Influenza-associated Mortality Research Articles

Post-discharge mortality among patients hospitalised with severe acute respiratory infection, Bangladesh, 2012–2019: a prospective observational study

Enhancing outcomes post-hospitalisation requires an understanding of predictive factors for adverse events. This study aimed to estimate post-discharge mortality rates among patients with severe acute respiratory infection (SARI) in Bangladesh, identify associated factors, and document reported causes of death. From January 2012 to December 2019, we conducted follow-up calls to patients or their families 30 days after discharge to assess the status of patients with SARI. Proportions of deaths within 30 days of discharge were estimated, and a comparative analysis of demographics, clinical characteristics, and influenza illness between decedents and survivors was performed using multivariable Cox regression models. Among 23,360 patients with SARI (median age: 20 years, IQR: 1.5-48, 65% male), 351 (1.5%) died during hospitalisation. Of 23,009 patients alive at discharge, 20,044 (87%) were followed, with 633 (3.2%) deaths within 30days of discharge. In children (<18 years), difficulty breathing (adjusted hazard ratio [aHR] 1.8; 95% CI 1.1-3.0), longer hospital stay (aHR 1.1; 95% CI 1.1-1.1), and heart diseases (aHR 8.5; 95% CI 3.2-23.1) were associated with higher post-discharge death risk. Among adults (≥18 years), difficulty breathing (aHR 2.3; 95% CI 1.7-3.0), chronic obstructive pulmonary disease (aHR 1.7; 95% CI 1.4-2.2), and intensive care unit admission (aHR 5.2; 95% CI 1.9-14.0) were linked to elevated post-discharge death risk. Influenza virus was detected in 13% (46/351) of in-hospital SARI deaths and 10% (65/633) of post-discharge SARI deaths. Nearly one in twenty patients with SARI died during hospitalisation or within 1 month of discharge, with two-thirds of deaths occurring post-discharge. Seasonal influenza vaccination is recommended to mitigate influenza-associated mortality. To enhance post-discharge outcomes, hospitals should consider developing safe-discharge algorithms, reinforcing post-discharge care plans, and establishing outpatient monitoring for recently discharged patients. Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA [U01GH002259].

Characterizing deaths among adult patients with severe acute respiratory infection: during the pre- and COVID-19 pandemic periods in Bangladesh, 2018–2022

BackgroundSevere acute respiratory infection (SARI) is a leading cause of mortality globally, peaking during the COVID-19 pandemic. We analyzed SARI-associated deaths during the pre-and-pandemic periods in Bangladesh to identify the contributing factors.MethodsWe analyzed data from hospital-based influenza surveillance at nine tertiary-level hospitals in Bangladesh. We considered March 2018–February 2020 as the pre-pandemic period and March 2020–February 2022 as the pandemic period and included adult (≥ 18 years) participants in our study. Surveillance physicians identified WHO-SARI case definition meeting inpatients and collected demographics, clinical characteristics, and outcomes at hospital discharge and 30 days post-discharge. We performed rRT-PCR for influenza and SARS-CoV-2 viruses on collected nasopharyngeal and oropharyngeal swabs. We used multivariable Cox's regression models to calculate the hazard ratio (HR) for factors associated with SARI deaths in these adult patients.ResultsWe enrolled 4392 SARI patients during the pre-pandemic and 3824 SARI patients during the pandemic period. Case fatality ratio was higher during the pandemic: 13.62% (521) [in-hospital: 6.45% (247); post-discharge: 7.17% (274)] compared to pre-pandemic, 6.01% (264) [in-hospital: 2.01% (89), post-discharge: 4% (175)] (p < 0.001). Pre-pandemic, influenza was detected in 14% (37/264) of SARI deaths. Influenza was detected during the pandemic in 2.3% (12/521), SARS-CoV-2 in 41.8% (218/521), and both viruses in only one SARI death. History of smoking and the presence of 1 or more co-morbid conditions independently attributed to SARI deaths in adults in the pre-pandemic period. SARI deaths in such patients were also associated with respiratory difficulties on admission in both pre-pandemic (aHR 2.36; 95% CI:1.65–3.36) and pandemic period (aHR 2.30; 95% CI: 1.57–3.35) after accounting for age, sex, smoking status, presence of 1 or more co-morbid conditions, and detection of influenza and SARS-CoV-2 viruses.ConclusionsDuring the pandemic, SARI mortality increased; influenza-associated mortality declined, and SARS-CoV-2 caused over a third of SARI deaths. Post-discharge mortality was higher than in-hospital mortality during both periods. Limiting premature discharge and strengthening post-discharge monitoring and nursing services could reduce unexpected deaths. Formative research to better understand post-discharge mortality is essential to reduce SARI deaths.

From respiratory diseases to nervous system disorders: Unraveling the certified causes of influenza-associated deaths in Poland from 2000 to 2019.

This study aims to accurately estimate influenza-associated deaths in Poland and their certified cause of death, due to significant discrepancies between official numbers and expected impact. Excess influenza-associated mortality in Poland from 2000 to 2019 was calculated using Seasonal-Trend Decomposition Procedure based on LOESS (STL), which can detect non-linear trends and non-sinusoidal cycles. Excess mortality was then used as an explanatory variable in a model predicting monthly fluctuations of officially recorded causes of death from 2010 to 2019. A total of 142,000 conservative estimates of influenza-associated deaths were identified, representing 1.86% of overall mortality. Only 0.61% of influenza-associated deaths were officially recorded as influenza. Nearly half of certified influenza deaths were attributed to the seasonal baseline mortality, potentially doubling estimated impact based solely on influenza peaks. Influenza-associated deaths were frequently recorded as respiratory diseases (24.36%), with majority attributed to underlying conditions such as cardiovascular diseases (45.31%), cancer (9.06%), or diabetes (2.66%). Influenza-associated deaths were more commonly certified as nervous system diseases (1.84%) or mental disorders (1.04%), rather than influenza itself. There was a noticeable impact of influenza on secondary infections, such as meningococcal and gastrointestinal infections. These findings highlight the importance of improved estimation for informing public health policy decisions.

Cost-effectiveness of seasonal influenza vaccination of children in China: a modeling analysis

BackgroundChina has a high burden of influenza-associated illness among children. We aimed to evaluate the cost-effectiveness of introducing government-funded influenza vaccination to children in China (fully-funded policy) compared with the status quo (self-paid policy).MethodsA decision tree model was developed to calculate the economic and health outcomes, from a societal perspective, using national- and provincial-level data. The incremental cost-effectiveness ratio (ICER) [incremental costs per quality-adjusted life year (QALY) gained] was used to compare the fully-funded policy with the self-paid policy under the willingness-to-pay threshold equivalent to national and provincial GDP per capita. Sensitivity analyses were performed and various scenarios were explored based on real-world conditions, including incorporating indirect effect into the analysis.ResultsCompared to the self-paid policy, implementation of a fully-funded policy could prevent 1,444,768 [95% uncertainty range (UR): 1,203,446–1,719,761] symptomatic cases, 92,110 (95% UR: 66,953–122,226) influenza-related hospitalizations, and 6494 (95% UR: 4590–8962) influenza-related death per season. The fully-funded policy was cost-effective nationally (7964 USD per QALY gained) and provincially for 13 of 31 provincial-level administrative divisions (PLADs). The probability of a funded vaccination policy being cost-effective was 56.5% nationally, and the probability in 9 of 31 PLADs was above 75%. The result was most sensitive to the symptomatic influenza rate among children under 5 years [ICER ranging from − 25,612 (cost-saving) to 14,532 USD per QALY gained]. The ICER of the fully-funded policy was substantially lower (becoming cost-saving) if the indirect effects of vaccination were considered.ConclusionsIntroducing a government-funded influenza policy for children is cost-effective in China nationally and in many PLADs. PLADs with high symptomatic influenza rate and influenza-associated mortality would benefit the most from a government-funded influenza vaccination program.

The use of trifluoromethyl tubercidin as a novel treatment of influenza in an overwhelmed health care setting: a correspondence

The use of trifluoromethyl tubercidin as a novel treatment of influenza in an overwhelmed health care setting: a correspondence

Influenza-associated hospitalisation and mortality rates among global Indigenous populations; a systematic review and meta-analysis.

More than 50 million influenza infections and over 100,000 deaths from influenza occur annually. While Indigenous populations experience an inequitable influenza burden, the magnitude of this inequity has not previously been estimated on a global scale. This study compared rates of influenza-associated hospitalisation and mortality between Indigenous and non-Indigenous populations globally. A systematic review and meta-analysis was conducted including literature published prior to 13 July 2021. Eligible articles either reported a rate ratio (RR) comparing laboratory-confirmed influenza-associated hospitalisation and/or mortality between an Indigenous population and a corresponding benchmark population, or reported sufficient information for this to be calculated using publicly available data. Findings were reported by country/region and pooled by country and period (pandemic/seasonal) when multiple studies were available using a random-effects model. The I2 statistic assessed variability between studies. Thirty-six studies (moderate/high quality) were included; all from high or high-middle income countries. The pooled influenza-associated hospitalisation RR (HRR) for indigenous compared to benchmark populations was 5·7 (95% CI: 2·7-12·0) for Canada, 5·2 (2.9-9.3) for New Zealand, and 5.2 (4.2-6.4) for Australia. Of the Australian studies, the pooled HRR for seasonal influenza was 3.1 (2·7-3·5) and for pandemic influenza was 6·2 (5·1-7·5). Heterogeneity was slightly higher among studies of pandemic influenza than seasonal influenza. The pooled mortality RR was 4.1 (3·0-5.7) in Australia and 3·3 (2.7-4.1) in the United States. Ethnic inequities in severe influenza persist and must be addressed by reducing disparities in the underlying determinants of health. Influenza surveillance systems worldwide should include Indigenous status to determine the extent of the disease burden among Indigenous populations. Ethnic inequities in pandemic influenza illustrate the need to prioritise Indigenous populations in pandemic response plans.

Excess hospitalizations and mortality associated with seasonal influenza in Spain, 2008–2018

BackgroundInfluenza may trigger complications, particularly in at-risk groups, potentially leading to hospitalization or death. However, due to lack of routine testing, influenza cases are infrequently coded with influenza-specific diagnosis. Statistical models using influenza activity as an explanatory variable can be used to estimate annual hospitalizations and deaths associated with influenza. Our study aimed to estimate the clinical and economic burden of severe influenza in Spain, considering such models.MethodsThe study comprised ten epidemic seasons (2008/2009–2017/2018) and used two approaches: (i) a direct method of estimating the seasonal influenza hospitalization, based on the number of National Health Service hospitalizations with influenza-specific International Classification of Diseases (ICD) codes (ICD-9: 487–488; ICD-10: J09-J11), as primary or secondary diagnosis; (ii) an indirect method of estimating excess hospitalizations and deaths using broader groups of ICD codes in time-series models, computed for six age groups and four groups of diagnoses: pneumonia or influenza (ICD-9: 480–488, 517.1; ICD-10: J09–J18), respiratory (ICD-9: 460–519; ICD-10: J00–J99), respiratory or cardiovascular (C&R, ICD-9: 390–459, 460–519; ICD-10: I00–I99, J00–J99), and all-cause. Means, excluding the H1N1pdm09 pandemic (2009/2010), are reported in this study.ResultsThe mean number of hospitalizations with a diagnosis of influenza per season was 13,063, corresponding to 28.1 cases per 100,000 people. The mean direct annual cost of these hospitalizations was €45.7 million, of which 65.7% was generated by patients with comorbidities. Mean annual influenza-associated C&R hospitalizations were estimated at 34,894 (min: 16,546; max: 52,861), corresponding to 75.0 cases per 100,000 (95% confidence interval [CI]: 63.3–86.3) for all ages and 335.3 (95% CI: 293.2–377.5) in patients aged ≥ 65 years. We estimate 3.8 influenza-associated excess C&R hospitalizations for each hospitalization coded with an influenza-specific diagnosis in patients aged ≥ 65 years. The mean direct annual cost of the estimated excess C&R hospitalizations was €142.9 million for all ages and €115.9 million for patients aged ≥ 65 years. Mean annual influenza-associated all-cause mortality per 100,000 people was estimated at 27.7 for all ages.ConclusionsResults suggest a relevant under-detected burden of influenza mostly in the elderly population, but not neglectable in younger people.

Antiviral Approaches against Influenza Virus.

Preventing and controlling influenza virus infection remains a global public health challenge, as it causes seasonal epidemics to unexpected pandemics. These infections are responsible for high morbidity, mortality, and substantial economic impact. Vaccines are the prophylaxis mainstay in the fight against influenza. However, vaccination fails to confer complete protection due to inadequate vaccination coverages, vaccine shortages, and mismatches with circulating strains. Antivirals represent an important prophylactic and therapeutic measure to reduce influenza-associated morbidity and mortality, particularly in high-risk populations. Here, we review current FDA-approved influenza antivirals with their mechanisms of action, and different viral- and host-directed influenza antiviral approaches, including immunomodulatory interventions in clinical development. Furthermore, we also illustrate the potential utility of machine learning in developing next-generation antivirals against influenza.

Influenza-Associated Excess Mortality by Age, Sex, and Subtype/Lineage: Population-Based Time-Series Study With a Distributed-Lag Nonlinear Model.

Accurate estimation of the influenza death burden is of great significance for influenza prevention and control. However, few studies have considered the short-term harvesting effects of influenza on mortality when estimating influenza-associated excess deaths by cause of death, age, sex, and subtype/lineage. This study aimed to estimate the cause-, age-, and sex-specific excess mortality associated with influenza and its subtypes and lineages in Guangzhou from 2015 to 2018. Distributed-lag nonlinear models were fitted to estimate the excess mortality related to influenza subtypes or lineages for different causes of death, age groups, and sex based on daily time-series data for mortality, influenza, and meteorological factors. A total of 199,777 death certificates were included in the study. The average annual influenza-associated excess mortality rate (EMR) was 25.06 (95% empirical CI [eCI] 19.85-30.16) per 100,000 persons; 7142 of 8791 (81.2%) deaths were due to respiratory or cardiovascular mortality (EMR 20.36, 95% eCI 16.75-23.74). Excess respiratory and cardiovascular deaths in people aged 60 to 79 years and those aged ≥80 years accounted for 32.9% (2346/7142) and 63.7% (4549/7142) of deaths, respectively. The male to female ratio (MFR) of excess death from respiratory diseases was 1.34 (95% CI 1.17-1.54), while the MFR for excess death from cardiovascular disease was 0.72 (95% CI 0.63-0.82). The average annual excess respiratory and cardiovascular mortality rates attributed to influenza A (H3N2), B/Yamagata, B/Victoria, and A (H1N1) were 8.47 (95% eCI 6.60-10.30), 5.81 (95% eCI 3.35-8.25), 3.68 (95% eCI 0.81-6.49), and 2.83 (95% eCI -1.26 to 6.71), respectively. Among these influenza subtypes/lineages, A (H3N2) had the highest excess respiratory and cardiovascular mortality rates for people aged 60 to 79 years (20.22, 95% eCI 14.56-25.63) and ≥80 years (180.15, 95% eCI 130.75-227.38), while younger people were more affected by A (H1N1), with an EMR of 1.29 (95% eCI 0.07-2.32). The mortality displacement of influenza A (H1N1), A (H3N2), and B/Yamagata was 2 to 5 days, but 5 to 13 days for B/Victoria. Influenza was associated with substantial mortality in Guangzhou, occurring predominantly in the elderly, even after considering mortality displacement. The mortality burden of influenza B, particularly B/Yamagata, cannot be ignored. Contrasting sex differences were found in influenza-associated excess mortality from respiratory diseases and from cardiovascular diseases; the underlying mechanisms need to be investigated in future studies. Our findings can help us better understand the magnitude and time-course of the effect of influenza on mortality and inform targeted interventions for mitigating the influenza mortality burden, such as immunizations with quadrivalent vaccines (especially for older people), behavioral campaigns, and treatment strategies.

Influenza vaccination in failing hearts

Estimates of influenza infection show that up to 1 billion people are affected each year, with up to 5 million of affected people having a severe course of illness.1 Influenza is persistently one of the largest challenges to global health, the economy, and society.1 Major cardiovascular events are an essential contributor to influenza-associated morbidity and mortality; influenza triggers cardiovascular events, and patients with a previous major cardiovascular event have a higher risk of both a major cardiovascular event recurrence and death than patients without a previous major cardiovascular event.

Development of a road map to scale up the uptake and utilization of influenza vaccine in 22 countries of Eastern Mediterranean Region

BackgroundThe aim of this project was to develop a road map to support countries in Eastern Mediterranean Region in developing and implementing evidence-based seasonal influenza vaccination policy, strengthen influenza vaccination delivery program and address vaccine misperceptions and hesitancy. MethodsThe road map was developed through consultative meetings with countries’ focal points, review of relevant literature and policy documents and analysis of WHO/UNICEF Joint Reporting Form on immunization ((JRF 2015–2020) data. Countries were categorised into three groups, based on the existence of influenza vaccination policy and national regulatory authority, availability of influenza vaccine in the country and number of influenza vaccine doses distributed/ 1000 population. The final road map was shared with representatives of all countries in Eastern Mediterranean Region and other stakeholders during a meeting in September 2021. ResultThe goal for next 5 years is to increase access to and use of utilization of seasonal influenza vaccine in Eastern Mediterranean Region to reduce influenza-associated morbidity and mortality among priority groups for vaccination. Countries in the Eastern Mediterranean Region are at different stages of implementation of the influenza vaccination program, so activities are planned under four strategic priority areas based on current situations in countries. The consultative body recommended that some countries should establish a new seasonal influenza vaccination programme and ensure the availability of vaccines, while other countries need to reduce vaccine hesitancy and enhance current seasonal influenza vaccination coverage, particularly in all high-risk groups. Countries are also encouraged to leverage COVID-19 adult vaccination programs to improve seasonal influenza vaccine uptake. ConclusionThis road map was developed through a consultative process to scale up the uptake and utilization of influenza vaccine in all countries of Eastern Mediterranean Region. The road map proposes activities that should be adopted in the local context to develop/ update national policies and programs.

Age-dependent and sex-dependent differences in mortality from influenza-associated cardiovascular diseases among older adults in Shanghai, China: a population-based study

ObjectivesInfluenza epidemics lead to substantial morbidity and mortality among older adults. This study aimed to analyse and assess the age-specific and sex-specific differences in mortality rates for cardiovascular disease (CVD)...

Development of a pentavalent broadly protective nucleoside-modified mRNA vaccine against influenza B viruses

Messenger RNA (mRNA) vaccines represent a new, effective vaccine platform with high capacity for rapid development. Generation of a universal influenza virus vaccine with the potential to elicit long-lasting, broadly cross-reactive immune responses is a necessity for reducing influenza-associated morbidity and mortality. Here we focus on the development of a universal influenza B virus vaccine based on the lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) platform. We evaluate vaccine candidates based on different target antigens that afford protection against challenge with ancestral and recent influenza B viruses from both antigenic lineages. A pentavalent vaccine combining all tested antigens protects mice from morbidity at a very low dose of 50 ng per antigen after a single vaccination. These findings support the further advancement of nucleoside-modified mRNA-LNPs expressing multiple conserved antigens as universal influenza virus vaccine candidates.

Promotion of influenza vaccination in hospital workers

IntroductionVaccination is the most effective form of prevention against influenza. Influenza vaccination aims to reduce influenza-associated mortality and morbidity and the impact of the disease on the community. Therefore, it should be aimed primarily at protecting people who have a higher risk of complications in the event of suffering from the flu and those who can transmit the disease to others who have a high risk of complications. In this last group are health personnel where vaccination results are very low.The objective of this work is to describe the impact of the vaccination incentive programs in workers, which were carried out during the period 2015–2019 at the Hospital Clínico Universitario de Valladolid. MethodRetrospective descriptive observational study. The vaccination ratios among hospital workers and professionals during the 2015–2019 five-year period and the interventions that were implemented in the different annual vaccination campaigns throughout said period were analysed. ResultsWith the measures that are implemented in detail, it has gone from 681 vaccinated workers in 2015 to 1442 in 2019, which represents an increase in vaccination coverage of 27 percentage points. ConclusionThe implementation and monitoring of the measures developed in a hospital center during the influenza campaign leads to the improvement of the vaccination results obtained.

Assessing influenza vaccination coverage and predictors in persons living with HIV/AIDS in Louisiana, June 2002-June 2013.

SummaryBackgroundDespite the burden of disease and increased risk of influenza-associated morbidity and mortality among PLWHA, influenza vaccination has been understudied in this population.MethodsWe built an 11-year cohort of HIV-infected adults from medical records of PLWHA seeking care within the Louisiana State University medical system from June 2002-June 2013. Influenza vaccination uptake among PLWHA was calculated overall and for each medical facility for each influenza season. Linear regression was used to assess influenza vaccination uptake over time, both overall and by facility. Data were restricted to the final influenza season (2012-13) to assess predictors of PLWHA vaccination. Individuals were nested within medical facilities in order to assess the amount of variability in influenza vaccination rates across medical facilities.ResultsInfluenza vaccination uptake among PLWHA increased over the study period (p < 0.01). The overall proportion of PLWHA vaccinated during the 2012-13 influenza season was 33.7%. 37.9% of the variability in the model occurred at the facility-level.ConclusionsAlthough there was an increase in influenza vaccination within the PLWHA cohort over the course of the study, vaccination rates remained low overall. Special efforts must be made to increase vaccination uptake among PLWHA, with particular focus on those within the population who are likely to be at highest risk. The substantial variability at the facility-level indicates that there are unmeasured facility-level factors that contribute significantly to PLWHA vaccination.

A Review and Meta-Analysis of Influenza Interactome Studies.

Annually, the influenza virus causes 500,000 deaths worldwide. Influenza-associated mortality and morbidity is especially high among the elderly, children, and patients with chronic diseases. While there are antivirals available against influenza, such as neuraminidase inhibitors and adamantanes, there is growing resistance against these drugs. Thus, there is a need for novel antivirals for resistant influenza strains. Host-directed therapies are a potential strategy for influenza as host processes are conserved and are less prone mutations as compared to virus-directed therapies. A literature search was performed for papers that performed viral–host interaction screens and the Reactome pathway database was used for the bioinformatics analysis. A total of 15 studies were curated and 1717 common interactors were uncovered among all these studies. KEGG analysis, Enrichr analysis, STRING interaction analysis was performed on these interactors. Therefore, we have identified novel host pathways that can be targeted for host-directed therapy against influenza in our review.

Fomento de la vacunación antigripal en los trabajadores de un hospital

IntroductionVaccination is the most effective form of prevention against influenza. Influenza vaccination aims to reduce influenza-associated mortality and morbidity and the impact of the disease on the community. Therefore, it should be aimed primarily at protecting people who have a higher risk of complications in the event of suffering from the flu and those who can transmit the disease to others who have a high risk of complications. In this last group are health personnel where vaccination results are very low.The objective of this work is to describe the impact of the vaccination incentive programs in workers, which were carried out during the period 2015-2019 at the Hospital Clínico Universitario de Valladolid. MethodRetrospective descriptive observational study. The vaccination ratios among hospital workers and professionals during the 2015-2019 five-year period and the interventions that were implemented in the different annual vaccination campaigns throughout said period were analyzed. ResultsWith the measures that are implemented in detail, it has gone from 681 vaccinated workers in 2015 to 1,442 in 2019, which represents an increase in vaccination coverage of 27 percentage points. ConclusionThe implementation and monitoring of the measures developed in a hospital center during the influenza campaign leads to the improvement of the vaccination results obtained.

All-cause versus cause-specific excess deaths for estimating influenza-associated mortality in Denmark, Spain, and the United States.

BackgroundSeasonal influenza‐associated excess mortality estimates can be timely and provide useful information on the severity of an epidemic. This methodology can be leveraged during an emergency response or pandemic.MethodFor Denmark, Spain, and the United States, we estimated age‐stratified excess mortality for (i) all‐cause, (ii) respiratory and circulatory, (iii) circulatory, (iv) respiratory, and (v) pneumonia, and influenza causes of death for the 2015/2016 and 2016/2017 influenza seasons. We quantified differences between the countries and seasonal excess mortality estimates and the death categories. We used a time‐series linear regression model accounting for time and seasonal trends using mortality data from 2010 through 2017.ResultsThe respective periods of weekly excess mortality for all‐cause and cause‐specific deaths were similar in their chronological patterns. Seasonal all‐cause excess mortality rates for the 2015/2016 and 2016/2017 influenza seasons were 4.7 (3.3–6.1) and 14.3 (13.0–15.6) per 100,000 population, for the United States; 20.3 (15.8–25.0) and 24.0 (19.3–28.7) per 100,000 population for Denmark; and 22.9 (18.9–26.9) and 52.9 (49.1–56.8) per 100,000 population for Spain. Seasonal respiratory and circulatory excess mortality estimates were two to three times lower than the all‐cause estimates.DiscussionWe observed fewer influenza‐associated deaths when we examined cause‐specific death categories compared with all‐cause deaths and observed the same trends in peaks in deaths with all death causes. Because all‐cause deaths are more available, these models can be used to monitor virus activity in near real time. This approach may contribute to the development of timely mortality monitoring systems during public health emergencies.

Regional-based within-year seasonal variations in influenza-related health outcomes across mainland China: a systematic review and spatio-temporal analysis

BackgroundChina experiences large variations in influenza seasonal activity. We aim to update and improve the current understanding of regional-based within-year variations of influenza activity across mainland China to provide evidence for the planning and optimisation of healthcare strategies.MethodsWe conducted a systematic review and spatio-temporal meta-analysis to assess regional-based within-year variations of ILI outpatient consultation rates, influenza test positivity rates amongst both ILI outpatients and SARI inpatients, and influenza-associated excess mortality rates. We searched English and Chinese databases for articles reporting time-series data on the four influenza-related outcomes at the sub-national and sub-annual level. After synthesising the data, we reported on the mean monthly rate, epidemic onset, duration, peak and intensity.ResultsWe included 247 (7.7%) eligible studies in the analysis. We found within-year influenza patterns to vary across mainland China in relation to latitude and geographic location. High-latitude provinces were characterised by having short and intense annual winter epidemics, whilst most mid-latitude and low-latitude provinces experience semi-annual epidemics or year-round activity. Subtype activity varied across the country, with A/H1N1pdm09 and influenza B occurring predominantly in the winter, whereas A/H3N2 activity exhibited a latitudinal divide with high-latitude regions experiencing a winter peak, whilst mid and low-latitude regions experienced a summer epidemic. Epidemic onsets and peaks also varied, occurring first in the north and later in the southeast. We found positive associations between all influenza health outcomes. In addition, seasonal patterns at the prefecture and county-level broadly resembled their wider province.ConclusionsThis is the first systematic review to simultaneously examine the seasonal variation of multiple influenza-related health outcomes at multiple spatial scales across mainland China. The seasonality information provided here has important implications for the planning and optimisation of immunisation programmes and healthcare provision, supporting the need for regional-based approaches to address variations in local epidemiology.

Estimates of mortality associated with seasonal influenza for the European Union from the GLaMOR project

BackgroundThe European Centres for Disease Prevention and Control (ECDC) estimates that seasonal influenzacauses 4–50 million symptomatic infections in the EU/EEA each year and 15,000–70,000 European citizens die of causes associated with influenza. We used modelling methods to estimate influenza-associated mortality for the European Union by age group and country. MethodsWe compiled influenza-associated respiratory mortality estimates for 31 countries around the world (11 countries in the EU) during 2002–2011 (excluding the 2009 pandemic). From these we extrapolated the influenza mortality burden for all 193 countries of the world, including the 28 countries of the EU, using a multiple imputation approach. To study the effect of vaccination programs, we obtained data from the EU-funded VENICE project regarding the percentage of persons over 65 who were vaccinated in each country; the data ranged from 2% to 82% between the 21 countries which provided estimates for the 2006/07 reference season. ResultsWe estimated that an average of 27,600 (range 16,200-39,000) respiratory deaths were associated with seasonal influenza in the 28 EU countries per winter; 88% were among people 65 years and older, and the rates of mortality in this age group were roughly 35 times higher compared with those < 65 years. Estimates varied considerably across the EU; for example, rates in the elderly ranged from 21.6 (12.5–35.1) per 100,000 in Portugal to 36.5 (16.4–62.5) in Luxembourg, a difference of nearly 70%. We were unable to find a negative correlation between vaccination coverage rates and influenza-associated mortality estimates in the elderly. ConclusionOur EU estimate of influenza-associated respiratory mortality is broadly consistent with the ECDC estimate. More research is needed to explain the observed variation in mortality across the EU, and on possible bias that could explain the unexpected lack of mortality benefits associated with European elderly influenza vaccination programs.