Shuji Hatakeyama

Lower Clinical Effectiveness of Oseltamivir against Influenza B Contrasted with Influenza A Infection in Children

BACKGROUND Recently, many Japanese physicians have claimed that oseltamivir is less effective in children with influenza B virus infection. This study assesses the effectiveness of oseltamivir against influenza A (H3N2) and influenza B in children on the basis of the duration of febrile illness. METHODS We used oseltamivir to treat 127 children with influenza A (H3N2; mean age, 6.97 years [range, 1-15 years]) and 362 children with influenza B (mean age, 5.16 years [range, 1-15 years]) in outpatient clinics. The duration of fever after the start of oseltamivir therapy was compared in the influenza A group and the influenza B group. RESULTS The mean duration of fever after the start of oseltamivir therapy was significantly greater in the influenza B group than in the influenza A (H3N2) group (2.18 days vs. 1.31 days, respectively; P<.001). The difference was marked in young children (1-5 years old; 2.37 days for the influenza B group vs. 1.42 days for the influenza A group) but was not significant among older children (11-15 years old). The 50% inhibitory concentration of oseltamivir against influenza B virus was 75.4+/-41.7 nmol/L and was substantially higher than that for type A (H3N2) virus (0.3+/-0.1 nmol/L). Only 3 (1.6%) of 192 influenza B viruses were resistant to oseltamivir. CONCLUSIONS Oseltamivir is much less effective against influenza B virus infection in young children, probably because of the low sensitivity of influenza B viruses to oseltamivir. The effectiveness of oseltamivir against influenza B is influenced by age and host immunity. A few oseltamivir-resistant influenza B strains were isolated before the start of oseltamivir therapy.

Enhanced Expression of an α2,6-Linked Sialic Acid on MDCK Cells Improves Isolation of Human Influenza Viruses and Evaluation of Their Sensitivity to a Neuraminidase Inhibitor

ABSTRACT The extensive use of neuraminidase (NA) inhibitors to treat influenza virus infections mandates close monitoring for resistant variants. Cultured cells do not provide a reliable means of evaluating the susceptibility of human influenza virus isolates to NA inhibitors. That is, the growth of such viruses in cell lines (e.g., Madin-Darby canine kidney [MDCK] cells) is not inhibited by these drugs, even though their sialidase activity is drug-sensitive. Matrosovich et al. (J. Virol. 77:8418-8425, 2003) showed that an MDCK cell line overexpressing the human β-galactoside α2,6-sialyltransferase I (ST6Gal I) gene has the potential to assess the sensitivity of human influenza virus isolates to NA inhibitors, based on studies with a limited number of viruses. Here, we asked whether clinical isolates of influenza virus are universally sensitive to an NA inhibitor (oseltamivir) in an MDCK cell line expressing the ST6Gal I gene. The sensitivity of viruses to oseltamivir correlated with the sensitivity of viral sialidase to the compound, demonstrating the potential utility of this modified cell line for detecting NA inhibitor-resistant viruses. Moreover, in ST6Gal I-overexpressing cells, the growth of human influenza viruses was up to 2 logs higher than in MDCK cells. We conclude that the human ST6Gal I-expressing MDCK cell line is useful not only for evaluating their sensitivity to NA inhibitors, but also for isolation of influenza viruses from clinical samples.

Cryptococcus gattii Genotype VGIIa Infection in Man, Japan, 2007

We report a patient in Japan infected with Cryptococcus gattii genotype VGIIa who had no recent history of travel to disease-endemic areas. This strain was identical to the Vancouver Island outbreak strain R265. Our results suggest that this virulent strain has spread to regions outside North America.

High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia

OBJECTIVES Thrombocytopenia is sometimes observed during linezolid therapy. Here, we aimed to investigate the factors affecting linezolid-induced thrombocytopenia. METHODS A prospective observational study was performed between October 2009 and February 2011; 30 patients were included. Plasma linezolid trough concentrations were measured on days 3, 7 and 14 after initial drug administration. Platelet counts and haemoglobin levels were also monitored. RESULTS Thrombocytopenia occurred in 17 patients (56.7%). Median linezolid trough concentrations on day 3 were significantly higher in patients with renal impairment (creatinine clearance <60 mL/min) than in patients without renal impairment (14.7 versus 4.8 mg/L; P < 0.0001). Median linezolid trough concentrations on day 3 in patients who developed thrombocytopenia were also significantly higher than those in patients who did not (13.4 versus 4.3 mg/L, P < 0.0001). Development of thrombocytopenia occurred significantly more frequently in patients with linezolid trough concentration >7.5 mg/L (OR, 90.0; P < 0.0001) and renal impairment (OR, 39.0; P = 0.0002). The Kaplan-Meier plot showed that the median time from the initiation of therapy to development of thrombocytopenia was 11 days. CONCLUSIONS Patients with renal impairment are more likely to have a high plasma linezolid concentration. In addition, a high plasma linezolid concentration and renal impairment significantly affected the development of linezolid-induced thrombocytopenia. Further studies are required to evaluate whether therapeutic drug monitoring-guided dosage adjustment of linezolid decreases the adverse effects while maintaining treatment efficacy in patients with renal dysfunction.

Prevalence of measles, rubella, mumps, and varicella antibodies among healthcare workers in Japan

OBJECTIVES To evaluate the immune status of healthcare workers (HCWs) against measles, rubella, mumps, and varicella in Japan, and to promote an adequate vaccination program among HCWs. SETTING University of Tokyo Hospital. PARTICIPANTS Eight hundred seventy-seven HCWs. DESIGN Serologic screening for measles, rubella, mumps, and varicella was performed on HCWs. Antibodies against measles, rubella, and mumps were detected using hemagglutination inhibition (HI) assay (

Persisting Humoral Antiviral Immunity within the Japanese Population after the Discontinuation in 1976 of Routine Smallpox Vaccinations

4.20 per test). If serum was negative by HI assay, enzyme-linked immunosorbent assay (EIA) was performed (

Unadjuvanted pandemic H1N1 influenza vaccine in HIV-1-infected adults

12.60 per test). Anti-varicella antibodies were detected by EIA only. RESULTS Among tested HCWs, 98.5%, 90.4%, 85.8%, and 97.2% had immunity to measles, rubella, mumps, and varicella, respectively. All those born before 1970 were seropositive for measles. However, individuals susceptible to rubella, mumps, and varicella were present in all age groups. The sensitivities and negative predictive values of HI assay compared with EIA were 86.6% and 11.3% for measles, 99.1% and 92.2% for rubella, and 47.8% and 24.1% for mumps, respectively. For measles and mumps, prevaccination screening by HI assay in combination with EIA led to significant savings compared with EIA only. In contrast, it was estimated that prevaccination screening using only HI assay would be more economical for rubella. CONCLUSIONS Aggressive screening and vaccination of susceptible HCWs was essential regardless of age. Prevaccination serologic screening using a combination of HI assay and EIA was more economical for measles and mumps.

Seroprevalence of Pandemic 2009 (H1N1) Influenza A Virus among Schoolchildren and Their Parents in Tokyo, Japan

ABSTRACT Concerns have arisen recently about the possible use of smallpox for a bioterrorism attack. Routine smallpox vaccination was discontinued in Japan in 1976; however, it is uncertain exactly how long vaccination-induced immunity lasts. We sought to evaluate the seroprevalence and intensity of anti-smallpox immunity among representatives of the present Japanese population. The subjects included 876 individuals who were born between 1937 and 1982. Vaccinia virus-specific immunoglobulin G (IgG) levels were measured by enzyme-linked immunosorbent assay (ELISA), and 152 of 876 samples were also tested for the presence of neutralizing antibodies. Of the subjects who were born before 1962, between 1962 and 1968, and between 1969 and 1975, 98.6, 98.6, and 66.0%, respectively, still retained the vaccinia virus-specific IgG with ELISA values for optical density at 405 nm (OD405) of ≥0.10. The corresponding figures for retained IgGs with OD405 values of ≥0.30 were 91.0, 90.3, and 58.2%, respectively. Neutralizing antibodies were also maintained. The sera with OD405 values of ≥0.30 showed 89% sensitivity and a 93% positive predictive value for detection of neutralizing antibodies (≥4). Thus, approximately 80% of persons born before 1969 and 50% of those born between 1969 and 1975 were also found to have maintained neutralizing antibodies against smallpox. A considerable proportion of the previous vaccinated individuals still retain significant levels of antiviral immunity. This long-lasting immunity may provide some protective benefits in the case of reemergence of smallpox, and the disease may not spread as widely and fatally as generally expected.

In vitro selection of influenza B viruses with reduced sensitivity to neuraminidase inhibitors

We evaluated the immune response to a 2009 influenza A (H1N1) unadjuvanted vaccine in HIV-infected patients and assessed the boosting effect of a second dose. HIV-infected adults were enrolled and scheduled to receive the H1N1 unadjuvanted vaccine containing 15μg of A/California/7/2009 haemagglutinin. Anti-H1N1 antibody titers were measured at enrollment and 4-8 weeks after each vaccination by using haemagglutination inhibition (HI) and virus neutralization (NT) assays. One hundred and four patients were analyzed. Seroconversion, as measured by using HI and NT assays, was observed in 52 (50.0%) patients and 49 (47.1%) patients, respectively, after the first dose. Seroconversion rate evaluated by using NT, but not HI, antibody titers was associated with HIV RNA levels of <400copies/ml (odds ratio, 3.21; 95% CI, 1.15-8.96). Other parameters, including CD4 cell count, were not associated with seroconversion. In a cohort that received two vaccine doses at a 4-8-week interval (n=54), the seroconversion rate and geometric mean titer for HI antibodies were 44.4% (95% CI, 30.8-58.1%) and 30.5 (95% CI, 19.9-46.9) after the first dose, respectively, and 48.1% (95% CI, 34.4-61.9%) and 39.0 (95% CI, 26.1-58.2) after the second dose, respectively. Among HIV-infected patients, the seroconversion rate was around 50% after the first dose of unadjuvanted vaccine. A second dose of vaccine had a limited boosting effect on immunity in this patient cohort.

Infected subdural haematoma due to Salmonella enterica serovar Typhimurium in an adult.

ABSTRACT Since its emergence, the 2009 pandemic H1N1 virus has spread rapidly throughout the world. Previously, we reported that most individuals born after 1920 do not have cross-reactive virus-neutralizing antibodies against pandemic (H1N1) 2009 virus, indicating that they were immunologically naïve to the pandemic virus prior to its emergence. This finding provided us with an excellent opportunity for a seroepidemiological investigation of the transmission mode of the pandemic virus in the community. To gain insight into its transmission within communities, we performed a serosurvey for pandemic virus infection with schoolchildren at an elementary school in Tokyo, Japan, and their parents. We observed a high prevalence of neutralizing antibodies to the pandemic virus in the children at this school, although the percentage of children positive for the neutralizing antibodies varied among classrooms. While a much lower prevalence was observed among parents, seropositivity of the parents correlated with that of their schoolchildren. Moreover, many adults appeared to have experienced asymptomatic infection with the pandemic virus. These data suggest that the pandemic virus was readily transmitted among schoolchildren in elementary schools and that it was also transmitted from schoolchildren to their parents.