Yoshinori Yasui

Molecular Evolutionary Analysis of the Influenza A(H1N1)pdm, May–September, 2009: Temporal and Spatial Spreading Profile of the Viruses in Japan

Background In March 2009, pandemic influenza A(H1N1) (A(H1N1)pdm) emerged in Mexico and the United States. In Japan, since the first outbreak of A(H1N1)pdm in Osaka and Hyogo Prefectures occurred in the middle of May 2009, the virus had spread over 16 of 47 prefectures as of June 4, 2009. Methods/Principal Findings We analyzed all-segment concatenated genome sequences of 75 isolates of A(H1N1)pdm viruses in Japan, and compared them with 163 full-genome sequences in the world. Two analyzing methods, distance-based and Bayesian coalescent MCMC inferences were adopted to elucidate an evolutionary relationship of the viruses in the world and Japan. Regardless of the method, the viruses in the world were classified into four distinct clusters with a few exceptions. Cluster 1 was originated earlier than cluster 2, while cluster 2 was more widely spread around the world. The other two clusters (clusters 1.2 and 1.3) were suggested to be distinct reassortants with different types of segment assortments. The viruses in Japan seemed to be a multiple origin, which were derived from approximately 28 transported cases. Twelve cases were associated with monophyletic groups consisting of Japanese viruses, which were referred to as micro-clade. While most of the micro-clades belonged to the cluster 2, the clade of the first cases of infection in Japan originated from cluster 1.2. Micro-clades of Osaka/Kobe and the Fukuoka cases, both of which were school-wide outbreaks, were eradicated. Time of most recent common ancestor (tMRCA) for each micro-clade demonstrated that some distinct viruses were transmitted in Japan between late May and early June, 2009, and appeared to spread nation-wide throughout summer. Conclusions Our results suggest that many viruses were transmitted from abroad in late May 2009 irrespective of preventive actions against the pandemic influenza, and that the influenza A(H1N1)pdm had become a pandemic stage in June 2009 in Japan.

Human H5N2 Avian Influenza Infection in Japan and the Factors Associated with High H5N2-Neutralizing Antibody Titer

Background H5N2 avian influenza virus infection of humans has not been reported thus far. The first H5N2 avian influenza infection of poultry in Japan occurred in Ibaraki. Methods The subjects were workers at 35 chicken farms in Ibaraki Prefecture, where the H5N2 virus or antibody was isolated from chickens. None of the subjects exhibited influenza symptoms. The H5N2-neutralizing antibody titers of the first and second paired sera samples were compared. To investigate the possible factors for this increase, the H5N2-neutralizing antibody titer (1:40 or more) was calculated for the second samples. A logistic regression analysis was performed to examine the association of these factors with H5N2-neutralizing antibody positivity. Results We performed Wilcoxon matched-pairs signed-ranked test on data collected from 257 subjects, and determined that the H5N2 antibody titers of the second paired sera samples were significantly higher than those of the first samples (P < 0.001). The H5N2 antibody titers of paired sera of 13 subjects without a history of seasonal influenza vaccination within the previous 12 months increased 4-fold or more. The percentage of antibody positivity was 32% for subjects with a history of seasonal influenza vaccination (28% of all subjects) and 13% for those without a history of the same. The adjusted odds ratio of H5N2-neutralizing antibody positivity was 4.6 (95% confidence interval: 1.6-13.7) for those aged over 40 and 3.1 (95% confidence interval: 1.6-6.1) for those with a history of seasonal influenza vaccination within the previous 12 months. Conclusion The results suggest that this may have been the first avian influenza H5N2 infection of poultry to affect humans. A history of seasonal influenza vaccination might be associated with H5N2-neutralizing antibody positivity.

Epidemics of Vector-borne Diseases Observed in Infectious Disease Surveillance in Japan, 2000-2005

BACKGROUND Observing the epidemics of vector-borne diseases is important. One or more cases of 6 vector-borne diseases were reported to the National Epidemiological Surveillance of Infectious Diseases in Japan in 2000-2005. METHODS The reports of those cases were available. The incidence was observed by region of acquired infection, prefecture reporting, and week and year of diagnosis. RESULTS The incidence rate per year per 1,000,000 population was 0.36 for dengue fever, 0.04 for Japanese encephalitis, 0.38 for Japanese spotted fever, 0.08 for Lyme disease, 0.74 for malaria, and 3.50 for scrub typhus. There were no cases of dengue fever or malaria derived from domestic infections. The yearly incidence rate increased for dengue fever and Japanese spotted fever, and declined for malaria and scrub typhus. The proportion of cases reported in Tokyo was 44% for dengue fever and 37% for malaria. The number of prefectures reporting one or more cases of Japanese spotted fever increased in western Japan. The cases of scrub typhus increased in autumn-winter in prefectures of eastern Japan, and increased both in autumn-winter and spring in western prefectures. CONCLUSIONS The study reveals the epidemiologic features of both temporal and geographic distributions of cases of 6 vector-borne diseases in Japan, 2000-2005.

Sex- and age-related differences in morbidity rates of 2009 pandemic influenza A H1N1 virus of swine origin in Japan.

Background The objective of the present study was to determine whether the morbidity rates of the 2009 pandemic influenza A H1N1 virus (pdmH1N1) varied by age and/or sex. Methods and Findings Retrospective analysis of 2,024,367 cases of pdmH1N1 was performed using the national surveillance data from influenza sentinel points in Japan. The male-to-female morbidity ratios (M/F ratios) in nineteen age groups were estimated as the primary outcome. The M/F ratios for pdmH1N1 influenza were: >1 in age groups <20 years and ≥80 years (p<0.001); <1 in age groups 20–79 years (p<0.001). This data suggests that males <20 years of age may be more likely to suffer from pdmH1N1 influenza than females in the same age categories. When the infection pattern for pdmH1N1was compared with that of seasonal influenza outbreaks between 2000 and 2008, the M/F ratio for pdmH1N1 influenza was higher in ages 3–29 years and lower in ages 40–79 years. Because the present study was based on the national surveillance, it was impossible to estimate the morbidity rate for the Japanese population. It is also likely that the data did not capture asymptomatic or mild infections. Conclusions Although exposure to the pdmH1N1 virus is assumed to be similar in both boys and girls, M/F ratios were >1 in those younger than 20 years. The subsequent reversal of the M/F ratio in the adult generation could be due to several possibilities, including: greater immunity among adult males, more asymptomatic infections among males, less reporting of illness by males, or differences in exposure to the virus and probability of visiting a clinic. These results suggest that the infection and virulence patterns of pdmH1N1 are more complex than previously considered.

Nosocomial Serratia marcescens outbreak in Osaka, Japan, from 1999 to 2000.

OBJECTIVES To investigate and control an outbreak of bloodstream infections (BSIs) caused by Serratia marcescens and to identify risk factors for respiratory colonization or infection with S. marcescens. DESIGN Epidemiologic investigation, including review of medical and laboratory records, procedural investigations, pulsed-field gel electrophoresis (PFGE) typing of environmental and patient isolates, statistical study, and recommendation of control measures. PATIENTS AND SETTING All patients admitted to a 380-bed, secondary-care hospital in Osaka Prefecture, Japan, from July 1999 through June 2000 (study period). RESULTS Seventy-one patients were colonized or infected with S. marcescens; 3 patients who developed primary BSIs on the same ward within 5 days in June 2000 had isolates with indistinguishable PFGE patterns and indwelling intravenous catheters for more than 5 days. On multivariate analysis, among 36 case-patients with positive sputum specimens and 95 control-patients, being bedridden (odds ratio [OR], 15.91; 95% confidence interval [CI95], 4.17-60.77), receiving mechanical ventilation (OR, 7.86; CI95, 2.27-27.16), being older than 80 years (OR, 3.12; CI95, 1.05-9.27), and receiving oral cleaning care (OR, 3.10; CI95, 1-9.58) were significant risk factors. S. marcescens was isolated from the fluid tanks of three nebulizers and a liquid soap dispenser. The hospital did not have written infection control standards, and many infection control practices were found to be inadequate (eg, respiratory equipment was used without disinfection between patients). CONCLUSIONS Poor hospital hygiene and the lack of standard infection control measures contributed to infections hospital-wide. Recommendations to the hospital included adoption of written infection control policies.

National Surveillance of Influenza-Associated Encephalopathy in Japan over Six Years, before and during the 2009–2010 Influenza Pandemic

Influenza-associated encephalopathy (IAE) is a serious complication of influenza and is reported most frequently in Japan. This paper presents an assessment of the epidemiological characteristics of influenza A (H1N1) 2009-associated encephalopathy in comparison to seasonal IAE, based on Japanese national surveillance data of influenza-like illness (ILI) and IAE during flu seasons from 2004–2005 through 2009–2010. In each season before the pandemic, 34–55 IAE cases (mean 47.8; 95% confidence interval: 36.1–59.4) were reported, and these cases increased drastically to 331 during the 2009 pandemic (6.9-fold the previous seasons). Of the 331 IAE cases, 322 cases were reported as influenza A (H1N1) 2009-associated encephalopathy. The peaks of IAE were consistent with the peaks of the influenza epidemics and pandemics. A total of 570 cases of IAE (seasonal A, 170; seasonal B, 50; influenza A (H1N1) 2009, 322; unknown, 28) were reported over six seasons. The case fatality rate (CFR) ranged from 4.8 to 18.2% before the pandemic seasons and 3.6% in the 2009 pandemic season. The CFR of pandemic-IAE was 3.7%, which is lower than that of influenza A−/B-associated encephalopathy (12.9%, p<0.001; 14.0%, p = 0.002; respectively). The median age of IAE was 7 years during the pandemic, which is higher than that of influenza A−/B-associated encephalopathy (4, p<0.001; 4.5, p = 0.006; respectively). However, the number of pandemic-IAE cases per estimated ILI outpatients peaked in the 0–4-year age group and data both before and during the pandemic season showed a U-shape pattern. This suggests that the high incidence of influenza infection in the 0–4 year age group may lead to a high incidence of IAE in the same age group in a future influenza season. Further studies should include epidemiologic case definitions and clinical details of IAE to gain a more accurate understanding of the epidemiologic status of IAE.

Pandemic (H1N1) 2009 Transmission during Presymptomatic Phase, Japan

During an epidemiologic investigation of pandemic influenza (H1N1) 2009 virus infection in May 2009 in Osaka, Japan, we found 3 clusters in which virus transmission occurred during the presymptomatic phase. This finding has public health implications because it indicates that viral transmission in communities cannot be prevented solely by isolating symptomatic case-patients.

Epidemics of Drug-Resistant Bacterial Infections Observed in Infectious Disease Surveillance in Japan, 2001-2005

BACKGROUND Drug-resistant bacteria have been increasing together with advancement of antimicrobial chemotherapy in recent years. In Japan, the target diseases in the National Epidemiological Surveillance of Infectious Diseases (NESID) include some drug-resistant bacterial infections. METHODS We used the data in the NESID in Japan, 2001-2005. Target diseases were methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and multi-drug-resistant Pseudomonas aeruginosa (MDRPA) infections. The numbers of patients reported by sentinel hospitals (about 500) on a monthly basis were observed. RESULTS The numbers of patients per month per sentinel hospital of 2001-2005 were 3.37-3.98 in MRSA, 0.96-1.19 in PRSP, and 0.11-0.13 in MDRPA infections. The sex ratios (male / female) of patients were 1.69-1.82, 1.34-1.43, and 1.71-2.52, respectively. More than 50% of all patients were adults aged 70 years or older in MRSA and MDRPA infections, but more than 60% were children under 10 years in PRSP infections. The number of patients per sentinel hospital in MRSA infections showed little variation between months, but evidenced a large variation in PRSP and MDRPA infections. The annual trend in the number of patients per sentinel hospital was increasing significantly for the 5-year period in MRSA and PRSP infections, but not in MDRPA infections. CONCLUSIONS We revealed sex-age distributions of the patients reported to NESID in Japan, 2001-2005. An increasing incidence of MRSA and PRSP infections and monthly variation in PRSP and MDRPA infections were observed for the 5-year period. Extended observation would be necessary to confirm these trends and variations.

Annual and weekly incidence rates of influenza and pediatric diseases estimated from infectious disease surveillance data in Japan, 2002-2005.

BACKGROUND The method for estimating incidence of infectious diseases from sentinel surveillance data has been proposed. In Japan, although the annual incidence rates of influenza and pediatric diseases estimated using the method were reported, their weekly incidence rates have not. METHODS The weekly sex- and age-specific numbers of cases in the sentinel medical institutions in the National Epidemiological Surveillance of Infectious Diseases in Japan in 2002-2005 were used. Annual and weekly incidence rates of influenza and 12 pediatric diseases were estimated by the above-mentioned method, under the assumption that sentinels are randomly selected from all medical institutions. RESULTS The annual incidence rate of influenza in 2002-2005 was 57.7-142.6 per 1,000 population. The highest weekly incidence rate was 7.4 at week 8 in 2002, 14.9 at week 4 in 2003, 14.1 at week 5 in 2004, and 21.2 at week 9 in 2005. The annual incidence rate per 1,000 population of 0-14 years old in 2002-2005 was less than 5.0 for pertussis, rubella and measles, 293.2-320.8 for infectious gastroenteritis, and 5.3-89.6 for 8 other diseases. The highest weekly incidence rate was less than 1.0 for exanthem subitum, and was more than 5.0 for infectious gastroenteritis, hand-foot-mouth disease and herpangina. CONCLUSION We estimated annual and weekly incidence rates of influenza and pediatric diseases in Japan in 2002-2005, and described their temporal variation.

Epidemics of Influenza and Pediatric Diseases Observed in Infectious Disease Surveillance in Japan, 1999-2005

BACKGROUND A method for determining epidemics in small areas from the sentinel surveillance data has been proposed and applied in the National Epidemiological Surveillance of Infectious Diseases (NESID) in Japan. We observed epidemics of influenza and 11 pediatric diseases by the method in the NESID in Japan during 1999-2005. METHODS We assumed that an epidemic in a public health center area began in a week when the number of cases reported to the NESID per sentinel clinic and hospital in the area in the week exceeded a given value, and that the epidemic ended when the number was lower than another given value. The proportion of public health center areas with epidemics (epidemic area proportion) by week in fiscal 1999-2005 was calculated. Total public health center area-weeks observed were about 30,000 each year. RESULTS The mean epidemic area proportion in the 7 years was 6.0% for influenza and 0.2-7.4% for pediatric diseases. The proportion increased in pharyngoconjunctival fever and group A streptococcal pharyngitis, decreased in measles and was less than 1.0% in pertussis and rubella. In influenza, the height of the peak in the weekly epidemic area proportion varied between 6 and 90% in the 7 years and the week of the peak varied widely. In some pediatric diseases, the height of the peak varied, while the week of the peak was relatively constant. CONCLUSION The frequency and temporal change were described in the epidemics of influenza and pediatric diseases in public health center areas from the NESID data in Japan, 1999-2005.