Redefining pandemic preparedness: Multidisciplinary insights from the CERP modelling workshop in infectious diseases, workshop report.

In July 2023, the Center of Excellence in Respiratory Pathogens organized a two-day workshop on infectious diseases modelling and the lessons learnt from the Covid-19 pandemic. This report summarizes the rich discussions that occurred during the workshop. The workshop participants discussed multisource data integration and highlighted the benefits of combining traditional surveillance with more novel data sources like mobility data, social media, and wastewater monitoring. Significant advancements were noted in the development of predictive models, with examples from various countries showcasing the use of machine learning and artificial intelligence in detecting and monitoring disease trends. The role of open collaboration between various stakeholders in modelling was stressed, advocating for the continuation of such partnerships beyond the pandemic. A major gap identified was the absence of a common international framework for data sharing, which is crucial for global pandemic preparedness. Overall, the workshop underscored the need for robust, adaptable modelling frameworks and the integration of different data sources and collaboration across sectors, as key elements in enhancing future pandemic response and preparedness.

High-Dose Influenza Vaccine Is Associated With Reduced Mortality Among Older Adults With Breakthrough Influenza Even When There Is Poor Vaccine-Strain Match.

BACKGROUND: High-dose (HD) influenza vaccine offers improved protection from influenza virus infection among older adults compared with standard-dose (SD) vaccine. Here, we explored whether HD vaccine attenuates disease severity among older adults with breakthrough influenza. METHODS: This was a retrospective cohort study of US claims data for influenza seasons 2016-2017, 2017-2018, and 2018-2019, defined as 1 October through 30 April, among adults aged ≥65 years. After adjusting the different cohorts for the probability of vaccination conditional on patients' characteristics, we compared 30-day mortality rate post-influenza among older adults who experienced breakthrough infection after receipt of HD or SD influenza vaccines and among those not vaccinated (NV). RESULTS: We evaluated 44 456 influenza cases: 23 109 (52%) were unvaccinated, 15 037 (33.8%) received HD vaccine, and 6310 (14.2%) received SD vaccine. Significant reductions in mortality rates among breakthrough cases were observed across all 3 seasons for HD vs NV, ranging from 17% to 29% reductions. A significant mortality reduction of 25% was associated with SD vaccination vs NV in the 2016-2017 season when there was a good match between circulating influenza viruses and selected vaccine strains. When comparing HD vs SD cohorts, mortality reductions were higher among those who received HD in the last 2 seasons when mismatch between vaccine strains and circulating H3N2 viruses was documented, albeit not significant. CONCLUSIONS: HD vaccination was associated with lower post-influenza mortality among older adults with breakthrough influenza, even during seasons when antigenically drifted H3N2 circulated. Improved understanding of the impact of different vaccines on attenuating disease severity is warranted when assessing vaccine policy recommendations.

Global and national influenza-associated hospitalisation rates: Estimates for 40 countries and administrative regions.

Background: WHO estimates that seasonal influenza epidemics result in three to five million cases of severe illness (hospitalisations) every year. We aimed to improve the understanding of influenza-associated hospitalisation estimates at a national and global level. Methods: We performed a systematic literature review of English- and Chinese-language studies published between 1995 and 2020 estimating influenza-associated hospitalisation. We included a total of 127 studies (seven in Chinese) in the meta-analysis and analyzed their data using a logit-logistic regression model to understand the influence of five study factors and produce national and global estimates by age groups. The five study factors assessed were: 1) the method used to calculate the influenza-associated hospitalisation estimates (rate- or time series regression-based), 2) the outcome measure (divided into three envelopes: narrow, medium, or wide), 3) whether every case was laboratory-confirmed or not, 4) whether the estimates were national or sub-national, 5) whether the rates were based on a single year or multiple years. Results: The overall pooled influenza-associated hospitalisation rate was 40.5 (95% confidence interval (CI) = 24.3-67.4) per 100 000 persons, with rates varying substantially by age: 224.0 (95% CI = 118.8-420.0) in children aged 0-4 years and 96.8 (95% CI = 57.0-164.3) in the elderly aged >65 years. The overall pooled hospitalisation rates varied by calculation method; for all ages, the rates were significantly higher when they were based on rate-based methods or calculated on a single season and significantly lower when cases were laboratory-confirmed. The national hospitalisation rates (all ages) varied considerably, ranging from 11.7 (95% CI = 3.8-36.3) per 100 000 in New Zealand to 122.1 (95% CI = 41.5-358.4) per 100 000 in India (all age estimates). Conclusions: Using the pooled global influenza-associated hospitalisation rate, we estimate that seasonal influenza epidemics result in 3.2 million cases of severe illness (hospitalisations) per annum. More extensive analyses are required to assess the influence of other factors on the estimates (e.g. vaccination and dominant virus (sub)types) and efforts to harmonize the methods should be encouraged. Our study highlights the high rates of influenza-associated hospitalisations in children aged 0-4 years and the elderly aged 65+ years.

Global, regional and national estimates of influenza-attributable ischemic heart disease mortality.

Background: Influenza virus infection is associated with incident ischemic heart disease (IHD) events. Here, we estimate the global, regional, and national IHD mortality burden attributable to influenza. Methods: We used vital registration data from deaths in adults ≥50 years (13.2 million IHD deaths as underlying cause) to assess the relationship between influenza activity and IHD mortality in a non-linear meta-regression framework from 2010 to 2019. This derived relationship was then used to estimate the global influenza attributable IHD mortality. We estimated the population attributable fraction (PAF) of influenza for IHD deaths based on the relative risk associated with a given level of weekly influenza test positivity rate and multiplied PAFs by IHD mortality from the Global Burden of Disease study. Findings: Influenza activity was associated with increased risk of IHD mortality across all countries analyzed. The mean PAF of influenza for IHD mortality was 3.9% (95% uncertainty interval [UI] 2.5-5.3%), ranging from <1% to 10%, depending on country and year. Globally, 299,858 IHD deaths (95% UI 191,216-406,809) in adults ≥50 years could be attributed to influenza, with the highest rates per 100,000 population in the Central Europe, Eastern Europe and Central Asia Region (32.3; 95% UI 20.6-43.8), and in the North Africa and Middle East Region (26.7; 95% UI 17-36.2). Interpretation: Influenza may contribute substantially to the burden of IHD. Our results suggest that if there were no influenza, an average of 4% of IHD deaths globally would not occur. Funding: Collaborative study funded by Sanofi Vaccines.

The value of public-private collaborative real-world evidence platforms to monitor vaccine performance post authorization: DRIVE - a European initiative.

INTRODUCTION: Fighting pandemics requires an established infrastructure for pandemic preparedness, with existing, sustainable platforms ready to be activated. This includes platforms for disease surveillance, virus circulation, and vaccine performance monitoring based on Real-World data, to complement clinical trial evidence. AREAS COVERED: Because of its complexity, this can best be done by combining efforts between public and private sectors, developing a multi-stakeholder approach. Public-Private-Partnerships increasingly play a critical role in combating infectious diseases but are still looked at with hesitancy. The Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project, which established a platform for measuring brand-specific influenza vaccine effectiveness in Europe, exemplifies how to build a collaborative platform with transparent governance, state-of-the-art methodology, and a large network of participating sites. Lessons learned from DRIVE have been cardinal to set up COVIDRIVE, a platform for brand-specific COVID-19 vaccine effectiveness monitoring. EXPERT OPINION: The DRIVE partners propose that a debate on the benefits of Public-Private-Partnership-generated real-world evidence for vaccine effectiveness monitoring should be pursued to clarify roles and responsibilities, set up expectations, and decide the future environment for vaccine monitoring in Europe. In parallel, the driving factors behind PPP hesitancy should be studied.

Predictors of influenza severity among hospitalized adults with laboratory confirmed influenza: Analysis of nine influenza seasons from the Valencia region, Spain.

PURPOSE: Influenza hospitalizations contribute substantially to healthcare disruption. We explored the impact of ageing, comorbidities and other risk factors to better understand associations with severe clinical outcomes in adults hospitalized with influenza. METHODS: We analysed multi-season data from adults ≥18 years, hospitalized with laboratory-confirmed influenza in Valencia, Spain. Severity was defined as intensive care unit (ICU) admission, assisted ventilation and/or death. Generalized estimating equations were used to estimate associations between risk factors and severity. Rate of hospital discharge was analysed with a cumulative incidence function. RESULTS: Only 26% of influenza patients had their primary discharge diagnosis coded as influenza. Comorbidities were associated with severity among adults aged 50-79 years, with the highest odds ratio (OR) in patients with ≥3 comorbidities aged 50-64 years (OR = 6.7; 95% CI: 1.0-44.6). Morbid obesity and functional dependencies were also identified risk factors (ORs varying from 3 to 5 depending on age). The presence of increasing numbers of comorbidities was associated with prolonged hospital stay. CONCLUSIONS: Influenza clinical outcomes are aggravated by the presence of comorbidities and ageing. Increased awareness of influenza among hospitalized patients could prompt clinical and public health interventions to reduce associated burden.

Hospital utilization rates for influenza and RSV: a novel approach and critical assessment.

BACKGROUND: Influenza and respiratory syncytial virus (RSV) contribute significantly to the burden of acute lower respiratory infection (ALRI) inpatient care, but heterogeneous coding practices and availability of inpatient data make it difficult to estimate global hospital utilization for either disease based on coded diagnoses alone. METHODS: This study estimates rates of influenza and RSV hospitalization by calculating the proportion of ALRI due to influenza and RSV and applying this proportion to inpatient admissions with ALRI coded as primary diagnosis. Proportions of ALRI attributed to influenza and RSV were extracted from a meta-analysis of 360 total sources describing inpatient hospital admissions which were input to a Bayesian mixed effects model over age with random effects over location. Results of this model were applied to inpatient admission datasets for 44 countries to produce rates of hospital utilization for influenza and RSV respectively, and rates were compared to raw coded admissions for each disease. RESULTS: For most age groups, these methods estimated a higher national admission rate than the rate of directly coded influenza or RSV admissions in the same inpatient sources. In many inpatient sources, International Classification of Disease (ICD) coding detail was insufficient to estimate RSV burden directly. The influenza inpatient burden estimates in older adults appear to be substantially underestimated using this method on primary diagnoses alone. Application of the mixed effects model reduced heterogeneity between countries in influenza and RSV which was biased by coding practices and between-country variation. CONCLUSIONS: This new method presents the opportunity of estimating hospital utilization rates for influenza and RSV using a wide range of clinical databases. Estimates generally seem promising for influenza and RSV associated hospitalization, but influenza estimates from primary diagnosis seem highly underestimated among older adults. Considerable heterogeneity remains between countries in ALRI coding (i.e., primary vs non-primary cause), and in the age profile of proportion positive for influenza and RSV across studies. While this analysis is interesting because of its wide data utilization and applicability in locations without laboratory-confirmed admission data, understanding the sources of variability and data quality will be essential in future applications of these methods.

Potential impact of introducing vaccines against COVID-19 under supply and uptake constraints in France: A modelling study.

BACKGROUND: The accelerated vaccine development in response to the COVID-19 pandemic should lead to a vaccine being available early 2021, albeit in limited supply and possibly without full vaccine acceptance. We assessed the short-term impact of a COVID-19 immunization program with varying constraints on population health and non-pharmaceutical interventions (NPIs) needs. METHODS: A SARS-CoV-2 transmission model was calibrated to French epidemiological data. We defined several vaccine implementation scenarios starting in January 2021 based on timing of discontinuation of NPIs, supply and uptake constraints, and their relaxation. We assessed the number of COVID-19 hospitalizations averted, the need for and number of days with NPIs in place over the 2021-2022 period. RESULTS: An immunisation program under constraints could reduce the burden of COVID-19 hospitalizations by 9-40% if the vaccine prevents against infections. Relaxation of constraints not only reduces further COVID-19 hospitalizations (30-39% incremental reduction), it also allows for NPIs to be discontinued post-2021 (0 days with NPIs in 2022 versus 11 to 125 days for vaccination programs under constraints and 327 in the absence of vaccination). CONCLUSION: For 2021, COVID-19 control is expected to rely on a combination of NPIs and the outcome of early immunisation programs. The ability to overcome supply and uptake constraints will help prevent the need for further NPIs post-2021. As the programs expand, efficiency assessments will be needed to ensure optimisation of control policies post-emergency use.

National burden estimates of hospitalisations for acute lower respiratory infections due to respiratory syncytial virus in young children in 2019 among 58 countries: a modelling study.

BACKGROUND: Respiratory syncytial virus (RSV) is the predominant viral pathogen associated with acute lower respiratory infection (ALRI) in children who are younger than 5 years. Little is reported on the national estimates of RSV-associated ALRI hospitalisations in these children on the basis of robust epidemiological data. We aimed to generate national level estimates for RSV-associated ALRI hospitalisations in children aged younger than 5 years. METHODS: We included data for RSV and ALRI hospitalisation in children who were younger than 5 years from systematic literature reviews (including unpublished data) and from inpatient databases, representing 58 countries. We used two different methods, the rate-based method and the proportion-based method, to estimate national RSV-associated ALRI hospitalisations in children younger than 5 years in 2019. The rate-based method synthesised data for laboratory-confirmed RSV-associated ALRI hospitalisation rates using a spatiotemporal Gaussian process meta-regression (ST-GPR). The proportion-based method applied data for RSV positive proportions among ALRI to all-cause ALRI hospitalisation envelopes (ie, total disease burden of ALRI hospitalisations of any cause) using a Bayesian regularised trimmed meta-regression (MR-BRT). Where applicable, we reported estimates by both methods to provide a plausible range for each country. FINDINGS: A total of 334 studies and 1985 data points (defined as an individual estimate for one age group and 1 year for each study) were included in our analysis, accounting for 398 million (59%) of the 677 million children aged younger than 5 years worldwide representing 58 countries. We reported the number of annual national RSV-associated ALRI hospitalisations for 29 countries using the rate-based method, and for 42 countries using the proportion-based method. The median number of RSV-associated ALRI hospitalisations in children younger than 5 years was 8·25 thousand (IQR 1·97-48·01), and the median rate of RSV-associated ALRI hospitalisations was 514 (339-866) hospitalisations per thousand children younger than 5 years. Despite large variation among countries, a high proportion of the RSV-associated ALRI hospitalisations were in infants aged younger than 1 year in all countries (median proportion 45%, IQR 32-56). In 272 (76%) of the 358 years included in the analysis, the RSV-associated ALRI hospitalisation rate fluctuated between 0·8 and 1·2 times the country's median yearly rate. General agreement was observed between estimates by the rate-based method and proportion-based method, with the exceptions of India, Kenya, Norway, and Philippines. INTERPRETATION: By incorporating data from various sources, our study provides robust estimates on national level burden of RSV-associated ALRI hospitalisation in children aged younger than 5 years. These estimates are important for informing policy for the introduction of RSV immunisations and also serve as baseline data for the RSV disease burden in young children. FUNDING: The Foundation for Influenza Epidemiology.

Performance of laboratory tests for detection for Clostridioides difficile: A multicenter prospective study in Japan.

BACKGROUND: The optimal and practical laboratory diagnostic approach for detection of Clostridioides difficile to aid in the diagnosis of C. difficile infection (CDI) is controversial. A two-step algorithm with initial detection of glutamate dehydrogenase (GDH) or nucleic acid amplification test (NAAT) alone are recommended as a predominant method for C. difficile detection in developed countries. The aim of this study was to compare the performance of enzyme immunoassays (EIA) detecting toxins A and B, NAAT detecting the toxin B gene, and GDH compared to toxigenic culture (TC) for C. difficile as the gold standard, in patients prospectively and actively assessed with clinically significant diarrhea in 12 medical facilities in Japan. METHODS: A total of 650 stool specimens were collected from 566 patients with at least three diarrheal bowel movements (Bristol stool grade 6-7) in the preceding 24 h. EIA and GDH were performed at each hospital, and NAAT and toxigenic C. difficile culture with enriched media were performed at the National Institute of Infectious Diseases. All C. difficile isolates recovered were analyzed by PCR-ribotyping. RESULTS: Compared to TC, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of EIA were 41%, 96%, 75% and 84%, respectively, and for NAAT were 74%, 98%, 91%, and 92%, respectively. In 439 specimens tested with GDH, the sensitivity, specificity, PPV, and NPV were 73%, 87%, 65%, and 91%, and for an algorithm (GDH plus toxin EIA, arbitrated by NAAT) were 71%, 96%, 85%, and 91%, respectively. Among 157 isolates recovered, 75% of isolates corresponded to one of PCR-ribotypes (RTs) 002, 014, 018/018", and 369; RT027 was not isolated. No clear differences in the sensitivities of any of EIA, NAAT and GDH for four predominant RTs were found. CONCLUSION: The analytical sensitivities of NAAT and GDH-algorithm to detect toxigenic C. difficile in this study were lower than most previous reports. This study also found low PPV of EIAs. The optimal method to detect C. difficile or its toxins to assist in the diagnosis of CDI needs further investigation.

Guidance for the governance of public-private collaborations in vaccine post-marketing settings in Europe.

INTRODUCTION: The 2009 influenza pandemic highlighted challenges for vaccine post-marketing monitoring in Europe, particularly the need to have appropriate infrastructures to strengthen public-private collaborations (PPCs) with suitable processes to improve stakeholder interactions and collection and analysis of safety and effectiveness data. The ADVANCE consortium comprises public and private stakeholders who have worked together to build and test new system components for vaccine post-marketing projects, one component being a governance framework for efficient, transparent and trustworthy PPCs. METHODS: Based on the results of a landscape analysis and screening of formalised existing governance structures, we identified the elements of a governance framework and developed recommendations to support stakeholders willing and able to implement collaborative projects. These proposals and their implementation were discussed by 70 experts during a workshop to gain from their experience. RESULTS: We identified core governance principles and defined five fundamental functions (decision-making, scientific advice, quality control and audit, implementation and management, and financial administration) that can be attributed to individual partner organisations or to a committee with representatives from more than one partner organisation. We propose a generic governance model with options for its adaptation to specific contexts and projects. The advantages and disadvantages of PPCs were also examined. Stakeholders' concerns (e.g. scientific integrity and public trust) were addressed through recommendations about transparent decision-making rules and conflict of interest management. CONCLUSIONS: No one-size-fits-all solution for PPC governance exists but our recommendations could be used to set-up a tailored-made and fully transparent governance structure supporting collaborative projects in the European vaccine post-marketing environment. To allow the rapid establishment of robust projects, the next steps will involve this guidance being used by real-world collaborations to assess what works and what does not work and what added-value can be obtained from these collaborations.

Clostridioides (Clostridium) difficile infection burden in Japan: A multicenter prospective study.

Clostridioides (Clostridium) difficile is the leading cause of healthcare-associated infectious diarrhea in the developed world. Retrospective studies have shown a lower incidence of C. difficile infection (CDI) in Japan than in Europe or North America. Prospective studies are needed to determine if this is due lack of testing for C. difficile or a true difference in CDI epidemiology. A prospective cohort study of CDI was conducted from May 2014 to May 2015 at 12 medical facilities (20 wards) in Japan. Patients with at least three diarrheal bowel movements (Bristol stool grade 6-7) in the preceding 24 h were enrolled. CDI was defined by positive result on enzyme immunoassay for toxins A/B, nucleic acid amplification test for the toxin B gene or toxigenic culture. C. difficile isolates were subjected to PCR-ribotyping (RT), slpA-sequence typing (slpA-ST), and antimicrobial susceptibility testing. The overall incidence of CDI was 7.4/10,000 patient-days (PD). The incidence was highest in the five ICU wards (22.2 CDI/10,000 PD; range: 13.9-75.5/10,000 PD). The testing frequency and CDI incidence rate were highly correlated (R2 = 0.91). Of the 146 isolates, RT018/018″ was dominant (29%), followed by types 014 (23%), 002 (12%), and 369 (11%). Among the 15 non-ICU wards, two had high CDI incidence rates (13.0 and 15.9 CDI/10,000 PD), with clusters of RT018/slpA-ST smz-02 and 018"/smz-01, respectively. Three non-RT027 or 078 binary toxin-positive isolates were found. All RT018/018" isolates were resistant to moxifloxacin, gatifloxacin, clindamycin, and erythromycin. This study identified a higher CDI incidence in Japanese hospitals than previously reported by actively identifying and testing patients with clinically significant diarrhea. This suggests numerous patients with CDI are being overlooked due to inadequate diagnostic testing in Japan.

The burden of clostridium difficile infection: estimates of the incidence of CDI from U.S. Administrative databases.

BACKGROUND: Many administrative data sources are available to study the epidemiology of infectious diseases, including Clostridium difficile infection (CDI), but few publications have compared CDI event rates across databases using similar methodology. We used comparable methods with multiple administrative databases to compare the incidence of CDI in older and younger persons in the United States. METHODS: We performed a retrospective study using three longitudinal data sources (Medicare, OptumInsight LabRx, and Healthcare Cost and Utilization Project State Inpatient Database (SID)), and two hospital encounter-level data sources (Nationwide Inpatient Sample (NIS) and Premier Perspective database) to identify CDI in adults aged 18 and older with calculation of CDI incidence rates/100,000 person-years of observation (pyo) and CDI categorization (onset and association). RESULTS: The incidence of CDI ranged from 66/100,000 in persons under 65 years (LabRx), 383/100,000 in elderly persons (SID), and 677/100,000 in elderly persons (Medicare). Ninety percent of CDI episodes in the LabRx population were characterized as community-onset compared to 41 % in the Medicare population. The majority of CDI episodes in the Medicare and LabRx databases were identified based on only a CDI diagnosis, whereas almost ¾ of encounters coded for CDI in the Premier hospital data were confirmed with a positive test result plus treatment with metronidazole or oral vancomycin. Using only the Medicare inpatient data to calculate encounter-level CDI events resulted in 553 CDI events/100,000 persons, virtually the same as the encounter proportion calculated using the NIS (544/100,000 persons). CONCLUSIONS: We found that the incidence of CDI was 35 % higher in the Medicare data and fewer episodes were attributed to hospital acquisition when all medical claims were used to identify CDI, compared to only inpatient data lacking information on diagnosis and treatment in the outpatient setting. The incidence of CDI was 10-fold lower and the proportion of community-onset CDI was much higher in the privately insured younger LabRx population compared to the elderly Medicare population. The methods we developed to identify incident CDI can be used by other investigators to study the incidence of other infectious diseases and adverse events using large generalizable administrative datasets.

Identification of Medicare Recipients at Highest Risk for Clostridium difficile Infection in the US by Population Attributable Risk Analysis.

BACKGROUND: Population attributable risk percent (PAR%) is an epidemiological tool that provides an estimate of the percent reduction in total disease burden if that disease could be entirely eliminated among a subpopulation. As such, PAR% is used to efficiently target prevention interventions. Due to significant limitations in current Clostridium difficile Infection (CDI) prevention practices and the development of new approaches to prevent CDI, such as vaccination, we determined the PAR% for CDI in various subpopulations in the Medicare 5% random sample. METHODS: This was a retrospective cohort study using the 2009 Medicare 5% random sample. Comorbidities, infections, and healthcare exposures during the 12 months prior to CDI were identified. CDI incidence and PAR% were calculated for each condition/exposure. Easy to identify subpopulations that could be targeted from prevention interventions were identified based on PAR%. FINDINGS: There were 1,465,927 Medicare beneficiaries with 9,401 CDI cases for an incidence of 677/100,000 persons. Subpopulations representing less than 15% of the entire population and with a PAR% ≥ 30% were identified. These included deficiency anemia (PAR% = 37.9%), congestive heart failure (PAR% = 30.2%), fluid and electrolyte disorders (PAR% = 29.6%), urinary tract infections (PAR% = 40.5%), pneumonia (PAR% = 35.2%), emergent hospitalization (PAR% = 48.5%) and invasive procedures (PAR% = 38.9%). Stratification by age and hospital exposures indicates hospital exposures are more strongly associated with CDI than age. SIGNIFICANCE: Small and identifiable subpopulations that account for relatively large proportions of CDI cases in the elderly were identified. These data can be used to target specific subpopulations for CDI prevention interventions.

Clostridium difficile Infection Among Veterans Health Administration Patients.

OBJECTIVE: To report on the prevalence and incidence of Clostridium difficile infection (CDI) from 2009 to 2013 among Veterans Healthcare Administration patients DESIGN: A retrospective descriptive analysis of data extracted from a large electronic medical record (EMR) database SETTING: Data were acquired from VHA healthcare records from 2009 to 2013 that included outpatient clinical visits, long-term care, and hospitalized care as well as pharmacy and laboratory information. RESULTS: In 2009, there were 10,207 CDI episodes, and in 2013, there were 12,143 CDI episodes, an increase of 19.0%. The overall CDI rate increased by 8.4% from 193 episodes per 100,000 patient years in 2009 to 209 episodes per 100,000 patient years in 2013. Of the CDI episodes identified in 2009, 58% were identified during a hospitalization, and 42% were identified in an outpatient setting. In 2013, 44% of the CDI episodes were identified in an outpatient setting. CONCLUSION: This is one of the largest studies that has utilized timely EMR data to describe the current CDI epidemiology at the VHA. Despite an aging population with greater burden of comorbidity than the general US population, our data show that VHA CDI rates stabilized between 2011 and 2013 following increases likely attributable to the introduction of the more sensitive nucleic acid amplification tests (NAATs). The findings in this report will help establish an accurate benchmark against which both current and future VA CDI prevention initiatives can be measured.

First-year results of the Global Influenza Hospital Surveillance Network: 2012-2013 Northern hemisphere influenza season.

BACKGROUND: The Global Influenza Hospital Surveillance Network (GIHSN) was developed to improve understanding of severe influenza infection, as represented by hospitalized cases. The GIHSN is composed of coordinating sites, mainly affiliated with health authorities, each of which supervises and compiles data from one to seven hospitals. This report describes the distribution of influenza viruses A(H1N1), A(H3N2), B/Victoria, and B/Yamagata resulting in hospitalization during 2012-2013, the network's first year. METHODS: In 2012-2013, the GIHSN included 21 hospitals (five in Spain, five in France, four in the Russian Federation, and seven in Turkey). All hospitals used a reference protocol and core questionnaire to collect data, and data were consolidated at five coordinating sites. Influenza infection was confirmed by reverse-transcription polymerase chain reaction. Hospitalized patients admitted within 7 days of onset of influenza-like illness were included in the analysis. RESULTS: Of 5034 patients included with polymerase chain reaction results, 1545 (30.7%) were positive for influenza. Influenza A(H1N1), A(H3N2), and both B lineages co-circulated, although distributions varied greatly between coordinating sites and over time. All age groups were affected. A(H1N1) was the most common influenza strain isolated among hospitalized adults 18-64 years of age at four of five coordinating sites, whereas A(H3N2) and B viruses were isolated more often than A(H1N1) in adults ≥65 years of age at all five coordinating sites. A total of 16 deaths and 20 intensive care unit admissions were recorded among patients with influenza. CONCLUSIONS: Influenza strains resulting in hospitalization varied greatly between coordinating sites and over time. These first-year results of the GIHSN are relevant, useful, and timely. Due to its broad regional representativeness and sustainable framework, this growing network should contribute substantially to understanding the epidemiology of influenza, particularly for more severe disease.

Cost-effectiveness of cervical-cancer screening in five developing countries.

BACKGROUND: Cervical-cancer screening strategies that involve the use of conventional cytology and require multiple visits have been impractical in developing countries. METHODS: We used computer-based models to assess the cost-effectiveness of a variety of cervical-cancer screening strategies in India, Kenya, Peru, South Africa, and Thailand. Primary data were combined with data from the literature to estimate age-specific incidence and mortality rates for cancer and the effectiveness of screening for and treatment of precancerous lesions. We assessed the direct medical, time, and program-related costs of strategies that differed according to screening test, targeted age and frequency, and number of clinic visits required. Single-visit strategies involved the assumption that screening and treatment could be provided in the same day. Outcomes included the lifetime risk of cancer, years of life saved, lifetime costs, and cost-effectiveness ratios (cost per year of life saved). RESULTS: The most cost-effective strategies were those that required the fewest visits, resulting in improved follow-up testing and treatment. Screening women once in their lifetime, at the age of 35 years, with a one-visit or two-visit screening strategy involving visual inspection of the cervix with acetic acid or DNA testing for human papillomavirus (HPV) in cervical cell samples, reduced the lifetime risk of cancer by approximately 25 to 36 percent, and cost less than 500 dollars per year of life saved. Relative cancer risk declined by an additional 40 percent with two screenings (at 35 and 40 years of age), resulting in a cost per year of life saved that was less than each country's per capita gross domestic product--a very cost-effective result, according to the Commission on Macroeconomics and Health. CONCLUSIONS: Cervical-cancer screening strategies incorporating visual inspection of the cervix with acetic acid or DNA testing for HPV in one or two clinical visits are cost-effective alternatives to conventional three-visit cytology-based screening programs in resource-poor settings.

Platelet transfusion containing ABO-incompatible plasma and hepatic veno-occlusive disease after hematopoietic transplantation in young children.

BACKGROUND: Hepatic veno-occlusive disease is a major limiting factor of high-dose chemotherapy in children. The cells lining the hepatic vascular endothelium express blood group A and/or B antigens according to the patient's blood group. We designed a study evaluating the impact of platelet concentrates containing ABO-incompatible plasma transfused to young children with a high risk of hepatic veno-occlusive disease. METHODS: In all, 186 consecutive children (median age: 4 years, range: 0.75-17 years), treated with high-dose chemotherapy containing busulfan followed by hematopoietic stem cell transplantation for neuroblastoma (n=112) or brain tumor (n=74) between 1988 and 1998, were investigated. The main endpoint was the occurrence of hepatic veno-occlusive disease. Multivariate analysis was performed using a Cox's regression model with transfusion of platelet concentrates containing ABO-incompatible plasma as a time-dependent covariate. RESULTS: We found that 73 out of 186 (39%) children developed hepatic veno-occlusive disease after transplantation. Multivariate analysis demonstrated that two factors significantly increased the risk of hepatic veno-occlusive disease occurrence: transfusion of platelet concentrates containing ABO-incompatible plasma (P=0.003) and use of melphalan in the conditioning regimen (P=0.006). Conversely, the number of platelet concentrates transfusions per week, child's age, weight, sex, and use of cyclophosphamide in the conditioning regimen had no effect. CONCLUSIONS: Transfusion of platelet concentrates containing ABO-incompatible plasma increases the risk of hepatic veno-occlusive disease in young children treated with a busulfan-containing regimen. Binding of A and/or B antigens expressed on the surface of hepatic endothelial cells may promote this complication. Transfusion of platelet concentrates containing ABO-incompatible plasma should be avoided in these children.

Screening test accuracy studies: how valid are our conclusions? Application to visual inspection methods for cervical screening.

While the basic concepts associated with screening are simple, studying the value of new tests requires a very strict methodology. This paper summarizes lessons learned regarding appropriate methodologies to assess the value of new screening approaches using visual inspection with acetic acid (VIA), a screening test for cervical pre-cancerous lesions, as an example. In addition to being convenient to, safe for and acceptable by target community members, a screening test should be reliable and have good test characteristics (i.e. be able to discriminate well between early disease and non disease). Test reliability assesses the degree to which repeated measurements of the test yields the same result. To ensure reproducibility of study findings, test reliability should be assessed before any evaluation of test accuracy. The accuracy of a test (specificity and sensitivity) is measured using cross-sectional studies with adequate sample size. Several basic features are necessary to ensure internal validity for such studies: (a) final disease status data should be obtained for all subjects, (b) all tests results must be determined independently of previous results, (c) the reference standard used to determine the disease status should be accurate, (d) the full "spectrum" of the disease should be included in the study. The study results should also have external validity to be applicable to other populations to which the test will be applied. All these consideration are exemplified by 17 very heterogeneous studies published to date assessing VIA test accuracy. The assessment of a new screening test is the first step in researching a new cancer prevention strategy. For this reason, this step should be carefully addressed through rigorous studies.