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Estimates of global seasonal influenza-associated respiratory mortality: A modelling study
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 Previous estimates of 250 000-500 000 annual influenza deaths are outdated.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.
... Human H1N1 and H3N2 IAVs cause regular seasonal outbreaks in the human population where the disease can result in severe clinical outcomes in children, elderly, pregnant women, and immune compromised individuals. The public health burden of these annual outbreaks is significant with up to 650,000 excess deaths estimated annually by the WHO from influenza infections [1]. In addition, a vast array of different IAV subtypes circulate in the natural reservoir population of wild aquatic birds and sporadically these avian IAVs can cross the host species barrier and result in infection of humans, often with high case fatality rates, such as H7N9 or H5N1 [2][3][4]. ...
... for most strains tested, H1N1 A/Michigan/45/2015 being the only exception which showed significant binding at 200µg/ml (20µg/well) (Figure 1B).FH is composed of 20 complement control protein (CCP) modules(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), with CCPs 1-4 known to be involved in C3b binding, decay acceleration of C3 convertase and binding as a cofactor for factor I. Two other C3b binding sites have been mapped to CCP7-15 and CCP19-20, whereas the predominant binding to "self" cells via polyanions is via CCP19-20[32,33]. Interestingly, studies involving the mapping of FH-binding sites on other pathogens such as Borrelia spp., Neisseria spp.,Haemophilus influenzae, Pseudomonas aeruginosa, Candida albicans andStaphylococcus aureus have implicated a common binding footprint for these diverse interaction molecules with either CCP5-7 and/ or CCP19-20. ...
The complement system is an innate immune mechanism against microbial infection. It involves a cascade of effector molecules that is activated via classical, lectin and alternative pathways. Consequently, many pathogens bind to or incorporate in their structures host negative regulators of the complement pathways as an evasion mechanism. Factor H (FH) is a negative regulator of the complement alternative pathway that protects "self" cells of the host from non-specific complement attack. Viruses including human influenza A viruses (IAVs) have been shown to bind to FH. Here we show that IAVs of both human and avian origin can bind directly to human FH and the interaction is mediated via the IAV surface glycoprotein haemagglutinin (HA). HA bound to common pathogen binding footprints on the FH structure, complement control protein modules, CCP 5-7 and CCP 15-20. The FH binding to H1 and H3 showed that the interaction overlapped with the receptor binding site of both HAs but the footprint was more extensive for the H3 HA than the H1 HA. The HA-FH interaction impeded the initial entry of H1N1 and H3N2 IAV strains but its impact on viral multicycle replication in human lung cells was strain specific. The H3N2 virus binding to cells was significantly inhibited by preincubation with FH, whereas there was no alteration in replicative rate and progeny virus release for human H1N1 or avian H9N2 and H5N3 IAV strains. We have mapped the interaction between IAV and FH, the significance of which for the virus or host is yet to be elucidated. 3
... Keywords: influenza epidemiology; LMIC; global health; surveillance; disease severity BACKGROUND An estimated 3 to 5 million severe influenza cases occur worldwide each year, resulting in 290,000 to 650,000 influenza-related deaths. 1,2 Patients with prior comorbidities are at high risk of severe influenza outcomes (e.g., hospital and/or intensive care unit admission, ventilation requirements, and death), but those who are otherwise healthy may also develop clinical complications. [3][4][5] Given lack of routine testing for influenza, and the complex pathway by which influenza can exacerbate chronic conditions and lead to severe disease 6 , influenza burden estimates remain uncertain, especially in data-poor settings. ...
... Global estimates of influenza-related excess deaths require extrapolation from data-rich countries with established vital statistics systems to those without, with rare opportunities for direct validation in lower-income settings. 1,7 And while most global studies have focused on influenza-associated respiratory disease deaths, few have studied hospital outcomes. Further, global estimation of influenza hospitalization rates remains challenging due to the heterogeneity of data collection methods and case definitions. ...
Background:
The Global Influenza Hospital Surveillance Network (GIHSN) has since 2012 provided patient-level data on severe influenza-like illnesses from over 100 participating clinical sites worldwide based on a core protocol and consistent case definitions. To our knowledge, this is the first study to analyze multiple years of global, patient-level data generated by prospective, hospital-based surveillance across a large number of countries to investigate geographic differences in influenza severity.
Methods:
We used multivariable logistic regression to assess the risk of intensive care unit admission, mechanical ventilation, and in-hospital death among hospitalized patients with influenza and explored the role of patient-level covariates and country income.
Results:
The dataset included 73,121 patients hospitalized with respiratory illness in 22 countries, with 15,660 laboratory-confirmed for influenza. After adjusting for patient-level covariates we found a 7-fold increase in the risk of influenza-related intensive care unit admission in lower middle-income countries, compared to high-income countries (p = 0.01). The risk of mechanical ventilation and in-hospital death also increases by four-fold in lower middle-income countries, though these values were not statistically significant. We also find that influenza severity increased with older age and number of comorbidities. Across all severity outcomes studied and after controlling for patient characteristics, infection with influenza A/H1N1pdm09 was more severe than with A/H3N2.
Conclusions:
Our study provides new information on influenza severity in under-resourced populations, particularly those in lower middle-income countries. Understanding the mechanisms responsible for these disparities will be important to improve management of influenza, optimize vaccine allocation, and mitigate global disease burden.
... Influenza virus infections represent an ongoing major public health issue inflicting high numbers of hospitalizations and casualties, with the most vulnerable groups consisting of children, elders, and immunocompromised individuals [1]. As of December 2017, influenzarelated respiratory deaths per year were estimated to be 290,000-650,000 worldwide [2], while preliminary in-season estimates for the most recent flu season in the United States reached 27-54 million illnesses and 19,000-58,000 deaths [3]. High infection rate peaks occur periodically, usually once per year, in each hemisphere due to continuous antigenic drift that hinders long-lasting immunity. ...
Influenza virus infections represent an ongoing public health threat as well as an economic burden. Although seasonal influenza vaccines have been available for some decades, efforts are being made to generate new efficient, flexible, and cost-effective technologies to be transferred into production. Our work describes the development of a model influenza hemagglutinin antigen that is capable of inducing protection against viral challenge in mice. High amounts of the H1 hemagglutinin ectodomain, HA18–528, were expressed in a bacterial system as insoluble inclusion bodies. Solubilization was followed by a thorough differential scanning fluorimetry (DSF)-guided optimization of refolding, which allows for fast and reliable screening of several refolding conditions, yielding tens of milligrams/L of folded protein. Structural and functional analysis revealed native-like folding as well as the presence of a mix of monomers and oligomers in solution. Mice immunized with HA18–528 were protected when exposed to influenza A virus as opposed to mice that received full-length denatured protein. Sera of mice immunized with HA18–528 showed both high titers of antigen-specific IgG1 and IgG2a isotypes as well as viral neutralization activity. These results prove the feasibility of the recombinant bacterial expression system coupled with DSF-guided refolding in providing influenza hemagglutinin for vaccine development.
... The US Centers for Disease Control and Prevention (CDC) reported that influenza contributed to 35 million illnesses, 16 million medical visits, 380,000 hospitalizations, and 20,000 deaths in the United States during the prototypical 2019-2020 influenza season. 1 A recent estimate of worldwide influenza disease found that seasonal influenza is responsible for around half a million deaths each year. 2 This translates into a significant economic burden, with lost worker productivity costing the United States economy an average of $11.2 billion annually and increased health care use contributing $3.2 billion in direct medical costs each year. 3 These public health and economic impacts of influenza highlight the need for rapid and appropriate risk stratification of patients diagnosed with symptomatic disease in acute care settings to optimize the use of limited health care resources. ...
Objectives
We sought to develop an evidence‐based tool to risk stratify patients diagnosed with seasonal influenza in the emergency department (ED).
Methods
We performed a single‐center retrospective cohort study of all adult patients diagnosed with influenza in a large tertiary care ED between 2008 and 2018. We evaluated demographics, triage vital signs, chest x‐ray and laboratory results obtained in the ED. We used univariate and multivariate statistics to examine the composite primary outcome of death or need for intubation. We validated our findings in patients diagnosed between 2018 and 2020.
Results
We collected data from 3128 subjects; 2196 in the derivation cohort and 932 in the validation cohort. Medical comorbidities, multifocal opacities or pleural effusion on chest radiography, older age, elevated respiratory rate, hypoxia, elevated blood urea nitrogen, blood glucose, blood lactate, and red blood cell distribution width were factors associated with intubation or death. We developed the Predicting Intubation in seasonal Influenza Patients diagnosed in the ED (PIIPED) risk‐stratification tool from these factors. The PIIPED tool predicted intubation or death with an area under the receiver operating characteristic curve (AUC) of 0.899 in the derivation cohort and 0.895 in the validation cohort. A version of the tool including only factors available at ED triage, before laboratory or radiographic evaluation, exhibited AUC of 0.852 in the derivation cohort and 0.823 in the validation cohort.
Conclusion
Clinical findings during an ED visit predict severe outcomes in patients with seasonal influenza. The PIIPED risk stratification tool shows promise but requires prospective validation.
... The influenza A virus (IAV) is a serious public health threat, causing significant yearly morbidity and mortality and concerns due to the potential emergence of new pandemic viruses (1)(2)(3). After infection or vaccination, most antibodies (Abs) against IAV target the surface glycoprotein hemagglutinin (HA), which undergoes constant antigenic drift (4). ...
The influenza virus is a persistent burden on global health, with seasonal vaccines providing incomplete protection. CD4 ⁺ T cells help shape B cell and antibody responses; however, the selectivity of help and the effect on various antigen-specific B cell populations have not been fully elucidated. Here, we studied the specificity, selectivity, and influence of nucleoprotein (NP) CD4 ⁺ T cells on the magnitude and quality of hemagglutinin (HA) and NP-specific B cells and antibody responses. We identified immunodominant peptides and showed that peptide immunization was sufficient to induce CD4 ⁺ cells with Th1 and Tfh phenotypes. Surprisingly, while preexisting CD4 ⁺ T cells enhanced the influx of total germinal center (GC) B cells in the mediastinal lymph node after infection, this was not reflected by an increase in the frequency of antigen-specific cells within the GC. Furthermore, we demonstrated that NP-specific help was able to accelerate the kinetics and magnitude of the Ab response for NP but not for HA. Overall, our results showed that pre-existing CD4 ⁺ T cells provide strong cognate help during immunization or infection to enhance Ab production but not antigen-specific GC or memory B cells.
... In uenza is an acute respiratory disease, which remains a major public health concern, and contributes signi cantly to both morbidity and mortality (Cozza et al. 2021). Globally, between 1995 to 2015, there was an estimated 290,000 to 650,000 deaths annually related to seasonal in uenza-associated respiratory (Iuliano et al. 2018 In the tropics and subtropics, many studies suggest that the burden of in uenza is not notably lower than in temperate regions (Ng and Climate factors are suggested to be the main driver for the seasonal pattern of in uenza in diverse regions (Dave and Lee 2019). The study of Tamerius suggests that cold-dry conditions are associated with the seasonal pattern in temperate regions, whereas, in tropical regions, the humid-rainy contributes to the seasonal patterns (Tamerius et al. 2013). ...
This study investigates the seasonality pattern and association between meteorological factors and particulate matter (PM10) concentration, and influenza incidence in Bangkok, Thailand. We analyze monthly averaged temperature, relative humidity, precipitation, PM10 concentrations, and influenza cases collected from 2003 to 2019 using wavelet analysis and a generalized additive model (GAM). The wavelet transforms analysis shows the periodic patterns of influenza with distinct periods of 0.5 years prior to the influenza pandemic in 2009 and 0.5 and 1 year following the pandemic, demonstrating an important shift after the 2009 pandemic. The result also reveals a significant coherence between climate factors, PM10, and influenza incidence. By using the maximum lag time obtained from the wavelet analysis, our GAM model shows the linear relationships between PM10, relative humidity, precipitation, and influenza incidence, whereas temperature exhibits a nonlinear relationship with influenza cases. These findings contribute to a better understanding of the temporal dynamics of influenza seasonality driven by climate factors and PM10 during the past 17 years. This knowledge would be useful for planning clinical resources and supporting public health under the climate situation in Thailand.
... Seasonal influenza is an infectious respiratory disease caused by influenza viruses and poses substantial morbidity and mortality annually (1). Young children have a great disease burden and are particularly vulnerable to influenza. ...
Background
Young children have a great disease burden and are particularly vulnerable to influenza. This study aimed to assess the direct effect of influenza vaccination among children and to evaluate the indirect benefit of immunizing children.
Methods
The influenza vaccination records for all children born during 2013–2019 in Minhang District and surveillance data for reported influenza cases were obtained from the Minhang CDC. 17,905 children were recorded in the vaccination system and included in this study. Descriptive epidemiology methods were used for data analysis, including an ecological approach to estimate the number of influenza cases averted by vaccination and linear regression to estimate the reduction in influenza cases in the general population per thousand additional childhood vaccination doses.
Results
During the study period, the annual vaccination coverage rate ranged from 10.40% in 2013–2014 to 27.62% in 2015–2016. The estimated number of influenza cases averted by vaccination ranged from a low of 0.28 (range: 0.23–0.34) during 2013–2014 (PF: 6.15%, range: 5.11–7.38%) to a high of 15.34 (range: 12.38–18.51) during 2017–2018 (PF: 16.54%, range: 13.79–19.30%). When increasing vaccination coverage rate by 10% in each town/street, a ratio of 7.27–10.69% cases could be further averted on the basis of observed cases. In four selected periods, the number of influenza cases in the general population was most significantly correlated with the cumulative childhood vaccination doses in the prior 2–5 months, and the reduction in influenza cases ranged from 0.73 to 3.18 cases per thousand additional childhood vaccination doses.
Conclusion
Influenza vaccination among children is estimated to have direct effects in terms of averted cases and might provide an underlying indirect benefit to the general population. Vaccination coverage in high-coverage areas should be further expanded to avert more influenza cases.
... Influenza causes considerable morbidity and mortality worldwide, resulting in an estimated 1 billion influenza cases, with 3-5 million severe illnesses and 290,000-650,000 influenza-related respiratory deaths (0.1-0.2% case fatality rate) each year [1,2]. In China, an estimated annual mean of 88,100 influenza-associated excess respiratory deaths were caused by seasonal influenza between 2010 and 2015 [3]. ...
Influenza is a major cause of morbidity and mortality. The protective effect of a trivalent influenza vaccine (TIV) is undetermined in military personnel. We conducted an open-label, cluster randomized trial on active-duty servicemen of Beijing, Tianjin, and Shijiazhuang, who were randomly assigned to receive either a single dose of TIV or no treatment, according to cluster randomized sampling. The subjects were then followed for a maximum of six months to assess the incidence of laboratory-confirmed influenza. A total of 5445 subjects in 114 clusters received one dose of TIV before the 2015/2016 influenza season. Laboratory-confirmed influenza was identified in 18 in the vaccine group compared with 87 in the control group (6031 subjects in 114 clusters), resulting in a vaccine effectiveness (VE) of 76.4% (95%CI: 60.7 to 85.8) against laboratory-confirmed influenza. Influenza-like illness was diagnosed in 132 in the vaccine group compared with 420 in the control group, resulting in a VE of 64.1% (95%CI: 56.2 to 70.6). The estimated VE against influenza B viruses was 80.5% (95%CI: 65.6 to 88.9) and 8.6% (95%CI: −241 to 75.5) against influenza A viruses. In conclusion, the trivalent influenza vaccine is moderately effective, highly immunogenic, and generally safe to use in healthy male military servicemen.
... Influenza remains one of the world's greatest public health challenges with an estimated 1 billion cases of seasonal influenza every year. About 3-5 million of these cases are severe, leading to 290,000-650,000 deaths globally [3,4]. The 2009 "swine flu" pandemic resulted in an estimated 60 million cases, 274,304 hospitalizations, and 12,469 deaths in the USA alone [5]. ...
Background:
Several studies have documented that specific Indigenous groups have been disproportionately affected by previous pandemics. The objective of this paper is to describe the protocol to be used in a review and meta-analysis of the literature on Indigenous groups and influenza. Using this protocol as a guide, a future study will provide a comprehensive historical overview of pre-COVID impact of influenza on Indigenous groups by combining data from the last five influenza pandemics and seasonal influenza up to date.
Methods/principle findings:
The review will include peer-reviewed original studies published in English, Spanish, Portuguese, Swedish, Danish, and Norwegian. Records will be identified through systematic literature search in eight databases: Embase, MEDLINE, CINAHL, Web of Science, Academic Search Ultimate, SocINDEX, ASSIA, and Google Scholar. Results will be summarized narratively and using meta-analytic strategies.
Discussion:
To our knowledge, there is no systematic review combining historical data on the impact of both seasonal and pandemic influenza on Indigenous populations. By summarizing results within and across Indigenous groups, different countries, and historical periods, as well as research in six different languages, we aim to provide information on how strong the risk for influenza is among Indigenous groups and how consistent this risk is across groups, regions, time, and seasonal versus the specific pandemic influenza strains.
Systematic review registration:
PROSPERO CRD42021246391.
... Influenza infection in pregnancy is accompanied by increased maternal morbidity and adverse neonatal outcomes. The inactivated influenza vaccination administered during pregnancy can mitigate the potential detrimental effects of influenza in the newborn, as recommended by WHO [36], during the first months of life specifically [46]. Thus, before COVID-19, the influenza vaccine was the most widely recommended during pregnancy worldwide, mainly due the protective role played against potentially life-threatening disease in both pregnant people and their infants up to six months of age [47,48]. ...
Childbirth education classes represent an antenatal tool for supporting pregnant women and couples in increasing knowledge on pregnancy, delivery, breastfeeding, and newborn care. The aim of this study was to investigate the impact of an additional lesson during the prenatal course regarding the advantage of vaccination to mitigation of maternal anxiety. An observational study was designed that included participants in childbirth education classes and compared courses enhanced by the extra lesson on vaccination during pregnancy versus those who did not receive it. Assessment of the impact of prenatal educational on vaccination was measured by using validated questionnaires (State-Trait Anxiety Inventory, STAI; Perceived Stress Scale, PSS; World Health Organization- Five Well-Being Index, WHO-5). A total of 145 pregnant women participated to the investigation by answering to the online survey. Of them, 33 patients (22.8%) belonged to the course without a lesson on vaccine, while 112 (77.2%) participated to online prenatal education that included an additional meeting on the usefulness of getting vaccinated during pregnancy. No statistical differences were found between study groups in terms of demographics and perinatal outcomes. Participants in the enriched course reported lower basal anxiety levels than those without the vaccine lesson (STAI-State, normal score < 40, 30 vs. 19%, p-value 0.041; STAI-State, mild score 40–50, 78 vs. 67%, p-value 0.037). With reference to the prior two weeks, maternal wellbeing level was improved by the added class (score > 13 as measurement of wellbeing: 62% vs. 80%, p-value < 0.05). Moderate perceived stress assessed by PSS was found in those pregnant women without prenatal education on vaccination (64 vs. 50%, p-value 0.042). The introduction of a lesson regarding vaccination during pregnancy in the program of prenatal education courses improved maternal anxiety levels and wellbeing, in addition to reducing perceived stress.
... Recently, the GLaMOR Project has reported an uncertainty range of 294 000 -518 000, which is close to the previous global estimate by the World Health Organization (Paget, et al., 2019). Moreover, the H5N1 and H7N9 subtypes of human pathogenic avian viruses pose a serious threat to public health, highlighting the need for better understanding of influenza A viruses (IAV) and development of new therapies (Iuliano et al., 2018;Li et al., 2018;Paget, et al., 2019). ...
Influenza viruses pose a serious threat to public health, with severe cases often characterized by lung damage and inflammation. However, the underlying mechanisms of these processes remain poorly understood. This study aimed to investigate the essential role of megakaryocytes (MKs) and platelets (PLTs) in influenza A virus (IAV) infections. Conducted at the Department of Rare Respiratory Diseases, Cystic Fibrosis, and Pulmonology, Nord University Hospital, Marseille, France, the study collected seventy blood samples between October 2018 and March 2019. Samples were obtained from healthy individuals and patients diagnosed with IAV. Messenger RNA was extracted from isolated PLTs and subjected to quantitative real-time-polymerase chain reaction using sets of primers targeting immune marker genes. Western blot analysis was also performed for confirmation, focusing on Fas Ligand (FasL). Results showed that PLTs from IAV-infected individuals expressed the FasL, tumor necrosis factor-related apoptosis-inducing ligand, and Granulysin (GNLY) receptors when activated. Furthermore, an in vitro assay revealed the presence of FasL receptors on infected CMK cell lines. In vivo investigations demonstrated that activated MKs and PLTs in mice also expressed FasL. Interestingly, none of the immune receptors under investigation were found in both MKs and PLTs in mouse model studies. In conclusion, MKs and PLTs play a significant role in influencing immune responses that may help prevent viral spread during infection. However, further examination of their mechanisms of action is warranted. Understanding the involvement of these cells in influenza pathogenesis could offer valuable insights for developing potential therapeutic strategies.
... Seasonal influenza is the most frequently encountered viral disease by mankind, but this seemingly innocent disease takes the life of 290,000-650,000 people each year causing respiratory disease alone (World Health Organization, 2015a). According to WHO (World Health Organization), this estimate is excluding the deaths due to influenza-related cardiovascular disease (Iuliano et al., 2018). Different types of influenza virus caused epidemics and pandemics during 2000-2020. ...
The spread of coronavirus disease has globally affected all aspects of lives. Its impact on the environment and climate change in particular cannot be over-emphasized. Within a few months of trying to contain the spread of the disease, carbon dioxide emissions across the world decreased drastically to about one billion tons from the recorded 2019 industry and energy emissions of about 37 billion tons. Therefore, the present study utilized secondary high-frequency (quarterly) panel data generated among 40 sub-Saharan African countries and adopted the impulse response function of the panel vector autoregressive model to examine the response of environmental pollution and climate change to coronavirus pandemic. It was found that one standard innovation in environmental pollution and climate change produces significant positive effects on the pandemic. The implication of this result is that with a cumulative continuous rise in pandemic cases by one person, with a continuous observance of lockdown and other protocols, environmental pollution and unfavorable climate change would go down and/or improve by half in the next period. However, the impact of a shock on the pandemic today on future environmental pollution and unfavorable climate change decays or reverts to zero fast. The study therefore recommends that people and governments in SSA should strive to continue observing pandemic protocols and reduce environmental pollution.KeywordsCOVID-19PollutionClimate changePandemicGreenhousePanel vector autoregressive
... By the end of May 2009, 41 countries had reported 11,000 cases and 85 deaths due to H1H1, prompting the WHO to declare its first Public Health Emergency of International Concern (PHEIC). In 2018, global cases of influenza-associated respiratory mortality were at a higher rate than previously recorded (3)(4)(5). ...
Background: Swine flu (H1N1) and Coronavirus diseases (COVID-19) have been compared in the past few months. Both
pandemics sparked a worldwide major panic. Although both have some common symptoms and diagnoses, they are quite different in
many aspects. The current study aimed to investigate the differences in clinical and viral behaviors between H1N1 Influenza and
COVID-19 pneumonia.
Methods: This was a retrospective study of adult patients hospitalized with H1N1 influenza pneumonia between January 2019 and
February 2020, and patients hospitalized with COVID-19 during the outbreak. A demographic and clinical characteristic of H1N1
influenza and COVID-19 patients were recorded. Both groups were compared—using an independent samples student t test for
continuous variables and a chi-square test for categorical data—to identify significantly different parameters between the 2 diseases.
Results: A total of 78 patients were included and divided into 2 groups: 33 patients (42.3%) with H1N1 and 45 patients (57.7%)
with COVID-19. The mean age of the patients was 43.3 ± 10.6 years. Bronchial asthma was significantly higher among patients with
H1N1, while diabetes mellitus was significantly higher among patients with COVID-19. Right lower lobe affection was significantly
present among those with H1N1 than those with COVID (100% vs 0%). The monocytic count was significantly higher among those
with H1N1 than COVID-19 (11.63 ± 1.50 vs 7.76 ± 1.68; P < 0.001). Respiratory rates of more than 22 c/min significantly increased
in patients with HINI than in those with COVID-19 (18.2% vs 4.4%; P = 0.05). Mortality increased in patients with HINI than in those
with COVID-19 (18.2% vs 6.7%). However, the difference did not reach statistical significance (P = 0.15).
Conclusion: Clinically, it is difficult to distinguish between H1N1 and COVID-19. Thus, a polymerase chain reaction is
recommended for all patients suffering from influenza-like symptoms to rule out influenza A subtype H1N1 and/or SARS-CoV2
... Influenza infections have been a leading cause of death worldwide, with an estimated annual mortality rate of approximately half a million people [5,11]. Furthermore, the economic burden associated with influenza is substantial, estimated at $87.1 billion in 2007 [9]. ...
Background
The emergence of COVID-19 and the implementation of preventive measures and behavioral changes have led to a significant decrease in the prevalence of other respiratory viruses. However, the manner in which seasonal viruses will reemerge in the absence of COVID-19-related restrictions remains unknown.
Methods
Patients presenting with influenza-like illness in two hospitals in Beijing were subjected to testing for COVID-19, influenza A, and influenza B to determine the causative agent for viral infections. The prevalence of influenza B across China was confirmed using data from the Centers for Disease Control, China (China CDC). Clinical characteristics, laboratory findings, imaging results, and mortality data were collected for a cohort of 70 hospitalized patients with confirmed influenza B from 9 hospitals across China.
Results
Starting from October 2021, a substantial increase in the number of patients visiting the designated fever clinics in Beijing was observed, with this trend continuing until January 2022. COVID-19 tests conducted on these patients yielded negative results, while the positivity rate for influenza rose from approximately 8% in October 2021 to over 40% by late January 2022. The cases started to decline after this peak. Data from China CDC confirmed that influenza B is a major pathogen during the season. Sequencing of the viral strain revealed the presence of the Victoria-like lineage of the influenza B strain, with minor variations from the Florida/39/2018 strain. Analysis of the hospitalized patients' characteristics indicated that severe cases were relatively more prevalent among younger individuals, with an average age of 40.9 ± 24.1 years. Among the seven patients who succumbed to influenza, the average age was 30 ± 30.1 years. These patients exhibited secondary infections involving either bacterial or fungal pathogens and displayed elevated levels of cell death markers (such as LDH) and coagulation pathway markers (D-dimer).
Conclusion
Influenza B represents a significant infection threat and can lead to substantial morbidity and mortality, particularly among young patients. To mitigate morbidity and mortality rates, it is imperative to implement appropriate vaccination and other preventive strategies.
... Influenza infection in pregnancy has been associated with increased maternal morbidity and possible adverse neonatal outcomes. Also, during the first months of life, maternal antibodies offer some protection to the newborn [46]. Thus, inactivated influenza vaccination during pregnancy can be a way to increase protection against influenza in the newborn, as recommended by WHO [36]. ...
Childbirth education classes represent an antenatal tool for supporting pregnant women and couples in increasing knowledge on pregnancy, delivery, breastfeeding, and newborn care. The aim of this study was to investigate the impact of the additional lesson to the prenatal course regarding the advantage of the vaccination on mitigation of maternal anxiety. An observational study was designed including participants in childbirth education classes, comparing courses enhanced by the extra lesson on vaccination during pregnancy versus those lacking it. Assessment of the impact of prenatal educational on vaccine was measured by using validated questionnaires (State-Trait Anxiety Inventory, STAI; Perceived Stress Scale, PSS; World Health Organization- Five Well-Being Index, WHO-5). A total of 145 pregnant women participated to the investigation by answering to the online survey. Of them, 33 patients (22.8%) belong to the course without lesson on vaccine, while 112 (77.2%) participated to online prenatal education inclusive of additional meeting on usefulness to get vaccinated during pregnancy. No statistical differences were found between study groups in demographics and perinatal outcomes. Participants to enriched course reported lower basal anxiety levels than those without lesson on vaccine (STAI-State, normal score <40, 30 vs. 19%, p-value 0.041; STAI-State, mild score 40-50, 78 vs 67%, p-value 0.037). With reference to the last two weeks, maternal wellbeing level was improved by the added class (score >13 as measurement of wellbeing: 62% vs 80%, p-value<0.05). Moderate perceived stress assessed by PSS was found in those pregnant women without prenatal education on vaccine (64 vs 50%, p-value 0.042). The introduction of a lesson regarding on vaccination during pregnancy in the program of prenatal education courses improves maternal anxiety levels and wellbeing, in addition to reducing perceived stress.
... Although vaccination programs and antiviral drug treatments are widely applied, influenza virus infections still cause significant morbidity and mortality worldwide [1,2]. A previous study estimated that more than 290,000 seasonal influenza-associated respiratory deaths occur annually; people older than 75 and younger than 5 years are susceptible to influenza [3]. The innate immune system is the first line of immune defense against viral infection. ...
Microbiota-derived desaminotyrosine (DAT) protects the host from influenza by modulating the type I interferon (IFN) response. The aim of this study was to investigate the antivirus effects of a DAT-producing bacteria strain. A comparative genomics analysis and UHPLC Q-Exactive MS were used to search for potential strains and confirm their ability to produce DAT, respectively. The anti-influenza functions of the DAT producer were evaluated using an antibiotic-treated mouse model by orally administering the specific strain before viral infection. The results showed the Lactiplantibacillus pentosus CCFM1227 contained the phy gene and produced DAT by degrading phloretin. In vivo, L. pentosus CCFM1227 re-inoculation increased the DAT level in feces, and protected from influenza through inhibiting viral replication and alleviating lung immunopathology. Furthermore, CCFM1227-derived DAT was positively correlated with the IFN-β level in the lung. The transcriptome results showed that CCFM1227 activated gene expression in the context of the defense response to the virus, and the response to interferon-beta. Moreover, CCFM1227 treatment upregulated the expression of MHC-I family genes, which regulate the adaptive immune response. In conclusion, L. pentosus CCFM1227 exerted antiviral effects by producing DAT in the gut, and this may provide a potential solution for creating effective antiviral probiotics.
... In recent years, extensive research has been conducted to understand the role of platelets in the pathogenesis of sepsis, revealing them as essential bridges connecting the hemostatic/coagulation system with the immune system [64,65]. Platelets exhibit complex interactions with bacteria during infection, constituting an important part of the immune response and thrombus formation [66]. Studies have shown that platelets are among the first cells to be activated during sepsis [47]. ...
Sepsis is a major global health problem that results from a dysregulated and uncontrolled host response to infection, causing organ failure. Despite effective anti-infective therapy and supportive treatments, the mortality rate of sepsis remains high. Approximately 30-80% of patients with sepsis may develop disseminated intravascular coagulation (DIC), which can double the mortality rate. There is currently no definitive treatment approach for sepsis, with etiologic treatment being the cornerstone of therapy for sepsis-associated DIC. Early detection, diagnosis, and treatment are critical factors that impact the prognosis of sepsis-related DIC. Over the past several decades, researchers have made continuous efforts to better understand the mechanisms of DIC in sepsis, as well as improve its quantitative diagnosis and treatment. This article aims to provide a comprehensive overview of the current understanding of sepsis-related DIC, focusing on common causes and diagnoses, with the goal of guiding healthcare providers in the care of patients with sepsis.
... Seasonal influenza is associated with significant morbidity and mortality [1], particularly in immunocompromised patients [2]. Solid-organ transplant (SOT) recipients with influenza have higher rates of hospital admission, need for mechanical ventilation, and mortality compared with the general population [3][4][5]. ...
Background
The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so that new vaccination strategies are needed in this population.
Methods
Adult SOT recipients from nine transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. High, with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least one vaccine strain at 28 days post-vaccination. Secondary outcomes included PCR-confirmed influenza and vaccine reactogenicity.
Results
619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n=198; MF59-adjuvanted, n=205; high-dose, n=195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs. standard vaccine, 0.20 [97.5% CI 0.12-1]; p<0.001; difference in high-dose vs. standard vaccine, 0.24 [95% CI 0.16-1]; p<0.001; difference in MF59-adjuvanted vs. standard vaccine, 0.17 [97.5% CI 0.08-1]; p<0.001). Influenza occurred in 6% the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild.
Conclusions
In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate.
Trial registration
Clinicaltrials.gov NCT03699839
... In recent decades, influenza A viruses of the H1N1 and H3N2 subtypes, together with viruses representing the two lineages of influenza B viruses, have circulated in humans, although one of the influenza B virus lineages has not been detected since the start of the COVID-19 pandemic [1]. Annually, about 3 to 5 million cases of severe influenza virus infections and an estimated 290,000 to 650,000 deaths worldwide are attributed to influenza virus infections [2,3]. Moreover, influenza also imposes a considerable economic burden on society. ...
Vaccination is an efficient approach to preventing influenza virus infections. Recently, we developed influenza A and B virus vaccine backbones that increased the yield of several vaccine viruses in Madin–Darby canine kidney (MDCK) and African green monkey kidney (Vero) cells. These vaccine backbones also increased viral replication in embryonated chicken eggs, which are the most frequently used platform for influenza vaccine manufacturing. In this study, to further increase the viral titers in embryonated chicken eggs, we introduced random mutations into the ‘internal genes’ (i.e., all influenza viral genes except those encoding the hemagglutinin and neuraminidase proteins) of the influenza A virus high-yield virus backbone we developed previously. The randomly mutated viruses were sequentially passaged in embryonated chicken eggs to select variants with increased replicative ability. We identified a candidate that conferred higher influenza virus growth than the high-yield parental virus backbone. Although the observed increases in virus growth may be considered small, they are highly relevant for vaccine manufacturers.
... Influenza is a serious threat to human health, especially to those in risk groups, including the immunocompromised, elderly, and very young adults [4]. The WHO estimates that influenza-related respiratory illnesses alone cause 3-5 million cases of severe sickness and 290,000-650,000 fatalities worldwide each year [5]. Pakistan has a high burden of infectious diseases due to its favorable climate and population density (the population of Pakistan is 225 million) [6]. ...
Background
Influenza and tuberculosis both cause significant morbidity and mortality worldwide. Therefore, this study aimed to estimate the burden of influenza A (H1N1)pdm09 virus infection among human tuberculosis patients and the general population.
Methods
A prospective cohort study was conducted among a cohort group (TB positive patients) as exposed and a comparison group (general population) as non-exposed. A total of 304 participants were recruited in both groups and followed for a period of 12 weeks. Of the 304 concurrently enrolled individuals, 152 were TB-positive patients (cohort group) and 152 were from the general population (comparison group).To calculate the sample size, the power of study was kept at 80% for detecting a difference at 5% alpha level assuming the 25% prevalence of respiratory viruses in cohort group compared to 12.5% in general population. An oropharyngeal swab was taken from a participant with symptoms of influenza-like illness (ILI). Samples were tested by conventional reverse transcription polymerase chain reaction (RT-PCR) for the detection of influenza A (H1N1)pdm09. All statistical analyses were conducted using R software.
Results
A total of 95 participants developed influenza-like illness (ILI) symptoms. Among these, 64 tested positive for influenza A(H1N1)pdm09, of which 39 were from the exposed group and 25 were from the non-exposed group. During the 12-week period of follow-up, the influenza A (H1N1)pdm09 incidence rate was 20 per 1000 people. The risk of testing positive for influenza A (H1N1)pdm09 was 1.66 times higher in the exposed group compared to the non-exposed group. The cumulative incidence indicated that 25% of the TB cohort and 16% of the comparison group were at risk of getting influenza A (H1N1)pdm09 during the 12 weeks of follow-up.
Conclusion
Participants from the TB cohort had a higher incidence of influenza A (H1N1)pdm09 than the general population suggesting that they should be prioritized for influenza vaccination.
... Thus, old patients are at greater risk of developing septic shock and mortality is higher than in the younger population [30]. Viral infections such as influenza or Varicella Zoster Virus (VZV) are also more frequent and more severe [31,32]. Vaccine efficacy is reduced in the old patients, in particular because of the lack of priming of T-cells and the reduced capacity of plasma cells to produce antibodies [33,34]. ...
In this narrative review, we describe the most important age-related “syndromes” found in the old ICU patients. The syndromes are frailty, comorbidity, cognitive decline, malnutrition, sarcopenia, loss of functional autonomy, immunosenescence and inflam-ageing. The underlying geriatric condition, together with the admission diagnosis and the acute severity contribute to the short-term, but also to the long-term prognosis. Besides mortality, functional status and quality of life are major outcome variables. The geriatric assessment is a key tool for long-term qualitative outcome, while immediate severity accounts for acute mortality. A poor functional baseline reduces the chances of a successful outcome following ICU. This review emphasises the importance of using a geriatric assessment and considering the older patient as a whole, rather than the acute illness in isolation, when making decisions regarding intensive care treatment.
... Due to age-related decline in immune function and increased comorbidities [2], adults 65 years of age and older are at increased risk of influenza infection and associated complications, and show a poorer response to vaccination compared with younger adults [2,3]. A recent modelling study demonstrated that influenza disproportionately burdens older adults, with nearly five times the risk of death in those ≥75 years of age compared with those 65-74 years of age [4]. In addition, older individuals have higher rates of influenza-attributable emergency department visits, as well as intensive care unit attendance [5,6]. ...
Background:
Standard dose influenza vaccine provides moderate protection from infection, but with lower effectiveness among the elderly. High dose and adjuvanted vaccines (HD-TIV and aTIV) were developed to address this. This study aims to estimate the incremental health and economic impact of using HD-TIV (high dose trivalent vaccine) instead of aTIV (adjuvanted trivalent vaccine) on respiratory and circulatory plus respiratory hospitalizations of older people (≥65 years) in Australia.
Methods:
This is a modelling study comparing predicted hospitalization outcomes in people receiving HD-TIV or aTIV during an average influenza season in Australia. Hospitalization records of Australian adults ≥65 years of age from 01 April to 30 November during 15 influenza seasons (2002-2017 excluding 2009, which was a pandemic) were extracted from the Australian Institute of Health and Welfare [AIHW] and used to calculate hospitalisation rates during an average season. Relative vaccine effectiveness data for aTIV and HD-TIV were used to estimate morbidity burden related to influenza.
Results:
Between 2002 and 2017, the average respiratory hospitalization rate among older people during influenza season (April-November) was 3,445/100,000 population-seasons, with an average cost of AU$ 7,175 per admission. The average circulatory plus respiratory hospitalization rate among older Australian people during that time was 10,393/100,000 population-seasons, with an average cost of AU$ 7829 per admission. For older Australians, HD-TIV may avert an additional 6,315-9,410 respiratory admissions each year, with an incremental healthcare cost saving of AU$ 15.9-38.2 million per year compared to aTIV. Similar results were also noted for circulatory plus respiratory hospitalizations.
Conclusions:
From the modelled estimations, HD-TIV was associated with less economic burden and fewer respiratory, and circulatory plus respiratory hospitalizations than aTIV for older Australians.
... Influenza (flu) is an acute respiratory infectious disease due to the influenza virus, which often causes a series of local outbreaks and seasonal epidemics, then resulting in socioeconomic burden [1]. Influenza-like illness (ILI), including influenza infection, is an important public health concern, but the timing and peak intensity vary considerably from season to season and regionally [2]. ...
Abstract Background Since the Non-pharmaceutical Intervention (NPI) by COVID-19 emerged, influenza activity has been somewhat altered. Objectives The aim of this study was to explore changes in influenza activities in the context of COVID-19 based on the sentinel hospitals/units in Guangdong, southern China. Methods The surveillance data in influenza-like illness (ILI) were collected from 21 cities in Guangdong between September 2017 and August 2021, while 43 hospitals/units were selected to analyze the predominant types of influenza, population characteristics, and seasonal features by three methods (the concentration ratio, the seasonal index, and the circulation distribution), based on a descriptive epidemiological approach. Results During the four consecutive influenza seasons, a total of 157345 ILIs were tested, of which 9.05% were positive for influenza virus (n = 14238), with the highest positive rates for both IAV (13.20%) and IBV (5.41%) in the 2018–2019 season. After the emergence of COVID-19, influenza cases decreased near to zero from March 2020 till March 2021, and the dominant type of influenza virus changed from IAV to IBV. The highest positive rate of influenza existed in the age-group of 5
... Influenza is a viral infectious disease that causes around 3-5 million hospitalizations per year and 650,000 deaths worldwide. 1 However, these values are underestimated because influenza plays an essential role in the development and evolution of other pathologies, such as cardiovascular diseases, on which it has a direct and indirect impact. 2 The best way to prevent influenza is vaccination. There are different approaches to influenza vaccination. ...
The aim of this work is to describe the dynamics of influenza antibodies after vaccination in adults. We conducted a case-cohort serological study in the automobile manufacturing plants of the Renault España S.A. group in Valladolid and Palencia (Spain), including 550 workers (66.9%) previously vaccinated against influenza (group V), and 272 (33.1%) never vaccinated (group NV). A pre-vaccination serum sample was collected, another after 30-40 days and another after 6 months. The dynamics of antibodies were analyzed. A lower seroprotection of NV before vaccination was observed, but an antibody response between 2 and 4 times higher than in V was assessed. After 6 months, antibodies declined in both groups until equalize. Antibodies titers decrease with age, and no differences were found among underlying pathologies. Adults never vaccinated against influenza had lower seroprotection than those previously vaccinated, but influenza vaccination produces a more intense serological response in them, acquiring significantly higher antibody titers than those previously vaccinated. The antibodies, although in lower titers, persist and equalize among both groups at least 6 months after vaccination, which allows the individual to be protected during the entire circulation of the influenza virus in the same season.
... The mortality rate of influenza infection is significantly higher in people with lung disease. Influenza-triggered epidemics cause 3-5 million cases of severe illness each year and up to 650,000 deaths annually worldwide [3]. Seasonal influenza A virus is the most common cause of infection in humans [4], causing an overall incidence of acute respiratory distress syndrome of approximately 2.7 cases per 100,000 people per year [5], accounting for approximately 4% of all hospitalizations for respiratory failure. ...
Background:
Influenza is an important respiratory tract pathogen that causes substantial seasonal and pandemic morbidity and mortality. The aim of this study was to systematically analyze the transcriptome characteristics of peripheral blood mononuclear cells (PBMCs) after influenza A virus infection by constructing a human lung microarray model composed of PBMCs to simulate the influenza A virus infection process.
Methods:
A human lung microarray model was constructed using alveolar epithelial cells, vascular endothelial cells, alveolar macrophages and PBMCs, for simulation of the process of influenza A virus infection. The transcriptome characteristics of PBMCs after influenza A virus infection were analyzed by a single-cell RNA sequencing system.
Results:
The study could realistically mimic the structure and physiological functions of the alveoli in vitro using immunofluorescence staining and expression of the specific marker. After the influenza A virus infected the upper lung chip channels, the epithelial cells underwent a high inflammatory response and spread to endothelial cells. Under experimental conditions, the Influenza A virus infection did not compromise the integrity of epithelial cells, but caused damage to endothelial cells and barrier dysfunction. Single-cell RNA sequencing of PBMCs showed that B and cluster of differentiation 4 (CD4) T cells played important immunomodulatory roles in response to influenza A virus infection, including significantly activating type I interferon signaling pathway, regulating cytokine and chemokine signaling pathway. Especially genes involved in cellular communication were significantly highly expressed post-infection.
Conclusions:
All these results suggested that the interactions among immune cells played a crucial role in endothelial cell injury and immune cell recruitment after influenza virus infection. This lung-on-chip infection model combined with single-cell RNA sequencing provided a unique platform that can closely investigate the lung immune response to influenza A virus infection and new therapeutic strategies for influenza.
... Seasonal influenza causes significant morbidity and mortality each year. The highest burden of severe disease and deaths disproportionally occurs in older adults, particularly those over 75 years of age [1]. Not only does influenza infection cause acute respiratory illness, it can also lead to exacerbation of comorbid chronic conditions, such as cardiovascular diseases in older adults; substantial evidence indicates protective effects of influenza vaccination against both [2][3][4][5]. ...
Abstract Background Seasonal influenza causes significant morbidity and mortality with a disproportionately high disease burden in older adults. Strain-specific hemagglutination-inhibition (HAI) antibody titer is a well-established measure of humoral immunity against influenza and pre-vaccination HAI titer is a valuable indicator of pre-existing humoral immunity at the beginning of each influenza season in highly vaccinated older adults. While vaccine-induced HAI antibody titers are known to wane over time, accurate assessment of their interseason waning has been challenging. This is because pre-vaccination HAI titers are routinely measured using current season vaccine strain antigens instead of the prior season vaccines with which individuals were immunized; as such, they do not accurately represent residual antibody titers from prior season vaccination. This study took advantage of available pre-vaccination HAI titers measured using both current and prior season vaccine strain antigens in a longitudinal influenza immunization study with participants enrolled for multiple consecutive influenza seasons from 2014 through 2017. Influenza A virus (IAV) H3N2 and influenza B virus (IBV) strains in the vaccine formula changed in 2015 and again in 2016 season. IAV H1N1 vaccine strain remained the same from 2014 through 2016 seasons, but changed in 2017. We also investigated factors contributing to pre-existing humoral immunity. Results Interseason waning of HAI titers was evident, but rates of waning varied among vaccine strains and study seasons, from 18% (p = .43) to 61% (p
Background
COVID-19 pandemic mitigation measures, including travel restrictions, limited global circulation of influenza viruses. In Australia, travel bans for non-residents and quarantine requirements for returned travellers were eased in November 2021, providing pathways for influenza viruses to be re-introduced.
Aim
We aimed to describe the epidemiological and virological characteristics of the re-emergence of influenza in Victoria, Australia to inform public health interventions.
Methods
From 1 November 2021 to 30 April 2022, we conducted an epidemiological study analysing case notification data from the Victorian Department of Health to describe case demographics, interviewed the first 200 cases to establish probable routes of virus reintroduction and examined phylogenetic and antigenic data to understand virus diversity and susceptibility to current vaccines.
Results
Overall, 1,598 notifications and 1,064 positive specimens were analysed. The majority of cases (61.4%) occurred in the 15–34 years age group. Interviews revealed a higher incidence of international travel exposure during the first month of case detections, and high levels of transmission in university residential colleges were associated with return to campus. Influenza A(H3N2) was the predominant subtype, with a single lineage predominating despite multiple importations.
Conclusion
Enhanced testing for respiratory viruses during the COVID-19 pandemic provided a more complete picture of influenza virus transmission compared with previous seasons. Returned international travellers were important drivers of influenza reemergence, as were young adults, a group whose role has previously been under-recognised in the establishment of seasonal influenza epidemics. Targeting interventions, including vaccination, to these groups could reduce future influenza transmission.
Respiratory viruses can cause epidemics or pandemics, which are worldwide outbreaks of disease. The severity of these events varies depending on the virus, its characteristics, along with environmental factors. The frequency of epidemics and pandemics caused by respiratory viruses is difficult to predict, but the potential severity of such events underlines the importance of continued monitoring, research, and preparation for emerging infectious diseases. To help improve pandemic preparedness, we created a fully integrated duplex reverse transcription loop-mediated isothermal amplification (RT-LAMP) device targeting two respiratory viruses, influenza A/X-31 virus and bovine coronavirus, as a replacement for SARS-CoV-2. This device can be adapted to any other respiratory virus. In this study, we showed and evaluated a prototype of a microfluidic system, and showed that duplex RT-LAMP can detect and distinguish between the two viruses, with LoDs of 2,000 copies/ml for bovine coronavirus and 200 copies/ml for influenza A/X-31 virus.
Graphical abstract
Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations occur is poorly understood. Our previous screen to identify cellular deubiquitylases (DUBs) activated during influenza virus infection revealed Usp25 as a prominent hit. Here, we show that Usp25-deleted human lung epithelial A549 cells display a >10-fold increase in pathogenic influenza virus production, which was rescued upon reconstitution with the wild type but not the catalytically deficient (C178S) variant. Proteomic analysis of Usp25 interactors revealed a strong association with Erlin1/2, which we confirmed as its substrate. Newly synthesized Erlin1/2 were degraded in Usp25-/- or Usp25C178S cells, activating Srebp2, with increased cholesterol flux and attenuated TLR3-dependent responses. Our study therefore defines the function of a deubiquitylase that serves to restrict a range of viruses by reprogramming lipid biosynthetic flux to install appropriate inflammatory responses.
Exacerbations of COPD are associated with worsening of the airflow obstruction, hospitalisation, reduced quality of life, disease progression and death. At least 70% of COPD exacerbations are infectious in origin, with respiratory viruses identified in approximately 30% of cases. Despite long-standing recommendations to vaccinate patients with COPD, vaccination rates remain suboptimal in this population.
Streptococcus pneumoniae is one of the leading morbidity and mortality causes of lower respiratory tract infections. The Food and Drug Administration recently approved pneumococcal conjugate vaccines that showed strong immunogenicity against all 20 included serotypes. Influenza is the second most common virus linked to severe acute exacerbations of COPD. The variable vaccine efficacy across virus subtypes and the impaired immune response are significant drawbacks in the influenza vaccination strategy. High-dose and adjuvant vaccines are new approaches to tackle these problems. Respiratory syncytial virus is another virus known to cause acute exacerbations of COPD. The vaccine candidate RSVPreF3 is the first authorised for the prevention of RSV in adults ≥60 years and might help to reduce acute exacerbations of COPD. The 2023 Global Initiative for Chronic Lung Disease report recommends zoster vaccination to protect against shingles for people with COPD over 50 years.
Influenza virus is a prominent cause of respiratory illness in humans. Current influenza vaccines offer strain-specific immunity, while provide limited protection against drifted strains. Broad-spectrum influenza vaccines can induce broad and long-term immunity, and thus is regarded as a future direction for the development of next-generation influenza vaccines. In this study, we have conceptualized a novel mRNA-based multi-antigen influenza vaccine consisting of three conserved antigens of influenza A virus, including the ectodomain of the M2 ion channel (M2e), the long alpha helix of haemagglutinin stalk region (LAH), and nucleoprotein (NP). The vaccine design aims to enhance its potency and promote the development of a future broad-spectrum influenza vaccine. Our mRNA-based vaccine demonstrated potent humoral and cellular responses throughout the time points of the murine model, inducing viral neutralizing antibodies, antibody-dependent cell cytotoxicity effect mediating antibodies and cross-reactive CD8+ T cell immune responses. The vaccine conferred broad protection against H1N1, H3N2, and H9N2 viruses. Moreover, the single-cell transcriptional profiling of T cells in the spleens of vaccinated mice revealed that the mRNA-based vaccine significantly promoted CD8+ T cells and memory T cells by prime-boost immunization. Our results suggest that the mRNA-based influenza vaccine encoding conserved proteins is a promising approach for eliciting broadly protective humoral and cellular immunity against various influenza viruses.
In a race to manage the COVID-19 pandemic, innovations in nanomedicine were crucial for vaccine development. This study compares nanotechnology research on coronaviruses (nanocovid) and nanotechnology research on influenza (nanoflu) to understand the unique characteristics and drivers of nanocovid research. The main differences between nanoflu and nanocovid relate to the number of publications. We find that from 2000 to the summer of 2022, there were 3445 nanocovid articles and 1643 nanoflu articles. Moreover, from 2000 to 2018, there was limited nanocovid research, despite prominent coronaviruses such as severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). Nanocovid research gained substantial momentum only during the COVID-19 pandemic. Nanoflu research, on the other hand, had consistent but slow growth since 2000. Nanocovid and nanoflu researches are similar in many aspects. The most active countries and institutions researching nanocovid and nanoflu are similar, the research is published in similar journals, and both fields use similar keywords. Despite the severity of influenza on global health and well-being, it receives little attention from nanotechnology researchers. Coronavirus research only got significant attention after the COVID-19 pandemic. These findings show that factors other than disease severity drive research portfolios.
Background
High morbidity and mortality of influenza virus infection have made it become one of the most lethal diseases threatening public health; the lack of drugs with strong antiviral activity against virus strains exacerbates the problem.
Methods
Two independent researchers searched relevant studies using Embase, PubMed, Web of Science, Google Scholar, and MEDLINE databases from its inception to December 2022.
Results
Based on the different antiviral mechanisms, current antiviral strategies can be mainly classified into virus‐targeting approaches such as neuraminidase inhibitors, matrix protein 2 ion channel inhibitors, polymerase acidic protein inhibitors and other host‐targeting antivirals. However, highly viral gene mutation has underscored the necessity of novel antiviral drug development. Arbidol (ARB) is a Russian‐made indole‐derivative small molecule licensed in Russia and China for the prevention and treatment of influenza and other respiratory viral infections. ARB also has inhibitory effects on many other viruses such as severe acute respiratory syndrome coronavirus 2, Coxsackie virus, respiratory syncytial virus, Hantaan virus, herpes simplex virus, and hepatitis B and C viruses. ARB is a promising drug which can not only exert activity against virus at different steps of virus replication cycle, but also directly target on hosts before infection to prevent virus invasion.
Conclusion
ARB is a broad‐spectrum antiviral drug that inhibits several viruses in vivo and in vitro, with high safety profile and low resistance; the antiviral mechanisms of ARB deserve to be further explored and more high‐quality clinical studies are required to establish the efficacy and safety of ARB.
Infectious viral diseases are emerging worldwide and become a major threat to human life and economy. The emergence of viral pandemics is thought to be driven mostly by environmental changes; however, systemic study is lacking in this field. The aim of this study is to investigate thoroughly the impact of climate change, pollution and deforestation on viral pandemic events and host–virus interactions for the period of 2000–2020 using statistical tools. During the study period several pandemic viral diseases occur globally, the most devastating of which is the infection of SARS-CoV-2 or Covid-19. Besides, Ebola haemorrhagic fever, Rift Valley fever, West Nile fever, yellow fever and Zika viral disease cause death of thousands of people every year all over the world. Influenza outbreaks are also increasing and many animal influenza viruses cross the zoonotic barrier in recent times and becoming fatal for human being, such as highly pathogenic avian influenza A(H7N9), A(H5N1) and A(H5N6). Increasing deforestation causes more contact of wild animals with human and may help in disease transmission. The number of viral-affected individuals during the study period is positively correlated with global average temperature, nitric oxide emission and carbon dioxide emission, whereas negatively correlated with the percentage of forest area. Modern medicine cures many of the viral diseases, but newer viruses intrude into the human domain due to altered human activities. So, restoration of global climate should be the foremost goal of mankind for saving own lives.KeywordsVirusEpidemicPandemicClimate changeDeforestationPollution
The numerous influenza infections that occur every year present a major public health problem. Influenza vaccines are important for the prevention of the disease; however, their effectiveness against infection can be suboptimal. Particularly in the elderly, immune induction can be insufficient, and the vaccine efficacy against infection is usually lower than that in young adults. Vaccine efficacy can be improved by the addition of adjuvants, and an influenza vaccine with an oil-in-water adjuvant MF59, FLUAD, has been recently licensed in the United States and other countries for persons aged 65 years and older. Although the adverse effects of adjuvanted vaccines have been a concern, many adverse effects of currently approved adjuvanted influenza vaccines are mild and acceptable, given the overriding benefits of the vaccine. Since sufficient immunity can be induced with a small amount of vaccine antigen in the presence of an adjuvant, adjuvanted vaccines promote dose sparing and the prompt preparation of vaccines for pandemic influenza. Adjuvants not only enhance the immune response to antigens but can also be effective against antigenically different viruses. In this narrative review, we provide an overview of influenza vaccines, both past and present, before presenting a discussion of adjuvanted influenza vaccines and their future.
The World Health Organization noted that COVID-19 vaccination programmes could be leveraged to deliver influenza vaccination. In 2008, the International Federation of Pharmaceutical Manufacturers and Associations' (IFPMA) Influenza Vaccine Supply International Task Force (IVS) developed a survey method using the number of influenza vaccine doses distributed globally to estimate vaccination coverage rates. Seven hundred and ninety-seven million doses were distributed in 2021, representing a 205% increase over the 262 million doses distributed in 2004, exceeding the number of doses distributed during and after the 2009-2010 influenza pandemic. The most obvious explanation for the global increase is the enabling of critical elements of the vaccine ecosystem by decision-makers during the COVID-19 pandemic to reinforce implementation of influenza vaccination programs. Most of the improvements in performance of influenza programs during the COVID-19 pandemic can be classified in four categories: 1) promoting vaccination using tailored approaches for specific populations; 2) improving convenient access to influenza vaccines in COVID-safe settings; 3) improving reimbursement of seasonal influenza vaccination for priority groups; 4) maintaining the timing of vaccination to the autumn. In spite of the increase in rates of seasonal influenza vaccines distributed during the COVID-19 pandemic, globally, the rate of influenza dose distribution is sub-optimal, and a considerable proportion of the influenza infections remains preventable. To sustain the benefits from increased uptake of influenza vaccines, governments need to sustain the efforts made during the COVID-19 pandemic, and a number of global policy endeavours should be undertaken, including developing a clear global roadmap for achieving influenza control objectives, adopted by a WHA resolution, in line with the strategic objective 3 of the Global Influenza Strategy 2030, embedded in the Immunization Agenda 2030 (IA2030).
Evidence suggests that innate and adaptive cellular responses mediate resistance to the influenza virus and confer protection after vaccination. However, few studies have resolved the contribution of cellular responses within the context of preexisting antibody titers. Here, we measured the peripheral immune profiles of 206 vaccinated or unvaccinated adults to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza. Protection correlated with diverse and polyfunctional CD4⁺ and CD8⁺ T, circulating T follicular helper, T helper type 17, myeloid dendritic and CD16⁺ natural killer (NK) cell subsets. Conversely, increased susceptibility was predominantly attributed to nonspecific inflammatory populations, including γδ T cells and activated CD16⁻ NK cells, as well as TNFα⁺ single-cytokine-producing CD8⁺ T cells. Multivariate and predictive modeling indicated that cellular subsets (1) work synergistically with humoral immunity to confer protection, (2) improve model performance over demographic and serologic factors alone and (3) comprise the most important predictive covariates. Together, these results demonstrate that preinfection peripheral cell composition improves the prediction of symptomatic influenza susceptibility over vaccination, demographics or serology alone.
Both cancer patients and the elderly are at high risk of developing flu complications, so influenza vaccination is recommended. We aimed to evaluate potential adverse events (AEs) following influenza vaccination in elderly cancer patients using the self-controlled tree-temporal scan statistic method. From a large linked database of Korea Disease Control and Prevention Agency vaccination data and the National Health Insurance Service claims data, we identified cancer patients aged over 65 who received flu vaccines during the 2016/2017 and 2017/2018 seasons. We included all the outcomes occurring on 1–84 days post-vaccination and evaluated all temporal risk windows, which started 1–28 days and ended 2–42 days. Patients who were diagnosed with the same disease during a year prior to vaccination were excluded. We used the hierarchy of ICD-10 to identify statistically significant clustering. This study included 431,276 doses of flu vaccine. We detected signals for 1 set: other dorsopathies on 1–15 days (attributable risk 16.5 per 100,000, P = 0.017). Dorsopathy is a known AE of influenza vaccine. No statistically significant clusters were found when analyzed by flu season. Therefore, influenza vaccination is more recommended for elderly patients with cancer and weakened immune systems.
Constructed wetlands (CWs) were responsible for the in-depth purification of wastewater, providing an ideal environment for the transport, acquisition, and dissemination of antibiotic resistance genes (ARGs). A better understanding of influencing factors and risks of ARGs in CWs was deemed indispensable. In this research, the abundance of ARGs and mobile genetic elements (MGEs) was determined to be higher in summer and spring, ranging from 53.7 to 8.51 × 106 and 30.9-6.02 × 106 copies/mL, respectively. Seasonal variation significantly influenced the abundance of ARGs and MGEs, as well as the co-occurrence patterns among ARGs, MGEs and bacteria. However, the environmental gradients, from the influent (CW01) to the effluent (CW10), did not impose significant effects on the abundance of ARGs and MGEs. Furthermore, the ratios of pathogenic bacteria to ARG hosts and ARG risks index decreased by 50.4% and 88.54% along with the environmental gradients, indicating that CWs could act as barriers to the transfer of ARGs. Partial least squares-path modeling (PLSPM) revealed that temperature was the main driving factor of ARGs, followed by MGEs, stable and differential bacteria. This finding effectively and innovatively explored the driving indicators for the variations and risks of ARGs caused by spatial-temporal variations, providing new insights into the evaluation and control of ARGs in CWs.
H7 avian influenza virus has caused multiple human infections and poses a severe public health threat. In response to the highly variable nature of AIVs, a novel, easily regenerated DNA vaccine has great potential in treating or preventing avian influenza pandemics. Nevertheless, DNA vaccines have many disadvantages, such as weak immunogenicity and poor in vivo delivery. To further characterize and solve these issues and develop a novel H7 AIV DNA vaccine with enhanced stability and immunogenicity, we constructed nine AIV DNA plasmids, and the immunogenicity screened showed that mice immunized with pβH7N2SH9 elicited stronger hemagglutination-inhibiting (HI) antibodies than other eight plasmid DNAs. Then, to address the susceptibility to degradation and low transfection rate of DNA vaccine in vivo, we developed pβH7N2SH9/DGL NPs by encapsulating the pβH7N2SH9 within the dendrigraft poly-l-lysines nanoparticles. As expected, these NPs exhibited excellent physical and chemical properties, were capable of promote lymphocyte proliferation, and induce stronger humoral and cellular responses than the naked pβH7N2SH9, including higher levels of HI antibodies than naked pβH7N2SH9, as well as the production of cytokines, namely, IL-2, IFN-α. Taken together, our results suggest that the construction of an immune-enhanced H7-AIV DNA nanovaccine may be a promising strategy against most influenza viruses.
Neuraminidase inhibitors (NAIs) are recommended for influenza treatment and prevention worldwide. The most widely prescribed NAI is oral oseltamivir, while inhaled zanamivir is less commonly used. Using phenotypic neuraminidase (NA) enzymatic assays and molecular modeling approaches, we examined the ability of the investigational orally-dosed NAI AV5080 to inhibit viruses of the influenza A (H1N1)pdm09, A (H3N2), A (H5N1), and A (H7N9) subtypes and the influenza B/Victoria- and B/Yamagata-lineages containing NA substitutions conferring oseltamivir or zanamivir resistance including: NA-R292K, NA-E119 G/V, NA-H274Y, NA-I122 L/N, and NA-R150K. Broadly, AV5080 showed enhanced in vitro efficacy when compared with oseltamivir and/or zanamivir. Reduced AV5080 inhibition was determined for influenza A viruses with NA-E119G and NA-R292K, and for B/Victoria-lineage viruses with NA-I122 N/L and B/Yamagata-lineage virus with NA-R150K. Molecular modeling suggested loss of the short hydrogen bond to the carboxyl group of AV5080 affected inhibition of NA-R292K viruses, whereas loss of the salt bridge with the guanidine group of AV5080 affected inhibition of NA-E119G. The resistance profiles and predicted binding modes of AV5080 and zanamivir are most similar, but dissimilar to those of oseltamivir, in part because of a guanidine moiety compensatory binding effect. Overall, our data suggests that AV5080 is a promising oral-dosed NAI that exhibited similar or superior in vitro efficacy against viruses with reduced or highly reduced inhibition phenotypes with respect to currently approved NAIs.
In October/December 2021, World Health Organization and other international agencies recommended the offer of the third dose of anti-SARS-CoV-2 vaccine. In this period, the routine offer of seasonal influenza vaccination was also guaranteed and simultaneous administration of the two vaccines was encouraged. This study aims to evaluate the safety profile and to estimate the incidence of SARS-CoV-2 breakthrough infections in subjects receiving the anti-SARS-CoV-2 and influenza vaccines simultaneously. The study population was represented by healthcare workers (HCWs) of Bari Policlinico General Hospital who received the influenza (Flucelvax Tetra®) and/or anti-SARS-CoV-2 vaccination (BNT162b2 mRNA COVID-19 vaccine, Comirnaty®) either in coadministration or separately in October 2021. Reports of adverse events following immunization (AEFIs) were investigated to study the safety of both vaccines in coadministration and in separate-instance administration. Post-vaccination SARS-CoV-2 breakthrough infection was also studied. 942 HCWs accepted to join our study. 610/942 received both vaccines simultaneously. 25.26 % subjects (238/942) were only vaccinated against SARS-CoV-2, while the remaining 94 HCWs received the influenza vaccination first and subsequently received the anti-SARS-CoV2 booster dose. 717 HCWs reported AEFIs (Reporting Rate 76.1 per 100 subjects). Simultaneous administration of the two vaccines was not related with an increase of the rate of AEFIs compared to the single administration of SARS-CoV-2 vaccine, but the AEFIs' rate was lower among subjects who received only influenza vaccine. Post-vaccination SARS-CoV-2 infections were notified for 41.5 % of enrolled subjects (391/942). Incidence of breakthrough infection and symptomatic disease was not significantly different between the simultaneous administration group and other subjects. Our data suggests that simultaneous administration of a quadrivalent influenza vaccine and an mRNA anti-SARS-CoV-2 vaccine neither affected the safety of said products nor was associated with a higher risk of SARS-CoV-2 breakthrough infection.
Post-viral aspergillosis (PVA) is a clinical form of Aspergillus infection that occurs after some viral infections. Aspergillus is the most common respiratory fungal co-pathogen in patients with viral infections. Most cases of PVA have been reported as invasive pulmonary aspergillosis (IPA) after influenza, COVID-19, and the cytomegalovirus infection. PVA is more commonly reported in critically ill patients with viral pneumonia. Suggested risk factors for PVA include cellular immune deficiency, ARDS, pulmonary tracts and parenchyma damage, and corticosteroid therapy. New pulmonary nodules such as dense, well-circumscribed lesions with or without a halo sign, air crescent sign, or cavity, or wedge-shaped and segmental or lobar consolidation on the chest CT scan can suggest PVA. As in the treatment of invasive aspergillosis in other settings, triazoles, such as voriconazole or isavuconazole, have been suggested as the first-line treatment for PVA. It seems that the presence of PVA has significantly decreased the survival rate in patients with viral infections.
The aim of this study is to investigate the effectiveness of prolonged versus standard course oseltamivir treatment among critically ill patients with severe influenza. A retrospective study of a prospectively collected database including adults with influenza infection admitted to 184 intensive care units (ICUs) in Spain from 2009 to 2018. Prolonged oseltamivir was defined if patients received the treatment beyond 5 days, whereas the standard-course group received oseltamivir for 5 days. The primary outcome was all-cause ICU mortality. Propensity score matching (PSM) was constructed, and the outcome was investigated through Cox regression and RCSs. Two thousand three hundred and ninety-seven subjects were included, of whom 1943 (81.1%) received prolonged oseltamivir and 454 (18.9%) received standard treatment. An optimal full matching algorithm was performed by matching 2171 patients, 1750 treated in the prolonged oseltamivir group and 421 controls in the standard oseltamivir group. After PSM, 387 (22.1%) patients in the prolonged oseltamivir and 119 (28.3%) patients in the standard group died (p = 0.009). After adjusting confounding factors, prolonged oseltamivir significantly reduced ICU mortality (odds ratio [OR]: 0.53, 95% confidence interval [CI]: 0.40-0.69). Prolonged oseltamivir may have protective effects on survival at Day 10 compared with a standard treatment course. Sensitivity analysis confirmed these findings. Compared with standard treatment, prolonged oseltamivir was associated with reduced ICU mortality in critically ill patients with severe influenza. Clinicians should consider extending the oseltamivir treatment duration to 10 days, particularly in higher-risk groups of prolonged viral shedding. Further randomized controlled trials are warranted to confirm these findings.
Seasonal influenza viruses cause recurring global epidemics by continually evolving to escape host immunity. The viral constraints and host immune responses that limit and drive the evolution of these viruses are increasingly well understood. However, it remains unclear how most of these advances improve the capacity to reduce the impact of seasonal influenza viruses on human health. In this Review, we synthesize recent progress made in understanding the interplay between the evolution of immunity induced by previous infections or vaccination and the evolution of seasonal influenza viruses driven by the heterogeneous accumulation of antibody-mediated immunity in humans. We discuss the functional constraints that limit the evolution of the viruses, the within-host evolutionary processes that drive the emergence of new virus variants, as well as current and prospective options for influenza virus control, including the viral and immunological barriers that must be overcome to improve the effectiveness of vaccines and antiviral drugs.
Background:
The epidemiology of respiratory viral infections is complex. How infection with one respiratory virus affects risk of subsequent infection with the same or another respiratory virus is not well described.
Methods:
We retrospectively analyzed data from a longitudinal household cohort study from October 2019-June 2021. Enrolled households completed active surveillance for acute respiratory illness (ARI), and participants with ARI self-collected nasal swabs; after April 2020, participants with ARI or laboratory-confirmed SARS-CoV-2 and their household members self-collected nasal swabs. Specimens were tested via multiplex RT-PCR for respiratory viruses. A Cox regression model with a time-dependent covariate examined risk of subsequent detections following a specific primary viral detection.
Results:
Rhinovirus was the most frequently detected pathogen in study specimens (n=406, 9.5%). Among 51 participants with multiple viral detections, rhinovirus to seasonal coronavirus (8, 14.8%) was the most common viral detection pairing. Relative to no primary detection, there was a 1.03-2.06-fold increase in risk of subsequent virus detection in the 90 days following primary detection; risk varied by primary virus: parainfluenza, rhinovirus, and respiratory syncytial virus were statistically significant.
Conclusions:
Primary virus detection was associated with higher risk of subsequent virus detection within the first 90 days after primary detection.
Background:
Estimates of influenza- and respiratory syncytial virus (RSV)-associated mortality burden are important to guide policy for control. Data are limited on the contribution of out-of-hospital deaths to this mortality.
Methods:
We modeled excess mortality attributable to influenza and RSV infection by applying regression models to weekly deaths from national vital statistics from 2009 through 2013, using influenza and RSV laboratory surveillance data as covariates. We fitted separate models for in- and out-of-hospital deaths.
Results:
There were 509791 average annual deaths in South Africa, of which 44% (95% confidence interval [CI] 43%-45%) occurred out-of-hospital. Seasonal influenza and RSV all-cause mortality rates were 23.0 (95% CI 11.0-30.6) and 13.2 (95% CI 6.4-33.8) per 100000 population annually (2.3% [95%CI 2.3%-2.4%] and 1.3% [95% CI 1.2%-1.4%] of all deaths respectively). The peak mortality rate was in individuals aged ≥75 years (386.0; 95% CI 176.5-466.3) for influenza and in infants (143.4; 95% CI 0-194.8) for RSV. Overall, 63% (95% CI 62%--65%) of seasonal influenza and 48% (95% CI 47%-49%) of RSV-associated deaths occurred out-of-hospital. Among children aged <5 years, RSV-associated deaths were more likely to occur in-hospital, whereas influenza-associated deaths were more likely to occur out-of-hospital. The mortality rate was 6.7 (95% CI 6.4-33.8) in the first influenza A(H1N1)pdm09 wave in 2009 and 20.9 (95% CI 6.4-33.8) in the second wave in 2011, with 30% (95% CI 29%-32%) of A(H1N1)pdm09-associated deaths in 2009 occurring out-of-hospital.
Discussion:
More than 45% of seasonal influenza- and RSV-associated deaths occur out-of-hospital in South Africa. These data suggest that hospital-based studies may substantially underestimate mortality burden.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 findingsWe 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
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.
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.
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.
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.
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.AimTo 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
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.
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.
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.
: 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.
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.
Cited By (since 1996): 1, Export Date: 25 April 2012, Source: Scopus, Art. No.: e31197
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.
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.
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.
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 aga