Masayoshi Shinjoh

Very low pandemic influenza A (H1N1) 2009 mortality associated with early neuraminidase inhibitor treatment in Japan: Analysis of 1000 hospitalized children

OBJECTIVE There were many cases of pandemic influenza A (H1N1) 2009 (H1N1/09) in Japan during the 2009-2010 epidemic. They accounted for 16% of the total population (20.7 million/128 million), and 59% of the patients were children 15 years of age and under (12.2 million/20.7million). However, there were only 38 paediatric deaths. We analyzed the clinical manifestations and treatment of children hospitalized because of H1N1/09 infection in order to clarify the association between treatment with neuraminidase inhibitors and the low mortality rate. METHODS A retrospective chart review was performed on a total of 1000 paediatric inpatients. RESULTS The causes of the hospitalizations were respiratory complications in 651 cases (65.1%), neurological complications in 255 cases (25.5%) and other complications in 94 cases. Neuraminidase inhibitors, primarily oseltamivir, had been used to treat 984 (98.4%) of the 1000 patients, and in 88.9% of the patients, treatment with neuraminidase inhibitors was initiated within 48 h after the onset of illness. Only 12 (1.2%) of the 1000 patients underwent mechanical ventilation, and one patient died of H1N1/09 infection. CONCLUSIONS Although a high proportion of the patients in this study had severe respiratory complications, the case fatality rate was only 0.1%. The low mortality rate of children due to the H1N1/09 epidemic in Japan was probably attributable to the universal implementation of early treatment with neuraminidase inhibitors.

Effective and safe immunizations with live-attenuated vaccines for children after living donor liver transplantation.

Immunizations using live-attenuated vaccines are not recommended for post-liver transplant children due to its theoretical risks. However, they will encounter vaccine-preventable viral diseases upon returning to real-life situations. We performed a total of 70 immunizations with four individual live-attenuated vaccines to 18 pediatric post-living donor liver transplant (LDLT) recipients who fulfilled a clinical criteria including humoral and cell-mediated immunity. The seroconversion rates at the first dose for measles (strain AIK-C), rubella (strain TO-336), varicella (strain Oka), and mumps (strains Hoshino) were 100% (15/15), 100% (15/15), 82% (9/11), and 82% (9/11), respectively. During observed period (-5 years 11 months), a few cases with waning immunity (antibodies were once produced but the levels fell over time) were seen except after rubella immunization. Clinical diseases after seroconversion or definite serious adverse effects due to immunization were not observed. Immunizations using selected live-attenuated vaccines were safe and effective for post-LDLT children who were not severely immunosuppressed.

Influenza-related mortality trends in Japanese and American seniors: evidence for the indirect mortality benefits of vaccinating schoolchildren.

Background The historical Japanese influenza vaccination program targeted at schoolchildren provides a unique opportunity to evaluate the indirect benefits of vaccinating high-transmitter groups to mitigate disease burden among seniors. Here we characterize the indirect mortality benefits of vaccinating schoolchildren based on data from Japan and the US. Methods We compared age-specific influenza-related excess mortality rates in Japanese seniors aged ≥65 years during the schoolchildren vaccination program (1978–1994) and after the program was discontinued (1995–2006). Indirect vaccine benefits were adjusted for demographic changes, socioeconomics and dominant influenza subtype; US mortality data were used as a control. Results We estimate that the schoolchildren vaccination program conferred a 36% adjusted mortality reduction among Japanese seniors (95%CI: 17–51%), corresponding to ∼1,000 senior deaths averted by vaccination annually (95%CI: 400–1,800). In contrast, influenza-related mortality did not change among US seniors, despite increasing vaccine coverage in this population. Conclusions The Japanese schoolchildren vaccination program was associated with substantial indirect mortality benefits in seniors.

Effectiveness of Trivalent Inactivated Influenza Vaccine in Children Estimated by a Test-Negative Case-Control Design Study Based on Influenza Rapid Diagnostic Test Results

We assessed vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza in children 6 months to 15 years of age in 22 hospitals in Japan during the 2013–14 season. Our study was conducted according to a test-negative case-control design based on influenza rapid diagnostic test (IRDT) results. Outpatients who came to our clinics with a fever of 38°C or over and had undergone an IRDT were enrolled in this study. Patients with positive IRDT results were recorded as cases, and patients with negative results were recorded as controls. Between November 2013 and March 2014, a total of 4727 pediatric patients (6 months to 15 years of age) were enrolled: 876 were positive for influenza A, 66 for A(H1N1)pdm09 and in the other 810 the subtype was unknown; 1405 were positive for influenza B; and 2445 were negative for influenza. Overall VE was 46% (95% confidence interval [CI], 39–52). Adjusted VE against influenza A, influenza A(H1N1)pdm09, and influenza B was 63% (95% CI, 56–69), 77% (95% CI, 59–87), and 26% (95% CI, 14–36), respectively. Influenza vaccine was not effective against either influenza A or influenza B in infants 6 to 11 months of age. Two doses of influenza vaccine provided better protection against influenza A infection than a single dose did. VE against hospitalization influenza A infection was 76%. Influenza vaccine was effective against influenza A, especially against influenza A(H1N1)pdm09, but was much less effective against influenza B.

Updated data on effective and safe immunizations with live-attenuated vaccines for children after living donor liver transplantation.

BACKGROUND Although immunizations using live-attenuated vaccines are not recommended for children post-liver transplant due to their theoretical risks, they will inevitably encounter vaccine-preventable viral diseases upon returning to real-life situations. The window of opportunity for vaccination is usually limited prior to transplantation because these children often have unstable disease courses. Also, vaccine immunity does not always persist after transplantation. METHODS Beginning in 2002, subcutaneous immunizations with four individual live-attenuated vaccines (measles, rubella, varicella, and mumps) to pediatric patients following living donor liver transplantation (LDLT) were performed for those who fulfilled the clinical criteria, including humoral and cell-mediated immunity. Written informed consent was collected. We included the study on 70 immunizations for 18 cases that we reported in 2008 (Shinjoh et al., 2008). RESULTS A total of 196 immunizations were administered to 48 pediatric post-LDLT recipients. Of these, 144 were first immunizations and 52 were repeated immunizations following LDLT. The seroconversion rates at the first dose for measles (AIK-C), rubella (TO-336), varicella (Oka), and mumps (Hoshino) were 100% (36/36), 100% (35/35), 70% (23/33), and 75% (24/32), respectively. Antibody levels did not fall over time in patients immunized with rubella vaccine. Three mild cases of breakthrough varicella were observed. Two cases with transient parotid gland swelling were observed after mumps immunization. Two admissions because of fever at 2-3 weeks after the measles vaccine were reported but the patients had no symptoms of measles. CONCLUSIONS Immunizations using selected live-attenuated vaccines were safe and effective for post-LDLT children who were not severely immunosuppressed. However, with the exception of rubella, repeated immunization may be necessary.

Trivalent inactivated influenza vaccine effective against influenza A(H3N2) variant viruses in children during the 2014/15 season, Japan.

The 2014/15 influenza season in Japan was characterised by predominant influenza A(H3N2) activity; 99% of influenza A viruses detected were A(H3N2). Subclade 3C.2a viruses were the major epidemic A(H3N2) viruses, and were genetically distinct from A/New York/39/2012(H3N2) of 2014/15 vaccine strain in Japan, which was classified as clade 3C.1. We assessed vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children aged 6 months to 15 years by test-negative case–control design based on influenza rapid diagnostic test. Between November 2014 and March 2015, a total of 3,752 children were enrolled: 1,633 tested positive for influenza A and 42 for influenza B, and 2,077 tested negative. Adjusted VE was 38% (95% confidence intervals (CI): 28 to 46) against influenza virus infection overall, 37% (95% CI: 27 to 45) against influenza A, and 47% (95% CI: -2 to 73) against influenza B. However, IIV was not statistically significantly effective against influenza A in infants aged 6 to 11 months or adolescents aged 13 to 15 years. VE in preventing hospitalisation for influenza A infection was 55% (95% CI: 42 to 64). Trivalent IIV that included A/New York/39/2012(H3N2) was effective against drifted influenza A(H3N2) virus, although vaccine mismatch resulted in low VE.

Recent trends in pediatric bacterial meningitis in Japan – A country where Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines have just been introduced

To investigate the trends in incidence and the characteristics of bacterial meningitis in Japan where Haemophilus influenzae type b (Hib) vaccine and 7-valent pneumococcal conjugated vaccine (PCV7) were introduced in 2008 and 2010, respectively, which was 5-20 years after their introduction in western countries. The nationwide Japanese survey of pediatric and neonatal bacterial meningitis was performed in 2011 and 2012. We analyzed the epidemiological and clinical data, and compared the information obtained in the previous nationwide survey database. We also investigated the risk factors for disease outcome. In the 2011-2012 surveys, 357 patients were evaluated. H. influenzae, Streptococcus pneumoniae, Streptococcus agalactiae and Escherichia coli were the main organisms. The number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.31 in 2009 to 0.43 in 2012 (p < 0.001). The incidence of H. influenzae and S. pneumoniae meningitis also decreased from 0.66 to 0.08 (p < 0.001), and 0.30 to 0.06 (p < 0.001), respectively. Only 0-2 cases with Neisseria meningitidis were reported each year throughout 2001-2012. The median patient age was 10-12 months in 2001-2011, and became lower in 2012 (2 month old) (p < 0.001). The fatality rate for S. agalactiae is the highest (5.9% (11/187)) throughout 2001-2012 among the four organisms. Risk factors for death and sequelae were convulsions at onset, low CSF glucose, S. agalactiae etiology, and persistent positive CSF culture. Hib vaccine and PCV7 decreased the rate of bacterial meningitis. Earlier introduction of these vaccines may have prevented bacterial meningitis among Japanese children.

High rate of inducible clindamycin resistance in Staphylococcus aureus isolates – A multicenter study in Tokyo, Japan

The resistance of Staphylococcus aureus (S. aureus) to antibiotics is an increasing problem. Clindamycin has been used as empiric therapy for the rising incidence of community-acquired methicillin-resistant S. aureus (MRSA). As such, the local rate of inducible resistance against clindamycin is an important consideration. This multicenter study was conducted to identify the incidence of inducible clindamycin resistance of S. aureus isolates in Tokyo, the most populous city in Japan. A total of 2408 adult and pediatric samples were collected from a university hospital and two pediatric hospitals between January 2011 and December 2011. Among the 2341 samples analyzed, the incidence of inducible clindamycin resistance in erythromycin-resistant and clindamycin-susceptible/intermediate isolates was found to be 91% (n = 585), a figure much higher compared to most reports from other countries. In conclusion, we found a very high rate of inducible clindamycin resistance in macrolide-resistant S. aureus isolates in our geographic area.

Cryptococcal meningitis in an immunocompetent child

An immunocompetent child infected with cryptococcal meningitis was cured without any sequelae or relapse with six months of antifungal treatment. An 11-year old Japanese boy who presented with headache and vomiting without high fever was admitted to a local hospital with a diagnosis of aseptic meningitis and discharged after symptomatic relief. Cryptococcus neoformans was later detected in the cerebrospinal fluid (CSF) culture and he was referred to our hospital. His physical and neurological examination was unremarkable except for a mild stiff neck. Cryptococcus neoformans was detected in an India ink stain and culture of the CSF upon admission (Fig. 1), and the cryptococcal antigen with latex agglutination was positive. CSF revealed leukocytosis, increased protein and high opening pressure with normal glucose (53 mg/dl) (Fig. 2). Blood leukocyte count was 7600/ll. Although chest Xray was normal, CT revealed mild peribronchial inflammation in the left lower lobe (S7). An enhanced head MR imaging was negative. The initial treatment with intravenous amphotericin B (AMPH-B) and oral flucytocin (FC) was discontinued after ten days due to fever and skin rash: fluconazole (FLCZ) was administered orally for six months thereafter (Fig 2). No relapses or sequelae have been observed. A detailed developmental and medical history was unremarkable except that he had a history of repeated hospitalizations for asthma until eight years of age. It is noteworthy that he had occasionally been exposed to guano of wild pigeons. His humoral and cellular immunological parameters (CD4 900/ll, CD4/8 2.25), complement and neutrophil functions were normal. Anti-HIV antibody was negative. Although cryptococcal meningitis is uncommon among HIV-negative patients [1, 2, 6, 7, 8], severe pediatric cases have been reported [3, 4]. We infer that, in the case reported here, a pulmonary cryptococcal infection was the primary lesion preceding meningitis because of the exposure to guano of pigeons, repeated

Postexposure prophylaxis for influenza in pediatric wards oseltamivir or zanamivir after rapid antigen detection.

Background: Postexposure prophylaxis (PEP) using neuraminidase inhibitors against exposure to influenza virus has been well studied in household settings but not in nosocomial settings in pediatric wards. Methods: We used oseltamivir or zanamivir as PEP in our pediatric wards. All influenza cases were diagnosed by the influenza rapid diagnostic test. Results: Between 2003 and 2011, there were 20 nosocomial introductions of influenza (10 were A, 9 were B and 1 was undetermined). The index cases consisted of 17 inpatients, 2 parents and 1 medical staff member. The 17 inpatients had been admitted to the hospital for reasons other than infectious disease and they developed influenza after hospitalization. Among the 81 contacts, 28 (35%) were exposed to influenza A, and 52 (64%) were exposed to influenza B. The rate of secondary infection among contacts not given PEP was 29% (5/17), and the rate among contacts given PEP was significantly lower, 3% (2/63; P = 0.004). The 2 infected contacts who had been given PEP were both influenza B cases, and both had received oseltamivir. The contacts who received PEP within 24 hours (59), for influenza A (23) and those who received zanamivir (15) did not develop influenza. No adverse events were reported. Conclusions: PEP using oseltamivir or zanamivir for unexpected occurrences of nosocomial influenza in pediatric wards is safe and effective. The influenza rapid diagnostic test that we used was helpful for detecting nosocomial influenza in children.