factor for posterior reversible encephalopathy syndrome in children with hematological malignancies.

Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by seizures, altered mental status and visual disorders, along with characteristic radiological findings. It is strongly related to hypertension induced by steroids and other immunosuppressive agents. There are an increasing number of reports regarding PRES arising during the course of chemotherapy for hematological malignancies. To clarify the risk factors for this phenomenon, we retrospectively analyzed pediatric patients undergoing treatment for hematological malignancies. Of 161 patients, six patients (3.7%) developed PRES with characteristic clinical and radiographic findings. Univariate analysis revealed that tumor lysis syndrome (TLS) was a significant risk factor for the onset of PRES. TLS is a significant risk factor for the development of PRES in pediatric patients receiving chemotherapy for hematological malignancies.

Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption.

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency.

Effect of meropenem with or without immunoglobulin as second-line therapy for pediatric febrile neutropenia.

BACKGROUND: Meropenem (MEPM) is widely used for treatment of febrile neutropenia. There have been many reports on MEPM for pediatric febrile neutropenia showing success rates of approximately 50-75%. Although i.v. immunoglobulin (IVIG) is widely used for treatment of infection with antibiotics, there has been no report on the efficacy of IVIG for pediatric febrile neutropenia. This prospective randomized study was therefore carried out to clarify the usefulness of MEPM with or without IVIG as second line-therapy for pediatric febrile neutropenia. METHODS: A total of 61 pediatric patients with 146 episodes were judged to have failure of first-line therapy (August 2008-April 2010: cefozopran vs cefepime; April 2010-April 2012: cefepime vs piperacillin/tazobactam) for febrile neutropenia, and were randomized to MEPM and MEPM + IVIG groups. RESULTS: MEPM with or without IVIG as second-line therapy was effective in 68.1% of a total of 144 episodes. Success rates in the MEPM and MEPM + IVIG groups were 66.3% and 70.5%, respectively. Furthermore, success rates for patients with IgG <500 mg/dL were 62.5% in the MEPM group and 81.3% in the MEPM + IVIG group. This result, however, was not statistically significant, possibly because of the small sample size. CONCLUSIONS: MEPM is effective and safe for second-line treatment of febrile episodes in neutropenic pediatric patients. Moreover, IVIG is effective for patients with low serum IgG.

Spontaneous remission of 2-chlorodeoxyadenosine (2-CdA)-related secondary myelodysplastic syndrome in a patient with refractory Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is sometimes resistant to conventional chemotherapies, and treatment with 2-chlorodeoxyadenosine (2-CdA) is gaining importance as a salvage treatment for refractory or recurrent LCH. Secondary malignancies such as acute myelogenous leukemia and myelodysplastic syndrome (MDS) due to 2-CdA have recently been reported. However, there have been no reports to date of cases of 2-CdA-related secondary MDS in which spontaneous remission was achieved. Here, we report the case of a 1-year-old boy with an occipital tumor who was diagnosed with LCH by biopsy and underwent chemotherapy. However, the disease relapsed and became refractory to chemotherapy. He received 2-CdA treatment, which was effective. However 6 months after the start of treatment, he developed MDS with chromosomal abnormality of 7q-. After 1-year observation without any intervention, his hematological findings had returned to normal, and the chromosomal abnormality had also disappeared. To our knowledge, this is the first report of 2-CdA-related MDS with spontaneous hematological remission.

Bacteremia during neutropenia is a predictive factor for invasive fungal infection in children.

BACKGROUND: Invasive fungal infection (IFI) is a critical complication in the management of hematologic and malignant disease. Given that there is a tendency for IFI to occur after bacteremia following febrile episodes during neutropenia, the aim of this study was to determine if bacteremia was a predictive factor for IFI in pediatric patients with hematologic and malignant disease. METHODS: Sixty-two patients (32 boys, 30 girls; median age, 4 years) with hematologic or malignant disease who had received chemotherapy, immunosuppressive therapy, and/or hematopoietic stem cell transplantation, and experienced febrile episodes during neutropenia were enrolled. In patient-based analysis, clinical features of 62 patients were compared between those with and without IFI. Meanwhile, in febrile episode-based analysis, clinical features were analyzed for 268 febrile episodes occurring during neutropenia in the 62 patients. RESULTS: Patient-based analysis showed that relapse of original disease and acute myeloid leukemia were risk factors for IFI. Meanwhile, febrile episode-based analysis identified bacteremia following febrile episodes during neutropenia as a potential risk factor for IFI. CONCLUSIONS: This is the first report to identify bacteremia following febrile episodes during neutropenia as a predictive factor for IFI in pediatric patients with hematologic or malignant disease. When bacteremia is detected in such patients, sufficient preventive measures against IFI, including intensive use of antifungal agents, are warranted.

Wiskott-Aldrich syndrome with unusual clinical features similar to juvenile myelomonocytic leukemia.

A male infant exhibited thrombocytopenia at birth, and later developed leukocytosis, monocytosis, and bloody stool. The bone marrow was hypercellular with dysplasia. Spontaneous granulocyte/macrophage-colony formation and hypersensitivity to granulocyte/macrophage-colony stimulating factor were confirmed by in vitro culture. These findings fulfilled most of the diagnostic criteria for juvenile myelomonocytic leukemia (JMML), with the exception of splenomegaly. However, no mutations in the PTPN11, RAS, and CBL genes, or clinical features of neurofibromatosis type 1, which are associated with JMML, were detected. The patient subsequently developed refractory eczema with undetectable serum IgM, which led to the consideration of Wiskott-Aldrich syndrome (WAS). Lack of WASP expression and a 4-nucleotide deletion mutation in WASP were identified. Approximately 20 % of patients with JMML show none of the abovementioned molecular abnormalities. Careful differential diagnosis, including the consideration of WAS, is, therefore, recommended in patients with clinical features and laboratory findings consistent with JMML.

Congenital dermatofibrosarcoma protuberans in a newborn infant with a massive back tumor: favorable effects of oral imatinib on the control of residual tumor growth.

Dermatofibrosarcoma protuberans (DFSP) is known as a very rare malignant tumor of the deep dermis and subcutaneous tissue. It typically develops during adolescence and adulthood, with pediatric and infantile cases, particularly congenital ones, being much less frequent. We report a neonate with congenital DFSP. A newborn girl presented with a massive back tumor at birth. The tumor was at first suspected to be infantile fibrosarcoma (IFS) after immunohistochemical analysis of biopsy material, although the results were not fully compatible with IFS. She received chemotherapy under a tentative diagnosis of IFS, but this was unsuccessful. Partial resection was therefore performed at the age of 8 months to reduce the tumor mass and to reexamine its immunohistochemical characteristics. Positive CD34 staining and Collagen α1α/platelet-derived growth factor beta chimera gene signals on analysis of the excised tumor tissues enabled a definitive diagnosis of DFSP. She then underwent local irradiation and was given a daily dose of oral tyrosine kinase inhibitor (imatinib). After almost 1 year, the patient is doing well without enlargement of the residual tumor.

Precursor-T lymphoblastic lymphoma after unrelated bone marrow transplantation in a patient with Fanconi anemia.

Lymphoid malignancies are rare in patients with Fanconi anemia (FA), particularly after bone marrow transplantation. A boy, who was diagnosed with FA at the age of 5; underwent successful bone marrow transplantation at the age of 11. One year later, he presented with fever and dry cough, and was found to have an anterior mediastinal tumor. Biopsy of the tumor revealed precursor-T cell lymphoblastic lymphoma. Human leukocyte antigen analysis confirmed that the tumor cells were derived from the patient's own cells. He received mild chemotherapy for lymphoma, but his condition deteriorated rapidly and he died from excessive chemotherapy-related toxicity. The literature contains no reports of successful chemotherapy for lymphoid tumors in patients with FA, and therefore, alternatives to chemotherapy should be considered in the treatment of such patients.