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Abstract

Background: Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000-500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999-2015. Methods: We estimated country-specific influenza-associated respiratory excess mortality rates (EMR) for 33 countries using time series log-linear regression models with vital death records and influenza surveillance data. To extrapolate estimates to countries without data, we divided countries into three analytic divisions for three age groups (<65 years, 65-74 years, and ≥75 years) using WHO Global Health Estimate (GHE) respiratory infection mortality rates. We calculated mortality rate ratios (MRR) to account for differences in risk of influenza death across countries by comparing GHE respiratory infection mortality rates from countries without EMR estimates with those with estimates. To calculate death estimates for individual countries within each age-specific analytic division, we multiplied randomly selected mean annual EMRs by the country's MRR and population. Global 95% credible interval (CrI) estimates were obtained from the posterior distribution of the sum of country-specific estimates to represent the range of possible influenza-associated deaths in a season or year. We calculated influenza-associated deaths for children younger than 5 years for 92 countries with high rates of mortality due to respiratory infection using the same methods. Findings: EMR-contributing countries represented 57% of the global population. The estimated mean annual influenza-associated respiratory EMR ranged from 0·1 to 6·4 per 100 000 individuals for people younger than 65 years, 2·9 to 44·0 per 100 000 individuals for people aged between 65 and 74 years, and 17·9 to 223·5 per 100 000 for people older than 75 years. We estimated that 291 243-645 832 seasonal influenza-associated respiratory deaths (4·0-8·8 per 100 000 individuals) occur annually. The highest mortality rates were estimated in sub-Saharan Africa (2·8-16·5 per 100 000 individuals), southeast Asia (3·5-9·2 per 100 000 individuals), and among people aged 75 years or older (51·3-99·4 per 100 000 individuals). For 92 countries, we estimated that among children younger than 5 years, 9243-105 690 influenza-associated respiratory deaths occur annually. Interpretation: These global influenza-associated respiratory mortality estimates are higher than previously reported, suggesting that previous estimates might have underestimated disease burden. The contribution of non-respiratory causes of death to global influenza-associated mortality should be investigated. Funding: None.

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... Over 8 million US children aged 5-11 (27%) have already received the vaccine. In Israel the vaccination campaign began on 23rd November 2021 [2]; to date (28th February) around 25% of children aged [5][6][7][8][9][10][11] have received at least one dose of the vaccine [3,11]. ...
... Child mortality from COVID in different countries has ranged from 0.8 per million in the Netherlands to 5 per million in the USA (compared to 1000-3000 per million in adults). This is comparable in children to seasonal flu risk [8,9]. ...
... In the 5-11 age group 460 children were hospitalized, of which 72 for severe disease (estimated risk 1 in 3,000), of which 3 died. In the USA over 5000 cases (45% in children aged [5][6][7][8][9][10][11] and 48 deaths resulting from MIS-C and positive for COVID-19 were reported in children [2]. In Israel, 150 children were hospitalized with MIS-C [13]. ...
Article
Background Children under 12 are now the largest unvaccinated group. Following FDA approval, vaccination of 5-11 year olds is now being encouraged in some countries. We present data on child COVID-related morbidity in Israel and discuss the complexities surrounding vaccinating children aged 5-11. Methods Data were obtained from Israel’s open COVID database regarding new confirmed daily COVID-19 cases, severe hospitalized cases and deaths by age group in Israel from February 2020-November 2021, as well as vaccination rate and adverse events following vaccination. Results In 5-11 year olds, there were 460 hospitalizations, including 72 moderate to critical (0.007% population rate), with 3 deaths (0.0003% population rate). Children (0-19) made up the largest proportion (41%) of cases, but comprised just <0.1% of deaths, and <1% of severe cases. Post-vaccine myocarditis was much lower than severe COVID risk except in boys aged 12-19 where it was equivalent to the risk of mechanical ventilation due to COVID in boys aged 10-19 (12 per 100,000). High numbers of children were quarantined. Conclusions COVID risk is minimal for most children though rare complications do occur. Israeli and US pediatric associations have recommended vaccinating children, particularly in high-incidence scenarios where risk-benefit balance is more clear-cut. However only a quarter of eligible parents have vaccinated their children. Parents may consider health grounds but also restrictions on children, population vaccination levels, waning immunity and new variants, and should be provided with clear information to help them make an informed decision. Policymakers should reevaluate the need for isolations, testing and mask-wearing in school age children, which are detrimental to their wellbeing.
... Influenza virus is a significant cause of morbidity and mortality in all age groups, with millions of illnesses, hundreds of thousands of hospitalizations, and tens of thousands of deaths annually in the United States [1,2]. It is also a global health issue, especially during pandemics, with hundreds of thousands of deaths attributable to influenza annually [3,4]. The burden of influenza in the Unites States during the 2017-2018 season included 959,000 hospitalizations and nearly 80,000 deaths (CDC, https:// www. ...
... Elderly individuals bear a disproportionate burden of illness, hospitalizations, and death due to influenza [2][3][4]. For example, mortality rates can be 10-20 times greater in individuals more than 75 years old compared to those less than 65 years old [3]. ...
... Elderly individuals bear a disproportionate burden of illness, hospitalizations, and death due to influenza [2][3][4]. For example, mortality rates can be 10-20 times greater in individuals more than 75 years old compared to those less than 65 years old [3]. In 2017-2018, individuals 65 years old and older accounted for 90% of all influenza related deaths with a mortality rate 60-100 times higher than those less than 50 years old. ...
Article
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Background Influenza causes a serious infection in older individuals who are at the highest risk for mortality from this virus. Changes in the immune system with age are well known. This study used transcriptomic analysis to evaluate how aging specifically affects the functional host response to influenza in the lung. Adult (12–16 weeks) and aged (72–76 weeks) mice were infected with influenza and lungs were processed for RNA analysis. Results Older mice demonstrated a delayed anti-viral response on the level of transcription compared to adults, similar to the immunologic responses measured in prior work. The transcriptional differences, however, were evident days before observable differences in the protein responses described previously. The transcriptome response to influenza in aged mice was dominated by immunoglobulin genes and B cell markers compared to adult animals, suggesting immune dysregulation. Despite these differences, both groups of mice had highly similar transcriptional responses involving non-immune genes one day after inoculation and T cell genes during resolution. Conclusions These results define a delayed and dysregulated immune response in the lungs of aged mice infected with influenza. The findings implicate B cells and immunoglobulins as markers or mechanisms of immune aging. In addition to discovering new therapeutic targets, the findings underscore the value of transcription studies and network analysis to characterize complex biological processes, and serve as a model to analyze the susceptibility of the elderly to infectious agents.
... Influenza is an acute respiratory infection caused by influenza A, B, and C viruses, which occurs in local outbreaks or seasonal epidemics [1]. The global annual number of influenza-associated respiratory deaths was estimated to be 290,000-650,000 [2]. The estimate does not take into account deaths from other diseases, e.g., cardiovascular diseases, which can be influenza-related [2]. ...
... The global annual number of influenza-associated respiratory deaths was estimated to be 290,000-650,000 [2]. The estimate does not take into account deaths from other diseases, e.g., cardiovascular diseases, which can be influenza-related [2]. In Europe, seasonal influenza causes 4-50 million symptomatic cases and 15,000-70,000 annual deaths [3]. ...
Article
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Background: Healthcare workers (HCWs) are a historical key target of influenza vaccination programs. For the 2021-2022 season, WHO considered the coadministration of a flu and a COVID-19 vaccine as acceptable and recommended it to allow for higher uptake of both vaccines. The aim of this study was to investigate demographic and occupational features of vaccinated HCWs, reasons behind flu vaccine acceptance and a possible effect of the coadministration of a COVID-19 vaccine, in order to potentially draw general conclusions on HCWs' attitude towards flu vaccination and inform further strategies for consistent improvement of vaccine acceptance. Methods: a promotional and educational campaign, a gaming strategy, and vaccination delivery through both a large central hub and on-site ambulatories, were the implemented strategies. In the central hub, the flu/COVID-19 vaccine coadministration was offered. Statistical descriptive analysis, multiple correspondence analysis (MCA) and logistic regression models were performed. Results: 2381 HCWs received the flu vaccine, prompting a vaccination coverage rate (VCR) of 52.0% versus 43.1% in the 2020-2021 campaign. Furthermore, 50.6% vaccinated HCWs belonged to the 18-39 years-old age group. The most expressed reasons for vaccine uptake were "Vaccination is the most effective strategy of prevention" (n = 1928, 81.0%), "As HCW it's my duty to get vaccinated to protect my patients" (n = 766, 32.2%), and the group of COVID-19-related reasons (n = 586, 24.6%). In addition, 23.3% HCWs received the flu vaccine in the current campaign but not in the previous one (newly vaccinated) and the flu/COVID-19 vaccine coadministration was more frequent in this group. A total of 51.0% HCWs were hesitant towards the coadministration, while residents and nurses showed the highest propensity to receive it. Conclusions: in the second year of the COVID-19 pandemic, the Fondazione's influenza VCR continued to increase, with the greatest participation among HCWs aged 18-39 years. A potential propelling role of the COVID-19 vaccine coadministration was highlighted.
... In policy scenarios 2-5, we set the vaccine coverage as 90% for everyone eligible for vaccination, which was assumed to be similar to vaccination against pandemic influenza [13] . We stratified the analysis for each scenario by setting various target age groups for vaccinations, where we assume there might be situations in which mass vaccination with or without age targeting may achieve desired health outcomes (defined as no higher than 100 infections or 10 deaths per 100,000 population on an annual basis, which is the consensus of clinical experts for seasonal influenza [25][26][27] ). ...
... Due to the stochastic nature of the Covasim model, each policy was simulated under 100 different random number seeds, and the results were represented with the median estimates along with ranges corresponding to the upper (97.5%) and lower (2.5%) bounds produced by these seeds [12] . We set the acceptable impact of cumulative numbers of infections and deaths no higher than 100 and 10 per 100,000 persons, respectively, on an annual basis, under which the disease burden was comparable with seasonal influenza in China [25][26][27] . To this end, we sought minimal age groups for vaccination for each policy scenario. ...
Article
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With the expansion of vaccination programs, the policy of terminating nonpharmaceutical interventions for preventing the SARS-CoV-2 pandemic should become more flexible. The current study investigated the clinical and economic outcomes of intervention policies combining nonpharmaceutical interventions and vaccination programs for dealing with the SARS-CoV-2 pandemic. An agent-based transmission model was adopted that describes how a SARS-CoV-2 virus spreads in the populations of China. The model inputs were derived from the literature and expert opinion. The following intervention policies were simulated: no intervention, strict nonpharmaceutical interventions, and nonpharmaceutical interventions for workplace, community, school and home gradually terminated by combining vaccination programs for specified age groups (vaccination age in years: 20–60, 20–70, 20–80, ≥20, ≥10 and whole population). Cumulative infections and deaths in one calendar year, costs and quality-adjusted life years (QALYs) were measured. When the vaccination program was taken up in at least the ≥20 years age group in all populations, nonpharmaceutical interventions for workplace and community settings could be gradually terminated because the cumulative number of infections was < 100 per 100,000 persons. Further ending nonpharmaceutical interventions in school and home settings could not meet the target even when the vaccination program had been taken up in all populations. When cumulative deaths were used as the endpoint, nonpharmaceutical interventions in workplace, community and school settings could be gradually terminated. Vaccine efficacy and coverage have substantial impacts. Terminating nonpharmaceutical interventions in workplace settings could produce the lowest cost when vaccination programs are taken up at least in the ≥10 years age group; this method dominates most intervention strategies due to its lower costs and higher QALYs. According to our findings, nonpharmaceutical interventions might be gradually terminated in Chinese settings.
... COVID-19 transmission and mortality are closely linked to local levels of air pollutants, according to early reports from countries and regions within a single country [8]. Delicate particulate matter with an aerodynamic diameter of less than 2.5m (PM2.5) or 10m (PM10), such as NO2, sulfur dioxide, ozone, and carbon monoxide, affect the airways via inhalation and exacerbate the severity of respiratory virus infections [9]. NO2 is generally produced through various anthropogenic, such as oxidation associated with traffic and industrial heaters. ...
Article
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The rapid spread of the Coronavirus has boosted researchers to find the reasons behind this spread. A relationship between nitrogen dioxide (NO2) concentration as an air pollutant and the number of infections and deaths of coronavirus, has been suggested. This paper mainly seeks to determine whether there is a relationship between exposure to NO2 contamination andexacerbations of infections and confirmed deaths of COVID-19 in different countries in Europe, Asia, and Africa. This paper compared NO2 emissions concentration before and after the governments' lockdown to battle the new pandemic by using The Copernicus Sentinel-5P satellite data. The time series of an average daily NO2 concentration and COVID-19 reported data for March-June 2020 in Italy, China, and Egypt were analyzed and modeled with Python. Pearson's correlation coefficient (PCC) has been applied to evaluate this relationship. The results showed a positive relation between NO2 and COVID-19 infections, as PCC values are 0.47, 0.48, and 0.78 for China, Italy, and Egypt. The PCC values of deaths have reached 0.29, 0.39, and 0.72 for China, Italy, and Egypt. The experimental results indicate that elevated levels of air pollution in Europe and Asia have a detrimental effect on COVID-19 fulminate and there is a positive correlation between NO2 and infections anddeaths of COVID-19. The lockdown activities have led to a significant decrease in NO2 emissions with additional benefits for the environment.
... Influenza is one of the important respiratory infections and is related to high morbidity and mortality in the community, which can cause about 290,000-650,000 deaths each year (Iuliano et al., 2018). Influenza vaccination and antiviral drugs are two important aspects for the prevention and treatment of influenza. ...
Article
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Background Oseltamivir resistance in influenza virus (IFV) has been of widespread concern. An increase in the frequency of viruses with reduced inhibition was observed. Whether oseltamivir is effective is uncertain. We conducted this study to understand the real-world situation in northern China and the clinical efficacy for patients with IFV infection after the use of oseltamivir. Methods The longitudinal study was performed on influenza-like illness (ILI) cases in a tertiary general hospital in Beijing, China during the flu season of 2018–2019. All ILI cases (≥18 years) were recruited into the study. We analyzed the effect of the oseltamivir therapy on the number of clinic visits, hospitalization frequency, and the duration of fever and cough. Results A total of 689 ILI patients were recruited in this study with 355 in the oseltamivir therapy group and 334 in the supportive therapy group. Among the ILI patients, 388 patients were detected for IFV infection (364 IFV-A and 24 IFV-B) and divided into two groups with or without the oseltamivir therapy (302 vs. 86). There were no significant differences in the basic characteristics between the oseltamivir and supportive therapy groups in the ILI patients or in the IFV positive patients (all p < 0.05). After adjusting for the potential confounders, oseltamivir therapy reduced the times of clinic visits in the ILI and IFV positive patients ( p = 0.043 and p = 0.011). No effectiveness with oseltamivir therapy was observed in the outcomes of hospitalization frequency, and the duration of fever and cough. Conclusion Oseltamivir use may reduce the times of clinic visits. However, we did not observe the differences in the duration of fever, cough, and the frequency of hospitalization between oseltamivir therapy and supportive therapy.
... Determination of global influenza burden remains challenging due to underreporting and lack of viral surveillance data worldwide. Before the COVID-19 pandemic, estimates indicate morbidity of about 50 million cases (68) and 650,000 deaths from influenza infections annually (69). Seasonal influenza outbreaks occur during FIGURE 2 | Life cycle, humoral immunity targets, and immune escape mechanisms of influenza viruses. ...
Article
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Flu, a viral infection caused by the influenza virus, is still a global public health concern with potential to cause seasonal epidemics and pandemics. Vaccination is considered the most effective protective strategy against the infection. However, given the high plasticity of the virus and the suboptimal immunogenicity of existing influenza vaccines, scientists are moving toward the development of universal vaccines. An important property of universal vaccines is their ability to induce heterosubtypic immunity, i.e., a wide immune response coverage toward different influenza subtypes. With the increasing number of studies and mounting evidence on the safety and efficacy of recombinant influenza vaccines (RIVs), they have been proposed as promising platforms for the development of universal vaccines. This review highlights the current progress and advances in the development of RIVs in the context of heterosubtypic immunity induction toward universal vaccine production. In particular, this review discussed existing knowledge on influenza and vaccine development, current hemagglutinin-based RIVs in the market and in the pipeline, other potential vaccine targets for RIVs (neuraminidase, matrix 1 and 2, nucleoprotein, polymerase acidic, and basic 1 and 2 antigens), and deantigenization process. This review also provided discussion points and future perspectives in looking at RIVs as potential universal vaccine candidates for influenza.
... Infectious diseases, mainly caused by viral pathogens, remain a primary global health issue that has already caused a high mortality rate [1]. Many of the most threatening or deadliest human infectious diseases are caused by viruses, such as human immunodeficiency viruses (HIVs) [2,3], influenza viruses [4,5], hepatitis viruses [3,6], and the recent emerging pandemic threat of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [7,8]. In spite of striking development in vaccines and small-molecule antiviral drugs, new emerging and re-emerging viral disease outbreaks and the progression of antiviral drug resistance and drug toxicity have forced scientists to perpetually probe novel antiviral agents. ...
Article
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The marine environment presents a favorable avenue for potential therapeutic agents as a reservoir of new bioactive natural products. Due to their numerous potential pharmacological effects, marine-derived natural products-particularly marine peptides-have gained considerable attention. These peptides have shown a broad spectrum of biological functions, such as antimicrobial, antiviral, cytotoxic, immunomodulatory, and analgesic effects. The emergence of new virus strains and viral resistance leads to continuing efforts to develop more effective antiviral drugs. Interestingly, antimicrobial peptides (AMPs) that possess antiviral properties and are alternatively regarded as antiviral peptides (AVPs) demonstrate vast potential as alternative peptide-based drug candidates available for viral infection treatments. Hence, AVPs obtained from various marine organisms have been evaluated. This brief review features recent updates of marine-derived AVPs from 2011 to 2021. Moreover, the biosynthesis of this class of compounds and their possible mechanisms of action are also discussed. Selected peptides from various marine organisms possessing antiviral activities against important human viruses-such as human immunodeficiency viruses, herpes simplex viruses, influenza viruses, hepatitis C virus, and coronaviruses-are highlighted herein.
... This was based on the survey results which stated that 90% of respondents stated that responsibility character education was needed and needed to be developed in schools. In line with Medison's (2018) statement citing survey results stating that America, which is known as a country that adheres to the ideology of freedom, also has a way of developing the character of responsibility through behavioral education programs and inculcating good moral values to students in schools (Luliano et al., 2018). Meanwhile, the development of the character of responsibility has also been carried out in the northern part of Indonesia by collaborating between teachers and counseling teachers using the Student Team Achievement Division method (Afnibar et al., 2020). ...
Article
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The purpose of this study was to analyze the character development of students through the use of the Puppet Sukuraga application. It can be seen that, during the Covid-19 pandemic, fulfilling the affective dimension tended to be ignored by teachers, who instead emphasized the cognitive dimension. In the affective dimension, Puppet Sukuraga is used as a character education tool in the form of applications that can develop students' character. This puppet can also be used on mobile phones by students who understand the Sukuraga wayang in depth. This study uses a mix-method conducted in one of the elementary schools in Indonesia that already uses the Puppet Sukuraga application. The number of participants in this study were two 10 teachers and 60 students in the second grade, so that overall, there were 60 participants. Data is provided in the form of a detailed description of the subject's activities from the subject's perspective through interviews and group discussion forums. Online survey for the descriptive statistical analysis was used and in-depth interviews were also used for teachers and students. It was conducted 45 min before and after learning in class. The results of the study show that the use of the Puppet Sukuraga application can develop students' character, particularly characteristics of tolerance and responsibility. Students' tolerance is more developed, and it can be seen from the attitude of respect for differences in religion, ethnicity, habits, and differences of opinions. The characteristic of responsibility is also more developed, such as being responsible for their duties in doing homework, being responsible for carrying out the teacher's orders, and being responsible for carrying out useful activities. This research has implications for elementary school teachers in Indonesia during the limited online and face-to-face learning period. It can be concluded that the cultural values on the Sukuraga Puppet Application can help teachers in schools teach students about character enhancement.
... To date, the 2019 SARS-CoV-2 virus has caused more than 470 million confirmed cases and more than 6.1 million deaths reported to WHO across the world (1). Likewise, influenza viruses are responsible for annual seasonal epidemics that cause 243,000-645,000 deaths (2) and sporadic pandemics, such as the 1918-1919 H1N1 pandemic, which lead to an estimated 50 million deaths worldwide (3,4). Outbreaks of the avian-derived H7N9 and H5N1 viruses have been associated with high rates of hospitalisation (both >99%) and death (39% H7N9 and 56% H5N1 case fatality ratio (CFR) (5)), highlighting the pandemic potential of these emerging novel influenza viruses. ...
Article
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CD8+ T cells are a pivotal part of the immune response to viruses, playing a key role in disease outcome and providing long-lasting immunity to conserved pathogen epitopes. Understanding CD8+ T cell immunity in humans is complex due to CD8+ T cell restriction by highly polymorphic Human Leukocyte Antigen (HLA) proteins, requiring T cell epitopes to be defined for different HLA allotypes across different ethnicities. Here we evaluate strategies that have been developed to facilitate epitope identification and study immunogenic T cell responses. We describe an immunopeptidomics approach to sequence HLA-bound peptides presented on virus-infected cells by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Using antigen presenting cell lines that stably express the HLA alleles characteristic of Indigenous Australians, this approach has been successfully used to comprehensively identify influenza-specific CD8+ T cell epitopes restricted by HLA allotypes predominant in Indigenous Australians, including HLA-A*24:02 and HLA-A*11:01. This is an essential step in ensuring high vaccine coverage and efficacy in Indigenous populations globally, known to be at high risk from influenza disease and other respiratory infections.
... Influenza is a highly contagious respiratory illness that results in as many as 650,000 respiratory deaths globally per year (Iuliano et al., 2018). Influenza spreads mainly through droplets, aerosols, or by direct contact (Lau et al., 2010), and up to 50% of infections are asymptomatic (Wilde et al., 1999). ...
Preprint
Influenza occurs every season and occasionally causes pandemics. Despite its low mortality rate, influenza is a major public health concern, as it can be complicated by severe diseases like pneumonia. A fast, accurate and low-cost method to predict the origin host and subtype of influenza viruses could help reduce virus transmission and benefit resource-poor areas. In this work, we propose multi-channel neural networks to predict antigenic types and hosts of influenza A viruses with hemagglutinin and neuraminidase protein sequences. An integrated data set containing complete protein sequences were used to produce a pre-trained model, and two other data sets were used for testing the model's performance. One test set contained complete protein sequences, and another test set contained incomplete protein sequences. The results suggest that multi-channel neural networks are applicable and promising for predicting influenza A virus hosts and antigenic subtypes with complete and partial protein sequences.
... The strategy of codon deoptimization that refers to viral genome misrepresented codons used for the development of LAVs has been adopted (3)(4)(5). Multiple synonymous mutations are incorporated in a single or many IAV genes to create attenuated viruses (127). ...
Article
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Introduction: : Influenza virus is a major cause of seasonal epidemics and intermittent pandemics. Despite the current molecular biology and vaccine development, influenza virus infection is a significant burden. Vaccines are considered an essential countermeasure for effective control and prevention of influenza virus infection. Even though current influenza virus vaccines provide efficient protection against seasonal influenza outbreaks, the efficacy of these vaccines is not suitable due to antigenic changes of the viruses. Areas covered: This review focuses on different live-attenuated platforms for influenza virus vaccine development and proposes essential considerations for a rational universal influenza virus vaccine design. Expert opinion: : Despite the recent efforts for universal influenza virus vaccines, there is a lack of broadly reactive antibodies induction that can confer broad and long-lasting protection. Various strategies using live-attenuated influenza virus vaccines (LAIVs) are investigated to induce broadly reactive, durable, and cross-protective immune responses. LAIVs based on NS segment truncation prevent influenza virus infection and have shown to be effective vaccine candidates among other vaccine platforms. Although many approaches have been used for LAIVs generation, there is still a need to focus on the LAIVs development platforms to generate a universal influenza virus vaccine candidate.
... Data source and design. A repeated annual cross-sectional study was performed by using data from the "Echantillon Généraliste des Bénéficiaires" (EGB), a representative sample of the French population, from January 1,2009 to December 31, 2018. The EGB database contains the healthcare data of about 660,000 people, representing 1/97th of the French population. ...
Article
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Abstract Pregnant women have a high risk of severe influenza, associated with obstetrical complications. The World Health Organization (WHO) has recommended influenza vaccination for all pregnant women since 2012. The vaccination coverage remains low worldwide, and in Europe, due to a lack of proposition from the health care providers, and a high refusal rate from the women. The primary aim of this study was to estimate the influenza vaccination coverage (IVC) in a population of pregnant women in France, and to analyse its evolution from 2009 to 2018. The secondary objective was to describe the vaccinated population and to find determinants associated with the vaccination. This retrospective cohort study is based on the EGB French health care database, a representative sample of the French population containing data from the health insurance system. All pregnant women who delivered medically or spontaneously over the 2009–2018 period were included. In the 2009–2018 period, only 1.2% pregnant women were vaccinated against influenza (n = 875/72,207; 95% CI 1.14–1.30). The IVC slightly increased after the 2012 WHO recommendation, from 0.33 to 1.79% (p
... The ease of transmissibility makes respiratory pathogens especially suited for epidemic spread (Kutter et al., 2018). Viral respiratory infections account for a large burden of annual morbidity and mortality worldwide (Iuliano et al., 2018) and are the cause of more than 400,000 hospitalizations in children less than 18 years old (Henrickson, 2004) in the United States every year, demonstrating the perpetual scale of the challenge. ...
Article
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The many respiratory viruses that cause influenza-like illness (ILI) are reported and tracked as one entity, defined by the CDC as a group of symptoms that include a fever of 100 degrees Fahrenheit, a cough, and/or a sore throat. In the United States alone, ILI impacts 9-49 million people every year. While tracking ILI assingle clinical syndrome is informative in many respects, the underlying viruses differ in parameters and outbreak properties. Most existing models treat either a single respiratory virus or ILI as a whole. However, there is a need for models capable of comparing several individual viruses that cause respiratory illness, including ILI. To address this need, here we present a flexible model and simulations of epidemics for influenza, RSV, rhinovirus, seasonal coronavirus, adenovirus, and SARS/MERS, parameterized by a systematic literature review and accompanied by a global sensitivity analysis. We find that for these biological causes of ILI, their parameter values, timing, prevalence, and proportional contributions differ substantially. These results demonstrate that distinguishing the viruses that cause ILI will be an important aspect of future work on diagnostics, mitigation, modeling, and preparation for future pandemics.
... In contrast to influenza C and D viruses, influenza A and B viruses pose a large burden on human health. It is estimated that they cause up to 1 billion infections annually, leading to 3-5 million cases of severe upper and lower respiratory tract infection and 290 000-650 000 deaths (Iuliano et al., 2018). Approximately 25% of these infections are due to viruses of the 2 influenza B virus (IBV) lineages, Victoria and Yamagata, which co-circulate in humans (Glezen, 2014). ...
Thesis
Influenza A viruses (IAVs) are a major cause of respiratory disease in swine as well as in humans. In swine, multiple distinct lineages of IAVs circulate, and currently available vaccines fail to protect against all variants. Therefore, more broadly protective influenza vaccines for swine are needed. Most IAVs of swine are derived from influenza viruses that circulated in humans in the past. Due to a separate IAV evolution in both species, contemporary human influenza viruses genetically and antigenically differ from those in swine. IAVs of birds and horses are also distinct from the current human influenza viruses. Because of these differences, immunity against human influenza viruses is unlikely to protect against infection with an animal influenza virus. IAVs sometimes cross the species barrier from animals to humans. Should an animal influenza virus adapt to efficient replication and transmission in the human population and population immunity is lacking, a pandemic is possible. In chapter 1, we give a general introduction to influenza virus classification, as well as a description of IAV structure, replication, and evolution. We also discuss implications of different aspects of the influenza A virus replication for their host range. Then, we summarize the epidemiology of IAVs in wild and domestic birds, horses, dogs, swine, and humans, with emphasis on swine and humans. We also describe cross-species transmissions and the pandemic potential of IAVs. Finally, we give an overview of the immune responses to influenza viruses in humans and swine. We describe innate and adaptive immune mechanisms upon influenza virus infection as well as current and alternative vaccination strategies. Chapter 2 outlines the aims of the thesis. The first aim was to investigate the safety and efficacy of a live attenuated swine influenza vaccine strain of the H3N2 subtype. The second aim was to assess the public health risk of different animal influenza viruses of subtypes H3 and H1. In chapter 3, we characterized a live attenuated influenza vaccine strain for swine, lvTX98. It belongs to the H3N2 subtype and was included in the first live attenuated swine influenza vaccine, which reached the US market in 2017. In chapter 3.1, we evaluated the level of attenuation of lvTX98 in pigs. We compared its excretion and pathogenesis with that of the wild type virus, from which the vaccine strain is derived by a deletion in the NS1 gene. Vaccine strain lvTX98 was partially attenuated in pigs. After intranasal inoculation, nasal shedding was lower than for the wild type virus but still substantial. After intratracheal inoculation, vaccine virus replication in the swine respiratory tract was reduced at early timepoints after infection, but lvTX98 could replicate to similar titers as the wild type virus by day 3. The vaccine strain caused significantly milder clinical signs as compared to the wild type virus. However, it caused comparable levels of macroscopic and microscopic lung lesions, neutrophil infiltration, and pro-inflammatory cytokine levels in the lungs. Based on findings in vitro, attenuation of lvTX98 was believed to result from the induction of elevated levels of type I interferon. These pro-inflammatory cytokines are important to induce an antiviral response in the host. However, we could not associate attenuation of the vaccine strain in pigs in vivo with higher type I interferon levels in the lungs as compared with the wild type virus. We conclude that influenza vaccine strain lvTX98 is not sufficiently attenuated to ensure its safety. We also conclude that its attenuation is due to the loss of viral NS1 functions other than interference with type I interferon-mediated antiviral host response. In chapter 3.2, we determined the efficacy of a single intranasal vaccination of pigs with lvTX98 against divergent swine influenza viruses of the H3 subtype. The vaccination offered complete protection against the homologous wild type virus and partial protection against divergent H3 viruses that represent major swine IAV lineages circulating in North America and Europe. These lineages included North American cluster IV, North American novel human-like, and European swine H3 influenza viruses. We could not detect virus neutralizing antibodies against the variable HA protein of these heterologous H3 swine viruses in serum of vaccinated pigs. Therefore, partial protection likely resulted from mucosal and cellular immune responses against conserved parts of the swine influenza virus proteins. We conclude that one vaccination with lvTX98 was not sufficient to provide the desired broad protection. However, this live attenuated influenza vaccine strain could be useful in combination with a second vaccine in a prime-boost regimen. Chapter 4 deals with the public health risk of different animal influenza A viruses of subtypes H3 and H1. Chapter 4.1 is about H3 influenza viruses of swine, birds, and horses. We selected viruses representative of the major contemporary H3 lineages in these species. We estimated human population immunity against these animal IAVs by testing serum of persons of different age groups for protective antibody levels. We also assessed the replication potential of these animal IAVs in human airway tissues. Population immunity was high for North American swine H3 IAVs: more than 50% of the test persons had protective antibody levels. We found intermediate population immunity against European swine H3 IAVs, with protective antibodies in 7%–37% of the persons. Less than 13% of the persons had protective serum antibody levels against H3 IAVs of birds and horses, suggesting that population immunity against these viruses is minimal. Antibody responses against H3 IAVs of swine, which are all derived from past human H3 IAVs, showed age-dependent trends that seemed to reflect exposure to related human influenza viruses. This indicates slow antigenic evolution of swine H3 influenza viruses and supports the role of swine as a reservoir for past human H3 influenza viruses. Antibody levels for avian and equine H3 IAVs were minimal in all age groups. Virus replication in human airway tissues was efficient for swine H3 IAVs and intermediate for a H3 IAV from horses and one from poultry. H3 IAVs from wild birds could not replicate in the human airway tissues. We conclude that among the H3 influenza viruses of different species, those of swine pose the highest threat to public health. In chapter 4.2, we used the same approach as in chapter 4.1 to estimate human population immunity against all major H1 influenza virus lineages of swine and their human ancestor IAVs. We found that at least 50% of the persons had protective serum antibody levels against viruses of 2 lineages called the European human-like and the classical swine H1 lineage. Population immunity was intermediate for viruses of 2 other lineages called the Asian avian-like and the North American human-like δ1a swine H1 lineage. At least 24% of the test persons had protective serum antibody levels against these IAVs. For viruses of the last 2 lineages designated the European avian-like and the North American human-like δ1b swine H1 lineage, antibody levels were minimal, with not more than 10% of the persons having protective antibody levels. As for swine H3 IAVs, human antibody responses against swine H1 IAVs showed age-dependent trends. Antibody levels against human-derived swine IAVs showed different extents of correlation with those against the presumed human ancestor IAV. Our results suggest that among the different H1 IAVs of swine, those belonging to the North American human-like δ1b and European avian-like swine H1 influenza virus lineages pose the highest public health risk. In chapter 5, we discuss the overall findings of all experimental studies performed during this doctoral research. Our pathobiology studies with live attenuated swine influenza vaccine strain lvTX98 suggest safety concerns. We discuss possible strategies to improve lvTX98 attenuation and safety. One vaccination with lvTX98 offered partial protection against a range of distinct swine H3 IAVs. We speculate about different applications of lvTX98 and similar live attenuated vaccine strains in heterologous prime-boost strategies that could provide broad protection against IAVs of one or multiple subtypes. We found that humans have varying levels of antibodies against animal H3 and H1 influenza viruses. We discuss the correlation between antibody levels against the animal IAVs and those against related human IAVs. Since animal IAVs might jump to humans, we compare the public health risk of different animal H3 and H1 influenza viruses based on serum antibody levels in humans and the replication potential of these animal viruses in human tissues. We also mention other attributes of influenza A viruses and humans that influence the public health risk of animal H3 and H1 influenza viruses.
... Influenza is an infectious disease caused by influenza viruses, killing 300,000 to 500,000 people worldwide every year [1,2]. The notorious "Spanish flu" of 1918, caused by the H1N1 virus, caused 50 million deaths worldwide [3], and the "swine flu", caused by the H1N1 virus in 2009, caused at least 16,000 deaths [4]. ...
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Influenza A is an acute respiratory infectious disease caused by the influenza A virus, which seriously threatens global human health and causes substantial economic losses every year. With the emergence of new viral strains, anti-influenza drugs remain the most effective treatment for influenza A. Research on traditional, innovative small-molecule drugs faces many challenges, while computer-aided drug design (CADD) offers opportunities for the rapid and effective development of innovative drugs. This literature review describes the general process of CADD, the viral proteins that play an essential role in the life cycle of the influenza A virus and can be used as therapeutic targets for anti-influenza drugs, and examples of drug screening of viral target proteins by applying the CADD approach. Finally, the main limitations of current CADD strategies in anti-influenza drug discovery and the field’s future directions are discussed.
... The influenza viruses cause annually about 3 to 5 million cases of severe illness, and about 290,000 to 650,000 influenza-related deaths [1]. Due to widespread complications and their severity, influenza poses a significant threat to public health. ...
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Humoral immunity to influenza neuraminidase (NA) was evaluated among different groups of people including patients with acute influenza infection and healthy people in different age groups using an enzyme linked lectin assay (ELLA). The amino acid composition of NA of seasonal influenza viruses A/Victoria/361/2011(H3N2) and A/Hong Kong/4801/2014(H3N2) differed by 2%, while cross-reacting neuraminidase-inhibiting (NI) antibodies to them in the same serum samples were detected in 10% of cases. Middle-aged patients born from 1977 to 2000 had a high level of hemagglutination-inhibiting (HI) antibodies to A/Hong Kong/4801/2014(H3N2), but almost no NI antibodies, which may indicate that in the case of a change in the hemagglutinin (HA) subtype, this age group will be susceptible to influenza A/H3N2 viruses. Therefore, it could mean there is a need for priority vaccination of this age group with a vaccine against the appropriate strain. It was shown that after intranasal administration of live influenza vaccine (LAIV) for the 2017–2018 season, serum antibody response was not lower compared to that during natural infection. In older people, antibodies to archival A/H2N2 viruses were detected more often than to modern A/H3N2. Since the conversion of antibodies to HA and NA often did not coincide, antibodies to NA can serve as an additional criterion for assessing the immunogenicity of influenza vaccines.
... Influenza tends to cause an epidemic among individuals globally, and the influenza pandemic was proposed as one of the ten threats to human health by the World Health Organization (WHO) [1]. Influenza leads to 290,000-640,000 deaths around the world annually, with 84%-95% of deaths occurring in old people [2][3][4]. With the rapidly aging population in China [5], influenza-related cases and complications could be a substantial disease burden for the old people. ...
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Background Influenza vaccination coverage rate among the elderly is low in China. We aimed to evaluate the impact of video-led educational intervention on influenza vaccine uptake among the Chinese elderly. Methods A randomized controlled trial was conducted in 8 communities of Xi’an, a representative city in western China. Elderly aged over 60 years were randomized to the control group and intervention group (12-minute video education on influenza and its vaccination). Participants’ knowledge, attitudes, and practices (KAP) of influenza was assessed by using a questionnaire survey before and after the intervention. The primary outcomes were participants’ willingness to get influenza vaccinated and their actual uptake rates in the 2020-21 flu season. Secondary outcomes were the variations of pre- and post-intervention KAP scores. Intention-to-treat analysis was performed to analyze the data, and sensitivity analyses were conducted to examine the robustness of the results. Results A total of 350 people were enrolled, with 175 individuals for each group. Participants in the intervention group were more willing to receive influenza vaccination than those in the control group (64.6% vs. 51.4%, p <0.05). The influenza vaccination uptake rate occurred in 10.3% of participants in the intervention group and 3.4% in the control group (odds ratio, 3.23; 95% CI 1.25-8.32, p< 0.001). The post-intervention KAP scores in the intervention group were significantly higher compared to those in the control group ( p< 0.001). Conclusion Video-led education was an effective and feasible approach to improve old people’s willingness and uptake of influenza vaccination in western China.
... Saharan Africa and southeast Asia [284,285]. The constant threat of newly emerging pandemic strains poses a huge threat to human health and societies. ...
... Seasonal influenza represents a significant clinical and economic burden globally, with an attack rate estimated of 5-10% in adults and 20-30% in children [1] and up to 650,000 deaths globally and 72,000 deaths in Europe resulting from influenza-associated complications in all ages each year [2]. Although surveillance systems that continuously monitor the virology and epidemiology of seasonal influenza are now in place in most countries [3,4], these are associated with varying degrees of success due to the unpredictable nature of influenza epidemics, the multiple data sources involved, and the varied degree of sophistication and funding in national surveillance systems [5]. ...
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Background Influenza surveillance systems vary widely between countries and there is no framework to evaluate national surveillance systems in terms of data generation and dissemination. This study aimed to develop and test a comparative framework for European influenza surveillance. Methods Surveillance systems were evaluated qualitatively in five European countries (France, Germany, Italy, Spain, and the United Kingdom) by a panel of influenza experts and researchers from each country. Seven surveillance sub-systems were defined: non-medically attended community surveillance, virological surveillance, community surveillance, outbreak surveillance, primary care surveillance, hospital surveillance, mortality surveillance). These covered a total of 19 comparable outcomes of increasing severity, ranging from non-medically attended cases to deaths, which were evaluated using 5 comparison criteria based on WHO guidance (granularity, timing, representativeness, sampling strategy, communication) to produce a framework to compare the five countries. Results France and the United Kingdom showed the widest range of surveillance sub-systems, particularly for hospital surveillance, followed by Germany, Spain, and Italy. In all countries, virological, primary care and hospital surveillance were well developed, but non-medically attended events, influenza cases in the community, outbreaks in closed settings and mortality estimates were not consistently reported or published. The framework also allowed the comparison of variations in data granularity, timing, representativeness, sampling strategy, and communication between countries. For data granularity, breakdown per risk condition were available in France and Spain, but not in the United Kingdom, Germany and Italy. For data communication, there were disparities in the timeliness and accessibility of surveillance data. Conclusions This new framework can be used to compare influenza surveillance systems qualitatively between countries to allow the identification of structural differences as well as to evaluate adherence to WHO guidance. The framework may be adapted for other infectious respiratory diseases.
... is a respiratory disease caused by infection with a segmented negative-sense RNA virus from one of the seven genera (all of which only contain one single species) in the family Orthomyxoviridae(1)(2)(3). In humans, influenza is caused by viruses from four genera known as influenza types A, B, C and D. It is not always possible to predict the severity outcome following infection, which presents a challenge for both disease prevention and treatment of infected patients. Influenza ('flu') symptoms range from the asymptomatic to fatal, and it has estimated between 300.000 and 650.000 deaths per annum in the world(109). The most severe forms of influenza are associated with pulmonary oedema as consequence of immunological cytokine storm, and the development of secondary bacterial infections (1,3).The use of anti-viral treatments for severe forms remains controversial (4).A recent meta-analysis indicated that non-steroidal anti-inflammatory drugs (NSAIDs) were effective in reducing mortality following influenza infection(5). ...
Thesis
Introduction. La grippe, responsable de pandémies mortelles, est aussi associée à une mortalité significative chaque hiver malgré un vaccin et des traitements antiviraux. L'inflammation peut être une cible thérapeutique nécessitant de bien en comprendre les mécanismes immuns. Les études évaluant la réaction immunitaire innée induite par Influenzavirus sont basées sur des méthodes quantitatives ou fonctionnelles. Les explorations anatomiques sont le plus souvent absentes ou n'intégrant qu'une vision globale sur coupes histologiques. La problématique de cette thèse a été d'étudier l'apport de la microscopie 2-photon (M2P) pour l'évaluation des conséquences pulmonaires après infection à Influenzavirus d'un modèle murin selon plusieurs modalités : sur poumon fixé, ex vivo et en comparant différentes souches virales. Méthodes. Pour l'analyse sur poumon fixé, nous avons infecté par A/Puerto Ricco/8/34 H1N1 (PR8) des souris C57BL6 transgéniques CD11C+YFP comparativement à des souris non infectées. Différentes analyses étaient effectuées : cytométrie en flux, dosages des cytokines, et observation en M2P après marquage par Ac anti F4/80 couplé au fluorochrome BV421. La méthode du « Live Lung Slice » a été modifiée sans agarose pour la microscopie intravitale ex vivo pour analyser sa faisabilité, la préservation de la viabilité cellulaire et l'évaluation de la mobilité cellulaire. Afin d'explorer plusieurs souches virales d'Influenzavirus, nous avons infecté le même modèle animal avec la souche A/WSN/1933 H1N1 (WSN) et appliqué les mêmes techniques. Pour comparer différents virus, nous avons exploré selon les mêmes modalités des poumons de hamsters infectés par SARS-Cov2. Les données ont été comparées à celles obtenues avec PR8. Résultats. Sur poumon fixé, M2P apporte des données complémentaires à la cytométrie en flux et au dosage des cytokines, par l'observation de lésions épithéliales bronchiques, de l'évolution de la localisation de l'infection. L'ajout du marquage F4/80 couplé au fluorochrome BV421 permet de visualiser le recrutement et la diffusion pulmonaire des macrophages. De plus, les interactions entre macrophages et cellules infectées sont observées par les reconstructions 3D permises par l'imagerie du poumon en profondeur. M2P intravitale ex vivo sans agarose démontre sa faisabilité et la préservation de la viabilité cellulaire mettant en évidence une mobilité accrue des macrophages significativement supérieures aux cellules dendritiques. L'infection par WSN induit les mêmes résultats que PR8. Par contre, après infection par SARS-Cov2, aucune lésion de l'épithélium bronchique n'est observée, le virus se localise exclusivement au niveau de l'épithélium alvéolaire et le recrutement macrophagique est localisé au site infecté alternant avec des zones de poumon sain, à la différence de la grippe durant laquelle on observe une homogénéité pulmonaire de l'infiltration macrophagique. Conclusion. M2P est bien supérieure à l'histologie conventionnelle et complémentaire aux explorations habituelles en apportant des données anatomiques lésionnelles, virologiques et recrutements cellulaires indispensables à la bonne compréhension des conséquences pulmonaires induites par Influenzavirus. La préservation de la viabilité cellulaire confirme la faisabilité de la méthode ex vivo de notre protocole de « Live Lung Slice » adapté. L'amplification de la mobilité des cellules dendritiques et des macrophages leur procure une disponibilité accrue pour optimiser leurs interactions avec les cellules infectées. M2P est également un excellent outil pour la comparaison des conséquences pulmonaires après infection par différentes souches virales. Au total, M2P semble indispensable par l'exploration anatomique des conséquences structurales et de la réaction immune innée après infection par Influenzavirus. Les perspectives de son application semblent immenses : études des co-infections, des surinfections, de l'impact de stratégie thérapeutique.
... In the United States, the Centers for Disease Control and Prevention (CDC) estimates ranged from 140,000 to 710,000 for flu-related hospitalizations and about 12,000 to 56,000 deaths since 2010 (56). A study estimating seasonal influenza-associated mortality suggested the highest mortality in sub-Saharan Africa was 2.8-16.5 deaths per 100,000 individuals and among older adults aged ≥75 years (57). Seasonal influenza also causes lower respiratory tract infections (LRTIs), which is the leading cause of infectious disease mortality. ...
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Vaccine preventable diseases (VPDs) are a prevailing concern among the adult population, despite availability of vaccines. Unlike pediatric vaccination programs, adult vaccination programs lack the required reach, initiative, and awareness. Clinical studies and real-world data have proven that vaccines effectively reduce the disease burden of VPDs and increase life expectancy. In Tunisia and Morocco, the national immunization program (NIP) focuses more on pediatric vaccination and have limited vaccination programs for adults. However, some vaccination campaigns targeting adults are organized. For example, influenza vaccination campaigns prioritizing at risk adults which includes healthcare professionals, elderly, and patients with comorbidities. Women of childbearing age who have never been vaccinated or whose information is uncertain are recommended to receive tetanus vaccination. Tunisia NIP recommends rubella vaccine mainly for women of childbearing age, while in Morocco, national vaccination campaigns were organized for girls and women (up to 24 years of age) to eliminate rubella. Further, travelers from both countries are recommended to follow all requirements and recommendations in the travel destination. The objective of this manuscript is to provide an overview of the global disease burden of common VPDs including (but not limited to) meningococcal diseases, pneumococcal diseases, hepatitis, and influenza. The review also provides an overview of clinical data and guidelines/recommendations on adult vaccination practices, with special focus on Tunisia and Morocco. Some European and North American countries have concrete recommendations and strategies for adult vaccination to keep the VPDs in check. In Morocco and Tunisia, although, there are sporadic adult vaccination initiatives, the efforts still need upscaling and endorsements to boost vaccination awareness and uptake. There is a need to strengthen strategies in both countries to understand the disease burden and spread awareness. Additional studies are needed to generate economic evidence to support cost-effectiveness of vaccines. Integration of private and public healthcare systems may further improve vaccination uptake in adults.
... Influenza epidemics have created a serious medical burden in many regions of the world and cause significant excess mortality rates in different ages [1]. Of the two influenza types, influenza A (H1N1 and H3N2) is associated with more severe symptoms and clinical outcomes than influenza B [2]. ...
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Two influenza A subtypes (H1N1 and H3N2) co-circulate and pose a serious disease burden globally. It is unclear about the extent of cross-protection between these two influenza A subtypes as well as the impact of cross-protection on influenza dynamics. Based on an evolution-driven mathematical transmission model, the interaction between H1N1 and H3N2 was explored based on monthly incidence data in the USA from the years 2012 to 2019. The results showed that significant cross-protection between H1N1 and H3N2 exists. Besides, the cross-protection for H1N1 from H3N2 is much stronger than the other way around. The results also show that cross-protection between H1N1 and H3N2 has substantial influence on the epidemics. The model was also validated in Germany, Austria and Norway. A forecasting framework was proposed based on the model with feasible accuracy for both retrospective and prospective forecasts of H1N1 and H3N2 in the USA. Our findings quantify and highlight the importance of cross-protection on the co-circulating of seasonal influenza A H1N1 and H3N2.
... Symptoms typically include fever, headache, myalgia, and respiratory distress and last between 5 and 15 days 3 . Importantly, morbidity and mortality from influenza infections are increased in at-risk patients, such as the elderly and immunocompromised 4,5 . While seasonal influenza epidemics cause a high global disease burden and are important public health concerns, the threat is significantly increased during influenza pandemics. ...
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There is a crucial need for an improved H3N2 influenza virus vaccine due to low vaccine efficacy rates and increased morbidity and mortality associated with H3N2-dominated influenza seasons. Here, we utilize a computational design strategy to produce epitope-optimized, broadly cross-reactive H3 hemagglutinins in order to create a universal H3N2 influenza vaccine. The Epigraph immunogens are designed to maximize the viral population frequency of epitopes incorporated into the immunogen. We compared our Epigraph H3 vaccine to the traditional egg-based inactivated influenza vaccine from 2018–19, FluZone. Epigraph vaccination-induced stronger cross-reactive antibody responses than FluZone against 18 H3N2 viruses isolated from 1968 to 2019 in both mice and ferrets, with protective hemagglutination inhibition titers against 93–100% of the contemporary H3N2 strains compared to only 27% protection measured from FluZone. In addition, Epigraph vaccination-induced strong cross-reactive T-cell immunity which significantly contributes to protection against lethal influenza virus infection. Finally, Epigraph vaccination protected ferrets from influenza disease after challenge with two H3N2 viruses. The superior cross-reactive immunity induced by these Epigraph immunogens supports their development as a universal H3N2 influenza vaccine.
... Most infected people generally recover within a few weeks, but occasionally, influenza can produce severe illness, possibly leading to death. It is estimated that, annually, there are from 3 to 5 million severe influenza infections worldwide [17], with from about 300,000 to 600,000 deaths [18,19]. Compared to IAV and IBV infection, ICV infection in humans is generally a mild upper respiratory disease, but it can be severe [20]. ...
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In humans and other mammals, the respiratory tract is represented by a complex network of polarized epithelial cells, forming an apical surface facing the external environment and a basal surface attached to the basement layer. These cells are characterized by differential expression of proteins and glycans, which serve as receptors during influenza virus infection. Attachment between these host receptors and the viral surface glycoprotein hemagglutinin (HA) initiates the influenza virus life cycle. However, the virus receptor binding specificities may not be static. Sialylated N-glycans are the most well-characterized receptors but are not essential for the entry of influenza viruses, and other molecules, such as O-glycans and non-sialylated glycans, may be involved in virus-cell attachment. Furthermore, correct cell polarity and directional trafficking of molecules are essential for the orderly development of the system and affect successful influenza infection; on the other hand, influenza infection can also change cell polarity. Here we review recent advances in our understanding of influenza virus infection in the respiratory tract of humans and other mammals, particularly the attachment between the virus and the surface of the polar cells and the polarity variation of these cells due to virus infection.
... Influenza illness is estimated to cause approximately 290,000-645,000 deaths annually, with 84% occurring in low-and middleincome countries (LMICs) [1]. While safe and effective influenza vaccines are available, they are seldom used in LMICs [2][3][4]. ...
Article
Introduction We conducted a systematic review of pediatric influenza vaccine efficacy trials to assess clinical outcome measures and whether the trials defined important public health endpoints. Material and methods We systematically identified phase 3 or 4 influenza vaccine randomized controlled trials among children ≤18 years of age with laboratory-confirmed influenza outcomes since 1980. We recorded countries, age groups, vaccine formulations, specimen collection criteria, laboratory diagnostics, primary and secondary outcome measures, and funders, and we determined income category for study countries. We used descriptive statistics to summarize study characteristics. We analyzed the studies overall and a subset of studies conducted in at least one low- and middle-income country (LMIC). Results From 6455 potentially relevant articles, we identified 41 eligible studies. Twenty-one studies (51%) were conducted in at least one LMIC, while the remaining studies (49%) were conducted in high-income countries only. Thirty-one studies (76%) included children younger than six years. We found 40 different primary outcome measures among the 41 eligible studies. Thirty-three studies (80%) reported standardized symptoms or findings which defined a primary outcome or triggered specimen collection. One study defined a primary outcome which captured more severe illness; however, cases were mostly due to high body temperature without other severity criteria. Of the 21 studies from at least one LMIC, 15 (71%) were published since 2010 and 17 (81%) enrolled children younger than six years. Eighteen (86%) studies from at least one LMIC reported standardized symptoms or findings which defined a primary outcome or triggered specimen collection. Conclusions Among pediatric influenza vaccine efficacy trials, primary outcome measures and clinical specimen collection criteria were highly variable and, with one exception, focused on capturing any influenza illness. As most LMICs do not have influenza vaccination programs, our study highlights a potential data limitation affecting policy and implementation decisions in these settings.
... Seasonal influenza virus infection is associated with substantial morbidity and mortality worldwide, with causing an estimated 290,000−650,000 deaths each year. 1 Internationally available vaccines for the control of seasonal influenza have the potential to prevent significant influenza morbidity and mortality. The World Health Organization (WHO) made recommendations for annual influenza vaccination defining specific groups at risk of influenza disease and reconfirming the safety profile of influenza vaccines identifying several groups with high risk for influenza infection including health workers (HWs) and elderly. 2 HWs is considered a high priority group because they are not only at increased risk of infection but also at risk of influenza transmission to vulnerable patients in healthcare settings, while elderly is another high priority group because of their high risk of having serious complications. ...
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Background A number of cost-effectiveness analysis of influenza vaccination have been conducted to estimate value of influenza vaccines in elderly and health workers (HWs). This study aims to summarize cost-effectiveness evidence by pooling the incremental net monetary benefit (INMB) of influenza vaccination. Methods A systematic review was performed in electronic databases from their inceptions to February 2022. Cost-effectiveness studies reporting quality-adjusted life year (QALY), or life year (LY) of influenza vaccination were included. Stratified meta-analyses by population, perspective, country income-level, and herd-effect were performed to pool INMB across studies. The protocol was registered at PROSPERO (CRD42021246746). Findings A total of 21 studies were included. Eighteen studies were conducted in elderly, two studies were conducted in HWs, and one study was conducted in both elderly and HWs. According to pre-specified analyses, studies for elderly in high-income economies (countries) (HIEs) and upper-middle income economies (UMIEs) without herd effect could be pooled. For HIEs under a societal perspective, the perspective which identify all relevant costs occurred in the society including direct medical cost, direct non-medical cost and indirect cost, pooled INMB was $217·38 (206·23, 228·53, I² =28.2%), while that for healthcare provider/payer perspective was $0·20 (-11,908·67, 11,909·07, I² = 0.0%). For societal perspective in UMIEs, pooled INMB was $28·39 (-190·65, 133·87, I² = 92.8%). The findings were robust across a series of sensitivity analyses for HIEs. Studies in HWs indicated that influenza vaccination was cost-effective compared to no vaccination or current practice. Interpretation Influenza vaccination might be cost-effective for HWs and elderly in HIEs under a societal perspective with relatively small variations among included studies, while there remains limited evidence for healthcare provider/payer perspective or other level of incomes. Further evidence is warranted. Funding This study was funded by a grant of Immunization, Vaccine and Biologicals department of the World Health Organization. The authors would like to acknowledge the contributions of the US CDC which provided financial support to the development and publication of this report. Grant number US CDC, WHO IVR (U50CK000431).
... One of the most significant risk factors of severe illness due to acute respiratory infection is aging. It is well recognized that the majority of deaths from seasonal influenza occurring among the elderly correlate with age after adulthood (48,49). The recent SARS-CoV-2 pandemic has confirmed the susceptibility of the elderly (50); hence, the elderly population requires vaccines the most. ...
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The primary goal of vaccines that protect against respiratory viruses appears to be the induction of neutralizing antibodies for a long period. Although this goal need not be changed, recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have drawn strong attention to another arm of acquired immunity, CD8+ T cells, which are also called killer T cells. Recent evidence accumulated during the coronavirus disease 2019 (COVID-19) pandemic has revealed that even variants of SARS-CoV-2 that escaped from neutralizing-antibodies that were induced by either infection or vaccination could not escape from CD8+ T cell-mediated immunity. In addition, although traditional vaccine platforms, such as inactivated virus and subunit vaccines, are less efficient in inducing CD8+ T cells, newly introduced platforms for SARS-CoV-2, namely, mRNA and adenoviral vector vaccines, can induce strong CD8+ T cell-mediated immunity in addition to inducing neutralizing antibodies. However, CD8+ T cells function locally and need to be at the site of infection to control it. To fully utilize the protective performance of CD8+ T cells, it would be insufficient to induce only memory cells circulating in blood, using injectable vaccines; mucosal immunization could be required to set up CD8+ T cells for the optimal protection. CD8+ T cells might also contribute to the pathology of the infection, change their function with age and respond differently to booster vaccines in comparison with antibodies. Herein, we overview cutting-edge ideas on CD8+ T cell-mediated immunity that can enable the rational design of vaccines for respiratory viruses.
Article
Subunit vaccines employing designer antigens such as Computationally Optimized Broadly Reactive Antigen (COBRA) hemagglutinin (HA) hold the potential to direct the immune response toward more effective and broadly-neutralizing targets on the Influenza virus. However, subunit vaccines generally require coadministration with an adjuvant to elicit a robust immune response. One such adjuvant is the stimulator of interferon genes (STING) agonist cyclic dinucleotide 3′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). We have shown that encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles through electrospray results in significantly greater biological activity. Electrospray is a continuous manufacturing process which achieves excellent encapsulation efficiency. However, the throughput of electrospray with a single spray head is limited. Here we report the development of a multiplexed electrospray apparatus with an order of magnitude greater throughput than a single-head apparatus. Physicochemical characterization and evaluation of adjuvant activity in vitro and in vivo indicated that microparticles produced with the higher throughput process are equally suited for use as a potent vaccine adjuvant to induce a balanced immune response to COBRA HA antigens.
Article
Real‐time trends from surveillance data are important to assess and develop preparedness for influenza outbreaks. The overwhelming testing demand and limited capacity of testing laboratories for viral positivity render daily confirmed case data inaccurate and delay its availability in preparedness. Using Bayesian dynamic downscaling models, we obtained posterior estimates for daily influenza incidences from weekly estimates of the Centers for Disease Control and Prevention and daily reported constitutional and respiratory complaints during emergency department (ED) visits obtained from the state health departments. Our model provides one‐day and seven‐day lead forecasts along with 95%$$ \% $$ prediction intervals. Our hybrid Markov Chain Monte Carlo and Kalman filter algorithms facilitate faster computation and enable us to update our estimates as new data become available. Our method is tested and validated using the State of Michigan data over the years 2009‐2013. Reported constitutional and respiratory complaints at the EDs showed strong correlations of 0.81 and 0.68 respectively, with influenza rates. In general, our forecast model can be adapted to track an outbreak with only one respiratory virus as a causative agent.
Article
A review of the intellectual and policy environment announces the absence of transparency and rational discourse in assessing the prevailing Covid-19 policy measures. Contextually, propaganda thrives in times of political uncertainty as it serves to either amplify confusion, induce moral dilemmas,or disguise meanings. To this end, this study examines the quality of political communication, underpinning South Africa’s public policy response to the Covid-19 pandemic. It aims to trace the influence of propaganda in informing policy origins and efficacy as it concerns the lethality of Covid-19. Importantly, informational irregularity must be treated with greater accountability and intellectual inquiry as it concerns masking and vaccine hesitancy. Following a qualitative approach and case study research strategy, this study begins by outlining the propagandistic assault on truth and rationality. Next, it confronts the seeming normality, with which the state, media, intellectual and scientific community have nonchalantly dismissed inconvenient truth in the name of misinformation. Of significance is the war on truth and the growing intellectual appetite for ideological realignment that esteems emotional triumph over empirical soundness. Ultimately, the research shows that scientific rationale has been demoted in favor of social solidarity. Finally, propagandist techniques and elements of deception theory entice the analytical appetite by exposing the modus operandi of deceptive operations at work in both masking and vaccine campaigns. The key findings indicate the use of propaganda and deception tactics at play in perception management with a view of influencing public action, corrupting public discourse and delegitimizing the need for factual accountability, concerning compliance with incoherent Covid-19 policy measures.
Article
Background: Respiratory syncytial virus (RSV) and influenza are important causes of disease in children and adults. In Australia, information on the burden of RSV in adults is particularly limited. Methods: We used time series analysis to estimate respiratory, acute respiratory infection, pneumonia and influenza, and bronchiolitis hospitalisations attributable to RSV and influenza in Australia during 2009 through 2017. RSV and influenza-coded hospitalisations in <5-year-olds were used as proxies for relative weekly viral activity. Results: From 2009 to 2017, the estimated all-age average annual rates of respiratory hospitalisations attributable to RSV and seasonal influenza (excluding 2009) were 54.8 (95% confidence interval [CI]: 20.1, 88.8) and 87.8 (95% CI: 74.5, 97.7) per 100,000, respectively. The highest estimated average annual RSV-attributable respiratory hospitalisation rate per 100,000 was 464.2 (95% CI: 285.9, 641.2) in <5-year-olds. For seasonal influenza, it was 521.6 (95% CI: 420.9, 600.0) in persons aged ≥75 years. In ≥75-year-olds, modelled estimates were approximately eight and two times the coded estimates for RSV and seasonal influenza, respectively. Conclusions: RSV and influenza are major causes of hospitalisation in young children and older adults in Australia, with morbidity underestimated by hospital diagnosis codes.
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Genomic characterization of circulating influenza type-A viruses (IAVs) directs the selection of appropriate vaccine formulations and early detection of potentially pandemic virus strains. However, longitudinal data on the genomic evolution and transmission of IAVs in Africa are scarce, limiting Africa’s benefits from potential influenza control strategies. We searched seven databases: African Journals Online, Embase, Global Health, Google Scholar, PubMed, Scopus, and Web of Science according to the PRISMA guidelines for studies that sequenced and/or genomically characterized Africa IAVs. Our review highlights the emergence and diversification of IAVs in Africa since 1993. Circulating strains continuously acquired new amino acid substitutions at the major antigenic and potential N-linked glycosylation sites in their hemagglutinin proteins, which dramatically affected vaccine protectiveness. Africa IAVs phylogenetically mixed with global strains forming strong temporal and geographical evolution structures. Phylogeographic analyses confirmed that viral migration into Africa from abroad, especially South Asia, Europe, and North America, and extensive local viral mixing sustained the genomic diversity, antigenic drift, and persistence of IAVs in Africa. However, the role of reassortment and zoonosis remains unknown. Interestingly, we observed substitutions and clades and persistent viral lineages unique to Africa. Therefore, Africa’s contribution to the global influenza ecology may be understated. Our results were geographically biased, with data from 63% (34/54) of African countries. Thus, there is a need to expand influenza surveillance across Africa and prioritize routine whole-genome sequencing and genomic analysis to detect new strains early for effective viral control.
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Yearly administration of influenza vaccine with recommendations can help control seasonal influenza epidemics in adults aged ≥60 years. Here, we describe the results of a prospective study observing the immunogenicity and persistence of induced immunity of a trivalent inactivated split-virion influenza vaccine (TIV) in adults aged ≥60 years during the 2018-2019 season in Taizhou City, Zhejiang Province in China. A total of 422 participants completed the study period. Vaccinated participants (284) received a single dose of TIV, but unvaccinated participants (138) didn't receive any vaccine. Study participants vaccinated with TIV had significantly higher GMTs of Hemagglutination Inhibition (HI) antibodies against AH1N1, AH2N3, and B/Victoria strains (all p < .0001) at day 30 post-vaccination compared with unvaccinated participants, but the antibody response to the B/Victoria strain was the weakest. Rates of seroprotection and seroconversion were generally higher in the TIV-vaccinated group. At day 180 post-vaccination, the seroconversion rates (95%CI) in the vaccinated group were 99.6% (99.0%-100.3%), 97.9% (96.2%-99.6%), and 68.3% (62.9%-73.8%) for antibodies against three influenza strains, respectively; these rates were significantly different compared with unvaccinated group only for strains AH3N2 and B/Victoria (p = .002 and p < .0001, respectively). These results confirm that in adults aged ≥60 years, a single dose of TIV can induce a protective immune response against influenza, but the protective HI antibody levels induced against strain B/Victoria do not persist through 6 months.
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Background: During the coronavirus disease 2019 (COVID-19) pandemic, seasonal influenza activity declined globally and remained below previous seasonal levels, but intensified in China since 2021. Preventive measures to COVID-19 accompanied by different epidemic characteristics of influenza in different regions of the world. To better respond to influenza outbreaks under the COVID-19 pandemic, we analyzed the epidemiology, antigenic and genetic characteristics, and antiviral susceptibility of influenza viruses in the mainland of China during 2020-2021. Methods: Respiratory specimens from influenza like illness cases were collected by sentinel hospitals and sent to network laboratories in Chinese National Influenza Surveillance Network. Antigenic mutation analysis of influenza virus isolates was performed by hemagglutination inhibition assay. Next-generation sequencing was used for genetic analyses. We also conducted molecular characterization and phylogenetic analysis of circulating influenza viruses. Viruses were tested for resistance to antiviral medications using phenotypic and/or sequence-based methods. Results: In the mainland of China, influenza activity recovered in 2021 compared with that in 2020 and intensified during the traditional influenza winter season, but it did not exceed the peak in previous years. Almost all viruses isolated during the study period were of the B/Victoria lineage and were characterized by genetic diversity, with the subgroup 1A.3a.2 viruses currently predominated. 37.8% viruses tested were antigenically similar to reference viruses representing the components of the vaccine for the 2020-2021 and 2021-2022 Northern Hemisphere influenza seasons. In addition, China has a unique subgroup of 1A.3a.1 viruses. All viruses tested were sensitive to neuraminidase inhibitors and endonuclease inhibitors, except two B/Victoria lineage viruses identified to have reduced sensitivity to neuraminidase inhibitors. Conclusions: Influenza activity increased in the mainland of China in 2021, and caused flu season in the winter of 2021-2022. Although the diversity of influenza (sub)type decreases, B/Victoria lineage viruses show increased genetic and antigenic diversity. The world needs to be fully prepared for the co-epidemic of influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus globally.
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We provide ethical criteria to establish when vaccine mandates for healthcare workers are ethically justifiable. The relevant criteria are the utility of the vaccine for healthcare workers, the utility for patients (both in terms of prevention of transmission of infection and reduction in staff shortage), and the existence of less restrictive alternatives that can achieve comparable benefits. Healthcare workers have professional obligations to promote the interests of patients that entail exposure to greater risks or infringement of autonomy than ordinary members of the public. Thus, we argue that when vaccine mandates are justified on the basis of these criteria, they are not unfairly discriminatory and the level of coercion they involve is ethically acceptable—and indeed comparable to that already accepted in healthcare employment contracts. Such mandates might be justified even when general population mandates are not. Our conclusion is that, given current evidence, those ethical criteria justify mandates for influenza vaccination, but not COVID-19 vaccination, for healthcare workers. We extend our arguments to other vaccines.
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In the current paper we present a hybrid modeling framework which allows to simulate co-circulation of influenza strains in urban settings. It comprises a detailed agent–based model coupled with SEIR-type compartmental model. While the former makes it possible to simulate the initial phase of an outbreak when the heterogeneity of the contact network is crucial, the latter approximates the disease dynamics after the occurrence of mass infection thus dramatically increasing the framework performance. The numerical experiments with the model are presented and their results are discussed.
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Objective: To perform a systematic review to assess the effectiveness and safety of Reduning Injection versus neuraminidase inhibitors in treatment of influenza. Methods: The MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Bio-medical Literature and Retrieval System (Sinomed), China National Knowledge Infrastructure Database (CNKI), China Science and Technology Journal Database (VIP), Wanfang Data Knowledge Service Platform and ClinicalTrails.gov were systematically searched from inception dates to May 2021 for randomized controlled trials (RCTs) exploring Reduning Injection alone or in combination with neuraminidase inhibitors in patients with influenza. Statistical analysis was performed using RevMan 5.4 and Stata 15.1. The qualities of the involved studies were assessed by the risk of bias according to the Cochrane handbook. The evidence quality of each outcome was evaluated by GRADEpro GDT. Results: Twelve trials with 1,460 patients were included. The included studies had a certain unclear or high risk of bias. Reduning Injection appeared to be more effective in shortening the fever clearance time (MD: -16.20 h, 95% CI: -19.40 to -12.99, 7 trials, 814 patients, I2=94%, very low certainty), fever alleviation time (MD: -4.09 h, 95% CI: -4.22 to -3.96, 3 trials, 366 patients, I2=0%, low certainty), cough alleviation time (MD: -21.34 h, 95% CI: -41.56 to -1.11, 2 trials, 228 patients, I2=89%, very low certainty), fatigue alleviation time (MD: -31.83 h, 95% CI: -36.88 to -26.77, 2 trials, 270 patients, I2=0%, low certainty), sore throat alleviation time (MD: -28.66 h, 95% CI: -32.23 to -25.10, 1 trial, 150 patients, low certainty), and improving the total effective rate (RR: 1.15, 95% CI: 1.06 to 1.25, 10 trials, 1,074 patients, I2=76%, very low certainty). Besides, Reduning Injection seemed generally safe. Conclusions: This study provided low or very low evidence indicating Reduning Injection may be effective in the treatment of influenza and might be safe. Further rigorously designed studies are needed to confirm the effectiveness and safety of Reduning Injection and support it as a recommendation for influenza.
Several epidemiologic and toxicological studies have commonly viewed ambient fine particulate matter (PM2.5), defined as particles having an aerodynamic diameter of less than 2.5 µm, as a significant potential danger to human health. PM2.5 is mostly absorbed through the respiratory system, where it can infiltrate the lung alveoli and reach the bloodstream. In the respiratory system, reactive oxygen or nitrogen species (ROS, RNS) and oxidative stress stimulate the generation of mediators of pulmonary inflammation and begin or promote numerous illnesses. According to the most recent data, fine particulate matter, or PM2.5, is responsible for nearly 4 million deaths globally from cardiopulmonary illnesses such as heart disease, respiratory infections, chronic lung disease, cancers, preterm births, and other illnesses. There has been increased worry in recent years about the negative impacts of this worldwide danger. The causal associations between PM2.5 and human health, the toxic effects and potential mechanisms of PM2.5, and molecular pathways have been described in this review.
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Objective The beneficial effect of influenza vaccination (IV) in patients with diabetes was not completely understood. Methods Using the research data of health insurance, we performed a cohort study of patients aged ≥ 20 years who were admitted to inpatient care due to diabetes in 2008-2013 in Taiwan. We performed the propensity score matching and the outcomes of complications and mortality following the diabetes admission was compared between patients with and without IV. Results Among 61002 patients with diabetes admission, IV reduced 30-day in-hospital mortality (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.66-0.84), particularly among patients with prior diabetes hospitalization, inadequate control for diabetes, and diabetes-related comorbidities, such as eye involvement, ketoacidosis, renal manifestations, and coma. Compared with non-IV control group, patients with IV also had decreased risks of pneumonia (OR 0.92, 95% CI 0.87-0.97), septicemia (OR 0.83, 95% CI 0.79-0.88), urinary tract infection (OR 0.94, 95% CI 0.90-0.97), and intensive care (OR 0.29, 95% CI 0.27-0.31). Conclusion In patients with diabetes admission, IV was associated with reduced risks of complications and mortality. Our study implicated the urgent need to promote influenza vaccination for this susceptible population with diabetes.
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Objectives The aim of this in vitro study was to investigate viruses’ stabilities on manual toothbrushes using feline coronavirus (FeCoV) as representative of coronaviruses and an Avian influenza A virus H1N1 for influenza viruses. Material and methods Two viruses, FeCoV (Strain Munich; titer 107.5 TCID50/ml) and H1N1 (RE 230/90; titer 106.5 TCID50/ml), were used in this study. Manual toothbrushes were disassembled into bristles, bristle fixation, and back of the toothbrush head, contaminated with the viruses and air-dried for 24 h. In a second experiment, whole toothbrush heads were contaminated, rinsed with water (5 ml for 15 s) and then air-dried. Results For FeCoV, immediately after contamination, the following average titers were recovered: fixation: 10 6.41 , back of head: 10 6.81 and bristles: 10 6.63 TCID 50 /ml. Following air-drying of 12 (fixation) and 24 h, titers of ≤ 10 2.5 , 10 3.75 , and 10 2.72 TCID 50 /ml were found in the respective groups, with a detection limit of 10 2.5 TCID 50 /ml. For H1N1, immediately after contamination, the following average titers could be recovered: fixation: 10 5.53 , back of head: 10 5.97 and bristles: 10 5.75 TCID 50 /ml. Following air-drying of 8 (fixation) and 24 h, titers were ≤ 10 2.5 , 10 3.63 , and 10 3.53 TCID 50 /ml in the respective group, again with 10 2.5 TCID 50 /ml being the detection limit. In case of water rinse, no infectious virus could be recovered after 12 h. Conclusion Viral load of both viruses is reduced by air-drying, especially following water rinsing. Clinical relevance The toothbrush itself plays an insignificant role in the self-transmission of coronavirus and influenza virus.
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Influenza A viruses (IAVs) in the swine reservoir constantly evolve, resulting in expanding genetic and antigenic diversity of strains that occasionally cause infections in humans and pose threat of emerging as a strain capable of human-to-human transmission. For these reasons, there is an ongoing need for surveillance and characterization of newly emerging strains to aid pandemic preparedness efforts, particularly for the selection of candidate vaccine viruses and conducting risk assessments. Here, we performed a parallel comparison of the pathogenesis and transmission of genetically and antigenically diverse swine-origin A(H1N1) variant (v) and A(H1N2)v, and human seasonal A(H1N1)pdm09 IAVs using the ferret model. Both groups of viruses were capable of replication in the ferret upper respiratory tract; however, variant viruses were more frequently isolated from the lower respiratory tract as compared to the human-adapted viruses. Regardless of virus origin, observed clinical signs of infection differed greatly between strains, with some viruses causing nasal discharge, sneezing and, in some instances, diarrhea in ferrets. The most striking difference between the viruses was the ability to transmit through the air. Human-adapted viruses were capable of airborne transmission between all ferret pairs. In contrast, only one out of the four tested variant viruses was able to transmit via the air as efficiently as the human-adapted viruses. Overall, this work highlights the need for sustained monitoring of emerging swine IAVs to identify strains of concern such as those that are antigenically different from vaccine strains and that possess adaptations required for efficient respiratory droplet transmission in mammals.
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Introduction: Chronic obstructive pulmonary disease (COPD) carries a tremendous societal and individual burden, posing significant challenges for public health systems worldwide due to its high morbidity and mortality. Due to aging and multimorbidity but also in the wake of important progress in deciphering the heterogeneous disease endotypes, an individualized approach to the prevention and management of COPD is necessary. Areas covered: This article tackles relevant immunization strategies that are available or still under development with a focus on the latest evidence but also controversies around different regional immunization approaches. Further, we present the crossover between chronic lung inflammation and lung microbiome disturbance as well as its role in delineating COPD endotypes. Moreover, the article attempts to underline endotype-specific treatment approaches. Lastly, we highlight non-pharmacologic prevention and management programs in view of the challenges and opportunities of the COVID-19 era. Expert opinion: Despite the remaining challenges, personalized medicine has the potential to offer tailored approaches to prevention and therapy and promises to improve the care of patients living with COPD.
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Objectives To investigate what factors affect parents’ influenza vaccination preference for their children and whether there exists preference heterogeneity among respondents in China. Design Cross-sectional study. A discrete choice experiment was conducted. Five attributes were identified based on literature review and qualitative interviews, including protection rate, duration of vaccine-induced protection, risk of serious side effects, location of manufacturer and out-of-pocket cost. Setting Multistage sampling design was used. According to geographical location and the level of economic development, 10 provinces in China were selected, and the survey was conducted at community healthcare centres or stations. Participants Parents with at least one child aged between 6 months and 5 years old were recruited and the survey was conducted via a face-to-face interview in 2019. In total, 600 parents completed the survey, and 449 who passed the internal consistency test were included in the main analysis. Main outcomes and measures A mixed logit model was used to estimate factors affecting parents’ preference to vaccinate their children. In addition, sociodemographic characteristics were included to explore the preference heterogeneity. Results In general, respondents preferred to vaccinate their children. All attributes were statistically significant and among them, the risk of severe side effects was the most important attribute, followed by the protection rate and duration of vaccine-induced protection. Contrary to our initial expectation, respondents have a stronger preference for the domestic than the imported vaccine. Some preference heterogeneity among parents was also found and in particular, parents who were older, or highly educated placed a higher weight on a higher protection rate. Conclusion Vaccination safety and vaccine effectiveness are the two most important characteristics that influenced parents’ decision to vaccinate against influenza for their children in China. Results from this study will facilitate future policy implementations to improve vaccination uptake rates.
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Background The Chinese elderly face a significant threat from seasonal influenza, owing to the consistently low vaccination coverage. This study investigated the prevalence and determinants of influenza vaccination hesitancy among the Chinese elderly. Methods In 2019, 3849 elderly individuals from 10 provinces in China were recruited in a cross-sectional survey. Multinomial logistic regression was applied to investigate the determinants of influenza vaccination hesitancy. Results Among the elderly respondents, 37.18% expressed some degree of hesitancy towards influenza vaccination: 19.28% were hesitant, and 17.90% refused influenza vaccination, including 19.28% acceptors with doubts and 17.90% refusers. Only 39.10% of the respondents considered themselves as the priority group for influenza vaccination, and 13.93% reported receiving a recommendation for vaccination from healthcare workers. Respondents with higher education levels and from urban areas had significantly higher odds of vaccine hesitancy than their counterparts. Confidence in the safety of vaccines was negatively associated with vaccine hesitancy, but confidence in vaccine efficacy had no such association. Respondents who perceived themselves as highly susceptible to influenza (AOR = 0.85; 95 %CI = 0.77–0.93) and those aware of the elderly as a priority group for influenza vaccination (AOR = 0.51; 95 %CI = 0.41–0.64) had a significantly lower odds of being refusers. Conclusion This study found a high prevalence of hesitancy towards influenza vaccination among the Chinese elderly, especially well-educated and urban-dwelling respondents. The government should address vaccine hesitancy through culturally appropriate communication, subsidies for vaccination, and actively promoting vaccines through primary care professionals.
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Neuraminidase (NA), an important enzyme for influenza virus replication, is a main target for influenza virus inhibition and detection. In this work, the aggregation-induced emission (AIE) and excited state intramolecular proton transfer (ESIPT)-active neuraminidase fluorescent probe SABP was firstly developed for influenza virus detection. The probe SABP showed high sensitivity towards NA with strong green fluorescence, which could be used for influenza virus detection and living cell imaging. In the presence of NA, SABP exhibited increased fluorescence signal by up to 30-fold at 524 nm. SABP detected NA activity in the range 0–5.0 U/mL, with a limit of detection (LOD) of 0.024 U/mL and detect influenza virus in the range of 2⁻⁴–2⁶ HAU with a LOD of 2⁻¹ HAU. Moreover, SABP was successfully applied to distinguish oseltamivir-resistant influenza virus from wild type.
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Seasonal influenza viruses are highly contagious, leading to 290,000–650,000 mortalities every year globally. Among the influenza viruses, influenza A virus (H3N2) has attracted much attention due to its high frequency of antigenic variations, resulting in poor protection by vaccination. We generated a panel of murine neutralizing monoclonal antibodies (mAbs) against A/Texas/50/2012 (H3N2) and identified the relevant epitopes that potentially influence the antigenicity by selecting mAb-resistant mutants. The epitopes were mainly in antigenic site A (1/9, 11.1%), B (6/9, 66.7%), and C (1/9, 11.1%), which is consistent with recent reports on the immunodominance of antigenic site B. The amino acid substitutions at positions 156, 157, 159, 160, and 189 at antigenic site B resulted in decreased mAb capability for blocking receptor binding. In addition, the neutralizing spectra of three mAbs (1F8, 1G9 and 1H5) were different, suggesting that their epitopes may be different but partially overlapping, and it required further study. Further, the mAb 3F9 selected a new substitution, D53G/N, at antigenic site C and showed in vitro neutralizing activity against A/Victoria/361/2011 (H3N2), A/Texas/50/2012 (H3N2), and A/Hong Kong/2671/2019 (H3N2), suggesting a potential epitope on H3 hemagglutinin for inducing broad neutralizing antibody responses. Continuous research and regular monitoring of novel epitopes are of great importance for improving vaccine strain selection.
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Influenza A virus (IAV) targets airway epithelial cells for infection. Large, heavily glycosylated molecules known as tethered mucins extend from the airway epithelial cell surface and may physically restrict pathogen access to underlying cells.
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Viral infections are responsible for the deaths of millions of people throughout the world. Since outbreak of highly contagious and mutant viruses such as contemporary sars-cov-2 pandemic, has challenged the conventional diagnostic methods, the entity of a thoroughly sensitive, specific, rapid and inexpensive detecting technique with minimum level of false-positivity or -negativity, is desperately needed more than any time in the past decades. Biosensors as minimized devices could detect viruses in simple formats. So far, various nucleic acid, immune- and protein-based biosensors were designed and tested for recognizing the genome, antigen, or protein level of viruses, respectively; however, nucleic acid-based sensing techniques, which is the foundation of constructing genosensors, are preferred not only because of their ultra-sensitivity and applicability in the early stages of infections but also for their ability to differentiate various strains of the same virus. To date, the review articles related to genosensors are just confined to particular pathogenic diseases; In this regard, the present review covers comprehensive information of the research progress of the electrochemical, optical, and surface plasmon resonance (SPR) genosensors that applied for human viruses’ diseases detection and also provides a well description of viruses’ clinical importance, the conventional diagnosis approaches of viruses and their disadvantages. This review would address the limitations in the current developments as well as the future challenges involved in the successful construction of sensing approaches with the functionalized nanomaterials and also allow exploring into core-research works regarding this area.
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Background The Global Influenza Hospital Surveillance Network (GIHSN) has operated with the aim of investigating epidemiological and clinical factors related to severe influenza-related hospitalisations. Study design A common GIHSN core protocol for prospective patient enrolment was implemented. Hospital personnel completed a standardized questionnaire regarding the included patients’ medical history, compiled a hospitalisation summary, collected an upper respiratory swab sample for laboratory diagnosis, and genome sequencing was performed for a subset of samples. Patient data were compared according to influenza subtype, lineage, and phylogenetic groups using the Fisher's exact test. Results From September 2019 to May 2020, 8,791 patients aged ≥5 years were included. Among them, 3,021 (34.4%) had a laboratory-confirmed influenza diagnosis. Influenza A(H1N1)pdm09 dominated the season among all age groups, while the B/Victoria-like lineage accounted for over half of the infections among younger age groups (5-49 years). Sequencing of the hemagglutinin segment was possible for 623 samples and revealed an influenza A and B clade frequency among severe influenza hospitalisations similar to other medically attended surveillance networks, such as the WHO GISRS. No phylogenetic clustering was observed among hemagglutinin substitutions depending on the administration of supplemental oxygen or vaccine failure. Conclusions The GIHSN confirms its ability as an international hospital-based active surveillance network to provide valuable information on influenza infection dynamics in hospital settings. Increasing the number of participating sites and compiling more complete data, such as genome sequencing, will allow the exploration of associations between viral factors, vaccine protection, and disease severity.
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Background: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Funding: Bill & Melinda Gates Foundation.
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During 2004-2009, the Centers for Disease Control and Prevention (CDC) partnered with 39 national governments to strengthen global influenza surveillance. Using World Health Organization data and program evaluation indicators collected by CDC in 2013, we retrospectively evaluated progress made 4-9 years after the start of influenza surveillance capacity strengthening in the countries. Our results showed substantial increases in laboratory and sentinel surveillance capacities, which are essential for knowing which influenza strains circulate globally, detecting emergence of novel influenza, identifying viruses for vaccine selection, and determining the epidemiology of respiratory illness. Twenty-eight of 35 countries responding to a 2013 questionnaire indicated that they have leveraged routine influenza surveillance platforms to detect other pathogens. This additional surveillance illustrates increased health-system strengthening. Furthermore, 34 countries reported an increased ability to use data in decision making; data-driven decisions are critical for improving local prevention and control of influenza around the world. © 2016, Centers for Disease Control and Prevention (CDC). All rights reserved.
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Introduction: It is important to determine the health impact of influenza in order to calibrate public health measures. The objective of this study was to estimate excess mortality associated with influenza in Korea in 2003-2013. Methods: The authors constructed multiple linear regression models in 2014 with weekly mortality rates stratified by age, region, and cause of death against weekly surveillance data on influenza virus collected in 2003-2013. Excess mortality rates were estimated using the difference between predicted mortality rates from the fitted model versus predicted mortality rates with the influenza covariate for each strain set to 0. Results: During the study period, influenza was associated with an average of 2,900 excess deaths per year. The impact of influenza on mortality was significantly higher in older people; the overall all-cause excess annual mortality rate per 100,000 people was 5.97 (95% CI=4.89, 7.19), whereas it was 46.98 (95% CI=36.40, 55.82) for adults aged ≥65 years. It also greatly varied from year to year, ranging from 2.04 in 2009-2010 to 18.76 in 2011-2012. Conclusions: The impact of influenza on mortality in Korea is substantial, particularly among the elderly and the rural population. More-comprehensive studies may be needed to estimate the full impact of influenza.
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Background: Laboratory testing is a fundamental component of influenza surveillance for detecting novel strains with pandemic potential and informing biannual vaccine strain selection. The United States (U.S.) Centers for Disease Control and Prevention (CDC), under the auspices of its WHO Collaborating Center for Influenza, is one of the major public health agencies which provides support globally to build national capacity for influenza surveillance. Our main objective was to determine if laboratory assessments supported capacity building efforts for improved global influenza surveillance. Methods: In 2010, 35 national influenza laboratories were assessed in 34 countries, using a standardized tool. Post-assessment, each laboratory received a report with a list of recommendations for improvement. Uptake of recommendations were reviewed 3.2 mean years after the initial assessments and categorized as complete, in-progress, no action or no update. This was a retrospective study; follow-up took place through routine project management rather than at a set time-point post-assessment. WHO data on National Influenza Centre (NIC) designation, External Quality Assessment Project (EQAP) participation and FluNet reporting was used to measure laboratory capacity longitudinally and independently of the assessments. All data was further stratified by World Bank country income category. Results: At follow-up, 81 % of 614 recommendations were either complete (350) or in-progress (145) for 32 laboratories (91 % response rate). The number of countries reporting to FluNet and the number of specimens they reported annually increased between 2005, when they were first funded by CDC, and 2010, the assessment year (p < 0.01). Improvements were also seen in EQAP participation and NIC designation over time and more so for low and lower-middle income countries. Conclusions: Assessments using a standardized tool have been beneficial to improving laboratory-based influenza surveillance. Specific recommendations helped countries identify and prioritize areas for improvement. Data from assessments helped CDC focus its technical assistance by country and region. Low and lower-middle income countries made greater improvements in their laboratories compared with upper-middle income countries. Future research could include an analysis of annual funding and technical assistance by country. Our approach serves as an example for capacity building for other diseases.
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Background: Influenza disease is a vaccine-preventable cause of morbidity and mortality. The Pan American Health Organization (PAHO) region has invested in influenza vaccines, but few estimates of influenza burden exist to justify these investments. We estimated influenza-associated deaths for 35 PAHO countries during 2002-2008. Methods: Annually, PAHO countries report registered deaths. We used respiratory and circulatory (R&C) codes from seven countries with distinct influenza seasonality and high-quality mortality data to estimate influenza-associated mortality rates by age group (0-64, 65-74, and ≥75 years) with a Serfling regression model or a negative binomial model. We calculated the percent of all R&C deaths attributable to influenza by age group in these countries (etiologic fraction) and applied it to the age-specific mortality in 13 countries with good mortality data but poorly defined seasonality. Lastly, we grouped the remaining 15 countries into WHO mortality strata and applied the age and mortality stratum-specific rate of influenza mortality calculated from the 20 countries. We summed each country's estimate to arrive at an average total annual number and rate of influenza deaths in the Americas. Results: For the 35 PAHO countries, we estimated an annual mean influenza-associated mortality rate of 2·1/100 000 among <65-year olds, 31·9/100 000 among those 65-74 years, and 161·8/100 000 among those ≥75 years. We estimated that annually between 40 880 and 160 270 persons (mean, 85 100) die of influenza illness in the PAHO region. Conclusion: Influenza remains an important cause of mortality in the Americas.
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The global burden of influenza is unknown but thought to be considerable. In 2008, the global estimate of influenza-associated severe acute lower respiratory illness in children <5 years was 1 million cases(1) , and the World Health Organization (WHO) suggests that 3-5 million severe cases occur in persons of all ages each (2) . In temperate regions, influenza usually causes annual outbreaks during the winter season (November-March in the Northern Hemisphere and June-September in the Southern Hemisphere)(3-4) . In contrast, influenza-associated mortality in subtropical or tropical regions, particularly in developing countries, remains poorly quantified and often underestimated. The pattern of influenza epidemics in tropical regions is less distinct and more diffuse. Seasonal influenza epidemics can sometimes occur twice or more throughout a year (5) . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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We estimated deaths attributable to influenza and respiratory syncytial virus (RSV) among persons >5 years of age in South Africa during 1998-2009 by applying regression models to monthly deaths and laboratory surveillance data. Rates were expressed per 100,000 person-years. The mean annual number of seasonal influenza-associated deaths was 9,093 (rate 21.6). Persons >65 years of age and HIV-positive persons accounted for 50% (n = 4,552) and 28% (n = 2,564) of overall seasonal influenza-associated deaths, respectively. In 2009, we estimated 4,113 (rate 9.2) influenza A(H1N1)pdm09-associated deaths. The mean of annual RSV-associated deaths during the study period was 511 (rate 1.2); no RSV-associated deaths were estimated in persons >45 years of age. Our findings support the recommendation for influenza vaccination of older persons and HIV-positive persons. Surveillance for RSV should be strengthened to clarify the public health implications and severity of illness associated with RSV infection in South Africa.
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Background Historically, counting influenza recorded in administrative health outcome databases has been considered insufficient to estimate influenza attributable morbidity and mortality in populations. We used database record linkage to evaluate whether modern databases have similar limitations. Methods Person-level records were linked across databases of laboratory notified influenza, emergency department (ED) presentations, hospital admissions and death registrations, from the population (∼6.9 million) of New South Wales (NSW), Australia, 2005 to 2008. Results There were 2568 virologically diagnosed influenza infections notified. Among those, 25% of 40 who died, 49% of 1451 with a hospital admission and 7% of 1742 with an ED presentation had influenza recorded on the respective database record. Compared with persons aged ≥65 years and residents of regional and remote areas, respectively, children and residents of major cities were more likely to have influenza coded on their admission record. Compared with older persons and admitted patients, respectively, working age persons and non-admitted persons were more likely to have influenza coded on their ED record. On both ED and admission records, persons with influenza type A infection were more likely than those with type B infection to have influenza coded. Among death registrations, hospital admissions and ED presentations with influenza recorded as a cause of illness, 15%, 28% and 1.4%, respectively, also had laboratory notified influenza. Time trends in counts of influenza recorded on the ED, admission and death databases reflected the trend in counts of virologically diagnosed influenza. Conclusions A minority of the death, hospital admission and ED records for persons with a virologically diagnosed influenza infection identified influenza as a cause of illness. Few database records with influenza recorded as a cause had laboratory confirmation. The databases have limited value for estimating incidence of influenza outcomes, but can be used for monitoring variation in incidence over time.
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Background: Assessing the mortality impact of the 2009 influenza A H1N1 virus (H1N1pdm09) is essential for optimizing public health responses to future pandemics. The World Health Organization reported 18,631 laboratory-confirmed pandemic deaths, but the total pandemic mortality burden was substantially higher. We estimated the 2009 pandemic mortality burden through statistical modeling of mortality data from multiple countries. Methods and findings: We obtained weekly virology and underlying cause-of-death mortality time series for 2005-2009 for 20 countries covering ∼35% of the world population. We applied a multivariate linear regression model to estimate pandemic respiratory mortality in each collaborating country. We then used these results plus ten country indicators in a multiple imputation model to project the mortality burden in all world countries. Between 123,000 and 203,000 pandemic respiratory deaths were estimated globally for the last 9 mo of 2009. The majority (62%-85%) were attributed to persons under 65 y of age. We observed a striking regional heterogeneity, with almost 20-fold higher mortality in some countries in the Americas than in Europe. The model attributed 148,000-249,000 respiratory deaths to influenza in an average pre-pandemic season, with only 19% in persons <65 y. Limitations include lack of representation of low-income countries among single-country estimates and an inability to study subsequent pandemic waves (2010-2012). Conclusions: We estimate that 2009 global pandemic respiratory mortality was ∼10-fold higher than the World Health Organization's laboratory-confirmed mortality count. Although the pandemic mortality estimate was similar in magnitude to that of seasonal influenza, a marked shift toward mortality among persons <65 y of age occurred, so that many more life-years were lost. The burden varied greatly among countries, corroborating early reports of far greater pandemic severity in the Americas than in Australia, New Zealand, and Europe. A collaborative network to collect and analyze mortality and hospitalization surveillance data is needed to rapidly establish the severity of future pandemics. Please see later in the article for the Editors' Summary.
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Very different influenza seasons have been observed from 2008/09-2011/12 in England and Wales, with the reported burden varying overall and by age group. The objective of this study was to estimate the impact of influenza on all-cause and cause-specific mortality during this period. Age-specific generalised linear regression models fitted with an identity link were developed, modelling weekly influenza activity through multiplying clinical influenza-like illness consultation rates with proportion of samples positive for influenza A or B. To adjust for confounding factors, a similar activity indicator was calculated for Respiratory Syncytial Virus. Extreme temperature and seasonal trend were controlled for. Following a severe influenza season in 2008/09 in 65+yr olds (estimated excess of 13,058 influenza A all-cause deaths), attributed all-cause mortality was not significant during the 2009 pandemic in this age group and comparatively low levels of influenza A mortality were seen in post-pandemic seasons. The age shift of the burden of seasonal influenza from the elderly to young adults during the pandemic continued into 2010/11; a comparatively larger impact was seen with the same circulating A(H1N1)pdm09 strain, with the burden of influenza A all-cause excess mortality in 15-64 yr olds the largest reported during 2008/09-2011/12 (436 deaths in 15-44 yr olds and 1,274 in 45-64 yr olds). On average, 76% of seasonal influenza A all-age attributable deaths had a cardiovascular or respiratory cause recorded (average of 5,849 influenza A deaths per season), with nearly a quarter reported for other causes (average of 1,770 influenza A deaths per season), highlighting the importance of all-cause as well as cause-specific estimates. No significant influenza B attributable mortality was detected by season, cause or age group. This analysis forms part of the preparatory work to establish a routine mortality monitoring system ahead of introduction of the UK universal childhood seasonal influenza vaccination programme in 2013/14.
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Poisson regression modelling has been widely used to estimate the disease burden attributable to influenza, though not without concerns that some of the excess burden could be due to other causes. This study aims to provide annual estimates of the mortality and hospitalization burden attributable to both seasonal influenza and the 2009 A/H1N1 pandemic influenza for Canada, and to discuss issues related to the reliability of these estimates. Weekly time-series for all-cause mortality and regression models were used to estimate the number of deaths in Canada attributable to influenza from September 1992 to December 2009. To assess their robustness, the annual estimates derived from different parameterizations of the regression model for all-cause mortality were compared. In addition, the association between the annual estimates for mortality and hospitalization by age group, underlying cause of death or primary reason for admission and discharge status is discussed. The crude influenza-attributed mortality rate based on all-cause mortality and averaged over 17 influenza seasons prior to the 2009 A/H1N1 pandemic was 11.3 (95%CI, 10.5 - 12.1) deaths per 100 000 population per year, or an average of 3,500 (95%CI, 3,200 - 3,700) deaths per year attributable to seasonal influenza. The estimated annual rates ranged from undetectable at the ecological level to more than 6000 deaths per year over the three A/Sydney seasons. In comparison, we attributed an estimated 740 deaths (95%CI, 350-1500) to A(H1N1)pdm09. Annual estimates from different model parameterizations were strongly correlated, as were estimates for mortality and morbidity; the higher A(H1N1)pdm09 burden in younger age groups was the most notable exception. With the exception of some of the Serfling models, differences in the ecological estimates of the disease burden attributable to influenza were small in comparison to the variation in disease burden from one season to another.
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Background: Influenza-associated deaths in children occur annually. We describe the epidemiology of influenza-associated pediatric deaths from the 2004-2005 through the 2011-2012 influenza seasons. Methods: Deaths in children <18 years of age with laboratory-confirmed influenza virus infection were reported to the Centers for Disease Control and Prevention by using a standard case report form to collect data on demographic characteristics, medical conditions, clinical course, and laboratory results. Characteristics of children with no high-risk medical conditions were compared with those of children with high-risk medical conditions. Results: From October 2004 through September 2012, 830 pediatric influenza-associated deaths were reported. The median age was 7 years (interquartile range: 1-12 years). Thirty-five percent of children died before hospital admission. Of 794 children with a known medical history, 43% had no high-risk medical conditions, 33% had neurologic disorders, and 12% had genetic or chromosomal disorders. Children without high-risk medical conditions were more likely to die before hospital admission (relative risk: 1.9; 95% confidence interval: 1.6-2.4) and within 3 days of symptom onset (relative risk: 1.6; 95% confidence interval: 1.3-2.0) than those with high-risk medical conditions. Conclusions: Influenza can be fatal in children with and without high-risk medical conditions. These findings highlight the importance of recommendations that all children should receive annual influenza vaccination to prevent influenza, and children who are hospitalized, who have severe illness, or who are at high risk of complications (age <2 years or with medical conditions) should receive antiviral treatment as early as possible.
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The goal of influenza vaccination programs is to reduce influenza-associated disease outcomes. Therefore, estimating the reduced burden of influenza as a result of vaccination over time and by age group would allow for a clear understanding of the value of influenza vaccines in the US, and of areas where improvements could lead to greatest benefits. To estimate the direct effect of influenza vaccination in the US in terms of averted number of cases, medically-attended cases, and hospitalizations over six recent influenza seasons. Using existing surveillance data, we present a method for assessing the impact of influenza vaccination where impact is defined as either the number of averted outcomes or as the prevented disease fraction (the number of cases estimated to have been averted relative to the number of cases that would have occurred in the absence of vaccination). We estimated that during our 6-year study period, the number of influenza illnesses averted by vaccination ranged from a low of approximately 1.1 million (95% confidence interval (CI) 0.6-1.7 million) during the 2006-2007 season to a high of 5 million (CI 2.9-8.6 million) during the 2010-2011 season while the number of averted hospitalizations ranged from a low of 7,700 (CI 3,700-14,100) in 2009-2010 to a high of 40,400 (CI 20,800-73,000) in 2010-2011. Prevented fractions varied across age groups and over time. The highest prevented fraction in the study period was observed in 2010-2011, reflecting the post-pandemic expansion of vaccination coverage. Influenza vaccination programs in the US produce a substantial health benefit in terms of averted cases, clinic visits and hospitalizations. Our results underscore the potential for additional disease prevention through increased vaccination coverage, particularly among nonelderly adults, and increased vaccine effectiveness, particularly among the elderly.
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Background: Official statistics under-estimate influenza deaths. Time series methods allow the estimation of influenza-attributable mortality. The methods often model background, non-influenza mortality using a cyclic, harmonic regression model based on the Serfling approach. This approach assumes that the seasonal pattern of non-influenza mortality is the same each year, which may not always be accurate. Aim: To estimate Australian seasonal and pandemic influenza-attributable mortality from 2003 to 2009, and to assess a more flexible influenza mortality estimation approach. Methods: We used a semi-parametric generalized additive model (GAM) to replace the conventional seasonal harmonic terms with a smoothing spline of time ('spline model') to estimate influenza-attributable respiratory, respiratory and circulatory, and all-cause mortality in persons aged <65 and ≥ 65 years. Influenza A(H1N1)pdm09, seasonal influenza A and B virus laboratory detection time series were used as independent variables. Model fit and estimates were compared with those of a harmonic model. Results: Compared with the harmonic model, the spline model improved model fit by up to 20%. In <65 year-olds, the estimated respiratory mortality attributable to pandemic influenza A(H1N1)pdm09 was 0.5 (95% confidence interval (CI), 0.3, 0.7) per 100,000; similar to that of the years with the highest seasonal influenza A mortality, 2003 and 2007 (A/H3N2 years). In ≥ 65 year-olds, the highest annual seasonal influenza A mortality estimate was 25.8 (95% CI 22.2, 29.5) per 100,000 in 2003, five-fold higher than the non-statistically significant 2009 pandemic influenza estimate in that age group. Seasonal influenza B mortality estimates were negligible. Conclusions: The spline model achieved a better model fit. The study provides additional evidence that seasonal influenza, particularly A/H3N2, remains an important cause of mortality in Australia and that the epidemic of pandemic influenza A (H1N1)pdm09 virus in 2009 did not result in mortality greater than seasonal A/H3N2 influenza mortality, even in younger age groups.
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Background: Although deaths associated with laboratory-confirmed influenza virus infections are rare, the excess mortality burden of influenza estimated from statistical models may more reliably quantify the impact of influenza in a population. Methods: We applied age-specific multiple linear regression models to all-cause and cause-specific mortality rates in Hong Kong from 1998 through 2009. The differences between estimated mortality rates in the presence or absence of recorded influenza activity were used to estimate influenza-associated excess mortality. Results: The annual influenza-associated all-cause excess mortality rate was 11.1 (95% confidence interval [CI], 7.2-14.6) per 100,000 person-years. We estimated an average of 751 (95% CI, 488-990) excess deaths associated with influenza annually from 1998 through 2009, with 95% of the excess deaths occurring in persons aged ≥65 years. Most of the influenza-associated excess deaths were from respiratory (53%) and cardiovascular (18%) causes. Influenza A(H3N2) epidemics were associated with more excess deaths than influenza A(H1N1) or B during the study period. Conclusions: Influenza was associated with a substantial number of excess deaths each year, mainly among the elderly, in Hong Kong in the past decade. The influenza-associated excess mortality rates were generally similar in Hong Kong and the United States.
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SUMMARY In order to estimate influenza-associated excess mortality in southern Brazil, we applied Serfling regression models to monthly mortality data from 1980 to 2008 for pneumonia/influenza- and respiratory/circulatory-coded deaths for all ages and for those aged ⩾60 years. According to viral data, 73·5% of influenza viruses were detected between April and August in southern Brazil. There was no clear influenza season for northern Brazil. In southern Brazil, influenza-associated excess mortality was 1·4/100 000 for all ages and 9·2/100 000 person-years for persons aged ⩾60 years using underlying pneumonia/influenza-coded deaths and 10·0/100 000 for all ages and 86·6/100 000 person-years for persons aged ⩾60 years using underlying respiratory/circulatory-coded deaths. Influenza-associated excess mortality rates for southern Brazil are similar to those published for other countries. Our data support the need for continued influenza surveillance to guide vaccination campaigns to age groups most affected by this virus in Brazil.
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The mortality burden of the 2009 A/H1N1 pandemic remains unclear in many countries due to delays in reporting of death statistics. We estimate the age- and cause-specific excess mortality impact of the pandemic in France, relative to that of other countries and past epidemic and pandemic seasons. We applied Serfling and Poisson excess mortality approaches to model weekly age- and cause-specific mortality rates from June 1969 through May 2010 in France. Indicators of influenza activity, time trends, and seasonal terms were included in the models. We also reviewed the literature for country-specific estimates of 2009 pandemic excess mortality rates to characterize geographical differences in the burden of this pandemic. The 2009 A/H1N1 pandemic was associated with 1.0 (95% Confidence Intervals (CI) 0.2-1.9) excess respiratory deaths per 100,000 population in France, compared to rates per 100,000 of 44 (95% CI 43-45) for the A/H3N2 pandemic and 2.9 (95% CI 2.3-3.7) for average inter-pandemic seasons. The 2009 A/H1N1 pandemic had a 10.6-fold higher impact than inter-pandemic seasons in people aged 5-24 years and 3.8-fold lower impact among people over 65 years. The 2009 pandemic in France had low mortality impact in most age groups, relative to past influenza seasons, except in school-age children and young adults. The historical A/H3N2 pandemic was associated with much larger mortality impact than the 2009 pandemic, across all age groups and outcomes. Our 2009 pandemic excess mortality estimates for France fall within the range of previous estimates for high-income regions. Based on the analysis of several mortality outcomes and comparison with laboratory-confirmed 2009/H1N1 deaths, we conclude that cardio-respiratory and all-cause mortality lack precision to accurately measure the impact of this pandemic in high-income settings and that use of more specific mortality outcomes is important to obtain reliable age-specific estimates.
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: Existing methods for estimation of mortality attributable to influenza are limited by methodological and data uncertainty. We have used proxies for disease incidence of the three influenza cocirculating subtypes (A/H3N2, A/H1N1, and B) that combine data on influenza-like illness consultations and respiratory specimen testing to estimate influenza-associated mortality in the United States between 1997 and 2007. : Weekly mortality rate for several mortality causes potentially affected by influenza was regressed linearly against subtype-specific influenza incidence proxies, adjusting for temporal trend and seasonal baseline, modeled by periodic cubic splines. : Average annual influenza-associated mortality rates per 100,000 individuals were estimated for the following underlying causes of death: for pneumonia and influenza, 1.73 (95% confidence interval = 1.53-1.93); for chronic lower respiratory disease, 1.70 (1.48-1.93); for all respiratory causes, 3.58 (3.04-4.14); for myocardial infarctions, 1.02 (0.85-1.2); for ischemic heart disease, 2.7 (2.23-3.16); for heart disease, 3.82 (3.21-4.4); for cerebrovascular deaths, 0.65 (0.51-0.78); for all circulatory causes, 4.6 (3.79-5.39); for cancer, 0.87 (0.68-1.05); for diabetes, 0.33 (0.26-0.39); for renal disease, 0.19 (0.14-0.24); for Alzheimer disease, 0.41 (0.3-0.52); and for all causes, 11.92 (10.17-13.67). For several underlying causes of death, baseline mortality rates changed after the introduction of the pneumococcal conjugate vaccine. : The proposed methodology establishes a linear relation between influenza incidence proxies and excess mortality, rendering temporally consistent model fits, and allowing for the assessment of related epidemiologic phenomena such as changes in mortality baselines.
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Two methodologies are used for describing and estimating influenza-related mortality: Individual-based methods, which use death certification and laboratory diagnosis and predominately determine patterns and risk factors for mortality, and population-based methods, which use statistical and modelling techniques to estimate numbers of premature deaths. The total numbers of deaths generated from the two methods cannot be compared. The former are prone to underestimation, especially when identifying influenza-related deaths in older people. The latter are cruder and have to allow for confounding factors, notably other seasonal infections and climate effects. There is no routine system estimating overall European influenza-related premature mortality, apart from a pilot system EuroMOMO. It is not possible at present to estimate the overall influenza mortality due to the 2009 influenza pandemic in Europe, and the totals based on individual deaths are a minimum estimate. However, the pattern of mortality differed considerably between the 2009 pandemic in Europe and the interpandemic period 1970 to 2008, with pandemic deaths in 2009 occurring in younger and healthier persons. Common methods should be agreed to estimate influenza-related mortality at national level in Europe, and individual surveillance should be instituted for influenza-related deaths in key groups such as pregnant women and children.
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To estimate influenza-associated mortality in urban China. Influenza-associated excess mortality for the period 2003-2008 was estimated in three cities in temperate northern China and five cities in the subtropical south of the country. The estimates were derived from models based on negative binomial regressions, vital statistics and the results of weekly influenza virus surveillance. Annual influenza-associated excess mortality, for all causes, was 18.0 (range: 10.9-32.7) deaths per 100,000 population in the northern cities and 11.3 (range: 7.3-17.8) deaths per 100,000 in the southern cities. Excess mortality for respiratory and circulatory disease was 12.4 (range: 7.4-22.2) and 8.8 (range: 5.5-13.6) deaths per 100,000 people in the northern and southern cities, respectively. Most (86%) deaths occurred among people aged ≥ 65 years. Influenza-associated excess mortality was higher in B-virus-dominant seasons than in seasons when A(H3N2) or A(H1N1) predominated, and more than half of all influenza-associated mortality was associated with influenza B virus. Between 2003 and 2008, seasonal influenza, particularly that caused by the influenza B virus, was associated with substantial mortality in three cities in the temperate north of China and five cities in the subtropical south of the country.
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We assessed the severity of the 2009 influenza pandemic by comparing pandemic mortality to seasonal influenza mortality. However, reported pandemic deaths were laboratory-confirmed - and thus an underestimation - whereas seasonal influenza mortality is often more inclusively estimated. For a valid comparison, our study used the same statistical methodology and data types to estimate pandemic and seasonal influenza mortality. We used data on all-cause mortality (1999-2010, 100% coverage, 16.5 million Dutch population) and influenza-like-illness (ILI) incidence (0.8% coverage). Data was aggregated by week and age category. Using generalized estimating equation regression models, we attributed mortality to influenza by associating mortality with ILI-incidence, while adjusting for annual shifts in association. We also adjusted for respiratory syncytial virus, hot/cold weather, other seasonal factors and autocorrelation. For the 2009 pandemic season, we estimated 612 (range 266-958) influenza-attributed deaths; for seasonal influenza 1,956 (range 0-3,990). 15,845 years-of-life-lost were estimated for the pandemic; for an average seasonal epidemic 17,908. For 0-4 yrs of age the number of influenza-attributed deaths during the pandemic were higher than in any seasonal epidemic; 77 deaths (range 61-93) compared to 16 deaths (range 0-45). The ≥75 yrs of age showed a far below average number of deaths. Using pneumonia/influenza and respiratory/cardiovascular instead of all-cause deaths consistently resulted in relatively low total pandemic mortality, combined with high impact in the youngest age category. The pandemic had an overall moderate impact on mortality compared to 10 preceding seasonal epidemics, with higher mortality in young children and low mortality in the elderly. This resulted in a total number of pandemic deaths far below the average for seasonal influenza, and a total number of years-of-life-lost somewhat below average. Comparing pandemic and seasonal influenza mortality as in our study will help assessing the worldwide impact of the 2009 pandemic.
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To estimate the excess deaths attributed to influenza in Spain, using age-specific generalized linear models (GLM) and the Serfling model for the period 1999-2005. We reviewed mortality from influenza and pneumonia and all-cause deaths. We used an additive GLM procedure, including the numbers of weekly deaths as a response variable and the number of influenza virus and respiratory syncytial virus weekly isolates, the population and two variables to adjust for annual fluctuations as covariates. Using the Serfling model, we removed the trend and applied a temporal regression model, excluding data from December to April to account for the expected baseline mortality in the absence of influenza activity. Globally, the excess mortality attributable to influenza was 1.1 deaths per 100,000 for influenza and pneumonia and 11 all-cause deaths per 100,000 using the GLM model. The highest mortality rates were obtained with the Serfling model in adults older than 64 years, with an excess mortality attributable to influenza of 57 and 164 deaths per 100,000 for influenza and pneumonia and all-cause, respectively. The GLM model, which takes viral activity into account, yields systematically lower estimates of excess mortality than the Serfling model. The GLM model provides independent estimates associated with the activity of different viruses and even with other factors, which is a significant advantage when trying to understand the impact of viral respiratory infections on mortality in the Spanish population.
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In temperate zones, all-cause mortality exhibits a marked seasonality, and one of the main causes of winter excess mortality is influenza. There is a tradition of using statistical models based on mortality from respiratory illnesses (Pneumonia and Influenza: PI) or all-cause mortality for estimating the number of deaths related to influenza. Different authors have applied different estimation methodologies. We estimated mortality related to influenza and periods with extreme temperatures in Denmark over the seasons 1994/95 to 2009/10. We applied a multivariable time-series model with all-cause mortality as outcome, activity of influenza-like illness (ILI) and excess temperatures as explanatory variables, controlling for trend, season, age, and gender. Two estimates of excess mortality related to influenza were obtained: (1) ILI-attributable mortality modelled directly on ILI-activity, and (2) influenza-associated mortality based on an influenza-index, designed to mimic the influenza transmission. The median ILI-attributable mortality per 100,000 population was 35 (range 6 to 100) per season which corresponds to findings from comparable countries. Overall, 88% of these deaths occurred among persons ≥ 65 years of age. The median influenza-associated mortality per 100,000 population was 26 (range 0 to 73), slightly higher than estimates based on pneumonia and influenza cause-specific mortality as estimated from other countries. Further, there was a tendency of declining mortality over the years. The influenza A(H3N2) seasons of 1995/96 and 1998/99 stood out with a high mortality, whereas the A(H3N2) 2005/6 season and the 2009 A(H1N1) influenza pandemic had none or only modest impact on mortality. Variations in mortality were also related to extreme temperatures: cold winters periods and hot summers periods were associated with excess mortality. It is doable to model influenza-related mortality based on data on all-cause mortality and ILI, data that are easily obtainable in many countries and less subject to bias and subjective interpretation than cause-of-death data. Further work is needed to understand the variations in mortality observed across seasons and in particular the impact of vaccination against influenza.