Disease burden of main bacterial infections in Japan, 2015-2020: A population-level study.

INTRODUCTION: Comprehensive evidence about the burden of infectious diseases in the Western Pacific Region is scarce. We thus examined the disease burden of infectious diseases in Japan in terms of disability-adjusted life years (DALYs). METHODS: We extracted national claims data from Japan's universal health insurance system to estimate the burden of disease for selected infections between 2015 and 2020 using DALYs. The mortality rate, disability duration and severity weight of each disease were estimated based on national data and literature reviews. RESULTS: Disease burden per 100,000 population was 1307.0 in 2015 and 972.1 in 2020 for bloodstream infections (BSI), 796.5 DALYs in 2015 and 498.9 DALYs in 2020 for pneumonia, 171.5 in 2015 and 149.4 in 2020 for meningitis and 11.6 in 2015 and 11.4 in 2020 for urinary tract infections (UTI). Only surgical site infections (SSI) showed a slightly increasing trend over the 5-year period, from 2.2 in 2015 to 2.8 in 2020. CONCLUSIONS: Our results showed that the disease burden of the five major infectious diseases was higher in Japan than in other countries. However, while the burden of SSI increased, the burden of pneumonia, meningitis, BSI and UTI gradually decreased year on year. The possible causes of the decreased morbidity should be examined in future work.

Benefit-Risk Assessment of mRNA COVID-19 Vaccines in Children Aged 6 Months to 4 Years in the Omicron Era.

BACKGROUND: There is no risk and benefit assessment of COVID-19 vaccination for children younger than 5 years using a single health outcomes scale. The objective of this study is to compare the expected risk and benefits of the mRNA primary series of COVID-19 vaccines for children aged 6 months to 4 years in the United States using a single health outcome scale in the Omicron era. METHODS: The expected benefits and risks of the primary two-dose series of mRNA COVID-19 vaccines for children aged 6 months to 4 years were stratified by sex, the presence of underlying medical conditions, the presence of infection-induced immunity, and the type of mRNA vaccine (BNT162b2 or mRNA-1273). A scoping literature review was conducted to identify the indicators in the decision tree model. The benefit-risk ratio was the outcome of interest. RESULTS: The benefit-risk ratios ranged from 200.4 in BNT162b2 for males aged 6-11 months with underlying medical conditions and without infection-induced immunity to 3.2 in mRNA-1273 for females aged 1-4 years without underlying medical conditions and with infection-induced immunity. CONCLUSIONS: The expected benefit of receiving the primary series of mRNA vaccines outweighed the risk among children ages 6 months to 4 years regardless of sex, presence of underlying medical conditions, presence of infection-induced immunity, or type of mRNA vaccines. However, the continuous monitoring of the COVID-19 epidemiology as well as vaccine effectiveness and safety is important.

Impact of Multiplex Polymerase Chain Reaction Test in Patients With Meningitis or Encephalitis.

Background: The objective of this study was to evaluate the impact of the FilmArray meningitis/encephalitis panel (FAME) on length of stay (LOS) and duration of antimicrobial treatment in children and adults in a Japanese community hospital. Methods: This retrospective cohort study was conducted in Japan between January 2016 and December 2022. We included hospitalized patients with cerebrospinal fluid (CSF) samples and those aged <2 months or who had 5 or more white blood cells/µL in the CSF. To compare the days of therapy (DOT) and LOS between the pre-FAME and FAME periods, multivariate Poisson regression analyses were conducted without an offset term. Results: The number of cases undergoing pathogen-specific polymerase chain reaction increased from 3.7% in the pre-FAME period to 57.5% in the FAME period (P < .001). The pathogen identification rate also increased during the FAME period, from 0.4% to 18.7% (P < .001). While the antibacterial DOT was not statistically different between the 2 periods (adjusted rate ratio [aRR], 1.06 [95% confidence interval {CI}, 1.00-1.13]; P = .063]), the antiviral DOT was significantly shorter in the FAME period (aRR, 0.80 [95% CI, .71-.89]; P < .001). Conclusions: This study revealed a significant reduction in antiviral use during the FAME period, whereas LOS and antibacterial use did not decrease. Given the possibility of factors (eg, the COVID-19 pandemic) affecting the epidemiology of meningitis and encephalitis, the indications and impact of the FAME test should be evaluated with continuous monitoring of the epidemiology of meningitis and encephalitis and its clinical impact.

Factors Associated with Geographical Variability of Antimicrobial Use in Japan.

INTRODUCTION: Evidence regarding the factors affecting the geographical variation of antimicrobial use (AMU) is relatively scarce. This study aimed to evaluate factors potentially associated with geographical variability of AMU per day per 1000 habitants in the 47 prefectures of Japan. METHODS: This is an observational ecological study using the Japanese national database in 2019. The outcome was the defined daily doses per 1000 inhabitants per day by prefecture. Multivariable negative binomial regression analysis was conducted using patient- and physician-level variables. RESULTS: The study included 605,391,054 defined daily doses of AMU in 2019 from the 47 prefectures. In the multivariable negative binomial regression analyses for the outcome of total AMU, the proportion of female individuals (adjusted rate ratio [aRR] 1.04 [1.01-1.08] per 1% increase, p = 0.021), the proportion of upper secondary graduates going to further education (aRR 1.01 [1.00-1.01] per 1% increase, p = 0.005), and the annual number of diagnoses related to upper respiratory infections (URIs) per 1000 inhabitants per day (aRR 1.21 [1.10-1.34], p < 0.001) were significantly correlated with total AMU. CONCLUSIONS: In this ecological study, the variability of total AMU by Japanese prefecture was associated with the proportion of female individuals, education level, and the number of URI diagnoses per population. The results suggest the potential need for additional stewardship efforts to reduce unnecessary antimicrobial prescriptions for URI.

Epidemiology of respiratory tract infections using multiplex PCR in a Japanese acute care hospital during the COVID19 pandemic.

Introduction: We aimed to investigate the epidemiology of respiratory infections by season and age during the COVID-19 pandemic in a Japanese acute care hospital using multiplex PCR testing. Methods: We detected 21 pathogens in specimens from outpatients with respiratory symptoms at the Nara Prefecture General Medical Center using the multiplex PCR-based FilmArray Respiratory Panel 2.1 (bioMérieux). Results: Of the 3177 cases, 1215 (38.2%) were infected with at least one causative virus, and 1641 viruses were detected. The most common viruses detected were human rhinovirus/enterovirus (n = 655) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 264). Additionally, 321 (10.1%) of these cases were infected with two or more overlapping viruses. There were 23 cases of co-infection with SARS-CoV-2 and other viruses. In the winter months from December 2020 to March 2021, the number of detected viruses was relatively low, followed by the surge of human rhinovirus/enterovirus, respiratory syncytial virus (RSV), and parainfluenza type 3 in the spring and summer of 2021. While the number of human rhinovirus/entero-virus remained relatively high after the 2021 summer, the number of other viruses detected since September 2021 was low. After December 2021, the number of SARS-CoV-2 increased rapidly. Conclusions: Continuous monitoring of the epidemiology of respiratory infection is important to understand the prolonged impact of the COVID-19 pandemic.

Risk and Benefit of mRNA COVID-19 Vaccines for the Omicron Variant by Age, Sex, and Presence of Comorbidity: A Quality-Adjusted Life Years Analysis.

The development of the mutant omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease 2019 (COVID-19) pandemic raised the importance of reevaluating the risk and benefit of COVID-19 vaccines. With a decision tree model, we calculated the benefit-risk ratio and the benefit-risk difference of receiving monovalent messenger RNA (mRNA) COVID-19 vaccine (primary 2 doses, a third dose, and a fourth dose) in the 4-5 months after vaccination using quality-adjusted life years. The analysis was stratified by age, sex, and the presence of comorbidity. Evidence from peer-reviewed publications and gray literature was reviewed on September 16, 2022, to inform the study. Benefit-risk ratios for receipt of the BNT162b2 vaccine (Pfizer-BioNTech) ranged from 6.8 for males aged 12-17 years without comorbidity for the primary doses to 221.3 for females aged ≥65 years with comorbidity for the third dose. The benefit-risk ratios for receipt of the mRNA-1273 vaccine (Moderna) ranged from 7.2 for males aged 18-29 years without comorbidity for the primary doses to 101.4 for females aged ≥65 years with comorbidity for the third dose. In all scenarios of the one-way sensitivity analysis, the benefit-risk ratios were more than 1, irrespective of age, sex, comorbidity status, and type of vaccine, for both primary and booster doses. The benefits of mRNA COVID-19 vaccines in protecting against the omicron variant outweigh the risks, irrespective of age, sex, and comorbidity.

Immunogenicity of a quadrivalent human papillomavirus vaccine in pediatric kidney and liver transplant recipients.

BACKGROUND: Solid-organ transplant recipients are at increased risk of developing human papillomavirus-related diseases. METHODS: To evaluate the immunogenicity of a quadrivalent vaccine, a prospective observational study included females aged 12-19 years who had received kidney or liver transplants, or were otherwise healthy volunteers. With the three-dose vaccination, serum antibodies were measured. RESULTS: The study included 17 transplant recipients (seven kidney and 10 liver) and 16 healthy participants. Six of seven kidney transplant recipients were on three immunosuppressive medications, whereas 9 of the 10 liver transplant recipients were on one. For the serology within 6 months from the last vaccine dose, the geometric mean titers of human papillomavirus types 6, 11, 16, and 18 were 26.7, 8.6, 35.7, and 42.4 (kidney transplant); 579.2, 569.3, 3097.3, and 835.7 (liver transplant); and 860.5, 638.8, 4391.6, and 902.6 milli-Merck Units/ml (healthy). The seropositivity rates of kidney transplant recipients for the four serotypes ranged from 50% to 75%, while all liver transplant recipients and healthy participants had 100% seropositivity rates for all four types. While there were no statistical differences of titers between liver transplant recipients and healthy participants, the titers of kidney transplant recipients were lower than those of healthy participants for type 6 (p = .034), type 11 (p = .032), and type 16 (p = .032). CONCLUSIONS: The results support the recommendation of human papillomavirus vaccination in pediatric transplant recipients given the significant risk of human papillomavirus-related diseases in this population, though immunogenicity was lower in kidney transplant recipients on multiple immunosuppressive medications.

Impact of the COVID-19 pandemic and multiplex polymerase chain reaction test on outpatient antibiotic prescriptions for pediatric respiratory infection.

This study aimed to evaluate the impact of the prolonged COVID-19 pandemic on outpatient antibiotic prescriptions for pediatric respiratory infections at an acute care hospital in Japan in order to direct future pediatric outpatient antibiotic stewardship. The impact of the COVID-19 pandemic and the FilmArray Respiratory Panel (RP) on outpatient antibiotic prescriptions was assessed from January 2019 to December 2021 using an interrupted time series analysis of children <20 years. The overall antimicrobial prescription rate decreased from 38.7% to 22.4% from the pre-pandemic period to the pandemic. The pandemic (relative risk [RR] level, 0.97 [0.58-1.61]; P = 0.90; RR slope, 1.05 [0.95-1.17] per month; P = 0.310) and FilmArray RP (RR level, 0.90 [0.46-1.75]; P = 0.75; RR slope, 0.95 [0.85-1.06] per month; P = 0.330) had no significant effect on the monthly antibiotic prescription rates. The COVID-19 pandemic was not significantly related to the antibiotic prescription rate, suggesting that it did not impact physicians' behavior toward antibiotic prescriptions. Replacing rapid antigen tests with the FilmArray RP introduced on December 1, 2020, did not affect the magnitude of the reduction in antibiotic prescription rate for pediatric respiratory infections.

The cost-effectiveness of maternal and neonatal screening for congenital cytomegalovirus infection in Japan.

Congenital cytomegalovirus infection is the most common congenital infection. Using a decision tree model, cost-effectiveness of maternal screening with subsequent prenatal valacyclovir treatment and newborn screening with neonatal valganciclovir treatment was evaluated. The incremental cost-effectiveness ratio (ICER) was calculated for (1) universal maternal antibody screening with prenatal valacyclovir treatment compared to targeted newborn screening, and (2) universal newborn screening with postnatal valganciclovir treatment compared to targeted newborn screening. We performed a one-way sensitivity analysis. Compared to targeted newborn screening, the ICERs for universal newborn screening and maternal screening were 2 966 296 Japanese Yen (JPY) (21 188 USD) and 1 026 984 JPY (7336 USD), respectively. In all scenarios in the one-way sensitivity analysis, the ICERs of the maternal screening and the universal newborn screening strategies were less than three gross domestic product per capita compared with the targeted newborn screening strategy. Both maternal and universal newborn screening strategies may be cost-effective than a targeted newborn screening program. The potential utility of the maternal screening with valacyclovir treatment strategy, while potentially cost effective in regions with lower baseline seroprevalence rates, requires further study as the modeling was based on limited evidence.

Antimicrobial stewardship in pediatric solid organ transplantation: Is it possible?

BACKGROUND: Solid organ transplant (SOT) recipients are at increased risk of severe outcomes associated with antimicrobial resistance (AMR). Antimicrobial stewardship programs (ASPs) play a vital role in mitigating the negative impacts of AMR. Pediatric evidence regarding ASP for SOT recipients is scarce, although many pediatric SOT centers have implemented different forms of ASP. METHODS: This article summarized the available evidence relating to AMR among pediatric SOT recipients and discussed key strategies for the successful implementation of ASP among this population. The focus is primarily on antibacterial and secondarily on antifungal management. RESULTS: The development of multidisciplinary antimicrobial stewardship teams for pediatric SOT recipients is essential for successful stewardship implementation. Key stakeholders may include but are not limited to SOT recipients and their caregivers, primary SOT teams (transplant physicians, transplant pharmacists, transplant unit nurses, and transplant outpatient care team), transplant surgery teams, transplant infectious diseases teams, hospital AST, microbiology teams, infection prevention teams, quality improvement teams, and information technology teams. CONCLUSION: As the evidence for optimal ASP in pediatric SOT is still evolving, it is important to measure the impact of implemented interventions.

A survey of healthcare workers' recommendations about human papillomavirus vaccination.

Purpose: The human papillomavirus (HPV) vaccine is safe and effective for preventing HPV-related diseases. However, HPV vaccination rates in Japan are low because the "Ministry of Health, Labour and Welfare" had stopped recommending vaccination. We assessed healthcare workers' (HCWs) current recommendations regarding the HPV vaccine and how the provision of information about HPV vaccination affected their recommendations. Materials and Methods: A survey was conducted among nurses and physicians in Nara prefecture from March 2021 to July 2021. The questionnaire asked about their understanding, recommendations, and opinions regarding HPV vaccination. Before answering the last two questions (optional), the HCWs read evidence-based information quantifying the risks and benefits of HPV vaccination. Results: A total of 441 HCWs completed the questionnaire. Only 19% of HCWs always recommended HPV vaccination for girls aged 12-16 years. The evidence-based information significantly improved the percentage of HCWs who would "always recommend" vaccination. Conclusion: This study showed that the proportion of HCWs who recommend HPV vaccination to adolescent girls remains low in Japan. However, we found that evidence-based information describing the causal relationship between adverse events and vaccination, quantifying the risks and benefits, noting the importance of HCW communications with families, and reporting the recommendations of national societies, might increase HCWs' recommendations for HPV vaccination.

Changing trends in HPV vaccination in Japan.

After the Japanese Ministry of Health, Labor and Welfare (MHLW) suspended its recommendation for the human papillomavirus (HPV) vaccine in June 2013, the rate of members of the new target population receiving of at least one of three doses of HPV vaccine declined, reaching 0.3% in 2016. Recently, however, the monthly number of vaccines delivered to healthcare facilities has significantly increased, from 878 doses over December 2016-April 2017 to 35,396 doses over January-March 2021. This may be due to governmental efforts to convey information about the HPV vaccination to the eligible population and their caregivers, as well as local educational programs, despite ongoing suspension of the recommendation. The incidence of reported adverse events per vaccine dose has not increased since 2016. While governmental recommendation of the HPV vaccination remains essential for optimal vaccine coverage, the recent increase in the number of doses delivered to healthcare facilities is promising.

Risk-Benefit Analysis of the 9-Valent HPV Vaccination for Adolescent Boys from an Individual Perspective.

Japan recently approved a quadrivalent human papillomavirus (HPV) vaccine for males, but the 9-valent vaccine has only been approved for females. Given the low female vaccination rate due to concerns about adverse events in Japan, quantifying the risks and benefits of the HPV vaccination for males may help in deciding whether to vaccinate adolescent boys in Japan. Using quality-adjusted life years, the risk-benefit ratio for an adolescent boy receiving the 9-valent HPV vaccination was calculated. The male HPV vaccination reduced the QALYs gained due to head and neck cancer, anal cancer, penile cancer, genital warts, and recurrent respiratory papillomatosis by 401.63, 20.38, 9.40, 28.79, and 69.13 per 100,000 vaccinated persons, respectively. The total risk of vaccination was 11.85. The risk-benefit ratio for a 12-year-old boy who received the HPV vaccination series was found to be 0.022 (benefit-risk ratio, 44.670). In the sensitivity analysis, the risk-benefit ratio ranged from 0.0001 to 0.11 for all scenarios. Hence, much larger benefits than risks linked with the male HPV vaccination were observed from an individual perspective. The results support the inclusion of sex-neutral HPV vaccinations into the national immunization program as well as strengthens the decision for adolescent boys to receive the vaccination.

The Impact of COVID-19 on Outpatient Antibiotic Prescriptions in Ontario, Canada; An Interrupted Time Series Analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has potentially impacted outpatient antibiotic prescribing. Investigating this impact may identify stewardship opportunities in the ongoing COVID-19 period and beyond. METHODS: We conducted an interrupted time series analysis on outpatient antibiotic prescriptions and antibiotic prescriptions/patient visits in Ontario, Canada, between January 2017 and December 2020 to evaluate the impact of the COVID-19 pandemic on population-level antibiotic prescribing by prescriber specialty, patient demographics, and conditions. RESULTS: In the evaluated COVID-19 period (March-December 2020), there was a 31.2% (95% CI, 27.0% to 35.1%) relative reduction in total antibiotic prescriptions. Total outpatient antibiotic prescriptions decreased during the COVID-19 period by 37.1% (95% CI, 32.5% to 41.3%) among family physicians, 30.7% (95% CI, 25.8% to 35.2%) among subspecialist physicians, 12.1% (95% CI, 4.4% to 19.2%) among dentists, and 25.7% (95% CI, 21.4% to 29.8%) among other prescribers. Antibiotics indicated for respiratory infections decreased by 43.7% (95% CI, 38.4% to 48.6%). Total patient visits and visits for respiratory infections decreased by 10.7% (95% CI, 5.4% to 15.6%) and 49.9% (95% CI, 43.1% to 55.9%). Total antibiotic prescriptions/1000 visits decreased by 27.5% (95% CI, 21.5% to 33.0%), while antibiotics indicated for respiratory infections/1000 visits with respiratory infections only decreased by 6.8% (95% CI, 2.7% to 10.8%). CONCLUSIONS: The reduction in outpatient antibiotic prescribing during the COVID-19 pandemic was driven by less antibiotic prescribing for respiratory indications and largely explained by decreased visits for respiratory infections.

The estimated burden of 15 vaccine-preventable diseases from 2008 to 2020 in Japan: A transition by the COVID-19 pandemic.

BACKGROUND: Evaluating the national burdens across multiple vaccine-preventable diseases (VPDs) can be informative to identify the areas for improvements in the national immunization program. METHODS: The annual burden of diseases from 2008 to 2020 in Japan were calculated with the incidence- and pathogen-based approach for the 15 VPDs (hepatitis B virus infection, human papillomavirus (HPV), influenza, invasive pneumococcal disease, invasive Haemophilus influenzae type b (Hib) disease, invasive meningococcal disease, Japanese encephalitis, measles, mumps, pertussis, rotavirus, rubella, tetanus, tuberculosis and varicella), using disability-adjusted life year (DALY). RESULTS: The average annual burden between 2008 and 2020 is the highest in influenza (114,129 DALY/year), followed by HPV infection, hepatitis B virus infection, tuberculosis and mumps (109,782, 69,883, 23,855 and 5693 DALY/year). In the pre-COVID-19 period (2008-2019), the decreasing trend of burden was observed in hepatitis B virus infection, invasive pneumococcal disease, invasive Hib disease, tuberculosis and varicella. HPV infection is the only VPD which had more than 100,000 DALY/year for all years during the study period. In 2020, the estimated annual burdens are decreased in influenza (71%), invasive pneumococcal disease (51%), invasive Hib diseases (54%), invasive meningococcal disease (64%), measles (98%), mumps (47%) pertussis (83%), rotavirus infection (95%), rubella (94%) and varicella (35%) compared with those in 2019. CONCLUSIONS: The study demonstrated decreasing trends of burdens for some VPDs, while a persistently high burden has been observed for other VPDs, including HPV infection. The COVID-19 pandemic has caused dramatic reductions in the burdens of many VPDs in 2020.

The incremental burden of invasive pneumococcal disease associated with a decline in childhood vaccination using a dynamic transmission model in Japan: A secondary impact of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has disrupted childhood vaccinations, including pneumococcal conjugate vaccine (PCV). Evaluating the possible impact on the invasive pneumococcal disease (IPD) incidence associated with a decline in childhood pneumococcal vaccination is important to advocate the PCV programs. Using a deterministic, dynamic transmission model, the differential incidence and burden of IPD in children younger than 5 years in Japan were estimated between the rapid vaccination recovery (January 2021) and the delayed vaccination recovery (April 2022) scenarios for the next 10 years. In our model, the IPD incidence was reduced from 11.9/100,000 in 2019 to 6.3/100,000 in 2020, caused by a reduced transmission rate due to the COVID-19 mitigation measures. Assuming a recovery in the transmission rate in 2022 April, the incidence of IPD was estimated to increase with maximal incidence of 12.1 and 13.1/100,000 children under 5 years in the rapid and the delayed vaccination recovery scenarios. The difference in the total IPD incidence between these two scenarios was primarily driven by vaccine serotypes IPD incidence. The difference of incidence was not observed between the two scenarios after 2025. The persistent decline in childhood pneumococcal vaccination rates due to the impact of COVID-19 might lead to an increased IPD incidence and an incremental disease burden.

Solid organ transplant-specific antibiogram in a tertiary pediatric hospital in Canada.

SOT recipients are more vulnerable to infections with antimicrobial-resistant organisms, and therefore, it may be useful for transplant centers to create transplant-specific antibiograms to direct empirical antimicrobial regimens and monitor trends in antimicrobial resistance. SOT-specific antibiograms were created using antimicrobial susceptibility data on isolates from 2012 to 2018 at The Hospital for Sick Children, Toronto, Ontario, Canada. The CLSI guidelines were followed to generate the antibiograms except that results from 2 years of data were pooled on a rolling basis to achieve larger sample sizes. The 3 most frequent organisms in one analysis period of the SOT antibiogram were Escherichia coli (average sample size ±standard deviation; n = 28.7 ± 3.8), Staphylococcus aureus (n = 27.8 ± 5.0), and Pseudomonas aeruginosa (non-CF) (n = 19.8 ± 8.8). For E.coli, susceptibilities in the SOT antibiogram were significantly lower than those in the hospital-wide antibiogram in 2017-2018 for ampicillin (27% vs 47%; p = .014), piperacillin/tazobactam (55% vs 88%; p < .001), cefotaxime (59% vs 89%; p < .001), ciprofloxacin (71% vs 88%; p = .007), and trimethoprim-sulfamethoxazole (41% vs 69%; p = .001), but not significantly different for aminoglycosides and meropenem. In the SOT antibiogram of E. coli, decreased susceptibility trend was confirmed in some antibiotics, including piperacillin/tazobactam (83% in 2012-2013 vs 55% in 2017-2018). At our center, the solid organ transplant-specific antibiogram revealed important differences in E. coli susceptibilities and trends in antimicrobial resistance. Developing a SOT antibiogram will assist in revising and improving empiric treatment guidelines as well as monitoring antimicrobial resistance in this population.