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Background: The annual administration of the influenza vaccine is the most effective method for preventing influenza. We have evaluated the effectiveness of the inactivated influenza vaccine in children aged 6 months to 15 years across the seasons from 2013/2014 to 2022/2023. This study aims to investigate the effectiveness of the inactivated influenza vaccine in the 2023/2024 season, the first year following the easing of strict COVID-19 measures, and possibly the last season when only the inactivated vaccine is available on the market., Methods: Adjusted vaccine effectiveness for the 2023/2024 season was assessed using a test-negative case-control design, with results based on polymerase chain reaction and rapid influenza diagnostic tests. Vaccine effectiveness was calculated by influenza type and patient hospitalization/outpatient status., Results: A total of 1832 children were recruited. The inactivated influenza vaccine was effective in preventing both symptomatic influenza A and B in both inpatient and outpatient settings. Overall vaccine effectiveness for influenza A was 51% (95% confidence interval [CI], 23%-69%, n = 930) in inpatient settings and 54% (95%CI, 27%-71%, n = 559) in outpatient settings. For influenza B, effectiveness was 60% (95%CI, 22%-79%, n = 859) in inpatient settings and 56% (95%CI, 26%-74%, n = 558) in outpatient settings. Analysis suggested that administering two doses enhanced effectiveness specifically against influenza B., Conclusions: This is the first study to demonstrate influenza vaccine effectiveness in children after the relaxation of strict COVID-19 measures in Japan (2023/2024). We recommend the current inactivated vaccine for preventing both influenza A and B in children, with consideration for the potential use of two doses to enhance effectiveness against influenza B., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masayoshi Shinjoh (Shinjo) reports a relationship with MSD KK that includes: speaking and lecture fees. Masayoshi Shinjoh (Shinjo) reports a relationship with Meiji Seika Pharma Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh (Shinjo) reports a relationship with Mitsubishi Tanabe Pharma Corporation that includes: speaking and lecture fees. Masayoshi Shinjoh (Shinjo) reports a relationship with KM Biologics Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh (Shinjo) reports a relationship with Shionogi and Co Ltd. that includes: speaking and lecture fees. Masayoshi Shinjoh (Shinjo) reports a relationship with DAIICHI SANKYO COMPANY, LIMITED that includes: speaking and lecture fees. Masayoshi Shinjoh (Shinjo) reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory and speaking and lecture fees. Masayoshi Shinjoh (Shinjo) reports a relationship with Pfizer Japan Inc. that includes: consulting or advisory. Masayoshi Shinjoh (Shinjo) reports a relationship with Janssen Pharmaceutical KK that includes: consulting or advisory. Masayoshi Shinjoh (Shinjo) reports a relationship with Astellas Pharma Inc. that includes: consulting or advisory. This work was supported by JSPS KAKENHI, Japan (Grant Number JP20K10546). Outside this study, the corresponding author received Health Labour Sciences Research Grant, Japan (2024). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Influenza viruses can cause zoonotic infections that pose public health risks. Surveillance of influenza A and B viruses is conducted globally; however, information on influenza C and D viruses is limited. Longitudinal monitoring of influenza C virus in humans has been conducted in several countries, but there has been no long-term monitoring of influenza D virus in humans. The public health risks associated with the influenza D virus therefore remain unknown., Methods: We established a duplex real-time RT-PCR to detect influenza C and D viruses and analyzed respiratory specimens collected from 2144 patients in Japan with respiratory diseases between January 2018 and March 2023. We isolated viruses and conducted hemagglutination inhibition tests to examine antigenicity and focus reduction assays to determine susceptibility to the cap-dependent endonuclease inhibitor baloxavir marboxil., Results: We detected three influenza C viruses belonging to the C/Kanagawa- or C/Sao Paulo-lineages, which recently circulated globally. None of the specimens was positive for the influenza D virus. The C/Yokohama/1/2022 strain, isolated from the specimen with the highest viral RNA load and belonging to the C/Kanagawa-lineage, showed similar antigenicity to the reference C/Kanagawa-lineage strain and was susceptible to baloxavir., Conclusions: Our duplex real-time RT-PCR is useful for the simultaneous detection of influenza C and D viruses from the same specimen. Adding the influenza D virus to the monitoring of the influenza C virus would help in assessing the public health risks posed by this virus., (© 2024 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

During influenza epidemics, Japanese clinicians routinely conduct rapid influenza diagnostic tests (RIDTs) in patients with influenza-like illness, and patients with positive test results are treated with anti-influenza drugs within 48 h after the onset of illness. We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children (6 months-15 years old, N = 4243), using a test-negative case-control design based on the results of RIDTs in the 2018/19 season. The VE against influenza A(H1N1)pdm and A(H3N2) was analyzed separately using an RIDT kit specifically for detecting A(H1N1)pdm09. The adjusted VE against combined influenza A (H1N1pdm and H3N2) and against A(H1N1)pdm09 was 39% (95% confidence interval [CI], 30%-46%) and 74% (95% CI, 39%-89%), respectively. By contrast, the VE against non-A(H1N1)pdm09 influenza A (presumed to be H3N2) was very low at 7%. The adjusted VE for preventing hospitalization was 56% (95% CI, 16%-77%) against influenza A. The VE against A(H1N1)pdm09 was consistently high in our studies. By contrast, the VE against A(H3N2) was low not only in adults but also in children in the 2018/19 season., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: within 36 months, Dr. Norio Sugaya has received speakers’ honoraria from Chugai, Shionogi, Daiichi Sankyo, Astellas, Merck, and Denka Seiken. Dr. Masayoshi Shinjoh has received speakers’ honoraria from Shionogi, Meiji Seika, Merck, Sumitomo Dainippon, Japan Vaccine, Maruho, Astellas, Daiichi Sankyo, and grant support from Janssen. Dr. Keiko Mitamura has received speakers’ honoraria from Shionogi, Meiji Seika, and manuscript fee from Astellas. Dr. Takao Takahashi has received speakers’ honoraria from Daiichi Sankyo, GlaxoSmithKline, Japan Vaccine, Pfizer, Merck, and grant support from Daiichi Sankyo, Japan Vaccine, Pfizer, Merck, Takeda, and Astellas. Other authors have no competing interests regarding this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: ID NOW™ Influenza A & B 2 (ID NOW 2) is a rapid molecular assay that combines two characteristics, namely the rapidness of rapid antigen detection test (RADT) and the high sensitivity of molecular assay., Methods: The clinical performance of ID NOW 2 compared with real-time RT-PCR was evaluated in adults., Results: The sensitivity of ID NOW 2 over multiple seasons from 2016/2017 to 2019/2020 was 97.3% (95% CI: 90.7-99.7) for Type A, 100% (95% CI: 81.9-100) for Type B, and 97.8% (95% CI: 92.2-99.7) for influenza (Type A + Type B), and it was significantly higher than the sensitivity of RADT, which was 80.0% (95% CI: 69.2-88.4) for Type A, 73.3% (95% CI: 44.9-92.2) for Type B, and 78.9% (95% CI: 69.0-86.8) for influenza. The sensitivity of RADT tended to be lower in patients in the particularly early period, within 12 h from disease onset; however, the sensitivity of ID NOW 2 remained high, increasing the difference between the sensitivity of RADT and ID NOW 2. The viral loads were low within 12 h from onset, and it was considered this affected the sensitivity of RADT due to its low analytical sensitivity. The specificity of ID NOW 2 was 98% or greater in all groups., Conclusions: Since ID NOW 2 has a high sensitivity and specificity in adults, it is anticipated to be used in clinical practice, particularly in patients who require early and accurate diagnosis., Competing Interests: Declaration of competing interest This study was sponsored by Abbott Diagnostics Medical Co., Ltd (Tokyo, Japan)., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Baloxavir marboxil is a new anti-influenza drug, but data on the clinical efficacy of a combination treatment of baloxavir and peramivir is scarce. We conducted a single-center retrospective analysis comparing the mortality of a combination of baloxavir and peramivir (B & P, n = 10) and peramivir without baloxavir (P-mono, n = 132) in hospitalized adults with influenza A between 2011 and 2019 in Yokohama City, Japan. Sequencing analysis was conducted in the B & P group to check the I38 mutation in polymerase acidic protein which is associated with baloxavir resistance. The 30-day mortality rates were 0 (0%) in the B & P group and 6 (4.5%) in the P-mono group, respectively, which was not statistically significant. The I38 mutation was not detected before and after the combination treatment. A combination treatment of baloxavir and peramivir might be more effective than peramivir without baloxavir and prevent the emergence of baloxavir resistance in hospitalized adults with influenza A.

In this study, we evaluated the performance of ID NOW Influenza A & B 2 (ID NOW 2), a rapid molecular point-of-care test for influenza within 13 min, in comparison with currently available tests. A total of 254 nasopharyngeal swabs (NPS) and 271 nasopharyngeal aspirates (NPA) collected from 373 children and 152 adults with influenza-like illness were tested using ID NOW 2, viral culture, rapid antigen detection test, and loop-mediated isothermal amplification test to evaluate the sensitivity and specificity compared with real-time reverse transcription polymerase chain reaction as the reference method. The sensitivities of ID NOW 2 for influenza A were 95.9% and 95.7% in NPS and NPA, respectively, and for influenza B were 100% and 98.7% in NPS and NPA, respectively. The specificity was 100% for both influenza A and influenza B in NPS and NPA. Sensitivity of each test method reflected the difference of analytical sensitivity among the tests, and ID NOW 2 was not affected by time after illness onset and patient age. In conclusion, ID NOW 2 demonstrated a high sensitivity and specificity that is useful for diagnosis of influenza in the clinical setting and infection control., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

In January 2019, two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir, were detected from epidemiologically unrelated hospitalised children in Japan. The viruses exhibited reduced susceptibility to baloxavir but were susceptible to neuraminidase inhibitors. Only one of the two children had been treated with baloxavir. An epidemiological analysis suggests possible transmission of the PA I38T mutant A(H3N2) virus among humans.

Background: Influenza A(H3N2) virus rapidly evolves to evade human immune responses, resulting in changes in the antigenicity of haemagglutinin (HA). Therefore, continuous genetic and antigenic analyses of A(H3N2) virus are necessary to detect antigenic mutants as quickly as possible., Aim: We attempted to phylogenetically and antigenically capture the epidemic trend of A(H3N2) virus infection in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons., Methods: We determined the HA sequences of A(H3N2) viruses detected in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons to identify amino acid substitutions and the loss or gain of potential N-glycosylation sites in HA, both of which potentially affect the antigenicity of HA. We also examined the antigenicity of isolates using ferret antisera obtained from experimentally infected ferrets., Results: Influenza A(H3N2) viruses belonging to six clades (clades 3C.2A1, 3C.2A1a, 3C.2A1b, 3C.2A2, 3C.2A3 and 3C.2A4) were detected during the 2016/17 influenza season, whereas viruses belonging to two clades (clades 3C.2A1b and 3C.2A2) dominated during the 2017/18 influenza season. The isolates in clades 3C.2A1a and 3C.2A3 lost one N-linked glycosylation site in HA relative to other clades. Antigenic analysis revealed antigenic differences among clades, especially clade 3C.2A2 and 3C.2A4 viruses, which showed distinct antigenic differences from each other and from other clades in the antigenic map., Conclusion: Multiple clades, some of which differed antigenically from others, co-circulated in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons.

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.

Seasonal influenza virus routinely causes epidemic infections throughout the world. Sporadic infections by H5N1, H5N6, and H7N9 viruses are also reported. To treat patients suffering from such viral infections, broadly reactive and highly sensitive influenza rapid diagnostic tests (IRDTs) are required. Here, we examined the reactivity and sensitivity of 25 IRDTs available in Japan for the detection of seasonal H1N1pdm09, H3N2, and type B viruses, as well as highly pathogenic H5 and H7 viruses. All of the IRDTs tested detected the seasonal viruses and H5 and H7 viruses albeit with different sensitivities. Several IRDTs detected the H5 and H7 viruses and the seasonal viruses with similar (high) sensitivity.

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., Competing Interests: NS has received speakers' honoraria from Astellas, Daiichi Sankyo, Denka Seiken and Takeda, none of which was in connection with the work presented here. MS has received speakers’ honoraria from Astellas, Daiichi Sankyo, Japan Vaccine and MSD; and grant support from Japan Vaccine, none of which was in connection with the work presented here. KM has received speakers’ honoraria from Japan Vaccine and MSD, none of which was in connection with the work presented here. For other authors, none declared., (This article is copyright of The Authors, 2016.)

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.

Background: Shedding of the pandemic virus during an influenza pandemic is thought to persist longer than shedding of influenza viruses during annual influenza seasons, because people have much less immunity against a pandemic influenza. A correlation is thought to exist between the length of virus shedding and the clinical severity of influenza illness., Methods: We compared the virus isolation rates of children with pandemic A H1N1/09 influenza infection and children with A H3N2 influenza infection after the patients had been treated with one of three neuraminidase inhibitors (NAI) such as peramivir, laninamivir and oseltamivir. The clinical effectiveness of each NAI was assessed on the basis of the duration of the febrile period after the start of treatment., Results: Influenza viruses were isolated from 15 of the 34 patients in the A H3N2 group (mean age 6.2 years) and from 4 of the 25 patients in the A H1N1/09 (mean age 5.6 years) virus group (44.1% versus 16.0%; P<0.05). However, the differences between the duration of fever in the patients in the A H3N2 group and A H1N1/09 group after treatment with the NAIs were not significant., Conclusions: The virus isolation rates after treatment with each of the NAIs were significantly lower in the A H1N1/09 group, suggesting that the pandemic A H1N1/09 virus was more sensitive to the NAIs than the seasonal A H3N2 virus was. Clinically, there were no significant differences in the effectiveness of the NAIs between the H1N1/09 infected group and H3N2 infected group.

In this study, the clinical usefulness of silver amplification immunochromatography (SAI) influenza virus detection kits, which employed a photographic development technology to increase the sensitivity of the conventional immunochromatographic assay was evaluated. Influenza A and B virus strains of nasopharyngeal aspirates obtained from influenza patients were tested at different dilutions on the SAI system and conventional immunochromatographic assay kit (ESPLINE Influenza A & B-N), and detection limits were calculated for comparison. The detection ability of the SAI system was 8 times higher for Influenza A viruses and 32-64 times higher for Influenza B viruses. Then 1118 respiratory specimens were obtained from patients who presented with influenza-like symptoms between 2009 and 2012. The sensitivities of the SAI system were 91.2% for type A and 94.4% for type B viruses and higher than those of the conventional kit. The SAI system also showed excellent specificities, 95.8% for type A and 98.0% for type B viruses, and was able to detect influenza viruses even within 6h after the disease onset with 90% sensitivity. In conclusion, the SAI system is useful for diagnosis of influenza from early stages of the illness., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We evaluated Clearline Influenza A/B/(H1N1)2009, a new multi-line immunochromatographic assay for rapid detection of antigens of influenza A (Flu A), B (Flu B), and A(H1N1)2009 viruses. Clearline detected Flu A, Flu B, and A(H1N1)2009 viruses with a detection limit of 4.6 × 10(3) to 7.5 × 10(4) pfu/assay. The sensitivity and specificity of detection of influenza virus by Clearline, using RT-PCR as reference standard, were determined for A(H1N1)2009, Flu A, and Flu B, in nasopharyngeal aspirate, nasopharyngeal swab, and self-blown nasal discharge specimens. Sensitivity for nasopharyngeal aspirate specimens was: A(H1N1)2009 = 97.3 %, Flu A = 94.5 %, and Flu B = 96.8 %, and specificity was Flu A = 99.1 % and Flu B = 100 %. Sensitivity for nasopharyngeal swab specimens was: A(H1N1)2009 = 91.9 %, Flu A = 92.8 %, and Flu B = 100 %, and specificity was Flu A = 98.2 % and Flu B = 100 %. Sensitivity for self-blown nasal discharge specimens was: A(H1N1)2009 = 75.7 %, Flu A = 86.5 %, and Flu B = 76.2 %, and specificity was Flu A = 98.4 % and Flu B = 100 %. Sensitivity and specificity of Clearline were sufficient for nasopharyngeal aspirate and swab specimens. For self-blown nasal discharge specimens, sensitivity was lower than for nasopharyngeal aspirates and nasopharyngeal swabs. The sensitivity of Clearline for A(H1N1)2009 was good even 6 h after the onset of symptoms. These findings suggest that Clearline may be useful for early clinical diagnosis of influenza.

Background: In 2009, a pandemic (pdm) influenza A(H1N1) virus infection quickly circulated globally resulting in about 18,000 deaths around the world. In Japan, infected patients accounted for 16% of the total population. The possibility of human-to-human transmission of highly pathogenic novel influenza viruses is becoming a fear for human health and society., Methodology: To address the clinical need for rapid diagnosis, we have developed a new method, the "RT-SmartAmp assay", to rapidly detect the 2009 pandemic influenza A(H1N1) virus from patient swab samples. The RT-SmartAmp assay comprises both reverse transcriptase (RT) and isothermal DNA amplification reactions in one step, where RNA extraction and PCR reaction are not required. We used an exciton-controlled hybridization-sensitive fluorescent primer to specifically detect the HA segment of the 2009 pdm influenza A(H1N1) virus within 40 minutes without cross-reacting with the seasonal A(H1N1), A(H3N2), or B-type (Victoria) viruses., Results and Conclusions: We evaluated the RT-SmartAmp method in clinical research carried out in Japan during a pandemic period of October 2009 to January 2010. A total of 255 swab samples were collected from outpatients with influenza-like illness at three hospitals and eleven clinics located in the Tokyo and Chiba areas in Japan. The 2009 pdm influenza A(H1N1) virus was detected by the RT-SmartAmp assay, and the detection results were subsequently compared with data of current influenza diagnostic tests (lateral flow immuno-chromatographic tests) and viral genome sequence analysis. In conclusion, by the RT-SmartAmp assay we could detect the 2009 pdm influenza A(H1N1) virus in patients' swab samples even in early stages after the initial onset of influenza symptoms. Thus, the RT-SmartAmp assay is considered to provide a simple and practical tool to rapidly detect the 2009 pdm influenza A(H1N1) virus.

Background: Although influenza virus resistance to the neuraminidase inhibitor zanamivir is reported less frequently than is resistance to the neuraminidase inhibitor oseltamivir in clinical settings, it is unknown whether this difference is due to the limited use of zanamivir or to an inherent property of the drug. We therefore compared the prevalence of drug-resistant viruses and virus shedding in seasonal influenza virus-infected children treated with either oseltamivir or zanamivir., Methods: Clinical specimens (throat or nasal swab) were collected from a total of 144 pediatric influenza patients during the 2005-2006, 2006-2007, 2007-2008, and 2008-2009 influenza seasons. Neuraminidase inhibitor-resistant mutants were detected among the isolated viruses by sequencing the viral hemagglutinin and neuraminidase genes. Sensitivity of the viruses to neuraminidase inhibitors was tested by neuraminidase inhibition assay., Results: In oseltamivir- or zanamivir-treated influenza patients who were statistically comparable in their age distribution, vaccination history, and type or subtype of virus isolates, the virus-shedding period in zanamivir-treated patients was significantly shorter than that in oseltamivir-treated patients. Furthermore, the frequency of zanamivir-resistant viruses was significantly lower than that of oseltamivir-resistant viruses., Conclusion: In comparison with treatment with oseltamivir, treatment of pediatric patients with zanamivir resulted in the emergence of fewer drug-resistant influenza viruses and a shorter virus-shedding period. We conclude that zanamivir shows promise as a better therapy for pediatric influenza patients.

Surveillance studies of the influenza viruses circulating in Europe and other countries in 2007 and 2008 have revealed rates of resistance to oseltamivir of up to 67% among H1N1 viruses. In the present study, we examined 202 clinical samples obtained from patients infected with H1N1 virus in Japan in 2007 and 2008 for oseltamivir resistance and found that three were oseltamivir resistant (1.5%). The 50% inhibitory concentrations (IC(50)s), as measured by a sialidase inhibition assay with these drug-resistant viruses, were >100-fold higher than those of the nonresistant viruses (median IC(50), 12.6 nmol/liter). The His274Tyr (strain N2 numbering) mutation of the neuraminidase protein, which is known to confer oseltamivir resistance, was detected in these three isolates. Phylogenetic analysis showed that one virus belonged to a lineage that is composed of drug-resistant viruses isolated in Europe and North America and that the other two viruses independently emerged in Japan. Continued surveillance studies are necessary to observe whether these viruses will persist.

Background: We compared the clinical effectiveness of oseltamivir and zanamivir in children with influenza A (H1N1) virus, influenza A (H3N2) virus, and influenza B virus infections., Methods: Total febrile period and the duration of fever after the start of treatment were compared between an oseltamivir-treated group (mean age, 8.9 years; range, 4.0-15.9 years) and a zanamivir-treated group (mean age, 10.0 years; range, 4.0-15.7 years) in the pediatric outpatient clinics of our hospitals. Oseltamivir was used to treat 91 children with influenza A (H3N2) infection and 24 children with influenza A (H1N1) infection. Zanamivir was used to treat 35 children with influenza A (H3N2) infection and 12 children with influenza A (H1N1) infection. Oseltamivir was also used to treat 128 children with influenza B virus infection, and zanamivir was used to treat 59 with influenza B virus infection., Results: There was no statistically significant difference in total febrile period or duration of fever after the start of treatment between the oseltamivir-treated group and the zanamivir-treated group of children with influenza A (H3N2) infection (mean duration of febrile period, 2.40 days vs. 2.39 days; mean duration of fever after the start of treatment, 1.35 days vs. 1.40 days), influenza A (H1N1) (mean duration of febrile period, 2.60 days vs. 2.46 days; mean duration of fever after the start of treatment, 1.79 days vs, 1.54 days), or influenza B (mean duration of febrile period, 2.95 days vs. 2.84 days; mean duration of fever after the start of treatment, 1.86 days vs. 1.67 days). Oseltamivir was more effective against influenza A (H3N2) than against influenza A (H1N1) or influenza B., Conclusions: Oseltamivir and zanamivir were equally effective in reducing the febrile period of children with influenza A (H1N1), influenza A (H3N2), and influenza B virus infection.

Context: Very little is known about the frequency of generation and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. Furthermore, transmission of resistant virus, whether influenza A or B, has not been recognized to date., Objective: To assess the prevalence and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors., Design, Setting, and Patients: Investigation of the neuraminidase inhibitor sensitivity of influenza B isolates from 74 children before and after oseltamivir therapy and from 348 untreated patients with influenza (including 66 adults) seen at 4 community hospitals in Japan during the 2004-2005 influenza season. Four hundred twenty-two viruses from untreated patients and 74 samples from patients after oseltamivir therapy were analyzed., Main Outcome Measure: Sialidase inhibition assay was used to test the drug sensitivities of influenza B viruses. The neuraminidase and hemagglutinin genes of viruses showing reduced sensitivity to neuraminidase inhibitors were sequenced to identify mutations that have the potential to confer reduced sensitivity to these drugs., Results: In 1 (1.4%) of the 74 children who had received oseltamivir, we identified a variant with reduced drug sensitivity possessing a Gly402Ser neuraminidase substitution. We also identified variants with reduced sensitivity carrying an Asp198Asn, Ile222Thr, or Ser250Gly mutation in 7 (1.7%) of the 422 viruses from untreated patients. Review of the clinical and viral genetic information available on these 7 patients indicated that 4 were likely infected in a community setting, while the remaining 3 were probably infected through contact with siblings shedding the mutant viruses., Conclusions: In this population, influenza B viruses with reduced sensitivity to neuraminidase inhibitors do not arise as frequently as resistant influenza A viruses. However, they appear to be transmitted within communities and families, requiring continued close monitoring.

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.

Background: Oseltamivir is an effective inhibitor of influenza virus neuraminidase. Although viruses resistant to oseltamivir emerge less frequently than those resistant to amantadine or rimantadine, information on oseltamivir-resistant viruses arising during clinical use of the drug in children is limited. Our aim was to investigate oseltamivir resistance in a group of children treated for influenza., Methods: We analysed influenza A viruses (H3N2) collected from 50 children before and during treatment with oseltamivir. We sequenced the genes for neuraminidase and haemagglutinin and studied the mutant neuraminidases for their sensitivity to oseltamivir carboxylate., Findings: We found neuraminidase mutations in viruses from nine patients (18%), six of whom had mutations at position 292 (Arg292Lys) and two at position 119 (Glu119Val), which are known to confer resistance to neuraminidase inhibitors. We also identified another mutation (Asn294Ser) in one patient. Sensitivity testing to oseltamivir carboxylate revealed that the neuraminidases of viruses that have an Arg292Lys, Glu119Val, or Asn294Ser mutation were about 10(4)-10(5)-fold, 500-fold, or 300-fold more resistant than their pretreatment neuraminidases, respectively. Oseltamivir-resistant viruses were first detected at day 4 of treatment and on each successive day of the study. More than 10(3) infectious units per mL of virus were detected in some of the patients who did not shed drug-resistant viruses, even after 5 days of treatment., Interpretation: Oseltamivir-resistant mutants in children being treated for influenza with oseltamivir arise more frequently than previously reported. Furthermore, children can be a source of viral transmission, even after 5 days of treatment with oseltamivir.

We evaluated the performance of an improved version of Espline Influenza A & B-N (Fujirebio Inc., Japan), an immunochromatography test using enzyme immunoassay for rapid diagnosis of influenza A and B. The test produced positive results for four strains of influenza viruses and thirty-one influenza viral antigens and negative results for all of thirty strains of other respiratory viruses that were tested. The detection limit of this test was 5.8 x 10(2) to 5.8 x 10(3) pfu/assay, which is more sensitive than the old version of Espline. Furthermore, 715 respiratory specimens collected from the patients (children, 79.4%; adults, 18.5%; unknown, 2.1%) with influenza-like illnesses during the 2002/2003 influenza season in Japan were tested as part of a clinical evaluation of this test. The relative performance of this test compared to cell culture and nested RT-PCR results were examined. In the cell cultures, influenza viruses were detected in 488 of the 715 specimens (overall, 68.3%; AH3, 41.7%; B, 26.4%; AH3 and B, 0.1%). For influenza A, the sensitivity of this test was 95.4% (125/131) for nasal aspirates, 96.8% (92/95) for nasal swabs, and 85.1% (63/74) for throat swabs. For influenza B, the sensitivity of this test was 91.2% (52/57) for nasal aspirates, 88.1% (59/67) for nasal swabs, and 71.6% (48/67) for throat swabs. The new test exhibited a remarkably higher sensitivity to influenza A in throat swabs than the old version of Espline. Only two false positive results were obtained out of a total of 223 virus negative specimens; the specificity of the test was 100% (88/88) for nasal aspirates, 97.6% (81/83) for nasal swabs, and 100% (52/52) for throat swabs. We conclude that the new Espline Influenza A&B-N rapid diagnostic test is easy to use and has a high sensitivity and specificity, especially for influenza A.

Rapid and accurate diagnosis is very important for the control of influenza, which is usually diagnosed on a clinical basis. Recently, some rapid diagnostic tests for detecting influenza viruses in respiratory specimens have become available and have proved to be clinically useful. The rapid confirmation of an influenza diagnosis enables prompt treatment with specific antiviral drugs and also decreases the use of unnecessary antibiotics. The rapid tests are also useful for detection of institutional influenza activity. It is important to understand the performance characteristics of the rapid tests.

Emergence of Influenza A H1N2 viruses was documented worldwide during the 2001-2002 influenza season. In Japan, H1N2 viruses were isolated from two students of a junior high school in an influenza outbreak in Yokohama City, February 2001. Genetic and antigenic analyses demonstrated that the H1N2 viruses isolated in Japan shared common features with those isolated in other countries.

Influenza-associated encephalopathy is often reported in young Japanese children, but its pathogenesis is unknown. Although influenza virus can be demonstrated by throat culture for patients with encephalopathy, cultures of samples of cerebrospinal fluids (CSF) do not yield the virus. Eight patients with encephalopathy or complicated febrile convulsions had influenza virus infection diagnosed by means of culture, polymerase chain reaction (PCR), or rapid diagnosis using throat swabs. In all 8 cases, the results of PCR testing of CSF specimens for influenza virus were negative. On the other hand, human herpesvirus 6 (HHV-6) DNA was demonstrated in CSF specimens obtained from 2 of 8 patients. In 3 of 8 patients, the presence of human herpesvirus 7 (HHV-7) DNA was demonstrated in CSF specimens. Some cases of influenza-associated encephalopathy reported in Japan may be attributable to a dual infection with influenza virus and HHV-6, -7, or both. Another possibility is that latent HHV-6 or HHV-7 in the brain is reactivated by influenza, causing encephalopathy or febrile convulsions.